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A computerized tomographic evaluation of brain morphology in first episode psychotic patients Smith, Geoffrey Norman 1986

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COMPUTERIZED TOMOGRAPHIC EVALUATION OF BRAIN MORPHOLOGY IN FIRST EPISODE PSYCHOTIC PATIENTS by GEOFFREY NORMAN SMITH M.A. , University of British Columbia, 1984 A THESIS IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY THE FACULTY OF GRADUATE STUDIES DEPARTMENT OF PSYCHOLOGY We accept this dissertation as conforming to the required standard The University of British Columbia August 1986 Geoffrey Norman Smith(]986 In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make i t freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission. Department of The University of British Columbia 1956 Main Mall Vancouver, Canada V6T 1Y3 Date / • 7 / R 1 ^ ABSTRACT A growing body of computerized tomography (CT) r e s e a r c h suggests t h a t a s i g n i f i c a n t p r o p o r t i o n of s c h i z o p h r e n i c p a t i e n t s have enlargement of the t h i r d and l a t e r a l c e r e b r a l v e n t r i c l e s and of the c o r t i c a l s u l c i . P r e l i m i n a r y r e s u l t s i n d i c a t e t h a t these anomalies are present at the onset of s c h i z o p h r e n i a and are a s s o c i a t e d with v a r i a b l e s p u t a t i v e l y l i n k e d t o poor p r o g n o s i s . Evidence of v e n t r i c u l a r d i l a t i o n i n n o n s c h i z o p h r e n i c p s y c h o t i c p a t i e n t s suggests that these m o r p h o l o g i c a l anomalies are not s p e c i f i c t o the d i a g n o s i s of s c h i z o p h r e n i a . There i s much v a r i a b i l i t y i n the estimated p r e v a l e n c e of v e n t r i c u l a r and s u l c a l d i l a t i o n and s e v e r a l r e c e n t s t u d i e s r e p o r t no enlargement. D i f f e r e n c e s between s t u d i e s i n methodology, i n the s e v e r i t y of i l l n e s s of the p a t i e n t s , and i n c o n t r o l group s e l e c t i o n have been proposed as probable b i a s e s c o n t r i b u t i n g to i n c o n s i s t e n c i e s i n the r e s e a r c h l i t e r a t u r e . The purpose of the present study was to t e s t a number of hypotheses suggested by the p r e v i o u s r e s e a r c h . The f i r s t t h ree p r e d i c t t h a t f i r s t episode s c h i z o p h r e n i c and n o n s c h i z o p h r e n i c p s y c h o t i c p a t i e n t s have 1. E n l a r g e d l a t e r a l v e n t r i c l e s , 2 . E n l a r g e d t h i r d v e n t r i c l e , and 3 . D i l a t e d c o r t i c a l s u l c i . The f o u r t h h y p o t h e s i s p r e d i c t s t h a t these t h r e e b r a i n anomalies are a s s o c i a t e d with v a r i a b l e s p u t a t i v e l y l i n k e d t o poor p r o g n o s i s (poor premorbid adjustment, n e g a t i v e symptoms, d i s r u p t e d smooth-pursuit eye movements). The f i f t h h y p o t h e s i s p r e d i c t s t h a t medical p a t i e n t s chosen from r a d i o l o g y r e c o r d s have s m a l l e r v e n t r i c l e s and s u l c i than do h e a l t h y c o n t r o l s u b j e c t s . Measurements were taken from the CT scans of a r e p r e s e n t a t i v e sample of c a r e f u l l y diagnosed f i r s t episode, f u n c t i o n a l l y p s y c h o t i c p a t i e n t s . There were 31 s c h i z o p h r e n i c , 20 s c h i z o - p h r e n i f o r m , 18 b i p o l a r , 16 depressed, t h r e e paranoid, and t h r e e s c h i z o a f f e c t i v e p a t i e n t s . A v o l u n t e e r c o n t r o l group of 44 h e a l t h y i n d i v i d u a l s was used f o r comparison. In order to e v a l u a t e p o s s i b l e b i a s e s due to the type of c o n t r o l s u b j e c t s that are used, a second group comprised of 30 medical p a t i e n t s was o b t a i n e d from r a d i o l o g y r e c o r d s . The r e s u l t s of t h i s study i n d i c a t e s i g n i f i c a n t enlargement of the t h i r d v e n t r i c l e i n s c h i z o p h r e n i c p a t i e n t s but f a i l e d t o d e t e c t s i g n i f i c a n t l a t e r a l v e n t r i c u l a r enlargement or c o r t i c a l atrophy i n t h i s p a t i e n t group. No b r a i n anomalies were found i n s c h i z o p h r e n i f o r m , b i p o l a r or depressed p a t i e n t groups and no s i g n i f i c a n t a s s o c i a t i o n was found between v a r i a b l e s p u t a t i v e l y a s s o c i a t e d with poor p r o g n o s i s and any b r a i n measure f o r any p a t i e n t group. The t h i r d v e n t r i c l e and c o r t i c a l s u l c i were s i g n i f i c a n t l y s m a l l e r i n the medical group than i n the v o l u n t e e r c o n t r o l group. The r e s u l t s are d i s c u s s e d i n terms of the i m p l i c a t i o n s they have f o r p r e v i o u s l y r e p o r t e d f i n d i n g s and f o r f u t u r e r e s e a r c h . The present f i n d i n g s a l s o underscore some metho d o l o g i c a l d i f f i c u l t i e s a s s o c i a t e d with u s i n g medical c o n t r o l s u b j e c t s . - i v -TABLE OF CONTENTS Page ABSTRACT i i TABLE OF CONTENTS i v LIST OF TABLES v i i i LIST OF FIGURES i x ACKNOWLEDGEMENTS x INTRODUCTION 1 D i a g n o s t i c Heterogeneity i n S c h i z o p h r e n i a 1 L a t e r a l V e n t r i c u l a r Enlargement 3 LVE i n Postmortem S t u d i e s 8 LVE i n Pneumoencephalographic S t u d i e s 8 LVE i n Computerized Tomographic S t u d i e s 9 L i n e a r Measures 10 V e n t r i c l e t o B r a i n R a t i o 11 The Prevalence of LVE i n S c h i z o p h r e n i a 12 L i n e a r Measures 12 Summary of L i n e a r Measures S t u d i e s 16 V e n t r i c l e t o B r a i n R a t i o 17 Reports of S i g n i f i c a n t LVE 17 Reports of no S i g n i f i c a n t LVE 29 Summary of LVE S t u d i e s 34 V a r i a b l e s A s s o c i a t e d with LVE i n S c h i z o p h r e n i a 45 Ge n e t i c and O b s t e t r i c F a c t o r s 45 Premorbid Adjustment 53 -v-Page Negative Symptoms 56 Response t o N e u r o l e p t i c s 59 Eye B l i n k s 63 Smooth P u r s u i t Eye Movements 64 Summary of V a r i a b l e s A s s o c i a t e d with LVE 67 The Prevalence of LVE i n A f f e c t i v e D i s o r d e r s 69 B i p o l a r D i s o r d e r 69 Major Depression 72 Mixed A f f e c t i v e D i s o r d e r P a t i e n t s 73 Summary of S t u d i e s of A f f e c t i v e D i s o r d e r P a t i e n t s . . . 7 5 Enlargement of the T h i r d V e n t r i c l e 76 Me t h o d o l o g i c a l Issues 77 Enlargement of the T h i r d V e n t r i c l e i n Schizophrenia.77 Summary of S t u d i e s of the T h i r d V e n t r i c l e 83 Atrophy of the C e r e b r a l Cortex 85 Me t h o d o l o g i c a l Issues 85 Prevalence of C o r t i c a l Atrophy i n S c h i z o p h r e n i a 86 C o r t i c a l Atrophy i n A f f e c t i v e D i s o r d e r s 92 Summary of S t u d i e s of C o r t i c a l Atrophy 94 Summary of the L i t e r a t u r e 94 F i n d i n g s from CT Scan S t u d i e s 95 Summary of Me t h o d o l o g i c a l Issues 97 RESEARCH OBJECTIVES 100 - v i -Page METHOD 102 S u b j e c t s 102 Apparatus and Interviews 106 Computerized Tomography 106 Interviews 108 Eye Movement Apparatus 110 Procedure 110 Data Q u a n t i f i c a t i o n 112 CT Scan Data 112 Interview Data 112 Eye Movement Data 113 RESULTS 113 R e l i a b i l i t y of Measures and R a t i n g s 114 Subject C h a r a c t e r i s t i c s 115 Age of S u b j e c t s 116 Sex of S u b j e c t s 116 P a r t i c i p a n t s and N o n p a r t i c i p a n t s 118 M e d i c a l C o n t r o l Group.... 120 A n a l y s i s of CT F i n d i n g s 120 L a t e r a l V e n t r i c l e s 121 T h i r d V e n t r i c l e 126 C o r t i c a l S u l c i 131 R e l a t i o n s h i p s Between M o r p h o l o g i c a l Measures 134 Summary of R e s u l t s 138 - v i i -Page DISCUSSION 139 Lateral Ventricles 141 Third Ventricle 149 Cortical Sulci 151 Control Groups 152 Conclusion 157 REFERENCES 160 APPENDIX A Linear Measures of the Lateral Ventricles 180 APPENDIX B Premorbid Status interview and Scales 181 APPENDIX C Symptom Checklists 189 APPENDIX D Consent Forms 204 APPENDIX E Screening Schedule for Patients 208 APPENDIX F Screening Schedule for Volunteer Controls..... 213 APPENDIX G Negative Symptom Ratings 215 Appendix H Correlations Between Age and Each CT Measure..219 Appendix I The Effects of Using RDC Diagnoses on the Results 220 Appendix J Mean Values for Scores of Premorbid Adjustment, Negative Symptoms, and Smooth Pursuit Eye Movements. 221 - v i i i -L i s t of Tables Page Tabl e 1 CT S t u d i e s of V e n t r i c u l a r and S u l c a l D i l a t i o n 4 Table 2 V e n t r i c l e S i z e i n the S t u d i e s Where the VBR was Used 39 Table 3 Demographic C h a r a c t e r i s t i c s of P a r t i c i p a n t s 104 Table 4 Demographic C h a r a c t e r i s t i c s of N o n p a r t i c i p a n t s . . . . 1 1 9 T a b l e 5 Mean Values f o r V e n t r i c l e and Cortex Measures f o r Each Group. 123 Table 6 C o r r e l a t i o n s Between VBR and Premorbid Adjustment Negative Symptoms and Smooth-Pursuit Eye Movements 127 T a b l e 7 C o r r e l a t i o n s Between T h i r d V e n t r i c l e S i z e and Premorbid Adjustment Negativ Symptoms and Smooth-P u r s u i t Eye Movements 132 T a b l e 8 C o r r e l a t i o n s Between C o r t i c a l Atrophy and Premorbid Adjustment Negative Symptoms and Smooth-P u r s u i t Eye Movements 135 Table 9 C o r r e l a t i o n s Between L a t e r a l V e n t r i c l e S i z e , T h i r d V e n t r i c l e Width, and C o r t i c a l Atrophy 137 - i x -L l s t of F i g u r e s Page F i g u r e 1 Mean V3R Values f o r Each Study and O v e r a l l Mean Values f o r S c h i z o p h r e n i c and C o n t r o l S u b j e c t s i n S t u d i e s of L a t e r a l V e n t r i c u l a r Enlargement... 41 F i g u r e 2 D i s t r i b u t i o n of V e n t r i c l e t o B r a i n R a t i o s i n each P a t i e n t and C o n t r o l Group 224 F i g u r e 3 D i s t r i b u t i o n of T h i r d V e n t r i c l e Width i n each P a t i e n t and C o n t r o l Group 128 F i g u r e 4 D i s t r i b u t i o n of C o r t i c a l Atrophy R a t i n g s i n each P a t i e n t and C o n t r o l Group 133 \ - x -ACKNOWLEDGMENTS I would l i k e t o extend s p e c i a l thanks t o Dr. W. G. Iacono f o r h i s i n v a l u a b l e guidance and encouragement w i t h my d i s s e r t a t i o n r e s e a r c h and throughout my graduate s t u d i e s . I am very g r a t e f u l t o Dr. D. Papageorgis f o r h i s generous a s s i s t a n c e w i t h and h e l p f u l comments cn my d i s s e r t a t i o n . My a p p r e c i a t i o n a l s o goes t o Dr. R. Tees f o r h i s help w i t h my d i s s e r t a t i o n and t o Dr. M. Moreau f o r her f r e q u e n t l y unusual and i n s i g h t -f u l c o n t r i b u t i o n s . The process o f l o c a t i n g p a r t i c i p a n t s and c o l l e c t i n g data i n t h i s study was a team e f f o r t . In a d d i t i o n t o Drs Iacono and Moreau, I am g r a t e f u l t o Dr. M. B e i s e r , Dr. S. L i n , Dr. J . Flemming, t o the r e s e a r c h team Dr. N. K y l e , K. K e e t l e y , J . Husted, and D. E r i c k s o n , and the s t a f f o f the Greater Vancouver Mental H e a l t h S e r v i c e . I a l s o thank Dr. B. F l a k f o r h i s a d v i c e on n e u r o r a d i o l o g i c a l i s s u e s . 1 D i a g n o s t i c Heterogeneity i n S c h i z o p h r e n i a The i n t r o d u c t i o n of DSM-III (American P s y c h i a t r i c A s s o c i a t i o n , 1980) has made the d i a g n o s i s of s c h i z o p h r e n i a more r e l i a b l e than ever b e f o r e . N e v e r t h e l e s s , t h i s d i a g n o s i s i s s t i l l based on course and p r e s e n t i n g s t a t e as d e f i n e d by the p a t i e n t ' s v e r b a l r e p o r t of s u b j e c t i v e e x p e r i e n c e s and b e h a v i o r a l o b s e r v a t i o n s made by o t h e r s . T h i s system al l o w s many i n d i v i d u a l d i f f e r e n c e s between persons who r e c e i v e t h i s d i a g n o s i s ( f o r a review of v a r i a b l e s p u t a t i v e l y r e l a t e d to s c h i z o p h r e n i a , see Carpenter, Bartko, Carpenter, & S t r a u s s , 1976; P e r r i s , Struwe, & Jansson, 1981; Seidman, 1983). These d i f f e r e n c e s , f o r the most p a r t , are not c o n s i d e r e d when making the d i a g n o s i s of s c h i z o p h r e n i a . There i s a l s o much v a r i a b i l i t y a c r o s s s c h i z o p h r e n i c p a t i e n t s i n response t o treatment regimens and pro g n o s i s ( f o r a review, see Neale & Oltmanns, 1980). In a d d i t i o n t o the many d i f f e r e n c e s between p a t i e n t s who are diagnosed s c h i z o p h r e n i c , t h e r e are many s i m i l a r i t i e s between s c h i z o p h r e n i a and other d i s o r d e r s . A f f e c t i v e d i s o r d e r s , f o r example, are d e f i n e d i n such a way that i t i s f r e q u e n t l y d i f f i c u l t to s p e c i f y whether an i n d i v i d u a l has s c h i z o p h r e n i a or an a f f e c t i v e d i s o r d e r (American P s y c h i a t r i c A s s o c i a t i o n , 1980). T h i s d e c i s i o n i s made on the b a s i s of which symptoms occured f i r s t and/or which symptoms are prominent. Unless a p a t i e n t p r e s e n t s h i m s e l f at the f i r s t s i g n of any problems, the d e c i s i o n as t o which symptoms oc c u r r e d f i r s t i s f r e q u e n t l y d i f f i c u l t t o make. For example, the d e c i s i o n as t o which symptoms are prominent i s confused 2 by the symptom overlap between the two diagnostic categories and the prevalence of depression in diagnosed schizophrenics (American Psychiatric Association, 1980). There are also a number of organic disorders such as epilepsy, cerebral tumor, and encephalitis that may present with symptoms that are indistinguishable from those found in schizophrenia (Davidson & Bagley, 1969). These diagnostic problems suggest that researchers should not assume that the diagnosis of schizophrenia identifies patients who have a common pathological process. Indeed the preponderance of heterogeneous results in the studies of schizophrenia suggests that this diagnosis reflects a number of disorders rather than a single illness (Meltzer,1979; Wyatt et a l . , 1981). One method of systematically investigating this diagnostic heterogeneity is to incorporate biological variables into the diagnosis of schiozophrenia in an attempt to identify homogeneous subtypes. Biological variables have the advantage of providing objectively verifiable factors and thus lead to more easily testable research hypotheses. Among biological variables that have received a great deal of attention in recent years, neuroanotomical indicators have produced some of the most provocative results. These include findings of lateral ventricular enlargement (LVE), enlargement of the third ventricle, and cortical atrophy. The research literature concerning these variables in schizophrenia and in other psychotic disorders wil l be reviewed in the following 3 s e c t i o n s . There i s a r a p i d l y growing body of r e s e a r c h concerning these m o r p h o l o g i c a l anomalies. These s t u d i e s may be c a t e g o r i z e d u s i n g a number of d i s t i n c t i o n s . These i n c l u d e the p a r t of the b r a i n t h a t i s being s t u d i e d ( l a t e r a l v e n t r i c l e s , t h i r d v e n t r i c l e , c o r t e x ) , and the d i a g n o s i s of the p a t i e n t s ( s c h i z o p h r e n i a , s c h i z o p h r e n i f o r m , b i p o l a r , d e p r e s s e d ) . The present review w i l l be d i v i d e d i n t o s e c t i o n s a c c o r d i n g t o these d i s t i n c t i o n s . Those s t u d i e s that do not f a l l e a s i l y i n t o any one s e c t i o n have been c i t e d more than once. Table 1 p r o v i d e s an overview of the s t u d i e s reviewed and t h e i r p a r t i c u l a r f o c u s . L a t e r a l V e n t r i c u l a r Enlargement L a t e r a l v e n t r i c u l a r enlargement, as with many mor p h o l o g i c a l anomalies i n the human b r a i n , may r e s u l t from a number o f causes. These i n c l u d e degeneration of b r a i n t i s s u e ( B i r d , 1982), o b s t r u c t i o n of c e r e b r o s p i n a l f l u i d flow (TerBrugge & Rao, 1983), or changes i n f l u i d , e l e c t r o l y t e and n u t r i t i o n a l s t a t u s (Bentson, Reza, Winter, & Wilson, 1978). B r a i n changes may be f o c a l or d i f f u s e . Some s p e c i f i c causes of f o c a l changes are trauma, i n f a r c t i o n , i n f l a m a t i o n , and v a s c u l a r a b n o r m a l i t i e s . These d i s o r d e r s f r e q u e n t l y i n v o l v e d i l a t i o n of a p a r t of the v e n t r i c u l a r system or atrophy i n an area o f the c o r t e x and o f t e n spare other b r a i n areas (TerBrugge & Rao, 1983). Numerous other c o n d i t i o n s can have d i f f u s e e f f e c t s on b r a i n morphology. These i n c l u d e Table 1 Previous CT Studies of Brain Anomalies in Psychotic Patients Diagnostic Number of Patients Control LVE a Study System Schiz Mania Depres Type # Method Present TVEb Sulci Andreasen et a l . , 1982b DSM-III 52 - - Med 47 VBR Yes - -Benes et a l . , 1982 Feighner 11 - - Med 26 VBR No - -Boronow et a l . , 1985 RDC 30 - - Med 26 VBR No Yes No DeLisi et a l . , 1986 DSM-III 26 - - Norm 20 VBR Yes - -DeMeyer et a l . , 1984 DSM-III 8 - - Med 15 VBR No Yes -Dewan et a l . , 1983 DSM-III 23 - - Med 23 - - Yes Yes Famuyiwa et a l . , 1979 Feighner 50 - - - - Linear Yes - -Gluck et a l . , 1980 not given 68 - - Med 68 Linear No No No Golden et a l . , 1980 DSM-III 42 - - - - VBR Yes - -Jernigan et a l . , 1982 DSM-III 30 - - Norm 33 VBR No - -Johnstone et a l . , 1978b Feighner 18 - - Med 10 VBR Yes - No Kling et a l . , 1982/83 DSM-III 26 - - Med 20 VBR Yes - Yes Luchins et a l . , 1984 RDC 45 6 14 Med 50 VBR Yes - -Nasrallah et a l . , 1982b DSM-III 55 24 - Med 27 VBR Yes - -Nasrallah et a l . , 1983b DSM-III 55 - - Med 27 - - - Yes Nasrallah et a l . , 1985 DSM-III 55 - - Med 27 - - No -Nyback et a l . , 1982 RDC 46 - - Norm 48 Linear Yes Yes Yes Okasha & Madkur, 1982 not given 43 - - Med 39 Linear Yes Yes -Owens et a l . , 1985 CATEGO 136 32 - Psyc 19 VBR Yes - -Pandurangi et a l . , 1984 DSM-III 23 - - Med 23 VBR Yes Yes Yes Pearlson & Veroff, 1981 DSM-III 22 16 - Psyc 35 VBR Yes - Yes Table 1 (continued) Diagnostic Number of Patients Control LVE a Study System Schiz Mania Depres Type # Method Present TVEb Sulci Pearlson et a l . , 1984a,b DSitf-III - 27 Norm 46 VBR Yes - . -Reveley et a l . , 1982 RDC 7 - Norm 38 VBR Yes - -Reveley et a l . , 1984 RDC 21 - Norm 18 Volume Yes - -Reider et a l . , 1983 RDC 28 - 19 - - VBR Yes - No Schulsinger et a l . , 1984 ICD-8 10 - Norm 16 VBR Yes - -Schulz et a l . , 1983 DSM-III 15 - Med 18 VBR Yes - -Scott et a l . , 1983 DSM-III - 10 Med 10 VBR Yes - -Shima et a l . , 1985 DSM-III 46 - Norm 38 VBR No - -Smith & Maser, 1983 RDC 30 - Med 19 VBR No Yes Yes Tanaka et a l . , 1981 not given 46 - Med 38 Linear Yes Yes No Targum et a l . , 1983 DSM-III - 38 Med 26 VBR Yes - -Trimble & Kingsley, 1978 not given 11 - - - Linear No - -Weinberger et a l . , 1979a RDC 65 - Norm 56 VBR Yes - -Weinberger et a l . , 1979b RDC 75 - Norm 62 - - - Yes Weinberger et a l . , 1982 DSM-III 52 23 Med 26 VBR Yes - Yes Williams et a l . , 1985 RDC 40 - Med 40 VBR Yes - -Woods & Wolf, 1983 RDC 19 - Med 29 Linear Yes - -aLVE = Lateral Ventricular Enlargement. TVE = Third Ventricular Enlargement. 6 hydrocephalus (TerBrugge 8c Rao, 1983) normal aging (Jacoby, Levy, & Dawson, 1980), v a r i o u s forms of dementia ( B i r d , 1982), a l c o h o l i s m ( C a r l e n , W i l k i n s o n , Wortzman, & Holgate, 1984), severe migraine headaches (Hungerford, duBoulay, & Z i l k h a , 1976), autism (Hauser, DeJong, & Rosman, 1975), s c h i z o p h r e n i a (Seidman, 1983), and a f f e c t i v e d i s o r d e r s ( P e a r l s o n & V e r o f f , 1981). D i f f u s e changes i n b r a i n morphology may i n v o l v e p r i m a r i l y the v e n t r i c l e s with l i t t l e e f f e c t on the c o r t e x whereas i n other i l l n e s s e s t h i s p a t t e r n i s r e v e r s e d . Huntington's chorea, f o r example, r e f l e c t s a d i f f u s e form of atrophy c h a r a c t e r i z e d by enlargement of the l a t e r a l v e n t r i c l e s and may not be a s s o c i a t e d with d i l a t i o n of the c o r t i c a l s u l c i u n t i l l a t e r stages of the d i s e a s e process (TerBrugge & Rao, 1983). L i k e w i s e , hydrocephalus normally p r e s e n t s with enlargement of the v e n t r i c l e s i n the absence of s u l c a l d i l a t i o n (TerBrugge &^  Rao, 1983). In c o n t r a s t , d i f f u s e c o r t i c a l atrophy, d i s p r o p o r t i o n a t e t o the degree of v e n t r i c u l a r d i l a t i o n has been r e p o r t e d i n c e r e b r a l anoxia (TerBrugge & Rao, 1983). Other d i s o r d e r s such as Alzheimer's d i s e a s e f r e q u e n t l y i n v o l v e both the v e n t r i c l e s and the c o r t e x but e i t h e r of these s t r u c t u r e s may be a f f e c t e d i n i s o l a t i o n (TerBrugge & Rao, 1983). Thus, l a t e r a l v e n t r i c u l a r enlargement i s not l i m i t e d to any s i n g l e p a t h o l o g i c a l process and i s observed i n a number of d i f f e r e n t types of i l l n e s s . In a d d i t i o n , because enlargement of the l a t e r a l v e n t r i c l e s i s f r e q u e n t l y found with other m o r p h o l o g i c a l b r a i n changes, i t cannot be assumed t o be an i s o l a t e d f i n d i n g i n the absence of 7 e x t e n s i v e i n v e s t i g a t i o n s . There i s some evidence that enlargement of the l a t e r a l v e n t r i c l e s may be r e v e r s i b l e i n some cases. Bentson et a l . (1978) r e p o r t e d that c e s s a t i o n of s t e r o i d s i n long term s t e r o i d u s e rs r e s u l t e d i n the r e d u c t i o n i n v e n t r i c u l a r s i z e i n some p a t i e n t s . Other s t u d i e s ( L a r g e n s t e i n , W i l l i g , & Kuhne, 1979; Okuna, I t o , K o n i s h i , Yoshloka, & Nakamo, 1980) have r e p o r t e d enlargement of the v e n t r i c l e s i n some p a t i e n t s when c o r t i c o t r o p h i n therapy was i n i t i a t e d and decreased v e n t r i c u l a r s i z e when t h i s treatment was terminated. Abstinence i n r e c e n t l y recovered a l c o h o l i c s has a l s o been shown t o r e s u l t i n a r e d u c t i o n i n the s i z e of the v e n t r i c l e s ( C a r l e n et a l . , 1984). In a d d i t i o n , a number of medical d i s o r d e r s can r e s u l t i n a decrease i n v e n t r i c l e s i z e . These i n c l u d e head trauma, hematoma, astrocytomas, and vasospasms (Schneider, Kahn, Crosby, & Taren, 1982). Two s t u d i e s have i n v e s t i g a t e d the p o s s i b i l i t y of changes i n v e n t r i c u l a r s i z e i n s c h i z o p h r e n i a . Weinberger and Wyatt (1982a) re-scanned f i v e s c h i z o p h r e n i c s f o r LVE a f t e r a two-to t h r e e - y e a r i n t e r v a l and found no changes f o r any p a t i e n t . Although t h i s r e s u l t suggests t h a t t h e r e are no f l u c t u a t i o n s i n v e n t r i c u l a r s i z e i n s c h i z o p h r e n i c s , the s m a l l sample s i z e i n d i c a t e s t h a t c a u t i o n i s needed i n g e n e r a l i z i n g from these r e s u l t s . In a second study, N a s r a l l a h , Olsen, M c C a l l e y - W h i t t e r s , Chapman and Jacoby (1986) repeated a CT scanning procedure on 11 male s c h i z o p h r e n i c s . The second CT scan was performed 8 t h r e e to four years a f t e r the f i r s t and no s i g n i f i c a n t o v e r a l l changes i n v e n t r i c l e s i z e were d e t e c t e d . However, the r e t e s t r e l i a b i l i t y of the measure of v e n t r i c l e s i z e was low (rho = .26). T h i s i n s t a b i l i t y suggests e i t h e r t h a t the method of measurement i s h i g h l y u n r e l i a b l e or that there were random changes i n v e n t r i c l e s i z e . These two s t u d i e s p r o v i d e p r e l i m i n a r y evidence s u g g e s t i n g that there are no c l e a r changes i n l a t e r a l v e n t r i c l e s i z e i n s c h i z o p h r e n i c s over two to f o u r y e a r s . However, the poor r e t e s t r e l i a b i l i t y o b t ained by N a s r a l l a h et a l . (1986) and the s m a l l number of s u b j e c t s used i n these s t u d i e s suggest t h a t i t i s premature to conclude t h a t v e n t r i c l e s i z e i s a s t a b l e c h a r a c t e r i s t i c i n s c h i z o p h r e n i c p a t i e n t s . I t i s necessary to rescan l a r g e r , r e p r e s e n t a t i v e groups with r e l i a b l e methods of assessment i n order to c o n f i r m these p r e l i m i n a r y r e s u l t s . LVE i n Postmortem S t u d i e s Postmortem i n v e s t i g a t i o n s have tended to r e v e a l no s i g n i f i c a n t v e n t r i c u l a r enlargement i n the b r a i n s of s c h i z o p h r e n i c s . However, the premortem events, changes that occur i n b r a i n t i s s u e with death, and postmortem e x t r a c t i o n and f i x a t i o n procedures may obscure v e n t r i c u l a r enlargement e s p e c i a l l y i f the enlargement i s modest (Messert, Wannamaker, & Dudley, 1972). In a d d i t i o n , the b r a i n tends t o s h r i n k a f t e r death thereby f u r t h e r o b s c u r i n g s u b t l e m o r p h o l o g i c a l changes (Jacobs, K i n k e l , & H e f f n e r , 1976). LVE i n Pneumoencephalographic S t u d i e s Haug (1962) reviewed the e a r l y l i t e r a t u r e and found more 9 than 30 s t u d i e s that r e p o r t e d enlarged v e n t r i c l e s i n s c h i z o p h r e n i c i n d i v i d u a l s . Haug noted, however, t h a t these s t u d i e s are d i f f i c u l t to i n t e r p r e t because most have used b i a s e d p a t i e n t s e l e c t i o n , inadequate c o n t r o l s , u n s p e c i f i e d or inadequate d i a g n o s t i c c r i t e r i a , and p o o r l y d e f i n e d standards f o r normal v e n t r i c u l a r s i z e . Weinberger and Wyatt (1982a) reviewed the l i t e r a t u r e s i n c e 1962 and concluded that whereas more recent s t u d i e s have many of the problems of the e a r l i e r i n v e s t i g a t i o n s , there have been c o n s i s t e n t r e p o r t s of LVE i n s c h i z o p h r e n i c s . T h i s c o n s i s t e n c y suggests t h a t there are m o r p h o l o g i c a l anomalies i n the b r a i n s of some s c h i z o p h r e n i c p a t i e n t s . LVE i n Computerized Tomographic S t u d i e s In r e c e n t y e a r s , r e s e a r c h e r s have begun t o use computerized tomography (CT) as a n o n - i n v a s i v e , r e l i a b l e method f o r a s s e s s i n g n e u r o l o g i c a l anomolies d u r i n g l i f e ( Gyldensted, 1977; Jacobs et a l . , 1976). T h i s method of assessment d i r e c t s X-rays, from sources l o c a t e d i n a t h i n band around the c i r c u m f e r a nce of the head, through the b r a i n at v a r i o u s a n g l e s . The X - r a d i a t i o n i s a t t e n u a t e d to some degree by the d e n s i t y of the n e u r o l o g i c a l t i s s u e i t passes through. Receptors, a l s o l o c a t e d around the head, convert the a t t e n u a t e d X - r a d i a t i o n t o e l e c t r i c a l s i g n a l s . The e l e c t r i c a l s i g n a l s are then used to mathematically r e c o n s t r u c t an image of one c r o s s - s e c t i o n ( s l i c e or scan) of the b r a i n . S e r i a l c r o s s - s e c t i o n s of the b r a i n are scanned to produce a number of images of the b r a i n at a number of 10 d i f f e r e n t l e v e l s . A number of d i f f e r e n t methods have been used to assess the s i z e of the l a t e r a l v e n t r i c l e s . The s i m p l e s t method i n v o l v e s the l i n e a r measurement of v a r i o u s a s p e c t s of the v e n t r i c l e s . The most commonly used technique i n c l u d e s the measurement of the area of the v e n t r i c l e s and of the b r a i n from a s i n g l e CT scan. L i n e a r Measures. The l i n e a r measures that are most commonly used are Evans' r a t i o , e e l l a media r a t i o , b i c a u d a t e r a t i o , and f r o n t a l horn r a t i o ( f o r d e f i n i t i o n s of these terms, see Appendix A) . Most of these measures are designed to be o b t a i n e d from the f r o n t a l p r o j e c t i o n of a pneumoencephalogram (Penn et a l . , 1978). Whereas these measures are r e l a t i v e l y c l e a r on a f r o n t a l p r o j e c t i o n of the b r a i n , they are i n f l u e n c e d by the l e v e l of the cut i n the h o r i z o n t a l plane of a CT scan. The r a p i d l y s l o p i n g v e n t r i c l e w a l l s are l i k e l y to obscure the t r u e d i s t a n c e s used i n these l i n e a r measures and r e s u l t i n i m p r e c i s e e s t i m a t e s of v e n t r i c l e s i z e (Penn et a l . , 1978). In a study comparing l i n e a r measures with v e n t r i c u l a r volume, Penn et a l . (1978) r e p o r t e d t h a t the l i n e a r i n d i c e s c o r r e l a t e d p o o r l y with the a c t u a l volume. There was c o n s i d e r a b l e v a r i a b i l i t y i n the l i n e a r measures e s p e c i a l l y when the s i z e of small v e n t r i c l e s was being e s t i m a t e d . 3 Furthermore, because v e n t r i c l e s i z e i s a volume measure (x ), a s m a l l l i n e a r (x) i n c r e a s e i n a l r e a d y l a r g e v e n t r i c l e s r e p r e s e n t s a l a r g e r i n c r e a s e than a s i m i l a r change i n s m a l l v e n t r i c l e s . Thus, although l i n e a r measures are more e a s i l y 11 d e r i v e d than other measures they are l e s s r e l i a b l e , are im p r e c i s e f o r small v e n t r i c l e s , and underestimate the s i z e of v e n t r i c u l a r enlargement i n l a r g e v e n t r i c l e s . There i s a l s o c o n s i d e r a b l e normal v a r i a b i l i t y i n the shape of the f r o n t a l horns of the l a t e r a l v e n t r i c l e s (LeMay & Kido, 1978) and t h i s i s l i k e l y to f u r t h e r reduce the value of l i n e a r measures t h a t make use of t h i s aspect of the b r a i n . The i m p r e c i s i o n of l i n e a r i n d i c e s and the f a c t t h at few s c h i z o p h r e n i a r e s e a r c h e r s use these measures makes i t d i f f i c u l t t o i n t e r p r e t r e s u l t s from s t u d i e s t h a t employ these methods. V e n t r i c l e t o B r a i n R a t i o . Most CT s t u d i e s of p s y c h i a t r i c p a t i e n t s i n v o l v e a method of measurement t h a t was developed by Synek and Reuben (1976). T h i s manual method i n v o l v e s p l a n i m e t r i c measurement of the area of the l a t e r a l v e n t r i c l e s i n the scan t h a t shows the v e n t r i c l e s a t t h e i r l a r g e s t . The v e n t r i c u l a r area i s d i v i d e d by the area of the t o t a l b r a i n i n the same s l i c e and the r e s u l t i s m u l t i p l i e d by 100. The r e s u l t i n g q u o t i e n t i s c a l l e d the v e n t r i c l e t o b r a i n r a t i o (VBR) and r e p r e s e n t s the percent of b r a i n space t h a t i s taken up by the l a t e r a l v e n t r i c l e s from a s i n g l e CT s l i c e . T h i s e s t imate of v e n t r i c l e s i z e i s h i g h l y r e l i a b l e and c o r r e l a t e s extremely w e l l with computerized methods f o r a s s e s s i n g volume (Jacobs, K i n k e l , & P a i n t e r , 1978; Penn, Belanger, & Yas n o f f , 1978). With computer a s s i s t e d measures of v e n t r i c u l a r volume, the area of the v e n t r i c l e s i s a u t o m a t i c a l l y assessed at each s l i c e and a l l of these areas are combined i n order t o compute the o v e r a l l volume. Because of the complexity of t h i s 12 method and the f a c t that i t o f f e r s no s i g n i f i c a n t advantages over the VBR (Weinberger, Wagner, & Wyatt, 1983) few r e s e a r c h e r s have made use of i t . D i f f e r e n c e s i n the c r i t e r i a t h a t are used to d e f i n e the v e n t r i c l e w a l l s can r e s u l t i n l a r g e between-study d i f f e r e n c e s i n r e p o r t e d mean VBR s i z e (Maser and K e i t h , 1983; J e r n i g a n et a l . , 1982). T h i s v a r i a b i l i t y underscores the need f o r c o n t r o l samples f o r each study and f o r the c o n s e c u t i v e assessment of CT p a t i e n t and c o n t r o l s u b j e c t scans. P u b l i s h e d normal v a l u e s should not be s u b s t i t u t e d f o r a c o n t r o l group. Prevalence of LVE i n S c h i z o p h r e n i a A l a r g e number of s t u d i e s of v e n t r i c u l a r enlargement i n s c h i z o p h r e n i c p a t i e n t s has been p u b l i s h e d . In the f o l l o w i n g d i s c u s s i o n , those s t u d i e s i n which l i n e a r measures were used w i l l be c o n s i d e r e d f i r s t f o l l o w e d by those i n v e s t i g a t i o n s i n which the v e n t r i c l e t o b r a i n r a t i o (VBR) was r e p o r t e d . L i n e a r Measures Famuyiwa, E c c l e s t o n , Donaldson, and Gar s i d e (1979) compared the CT scans of 45 c h r o n i c a l l y h o s p i t a l i z e d s c h i z o p h r e n i c p a t i e n t s with p u b l i s h e d normal v a l u e s . The mean d u r a t i o n of h o s p i t a l i z a t i o n was 14.6 y e a r s . Diagnoses were made us i n g Fieghner c r i t e r i a and 17 p a t i e n t s were r e p o r t e d to have t a r d i v e d y s k i n e s i a . Three l i n e a r measures were used t o assess l a t e r a l v e n t r i c l e s i z e (Huckman, c e l l a media, and v e n t r i c u l a r i n d i c e s ) . The r e s u l t s i n d i c a t e d that 31 (65%) of the p a t i e n t s were o u t s i d e the normal range. The f a c t s t h a t t h i s group was c h r o n i c a l l y h o s p i t a l i z e d , 13 r e l a t i v e l y o l d (mean age was 48 y e a r s ) , a c o n t r o l group was not i n c l u d e d , and l i n e a r measures were used to estimate v e n t r i c l e s i z e , makes the s i g n i f i c a n c e of these f i n d i n g s d i f f i c u l t to determine. T h i s study does, however, p r o v i d e p r e l i m i n a r y evidence i n d i c a t i n g t h at t h e r e may be s i g n i f i c a n t l y e n l a r g e d l a t e r a l v e n t r i c l e s i n c h r o n i c a l l y i l l s c h i z o p h r e n i c p a t i e n t s . Enlargement of the l a t e r a l v e n t r i c l e s was a l s o r e p o r t e d by Okasha and Madkour (1982). The c e l l a media index was used to e s timate v e n t r i c l e s i z e i n 43 c h r o n i c s c h i z o p h r e n i c s and 39 medical p a t i e n t s . A l l s c h i z o p h r e n i c s had been i l l f o r more than f i v e years and t h e i r age ranged from 15 to 59 y e a r s . Moderate v e n t r i c u l a r enlargement was found i n 20 (46%) p a t i e n t s . T h i s study i n c l u d e d p a t i e n t s with a wider age range than the s c h i z o p h r e n i c s i n the study by Famuyiwa et a l . (1979) and thus, because of the l a r g e number of s u b j e c t s with v e n t r i c u l a r enlargement, suggests that b r a i n anomalies are present i n both young and o l d p a t i e n t s . Nyback, W i e s e l , Berggren, and Hindmarsh (1982) a l s o o b t a i n e d evidence f o r the presence of v e n t r i c u l a r enlargement i n young s c h i z o p h r e n i c s . A l i n e a r measure u s i n g the f r o n t a l horns of the l a t e r a l v e n t r i c l e s , was used to estimate the s i z e of the v e n t r i c l e s i n 46 s c h i z o p h r e n i c p a t i e n t s (17 to 44 y e a r s ) and 46 v o l u n t e e r c o n t r o l s . Of the p a t i e n t group, 19 had r e c e n t l y experienced t h e i r f i r s t p s y c h o t i c episode and 27 had been h o s p i t a l i z e d two or more times p r e v i o u s l y . Separate a n a l y s e s were not computed f o r these two groups. The p a t i e n t 14 group had s i g n i f i c a n t l y l a r g e r v e n t r i c l e s than d i d the c o n t r o l group. A s c a t t e r p l o t of v e n t r i c l e s i z e by age i n d i c a t e d t h a t some of the youngest p a t i e n t s had LVE. T h i s f i n d i n g supports that of Okasha and Madkour (1982) and suggests t h a t v e n t r i c u l a r enlargement may be found i n s c h i z o p h r e n i c s of a l l ages. Woods and Wolf (1983), u s i n g l i n e a r e s t i m a t e s (bicaudate index, and b i f r o n t a l index) of v e n t r i c u l a r s i z e , a l s o r e p o r t e d v e n t r i c u l a r enlargement i n young s c h i z o p h r e n i c s . Mean age was 23 y e a r s . A group of 19 p a t i e n t s , diagnosed a c c o r d i n g t o Research D i a g n o s t i c C r i t e r i a (RDC, S p i t z e r , E n d i c o t t , & Robins, 1978) were compared to 29 medical p a t i e n t s over l a t e r a l v e n t r i c l e s i z e . The mean d u r a t i o n of i l l n e s s f o r these p a t i e n t s was f o u r y e a r s . The degree of enlargement, i s d e s c r i b e d as s l i g h t but the a c t u a l extent of LVE i s d i f f i c u l t t o a s c e r t a i n from the i n f o r m a t i o n g i v e n . Whereas the r e s u l t s of t h i s study support those of Okasha and Madkour (1982) and Nyback et a l . (1982) i n i n d i c a t i n g LVE i n young p a t i e n t s , the degree of enlargement r e p o r t e d by Woods and Wolf (1983) appears t o be lower than i n these other s t u d i e s . Tanaka, Hazama, Kawahara, and Kobayashi (1981) r e p o r t f i n d i n g s that suggest LVE i s p a r t of a degenerative p r o c e s s . Tanaka et a l . (1981) compared 49 s c h i z o p h r e n i c p a t i e n t s t o a c o n t r o l group of 38 age matched medical p a t i e n t s . Seven l i n e a r measures were ob t a i n e d and the data i n d i c a t e d s i g n i f i c a n t l y e n l a r g e d v e n t r i c l e s i n p a t i e n t s aged 41 to 60 15 as compared t o an age-matched c o n t r o l . There was, however, no s i g n i f i c a n t d i f f e r e n c e between younger p a t i e n t s (21-40) and c o n t r o l s over v e n t r i c l e s i z e . U n f o r t u n a t e l y , Tanaka e t a l . (1981) f a i l t o d e s c r i b e t h e i r p a t i e n t sample, d i a g n o s t i c c r i t e r i a , or s e l e c t i o n procedure. N e v e r t h e l e s s , the f i n d i n g s of t h i s study p r o v i d e some support f o r those of Famuyiwa et a l . (1982) and Okasha and Madkour (1982) i n i n d i c a t i n g LVE i n c h r o n i c s c h i z o p h r e n i c s . The absence of LVE i n young p a t i e n t s c o n t r a d i c t s the f i n d i n g s of Nyback e t a l . (1982) and Woods and Wolf (1983) i n sug g e s t i n g t h a t LVE i s not present i n the e a r l y stages of s c h i z o p h r e n i a . Two p u b l i s h e d s t u d i e s t h a t have used l i n e a r measures from CT scans r e p o r t no s i g n i f i c a n t v e n t r i c u l a r enlargement i n c h r o n i c s c h i z o p h r e n i c p a t i e n t s . Trimble and K i n g s l e y (1978) used Evans' r a t i o t o es t i m a t e the s i z e of the l a t e r a l v e n t r i c l e s of 11 c h r o n i c s c h i z o p h r e n i c s . The age of these p a t i e n t s ranged from 17 to 66 years (M = 34 y e a r s ) . No i n f o r m a t i o n i s given r e g a r d i n g d i a g n o s t i c c r i t e r i a or s e l e c t i o n procedures but i t i s noted that some were r e c e i v i n g o u t p a t i e n t treatment. Using a normal l i m i t of .30 f o r Evans r a t i o , these authors r e p o r t no s i g n i f i c a n t v e n t r i c u l a r enlargement. However, Evans (1942, c i t e d i n Weinberger & Wyatt, 1982a) used the f i g u r e of .25 to diagnose e a r l y or q u e s t i o n a b l e atrophy. I f t h i s f i g u r e i s used, seven of the 11 p a t i e n t s have enla r g e d v e n t r i c l e s . Given t h a t LVE i n s c h i z o p h r e n i c s i s g e n e r a l l y s m a l l compared to that of dementing or h y d r o c e p h a l i c p a t i e n t s , the p o s s i b i l i t y of e a r l y 16 atrophy (when u s i n g the .25 c u t o f f ) must be c o n s i d e r e d . A f i n d i n g of no s i g n i f i c a n t enlargement was a l s o r e p o r t e d by Gluck, Mundt, and Gerhardt (1980). The d i s t a n c e between the out e r t i p s of the f r o n t a l horns of the l a t e r a l v e n t r i c l e s was measured from the CT scans of 68 c h r o n i c s c h i z o p h r e n i c p a t i e n t s and 68 medical c o n t r o l s u b j e c t s . The method of d i a g n o s i s i s not given but i t i s noted t h a t 14 of the s c h i z o p h r e n i c s " d i d not communicate with the environment e i t h e r v e r b a l l y or e m o t i o n a l l y " . The d u r a t i o n of i l l n e s s was g r e a t e r than f i v e y e ars f o r a l l p a t i e n t s and age ranged from 22 t o 66 y e a r s . The f a c t s that some p a t i e n t s were r e l a t i v e l y o l d , a l l had been i l l f o r more than f i v e y e a r s , and a l l were h o s p i t a l i z e d suggests t h a t t h i s p a t i e n t sample was probably as impaired as those of the s t u d i e s where p o s i t i v e r e s u l t s were r e p o r t e d . T h i s f i n d i n g suggests t h a t LVE may be l e s s p r e v a l e n t than appears from the e a r l i e r i n v e s t i g a t i o n s . However, the method of measurement used i n t h i s study i s unusual and may account f o r the f a i l u r e t o o b t a i n s i g n i f i c a n t r e s u l t s . Summary of S t u d i e s i n which L i n e a r Measures were Used O v e r a l l , the r e s u l t s of those i n v e s t i g a t i o n s i n which l i n e a r measures of the l a t e r a l v e n t r i c l e s were ob t a i n e d suggest s i g n i f i c a n t enlargement. Four of the f i v e s t u d i e s i n v o l v i n g c h r o n i c s c h i z o p h r e n i c p a t i e n t s i n d i c a t e LVE. The v a r i e t y of methods of measurement t h a t were used makes comparison between these s t u d i e s d i f f i c u l t but suggests t h a t the f i n d i n g of LVE i s r e l a t i v e l y r o b u s t . The r e s u l t s from the s t u d i e s i n which young p a t i e n t s were i n c l u d e d are l e s s c o n s i s t e n t . Of the three s t u d i e s i n v o l v i n g young p a t i e n t s , one r e p o r t e d c l e a r LVE (Nyback et a l . , 1982), one r e p o r t e d o n l y s l i g h t enlargement (Woods and Wolf, 1983), and one r e p o r t e d no enlargement (Tanaka et a l . , 1981). F u r t h e r s t u d i e s are needed to r e s o l v e t h i s i s s u e . V e n t r i c l e t o B r a i n R a t i o Reports of S i g n i f i c a n t LVE. In the f i r s t s t u d i e s of s c h i z o p h r e n i a u s i n g computerized tomography, Johnstone, Crow, F r i t h , Husband, and K r e e l (1976) and Johnstone e t a l . (1978b) r e p o r t e d s i g n i f i c a n t l y l a r g e r l a t e r a l v e n t r i c l e s i n a group of 18 c h r o n i c s c h i z o p h r e n i c s than i n a group of ten c h r o n i c a l l y h o s p i t a l i z e d medical p a t i e n t s . Fourteen (94%) of 15 p a t i e n t s had v e n t r i c l e s l a r g e r than those of any c o n t r o l s u b j e c t . No s i g n i f i c a n t r e l a t i o n s h i p between v e n t r i c u l a r s i z e and past treatment or age was found. These r e s u l t s have been c r i t i c i z e d on a number of grounds. The mean d u r a t i o n of h o s p i t a l i z a t i o n was 32 y e a r s , most p a t i e n t s had been r e c e i v i n g n e u r o l e p t i c medication f o r a number of y e a r s , and p a t i e n t s were r e l a t i v e l y advanced i n age (M = 58 y e a r s ) . Any of these f a c t o r s may have accounted f o r the r e s u l t s that were obt a i n e d (Barron, Jacobs, & K i n k e l , 1976; J e l l i n e c k , 1976; Marsden, 1976). In a d d i t i o n t o these problems, the p a t i e n t and c o n t r o l group s i z e s were s m a l l , and f o u r leucotomized s c h i z o p h r e n i c p a t i e n t s were i n c l u d e d . Weinberger, Torrey, Neophytides, and Wyatt (1979a) r e p l i c a t e d the f i n d i n g of Johnstone e t a l . (1976) with a 18 l a r g e r , younger sample of 65 s c h i z o p h r e n i c s and 56 normal c o n t r o l s ( r e l a t i v e s of p a t i e n t s w i t h Huntington's Chorea). P a t i e n t s were under 50 years of age (M = 29 y e a r s ) , and had a mean d u r a t i o n of i l l n e s s of 10.6 y e a r s . The s c h i z o p h r e n i c group r e c e i v e d RDC diagnoses and c o n t a i n e d 42 p a t i e n t s who were c h r o n i c a l l y i l l and 23 f o r whom the present episode was l e s s than two years i n d u r a t i o n . Most p a t i e n t s (n = 58) responded p o o r l y to treatment. None had any i n d i c a t i o n of n e u r o l o g i c a l d i s o r d e r . The VBR was used to estimate the s i z e of the l a t e r a l v e n t r i c l e s . Of the s c h i z o p h r e n i c group, 52% were found to have s i g n i f i c a n t l y e n l a r g e d v e n t r i c l e s . No s i g n i f i c a n t d i f f e r e n c e s were found between c h r o n i c a l l y i l l s c h i z o p h r e n i c s and those who had been c o n t i n u o u s l y i l l f o r l e s s than two y e a r s . No r e l a t i o n s h i p was observed between age, l e n g t h of i l l n e s s , d u r a t i o n of h o s p i t a l i z a t i o n , or number of ECT treatments and v e n t r i c u l a r enlargement. Golden et a l . (1980) r e p o r t e d v e n t r i c u l a r enlargement i n 60% (25/42) of a group of p a t i e n t s who met the DSM-III c r i t e r i a f o r c h r o n i c s c h i z o p h r e n i a . The mean age of p a t i e n t s was 32 years and the average d u r a t i o n of i l l n e s s was 10 y e a r s . P u b l i s h e d normal v a l u e s were used i n s t e a d of a c o n t r o l group. T h i s l a r g e p r o p o r t i o n of abnormal scans may be i n f l u e n c e d by the f a c t t h a t 22 of the p a t i e n t s were r e f e r r e d f o r " s u s p i c i o n of b r a i n d y s f u n c t i o n " . In a d d i t i o n , methodological d i f f e r e n c e s i n a s s e s s i n g VBR are l i k e l y to occur among s t u d i e s : e.g., v e n t r i c u l a r s i z e may vary depending on the d e f i n i t i o n of the v e n t r i c u l a r margin, the CT 19 machine t h a t i s used, and the angle of the CT s l i c e (Weinberger et a l . , 1983; Revely, 1985). These meth o d o l o g i c a l d i f f e r e n c e s make i t unwise t o use normal v a l u e s from one study to e v a l u a t e the p r o p o r t i o n of abnormal scans i n another. I t was a l s o r e p o r t e d by J e r n i g a n , Zatz, Moses, and Berger (1982) that the method of a s s e s s i n g the VBR used by Golden et a l . (1980) was a t y p i c a l and r e s u l t e d i n i n f l a t e d e s t i m a t e s of LVE. The f a c t tha_.t Golden et a l . (1980) used p u b l i s h e d norms i n s t e a d of a c o n t r o l group and an a t y p i c a l method of a s s e s s i n g the VBR makes i t d i f f i c u l t t o i n t e r p r e t the r e s u l t s of t h i s i n v e s t i g a t i o n . A l a r g e p r o p o r t i o n of p a t i e n t s with LVE were a l s o r e p o r t e d by K l i n g , K u r t z , T a c h i k i , and Orzeck (1982/83). In t h i s study the v e n t r i c l e to b r a i n r a t i o was measured on 26 c h r o n i c s c h i z o p h r e n i c p a t i e n t s , 22 p a t i e n t s w i t h e i t h e r a l c o h o l i c or n e u r o l o g i c a l problems, and 20 medical c o n t r o l s . Medical c o n t r o l scans were taken from r a d i o l o g y r e c o r d s and only those read as " g r o s s l y normal" were used. T h i s s e l e c t i o n procedure suggests t h a t o n l y scans that showed s m a l l v e n t r i c l e s were used. I f t h i s i s the case, s p u r i o u s l y low "normal" v a l u e s would be obt a i n e d and LVE i n s c h i z o p h r e n i c p a t i e n t s c o u l d be overestimated i n t h i s study. S c h i z o p h r e n i c s u b j e c t s were diagnosed u s i n g DSM-III c r i t e r i a and a l l were nonresponsive t o treatment. The mean age o f s c h i z o p h r e n i c p a t i e n t s was 36 years (range 23 t o 45 years) and mean d u r a t i o n of i l l n e s s was 10 y e a r s . The s c h i z o p h r e n i c group had s i g n i f i c a n t l y e n l a r g e d v e n t r i c l e s and 20 50% exceeded the l a r g e s t value obtained by a c o n t r o l s u b j e c t . No s i g n i f i c a n t c o r r e l a t i o n s were obtained between v e n t r i c l e s i z e and age or d u r a t i o n of i l l n e s s . These f i n d i n g s support e a r l i e r s t u d i e s and i n d i c a t e t h a t a l a r g e number of c h r o n i c s c h i z o p h r e n i c s have s i g n i f i c a n t l y e n l a r g e d v e n t r i c l e s . P a t i e n t s i n t h i s study, l i k e those of Weinberger et a l . (1979a), were nonresponsive t o me d i c a t i o n s . S e v e r a l s t u d i e s have i n d i c a t e d t h a t the preva l e n c e of LVE i n c h r o n i c s c h i z o p h r e n i c s may be l e s s than 50 or 60%. P e a r l s o n and V e r o f f (1981) r e p o r t e d fewer p a t i e n t s w i t h e n l a r g e d v e n t r i c l e s than have been r e p o r t e d i n the s t u d i e s reviewed above. In t h i s study, t h e r e were 22 s c h i z o p h r e n i c s , 16 manic-depressives, and 35 age- and sex-matched p s y c h i a t r i c c o n t r o l s . Diagnoses were made u s i n g DSM-III c r i t e r i a . P a t i e n t s were d e s c r i b e d as a c u t e l y i l l but the mean age and d u r a t i o n o f i l l n e s s were not r e p o r t e d . Using the VBR as a measure of v e n t r i c u l a r s i z e , 41% (9/22) of the s c h i z o p h r e n i c s and 12% (2/16) of the manic-depressives were found to have s i g n i f i c a n t l y l a r g e r v e n t r i c l e s than those of the c o n t r o l group. V e n t r i c l e s i z e d i d not c o r r e l a t e with age, age at onset, or d u r a t i o n of h o s p i t a l i z a t i o n but age was p o s i t i v e l y r e l a t e d to v e n t r i c u l a r s i z e i n the c o n t r o l group. N a s r a l l a h , Jacoby, M c C a l l e y - W h i t t e r s , and Kuperman (1982a) compared 55 c o n s e c u t i v e l y admitted c h r o n i c s c h i z o p h r e n i c men with 27 age-matched medical c o n t r o l s . The mean age of p a t i e n t s was 30 ye a r s (range 20 t o 45 years ) and mean d u r a t i o n of i l l n e s s was 6.3 y e a r s . Diagnoses were made u s i n g DSM-III c r i t e r i a . The VBR was used t o assess the s i z e of the l a t e r a l v e n t r i c l e s . Of the s c h i z o p h r e n i c group, 34% (19/55) had s i g n i f i c a n t l y e n l a r g e d v e n t r i c l e s . V e n t r i c l e s i z e was not s i g n i f i c a n t l y r e l a t e d t o age or d u r a t i o n of i l l n e s s . Weinberger et a l . (1982) e v a l u a t e d the CT scans of 17 c h r o n i c s c h i z o p h r e n i c s , 35 s c h i z o p h r e n i f o r m p a t i e n t s , 50 p a t i e n t s with other p s y c h i a t r i c d i s o r d e r s , and 26 medical c o n t r o l s . The mean age of the s c h i z o p h r e n i c p a t i e n t s was 28 yea r s (range 17 t o 50), f o r s c h i z o p h r e n i f o r m p a t i e n t s was 21 yea r s (range 13 t o 40), and f o r other p s y c h i a t r i c p a t i e n t s was 30 years (range 18 t o 50). The d u r a t i o n of i l l n e s s i s not g i v e n f o r the s c h i z o p h r e n i c or other p s y c h i a t r i c p a t i e n t s but i s , by d e f i n i t i o n , l e s s than s i x months f o r the s c h i z o p h r e n i f o r m p a t i e n t s . Diagnoses were made u s i n g DSM-III c r i t e r i a . Twenty-four percent (4/17) of the c h r o n i c s c h i z o p h r e n i c s , and 20% (7/35) of the s c h i z o p h r e n i f o r m p a t i e n t s had l a t e r a l v e n t r i c l e s t h a t were s i g n i f i c a n t l y l a r g e r than those of the c o n t r o l group. No enlargement was r e p o r t e d f o r the no n - s c h i z o p h r e n i c p s y c h i a t r i c p a t i e n t s . I t i s n o t a b l e i n t h i s study t h a t the preva l e n c e of enlar g e d v e n t r i c l e s i n c h r o n i c s c h i z o p h r e n i c s i s much l e s s than i n the p r e v i o u s study by t h i s r e s e a r c h team (Weinberger et a l . , 1979a). In the e a r l i e r study, u s i n g the same methodology, the percentage of c h r o n i c p a t i e n t s w i t h LVE was twice t h a t of the 1982 study. I t i s not c l e a r whether or not t h i s d i s c r e p a n c y i s due t o d i f f e r e n c e s i n p a t i e n t samples. No c o r r e l a t i o n s were r e p o r t e d between age or d u r a t i o n of 22 i l l n e s s and v e n t r i c l e s i z e . However, the f a c t that 20% of the s c h i z o p h r e n i f o r m p a t i e n t s had s i g n i f i c a n t l y e nlarged v e n t r i c l e s suggests t h a t LVE i s present at the onset of p s y c h o s i s i n some p a t i e n t s and i s not the r e s u l t of somatic treatment, prolonged i l l n e s s , or advanced age. The f i n d i n g of LVE i n f i r s t episode p a t i e n t s was r e p l i c a t e d by Schulz et a l . (1983). In t h i s study, 53% (8/15) of teenage s c h i z o p h r e n i f o r m / s c h i z o p h r e n i c p a t i e n t s (diagnosed a c c o r d i n g t o DSM-III c r i t e r i a ) had l a t e r a l v e n t r i c l e s t h a t were s i g n i f i c a n t l y e n l a r g e d when compared t o those of e i t h e r a medical c o n t r o l group (n = 18) or of a group of b o r d e r l i n e p a t i e n t s (n = 8 ) . The estimated p r e v a l e n c e o f LVE i s g r e a t e r than has been r e p o r t e d i n most oth e r s t u d i e s with s c h i z o p h r e n i c s . The mean age of the p a t i e n t s was 16 years and the average d u r a t i o n of i l l n e s s was 13 months (range f i v e t o 24 months). No s i g n i f i c a n t c o r r e l a t i o n was ob t a i n e d between d u r a t i o n of i l l n e s s and v e n t r i c l e s i z e . The r e l a t i o n s h i p between age and v e n t r i c l e s i z e was not r e p o r t e d . I t i s p o s s i b l e t h a t e a r l y onset may i n d i c a t e a more severe i l l n e s s and poor p r o g n o s i s . However, i t i s noteworthy that mean v e n t r i c l e s i z e i n the c o n t r o l group i s s m a l l e r than t h a t r e p o r t e d i n any other study. T h i s suggests c o n t r o l group b i a s and thus the p r e v a l e n c e of LVE i n s c h i z o p h r e n i a t h a t i s r e p o r t e d may be an overestimate o f the t r u e p r e v a l e n c e . Schulz et a l . (1983) note t h a t the h i g h p r e v a l e n c e of LVE i n t h e i r sample may r e s u l t from the f a c t t h a t p a t i e n t s were ob t a i n e d 23 from a f a c i l i t y where s e v e r e l y a f f e c t e d p a t i e n t s were admitted. The r e s u l t s of t h i s study support those of Weinberger et a l . (1982) and suggest that v e n t r i c u l a r enlargement probably occurs at or b e f o r e the onset of p s y c h o s i s i n some p a t i e n t s . F i n d i n g s of minimal v e n t r i c u l a r enlargement were r e p o r t e d by W i l l i a m s , Kolakowska, Arden, and Mandelbrote (1985). Only s i x (15%) of 40 c h r o n i c s c h i z o p h r e n i c p a t i e n t s had l a t e r a l v e n t r i c l e s t h a t were s i g n i f i c a n t l y e n l a r g e d when compared to 40 medical c o n t r o l s u b j e c t s . RDC diagnoses were made and p a t i e n t s ranged i n age from 20 t o 50 years (M = 32 y e a r s ) . The VBR was used t o a s s e s s v e n t r i c l e s i z e . Twelve p a t i e n t s were d e s c r i b e d as poor outcome, 16 as i n t e r m e d i a t e outcome, and 12 as good outcome. V e n t r i c l e s i z e was not a s s o c i a t e d with age but was s i g n i f i c a n t l y r e l a t e d to "poor outcome" and c h r o n i c n e g a t i v e symptoms. T h i s f i n d i n g supports the e a r l i e r r e s u l t s of Johnstone et a l . (1976), Weinberger et a l . (1979a), and K l i n g et a l . (1982-83) and suggests that v e n t r i c u l a r d i l a t i o n i s g r e a t e s t i n p a t i e n t s who respond p o o r l y t o treatment and/or r e q u i r e long p e r i o d s of h o s p i t a l i z a t i o n . The d u r a t i o n of i l l n e s s ranged from two to 20 years but no a s s o c i a t i o n between d u r a t i o n o f i l l n e s s and v e n t r i c l e s i z e was r e p o r t e d . Most of the s c h i z o p h r e n i c s i n c l u d e d i n t h i s study were o u t p a t i e n t s . Pandurangi et a l . (1984) used the VBR to estimate the s i z e of the l a t e r a l v e n t r i c l e s of 23 c h r o n i c s c h i z o p h r e n i c s and 23 medical c o n t r o l s . The mean age of p a t i e n t s was 28 24 years (range 20 t o 40). A l l p a t i e n t s met DSM-III c r i t e r i a f o r s c h i z o p h r e n i a , and none had been h o s p i t a l i z e d f o r extended p e r i o d s . The d u r a t i o n of i l l n e s s ranged from 2 to 19 y e a r s . Three of 23 p a t i e n t s (13%) had s i g n i f i c a n t l y enlarged v e n t r i c l e s . There were no s i g n i f i c a n t c o r r e l a t i o n s between v e n t r i c l e s i z e and age or d u r a t i o n of i l l n e s s . A s m a l l p r o p o r t i o n of s c h i z o p h r e n i c s were a l s o found to have LVE i n a study by Luchins et a l . (1984). In t h i s study, the VBR was used t o assess v e n t r i c l e s i z e i n 45 s c h i z o p h r e n i c , 20 a f f e c t i v e d i s o r d e r , and 50 medical p a t i e n t s . RDC diagnoses were used to c l a s s i f y p a t i e n t s . T h i r t y - o n e o f the s c h i z o p h r e n i c p a t i e n t s were c h r o n i c a l l y i l l . Ages ranged from 18 t o 59 (M = 29 y e a r s ) . F i v e (11%) of the 45 s c h i z o p h r e n i c and f o u r (18%) of the a f f e c t i v e p a t i e n t s had l a t e r a l v e n t r i c l e s t h a t were l a r g e r than the c o n t r o l mean p l u s two standards d e v i a t i o n s . V e n t r i c u l a r s i z e was not r e l a t e d t o age. The c o r r e l a t i o n s between v e n t r i c l e s i z e and d u r a t i o n o f i l l n e s s were not r e p o r t e d . L u c h i n s et a l . (1984) note t h a t the low frequency of LVE i n these p a t i e n t s may be due t o the f a c t t h a t these p a t i e n t s are l e s s impaired than those of some other s t u d i e s ; i . e . , the p a t i e n t s i n the Luchins et a l . (1984) study were a b l e t o f u n c t i o n f o r much of the time i n the community. I t i s a l s o i n t e r e s t i n g t o note t h a t a s i g n i f i c a n t r e l a t i o n s h i p was obt a i n e d between v e n t r i c l e s i z e and response t o n e u r o l e p t i c s . T h i s f u r t h e r supports the c o n t e n t i o n t h a t LVE i s found most f r e q u e n t l y i n c h r o n i c a l l y h o s p i t a l i z e d p a t i e n t s and/or 25 p a t i e n t s who respond p o o r l y to treatment. Luchins and Melzer (1986) f o l l o w e d up t h e i r e a r l i e r study (Luchins et a l . , 1984) by u s i n g 11 of t h e i r o r i g i n a l s c h i z o p h r e n i c s , 11 of the medical c o n t r o l s , and adding 11 c h r o n i c , long term h o s p i t a l i z e d s c h i z o p h r e n i c s . The two groups of s c h i z o p h r e n i c s were matched over age (M = 28 years ) and d u r a t i o n o f i l l n e s s (M = 8 y e a r s ) . However, whereas the 11 s c h i z o p h r e n i c s from the o r i g i n a l study were h o s p i t a l i z e d f o r an average of 10% of t h e i r i l l n e s s , the 11 p a t i e n t s who were added had been h o s p i t a l i z e d f o r an average of 60% of t h e i r i l l n e s s . Diagnoses were made a c c o r d i n g t o DSM-III c r i t e r i a and the VBR was used t o as s e s s v e n t r i c l e s i z e . The mean age of the c o n t r o l s was 36 y e a r s . The long term h o s p i t a l i z e d p a t i e n t s had a mean v e n t r i c l e s i z e s i g n i f i c a n t l y g r e a t e r than both the s h o r t term h o s p i t a l i z e d p a t i e n t s and the c o n t r o l s u b j e c t s . Seven of these s c h i z o p h r e n i c s (64%) had s i g n i f i c a n t v e n t r i c u l a r d i l a t i o n ( l a t e r a l v e n t r i c l e s g r e a t e r than the c o n t r o l mean p l u s two standard d e v i a t i o n s ) . As with the o r i g i n a l study (Luchins et a l . , 1984), the 11 p a t i e n t s i n the acute p s y c h i a t r i c wards a l s o had s i g n i f i c a n t l y l a r g e r mean v e n t r i c l e s i z e than the c o n t r o l s u b j e c t s . However, o n l y three (27%) had s i g n i f i c a n t l y e n l a r g e d v e n t r i c l e s . The hig h p r e v a l e n c e o f LVE i n c h r o n i c a l l y h o s p i t a l i z e d p a t i e n t s and the d i f f e r e n c e between the c h r o n i c a l l y h o s p i t a l i z e d and sh o r t term h o s p i t a l i z e d p a t i e n t s s t r o n g l y suggest t h a t p a t i e n t s who do not respond w e l l t o treatment or are unable t o f u n c t i o n i n the community 26 are l i k e l y to have LVE. T h i s n o t i o n i s supported by the f a c t t h a t whereas no r e l a t i o n s h i p was obtained between VBR s i z e and d u r a t i o n of h o s p i t a l i z a t i o n or d u r a t i o n of i l l n e s s , a s i g n i f i c a n t p o s i t i v e r e l a t i o n was found between VBR s i z e and the percent of i l l n e s s spent i n h o s p i t a l . Luchins and Melzer (1986) i n d i c a t e t h a t the c o n t r o l group may be b i a s e d because of the e x c l u s i o n of i n d i v i d u a l s with "abnormal" scans; i . e . , s u b j e c t s with normal but l a r g e v e n t r i c l e s may have been excluded. Thus, the a b s o l u t e number of p a t i e n t s with e n l a r g e d v e n t r i c l e s may be o v e r e s t i m a t e d i n t h i s study. N e v e r t h e l e s s , t h i s study does p r o v i d e evidence f o r a r e l a t i o n s h i p between s e v e r i t y of i l l n e s s and v e n t r i c l e s i z e . R i e d e r et a l . (1983) r e p o r t e d that 7% (2/28) of a group of c h r o n i c s c h i z o p h r e n i c p a t i e n t s had s i g n i f i c a n t l y e n l a r g e d l a t e r a l v e n t r i c l e s when compared to p u b l i s h e d normal v a l u e s . A normal c o n t r o l group was not i n c l u d e d i n t h i s study. I t was a l s o r e p o r t e d t h a t one (7%) of 15 s c h i z o a f f e c t i v e and two (10%) of 19 b i p o l a r p a t i e n t s had LVE. P a t i e n t s were c l a s s i f i e d a c c o r d i n g t o RDC diagnoses. The mean age of the s c h i z o p h r e n i c p a t i e n t s was 26 y e a r s . A s i g n i f i c a n t r e l a t i o n s h i p was obtained between age and v e n t r i c l e s i z e over the t o t a l p a t i e n t sample ( r = .42, p < .001). The d u r a t i o n of i l l n e s s and r e l a t i o n s h i p between v e n t r i c l e s i z e and d u r a t i o n of i l l n e s s were not r e p o r t e d . P a t i e n t s used i n t h i s study are d e s c r i b e d as i n c l u d i n g a h i g h p r o p o r t i o n of t r e a t m e n t - r e s i s t a n t cases. Because Reider et a l . (1983) f a i l e d t o i n c l u d e a c o n t r o l group, these f i n d i n g s are 27 d i f f i c u l t to i n t e r p r e t . There are s y s t e m a t i c m e t h o d o l o g i c a l d i f f e r e n c e s between s t u d i e s that i n f l u e n c e o b t a i n e d VBR •values (Maser and K e i t h , 1983) and, thus, i t i s p o s s i b l e t h a t the r e s u l t s of Reider et a l . (1983) may r e f l e c t measurement a r t i f a c t . N e v e r t h e l e s s , these f i n d i n g s concur with a number of p r e v i o u s r e p o r t s and thus p r o v i d e t e n t a t i v e c o r r o b o r a t i n g evidence. Andreasen, Smith, Jacoby, Dennert, and Olsen (1982b) a l s o r e p o r t e d s i g n i f i c a n t group d i f f e r e n c e s between s c h i z o p h r e n i c and c o n t r o l s u b j e c t s over v e n t r i c l e s i z e . The VBR was assessed i n a group of 52 c h r o n i c s c h i z o p h r e n i c i n p a t i e n t s (diagnosed a c c o r d i n g to RDC and DSM-III c r i t e r i a ) and 47 medical c o n t r o l s u b j e c t s . A l l p a t i e n t s had spent most of t h e i r i l l n e s s as o u t p a t i e n t s . The mean age of p a t i e n t s was 30 years and the mean d u r a t i o n of i l l n e s s was 5 y e a r s . Using a comparable d e f i n i t i o n t o t h a t of Weinberger e t a l . (1979), Andreasen et a l . (1982b) r e p o r t e d that o n l y 6% (3/52) of s c h i z o p h r e n i c p a t i e n t s had v e n t r i c l e s t h a t were s i g n i f i c a n t l y e nlarged; i . e . , g r e a t e r than the c o n t r o l mean p l u s two standard d e v i a t i o n s . T h i s number i s low compared to th a t r e p o r t e d i n other s t u d i e s . In another recent study, Owens et a l . (1985) examined v e n t r i c u l a r enlargement i n 110 c h r o n i c a l l y h o s p i t a l i z e d , 18 o u t p a t i e n t , and 8 f i r s t break s c h i z o p h r e n i c s . Two other groups comprised 32 manic d e p r e s s i v e s and 19 " n e u r o t i c " o u t p a t i e n t s . S c h i z o p h r e n i c s were diagnosed a c c o r d i n g to the CATEGO computerized d i a g n o s t i c s y s t e m — t h i s system i s based 28 on items d e r i v e d from the Present S t a t e Examination (PSE; Wing, Cooper, & S a r t o r i u s , 1974). Manic and n e u r o t i c p a t i e n t s were diagnosed a c c o r d i n g t o Feighner d i a g n o s t i c c r i t e r i a . Ages ranged from 22 t o 87 years with a mean of 55 yea r s f o r the s c h i z o p h r e n i c group. The average age of the manic and n e u r o t i c p a t i e n t s was not giv e n and mean d u r a t i o n of i l l n e s s was not r e p o r t e d f o r any p a t i e n t group. A s i g n i f i c a n t l y g r e a t e r mean v e n t r i c l e s i z e was r e p o r t e d f o r the s c h i z o p h r e n i c group over the manic and n e u r o t i c groups. The p r o p o r t i o n of p a t i e n t s with s i g n i f i c a n t l y e n l a r g e d l a t e r a l v e n t r i c l e s (the c o n t r o l mean p l u s two standard d e v i a t i o n s ) i s not g i v e n . A s i g n i f i c a n t r e l a t i o n s h i p was r e p o r t e d between age and v e n t r i c l e s i z e . V e n t r i c l e s i z e was r e l a t i v e l y constant a c r o s s a l l age groups and i n c r e a s e d i n p a t i e n t s who were i n the s i x t h or seventh decade of l i f e . F i n a l l y , a s i g n i f i c a n t l y e n l a r g e d mean v e n t r i c l e s i z e (VBR) was r e p o r t e d by D e L i s i et a l . (1986). In t h i s study, CT scans were performed on 26 i n - and o u t - p a t i e n t s c h i z o p h r e n i c s , 10 w e l l r e l a t i v e s of the s c h i z o p h r e n i c p a t i e n t s , and 20 normal v o l u n t e e r s . S c h i z o p h r e n i c diagnoses were made a c c o r d i n g to DSM-III c r i t e r i a and the average d u r a t i o n o f h o s p i t a l i z a t i o n f o r these p a t i e n t s was 3.2 y e a r s . The mean age of the s c h i z o p h r e n i c p a t i e n t s was 32 ye a r s , of the r e l a t i v e s was 33 yea r s , and of the c o n t r o l s was 31 y e a r s . Whereas there was a s i g n i f i c a n t d i f f e r e n c e over mean v e n t r i c l e s i z e between the s c h i z o p h r e n i c p a t i e n t s and the c o n t r o l s u b j e c t s , t h e r e was no d i f f e r e n c e between the 29 r e l a t i v e s of the s c h i z o p h r e n i c p a t i e n t s and e i t h e r the s c h i z o p h r e n i c group or the c o n t r o l group. Using the d e f i n i t i o n o f Weinberger et a l . (1979a; c o n t r o l mean p l u s two standard d e v i a t i o n s ) to determine the number of p a t i e n t s with s i g n i f i c a n t v e n t r i c u l a r enlargement, o n l y one (4%) s c h i z o p h r e n i c had en l a r g e d v e n t r i c l e s (VBR > 14.39). D e L i s i et a l . (1986) a l s o measured the area of the f r o n t a l horns of the l a t e r a l v e n t r i c l e s and r e p o r t e d r e s u l t s from a f r o n t a l h o r n - b r a i n r a t i o . Using t h i s index of v e n t r i c u l a r enlargement, t h r e e (12%) of the s c h i z o p h r e n i c s had f r o n t a l horns t h a t were g r e a t e r than the c o n t r o l mean p l u s two standard d e v i a t i o n s . The minimal enlargement t h a t was obta i n e d i n t h i s study may be a t t r i b u t a b l e , i n p a r t , t o the f a c t t h a t 11 of the normal c o n t r o l s were found t o have p s y c h i a t r i c problems. Because t h e r e are r e p o r t s of v e n t r i c u l a r enlargement i n some non s c h i z o p h r e n i c p s y c h i a t r i c p a t i e n t s (see Prevalence of LVE i n A f f e c t i v e D i s o r d e r s below) i t i s p o s s i b l e t h a t t h i s c o n t r o l group may be b i a s e d towards enla r g e d v e n t r i c l e s . Reports of No S i g n i f i c a n t LVE. There are s e v e r a l r e p o r t s of no LVE i n s c h i z o p h r e n i c p a t i e n t s . Benes et a l . (1982) r e p o r t e d that none of ten young s c h i z o p h r e n i c p a t i e n t s had s i g n i f i c a n t l y e n l a r g e d l a t e r a l v e n t r i c l e s when compared to 26 medical c o n t r o l s u b j e c t s . T h i s was the case whether l i n e a r or VBR measures were used. Feighner c r i t e r i a were used to make diagnoses. The mean age of p a t i e n t s was 21 years and the mean d u r a t i o n o f i l l n e s s was fou r y e a r s . 30 C o r r e l a t i o n s between v e n t r i c l e s i z e and age or d u r a t i o n o f i l l n e s s are not r e p o r t e d . These p a t i e n t s showed v a r y i n g degrees of c o g n i t i v e impairment and the CT scans were done t o ev a l u a t e the presence of o r g a n i c b r a i n d i s e a s e . In a d d i t i o n , t h e r e was a p e r i o d o f seven years between the time the f i r s t and l a s t p a t i e n t s were scanned. The f a c t t h a t the CT scans were ob t a i n e d over a number of years suggests that the s e l e c t i o n c r i t e r i a and the CT scanners and scanning procedures may be d i f f e r e n t f o r d i f f e r e n t s u b j e c t s . A well-conducted study t h a t produced n e g a t i v e r e s u l t s was r e p o r t e d by J e r n i g a n et a l . (1982). In t h i s study, the v e n t r i c u l a r volume and VBR of 30 c h r o n i c s c h i z o p h r e n i c i n -and o u t - p a t i e n t s and 36 normal v o l u n t e e r s were measured from CT scans. Diagnoses were made u s i n g DSM-III c r i t e r i a . No s i g n i f i c a n t d i f f e r e n c e s were o b t a i n e d between the s c h i z o p h r e n i c and c o n t r o l groups whether the VBR or v e n t r i c u l a r volume was used to assess v e n t r i c l e s i z e . The mean d u r a t i o n o f i l l n e s s was 10 years and p a t i e n t s ranged i n age from 23 t o 58 years (M = 32 y e a r s ) . No s i g n i f i c a n t c o r r e l a t i o n s were ob t a i n e d between v e n t r i c l e s i z e and d u r a t i o n o f i l l n e s s or age. P a t i e n t s i n t h i s study were screened f o r n e u r o l o g i c a l d e f i c i t s and s e r i o u s medical problems. No s u b j e c t had a d e f i c i t i n any of these a r e a s . A l l o f the p a t i e n t s i n t h i s study are d e s c r i b e d as employed or employable. The s e l e c t i o n c r i t e r i a used i n t h i s study suggests t h a t t h i s group of p a t i e n t s may be l e s s impaired and have a b e t t e r p r o g n o s i s than the samples d e s c r i b e d i n other 31 s t u d i e s (Luchins, 1982). In order t o determine whether these n e g a t i v e r e s u l t s were due t o met h o d o l o g i c a l f a c t o r s , J e r n i g a n et a l . (1982) had the CT scans assessed by the r e s e a r c h teams of Golden and Weinberger. Each of these groups r e p o r t e d a d i f f e r e n t mean v e n t r i c l e s i z e from that of J e r n i g a n et a l . (1982) but the r e l a t i v e rank order of s u b j e c t s and mean group d i f f e r e n c e s were very s i m i l a r a c r o s s a l l three r e s e a r c h teams. No r e s e a r c h group ob t a i n e d s i g n i f i c a n t LVE f o r these data. The r e s u l t s of t h i s study suggest t h a t LVE i s l e s s l i k e l y t o be found i n m i l d l y impaired c h r o n i c s c h i z o p h r e n i c p a t i e n t s than i n p a t i e n t s who have a severe course of i l l n e s s . Smith and Maser (1983) a l s o r e p o r t e d no s i g n i f i c a n t enlargement of the l a t e r a l v e n t r i c l e s . In t h i s study, 30 RDC diagnosed s c h i z o p h r e n i c s were compared to 14 medical c o n t r o l s . Age and d u r a t i o n o f i l l n e s s are not giv e n nor are the c o r r e l a t i o n s between v e n t r i c l e s i z e and age or d u r a t i o n o f i l l n e s s . Some p a t i e n t s a re d e s c r i b e d as c h r o n i c nonresponders t o treatment but i t i s u n c l e a r how many f a l l i n t o t h i s category. The r e s u l t s of t h i s study, because c h r o n i c nonresponders t o treatment are i n c l u d e d , c o n t r a d i c t many of the f i n d i n g s reviewed above. T h i s f i n d i n g suggests t h a t LVE may not be apparent i n some s e v e r e l y impaired p a t i e n t s . However, the absence of d e t a i l e d i n f o r m a t i o n on s u b j e c t c h a r a c t e r i s t i c s and s e l e c t i o n procedures prevents any f i r m c o n c l u s i o n s . Using a s m a l l sample (n = 8) of DSM-III diagnosed 32 s c h i z o p h r e n i c s , DeMeyer e t a l . (1984) r e p o r t e d no d i f f e r e n c e i n l a t e r a l v e n t r i c u l a r s i z e between the p a t i e n t group and a medical c o n t r o l group. The s c h i z o p h r e n i c p a t i e n t s r e p o r t e d l y had a h i s t o r y of severe p s y c h o s i s and were r e l a t i v e l y u nresponsive t o n e u r o l e p t i c m e d i c a t i o n . The mean age of the p a t i e n t s was 26 y e a r s . D u r a t i o n o f i l l n e s s was not r e p o r t e d nor were the c o r r e l a t i o n s between v e n t r i c l e s i z e and age or d u r a t i o n o f i l l n e s s . I t i s p o s s i b l e t h a t the s m a l l s i z e of the sample r e s u l t e d i n a n o n r e p r e s e n t a t i v e group. However, the s e v e r i t y of i l l n e s s i n these p a t i e n t s suggests t h a t they were at l e a s t as impaired as p a t i e n t s used i n other s t u d i e s where h i g h l y s i g n i f i c a n t f i n d i n g s were r e p o r t e d . T h i s f i n d i n g supports that of Smith and Maser (1983) and suggests that some p a t i e n t s who are s e v e r e l y impaired ( i . e . , respond p o o r l y t o treatment) do not have s i g n i f i c a n t l a t e r a l v e n t r i c u l a r enlargement. Largen e t a l . (1984) a l s o r e p o r t e d no l a t e r a l v e n t r i c u l a r enlargement i n a group of 35 h o s p i t a l i z e d s c h i z o p h r e n i c s when compared to 17 medical c o n t r o l s . Most p a t i e n t s were c h r o n i c a l l y i l l but f o u r p a t i e n t s had r e c e n t l y e xperienced t h e i r f i r s t p s y c h o t i c e p isode. The average age of p a t i e n t s was 30 years and the d u r a t i o n o f i l l n e s s ranged from two weeks t o 24 y e a r s . V e n t r i c l e s i z e was assessed u s i n g the VBR and RDC diagnoses were made. I t i s r e p o r t e d t h a t most p a t i e n t s were r e l a p s i n g p s y c h o t i c s and were ab l e t o l i v e i n the community between e p i s o d e s . T h i s study adds support t o e a r l i e r n e g a t i v e f i n d i n g s and suggests that some 33 c h r o n i c p a t i e n t s have no s i g n i f i c a n t enlargement of the l a t e r a l v e n t r i c l e s . However, the f a c t t h a t these p a t i e n t s were a b l e t o l i v e i n the community suggests t h a t they responded to treatment and were not as impaired as the c h r o n i c a l l y h o s p i t a l i z e d p a t i e n t s used i n some s t u d i e s where p o s i t i v e r e s u l t s were o b t a i n e d . Shima et a l . (1985) used the VBR t o assess l a t e r a l v e n t r i c u l a r s i z e i n 46 c h r o n i c s c h i z o p h r e n i c i n p a t i e n t s . The mean age of the p a t i e n t s was 37 years (range 23 to 48 years) and average d u r a t i o n of i l l n e s s was 13 y e a r s . Diagnoses were made a c c o r d i n g t o DSM-III c r i t e r i a . A c o n t r o l group of 38 h e a l t h y v o l u n t e e r s was used f o r comparison. A n o n s i g n i f i c a n t t r e n d towards l a r g e r v e n t r i c l e s i n the s c h i z o p h r e n i c group i s r e p o r t e d . U n l i k e p r e v i o u s s t u d i e s , s i g n i f i c a n t c o r r e l a t i o n s were ob t a i n e d between v e n t r i c l e s i z e and both age and d u r a t i o n o f i l l n e s s . I t i s d i f f i c u l t t o determine the l e v e l o f impairment i n these p a t i e n t s from the i n f o r m a t i o n g i v e n . N e v e r t h e l e s s , t h i s r e s u l t p r o v i d e s support f o r oth e r n e g a t i v e r e s u l t s and suggests t h a t some c h r o n i c p a t i e n t s do not have enlar g e d v e n t r i c l e s . F i n a l l y , Boronow et a l . (1985), i n a w e l l - d e s c r i b e d study, r e p o r t e d a n o n s i g n i f i c a n t t r e n d towards enl a r g e d l a t e r a l v e n t r i c l e s i n 30 c h r o n i c s c h i z o p h r e n i c p a t i e n t s when compared t o 26 medical p a t i e n t s . The mean age of the s c h i z o p h r e n i c s was 25 years and the average d u r a t i o n o f i l l n e s s was f i v e y e a r s . No s i g n i f i c a n t c o r r e l a t i o n s were obt a i n e d between v e n t r i c l e s i z e and e i t h e r age or d u r a t i o n of 3 4 i l l n e s s . RDC diagnoses were made and v e n t r i c l e s i z e was assessed u s i n g the VBR. T h i s study i s p a r t i c u l a r l y notworthy i n t h a t s c h i z o p h r e n i c p a t i e n t s were d e s c r i b e d as s e v e r e l y i l l c h r o n i c s c h i z o p h r e n i c s . T h i s r e s u l t f u r t h e r q u e s t i o n s the assumption t h a t l a t e r a l v e n t r i c u l a r enlargement i s present i n a s i g n i f i c a n t p r o p o r t i o n of c h r o n i c s c h i z o p h r e n i c s . Summary of the S t u d i e s of LVE i n S c h i z o p h r e n i a From the pr e c e d i n g review, some c o n c l u s i o n s can be drawn. The c o n s i s t e n c y of LVE i n the o l d e r pneumoencephalographic s t u d i e s and i n the CT s t u d i e s where l i n e a r measures were employed has been supported by many f i n d i n g s from CT s t u d i e s where the VBR was used. The f i n d i n g s from these s t u d i e s suggest t h a t enlargement of the l a t e r a l v e n t r i c l e s i s found i n both young and o l d s c h i z o p h r e n i c p a t i e n t s and some p r e l i m i n a r y r e s u l t s suggest t h a t v e n t r i c u l a r enlargement may be present at the onset of p s y c h o s i s i n some s c h i z o p h r e n i c s . There i s , however, much v a r i a b i l i t y i n the r e p o r t e d p r e v a l e n c e o f t h i s anomaly. Esti m a t e s of the prevalence o f LVE have ranged from 7% to 94% with a median of 29% and seven s t u d i e s i n d i c a t e no s i g n i f i c a n t enlargement. In a d d i t i o n , t h e r e i s much v a r i a b i l i t y i n the mean s i z e of the l a t e r a l v e n t r i c l e s t h a t i s r e p o r t e d . These VBR v a l u e s range from 4.1 (Luchins et a l . , 1984) to 18.7 (Johnstone et a l . , 1976) f o r p a t i e n t s and 2.7 (Schulz et a l . , 1983) to 10.8 (Owens et a l . , 1985) f o r c o n t r o l s u b j e c t s . P r o c e d u r a l f a c t o r s probably account f o r some of the v a r i a b i l i t y i n the s i z e of the l a t e r a l v e n t r i c l e s t h at has been r e p o r t e d (Maser & K e i t h , 1983). In p a r t i c u l a r , d i f f e r e n c e s i n the d e f i n i t i o n of the v e n t r i c l e w a l l s t h a t are used when t r a c i n g the perimeter of the l a t e r a l v e n t r i c l e s have been shown to r e s u l t i n l a r g e d i f f e r e n c e s i n the e s t imated s i z e of t h i s aspect of the b r a i n ( J e r n i g a n et a l . , 1982). However, i f the same procedures are used f o r p a t i e n t s and c o n t r o l s u b j e c t s , then t h i s f a c t o r should not i n f l u e n c e the p r e v a l e n c e of LVE that i s found and would not account f o r the f a i l u r e t o f i n d enlargement i n s e v e r a l s t u d i e s . A more s e r i o u s m e t h o d o l o g i c a l problem would be one t h a t a f f e c t s s u b j e c t groups d i f f e r e n t i a l l y . An example would be a b i a s i n s u b j e c t s e l e c t i o n t h a t l e a d s to u n r e p r e s e n t a t i v e s c h i z o p h r e n i c or c o n t r o l samples. D i f f e r e n c e s between s t u d i e s i n the s e v e r i t y of impairment of s c h i z o p h r e n i c samples has been widely r e c o g n i z e d as a l i k e l y c o n t r i b u t i n g f a c t o r t o the i n c o n s i s t e n c i e s i n the CT r e s e a r c h f i n d i n g s . I f t h i s i s the case, then LVE c o u l d be l i m i t e d to those p a t i e n t s with severe pathology; i . e . , p a t i e n t s who respond p o o r l y t o treatment and/or r e q u i r e prolonged h o s p i t a l i z a t i o n . O v e r a l l , r e s e a r c h r e s u l t s support t h i s c o n t e n t i o n and suggest t h a t s e v e r e l y impaired p a t i e n t s are more l i k e l y t o have LVE than are l e s s impaired p a t i e n t s . However, th e r e i s some p r e l i m i n a r y evidence (Boronow et a l . , 1985; DeMeyer et a l . , 1984; Largen et a l . , 1984) to i n d i c a t e t h a t even i n some s e v e r e l y i l l p a t i e n t s , t h e r e may not be s i g n i f i c a n t v e n t r i c u l a r enlargement. 36 In a d d i t i o n , i t i s not always c l e a r from the d e s c r i p t i o n s of s u b j e c t s to what exten t , or i n what areas of f u n c t i o n i n g , p a t i e n t s are impaired. P a t i e n t s are l i k e l y t o d i f f e r s i g n i f i c a n t l y between c e n t e r s over such v a r i a b l e s as response t o treatment, type of symptoms, the presence of a s s s o c i a t e d p e r s o n a l i t y d i s o r d e r s , and the r o l e of p r e c i p i t a t i n g f a c t o r s (Maser & K e i t h , 1983). At the present time, t h e r e i s not a commonly agreed upon d e f i n i t i o n of l e v e l of impairment. Thus, whereas most r e s e a r c h f i n d i n g s suggest t h a t p a t i e n t s who are s e v e r e l y impaired are more l i k e l y t o have LVE, some s t u d i e s do not support t h i s h y p o t h e s i s and the absence of a common d e f i n i t i o n of s e v e r i t y p r e c l u d e s meaningful comparison o f s u b j e c t s between s t u d i e s over t h i s v a r i a b l e . Whereas d i f f e r e n c e s i n the p o p u l a t i o n s from which s c h i z o p h r e n i c s are drawn i s r e c o g n i s e d by most r e s e a r c h e r s as a probable c o n t r i b u t i n g f a c t o r t o the wide v a r i a b i l i t y i n f i n d i n g s , l i t t l e a t t e n t i o n has been drawn to the f a c t t h at CT s t u d i e s a l s o d i f f e r with r e s p e c t to the s e l e c t i o n of c o n t r o l groups. The c o n t r o l groups t h a t have been used i n c l u d e p s y c h i a t r i c p a t i e n t s , v a r i o u s types of medical p a t i e n t s , and normal v o l u n t e e r s . As was noted above ( L a t e r a l V e n t r i c u l a r Enlargement), a number of p h y s i c a l d i s o r d e r s may r e s u l t i n e n l a r g e d v e n t r i c l e s or i n decreased v e n t r i c u l a r s i z e . Thus, the c h a r a c t e r i s t i c s of the medical p o p u l a t i o n that i s sampled from can p o t e n t i a l l y i n f l u e n c e the o b t a i n e d mean v e n t r i c l e s i z e and, as a consequence, the p r e v a l e n c e of LVE t h a t i s d e t e c t e d i n p s y c h i a t r i c p a t i e n t s . 37 In a d d i t i o n , normal v a r i a b i l i t y i n b r a i n morphology i s p o o r l y understood (Maser & K e i t h , 1983) and the extent of t h i s v a r i a b i l i t y i s l i k e l y to go unrecognized by d i a g n o s t i c i a n s who normally examine CT scans t o d e t e c t neuropathology. T h i s f a c t o r i s p a r t i c u l a r l y p e r t i n e n t to the s t u d i e s of LVE i n s c h i z o p h r e n i a because many i n v e s t i g a t o r s use medical p a t i e n t s as c o n t r o l s u b j e c t s . S e l e c t i o n o f "normal" CT scans c o u l d l e a d to the s y s t e m a t i c e x c l u s i o n of p a t i e n t s with normal but l a r g e v e n r i c l e s and the i n c l u s i o n o f s u b j e c t s who, because of neuropathology, have abnormally s m a l l v e n t r i c l e s . T h i s would exagerate the preva l e n c e of LVE i n s c h i z o p h r e n i c p a t i e n t s . I f , as i s u s u a l l y h y p o t h e s i s e d , v e n t r i c u l a r enlargement i s a f e a t u r e o f the s c h i z o p h r e n i c i l l n e s s i n a sm a l l t o moderate p r o p o r t i o n o f s e v e r e l y i l l p a t i e n t s , then those s t u d i e s t h a t i n d i c a t e LVE ( i . e . , those t h a t i n c l u d e a s i g n i f i c a n t p r o p o r t i o n o f p a t i e n t s who have en l a r g e d v e n t r i c l e s ) should r e p o r t g r e a t e r mean VBR v a l u e s than those s t u d i e s t h a t d e t e c t no LVE. C o n t r o l s u b j e c t s , on the other hand, should have r e l a t i v e l y s i m i l a r VBR value s a c r o s s s t u d i e s r e g a r d l e s s of the r e s u l t s of the i n v e s t i g a t i o n . In order t o t e s t t h i s h y p o t h e s i s , a l l s t u d i e s that assessed the p r e v a l e n c e of LVE i n s c h i z o p h r e n i a and i n c l u d e d a c o n t r o l group were i n c l u d e d . Because l i n e a r measures cannot e a s i l y be compared a c r o s s s t u d i e s , o n l y those i n v e s t i g a t i o n s t h a t i n c l u d e d the VBR were used i n t h i s a n a l y s i s . Twenty-three s t u d i e s used the VBR as a measure of v e n t r i c l e s i z e and 38 i n c l u d e d a c o n t r o l group (Table 2 ) . The mean VBR f o r a l l s u b j e c t s i n 14 s t u d i e s where p o s i t i v e r e s u l t s were ob t a i n e d was compared to t h a t of the s u b j e c t s i n the seven s t u d i e s where no LVE was r e p o r t e d . Because Johnstone et a l . (1976) and Owens et a l . (1985) used o l d s u b j e c t s and r e p o r t e d VBR va l u e s f a r g r e a t e r than those of other r e s e a r c h e r s , these s t u d i e s were not i n c l u d e d i n the f o l l o w i n g c a l c u l a t i o n s . A l l but one o f the remaining r e p o r t s p r o v i d e group means and standard d e v i a t i o n s f o r VBR measures, making i t p o s s i b l e t o c a l c u l a t e means and standard d e v i a t i o n s a c r o s s groups of s t u d i e s and to compute t - s t a t i s t i c s t o e v a l u a t e s i g n i f i c a n t d i f f e r e n c e s . For the one i n v e s t i g a t i o n t h a t d i d not r e p o r t standard d e v i a t i o n s , they were estimated from o t h e r s t u d i e s t h a t used s i m i l a r s u b j e c t groups. As can be seen i n F i g u r e 1, the mean va l u e s f o r the s c h i z o p h r e n i c groups are very s i m i l a r a c r o s s p o s i t i v e (M = 6.84, n = 454) and ne g a t i v e (M = 6.74, n = 190) r e s u l t s . The mean va l u e s f o r the c o n t r o l s u b j e c t s , on the other hand, d i f f e r s u b s t a n t i a l l y between those r e p o r t i n g LVE (M = 3.97, n = 444) and those f i n d i n g no LVE (M = 6.34, n = 182; t = 10.14, p<.001). As F i g u r e 1 i n d i c a t e s , t h e r e i s l i t t l e o v e r l a p i n range between those s t u d i e s r e p o r t i n g p o s i t i v e r e s u l t s and those with n e g a t i v e f i n d i n g s . I f the mean VBR val u e f o r a l l c o n t r o l s u b j e c t s (M = 4.69) i s used to dichotomize c o n t r o l groups i n t o those with l a r g e (M VBR > 4.69) and those with s m a l l (M VBR < 4.69) l a t e r a l v e n t r i c l e s , then most (11/14, 79%) c o n t r o l groups i n the s t u d i e s that 39 Table 2 V e n t r i c l e S i z e i n S t u d i e s Where the VBR was Used S c h i z o p h r e n i c C o n t r o l a Reports of LVE # VBR # VBR Type Andreasen et a l . , 1982a 52 6. 0 47 4. 5 Medical D e L i s i et a l . , 1986 26 8. 2 20 6. 4 Normal Johnstone e t a l . , 1976 18 18. 7 10 10. 5 Med i c a l K l i n g et a l . , 1982/83 26 8. 4 20 4. 7 M e d i c a l Luchins et a l . , 1984 45 4. 1 62 3. 0 Med i c a l N a s r a l l a h e t a l . , 1982 55 8. 7 27 4. 5 Med i c a l Owens et a l . , 1985 136 11. 9 19 10. 1 P s y c h i a t r i c Pandurangi et a l . , 1984 23 5. 4 23 3. 5 Med i c a l P e a r l s o n & V e r o f f , 1981 22 7. 5 35 3. 6 P s y c h i a t r i c P e a r l s o n et a l . , 1984 19 6. 2 19 4. 5 Normal Revely et a l . , 1982 7 8. 6 38 4. 6 Normal S c h u l s i n g e r et a l . , 1984 7 9. 8 13 7. 5 Normal Schulz e t a l . , 1983 15 8. 4 18 2. 7 M e d i c a l Weinberger et a l . , 1979a 65 8. 7 56 3. 5 Normal Weinberger et a l . , 1982 52 5. 5 26 2. 9 M e d i c a l W i l l i a m s et a l . , 1985 40 4. 6 40 3. 4 Med i c a l D Average V e n t r i c l e S i z e 545 6. 8 444 4. 0 a Reports of No LVE Benes et a l . , 1982 11 8. 5 26 8. 8 Med i c a l Boronow e t a l . , 1985 30 5. 7 26 4. 9 Med i c a l DeMeyer et a l . , 1984 8 5. 8 15 4. 3 Med i c a l Continued on the next page. Table 2 (Continued) S c h i z o p h r e n i a C o n t r o l a Reports of No LVE VBR # VBR Type J e r n i g a n e t a l . , 1982 30 5.2 33 5.0 Normal Largen et a l . , 1984 35 6.7 17 6.5 M e d i c a l Shima et a l . , 1985 46 8.2 46 7.6 Normal Smith & Maser, 1983 30 6.8 19 5.8 M e d i c a l Average V e n t r i c l e S i z e 190 6.7 182 6.3 a LVE = L a t e r a l V e n t r i c u l a r Enlargement b The s t u d i e s of Johnstone et a l . , (1976) and Owens et a l . , (1985) were not i n c l u d e d i n these c a l c u l a t i o n s . 41 S c h l z C o n t r o l Enlargement Reported S c h l z C o n t r o l No Enlargement Reported F i g u r e _1. Mean VBR Values f o r Each Study and O v e r a l l Mean Values f o r S c h i z o p h r e n i c and C o n t r o l S u b j e c t s i n S t u d i e s of L a t e r a l V e n t r i c u l a r Enlargement. 42 r e p o r t e d LVE have smal l v e n t r i c l e s and most (6/7, 86%) of the s t u d i e s r e p o r t i n g no LVE have c o n t r o l groups with l a r g e v e n t r i c l e s (p<.01, F i s h e r exact t e s t ) . C l e a r l y the f i n d i n g s from the p r e v i o u s s t u d i e s f a i l to support the h y p o t h e s i s t h a t the type of s c h i z o p h r e n i c sample accounts f o r the v a r i a b i l i t y i n the estimated p r e v a l e n c e of LVE. O v e r a l l , the s i g n i f i c a n c e o f obt a i n e d CT r e s u l t s depends on the mean s i z e of the v e n t r i c l e s i n the c o n t r o l s u b j e c t but not i n the s c h i z o p h r e n i c p a t i e n t s . I t i s p o s s i b l e t h a t the c o n t r o l groups i n those s t u d i e s where no LVE was r e p o r t e d have i n f l a t e d VBR v a l u e s or c o n t r o l s u b j e c t s i n i n v e s t i g a t i o n s where p o s i t i v e r e s u l t s were o b t a i n e d c o u l d have s p u r i o u s l y s m a l l v e n t r i c l e s ; i . e . , e i t h e r the pr e v a l e n c e of LVE has been overestimated or underestimated. As was noted above, v e n t r i c l e s i z e i n medical p a t i e n t s can be i n f l u e n c e d by p h y s i c a l d i s o r d e r s or b i a s e d s e l e c t i o n c r i t e r i a . However the mean VBR f o r a l l h e a l t h y v o l u n t e e r c o n t r o l s should r e f l e c t v e n t r i c l e s i z e i n the normal p o p u l a t i o n . I f the s t u d i e s t h a t have r e p o r t e d LVE i n s c h i z o p h r e n i a a re a c c u r a t e , then the medical c o n t r o l s u b j e c t s from these s t u d i e s should have a mean VBR val u e s i m i l a r t o tha t of normal i n d i v i d u a l s . I f , on the other hand, the v e n t r i c l e s of s c h i z o p h r e n i c s are not normally e n l a r g e d , then the mean VBR of c o n t r o l s u b j e c t s i n the s t u d i e s t h a t r e p o r t no LVE should approximate t h a t of normal c o n t r o l s u b j e c t s . The data from the s t u d i e s reviewed here are e q u i v o c a l . The VBR value f o r normal i n d i v i d u a l s (M = 5.3, n = 225) f a l l s 43 between medical p a t i e n t s from s t u d i e s where enlargement was r e p o r t e d (M - 3.6, n = 263) and those from i n v e s t i g a t i o n s where no LVE was found (M = 6.2, n = 103). Furthermore, whereas f i v e s t u d i e s that i n c l u d e d normal c o n t r o l s u b j e c t s r e p o r t e d LVE i n s c h i z o p h r e n i c p a t i e n t s ( D e L i s i e t a l . , 1986; P e a r l s o n et a l . , 1984; Reveley et a l . , 1982; S c h u l s i n g e r et a l . , 1984; Weinberger et a l . , 1979a), two w e l l conducted s t u d i e s ( J e r n i g a n et a l . , 1982; Shima et a l . , 1985) used normal s u b j e c t s and found no v e n t r i c u l a r enlargement i n s c h i z o p h r e n i c p a t i e n t s . D i f f e r e n c e s i n c o n t r o l group samples may r e s u l t from b i a s e d s e l e c t i o n c r i t e r i a . U n f o r t u n a t e l y , t h i s i s s u e i s d i f f i c u l t t o i n v e s t i g a t e because most s t u d i e s p r o v i d e sparse i n f o r m a t i o n about the composition of c o n t r o l groups and few d e s c r i b e f u l l y how s u b j e c t s were s e l e c t e d . I t i s p o s s i b l e t h a t t h e r e are d i f f e r e n c e s between c o n t r o l groups c o n t a i n i n g medical p a t i e n t s and those composed of normal i n d i v i d u a l s . As noted above, v e n t r i c l e s i z e i n medical p a t i e n t s can be i n c r e a s e d or decreased by p h y s i c a l d i s o r d e r s or i n f l u e n c e d by b i a s e d s e l e c t i o n c r i t e r i a . Seventy-one percent (5/7) of the s t u d i e s f a i l i n g t o f i n d enlargement and 64% (9/14) of those r e p o r t i n g LVE used CT scans from medical or p s y c h i a t r i c p a t i e n t s . M e d i c a l p a t i e n t s i n i n v e s t i g a t i o n s r e p o r t i n g n e g a t i v e r e s u l t s produced l a r g e r VBRs (M = 6.22, n = 103) than those from s t u d i e s with p o s i t i v e r e s u l t s (M = 3.63, n = 263; t = 8.38, p<.001); and normal s u b j e c t s i n those r e p o r t s f a i l i n g t o f i n d LVE had l a r g e r v e n t r i c l e s (M = 6.51, n = 79) 44 than d i d normal people i n s t u d i e s r e p o r t i n g LVE (M = 4.61, n = 146; t^  = 5.15, p<.001). Hence, problems with c o n t r o l groups cannot be e x p l a i n e d i n a simple way by c o n s i d e r i n g the h e a l t h or p a t i e n t s t a t u s of the c o n t r o l samples. I t i s worth n o t i n g t h a t a c r o s s a l l s t u d i e s , t h e r e i s a tendency f o r h e a l t h y v o l u n t e e r s to have l a r g e r VBRs (M = 5.28, n = 225) than medical p a t i e n t c o n t r o l s (M - 4.36, n = 366; t = 3.80, p<.001). I f the median VBR f o r a l l the c o n t r o l groups i s used to d i v i d e these samples, 86% of the normal groups f a l l above the median and 62% of the medical p a t i e n t groups f a l l below or at the median (p<.05, F i s h e r exact t e s t ) . U n f o r t u n a t e l y , i t i s not p o s s i b l e , from the i n f o r m a t i o n p r o v i d e d i n these r e p o r t s , to determine the extent t o which authors may have used b i a s e d s e l e c t i o n c r i t e r i a and excluded medical p a t i e n t s w i t h normal but l a r g e v e n t r i c l e s . In summary, a number of s t u d i e s have i n d i c a t e d that s c h i z o p h r e n i c p a t i e n t s have d i l a t e d l a t e r a l v e n t r i c l e s . There i s , however, no consensus on the p r e v a l e n c e of t h i s phenomenon and some recent r e s e a r c h has f a i l e d t o d e t e c t s i g n i f i c a n t v e n t r i c u l a r enlargement. The CT r e s e a r c h t e n t a t i v e l y suggests t h a t i t i s those p a t i e n t s who are most impaired who tend to have d i l a t e d v e n t r i c l e s . Because of the absence of a common d e f i n i t i o n of s e v e r i t y , t h i s i s s u e i s d i f f i c u l t to r e s o l v e from the present data. An a n a l y s i s of the s t u d i e s i n which VBR v a l u e s have been r e p o r t e d suggests that d i f f e r e n c e s i n the r e p o r t e d s i z e of v e n t r i c l e s i n 45 c o n t r o l s u b j e c t s account f o r many of the i n c o n s i s t e n c i e s i n the l i t e r a t u r e . I t i s u n c l e a r , however, whether d i f f e r e n c e s i n VBR va l u e s a c r o s s c o n t r o l groups are due to d i f f e r e n c e s i n p o p u l a t i o n s , s e l e c t i o n c r i t e r i a , or metho d o l o g i c a l f a c t o r s but i t does appear t h a t c o n t r o l groups composed of h e a l t h y v o l u n t e e r s have l a r g e r v e n t r i c l e s than those composed of v a r i o u s types of medical p a t i e n t s . Systematic r e s e a r c h i n t o t h i s i s s u e i s c l e a r l y needed. There i s some a d d i t i o n a l r e s e a r c h d e a l i n g w i t h f a c t o r s t h a t are a s s o c i a t e d with l a t e r a l v e n t r i c u l a r enlargement. The f i n d i n g s from t h i s r e s e a r c h can he l p r e s o l v e some of the a m b i g u i t i e s i n CT r e s e a r c h . V a r i a b l e s A s s o c i a t e d with LVE i n S c h i z o p h r e n i a G e n e t i c and O b s t e t r i c F a c t o r s . As was noted above, LVE has been r e p o r t e d i n both f i r s t episode and i n young s c h i z o p h r e n i c s . I f some p a t i e n t s have d i l a t e d v e n t r i c l e s at the onset of p s y c h o s i s , then v e n t r i c u l a r enlargement c o u l d have r e s u l t e d from g e n e t i c f a c t o r s , o b s t e t r i c c o m p l i c a t i o n s , n u t r i t i o n a l f a c t o r s or from d i s e a s e or i n j u r y s u s t a i n e d d u r i n g c h i l d h o o d or adolesence. A great d e a l o f r e s e a r c h has e s t a b l i s h e d a g e n e t i c c o n t r i b u t i o n i n the e t i o l o g y of s c h i z o p h r e n i a ( f o r a review, see Gottesman & S h e i l d s , 1982). The r e l a t i o n s h i p between f a m i l y h i s t o r y of p s y c h i a t r i c problems and s c h i z o p h r e n i a i s , however, f a r from p e r f e c t . I t i s l i k e l y t h a t environmental f a c t o r s i n t e r a c t with g e n e t i c p r e d i s p o s i t i o n t o produce a s c h i z o p h r e n i c i l l n e s s . O b s t e t r i c c o m p l i c a t i o n s have been 46 proposed as one such c o n t r i b u t i n g f a c t o r i n s c h i z o p h r e n i a (McNeil & K a i j , 1978). In support of t h i s n o t i o n , there i s evidence of a r e l a t i o n s h i p between p e r i n a t a l c o m p l i c a t i o n s , minimal b r a i n damage, and poor outcome i n s c h i z o p h r e n i a (Parnas, et a l . , 1982a; Parnas, S c h u l s i n g e r , S c h u l s i n g e r , Mednick, & Teasdale, 1982b). A number of i n v e s t i g a t o r s have looked at v e n t r i c u l a r enlargement i n r e l a t i o n t o both f a m i l y h i s t o r y of s c h i z o p h r e n i a and to b i r t h c o m p l i c a t i o n s i n s c h i z o p h r e n i c p a t i e n t s i n order t o i n v e s t i g a t e the p o s s i b i l i t y t h a t LVE i s p r e s e n t b e f o r e the onset of s c h i z o p h r e n i a . In an attempt to a s s e s s the r e l a t i v e c o n t r i b u t i o n s of genes and environment to l a t e r a l v e n t r i c l e s i z e i n c h r o n i c s c h i z o p h r e n i a , Reveley, Reveley, C l i f f o r d , and Murray (1982) compared CT scans of 11 normal monozygotic (MZ) and e i g h t normal d i z y g o t i c (DZ) twins w i t h those of seven p a i r s of MZ twins t h a t were d i s c o r d a n t f o r s c h i z o p h r e n i a (aged 22 to 60 y e a r s ) . P a t i e n t s were c l a s s i f i e d a c c o r d i n g to RDC diagnoses. The v e n t r i c l e s i z e i n normal MZ twins was h i g h l y c o r r e l a t e d (r=.98) whereas the c o r r e l a t i o n f o r normal DZ twins was c o n s i d e r a b l y lower (r=.45). The mean i n t e r p a i r d i f f e r e n c e i n v e n t r i c u l a r s i z e was a l s o lower f o r the normal MZ (.36 VBR u n i t s ) than f o r the DZ twins (1.90 VBR u n i t s ) . The MZ twins d i s c o r d a n t f o r s c h i z o p h r e n i a , l i k e the normal MZ twins, showed a h i g h c o r r e l a t i o n f o r v e n t r i c l e s i z e (r=.87) but had a much g r e a t e r i n t e r p a i r d i f f e r e n c e (2.6 VBR u n i t s ) than the normal MZ twins. In a l l but one case, the s c h i z o p h r e n i c twin 47 had the l a r g e r v e n t r i c l e s . The s i m i l a r i t y i n v e n t r i c l e s i z e between normal twins suggests t h a t the s i z e of the v e n t r i c l e s i s h i g h l y i n f l u e n c e d by genes but th a t the i n f l u e n c e of some t h i r d v a r i a b l e r e s u l t s i n LVE i n the s c h i z o p h r e n i c twins of d i s c o r d a n t monozygotic twin p a i r s . I t i s i n t e r e s t i n g t o note i n t h i s study that whereas some s c h i z o p h r e n i c MZ twins do not have v e n t r i c l e s t h a t would normally be c o n s i d e r e d as enl a r g e d , they do have l a r g e r v e n t r i c l e s than t h e i r co-twin. T h i s suggests t h a t much v e n t r i c u l a r enlargement i n s c h i z o p h r e n i c s may go unnoticed because v e n t r i c l e s are not enlarged beyond the normal range. The r e s u l t s of t h i s study i n d i c a t e an i n t e r a c t i o n between genes and environment i n c a u s i n g e n l a r g e d v e n t r i c l e s . Whereas v e n t r i c l e s i z e appears t o be g e n e t i c a l l y determined i n normal i n d i v i d u a l s , some other f a c t o r appears t o i n f l u e n c e t h i s c h a r a c t e r i s t i c i n s c h i z o p h r e n i c s . Using a sample of s c h i z o p h r e n i c p a t i e n t s from a p r e v i o u s study (Weinberger et a l . , 1979a), Weinberger, D e L i s i , Neophytides, and Wyatt (1981) i n v e s t i g a t e d the p o s s i b i l i t y t h a t l a t e r a l v e n t r i c l e s i z e i s under g e n e t i c c o n t r o l . V e n t r i c l e s i z e (VBR) was compared a c r o s s ten s c h i z o p h r e n i c p a t i e n t s (diagnosed a c c o r d i n g t o RDC c r i t e r i a ) , 12 w e l l s i b l i n g s of these p a t i e n t s ( at l e a s t one f o r each p a t i e n t ) , and a c o n t r o l group of 17 asymptomatic i n d i v i d u a l s . The c o n t r o l s u b j e c t s came from seven s i b s h i p s w i t h at l e a s t two s i b l i n g s from each f a m i l y . Mean v e n t r i c l e s i z e i n the 48 s c h i z o p h r e n i c group was s i g n i f i c a n t l y g r e a t e r than that of t h e i r s i b l i n g s and of the c o n t r o l group. In a d d i t i o n , l a t e r a l v e n t r i c l e s i z e was very s i m i l a r w i t h i n each c o n t r o l s i b s h l p but not f o r the s i b s h i p s that i n c l u d e d a s c h i z o p h r e n i c p a t i e n t . In each f a m i l y , the s c h i z o p h r e n i c p a t i e n t had l a r g e s t v e n t r i c l e s . These f i n d i n g s support those of Reveley et a l . (1982) and i n d i c a t e t h a t whereas l a t e r a l v e n t r i c l e s i z e tends t o be g e n e t i c a l l y determined i n the normal p o p u l a t i o n , some a d d i t i o n a l f a c t o r a f f e c t s v e n t r i c l e s i z e i n s c h i z o p h r e n i c p a t i e n t s . In a f u r t h e r attempt t o study g e n e t i c a s p e c t s of v e n t r i c u l a r enlargement, N a s r a l l a h , Kuperman, Hamra, and M c C a l l e y - W h i t t e r s (1983) i n v e s t i g a t e d the r e l a t i o n s h i p between LVE and f a m i l y h i s t o r y of s c h i z o p h r e n i a . V e n t r i c l e s were d e f i n e d as e n l a r g e d i f the VBR was g r e a t e r than the c o n t r o l group mean p l u s two standard d e v i a t i o n s . The c o n t r o l group comprised 27 age and sex matched medical p a t i e n t s . A s i g n i f i c a n t l y higher frequency of f a m i l y h i s t o r y of s c h i z o p h r e n i a was r e p o r t e d i n a group of 19 c h r o n i c s c h i z o p h r e n i c p a t i e n t s with LVE than i n 36 p a t i e n t s with normal v e n t r i c l e s . S i x (32%) of the 19 p a t i e n t s with LVE and o n l y two (6%) of 36 p a t i e n t s with normal v e n t r i c l e s had a f a m i l y h i s t o r y of s c h i z o p h r e n i a . V e n t r i c u l a r enlargement was not a s s o c i a t e d with age at onset of s c h i z o p h r e n i a , or d u r a t i o n of treatment. The r e s u l t s of t h i s study suggest that s c h i z o p h r e n i c s w i t h a f a m i l y h i s t o r y of s c h i z o p h r e n i a are more l i k e l y to have enla r g e d v e n t r i c l e s (6/8, 75%) than 49 are i n d i v i d u a l s with no f a m i l y h i s t o r y (13/47, 28%). However, most of the p a t i e n t s i t t h i s study who had enlarged v e n t r i c l e s had no f a m i l y h i s t o r y of s c h i z o p h r e n i a . T h i s r e s u l t p r o v i d e s some support f o r the f i n d i n g s of Reveley et a l . (1982) and Weinberger et a l . (1981) and suggests a g e n e t i c f a c t o r i s i n v o l v e d i n det e r m i n i n g v e n t r i c l e s i z e . The r e s u l t s of N a s r a l l a h et a l . (1983) a l s o suggest t h a t a f a m i l y h i s t o r y of s c h i z o p h r e n i a may pr e d i s p o s e i n d i v i d u a l s t o LVE but a f a m i l y h i s t o r y i s not n e c e s s a r i l y a s s o c i a t e d with LVE i n s c h i z o p h r e n i c p a t i e n t s . In a complex study, Reveley, Reveley, and Murray (1984) assessed the r e l a t i o n s h i p between v e n t r i c l e s i z e , b i r t h c o m p l i c a t i o n s and f a m i l y h i s t o r y of p s y c h i a t r i c d i s o r d e r s i n 21 s c h i z o p h r e n i c s and 18 h e a l t h y c o n t r o l s . A l l s u b j e c t s were from MZ twin p a i r s . P a t i e n t s were diagnosed a c c o r d i n g t o RDC c r i t e r i a . S i x (28%) of the 21 p a t i e n t s and e i g h t (44%) of the of 18 c o n t r o l s had b i r t h c o m p l i c a t i o n s and no f a m i l y h i s t o r y of p s y c h i a t r i c d i s o r d e r s . Seven (33%) of the 21 s c h i z o p h r e n i c s had a f a m i l y h i s t o r y of p s y c h i a t r i c d i s o r d e r and no b i r t h c o m p l i c a t i o n s . The remaining e i g h t s c h i z o p h r e n i c s and ten c o n t r o l s u b j e c t s had n e i t h e r a f a m i l y h i s t o r y of s c h i z o p h r e n i a nor b i r t h c o m p l i c a t i o n s . No p a t i e n t had both f a m i l y h i s t o r y of p s y c h i a t r i c d i s o r d e r and b i r t h c o m p l i c a t i o n s . S c h i z o p h r e n i c s with a f a m i l y h i s t o r y of p s y c h i a t r i c d i s o r d e r (n = 7) had s i g n i f i c a n t l y s m a l l e r v e n t r i c l e s than p a t i e n t s without t h i s f a m i l y h i s t o r y (n = 14). However, 50 because no p a t i e n t with a f a m i l y h i s t o r y of p s y c h i a t r i c d i s o r d e r had b i r t h c o m p l i c a t i o n s , and s i x of the 14 p a t i e n t s without a f a m i l y h i s t o r y had o b s t e t r i c c o m p l i c a t i o n s , s m a l l v e n t r i c l e s i n these i n d i v i d u a l s may be due to the normal b i r t h r a t h e r than f a m i l y h i s t o r y of p s y c h i a t r i c problems. T h i s p o s s i b i l i t y i s made more l i k e l y by the f i n d i n g that c o n t r o l s with normal b i r t h s had s i g n i f i c a n t l y s m a l l e r v e n t r i c l e s than c o n t r o l s with b i r t h c o m p l i c a t i o n s . No r e l a t i o n s h i p was found between v e n t r i c l e s i z e and b i r t h c o m p l i c a t i o n s f o r the s i x s c h i z o p h r e n i c s w i t h b i r t h problems. There was no r e l a t i o n s h i p between LVE and d u r a t i o n of i l l n e s s , d u r a t i o n of h o s p i t a l i z a t i o n , or age. There was a s i g n i f i c a n t n e g ative r e l a t i o n s h i p between age at onset of s c h i z o p h r e n i a and v e n t r i c u l a r s i z e ; i . e . , p a t i e n t s who were young when they developed s c h i z o p h r e n i a tended to have l a r g e v e n t r i c l e s . These f i n d i n g s are d i f f i c u l t t o i n t e r p r e t but suggest t h a t b i r t h c o m p l i c a t i o n s f r e q u e n t l y r e s u l t i n e n l a r g e d v e n t r i c l e s i n normal i n d i v i d u a l s and t h a t t h i s may not be the s o l e determinant of v e n t r i c u l a r enlargement i n s c h i z o p h r e n i a . U n l i k e the study of Nasralah et a l . (1983), no r e l a t i o n s h i p was found between LVE and f a m i l y h i s t o r y of p s y c h i a t r i c d i s o r d e r . D e L i s i et a l . (1986) i n c l u d e d s c h i z o p h r e n i c p a t i e n t s and t h e i r n o n s c h i z o p h r e n i c s i b l i n g s i n an e f f o r t to i n v e s t i g a t e the i n f l u e n c e of p e r i n a t a l problems on v e n t r i c u l a r enlargement. Both l a t e r a l v e n t r i c l e s i z e (VBR) and the s i z e 51 of the f r o n t a l horns of the l a t e r a l v e n t r i c l e s were asseesed. CT scans were ob t a i n e d on 26 s c h i z o p h r e n i c s from 11 s i b s h i p s (two or more p a t i e n t s from each f a m i l y ) , Nine n o n s c h i z -o p h r e n i c s i b l i n g s (one or more i n d i v i d u a l from each of nine f a m i l i e s ) , and 20 normal u n r e l a t e d v o l u n t e e r s . DSM-III c r i t e r i a were used t o diagnose p a t i e n t s . S c h i z o p h r e n i c p a t i e n t s were found to have l a r g e r l a t e r a l v e n t r i c l e s and f r o n t a l horns than d i d the c o n t r o l s u b j e c t s . There was no d i f f e r e n c e i n v e n t r i c l e s i z e between the s c h i z o p h r e n i c s and t h e i r s i b l i n g s . In a d d i t i o n , a s i g n i f i c a n t r e l a t i o n s h i p was r e p o r t e d between b i r t h c o m p l i c a t i o n s and f r o n t a l horn s i z e f o r s c h i z o p h r e n i c s . None of the no n s c h i z o p h r e n i c s i b l i n g s or the c o n t r o l s u b j e c t s had a h i s t o r y of b i r t h c o m p l i c a t i o n s . The r e s u l t s of t h i s study are i n c o n f l i c t w i t h those of Revely e t a l . (1984) and suggests t h a t p e r i n a t a l c o m p l i c a t i o n s may c o n t r i b u t e t o v e n t r i c u l a r enlargement i n s c h i z o p h r e n i a . The r e l a t i o n s h i p s between LVE and both p e r i n a t a l c o m p l i c a t i o n s and f a m i l y h i s t o r y of s c h i z o p h r e n i a were i n v e s t i g a t e d by P e a r l s o n et a l . (1985). In t h i s study, mean l a t e r a l v e n t r i c l e s i z e f o r 19 s c h i z o p h r e n i c p a t i e n t s was found t o be l a r g e r than t h a t f o r 19 normal v o l u n t e e r s . Diagnoses were made a c c o r d i n g t o DSM-III c r i t e r i a . No s i g n i f i c a n t r e l a t i o n s h i p s were found between LVE and e i t h e r b i r t h c o m p l i c a t i o n s or f a m i l y h i s t o r y of s c h i z o p h r e n i a . However, onl y f o u r p a t i e n t s had b i r t h c o m p l i c a t i o n s and whereas these f o u r i n d i v i d u a l s tended t o have l a r g e r 52 v e n t r i c l e s and an e a r l i e r onset of s c h i z o p h r e n i a than p a t i e n t s without p e r i n a t a l problems, these d i f f e r e n c e s f a i l e d t o reach s t a t i s t i c a l s i g n i f i c a n c e . An i n t e r e s t i n g study of a group of p a t i e n t s f o l l o w e d up from the 1962 Copenhagen High-Risk P r o j e c t (Mednick & S c h u l s i n g e r , 1965) was conducted by S c h u l s i n g e r et a l . (1984). A l l s u b j e c t s i n t h i s study were taken from the i n i t i a l h i g h - r i s k p r o j e c t ( i . e . , a l l had a f a m i l y h i s t o r y of s c h i z o p h r e n i a ) . The sample comprised 10 s c h i z o p h r e n i c s , 10 b o r d e r l i n e s c h i z o p h r e n i c s , and 16 i n d i v i d u a l s d e s c r i b e d as f r e e of mental i l l n e s s . Diagnoses were made u s i n g ICD-8 c r i t e r i a . The s c h i z o p h r e n i c group had the l a r g e s t mean v e n t r i c u l a r s i z e , f o l l o w e d by the c o n t r o l s , with the b o r d e r l i n e group having the s m a l l e s t v e n t r i c l e s . T h i s f i n d i n g of s m a l l v e n t r i c l e s i n b o r d e r l i n e p a t i e n t s was a l s o r e p o r t e d by Sch u l z et a l . (1983). V e n t r i c l e s i z e i n the c o n t r o l s was not s i g n i f i c a n t l y d i f f e r e n t from that of the b o r d e r l i n e p a t i e n t s . No r e l a t i o n s h i p was found between p e r i n a t a l c o m p l i c a t i o n s and LVE. The f i n d i n g s of t h i s study support the f i n d i n g s of Reveley e t a l . (1984) and P e a r l s o n e t a l . (1985) and i n d i c a t e t h a t v e n t r i c u l a r s i z e i s not r e l a t e d t o b i r t h c o m p l i c a t i o n s . The absence of LVE i n b o r d e r l i n e p a t i e n t s and i n d i v i d u a l s with no mental i l l n e s s , a l l of whom have a f a m i l y h i s t o r y of s c h i z o p h r e n i a , suggests that e n l a r g e d v e n t r i c l e s may be necessary b e f o r e the f u l l s c h i z o p h r e n i c syndrome appears i n some p a t i e n t s with a g e n e t i c p r e d i s p o s i t i o n . 53 The p r e c e d i n g s t u d i e s suggest that v e n t r i c l e s i z e i s g e n e t i c a l l y determined i n normal i n d i v i d u a l s but that other f a c t o r s c o n t r i b u t e to v e n t r i c u l a r d i l a t i o n i n s c h i z o p h r e n i c s . There i s a r e l a t i o n s h i p between LVE and o b s t e t r i c c o m p l i c a t i o n s i n normal i n d i v i d u a l s but t h i s f i n d i n g appears t o be a t t e n u a t e d i n p s y c h o t i c p a t i e n t s . Most i n v e s t i g a t o r s r e p o r t a r e l a t i o n s h i p between LVE and a f a m i l y h i s t o r y of p s y c h i a t r i c problems i n s c h i z o p h r e n i c p a t i e n t s . The nature o f t h i s r e l a t i o n s h i p i s i n d i s p u t e at the present time and f u r t h e r r e s e a r c h i s needed to c l a r i f y the i s s u e . The r e s e a r c h i n t o g e n e t i c and p e r i n a t a l c o m p l i c a t i o n s has not r e s o l v e d the i s s u e as t o whether LVE predates the onset of s c h i z o p h r e n i a . A second l i n e of r e s e a r c h has f o c u s s e d on the r e l a t i o n s h i p between LVE and premorbid adjustment. I f v e n t r i c u l a r enlargement o c c u r s b e f o r e the onset of p s y c h o s i s , i t i s p o s s i b l e t h a t the b r a i n anomalies would be a s s o c i a t e d with poor premorbid f u n c t i o n i n g . Thus, a r e l a t i o n s h i p between LVE and poor premorbid adjustment would support the c o n t e n t i o n that v e n t r i c u l a r d i l a t i o n o ccurs b e f o r e the onset of s c h i z o p h r e n i a . Premorbid Adjustment. Poor premorbid adjustment has proven to be the most powerful p r e d i c t o r of poor prognosis i n s c h i z o p h r e n i a (Neale & Oltmanns, 1980, p.28). I f , as the r e s e a r c h evidence suggests, LVE i s a s s o c i a t e d with poor p r o g n o s i s , then i t i s p o s s i b l e t h a t LVE and poor premorbid adjustment are r e l a t e d . In order to i n v e s t i g a t e t h i s 54 p o s s i b i l i t y , Weinberger, Canon-Spoor, and P o t k i n (1980b) assessed v e n t r i c u l a r enlargement and premorbid s t a t u s i n 51 s c h i z o p h r e n i c i n p a t i e n t s and 78 normal v o l u n t e e r s . These r e s e a r c h e r s c o n s t r u c t e d t h e i r own i n v e n t o r y to assess premorbid adjustment. The s c h i z o p h r e n i c group had s i g n i f i c a n t l y poorer adjustment i n t h e i r e a r l y a d u l t years than d i d the c o n t r o l s . A s m a l l but s i g n i f i c a n t premorbid d e f i c i t was r e p o r t e d i n the s c h i z o p h r e n i c s with e n l a r g e d v e n t r i c l e s compared with the s c h i z o p h r e n i c s who had normal v e n t r i c l e s . The nine p a t i e n t s w i t h the poorest adjustment a l l had e n l a r g e d v e n t r i c l e s as compared with o n l y three of the 14 with the best adjustment s c o r e s . J e s t e et a l . (1982) used the same i n v e n t o r y as Weinberger et a l . (1980b) and used a median c u t t i n g score t o dichotomize the s c h i z o p h r e n i c group i n t o good and poor premorbid adjustment. Of the s c h i z o p h r e n i c s u b j e c t s who were judged to have good premorbid adjustment, 77% (17/22) had normal v e n t r i c l e s . Those s c h i z o p h r e n i c s who were judged to have poor premorbid adjustment were as l i k e l y t o have normal v e n t r i c l e s (12/22) as LVE (10/22). D e L i s i et a l . (1986) a l s o used the s c a l e c o n s t r u c t e d by Weinberger et a l . (1980b) but found no r e l a t i o n s h i p between l a t e r a l v e n t r i c l e s i z e (VBR) and l e v e l premorbid adjustment. CT scans were ob t a i n e d on 26 s c h i z o p h r e n i c s and d i a g n i o s e s were made a c c o r d i n g t o DSM-III c r i t e r i a . The r e s u l t s of the three s t u d i e s of premorbid adjustment and v e n t r i c u l a r enlargement suggest that the s c a l e c o n s t r u c t e d by Weinberger 55 et a l . (1980b), has l i m i t e d value f o r p r e d i c t i n g LVE. Two of the three s t u d i e s p r o v i d e p r e l i m i n a r y evidence s u g g e s t i n g e i t h e r t h a t good premorbid adjustment decreases the r i s k of d e v e l o p i n g LVE or p o s s i b l y that v e n t r i c u l a r enlargement i s an i n d i c a t i o n of an e a r l y developmental b r a i n d i s o r d e r that i n t e r f e r e s with s o c i a l development i n s c h i z o p h r e n i c s . The c o n f i d e n c e we can have i n even these very ( t e n t a t i v e c o n c l u s i o n s i s l i m i t e d by the unknown v a l i d i t y of the premorbid adjustment s c a l e developed by Weinberger et a l . (1980b). The s c a l e was c o n s t r u c t e d from items s e l e c t e d from the P h i l l i p s Premorbid H i s t o r y S c a l e and the Premorbid A s o c i a l Adjustment S c a l e ( f o r a review, see Kokes, S t r a u s s , & Klorman, 1977). Weinberger's s c a l e c o n s i s t s of 28 items d i v i d e d among f i v e s u b s c a l e s . No r e l i a b i l i t y checks were made on t h i s s c a l e . The format of the items, s c o r i n g range, and d i s t r i b u t i o n of s c o r e s are not g i v e n . I t i s r e p o r t e d t h a t some of the items c o u l d not be answered f o r some s c h i z o p h r e n i c s , although no a n a l y s i s was made concerning which s u b j e c t s f a i l e d t o answer which q u e s t i o n s . I t i s u n c l e a r how the unknown psychometric p r o p e r t i e s of t h i s s c a l e a f f e c t e d the r e s u l t s of these s t u d i e s . F u r t h e r i n v e s t i g a t i o n s are needed, u s i n g p s y c h o m e t r i c a l l y sound instruments i n order to f u r t h e r e v a l u a t e these i n t e r e s t i n g f i n d i n g s of Weinberger and h i s c o l l e a g u e s . A more widely accepted method of a s s e s s i n g premorbid adjustment i s the s h o r t v e r s i o n of the P h i l l i p s Premorbid H i s t o r y s c a l e (PMH, H a r r i s , 1975, see Appendix B). The PMH 56 has been accepted as a r e l i a b l e and v a l i d measure of premorbid adjustment and has gained widespread use (Kokes et a l . , 1977). The r e l i a b i l i t y of t h i s measure i s r e p o r t e d l y h i g h ( r = mid .80s t o mid .90s) and there i s hig h concurrent v a l i d i t y with the long v e r s i o n of the PMH ( r = .95 f o r males and .85 f o r females; Kokes et a l . , 1977). The long v e r s i o n of t h i s measure was found to be s i g n i f i c a n t l y r e l a t e d to percent of l i f e t i m e spent i n p s y c h i a t r i c h o s p i t a l s (£ = .42 to .45; DeWolf, 1968, r e p o r t e d i n Kokes et a l . , 1977). Negative Symptoms. A number of symptoms t h a t are i n d i c a t i v e o f poor prognosis i n s c h i z o p h r e n i a were r e p o r t e d i n the e a r l y work of K r a e p e l i n and B l e u l e r (Neale & Oltmanns, 1980). Some of these symptoms were long accepted as fundamental c h a r a c t e r i s t i c s of s c h i z o p h r e n i a and i n d i c a t i v e of an e a r l y dementing p r o c e s s . These c h a r a c t e r i s t i c s have r e c e n t l y been termed n e g a t i v e symptoms (Crow, 1980) and i n c l u d e such symptoms as f l a t a f f e c t , psychomotor r e t a r d a t i o n and poverty of speech. F l o r i d p s y c h o t i c symptoms, on the other hand, have not been a s s o c i a t e d with poor p r o g n o s i s and have been l a b e l e d p o s i t i v e symptoms (Crow, 1980). P o s i t i v e symptoms have been l i n k e d t o d i s t u r b e d dopaminergic t r a n s m i s s i o n (see Crow, Cross, Johnstone, & Owen, 1982b, f o r a r e v i e w ) . These f a c t s l e d Crow (1980) t o hyp o t h e s i z e two types of s c h i z o p h r e n i a . P a t i e n t s w i t h type I syndrome are c h a r a c t e r i z e d by p o s i t i v e symptoms and are l i k e l y to respond t o n e u r o l e p t i c m e d i c a t i o n s . Type II p a t i e n t s , c h a r a c t e r i z e d by n e g a t i v e symptoms, are l i k e l y t o respond p o o r l y to 57 n e u r o l e p t i c s , have enlarged l a t e r a l v e n t r i c l e s , and have poor p r o g n o s i s . Evidence concerning t h i s d i s t i n c t i o n w i l l be reviewed below. There have been two s t u d i e s that have examined the r e l a t i o n s h i p between n e g a t i v e symptoms and e n l a r g e d v e n t r i c l e s i n s c h i z o p h r e n i a . In the f i r s t study, Johnstone et a l . (1978b) r e p o r t e d a s i g n i f i c a n t r e l a t i o n s h i p between neg a t i v e symptoms ( f l a t a f f e c t , psychomotor r e t a r d a t i o n , and poverty of speech) and e n l a r g e d v e n t r i c l e s i n a group of 17 c h r o n i c s c h i z o p h r e n i c s . There was no r e l a t i o n s h i p between LVE and p o s i t i v e symptoms. The p a t i e n t s i n t h i s study were c h r o n i c a l l y h o s p i t a l i z e d and thus the n e g a t i v e symptoms may have developed as a r e s u l t of prolonged i l l n e s s , i n s t i t u t i o n a l i z a t i o n and/or n e u r o l o g i c a l d y s f u n c t i o n . In ord e r to c l a r i f y t h i s i s s u e , a second study, u s i n g l e s s impaired p a t i e n t s was conducted (Andreasen, Olsen, Dennert, & Smith, 1982a). Two groups of s c h i z o p h r e n i c s ( e i g h t with normal v e n t r i c l e s and e i g h t with LVE) were e v a l u a t e d f o r presence of negative symptoms. P a t i e n t s were diagnosed u s i n g both DSM-III and RDC d i a g n o s t i c systems. The p a t i e n t s with LVE tended to have more ne g a t i v e symptoms but t h i s d i f f e r e n c e d i d not reach s t a t i s t i c a l s i g n i f i c a n c e . The n e g a t i v e symptoms t h a t were i d e n t i f i e d by Andreasen et a l . (1982a) were f l a t t e n e d or b l u n t e d a f f e c t , impoverished t h i n k i n g , a v o l i t i o n or apathy, a s o c i a l i t y , and impaired a t t e n t i o n . The r e l i a b i l i t y and v a l i d i t y of these c r i t e r i a were e v a l u a t e d by Andreasen (1982) and Andreasen and Olsen 58 (1982). Andreasen (1982) r e p o r t e d an o v e r a l l r e l i a b i l i t y of .92, and .70 to .92 f o r the i n d i v i d u a l r a t i n g s . Andreasen and Olsen (1982) r e p o r t e d that these symptoms are s i g n i f i c a n t l y r e l a t e d to P h i l l i p s Premorbid H i s t o r y r a t i n g s , M i n i Mental S t a t u s s c o r e s , and G l o b a l Adjustment S c a l e (GAS) r a t i n g s . In Andreasen*s p r e l i m i n a r y work (1982; Andreasen & Olsen, 1982), she appears to have i d e n t i f i e d a u s e f u l s e t of symptoms t h a t have p o t e n t i a l l y h i g h i n t e r r a t e r r e l i a b i l i t y and she has p r o v i d e d p r e l i m i n a r y evidence f o r c o n s t r u c t v a l i d i t y . N e v e r t h l e s s , a t the present time, t h e r e i s no consensus i n the l i t e r a t u r e r e g a r d i n g what symptoms should be c l a s s i f i e d as negative and no agreement r e g a r d i n g what c o n s t i t u t e s a negative symptom syndrome (Sommers, 1985). Although the work of Andreasen (1982, Andreasen & Olsen, 1982) r e p r e s e n t s a u s e f u l s t a r t i n g p o i n t f o r t e s t i n g the u s e f u l n e s s of negative symptoms i n the understanding of s c h i z o p h r e n i a , much s y s t e m a t i c r e s e a r c h remains t o be done. Other i n v e s t i g a t o r s have suggested t h a t n e g a t i v e symptoms are i n d i c a t i v e of normal or low dopamine a c t i v i t y and that p o s i t i v e symptoms i n d i c a t e i n c r e a s e d dopamine a c t i v i t y (Crow, 1981; Johnstone et a l . , 1978a). In order to t e s t t h i s h y p o t h e s i s , A n g r i s t , Retrosen and Gershon (1980) a d m i n i s t e r e d a dopamine a g o n i s t (amphetamine) and, at a l a t e r date, a dopamine a n t a g o n i s t ( p h e n o t h i a z i n e ) to two groups of s c h i z o p h r e n i c s (one with predominantly p o s i t i v e and one with n e g a t i v e symptoms). I n d i v i d u a l s with predominantly negative symptoms showed l i t t l e response t o e i t h e r drug, whereas 59 i n d i v i d u a l s with predominantly p o s i t i v e symptoms were s i g n i f i c a n t l y more a g i t a t e d a f t e r amphetamines and l e s s a g i t a t e d a f t e r n e u r o l e p t i c s were a d m i n i s t e r e d . These f i n d i n g s support those of Crow (1981) and Johnstone et a l . (1978b) and suggest t h a t s c h i z o p h r e n i c s with p o s i t i v e but not n e g a t i v e symptoms have i n c r e a s e d dopamine r e c e p t o r l e v e l s . I f n e u r o l e p t i c medications are r e l a t i v e l y i n e f f e c t i v e f o r p a t i e n t s with n e g a t i v e symptoms, and i f n e g a t i v e symptoms are a s s o c i a t e d with LVE then n e u r o l e p t i c medications should be r e l a t i v e l y i n e f f e c t i v e f o r p a t i e n t s with LVE. A number of r e s e a r c h e r s have i n v e s t i g a t e d the d i f f e r e n t i a l e f f e c t i v e n e s s of n e u r o l e p t i c s and i t s r e l a t i o n s h i p to LVE i n s c h i z o p h r e n i c p a t i e n t s . Response t o N e u r o l e p t i c s . Weinberger et a l . (1980a) i n v e s t i g a t e d the r e l a t i o n s h i p between v e n t r i c l e s i z e and response t o n e u r o l e p t i c medication i n 20 c h r o n i c a l l y h o s p i t a l i z e d s c h i z o p h r e n i c s . Improvement was monitored u s i n g the B r i e f P s y c h i a t r i c R a t i n g S c a l e . P a t i e n t s were grouped a c c o r d i n g to whether t h e i r VBR was i n s i d e or o u t s i d e two standard d e v i a t i o n s of the c o n t r o l mean of 62 s i m i l a r l y aged h e a l t h y v o l u n t e e r s t h a t were used i n a p r e v i o u s study (Weinberger et a l . , 1979a). Ten p a t i e n t s had LVE and ten had normal v e n t r i c l e s . The groups were matched f o r age, age at onset of i l l n e s s , y e ars of i l l n e s s and d u r a t i o n of h o s p i t a l i z a t i o n . An i n i t i a l drug f r e e t r i a l was conducted a f t e r which drug dosage and plasma n e u r o l e p t i c c o n c e n t r a t i o n were monitored and e q u a l i z e d a c r o s s groups. The i n i t i a t i o n 60 of m edication r e s u l t e d i n a s i g n i f i c a n t improvement i n the group with normal v e n t r i c l e s and no change i n the group with e n l a r g e d v e n t r i c l e s . T h i s w e l l c o n t r o l l e d study suggests t h a t , i n c h r o n i c a l l y i l l s c h i z o p h r e n i c p a t i e n t s , LVE i s a s s o c i a t e d with poor response to n e u r o l e p t i c m e d i c a t i o n . T h i s o b s e r v a t i o n was supported by K l i n g et a l . (1982/83) who r e p o r t e d t h a t a l a r g e p r o p o r t i o n (50%) of s c h i z o p h r e n i c s who were not r e s p o n s i v e to medication had s i g n i f i c a n t l y e n l a r g e d v e n t r i c l e s . In another c o n t r o l l e d medication study, L u c h i n s et a l . (1984) compared 19 s c h i z o p h r e n i c s who had v e n t r i c u l a r enlargement to 24 s c h i z o p h r e n i c s with normal v e n t r i c l e s . V e n t r i c l e s were d e s c r i b e d as e n l a r g e d i f they were at l e a s t one standard d e v i a t i o n g r e a t e r than the c o n t r o l group mean. The c o n t r o l group comprised 62 s i m i l a r l y aged medical p a t i e n t s . L e v e l of adjustment was assessed at the end of a medication washout p e r i o d , and a f t e r t h r e e and f i v e weeks of m e d i c a t i o n . A h i g h l y s i g n i f i c a n t i n t e r a c t i o n was r e p o r t e d between VBR and g l o b a l adjustment over the t h r e e assessment times. There was no d i f f e r e n c e i n adjustment r a t i n g s between the two groups a f t e r the drug washout p e r i o d . However, whereas p a t i e n t s w i t h normal v e n t r i c l e s showed much improvement a f t e r f i v e weeks of m e d i c a t i o n , p a t i e n t s with LVE showed a n o n s i g n i f i c a n t d e t e r i o r a t i n g t r e n d over the same t ime. J e s t e et a l . (1982) conducted a medication study u s i n g the same w e l l c o n t r o l l e d procedure as t h a t of Weinberger et 61 a l . (1980a). Of the 20 c h r o n i c s c h i z o p h r e n i c s t h a t underwent t h i s procedure, e i g h t were d e f i n e d as r e s p o n s i v e and 12 as nonresponsive to n e u r o l e p t i c m e d i c a t i o n . The B r i e f P s y c h i a t r i c R a t i n g S c a l e was used t o assess adjustment b e f o r e and d u r i n g medication treatment. Seven of the e i g h t p a t i e n t s who responded f a v o r a b l y t o the medication had normal v e n t r i c l e s (VBR g r e a t e r than the mean p l u s two standard d e v i a t i o n s of a c o n t r o l group used i n a p r e v i o u s study, Weinberger et a l . , 1979a). The s i t u a t i o n with the s c h i z o p h r e n i c s who d i d not respond f a v o r a b l y t o medication was l e s s c l e a r . E i g h t o f the 12 nonresponders had LVE and, although t h i s t r e n d i s i n the p r e d i c t e d d i r e c t i o n , t h e r e were f o u r of the nonresponders who had normal v e n t r i c l e s . The r e s u l t s of t h i s study are i n agreement with a l l p r e v i o u s s t u d i e s of LVE and response t o medication, and suggest a n e g a t i v e c o r r e l a t i o n between these v a r i a b l e s . The f i n d i n g s of J e s t e et a l . (1982), however, suggest t h a t whereas v e n t r i c u l a r enlargement i n s c h i z o p h r e n i a may be i n d i c a t i v e o f poor response t o medi c a t i o n , a number of i n d i v i d u a l s . with normal s i z e d v e n t r i c l e s may a l s o respond p o o r l y t o n e u r o l e p t i c s . One re c e n t study (Smith et a l . , 1985) f a i l e d to d e t e c t a r e l a t i o n s h i p between l a t e r a l v e n t r i c l e s i z e and response t o n e u r o l e p t i c m e d i c a t i o n s . The s c h i z o p h r e n i c s u b j e c t s used i n the study of Largen et a l . , (1984, n = 39) were given a one to three week drug f r e e t r i a l f o l l o w e d by f i x e d doses of me d i c a t i o n s . RDC diagnoses were made and the mean age of 62 s u b j e c t s was 31 y e a r s . L a t e r a l v e n t r i c u l a r s i z e was assessed u s i n g the VBR and l e v e l of adjustment was determined u s i n g the B r i e f P s y c h i a t r i c R a t i n g S c a l e . There was no s i g n i f i c a n t r e l a t i o n s h i p between l a t e r a l v e n t r i c l e s i z e and l e v e l of adjustment before the medication t r i a l or d u r i n g the drug t r i a l . I t i s p o s s i b l e that because Largen et a l . , (1984) r e p o r t e d no s i g n i f i c a n t v e n t r i c u l a r enlargement with these p a t i e n t s , t h i s group i s b i a s e d towards good prognosis i n d i v i d u a l s . In a d d i t i o n , the a d m i n i s t r a t i o n of f i x e d doses of m e d i c a t i o n i s l i k e l y t o r e s u l t i n v a r i a t i o n s i n plasma n e u r o l e p t i c c o n c e n t r a t i o n s and c o u l d have obscured any r e l a t i o n s h i p between medication response and v e n t r i c u l a r s i z e . O v e r a l l , the s t u d i e s of medication e f f e c t s i n s c h i z o p h r e n i a suggest t h a t n e u r o l e p t i c medication has i t s e f f e c t at the l e v e l of the dopamine r e c e p t o r s . T h i s treatment i s most u s e f u l f o r a m e l i o r a t i n g f l o r i d p s y c h o t i c symptoms and l e s s u s e f u l i n the treatment of negative symptoms. The e f f e c t i v e n e s s of n e u r o l e p t i c s i n t r e a t i n g s c h i z o p h r e n i a appears to be a t t e n u a t e d i n i n d i v i d u a l s with LVE. However, whereas the reduced e f f e c t i v e n e s s of t h i s treatment i s a s s o c i a t e d with LVE i t i s probably not l i m i t e d t o i n d i v i d u a l s with s i g n i f i c a n t l y e n l a r g e d v e n t r i c l e s . On the b a s i s of the f i n d i n g s c o n c e r n i n g LVE, type of symptoms, and dopaminergic a c t i v i t y , Crow (1980) p o s t u l a t e d that the u n d e r l y i n g p a t h o l o g i c a l process f o r i n d i v i d u a l s with predominantly p o s i t i v e symptoms (Type 1 s c h i z o p h r e n i c s ) i s a b3 d i s t u r b a n c e i n dopaminergic t r a n s m i s s i o n . Negative symptoms (Type 2 s c h i z o p h r e n i a ) on the other hand, are more c l o s e l y r e l a t e d to the dementias and r e s u l t from s t r u c t u r a l changes as evidenced i n LVE and poor response to n e u r o l e p t i c m e d i c a t i o n s . T h i s h y p o t h e s i s has gained support from one other source i n a d d i t i o n to those reviewed above. Eye B l i n k s . There i s c o n s i d e r a b l e evidence from the animal and human l i t e r a t u r e l i n k i n g b l i n k r a t e with dopaminergic a c t i v i t y (Kleinman et a l . 1984). The f a c t t h a t h i g h b l i n k r a t e s have been r e p o r t e d i n s c h i z o p h r e n i c s (Stevens, 1978) and low b l i n k r a t e s i n p a t i e n t s with P a r k i n s o n s ' s d i s e a s e (Karson, Berman, & LeWitt, 1983) suggests t h a t b l i n k r a t e s may r e f l e c t dopamine a c t i v i t y i n man. I f , as Crow (1980) has h y p o t h i s i z e d , type 1 s c h i z o p h r e n i a r e f l e c t s a d i s t u r b a n c e i n dopamine t r a n s m i s s i o n and no c e r e b r a l atrophy then a normally h i g h b l i n k r a t e i n these p a t i e n t s should be s i g n i f i c a n t l y reduced by the a d m i n i s t r a t i o n of dopamine a n t a g o n i s t s ( n e u r o l e p t i c m e d i c a t i o n ) . Type 2 s c h i z o p h r e n i a , because i t i s a s s o c i a t e d w i t h s t r u c t u r a l b r a i n changes (LVE) r a t h e r than e x e s s i v e dopaminergic a c t i v i t y , should present with a low or normal b l i n k r a t e t h a t i s not reduced as much as t h a t of p a t i e n t s with e x c e s s i v e dopamine a c t i v i t y . In o r d e r to t e s t t h i s h y p o t h e s i s , Kleinman et a l . (1984) assessed the b l i n k r a t e and VBR i n 55 c h r o n i c s c h i z o p h r e n i c i n p a t i e n t s (19 to 51 y e a r s ) . The c o n t r o l group of Weinberger et a l . (1979a) was used f o r comparison. RDC and Feighner 64 diagnoses were made. Two groups were formed on the b a s i s of v e n t r i c l e s i z e : There were 13 p a t i e n t s with LVE and 42 with v e n t r i c l e s w i t h i n the normal range. The c u t - o f f was equal to the mean VBR of the c o n t r o l group p l u s two standard d e v i a t i o n s . The b l i n k r a t e i n p a t i e n t s with normal v e n t r i c l e s was s i g n i f i c a n t l y h i g h e r than t h a t of the c o n t r o l s and was s i g n i f i c a n t l y reduced by n e u r o l e p t i c m e d i c a t i o n . The p a t i e n t s with e n l a r g e d v e n t r i c l e s a l s o had a h i g h e r b l i n k r a t e than the c o n t r o l s but t h i s was not s i g n i f i c a n t l y a f f e c t e d by the m e dication. These f i n d i n g s support the h y p o t h e s i s of Crow (1980) and suggest t h a t t h e r e may be two d i s t i n c t groups of s c h i z o p h r e n i c p a t i e n t s and t h a t these groups r e q u i r e d i f f e r e n t treatment approaches. In summary, neg a t i v e symptoms have been a s s o c i a t e d with a dementing course and poor p r o g n o s i s i n s c h i z o p h r e n i a . There i s a l s o some p r e l i m i n a r y evidence l i n k i n g n e g a t i v e symptoms t o s t r u c t u r a l b r a i n anomalies (LVE). Other s t u d i e s have r e p o r t e d an a s s o c i a t i o n between LVE, low or normal dopaminergic a c t i v i t y , and poor response to n e u r o l e p t i c m e d i c a t i o n . These f i n d i n g s have l e d to the h y p o t h e s i s t h a t t h e r e i s a d i s t i n c t subgroup of poor p r o g n o s i s p a t i e n t s with n e g a t i v e symptoms and v e n t r i c u l a r enlargement. Smooth-Pursuit Eye Movements. Smooth-pursuit eye movements make use of d i v e r s e n e u r o l o g i c a l pathways and r e q u i r e the i n t e g r a t i o n of a number of sources of i n f o r m a t i o n . D i s r u p t e d eye movements have been shown to r e f l e c t s p e c i f i c and widespread neuropathology i n 65 n o n p s y c h i a t r i c p a t i e n t s ( D a r o f f & T r o o s t , 1978). Although there i s only p r e l i m i n a r y evidence l i n k i n g smooth-pursuit d y s f u n c t i o n s and n e u r o l o g i c a l anomalies i n s c h i z o p h r e n i c s , t h e r e i s an e x t e n s i v e l i t e r a t u r e on both n e u r o l o g i c a l anomalies (e.g., LVE) and d i s r u p t e d smooth p u r s u i t eye movements i n s c h i z o p h r e n i a . The e a r l y works of Holzman and h i s a s s o c i a t e s (Holzman, P r o c t o r , & Hughes, 1973; Holzman et a l . , 1974) r e p o r t e d d i s r u p t e d smooth p u r s u i t eye movements i n some s c h i z o p h r e n i c s . A great d e a l of r e s e a r c h has been done on eye-movements s i n c e these i n i t i a l s t u d i e s . The e y e - t r a c k i n g impairment has been i d e n t i f i e d c o n s i s t e n t l y and i n v o l v e s numerous s a c c a d i c ( f a s t ) eye movements i n t r u d i n g upon a smooth f o l l o w i n g movement. T h i s t r a c k i n g d e f i c i t has been found i n r e m i t t e d s c h i z o p h r e n i c s (Iacono, P e l o q u i n , Lumry, V a l e n t i n e , & Tuason, 1982; Salzman, K l e i n , & S t r a u s s , 1978), i n both young (Kuechenmeister, L i n t o n , & M u e l l e r , 1977), and o l d e r s c h i z o p h r e n i c s (Holzman, K r i n g l e n , Levy, P r o c t o r , & Haberman, 1978) and the s u b j e c t ' s sex has not been shown to s i g n i f i c a n t l y i n f l u e n c e the d e f i c i t (Iacono & Koenig, 1983; Iacono, Tuason, & Johnson, 1981). N e u r o l e p t i c medication does not seem to i n f l u e n c e t h i s anomaly (Holzman e t a l . , 1974, 1975; M i a l e t & P i c h o t , 1981; Shagass, Amadeo, & Overton, 1974). F i n a l l y , a t t e n t i o n a l demands of the task probably do not account f o r the d e f i c i t . Only extremely d i s t r a c t i n g tasks d i s r u p t p u r s u i t movements ( L i p t o n , F r o s t , & Holzman, 1980; Pass, Salzman, Klorman, Kaskey, & K l e i n , 66 1978), and the d e f i c i t has been found by numerous i n v e s t i g a t o r s u s i n g v a r i o u s methodologies (see Iacono, 1983, f o r a r e v i e w ) . Because d i s r u p t e d smooth p u r s u i t eye movements are c o n s i s t e n t l y r e p o r t e d i n a p r o p o r t i o n of s c h i z o p h r e n i c s and t h i s anomaly i s f r e q u e n t l y a s s o c i a t e d with b r a i n damage i n n e u r o l o g i c a l p a t i e n t s , i t i s p o s s i b l e t h a t those s c h i z o p h r e n i c s who have e n l a r g e d v e n t r i c l e s are the same i n d i v i d u a l s who have d i s r u p t e d eye movements. Weinberger and Wyatt (1982b) r e p o r t some p r e l i m i n a r y r e s u l t s t h a t address t h i s i s s u e . The eye movements of 20 c h r o n i c s c h i z o p h r e n i c p a t i e n t s with normal v e n t r i c l e s were compared with those of 14 p a t i e n t s with LVE. S i g n i f i c a n t l y more p a t i e n t s with LVE had d i s r u p t e d eye-movements (9/14, 64%) than d i d p a t i e n t s with normal v e n t r i c l e s (6/20,30%). No i n f o r m a t i o n i s g i v e n r e g a r d i n g the p a t i e n t s that were used, the s e l e c t i o n c r i t e r i a or the methodolgy. However, these f i n d i n g s p r o v i d e p r e l i m i n a r y evidence s u g g e s t i n g an a s s o c i a t i o n between LVE and d i s r u p t e d p u r s u i t eye-movements. In a second study, B a r t f a i , Levander, Nyback, Berggren, and S c h a l l i n g (1985) assessed the r e l a t i o n s h i p between SPEM and l a t e r a l v e n t r i c l e s i z e , t h i r d v e n t r i c l e width, and s u l c a l d i l a t i o n . Measures were taken on 17 RDC diagnosed s c h i z o p h r e n i c s . The mean age of p a t i e n t s was 30 years (range 23 t o 42). A c o n t r o l group was n o t i n c l u d e d . A l i n e a r index of l a t e r a l v e n t r i c l e s i z e was used ( f r o n t a l horn r a t i o , see Appendix A) and no s i g n i f i c a n t r e l a t i o n s h i p was found between b7 l a t e r a l v e n t r i c u l a r d i l a t i o n and a r a t i n g of SPEM. Li k e w i s e , no r e l a t i o n s h i p was found between SPEM r a t i n g s and t h i r d v e n t r i c l e width or s u l c a l d i l a t i o n . L i t t l e i n f o r m a t i o n i s gi v e n r e g a r d i n g the CT r e s u l t s . The f a c t s t h at no c o n t r o l group was used, on l y a l i n e a r measure of the l a t e r a l v e n t r i c l e s was employed, and i n s u f f i c i e n t i n f o r m a t i o n c o n c e r n i n g CT r e s u l t s i s given make these r e s u l t s d i f f i c u l t t o i n t e r p r e t . The r e s u l t s of Weinberger and Wyatt (1982b) and B a r t f a i et a l . (1985) are i n c o n c l u s i v e . F u r t h e r r e s e a r c h i s needed t o i n v e s t i g a t e t h i s r e l a t i o n s h i p more s y s t e m a t i c a l l y . Summary of V a r i a b l e s A s s o c i a t e d with LVE i n S c h i z o p h r e n i a Many CT s t u d i e s of LVE i n s c h i z o p h r e n i a i n d i c a t e t h a t some s c h i z o p h r e n i c s have e n l a r g e d l a t e r a l v e n t r i c l e s . Research with f i r s t episode p a t i e n t s and p a t i e n t s who are r e l a t i v e l y young t e n t a t i v e l y suggests t h a t v e n t r i c u l a r d i l a t i o n may be present a t the time of the onset of p s y c h o s i s . There a r e , however, c o n t r a d i c t i o n s i n t h i s l i t e r a t u r e . F u r t h e r i n v e s t i g a t i o n s have f a i l e d to p r o v i d e c o n s i s t e n t evidence l i n k i n g o b s t e t r i c c o m p l i c a t i o n s with LVE. There i s some evidence f o r an a s s o c i a t i o n between a p o s i t i v e f a m i l y h i s t o r y of s c h i z o p h r e n i a and LVE but the nature o f t h i s r e l a t i o n s h i p i s i n d i s p u t e at the present time. F i n a l l y , t h e r e i s p r e l i m i n a r y evidence s u g g e s t i n g that poor premorbid adjustment i s p o s i t i v e l y a s s o c i a t e d with v e n t r i c u l a r enlargement. Together, t h i s body of r e s e a r c h t e n t a t i v e l y suggests that d i l a t i o n of the l a t e r a l v e n t r i c l e s 68 may occur b e f o r e the onset of p s y c h o s i s i n some p a t i e n t s . T h i s c o n c l u s i o n i s p r e l i m i n a r y and f u r t h e r r e s e a r c h i s needed to c o n f i r m t h i s h y p o t h e s i s . In a d d i t i o n t o sugges t i n g t h a t LVE may be present at the onset of p s y c h o s i s , the CT s t u d i e s reviewed above (see The Prevalence o f LVE i n S c h i z o p h r e n i a ) suggest t h a t e n l a r g e d v e n t r i c l e s may be more common i n s e v e r e l y i l l p a t i e n t s . Whereas th e r e i s not a commonly agreed upon index of s e v e r i t y , t h e r e i s evidence t o i n d i c a t e t h a t p a t i e n t s who respond p o o r l y to n e u r o l e p t i c medications tend to have l a r g e r l a t e r a l v e n t r i c l e s than do p a t i e n t s who respond w e l l . T h i s f i n d i n g suggests that i n d i v i d u a l s with LVE w i l l be more symptomatic than those with normal v e n t r i c l e s . There i s a l s o p r e l i m i n a r y evidence l i n k i n g n e g a t i v e symptoms and d i s r u p t e d smooth-pursuit eye movements wit h LVE. These f i n d i n g s t e n t a t i v e l y suggest n e u r o l o g i c a l d e f i c i t s . Together, t h i s r e s e a r c h supports the h y p o t h e s i s t h a t LVE i s most common i n s e v e r e l y impaired p a t i e n t s ; i . e . , p a t i e n t s who do not respond w e l l t o n e u r o l e p t i c treatment and/or p a t i e n t s who tend to spend extended p e r i o d s of time i n p s y c h i a t r i c h o s p i t a l s . Whereas th e r e i s r e l a t i v e l y good evidence i n d i c a t i n g t h a t l a t e r a l v e n t r i c u l a r enlargement i s present i n some s c h i z o p h r e n i c p a t i e n t s , i t i s not c l e a r whether t h i s c h a r a c t e r i s t i c i s s p e c i f i c t o s c h i z o p h r e n i a . I f enlarged v e n t r i c l e s are a l s o present i n no n s c h i z o p h r e n i c p s y c h i a t r i c p a t i e n t s , i t would suggest t h a t LVE r e f l e c t s a s i n g l e n e u r o p a t h o l o g i c a l process with d i v e r s e c l i n i c a l e x p r e s s i o n s 69 or that v a r i o u s forms of neuropathy r e s u l t i n p s y c h i a t r i c d i s o r d e r s . The Prevalence o f LVE i n A f f e c t i v e D i s o r d e r s In r e c e n t years, r e s e a r c h e r s have begun to measure l a t e r a l v e n t r i c u l a r s i z e i n no n s c h i z o p h r e n i c p s y c h i a t r i c p a t i e n t s i n or d e r t o determine whether LVE i s s p e c i f i c t o s c h i z o p h r e n i a . R e l a t i v e l y few s t u d i e s have been conducted and these are l i m i t e d i n scope. B i p o l a r D i s o r d e r . P e a r l s o n and V e r o f f (1981), and P e a r l s o n , V e r o f f , and McHugh (1981) compared the l a t e r a l v e n t r i c l e s of 22 s c h i z o p h r e n i c and 16 b i p o l a r manic p a t i e n t s with those o f 35 age- and sex-matched p a t i e n t s diagnosed as having adjustment or p e r s o n a l i t y d i s o r d e r s . Ages ranged from 16 t o 50 y e a r s . A l l s c h i z o p h r e n i c and b i p o l a r p a t i e n t s had r e p o r t e d h a l l u c i n a t i o n s and/or d e l u s i o n s and a l l were diagnosed u s i n g DSM-III c r i t e r i a . The mean v e n t r i c l e t o b r a i n r a t i o of the s c h i z o p h r e n i c and b i p o l a r groups was not s i g n i f i c a n t l y d i f f e r e n t and both groups had mean VBR's that were s i g n i f c a n t l y g r e a t e r than those o f the c o n t r o l s . Forty-one percent (9/22) of the s c h i z o p h r e n i c s and 12% (2/16) of the b i p o l a r p a t i e n t s were r e p o r t e d to have v e n t r i c l e s g r e a t e r than the c o n t r o l group mean p l u s two standard d e v i a t i o n s . The s e l e c t i o n c r i t e r i a r e q u i r e d the e l i m i n a t i o n of i n d i v i d u a l s with s i g n s o f n e u r o l o g i c a l problems or "lowered IQ" and thus may have b i a s e d t h i s sample i n f a v o r of good p r o g n o s i s i n d i v i d u a l s . P e a r l s o n et a l . (1981) r e p o r t t h a t t h e r e i s no r e l a t i o n s h i p between v e n t r i c l e s i z e and age, 70 age a t onset of i l l n e s s , d u r a t i o n of h o s p i t a l i z a t i o n , or n e u r o l e p t i c dosage. Using groups of 24 b i p o l a r manic p a t i e n t s with p s y c h o t i c symptoms, 55 c h r o n i c s c h i z o p h r e n i c s , and 27 age- and sex-matched medical c o n t r o l s (M = 32 y e a r s , range 20-45), N a s r a l l a h , M c C a l l e y - W h i t t e r s , and Jacoby (1982b) r e p l i c a t e d the f i n d i n g s of P e a r l s o n and V e r o f f (1981). Diagnoses were made a c c o r d i n g to DSM-III c r i t e r i a . The mean VBRs of the b i p o l a r and s c h i z o p h r e n i c p a t i e n t s were not s i g n i f i c a n t l y d i f f e r e n t from each other and both groups had s i g n i f i c a n t l y l a r g e r l a t e r a l v e n t r i c l e s than those of the c o n t r o l s . Seven (29%) of 24 b i p o l a r and 19 (34%) of 55 s c h i z o p h r e n i c p a t i e n t s were r e p o r t e d to have s i g n i f i c a n t l y e n l a r g e d v e n t r i c l e s . As with the study of P e a r l s o n et a l . (1981), a l l b i p o l a r p a t i e n t s i n t h i s study had p s y c h o t i c symptoms. Reider et a l . (1983) assessed l a t e r a l v e n t r i c u l a r s i z e i n 28 c h r o n i c s c h i z o p h r e n i c , 15 c h r o n i c s c h i z o a f f e c t i v e , and 19 manic p a t i e n t s . RDC diagnoses were used to c l a s s i f y p a t i e n t s and the VBR was used as a measure of v e n t r i c u l a r s i z e . A normal c o n t r o l group was not i n c l u d e d i n t h i s study. The mean age of the s c h i z o p h r e n i c group was 26 y e a r s , of the s c h i z o a f f e c t i v e group 25 y e a r s , and of the manic group 44 y e a r s . No s i g n i f i c a n t d i f f e r e n c e s i n v e n t r i c l e s i z e were found between the three groups. Using the recommended VBR c u t - o f f of 10, used by Weinberger e t a l . (1979a), 7% (2/28) s c h i z o p h r e n i c , 7% (1/15) s c h i z o a f f e c t i v e , and 10% (2/19) b i p o l a r p a t i e n t s were r e p o r t e d to have s i g n i f i c a n t l y e n l a r g e d 71 v e n t r i c l e s . There are s y s t e m a t i c d i f f e r e n c e s i n measuring v e n t r i c l e s a c r o s s s t u d i e s (Weinberger and Wyatt, 1982a) and, t h e r e f o r e , the use of a c o n t r o l group from a separate study makes the r e s u l t s of Reider et a l . (1983) d i f f i c u l t to i n t e r p r e t . In a f u r t h e r study, P e a r l s o n et a l . (1984a, 1984b) re p o r t e d a preva l e n c e of LVE i n b i p o l a r p a t i e n t s with p s y c h o t i c f e a t u r e s that was s i m i l a r t o t h a t r e p o r t e d by N a s r a l l a h et a l . (1982b). S u b j e c t s were 27 b i p o l a r p a t i e n t s and 27 age- and sex-matched normal c o n t r o l s . The mean age of the p a t i e n t s was 31 years (range 18 to 40) and mean d u r a t i o n of i l l n e s s was 10 y e a r s . Diagnoses were made u s i n g DSM-III c r i t e r i a . The mean VBR o f the b i p o l a r p a t i e n t s was s i g n i f i c a n t l y g r e a t e r than t h a t of the c o n t r o l s . E i g h t of the 27 b i p o l a r p a t i e n t s (30%) were r e p o r t e d to have s i g n i f i c a n t l y e n l a r g e d l a t e r a l v e n t r i c l e s . No s i g n i f i c a n t r e l a t i o n s h i p was found between v e n t r i c l e s i z e and age. There was a s i g n i f i c a n t p o s i t i v e c o r r e l a t i o n between LVE and both p e r s i s t e n t unemployment and number of h o s p i t a l i z a t o n s . No p a t i e n t s i n t h i s study had been c h r o n i c a l l y h o s p i t a l i z e d and a l l were l i v i n g i n the community a t the time of t e s t i n g . N a s r a l l a h , M c C a l l e y - W h i t t e r s and P f o h l (1984) r e p l i c a t e d the f i n d i n g of P e a r l s o n et a l . (1984a, 1984b) with 24 c o n s e c u t i v e l y admitted b i p o l a r manic males (aged 20 to 45 y e a r s ) . Diagnoses were made a c c o r d i n g to DSM-III c r i t e r i a . A c o n t r o l group was comprised o f 27 c a r a c c i d e n t v i c t i m s . N a s r a l l a h et a l . (1984) r e p o r t e d that e i g h t (33%) of the 72 b i p o l a r p a t i e n t s had s i g n i f i c a n t l y enlarged l a t e r a l v e n t r i c l e s . V e n t r i c u l a r enlargement was not r e l a t e d to age at onset, d u r a t i o n of i l l n e s s , or response t o drug treatment. F i n a l l y , i n a recent study of LVE i n s c h i z o p h r e n i a (Owens et a l . , 1985), 32 manic p a t i e n t s were i n c l u d e d f o r comparison. Diagnoses were made a c c o r d i n g to Feighner d i a g n o s t i c c r i t e r i a . A c o n t r o l group of 19 " n e u r o t i c " o u t p a t i e n t s was a l s o i n c l u d e d . The age of the manic group i s not g i v e n . However, the t o t a l p a t i e n t sample was o l d compared to that of other s t u d i e s (range 22 t o 87 ye a r s , M = 56 + 12.7 y e a r s ) . The f i n d i n g s of t h i s study t h a t r e l a t e t o the manic group are d i f f i c u l t to i n t e r p r e t from the i n f o r m a t i o n g i v e n . The v e n t r i c u l a r s i z e of the manic p a t i e n t s d i d not d i f f e r s i g n i f i c a n t l y from e i t h e r the s c h i z o p h r e n i c or c o n t r o l p a t i e n t s . However, the VBR v a l u e s r e p o r t e d i n t h i s study are f a r g r e a t e r than those found i n oth e r s t u d i e s . The m a j o r i t y of p a t i e n t s are over 50 years o f age and no i n f o r m a t i o n i s gi v e n r e g a r d i n g the age range i n each group. Thus, i t i s p o s s i b l e t h a t the absence of d i f f e r e n c e s between groups i n t h i s study i s i n f l u e n c e d by v e n t r i c u l a r enlargement due to aging. Major Depression. Other s t u d i e s have examined the pre v a l e n c e o f l a t e r a l v e n t r i c u l a r enlargement i n major d e p r e s s i o n . S c o t t , Golden, Ruedrich, and Bishop (1983) examined 10 p a t i e n t s diagnosed as having major d e p r e s s i o n a c c o r d i n g t o DSM-III c r i t e r i a and 10 age-matched medical c o n t r o l s . The mean age of p a t i e n t s was 39 y e a r s . Depressed 73 s u b j e c t s were i n p a t i e n t s and a l l e x h i b i t e d mood-congrugent h a l l u c i n a t i o n s and/or d e l u s i o n s . The depressed group had a mean VBR s i g n i f i c a n t l y g r e a t e r than t h a t of the c o n t r o l group. The p r o p o r t i o n of p a t i e n t s with s i g n i f i c a n t l y e n l a r g e d v e n t r i c l e s i s not r e p o r t e d . T h i s study p r o v i d e s p r e l i m i n a r y evidence f o r v e n t r i c u l a r enlargement i n some p a t i e n t s who have major d e p r e s s i o n with p s y c h o t i c f e a t u r e s . A f i n d i n g of en l a r g e d v e n t r i c l e s i n depressed p a t i e n t s was a l s o r e p o r t e d by Targum, Rosen, D e L i s i , Weinberger, and C i t r i n (1983). The VBR was ob t a i n e d from 38 p a t i e n t s who r e c e i v e d DSM-III diagnoses of major d e p r e s s i o n with m e l a n c h o l i a (20 were d e l u s i o n a l and 18 n o n d e l u s i o n a l ) and 26 n e u r o l o g i c a l p a t i e n t s . The mean age of d e l u s i o n a l and n o n d e l u s i o n a l groups of p a t i e n t s was 31 y e a r s . The mean VBR of the d e l u s i o n a l p a t i e n t s was s i g n i f i c a n t l y g r e a t e r than t h a t of the c o n t r o l p a t i e n t s but not th a t of the n o n d e l u s i o n a l group. There was no s i g n i f i c a n t d i f f e r e n c e between the n o n d e l u s i o n a l p a t i e n t s and the c o n t r o l group. F i v e (25%) of the 20 d e l u s i o n a l p a t i e n t s had VBR's g r e a t e r than the c o n t r o l mean p l u s two standard d e v i a t i o n s whereas none of the n o n d e l u s i o n a l p a t i e n t s reached t h i s c r i t e r i o n . The r e s u l t s of t h i s study support those of Sc o t t et a l . (1982) and suggest a p r o p o r t i o n of depressed p a t i e n t s with p s y c h o t i c f e a t u r e s have enla r g e d v e n t r i c l e s . Mixed A f f e c t i v e D i s o r d e r P a t i e n t s . Two other s t u d i e s have i n c l u d e d a f f e c t i v e d i s o r d e r p a t i e n t s as c o n t r o l s f o r comparison with s c h i z o p h r e n i c p a t i e n t s . Weinberger et a l . 74 (1982) used a group of 23 p a t i e n t s with "acute a f f e c t i v e d i s o r d e r " i n a d d i t i o n to groups of s c h i z o p h r e n i c and n e u r o l o g i c a l p a t i e n t s . DSM-III c r i t e r i a were used i n making diagnoses but no s p e c i f i c d i a g n o s t i c i n f o r m a t i o n i s given f o r the a f f e c t i v e group. The mean VBR of the a f f e c t i v e group i s not s i g n i f i c a n t l y d i f f e r e n t from that of the c o n t r o l group but i s s i g n i f i c a n t l y s m a l l e r than the mean of the s c h i z o p h r e n i c group. Without f u r t h e r i n f o r m a t i o n about the a f f e c t i v e d i s o r d e r p a t i e n t s , no s p e c i f i c c o n c l u s i o n s can be made from t h i s study. However, these r e s u l t s do suggest t h a t , whereas LVE may be present i n some s e v e r e l y i l l p a t i e n t s who have a f f e c t i v e d i s o r d e r s with p s y c h o t i c f e a t u r e s , t h i s anomaly may be absent i n p a t i e n t s with l e s s severe a f f e c t i v e symptoms. S i g n i f i c a n t l y enlarged v e n t r i c l e s i n a f f e c t i v e d i s o r d e r p a t i e n t s were r e p o r t e d by Luch i n s et a l . (1984). In t h i s study, a group of 22 i n d i v i d u a l s with a f f e c t i v e d i s o r d e r s were compared to 45 s c h i z o p h r e n i c p a t i e n t s and 50 headache c o n t r o l s u b j e c t s . A l l p s y c h i a t r i c s u b j e c t s were i n p a t i e n t s and r e c e i v e d RDC diagnoses. Of the a f f e c t i v e d i s o r d e r group, 14 were depressed and 6 were manic. Ages ranged from 18 to 59 (M = 35 y e a r s ) . There was no s i g n i f i c a n t d i f f e r e n c e i n mean VBR s i z e between the s c h i z o p h r e n i c and a f f e c t i v e d i s o r d e r groups and both of these groups had s i g n i f i c a n t l y l a r g e r mean VBR value s than the c o n t r o l group. Four (18%) of the 22 a f f e c t i v e d i s o r d e r and f i v e (11%) of the 45 s c h i z o p h r e n i c p a t i e n t s had s i g n i f i c a n t l y e n l a r g e d l a t e r a l 75 v e n t r i c l e s . In support of the other s t u d i e s that i n c l u d e d manic and depressed p a t i e n t s , e n l a r g e d v e n t r i c l e s were found to be a s s o c i a t e d with d e l u s i o n a l symptoms. Summary of S t u d i e s Examining A f f e c t i v e D i s o r d e r P a t i e n t s The s t u d i e s that have i n c l u d e d manic and depressed p a t i e n t s i n d i c a t e that v e n t r i c u l a r enlargement i s present i n some p a t i e n t s with a f f e c t i v e d i s o r d e r s and i s , t h e r e f o r e , not s p e c i f i c to s c h i z o p h r e n i a . The p r e v a l e n c e of LVE i n manic or d e p r e s s i v e p a t i e n t s i s d i f f i c u l t t o a s c e r t a i n from the few s t u d i e s t h a t have been conducted. In b i p o l a r p a t i e n t s , the p r e v a l e n c e has ranged from ze r o t o 33% (median value = 21%) and LVE has been observed i n f i v e of the s i x CT s t u d i e s t h a t have i n c l u d e d manic p a t i e n t s . Three s t u d i e s r e p o r t e d t h a t p a t i e n t s had p s y c h o t i c symptoms and LVE. The remaining three s t u d i e s d i d not i n d i c a t e whether or not p a t i e n t s were p s y c h o t i c . The r e s u l t s of both of the CT s t u d i e s of depressed p a t i e n t s have i n d i c a t e d t h a t a p r o p o r t i o n of these i n d i v i d u a l s have enla r g e d v e n t r i c l e s . Both s t u d i e s i n c l u d e d depressed p a t i e n t s who have p s y c h o t i c f e a t u r e s . The one study t h a t compared p s y c h o t i c with nonpsychotic p a t i e n t s r e p o r t e d that LVE was l i m i t e d t o depressed p a t i e n t s with p s y c h o t i c f e a t u r e s . One of the two s t u d i e s that used a f f e c t i v e d i s o r d e r samples not broken down i n t o manic and depressed groups r e p o r t e d s i g n i f i c a n t v e n t r i c u l a r enlargement. The p a t i e n t s i n t h i s study were p s y c h o t i c . Together the r e s u l t s of these s t u d i e s i n d i c a t e that LVE i s not s p e c i f i c t o s c h i z o p h r e n i a . These f i n d i n g s do, however, 76 suggest that LVE may be s p e c i f i c t o p s y c h o s i s . I f t h i s i s the case, enlarged l a t e r a l v e n t r i c l e s may be a s s o c i a t e d with a form of p s y c h o s i s t h a t cuts a c r o s s t r a d i t i o n a l d i a g n o s t i c d i v i s i o n s . The r e s e a r c h f i n d i n g s reviewed above suggest t h a t a s i g n i f i c a n t p r o p o r t i o n of s c h i z o p h r e n i c and n o n s c h i z o p h r e n i c p s y c h o t i c p a t i e n t s have LVE. However, a c e n t r a l q u e s t i o n t h a t i s not addressed by t h i s r e s e a r c h i s whether or not the observed b r a i n changes are s p e c i f i c t o the s t r u c t u r e s around the l a t e r a l v e n t r i c l e s or whether they are p a r t of more d i f f u s e b r a i n changes. In order to determine whether t h e r e are changes elsewhere i n the b r a i n , a number of r e s e a r c h e r s have i n v e s t i g a t e d the t h i r d v e n t r i c l e . Enlargement of the T h i r d V e n t r i c l e A number of medical c o n d i t i o n s may r e s u l t i n enlargement of the t h i r d and l a t e r a l v e n t r i c l e s (see L a t e r a l V e n t r i c u l a r Enlargement above). A number of i n v e s t i g a t o r s have a l s o r e p o r t e d enlargement of the t h i r d v e n t r i c l e i n s c h i z o p h r e n i c p a t i e n t s . Gluck, Radu, Mundt and Gerhardt (1980) reviewed the pneumoencephalographic s t u d i e s of s c h i z o p h r e n i c p a t i e n t s and noted that 80% of these s t u d i e s r e p o r t enlargement of the t h i r d v e n t r i c l e . The d i f f i c u l t i e s a s s o c i a t e d with the pneumo-encephalogram (see LVE i n Pneumoencephalographic S t u d i e s above) suggest t h a t these s t u d i e s should be i n t e r p r e t e d with c a u t i o n . More r e c e n t l y , r e s e a r c h e r s have made use of computed tomography to measure the s i z e of the t h i r d v e n t r i c l e . 77 M e t h o d o l o g i c a l Issues. A l l of the ten s t u d i e s that have assessed the s i z e of the t h i r d v e n t r i c l e i n s c h i z o p h r e n i c p a t i e n t s have measured the width of t h i s v e n t r i c l e at i t s widest p o i n t . In f o u r s t u d i e s , the width i s measured from an image on a cathode ray tube, i n one study a magnified r u l e was used, and i n one a measure was taken from an image p r o j e c t e d and enl a r g e d 40 times. Four o f the ten s t u d i e s f a i l t o d e s c r i b e how the width of the t h i r d v e n t r i c l e was measured. I t i s not c l e a r from the s t u d i e s of the t h i r d v e n t r i c l e whether the d i s t a n c e s r e p o r t e d are a c t u a l l i f e s i z e or are the d i s t a n c e s measured from the CT scans. T h i s ambiguity makes i t d i f f i c u l t t o compare measures between s t u d i e s . The f i l m t h a t i s used t o d i s p l a y CT images u s u a l l y shows the b r a i n at approximately one t h i r d l i f e s i z e . Because of t h i s , the a c t u a l d i s t a n c e t h a t i s measured on the scan ranges from approximately 0.33mm to 2.50mm. Theref o r e some m a g n i f i c a t i o n i s needed t o a c c u r a t e l y measure the t h i r d v e n t r i c l e . The v a r i a b i l i t y between s t u d i e s i n the r e p o r t e d width of the t h i r d v e n t r i c l e (M = 0.95 + 0.44mm to M = 7.4 + 1.6mm) suggests e i t h e r t h a t t h a t t h e r e may be some measurement e r r o r due t o the method used and/or some i n v e s t i g a t o r s r e p o r t measures d i r e c t l y from the CT scan whereas o t h e r s convert these measures t o l i f e s i z e . Future s t u d i e s need t o use w e l l - d e s c r i b e d and r e l i a b l e procedures. Enlargement of the T h i r d V e n t r i c l e i n S c h i z o p h r e n i a Dewan et a l . (1983) i n v e s t i g a t e d the d i e n c e p h a l i c r e g i o n 78 of the b r a i n s of 23 c h r o n i c s c h i z o p h r e n i c s and 23 medical c o n t r o l s u b j e c t s by measuring the width of the t h i r d v e n t r i c l e . Diagnoses were made a c c o r d i n g t o DSM-III c r i t e r i a . The width of the t h i r d v e n t r i c l e was s i g n i f i c a n t l y g r e a t e r f o r the s c h i z o p h r e n i c s than f o r the medical p a t i e n t s . T h i s measure was not s i g n i f i c a n t l y r e l a t e d to age or d u r a t i o n of i l l n e s s i n the s c h i z o p h r e n i c p a t i e n t s . However, age was s i g n i f i c a n t l y r e l a t e d t o t h i r d v e n t r i c l e width i n the medical c o n t r o l group. Only two s t u d i e s (Nyback et a l . , 1982; Okasha & Madkour, 1982) have r e p o r t e d enlargement of l a t e r a l and t h i r d v e n t r i c l e s . Nyback et a l . (1982) r e p o r t e d s i g n i f i c a n t enlargement of both the t h i r d and l a t e r a l c e r e b r a l v e n t r i c l e s i n young (17 t o 44 years) s c h i z o p h r e n i c s . RDC diagnoses were made. There was a s i g n i f i c a n t p o s i t i v e c o r r e l a t i o n between the s i z e of the t h i r d and l a t e r a l v e n t r i c l e s i n both the p a t i e n t s ( r = .46) and v o l u n t e e r c o n t r o l s u b j e c t s ( r = .52). In a d d i t i o n , a s i g n i f i c a n t p o s i t i v e r e l a t i o n s h i p was r e p o r t e d between age and the width of the t h i r d v e n t r i c l e . U n f o r t u n a t e l y , l i n e a r measures of the l a t e r a l v e n t r i c l e s were used and the method used t o measure the t h i r d v e n t r i c l e was not g i v e n . As a r e s u l t the f i n d i n g s of t h i s study are d i f f i c u l t t o i n t e r p r e t . These f i n d i n g s support the e a r l i e r pneumoencephalographic r e s u l t s and suggest that enlargement of the t h i r d v e n t r i c l e may be a p a r t of gen e r a l v e n t r i c u l a r enlargement i n s c h i z o p h r e n i a . The r e s u l t s of Nyback et a l . (1982) are, however, i n c o n f l i c t w i t h those of Dewan et a l . 79 (1983) who d i d not f i n d a p o s i t i v e r e l a t i o n s h i p between t h i r d v e n t r i c u l a r width and age. Enlargement of the t h i r d and l a t e r a l v e n t r i c l e s was a l s o r e p o r t e d by Okasha and Madkour (1982). In t h i s study, a group of 43 c h r o n i c s c h i z o p h r e n i c s (Mean age was 33 y e a r s ) had s i g n i f i c a n t l y l a r g e r t h i r d and l a t e r a l v e n t r i c l e s than d i d a group of 39 medical c o n t r o l s . As with Nyback et a l . (1982), Okasha and Madkour (1982) used a l i n e a r measure of the l a t e r a l v e n t r i c l e s and d i d not d e s c r i b e how the t h i r d v e n t r i c l e was measured. In a d d i t i o n , d i a g n o s t i c c r i t e r i a were not s p e c i f i e d and the p a t i e n t sample was i n c o m p l e t e l y d e s c r i b e d . There i s a l s o no i n d i c a t i o n whether enl a r g e d l a t e r a l v e n t r i c l e s were a s s o c i a t e d with an enlargement of the t h i r d v e n t r i c l e . Thus, w h i l e these r e s u l t s support those of Nyback et a l . (1982), the m e t h o d o l o g i c a l l i m i t a t i o n s of t h i s study warrant c a u t i o n i n drawing c o n c l u s i o n s . Tanaka et a l . (1981) a l s o used l i n e a r measures of the l a t e r a l v e n t r i c l e s but f a i l e d t o f i n d e i t h e r t h i r d or l a t e r a l v e n t r i c u l a r enlargement i n 32 young s c h i z o p h r e n i c s (aged 20 to 44 y e a r s ) . A second group of 14 o l d e r p a t i e n t s (aged 41 to 60 years) was found to have s i g n i f i c a n t l y enlarged t h i r d and l a t e r a l v e n t r i c l e s . T h i s f i n d i n g c o n t r a d i c t s that of Nyback et a l . (1982) who r e p o r t e d v e n t r i c u l a r enlargement i n a group of r e l a t i v e l y young p a t i e n t s . U n f o r t u n a t e l l y , Tanaka et a l . (1981) d i d not d e s c r i b e t h e i r p a t i e n t sample, d i a g n o s t i c c r i t e r i a , or s e l e c t i o n procedures. The a s s o c i a t i o n between age and t h i r d v e n t r i c l e s i z e t h a t was 8 0 r e p o r t e d by Nyback et a l . (1982) was supported by the f i n d i n g s of t h i s study. Tanaka et a l . (1981), however, d i d not r e p o r t a c o r r e l a t i o n c o e f f i c i e n t f o r t h i s r e l a t i o n s h i p . S e v e r a l recent s t u d i e s i n d i c a t e no l a t e r a l v e n t r i c u l a r enlargement but r e p o r t enlargement of the t h i r d v e n t r i c l e . Smith and Maser (1983) measured the l a t e r a l and t h i r d v e n t r i c l e s of 30 s c h i z o p h r e n i c p a t i e n t s (diagnosed a c c o r d i n g t o RDC c r i t e r i a ) and 14 medical p a t i e n t s . A s m a l l but s t a t i s t i c a l l y s i g n i f i c a n t i n c r e a s e i n the width of the t h i r d v e n t r i c l e was r e p o r t e d . No i n f o r m a t i o n was gi v e n r e g a r d i n g how the t h i r d v e n t r i c l e was measured. The v e n t r i c l e t o b r a i n r a t i o (VBR) of the l a t e r a l v e n t r i c l e s was r e p o r t e d to be no d i f f e r e n t f o r the s c h i z o p h r e n i c and medical c o n t r o l groups. Smith and Maser (1983) r e p o r t t h a t "a few" of t h e i r p a t i e n t s were c h r o n i c nonresponders t o me d i c a t i o n . In a l l p r e v i o u s s t u d i e s t h a t have used p a t i e n t s who respond p o o r l y t o med i c a t i o n ( J e s t e et a l . , 1982; K l i n g et a l . , 1982/83; Luch i n s et a l . , 1984; Weinberger et a l . , 1980a) s i g n i f i c a n t enlargement of the l a t e r a l v e n t r i c l e s was r e p o r t e d . I t i s thus unusual that Smith and Maser (1983) d i d not o b t a i n a s i g n i f i c a n t e f f e c t . No i n f o r m a t i o n was given r e g a r d i n g the r e l a t i o n s h i p between t h i r d and l a t e r a l v e n t r i c u l a r s i z e . Pandurangi et a l . (1984) r e p o r t e d l i t t l e l a t e r a l v e n t r i c u l a r enlargement i n 23 c h r o n i c s c h i z o p h r e n i c s when compared to 23 medical p a t i e n t s . In support of the f i n d i n g s of Smith and Maser (1983), the s c h i z o p h r e n i c s had a smal l but s i g n i f i c a n t enlargement of the t h i r d v e n t r i c l e . The s i z e of 81 the t h i r d v e n t r i c l e was p o s i t i v e l y c o r r e l a t e d with age but not with l a t e r a l v e n t r i c u l a r s i z e . T h i s p o s i t i v e r e l a t i o n s h i p between age and s i z e of the t h i r d v e n t r i c l e supports the f i n d i n g s of Nyback et a l . (1982) and Tanaka et a l . (1981) and i s c o n s i s t e n t w i t h the p o s s i b i l i t y t h a t enlargement of the t h i r d v e n t r i c l e may be a sequela or i a t r o g e n i c e f f e c t . DeMeyer et a l . (1984) r e p o r t e d that a smal l group (n=8) of s c h i z o p h r e n i c s (diagnosed a c c o r d i n g to DSM-III c r i t e r i a ) had s i g n i f i c a n t enlargement of the t h i r d v e n t r i c l e but not of the l a t e r a l v e n t r i c l e s (VBR) when compared t o 15 medical p a t i e n t s . A second group of i n d i v i d u a l s , i n c l u d i n g p a t i e n t s w i t h o r g a n i c h a l l u c i n o s i s , p e r v a s i v e developmental d i s o r d e r , and mental r e t a r d a t i o n , was added f o r f u r t h e r a n a l y s e s . T h i s a d d i t i o n makes i t d i f f i c u l t t o i n t e r p r e t subsequent r e s u l t s of t h i s study. N e v e r t h e l e s s , the f i n d i n g s of t h i s study support those of p r e v i o u s i n v e s t i g a t i o n s and suggest that a p r o p o r t i o n o f c h r o n i c s c h i z o p h r e n i c s have enlargement of the t h i r d v e n t r i c l e . The f i n d i n g of enlargement of the t h i r d v e n t r i c l e was a l s o r e p o r t e d i n a re c e n t , w e l l d e s c r i b e d study (Boronow et a l . , 1985). The s i z e of the t h i r d v e n t r i c l e was s i g n i f i c a n t l y g r e a t e r f o r a group of 30 c h r o n i c s c h i z o p h r e n i c p a t i e n t s (RDC diagnosed) than f o r a group of 26 medical p a t i e n t s . There was a n o n s i g n i f i c a n t t r e n d towards l a r g e r l a t e r a l v e n t r i c l e s (VBR) i n the s c h i z o p h r e n i c group. I t i s notworthy i n t h i s study that no s i g n i f i c a n t c o r r e l a t i o n s were obtained between 82 t h i r d and l a t e r a l v e n t r i c u l a r s i z e , nor between t h i r d or l a t e r a l v e n t r i c u l a r s i z e and age, age at onset of p s y c h o s i s , d u r a t i o n of i l l n e s s , cumulative h o s p i t a l i z a t i o n , or premorbid adjustment. Boronow et a l . (1985) suggest t h a t , w h i l e the p a t i e n t s i n t h i s study manifested s e r i o u s psychopathology, had been f r e q u e n t l y r e h o s p i t a l i z e d , and f o r the most p a r t were unable t o h o l d r e g u l a r j o b s , they d i d not r e q u i r e continuous h o s p i t a l i z a t i o n and thus d i d not r e p r e s e n t the most impaired of s c h i z o p h r e n i c s . There have been two r e p o r t s of no s i g n i f i c a n t enlargement of the t h i r d v e n t r i c l e i n s c h i z o p h r e n i c p a t i e n t s . Gluck e t a l . (1980) took l i n e a r measures of the l a t e r a l and t h i r d v e n t r i c l e s from 68 c h r o n i c s c h i z o p h r e n i c p a t i e n t s (22 to 68 y e a r s ) and 68 medical p a t i e n t s (matched on age, sex and i n n e r diameter of the s k u l l ) were used f o r c o n t r o l s . A n o n s i g n i f i c a n t t r e n d towards s m a l l e r t h i r d and l a t e r a l v e n t r i c l e s i n the s c h i z o p h r e n i c group was r e p o r t e d . Gluck et a l . (1980) r e p o r t e d t h a t the measures obtained from the s c h i z o p h r e n i c and c o n t r o l groups were comparable to p u b l i s h e d normal pneumoencephalographic v a l u e s (Huber, 1961, r e p o r t e d i n Gluck, 1980). S e l e c t i o n procedures and d i a g n o s t i c c r i t e r i a were not given. In a d d i t i o n , the use of a l i n e a r measure of the l a t e r a l v e n t r i c l e s makes i t d i f f i c u l t t o i n t e r p r e t these r e s u l t s . N a s r a l l a h , Jacoby, Chapman, and M c C a l l e y - W h i t t e r s (1985) a l s o r e p o r t e d no s i g n i f i c a n t enlargement of the t h i r d v e n t r i c l e i n 55 c h r o n i c s c h i z o p h r e n i c s (diagnosed a c c o r d i n g 83 to DSM-III c r i t e r i a ) . S i g n i f i c a n t enlargement of the l a t e r a l v e n t r i c l e s were r e p o r t e d f o r the same group of p a t i e n t s ( N a s r a l l a h et a l . , 1982a). The dimensions of the t h i r d v e n t r i c l e was obtained a f t e r p r o j e c t i n g the X-ray images onto a screen at 40x m a g n i f i c a t i o n and t r a c i n g the b r a i n image on paper. T h i s procedure r e s u l t s i n much l o s s of d e f i n i t i o n and thus may have r e s u l t e d i n measurement e r r o r . N a s r a l l a h et a l . (1985) do, however, r e p o r t a s i g n i f i c a n t r e l a t i o n s h i p between the width of the t h i r d v e n t r i c l e and the VBR of the l a t e r a l v e n t r i c l e s . T h i s f i n d i n g supports t h a t of Nyback e t a l . (1982) but c o n t r a d i c t s those of Boronow et a l . (1985) and Smith and Maser (1983). In support of Boronow e t a l . (1985), N a s r a l l a h et a l . (1985) found no s i g n i f i c a n t r e l a t i o n s h i p between age and the width of the t h i r d v e n t r i c l e . Summary of S t u d i e s of the T h i r d V e n t r i c l e Most p u b l i s h e d s t u d i e s i n d i c a t e t h a t s c h i z o p h r e n i c s tend t o have enlargement of the t h i r d v e n t r i c l e . E i g h t of the ten s t u d i e s t h a t measured the width of the t h i r d v e n t r i c l e r e p o r t e d s i g n i f i c a n t widening. Only f o u r of the ten s t u d i e s measured the r e l a t i o n s h i p between t h i r d and l a t e r a l v e n t r i c u l a r s i z e . Of these f o u r , two r e p o r t e d a s i g n i f i c a n t r e l a t i o n s h i p and two r e p o r t e d no r e l a t i o n s h i p . Two of f o u r s t u d i e s that c o r r e l a t e d age and the width of the t h i r d v e n t r i c l e r e p o r t e d a s i g n i f i c a n t r e l a t i o n s h i p and two r e p o r t e d no r e l a t i o n s h i p . No s t u d i e s have been done t o i n v e s t i g a t e t h i r d v e n t r i c l e s i z e i n f i r s t episode 84 s c h i z o p h r e n i c p a t i e n t s or i n any n o n s c h i z o p h r e n i c p s y c h i a t r i c p a t i e n t s . Many i n v e s t i g a t o r s who have s t u d i e d the l a t e r a l v e n t r i c l e s f a i l e d t o measure the t h i r d v e n t r i c l e and, of those who i n c l u d e d the t h i r d v e n t r i c l e many f a i l e d to measure the v e n t r i c u l a r bodies i n a comparable f a s h i o n . V a r i o u s l i n e a r measures of the l a t e r a l v e n t r i c l e s have been used i n these s t u d i e s and the method of measuring the t h i r d v e n t r i c l e i s f r e q u e n t l y not s p e c i f i e d or i d i o s y n c r a t i c . Whereas the m a j o r i t y of r e p o r t s i n d i c a t e s i g n i f i c a n t enlargement of the t h i r d v e n t r i c l e i n s c h i z o p h r e n i c p a t i e n t s , there i s c o n s i d e r a b l e v a r i a b i l i t y i n the r e p o r t e d s i z e . F i n a l l y , t h e r e i s no c o n c l u s i v e evidence l i n k i n g enlargement of the t h i r d v e n t r i c l e with enlargement of the l a t e r a l v e n t r i c l e s . Systematic i n v e s t i g a t i o n s are needed with c l e a r l y d e f i n e d p a t i e n t samples and w e l l - d e s c r i b e d , r e l i a b l e methods of measuring the v e n t r i c u l a r b o d i e s . None of the s t u d i e s of enlargement of the t h i r d v e n t r i c l e were done with f i r s t episode p a t i e n t s , p a t i e n t s a t r i s k , or d i s c o r d a n t monozygotic twins. U n t i l t h i s type of r e s e a r c h i s conducted, i t cannot be known whether enlargement of the t h i r d v e n t r i c l e i s r e l a t e d t o the onset of p s y c h o s i s or i s a sequela of the i l l n e s s p r o c e s s . Apart from the study of Boronow et a l . (1985), no s t u d i e s have i n v e s t i g a t e d the c o r r e l a t e s of the width of the t h i r d v e n t r i c l e . Systematic i n v e s t i g a t i o n s i n t o c l i n i c a l v a r i a b l e s a s s o c i a t e d with t h i s anomaly are needed at the present time. F i n a l l y , none of the CT s t u d i e s with 85 n o n s c h i z o p h r e n i c , p s y c h o t i c p a t i e n t s has i n c l u d e d a measure of the t h i r d v e n t r i c l e . Thus, i t i s not known whether t h i s enlargement of the t h i r d v e n t r i c l e i s s p e c i f i c t o s c h i z o p h r e n i a or whether i t i s a l s o found i n other p s y c h o t i c i l l n e s s e s . Atrophy of the C e r e b r a l Cortex C o r t i c a l atrophy i s a common r e s u l t of a number of medical c o n d i t i o n s (see L a t e r a l V e n t r i c u l a r Enlargement above). These i n c l u d e c e r e b r a l tumor, c e r e b r a l i n f e c t i o n , A lzheimer's d i s e a s e , Huntington's chorea, and anoxia (TerBrugge & Rao, 1983). Depending on the e t i o l o g y , c o r t i c a l atrophy may be f o c a l or d i f f u s e and may or may not i n v o l v e v e n t r i c u l a r enlargement. In a review of the l i t e r a t u r e , TerBrugge and Rao (1983) noted t h a t a l l s t u d i e s of c o r t i c a l atrophy and normal aging have shown an i n c r e a s e i n the s i z e of the c o r t i c a l s u l c i with i n c r e a s i n g age. Me t h o d o l o g i c a l Issues The measurement of c o r t i c a l atrophy from CT scans i s a complex and c o n t r o v e r s i a l i s s u e ( B i r d , 1982). One common procedure i n v o l v e s measuring the width of the i n d i v i d u a l s u l c i on the two or th r e e h i g h e s t CT scanning c u t s . The proponents of t h i s method admit that t h i s measure i s r e l a t i v e l y i m p r e c i s e and ass e s s e s o n l y s p e c i f i c areas of the c o r t e x r a t h e r than o b t a i n i n g an o v e r a l l r a t i n g ( B i r d , 1982). The p o s i t i o n i n g of the head and the l e v e l of the uppermost c u t s are sources of great v a r i a t i o n with t h i s type of measurement ( B i r d , 1982). Opponents of t h i s method of 8 6 a s s e s s i n g atrophy suggest that measuring s u l c a l width from CT scans i s too i n a c c u r a t e and u n r e l i a b l e to be of use (Jacoby, Levy, & Dawson, 1980). As an a l t e r n a t i v e , s e v e r a l authors have proposed g l o b a l r a t i n g s of atrophy based on a t h r e e -p o i n t (Reider, Donnelly, Herdt, & Waldman, 1979), f o u r - p o i n t (Boronow et a l . , 1985), or f i v e - p o i n t s c a l e (Largen et a l . , 1984. Even with these s c a l e s , t h e r e i s much v a r i a b i l i t y a c r o s s s t u d i e s r e g a r d i n g the amount of s u l c a l d i l a t i o n t h a t i s present f o r each r a t i n g of atrophy. Ratings made u s i n g these s c a l e s , l i k e the s u l c a l measures, are i n f l u e n c e d by the l e v e l of the c u t s t h a t are chosen. None of the s t u d i e s of c o r t i c a l atrophy i n s c h i z o p h r e n i a s p e c i f y which CT c u t s are used and many f a i l t o d e s c r i b e the procedures employed. The v a r i a b i l i t y i n methodology, i n a c c u r a c y i n assessment methods, and l a c k of p r o c e d u r a l i n f o r m a t i o n present major d i f f i c u l t i e s t o the i n t e r p r e t a t i o n of r e s u l t s . Prevalence of C o r t i c a l Atrophy i n S c h i z o p h r e n i a A f i n d i n g of s i g n i f i c a n t c o r t i c a l atrophy i n s c h i z o p h r e n i c p a t i e n t s was r e p o r t e d by N a s r a l l a h , Kuperman, Jacoby, M c C a l l e y - W h i t t e r s , and Hamra (1983). In t h i s study, 55 c h r o n i c s c h i z o p h r e n i c p a t i e n t s were compared to 27 medical c o n t r o l s . C o r t i c a l atrophy was assessed u s i n g a f o u r - p o i n t g l o b a l r a t i n g s c a l e . Twenty two of 55 s c h i z o p h r e n i c p a t i e n t s (40%) were found to have s u l c a l widening compared to one c o n t r o l s u b j e c t ( 4 % ) . The p a t i e n t s with c o r t i c a l atrophy had s i g n i f i c a n t l y worse c o g n i t i v e t e s t s c o r e s than the p a t i e n t s without atrophy. 87 Three s t u d i e s have i n c l u d e d measures of both c o r t i c a l atrophy and l a t e r a l v e n t r i c u l a r enlargement ( K l i n g et a l . , 1982/83; Weinberger, Torrey, Neophytides, & Wyatt, 1979b; Weinberger et a l . , 1982). Weinberger et a l . (1979b) e v a l u a t e d s u l c a l d i l a t i o n i n 75 c h r o n i c s c h i z o p h r e n i c s and 62 h e a l t h y v o l u n t e e r s . A number of l i n e a r measures of c o r t i c a l s u l c i from three separate CT c u t s were taken t o a s s e s s atrophy. Separate a n a l y s e s were done f o r each measure. The S y l v i a n f i s s u r e , i n t e r h e m i s p h e r i c f i s s u r e , and mean width of c o r t i c a l s u l c i were a l l s i g n i f i c a n t l y l a r g e r i n the p a t i e n t group. There was no s i g n i f i c a n t r e l a t i o n s h i p between these measures and age, l e n g t h of i l l n e s s , or d u r a t i o n o f h o s p i t a l i z a t i o n . These p a t i e n t s a l s o had s i g n i f i c a n t l y e n l a r g e d l a t e r a l v e n t r i c l e s (Weinberger et a l . , 1979a) but the r e was no r e l a t i o n s h i p between s u l c a l width and v e n t r i c u l a r s i z e . In a second study by the r e s e a r c h team of Weinberger (Weinberger e t a l . , 1982) s u l c a l width i n a d d i t i o n t o l a t e r a l v e n t r i c u l a r s i z e was assessed i n 35 s c h i z o p h r e n i f o r m p a t i e n t s and 26 medical p a t i e n t s . C o r t i c a l atrophy was assessed u s i n g a t h r e e - p o i n t g l o b a l r a t i n g s c a l e . F i v e of the 35 s c h i z o p h r e n i f o r m p a t i e n t s (14%) and none of the c o n t r o l s u b j e c t s were r e p o r t e d to have c o r t i c a l atrophy. There was no r e l a t i o n s h i p between c o r t i c a l atrophy and LVE. T h i s f i n d i n g suggests t h a t c o r t i c a l atrophy i s present at the onset of p s y c h o s i s i n some p a t i e n t s and i s independent of v e n t r i c u l a r enlargement. 88 The r e s u l t s of Weinberger et a l . (1979a, 1979b, 1982) were r e p l i c a t e d by K l i n g et a l . (1982/83). The width of the S y l v i a n f i s s u r e was s i g n i f i c a n t l y wider and v e n t r i c l e s were l a r g e r i n 26 c h r o n i c s c h i z o p h r e n i c p a t i e n t s than i n 20 medical c o n t r o l p a t i e n t s . However, u n l i k e the study of Weinberger et a l . (1979b, 1982), K l i n g et a l . (1982/83) r e p o r t e d that i n c r e a s e d v e n t r i c u l a r s i z e was s i g n i f i c a n t l y a s s o c i a t e d with S y l v i a n f i s s u r e widening. Dewan et a l . (1983) assessed t h i r d v e n t r i c u l a r and s u l c a l enlargement i n 23 c h r o n i c s c h i z o p h r e n i c s and 23 medical p a t i e n t s . The width of the S y l v i a n f i s s u r e s was used to assess c o r t i c a l atrophy. Both the t h i r d v e n t r i c l e and S y l v i a n f i s s u r e were s i g n i f i c a n t l y e n l a r g e d i n the s c h i z o p h r e n i c group. These two measures were s i g n i f i c a n t l y r e l a t e d . T h i s f i n d i n g p r o v i d e s t e n t a t i v e support f o r the r e s u l t s of K l i n g e t a l . (1982/83) and suggests that there may be g e n e r a l atrophy of the b r a i n r a t h e r than separate f o c a l a t r o p h i e s as was suggested by Weinberger et a l . (1979a, 1979b, 1982). S e v e r a l s t u d i e s have i n c l u d e d measurements of c o r t i c a l atrophy, and t h i r d and l a t e r a l v e n t r i c u l a r enlargement i n an attempt t o map the extent of the a t r o p h i c process i n s c h i z o p h r e n i a . Smith and Maser (1983) r e p o r t e d no LVE but s i g n i f i c a n t enlargement of the t h i r d v e n t r i c l e and c o r t i c a l s u l c i i n 30 c h r o n i c s c h i z o p h r e n i c p a t i e n t s . The method of a s s e s s i n g c o r t i c a l atrophy and the r e l a t i o n s h i p s between l a t e r a l v e n t r i c u l a r s i z e , t h i r d v e n t r i c l e width, and c o r t i c a l 89 atrophy are not r e p o r t e d . Pandurangi et a l . (1984) r e p o r t e d minimal enlargement of the l a t e r a l v e n t r i c l e s but enlargement of both the t h i r d v e n t r i c l e and c o r t i c a l s u l c i . S u b j e c t s were 23 c h r o n i c s c h i z o p h r e n i c s and 23 medical p a t i e n t s . C o r t i c a l atrophy was assessed by measuring the width of the S y l v i a n f i s s u r e and the maximum width of the l a r g e s t c o r t i c a l s u l c u s . The r e l a t i o n s h i p s between the v a r i o u s m o r p h o l o g i c a l measures are not r e p o r t e d . Largen et a l . (1984) compared 35 c h r o n i c s c h i z o p h r e n i c s w i t h 17 medical c o n t r o l s over the l a t e r a l and t h i r d v e n t r i c l e s and c o r t i c a l s u l c i . A g l o b a l r a t i n g of atrophy was made on a f i v e - p o i n t s c a l e . No s i g n i f i c a n t enlargement of the t h i r d or l a t e r a l v e n t r i c l e s was found but there was s i g n i f i c a n t l y more c o r t i c a l atrophy i n the s c h i z o p h r e n i c p a t i e n t s than i n c o n t r o l s u b j e c t s . No c o r r e l a t i o n s between these measures were r e p o r t e d . Tanaka et a l . (1981) compared a group of 32 young s c h i z o p h r e n i c p a t i e n t s (aged 21 t o 40) and 14 o l d e r s c h i z o p h r e n i c s (aged 41 t o 60) wit h 38 age matched medical c o n t r o l s . C o r t i c a l atrophy, i n a d d i t i o n t o t h i r d and l a t e r a l v e n t r i c u l a r s i z e , was measured. C o r t i c a l atrophy was assessed by measuring the width between the S y l v i a n f i s s u r e and the s k u l l , the width of the i n t e r h e m i s p h e r i c f i s s u r e , and the width of the broadest c o r t i c a l s u l c u s . L i n e a r measures of the l a t e r a l v e n t r i c l e s were used. The o l d e r group showed s i g n i f i c a n t enlargement of the c o r t i c a l s u l c i , the t h i r d , and 90 l a t e r a l v e n t r i c l e s . The younger group showed no d i f f e r e n c e s over any of these measures. The p a t i e n t sample, d i a g n o s t i c c r i t e r i a , and s e l e c t i o n procedures were not r e p o r t e d . These l i m i t a t i o n s make i t d i f f i c u l t t o compare these r e s u l t s with those of other s t u d i e s . U n l i k e the r e s u l t s of Weinberger et a l . (1982), the f i n d i n g s of Tanaka et a l . (1981) suggest t h a t c o r t i c a l atrophy i s not present i n young p a t i e n t s but develops with the i l l n e s s . None of the f o u r s t u d i e s of the t h i r d and l a t e r a l v e n t r i c l e s and c o r t i c a l atrophy assessed the r e l a t i o n s h i p between these v a r i a b l e s . In t h r e e s t u d i e s , no enlargement of the l a t e r a l v e n t r i c l e s was found, and i n one t h e r e was no enlargement of the t h i r d v e n t r i c l e . The c o n s i s t e n t f i n d i n g of c o r t i c a l atrophy i n the absence of these other anomalies and i n s p i t e of the d i f f e r i n g methodologies supports e a r l i e r r e s u l t s (Dewan et a l . 1983; K l i n g et a l . , 1982/83; Weinberger et a l . , 1979b, 1982) and suggests t h a t c o r t i c a l atrophy i s p r e v a l e n t i n c h r o n i c s c h i z o p h r e n i a . There have, however, been f o u r r e p o r t s of no c o r t i c a l atrophy i n c h r o n i c s c h i z o p h r e n i a . In the f i r s t CT study of b r a i n morphology i n s c h i z o p h r e n i a , Johnstone e t a l . ( 1976, 1978) r e p o r t e d no c o r t i c a l atrophy i n 17 c h r o n i c a l l y h o s p i t a l i z e d p a t i e n t s . The area of c o r t i c a l s u l c i (as opposed to the width t h a t was used i n other s t u d i e s ) i n the uppermost CT cut was used as a measure of atrophy. C o n t r o l s u b j e c t s were e i g h t c h r o n i c a l l y h o s p i t a l i z e d medical p a t i e n t s . Given the extreme c h r o n i c i t y of the s c h i z o p h r e n i c 91 s u b j e c t s and the f a c t that atrophy i s commonly r e p o r t e d i n c h r o n i c p a t i e n t s i t i s s u r p r i s i n g t h a t no atrophy was found i n t h i s study. I t i s p o s s i b l e t h a t the c h r o n i c i t y of the medical c o n t r o l s , the i d i o s y n c r a t i c method of a s s e s s i n g s u l c a l enlargement, or the c h o i c e of CT cut c o u l d have obscured any s i g n i f i c a n t atrophy. Gluck e t a l . (1980) r e p o r t e d no s i g n i f i c a n t enlargement of the t h i r d or l a t e r a l v e n t r i c l e s or c o r t i c a l s u l c i i n 68 c h r o n i c s c h i z o p h r e n i c s when compared to 68 medical p a t i e n t s . C o r t i c a l atrophy was assessed by co u n t i n g the number of enlar g e d s u l c i on the top two CT scans. T h i s unusual method of measuring c o r t i c a l atrophy may have c o n t r i b u t e d to the l a c k of s i g n i f i c a n t r e s u l t s . In a d d i t i o n , s e l e c t i o n procedures and d i a g n o s t i c c r i t e r i a were not r e p o r t e d . Nyback et a l . (1982) i n c l u d e d a young group of p a t i e n t s i n o r d e r t o i n v e s t i g a t e whether s t r u c t u r a l b r a i n a b n o r m a l i t i e s are present i n the e a r l y stages of s c h i z o p h r e n i a . C o r t i c a l s u l c i and t h i r d and l a t e r a l v e n t r i c l e s were assessed i n 46 s c h i z o p h r e n i c p a t i e n t s (aged 17 to 44 years) and 48 age matched h e a l t h y v o l u n t e e r s . A g l o b a l r a t i n g of c o r t i c a l atrophy was made u s i n g a f o u r - p o i n t s c a l e . L i n e a r measures of the l a t e r a l v e n t r i c l e s were made. There was no s i g n i f i c a n t c o r t i c a l atrophy i n the s c h i z o p h r e n i c p a t i e n t s . T h i r d and l a t e r a l v e n t r i c l e s were s i g n i f i c a n t l y l a r g e r i n the s c h i z o p h r e n i c p a t i e n t s than i n the c o n t r o l s u b j e c t s . F i n a l l y , a f i n d i n g of no c o r t i c a l atrophy was r e p o r t e d 92 by Boronow et a l . (1985). In t h i s w e l l d e s c r i b e d study, the t h i r d and l a t e r a l v e n t r i c l e s and c o r t i c a l s u l c i were assessed i n 30 c h r o n i c s c h i z o p h r e n i c s and 26 medical p a t i e n t s . The t h i r d v e n t r i c l e but not the l a t e r a l v e n t r i c l e s or c o r t i c a l s u l c i was s i g n i f i c a n t l y e n l a r g e d i n the s c h i z o p h r e n i c p a t i e n t s . C o r t i c a l atrophy was assessed u s i n g a f o u r - p o i n t r a t i n g s c a l e . S u l c a l s i z e was s i g n i f i c a n t l y r e l a t e d to age but not to t h i r d or l a t e r a l v e n t r i c u l a r s i z e , age at onset of p s y c h o s i s , d u r a t i o n of i l l n e s s , cumulative h o s p i t a l i z a t i o n , or premorbid adjustment. In summary, although nine of the 13 s t u d i e s of c o r t i c a l atrophy i n s c h i z o p h r e n i a r e p o r t p o s i t i v e r e s u l t s , the o v e r a l l p i c t u r e i s i n c o n c l u s i v e . Widely d i f f e r i n g methodologies were used to a s s e s s atrophy and i n s u f f i c i e n t p r o c e d u r a l i n f o r m a t i o n i s r e p o r t e d . F i v e i n v e s t i g a t o r s assessed the r e l a t i o n s h i p between c o r t i c a l atrophy and v e n t r i c u l a r enlargement. In one study, LVE was r e l a t e d to s u l c a l widening; i n a second, enlargement of the t h i r d v e n t r i c l e was r e l a t e d t o c o r t i c a l atrophy; and i n the remaining t h r e e s t u d i e s , no s i g n i f i c a n t r e l a t i o n s h i p s were o b t a i n e d . Of the three s t u d i e s t h a t have assessed c o r t i c a l atrophy i n the e a r l y stages of s c h i z o p h r e n i a o n l y one r e p o r t e d s i g n i f i c a n t s u l c a l widening. C o r t i c a l Atrophy i n A f f e c t i v e D i s o r d e r s There have been two CT s t u d i e s of c o r t i c a l atrophy i n b i p o l a r a f f e c t i v e d i s o r d e r p a t i e n t s . P e a r l s o n and V e r o f f (1981) and P e a r l s o n e t a l . (1981) i n v e s t i g a t e d c o r t i c a l 93 atrophy and l a t e r a l v e n t r i c u l a r s i z e i n 16 b i p o l a r manic, 22 s c h i z o p h r e n i c , and 35 p e r s o n a l i t y d i s o r d e r p a t i e n t s . A l l s u b j e c t s were between 16 and 50 years of age. S u l c a l width was assessed u s i n g a f o u r - p o i n t r a t i n g s c a l e . Two of the 16 b i p o l a r p a t i e n t s (12%) and fou r of 22 s c h i z o p h r e n i c p a t i e n t s (18%) had s i g n i f i c a n t c o r t i c a l atrophy when compared to the p e r s o n a l i t y d i s o r d e r p a t i e n t s . S u l c a l widening was r e l a t e d to v e n t r i c u l a r enlargement i n the s c h i z o p h r e n i c p a t i e n t s but not i n the b i p o l a r p a t i e n t s . In a second study, R i e d e r et a l . (1983) assessed c o r t i c a l atrophy and v e n t r i c u l a r s i z e i n 19 b i p o l a r , 15 s c h i z o a f f e c t i v e , and 28 c h r o n i c s c h i z o p h r e n i c p a t i e n t s . A normal c o n t r o l group was not i n c l u d e d . C o r t i c a l atrophy was assessed u s i n g a f o u r - p o i n t g l o b a l r a t i n g s c a l e . No s i g n i f i c a n t d i f f e r e n c e s i n c o r t i c a l atrophy were r e p o r t e d between the thr e e groups. However, the mean age of the manic p a t i e n t s was s i g n i f i c a n t l y g r e a t e r than t h a t of the other two groups. I f p a t i e n t s over 50 years of age were excluded, none of the b i p o l a r p a t i e n t s had s i g n i f i c a n t c o r t i c a l atrophy whereas some of the s c h i z o p h r e n i c p a t i e n t s had atrophy. The l i m i t e d data on c o r t i c a l atrophy i n a f f e c t i v e d i s o r d e r p a t i e n t s do not permit any f i r m c o n c l u s i o n s . Because n e i t h e r study i n c l u d e d normal c o n t r o l s , these i n v e s t i g a t i o n s are not w e l l s u i t e d t o determine the extent of c o r t i c a l atrophy but are o n l y s u i t e d t o determine the amount of atrophy i n one group r e l a t i v e t o o t h e r s . The study of P e a r l s o n and V e r o f f (1981) sugests t h a t a s m a l l p r o p o r t i o n of 94 b i p o l a r manic p a t i e n t s may have s i g n i f i c a n t atrophy but the study of Rieder et a l . (1983) c o n t r a d i c t s t h i s . F u r t h e r s t u d i e s are needed t o determine whether c o r t i c a l atrophy i s l i m i t e d to s c h i z o p h r e n i a or whether i t i s a l s o found i n b i p o l a r manic p a t i e n t s . F i n a l l y , no CT s t u d i e s w i t h depressed p a t i e n t s have i n c l u d e d a measure of c o r t i c a l atrophy. Summary of the S t u d i e s of C o r t i c a l Atrophy Research evidence suggests t h a t some s c h i z o p h r e n i c p a t i e n t s have c o r t i c a l atrophy. F u r t h e r r e s e a r c h u s i n g p a t i e n t s who are r e l a t i v e l y young i s i n c o n c l u s i v e . There i s no c l e a r evidence f o r a r e l a t i o n s h i p between c o r t i c a l atrophy and v e n t r i c u l a r enlargement. F i n a l l y , the s t u d i e s of s u l c a l widening i n non s c h i z o p h r e n i c p s y c h o t i c p a t i e n t s do not permit any c o n c l u s i o n s a t the present time. Summary of CT L i t e r a t u r e D i f f i c u l t i e s a s s o c i a t e d with the d i a g n o s i s of s c h i z o p h r e n i a have l e d many r e s e a r c h e r s t o search f o r b i o l o g i c a l concommitants t h a t can be i n c o r p o r a t e d i n t o e x i s t i n g d i a g n o s t i c systems. A b i o l o g i c a l f a c t o r would have the advantage of p r o v i d i n g an o b j e c t i v e l y v e r i f i a b l e , s t a b l e i n d i c a t o r of pathology. In a d d i t i o n , i t c o u l d p r o v i d e an important p r e d i s p o s i n g s i g n , have e t i o l o g i c a l s i g n i f i c a n c e , or be a sequela of the i l l n e s s p r o c e s s . Three p o t e n t i a l markers that have been the focus of a great d e a l of e m p i r i c a l r e s e a r c h are l a t e r a l v e n t r i c u l a r enlargement (LVE), enlargement of the t h i r d v e n t r i c l e , and c o r t i c a l atrophy. 95 F i n d i n g s from CT Scan S t u d i e s Many CT s t u d i e s of the l a t e r a l v e n t r i c l e s i n c h r o n i c p a t i e n t s i n d i c a t e LVE. Other s t u d i e s have i n c l u d e d f i r s t episode p a t i e n t s i n an attempt t o determine whether LVE i s present i n the e a r l y stages of s c h i z o p h r e n i a or whether i t i s a sequela of the i l l n e s s p r o c e s s . T h i s r e s e a r c h t e n t a t i v e l y suggests t h a t enlargement of the l a t e r a l v e n t r i c l e s may occur at the time of or bef o r e the f i r s t p s y c h o t i c episode. T h i s h y p o t h e s i s i s supported by p r e l i m i n a r y evidence l i n k i n g poor premorbid adjustment with LVE. There are, however, some c o n t r a d i c t o r y f i n d i n g s and f u r t h e r r e s e a r c h u s i n g a r e p r e s e n t a t i v e sample of p a t i e n t s who have r e c e n t l y experienced t h e i r f i r s t p s y c h o t i c episode i s needed to r e s o l v e t h i s i s s u e . S t u d i e s of the preva l e n c e of LVE i n s c h i z o p h r e n i c p a t i e n t s t e n t a t i v e l y suggest t h a t v e n t r i c u l a r d i l a t i o n i s most l i k e l y t o be found i n s e v e r e l y impaired p a t i e n t s . T h i s n o t i o n i s supported by f i n d i n g s that have i n d i c a t e d an a s s o c i a t i o n between LVE and poor response t o n e u r o l e p t i c medication, percent of i l l n e s s spent i n h o s p i t a l , n e g a t i v e symptoms, and d i s r u p t e d smooth p u r s u i t eye movements. S e v e r a l recent CT s t u d i e s have focused on non s c h i z o p h r e n i c p s y c h i a t r i c p a t i e n t s i n order to determine whether LVE i s s p e c i f i c t o s c h i z o p h r e n i a or whether i t cu t s a c r o s s t r a d i t i o n a l d i a g n o s t i c d i v i s i o n s . T h i s r e s e a r c h suggests that a p r o p o r t i o n of manic and depressed p a t i e n t s have enla r g e d l a t e r a l v e n t r i c l e s . In most s t u d i e s , t h i s 96 enlargement i s a s s o c i a t e d with the presence of p s y c h o t i c symptoms. The f i n d i n g s from these s t u d i e s a r e , however, r e l a t i v e l y l i m i t e d and more r e s e a r c h i s needed to determine whether l a t e r a l v e n t r i c u l a r enlargement i s present at the onset of p s y c h o s i s and what c l i n i c a l f a c t o r s LVE i s r e l a t e d t o i n these p a t i e n t s . In an attempt to determine whether b r a i n changes extend beyond the l a t e r a l v e n t r i c l e s , a number of r e s e a r c h e r s have i n v e s t i g a t e d changes s p e c i f i c t o the d i e n c e p h a l i c areas of the b r a i n . T h i s has been done by measuring the s i z e of the t h i r d v e n t r i c l e . Most of these s t u d i e s i n d i c a t e s i g n i f i c a n t enlargement of t h i s v e n t r i c l e . I t i s u n c l e a r from t h i s r e s e a r c h whether t h i r d and l a t e r a l v e n t r i c u l a r enlargement are r e l a t e d . In a d d i t i o n , no i n v e s t i g a t o r s have s t u d i e d whether there i s enlargement of the t h i r d v e n t r i c l e at the onset of p s y c h o s i s , whether t h i s enlargement i s s p e c i f i c t o s c h i z o p h r e n i a , or whether i t i s a s s o c i a t e d w i t h symptoms i n d i c a t i v e of poor p r o g n o s i s . F u r t h e r s t u d i e s are needed to address these q u e s t i o n s . S e v e r a l s t u d i e s of v e n t r i c u l a r enlargement have i n c l u d e d a measure of c o r t i c a l atrophy i n an attempt to assess the extent of a t r o p h i c p r o c e s s e s . The r e s u l t s of t h i s r e s e a r c h t e n t a t i v e l y suggest t h a t a p r o p o r t i o n of s c h i z o p h r e n i c p a t i e n t s has en l a r g e d c o r t i c a l s u l c i . I t i s u n c l e a r from the r e s e a r c h whether c o r t i c a l atrophy i s r e l a t e d t o enlargement of the t h i r d and l a t e r a l v e n t r i c l e s , whether i t i s a s s o c i a t e d with c l i n i c a l c h a r a c t e r i s t i c s s u g g e s t i v e of poor p r o g n o s i s , 97 or whether i t i s s p e c i f i c t o s c h i z o p h r e n i a . The CT r e s e a r c h leaves a number of important q u e s t i o n s unanswered. I t i s not c l e a r what p r o p o r t i o n of a r e p r e s e n t a t i v e sample of f i r s t - e p i s o d e s c h i z o p h r e n i c p a t i e n t s has enlargement of the l a t e r a l v e n t r i c l e s and c o r t i c a l s u l c i , and whether enlargement of the t h i r d v e n t r i c l e i s present at the onset of p s y c h o s i s . I n v e s t i g a t i o n s are a l s o needed to determine whether l a t e r a l and t h i r d v e n t r i c u l a r enlargement and s u l c a l atrophy are present at the onset of p s y c h o s i s i n n o n s c h i z o p h r e n i c p s y c h o t i c p a t i e n t s as they are with s c h i z o p h r e n i c p a t i e n t s . F i n a l l y , the r e l a t i o n s h i p between morp h o l o g i c a l b r a i n changes and c l i n i c a l c h a r a c t e r i s t i c s s u g g e s t i v e of poor p r o g n o s i s needs to be i n v e s t i g a t e d i n f i r s t - e p i s o d e p a t i e n t s to determine i f a syndrome can be d e f i n e d . Summary of M e t h o d o l o g i c a l Issues Three p o t e n t i a l sources of e r r o r t h a t were d i s c u s s e d i n the p r e c e d i n g l i t e r a t u r e are b i a s e d p a t i e n t samples, b i a s e d c o n t r o l samples, and p r o c e d u r a l v a r i a b i l i t y . Many of the e a r l y CT s t u d i e s of s c h i z o p h r e n i a appear to i n c l u d e s e v e r e l y i l l , o f t e n c h r o n i c a l l y h o s p i t a l i z e d p a t i e n t s . However, because t h e r e i s no commonly agreed upon index of s e v e r i t y , i t i s f r e q u e n t l y d i f f i c u l t t o assess how impaired p a t i e n t samples a r e . The f a c t t h a t poor response t o n e u r o l e p t i c medications and the number of n e g a t i v e symptoms appear to be r e l a t e d to l a t e r a l v e n t r i c l e s i z e supports the c o n t e n t i o n t h a t s e v e r e l y impaired p a t i e n t s have LVE. N e v e r t h e l e s s , the 98 absence of a common d e f i n i t i o n of s e v e r i t y has r e s u l t e d i n a m b i g u i t i e s i n the r e s e a r c h l i t e r a t u r e . Future s t u d i e s must r e p o r t more d e t a i l e d i n f o r m a t i o n r e g a r d i n g the c h a r a c t e r i s t i c s of the s u b j e c t s and s e l e c t i o n procedures i n order that s e v e r i t y of impairment of s u b j e c t s can be compared between s t u d i e s . The c o n t r o l group t h a t i s used i n most s t u d i e s i s comprised of medical p a t i e n t s who r e c e i v e d a CT scan f o r medical reasons. However, a number of medical problems are known t o decrease or t o i n c r e a s e v e n t r i c l e s i z e . In a d d i t i o n , the s e l e c t i o n of "normal" scans from medical r e c o r d s c o u l d l e a d to the e x c l u s i o n of p a t i e n t s with normal but l a r g e v e n t r i c l e s and the i n c l u s i o n of s u b j e c t s who because of neuropathology have abnormally small v e n t r i c l e s . The r e s u l t s from the s t u d i e s of the prevalence of LVE i n s c h i z o p h r e n i a suggest t h a t some f a c t o r a s s o c i a t e d with the c o n t r o l sample d i f f e r e n t i a l l y a f f e c t s the o b t a i n e d f i n d i n g s ; i . e . , s t u d i e s t h a t r e p o r t LVE i n s c h i z o p h r e n i a tend to use c o n t r o l s u b j e c t s with s m a l l l a t e r a l v e n t r i c l e s and s t u d i e s t h a t i n d i c a t e no v e n t r i c u l a r enlargement i n s c h i z o p h r e n i c s r e p o r t l a r g e v e n t r i c l e s i n c o n t r o l s u b j e c t s . I t i s c l e a r from the data a v a i l a b l e that many of the i n c o n s i s t e n c i e s i n the CT l i t e r a t u r e are due t o the s i z e of the v e n t r i c l e s i n the c o n t r o l sample. I t i s u n c l e a r from p r e v i o u s r e p o r t s whether the d i f f e r e n c e s i n VBR v a l u e s a c r o s s c o n t r o l groups are due t o p o p u l a t i o n d i f f e r e n c e s , s e l e c t i o n c r i t e r i a , measurement b i a s e s , or CT scanning procedures. Future 99 r e s e a r c h e r s must be cognizant of the problems a s s o c i a t e d with c o n t r o l groups. The method that i s used to a s s e s s s m o r p h o l o g i c a l b r a i n changes can a l s o r e s u l t i n v a r i a b i l i t y i n f i n d i n g s and makes i t d i f f i c u l t t o make comparisons a c r o s s s t u d i e s . Most s t u d i e s of l a t e r a l v e n t r i c u l a r s i z e i n v o l v e the v e n t r i c l e t o b r a i n r a t i o (VBR); i . e . , the percent of b r a i n space that i s taken up by the v e n t r i c l e s on the CT s l i c e t h a t shows the v e n t r i c l e s at t h e i r l a r g e s t . T h i s measure i s taken manually from a CT f i l m or s e m i - a u t o m a t i c a l l y from an image on a cathode ray tube. T h i s estimate i s h i g h l y r e l i a b l e and c o r r e l a t e s extremely w e l l with more complex measures of v e n t r i c u l a r volume. Even with the VBR, there are l a r g e d i f f e r e n c e s between s t u d i e s i n the c u t - o f f v alue t h a t i s used to d e f i n e LVE. Some of t h i s v a r i a b i l i t y r e s u l t s from the d e f i n i t i o n of the v e n t r i c l e w a l l t h a t i s used. At the present time there i s no commonly agreed upon d e f i n i t i o n and thus i t i s d i f f i c u l t to use the VBR v a l u e s from one study as a comparison f o r another study. S e v e r a l i n v e s t i g a t o r s have used v a r i o u s l i n e a r measures of the b r a i n . The use of these d i s p a r a t e measures does not a l l o w the comparison of r e s u l t s between s t u d i e s . A l l s t u d i e s of the t h i r d v e n t r i c l e have used a measure of the width of t h i s v e n t r i c u l a r body. However, because the t h i r d v e n t r i c l e i s normally s m a l l and the image on CT f i l m i s u s u a l l y reduced by a f a c t o r of approximately t h r e e , t h i s measure i s d i f f i c u l t to take without some m a g n i f i c a t i o n . In 100 h a l f of the i n v e s t i g a t i o n s of the t h i r d v e n t r i c l e , no method of measurement i s d e s c r i b e d . T h i s makes i t d i f f i c u l t t o assess the degree t o which v a r i a b i l i t y i n f i n d i n g s r e s u l t s from the method of measurement. In a d d i t i o n , i n v e s t i g a t o r s have f a i l e d to i n d i c a t e whether measurements are l i f e s i z e or are r e p o r t e d d i r e c t l y from the CT f i l m . Future s t u d i e s should d e s c r i b e the procedure used to measure the t h i r d v e n t r i c l e . There i s no consensus i n the l i t e r a t u r e r e g a r d i n g the method of a s s e s s i n g c o r t i c a l atrophy. The l e v e l of the uppermost CT cut that i s chosen f o r measurement can i n f l u e n c e c o n s i d e r a b l y the l i k e l i h o o d of f i n d i n g s i g n s of c o r t i c a l atrophy. N e v e r t h e l e s s , i n a l l s t u d i e s , the a c t u a l l e v e l s of the b r a i n t h a t are used to make these assessments are not r e p o r t e d , and some a l s o f a i l t o d e s c r i b e the procedures t h a t were employed. The v a r i a b i l i t y i n methodology and l a c k of p r o c e d u r a l i n f o r m a t i o n present major d i f i c u l t i e s t o the i n t e r p r e t a t i o n and comparison of r e s u l t s . Researchers need to i n c l u d e i n f o r m a t i o n r e g a r d i n g the l e v e l of CT cut and the procedure used when a s s e s s i n g c o r t i c a l atrophy. In a d d i t i o n , an endeavour should be made to take r a t i n g s from CT scans other than those that show the upper l i m i t s of the c o r t e x . Research O b j e c t i v e s The primary purposes of the present study are t o determine whether 1. enlargement of the l a t e r a l v e n t r i c l e s , 2. enlargement of the t h i r d v e n t r i c l e , and 3. enlargement of 101 the c o r t i c a l s u l c i are present at the onset of p s y c h o s i s i n p s y c h i a t r i c p a t i e n t s and, i f they are, to determine the p r e v a l e n c e of these anomalies. I f these m o r p h o l o g i c a l anomalies are present at the onset of p s y c h o s i s they may r e f l e c t p r e d i s p o s i n g f a c t o r s or markers of s u s c e p t i b i l i t y to p s y c h o s i s . No enlargement, on the other hand, would suggest t h a t the f i n d i n g s r e p o r t e d i n the r e s e a r c h l i t e r a t u r e are sequelae or i a t r o g e n i c phenomena. S p e c i f i c a l l y , the primary purposes of t h i s study are t o determine whether p a t i e n t s with s c h i z o p h r e n i a , s c h i z o p h r e n i f o r m d i s o r d e r , b i p o l a r d i s o r d e r or major d e p r e s s i o n have l a r g e r l a t e r a l v e n t r i c l e s , t h i r d v e n t r i c l e , and c o r t i c a l s u l c i than do normal c o n t r o l s u b j e c t s . A f o u r t h purpose of t h i s study i s to i n v e s t i g a t e the r e l a t i o n s h i p between s p e c i f i c m o r p h o l o g i c a l b r a i n anomalies and other p u t a t i v e l y r e l a t e d v a r i a b l e s at the onset of p s y c h o s i s i n s c h i z o p h r e n i c and a f f e c t i v e d i s o r d e r p a t i e n t s . A s i g n i f i c a n t p o s i t i v e r e l a t i o n s h i p between b r a i n measures and c l i n i c a l v a r i a b l e s would suggest t h a t a n e u r o p a t h o l o g i c a l process with c l i n i c a l m a n i f e s t a t i o n s i s present at the onset of p s y c h o s i s i n some p a t i e n t s . T h i s f i n d i n g c o u l d l e a d t o the s p e c i f i c a t i o n of a d i s t i n c t syndrome with i m p l i c a t i o n s f o r e t i o l o g i c a l p r o cesses, treatment d e c i s i o n s , and p r o g n o s i s . S p e c i f i c a l l y , the f o u r t h purpose of t h i s study i s t o determine whether l a t e r a l v e n t r i c u l a r enlargement, enlargement of the t h i r d v e n t r i c l e , and c o r t i c a l atrophy are a s s o c i a t e d with poor premorbid adjustment, n e g a t i v e symptoms, 102 and d i s r u p t e d smooth p u r s u i t eye movements i n f i r s t - e p i s o d e s c h i z o p h r e n i c and f i r s t - e p i s o d e p s y c h o t i c a f f e c t i v e d i s o r d e r p a t i e n t s . A f i f t h purpose of t h i s study i s to determine whether the type of c o n t r o l group that i s used i n f l u e n c e s the CT r e s u l t s t h at are o b t a i n e d . S p e c i f i c a l l y , a medical c o n t r o l group, s e l e c t e d from r a d i o l o g y r e c o r d s , w i l l be i n c l u d e d together with a normal c o n t r o l group. T h i s a d d i t i o n w i l l a l l o w the assessment of p o t e n t i a l s e l e c t i o n b i a s e s a s s o c i a t e d w i t h u s i n g medical p a t i e n t s as c o n t r o l s u b j e c t s . Method S u b j e c t s The p a r t i c i p a n t s i n t h i s study i n c l u d e d 91 p s y c h i a t r i c p a t i e n t s r e c r u i t e d as p a r t of an e x t e n s i v e study to determine the i n c i d e n c e of f i r s t episode p s y c h o s i s i n the Vancouver ar e a . T h i s study i n c l u d e d measures of p s y c h o s o c i a l and b i o l o g i c a l c h a r a c t e r i s t i c s of psychopathology. P a t i e n t s ranged from 15 to 47 years and both sexes were r e p r e s e n t e d . An o b j e c t i v e of the i n i t i a l study was t o determine the i n c i d e n c e of f i r s t break p s y c h o s i s i n the Vancouver m e t r o p o l i t a n a r e a . P a t i e n t s were r e f e r r e d from a l l p s y c h i a t r i c h o s p i t a l s and community mental h e a l t h c e n t r e s i n the Vancouver area as w e l l as from p r i v a t e p r a c t i c e p s y c h i a t r i s t s who agreed to a s s i s t the p r o j e c t . In a d d i t i o n , a random sample of one of every s i x g e n e r a l p r a c t i t i o n e r s i n the area was s o l i c i t e d t o r e f e r p a t i e n t s . A l l p a t i e n t s were r e c r u i t e d w i t h i n t h r e e months of being t r e a t e d f o r t h e i r 103 f i r s t p s y c h o t i c episode. Subj e c t s with s i g n s of n e u r o l o g i c a l problems or a l c o h o l / d r u g dependence were excluded (see Appendix E ) . Of the 302 p a t i e n t s i n i t i a l l y i d e n t i f i e d 126 re f u s e d to p a r t i c i p a t e i n the e p i d e m i o l o g i c a l study. Of the remaining 176, 63 r e f u s e d to p a r t i c i p a t e i n the CT e v a l u a t i o n , 16 moved out of the area before they c o u l d be asked t o p a r t i c i p a t e , f o u r d i e d b e f o r e they c o u l d be r e c r u i t e d , and two co u l d not be r e l e a s e d from h o s p i t a l f o r the CT scan. Three p a t i e n t s who p a r t i c i p a t e d i n the CT scanning procedure r e f u s e d the p s y c h o p h y s i o l o g i c a l t e s t i n g . F i n a l l y , t h e r e was i n s u f f i c i e n t i n f o r m a t i o n t o make r a t i n g s of negative symptoms on two p a t i e n t s and of premorbid adjustment on ten p a t i e n t s . Of the 91 p a t i e n t s who r e c e i v e d a CT scan, t h e r e were 67 males and 24 females. The average age was 23.5 years (range 15 to 47). Table 3 g i v e s the sex d i s t r i b u t i o n and mean age f o r p a t i e n t s i n each d i a g n o s t i c group. At the time s u b j e c t s were r e c r u i t e d , 81 were r e c e i v i n g i n p a t i e n t treatment and ten were i n o u t p a t i e n t c a r e . A l l p a t i e n t s r e p o r t e d p s y c h o t i c symptoms ( d e l u s i o n s and/or h a l l u c i n a t i o n s ) . D i a g n o s t i c d e c i s i o n s were based on DSM-III c r i t e r i a . Other d i a g n o s t i c systems, i n c l u d i n g Research D i a g n o s t i c C r i t e r i a (RDC, S p i t z e r et a l . , 1978) were a l s o used to c l a s s i f y p a t i e n t s . Information that was used t o make d i a g n o s t i c d e c i s i o n s was obt a i n e d from a s t r u c t u r e d i n t e r v i e w with the p a t i e n t (Present S t a t e Exam; Wing, Cooper and S a r t o r i u s , 1974), from a review of the h o s p i t a l c h a r t , and, where p o s s i b l e , from an 104 Table 3 Demographic c h a r a c t e r i s t i c s of P a r t i c i p a n t s Number of Su b j e c t s Age Groups Male Female T o t a l M SD Range DSM-III S c h i z o p h r e n i a 26 5 31 22 .8 5.7 15-37 Sc h i z o p h r e n i f o r m 17 3 20 20 .6 4.4 16-33 B i p o l a r 9 9 18 26 .6 7.6 18-43 Major Depression 11 5 16 22 .6 4.0 17-30 Paranoid D i s o r d e r 1 2 3 34 .0 8.3 23-47 S c h i z o a f f e c t i v e 3 0 3 29 .2 6.5 21-40 T o t a l P a t i e n t s \ 67 24 91 23 .5 6.5 16-47 V o l u n t e e r C o n t r o l 29 15 44 23 .2 5.6 15-42 Med i c a l C o n t r o l 13 17 30 22 .9 4.4 15-32 105 i n t e r v i e w with f a m i l y members and f r i e n d s . A case conference i n c l u d i n g at l e a s t two d i a g n o s t i c i a n s ( p s y c h i a t r i s t s and c l i n i c a l p s y c h o l o g i s t s ) was h e l d f o r each p a t i e n t . A consensus was reached f o r each symptom and symptom c h e c k l i s t s were used to complete diagnoses (Appendix C ) . A l l p a t i e n t s were r e c e i v i n g p s y c h o t r o p i c medication at the time they were r e c r u i t e d . P a r t i c i p a n t s gave informed consent f o r each p a r t of t h i s study ( p s y c h o p h y s i o l o g i c a l t e s t i n g and CT scan, see Appendix D) and were p a i d $20 f o r t h e i r p a r t i c i p a t i o n i n the CT scanning, and $10 f o r the p s y c h o p h y s i o l o g i c a l t e s t i n g . A normal c o n t r o l group of 44 v o l u n t e e r s was r e c r u i t e d from f a m i l y p r a c t i c e c l i n i c s , employment c e n t r e s , community c e n t r e s , and community c o l l e g e s i n the Vancouver a r e a . There were 29 males and 15 females between the ages of 15 and 42. A l l v o l u n t e e r s were given a s c r e e n i n g i n t e r v i e w (Appendix E) and r e p o r t e d that n e i t h e r themselves nor t h e i r f i r s t degree r e l a t i v e s had ever r e c e i v e d p s y c h i a t r i c treatment or had an a l c o h o l or drug abuse problem. In a d d i t i o n , a l l v o l u n t e e r s r e p o r t e d that they had no c h r o n i c i l l n e s s e s . More male than female p a t i e n t s were r e c r u i t e d and the r a t i o of males to females was d i f f e r e n t f o r each d i a g n o s t i c group (Table 3 ) . The sex r a t i o i n the v o l u n t e e r c o n t r o l s u b j e c t s approximated t h a t of the t o t a l p a t i e n t sample. C o n t r o l s u b j e c t s w i t h i n the age range of the t o t a l p a t i e n t sample were i n c l u d e d at approximately the same age d i s t r i b u t i o n as the p a t i e n t s ; i . e . , the age d i s t r i b u t i o n was p o s i t i v e l y skewed. A second c o n t r o l group was comprised of 30 i n d i v i d u a l s 106 who r e c e i v e d a CT scan as p a r t of a medical examination. There were 13 males and 17 females between the ages of 15 and 33. Reasons f o r r e f e r r a l t o the CT scanner were t o i n v e s t i g a t e headaches (n = 12), r u l e out space-occupying l e s i o n s (n = 9 ) , r u l e out m u l t i p l e s c l e r o s i s (n=4), i n v e s t i g a t e suspected s e i z u r e d i s o r d e r (n = 3 ) , i n v e s t i g a t e i n t r a c e r e b r a l c a l c i f i c a t i o n (n = 1), and assess p o s t - i n j u r y head trauma (n = 1 ) . A l l scans were r e p o r t e d t o be w i t h i n normal l i m i t s . The scanning procedure f o r these p a t i e n t s was the same as f o r the p s y c h i a t r i c p a t i e n t s and v o l u n t e e r c o n t r o l s u b j e c t s . A l l a g e - a p p r o p r i a t e medical p a t i e n t s who r e c e i v e d a CT scan i n a three month p e r i o d d u r i n g which the p s y c h i a t r i c p a t i e n t s and v o l u n t e e r c o n t r o l s u b j e c t s were scanned and who had no s i g n i f i c a n t r a d i o l o g i c a l f i n d i n g s served as s u b j e c t s i n t h i s c o n t r o l group. The age d i s t r i b u t i o n o f t h i s group approximated t h a t of the t o t a l p a t i e n t sample. Apparatus and Interviews Computerized Tomography. A l l scans were performed u s i n g a t h i r d g e n e r a t i o n , high r e s o l u t i o n , t o t a l body scanner (Siemens Somatom DR2). The window width was s e t at 80 and the l e v e l at 27 f o r a l l s u b j e c t s d u r i n g CT scanning. From 13 to 16 s e r i a l c r o s s - s e c t i o n s of the b r a i n , 8mm i n t h i c k n e s s , were scanned p a r a l l e l t o the cantho-meatal l i n e . Scans were made from the base of the s k u l l to the top of the c r a n i a l v a u l t . Scans f o r the p s y c h i a t r i c p a t i e n t s and v o l u n t e e r c o n t r o l s u b j e c t s were done without enhancement; i . e . , without 107 having a c o n t r a s t medium i n j e c t e d i n t o the p a t i e n t t o make s o f t t i s s u e such as tumors more v i s i b l e on an X-ray scan. Eleve n of the medical p a t i e n t s r e c e i v e d scans without enhancement and 19 r e c e i v e d o n l y enhanced scans. Data from a l l scans, represented i n the form of a 256x256 matrix of t i s s u e d e n s i t y v a l u e s , were s t o r e d on magnetic d i s c c a r t r i d g e s and a l s o reproduced on t r a n s p a r e n t X-ray f i l m . Four or s i x CT scans, each measuring 2 approximately 11.5cm x 8.5cm (98cm ), were p r i n t e d on a s i n g l e sheet of X-ray f i l m . The CT scan t h a t showed the l a t e r a l v e n t r i c l e s a t t h e i r l a r g e s t was s e l e c t e d f o r each 2 s u b j e c t and e n l a r g e d t o a 23.5cm x 17.5cm format (411cm ); i . e . , approximately f o u r times the o r i g i n a l scan s i z e . A Sokkish 19908 compensating p o l a r p l a n i m e t e r was used to measure the a r e a of the l a t e r a l v e n t r i c l e s and the area of the b r a i n from the e n l a r g e d scan. These measurements were taken w h i l e the CT scan was a f f i x e d t o a h o r i z o n t a l , white t r a n s l u c e n t p l a s t i c t a b l e t h a t was i l l u m i n a t e d from below. The width of the t h i r d v e n t r i c l e at i t s widest was measured from a 11.5cm X 8.5cm CT scan u s i n g a P r e c i s i o n Tool and Instrument Co t r a v e l l i n g microscope, type 2160. T h i s instrument i s comprised of a microscope f i x e d to a moveable t a b l e . The microscope may be moved to the l e f t or r i g h t and forwards or backwards u s i n g adjustment screws. The magnitude of each of these movements i s given on a v e r n i e r s c a l e and i s a c c u r a t e t o 0.001mm. The microscope has c r o s s h a i r s on the l e n s and a l l o w s a c c u r a t e p o s i t i o n i n g of the instrument along 108 the edges of the t h i r d v e n t r i c l e . The frame that holds the moving t a b l e i s mounted on a white t r a n s l u c e n t p l a s t i c t a b l e t hat was i l l u m i n a t e d from below. The CT scan t h a t showed the t h i r d v e n t r i c l e at i t s l a r g e s t was f i x e d to the i l l u m i n a t e d t a b l e w h i l e the microscope was p o s i t i o n e d and measurements were taken. Measurements were converted to l i f e s i z e by m u l t i p l y i n g the obt a i n e d measure by a co n s t a n t . T h i s procedure r e s u l t e d i n the a c t u a l width o f the t h i r d v e n t r i c l e i n mm. A r a t i n g of c o r t i c a l atrophy was made u s i n g a th r e e p o i n t s c a l e . One i n d i c a t e d no v i s i b l e s u l c i , two i n d i c a t e d some s u l c i were v i s i b l e but th a t they were not e x t e n s i v e , and three was res e r v e d f o r scans where s u l c i were both v i s i b l e and e x t e n s i v e . T h i s r a t i n g was made u s i n g the CT scan t h r e e s l i c e s above the scan t h a t showed the l a t e r a l v e n t r i c l e s at t h e i r l a r g e s t . One 11.5cm x 8.5cm scan from each p a r t i c i p a n t was matched t o a sample of nine scans ( t h r e e f o r each r a t i n g ) that showed the v a r i a b i l i t y allowed by each r a t i n g score (1, 2, or 3 ) . Int e r v i e w s . A s c r e e n i n g schedule was completed f o r each p a t i e n t based on i n f o r m a t i o n o b t a i n e d from the r e f e r r i n g agency (see Appendix E ) . T h i s schedule was used to determine an i n d i v i d u a l ' s s u i t a b i l i t y f o r i n c l u s i o n i n t h i s study. For p a t i e n t s who s a t i s f i e d the s c r e e n i n g c r i t e r i a and gave informed consent, the Present S t a t e Examination (PSE, Wing et a l . , 1974) was ad m i n i s t e r e d by a p s y c h i a t r i s t or c l i n i c a l p s y c h o l o g i s t t r a i n e d i n the a d m i n i s t r a t i o n of t h i s 109 instrument. The r e s u l t s of t h i s i n t e r v i e w were used as a b a s i s f o r making d i a g n o s t i c d e c i s i o n s . Premorbid adjustment was assessed u s i n g the s h o r t form of the P h i l l i p s Premorbid H i s t o r y s c a l e (PMH, H a r r i s , 1975, see Appendix B). T h i s measure i s comprised of two separate seven-point s c a l e s (premorbid s o c i a l adjustment and premorbid h e t e r o s e x u a l adjustment). Each of these s c a l e s i s normally scored from zero to s i x . Zero i n d i c a t e s very poor f u n c t i o n i n g and s i x i n d i c a t e s good f u n c t i o n i n g . In order t o i n c o r p o r a t e more i n f o r m a t i o n , these s c a l e s were adapted to form a continuous r a t i n g s c a l e scored from one to 70; i . e . , each of the o r i g i n a l seven p o s s i b l e r a t i n g p o i n t s was expanded to i n c l u d e v a l u e s of z e r o t o n i n e . T h i s was done t o a l l o w f i n e r d i s t i n c t i o n s t o be made between the o r i g i n a l r a t i n g s . The o r i g i n a l s c a l e d e s c r i p t i o n s were maintained as anchor p o i n t s . The r a t i n g of h e t e r o s e x u a l adjustment on the P h i l l i p s s c a l e i s designed to be used on l y w i t h i n d i v i d u a l s aged 20 and o l d e r . In o r d e r to r a t e p a t i e n t s under 20 y ears of age, r a t i n g s from an adapted form of the h e t e r o s e x u a l p a r t of the G i t t l e m a n - K l e i n s c a l e were s u b s t i t u t e d f o r the P h i l l i p s h e t e r o s e x u a l adjustment s c a l e r a t i n g s ( G i t t l e m a n - K l e i n 8s K l e i n , 1969; Appendix B). T h i s s c a l e i s designed to be used with i n d i v i d u a l s 16 to 20 y ears of age and i s comparable t o the P h i l l i p s s c a l e i n format and c o n t e n t . Negative symptoms were e v a l u a t e d a c c o r d i n g to the c r i t e r i a used by Andreasen (1982). These symptoms are f l a t t e n e d or b l u n t e d a f f e c t , impoverished t h i n k i n g , a v o l i t i o n 110 or apathy, a s o c i a l i t y , and impaired a t t e n t i o n . R a t i n g s made d u r i n g the PSE i n t e r v i e w were used to assess these negative symptoms i n the present study. A g l o b a l r a t i n g of negative symptoms was made by summing PSE items 36, 54, 58, 107, 108, 110, 119, 128, 129, 130, 133, 134, and 138 (Appendix G). Eye Movement Apparatus. Eye movements were monitored while each s u b j e c t observed a t a r g e t c o n s i s t i n g of a 5mm c i r c l e o f l i g h t with a dot i n i t s c e n t e r . The t a r g e t moved with a s i n u s o i d a l motion, h o r i z o n t a l l y a c r o s s the screen of a T e k t r o n i x type RM 15 single-beam o s c i l l o s c o p e . The s u b j e c t ' s eyes were approximately 30cm from the c e n t r e of the s c r e e n . A Wavetek D i g i t a l VCG model 113 s i n e wave generator was used to d r i v e the t a r g e t . S i l v e r / s i l v e r c h l o r i d e e l e c t r o d e s (1cm i n diameter) were a t t a c h e d t o the abraded o u t e r c a n t h i f o r h o r i z o n t a l EOG r e c o r d i n g . E l e c t r o d e s p l a c e d above and below the r i g h t eye were used t o monitor b l i n k s . A ground e l e c t r o d e was a t t a c h e d t o the l e f t ear lobe. S i g n a l s from both the EOG and t a r g e t were recorded s i m u l t a n e o u s l y on a Beckman R612 Dynograph and on a magnetic tape u s i n g a V e t t e r FM Model A tape r e c o r d e r . M o d i f i e d type 9806A AC c o u p l e r s , s e t t o a time constant of t h r e e seconds, were used f o r the EOG and t a r g e t i n p u t on the dynograph. AC c o u p l i n g was used t o reduce the c o n t r i b u t i o n o f b a s e l i n e s h i f t t o the r e c o r d s . A time constant of .1 seconds was used t o monitor b l i n k s . Procedure For those p a r t i c i p a n t s who gave consent, the Present S t a t e Examination (PSE) was conducted by a p s y c h i a t r i s t or I l l c l i n i c a l p s y c h o l o g i s t t r a i n e d i n the use of t h i s instrument. T h i s i n t e r v i e w was done at the time each s u b j e c t was r e c r u i t e d . The PSE was used to assess the symptom p i c t u r e f o r the month d u r i n g which the p a t i e n t was most symptomatic. The CT scanning procedure was conducted as soon as p o s s i b l e a f t e r r e c r u i t m e n t . A uniform scanning procedure was used. Scans were completed a t the r a d i o l o g y department i n the U n i v e r s i t y of B r i t i s h Columbia H e a l t h S c i e n c e s H o s p i t a l . Each s u b j e c t was asked to l i e on a movable t a b l e a t t a c h e d to the CT scanner. A moulded head-rest was used to s t a b i l i z e the p a r t i c i p a n t ' s head u n t i l 13 t o 16 c o n s e c u t i v e CT scans had been made. T h i s procedure took approximately 15 minutes. A measure o f eye movement i n t e g r i t y was o b t a i n e d as c l o s e as p o s s i b l e t o the time of the PSE i n t e r v i e w . P a r t i c i p a n t s were shown the apparatus and g i v e n an e x p l a n a t i o n o f the procedures b e f o r e the experiment began. EOG e l e c t r o d e s were a t t a c h e d and the s u b j e c t ' s head s t a b i l i z e d i n a c h i n and forehead r e s t . Tape recorded i n s t r u c t i o n s were used to request t h a t d u r i n g the eye t r a c k i n g t a s k s , the s u b j e c t r e f r a i n from b l i n k i n g , h o l d h i s or her head s t i l l , and f o l l o w the t a r g e t c l o s e l y . An o s c i l l a t i n g s i n u s o i d a l t a r g e t was presented at .4, .8, and 1.2Hz f o r 20 c y c l e s at each frequency. Each task was separated by a 20 second r e s t p e r i o d . A number of other measures were ob t a i n e d a f t e r the e y e t r a c k i n g t a s k s were completed. The d u r a t i o n of the t o t a l p s y c h o p h y s i o l o g i c a l s e s s i o n was from two to t h r e e hours. 112 Data Q u a n t i f i c a t i o n CT Scan Data. A l l measures were taken from the CT scans without knowledge of the s u b j e c t s i d e n t i t y or d i a g n o s i s . Using the p l a n i m e t e r , the area of each of the l a t e r a l v e n t r i c l e s was t r a c e d three times and the area of the b r a i n s i x times. The mean of the t h r e e measures was c a l c u l a t e d f o r each v e n t r i c l e . These mean value s were added together and d i v i d e d by the mean of the s i x measures of the b r a i n . T h i s r a t i o was m u l t i p l i e d by 100 to g i v e the v e n t r i c l e t o b r a i n r a t i o (VBR) as i t Is r e p o r t e d i n most p r e v i o u s s t u d i e s . T h i s procedure i s the same as t h a t used by Weinberger et a l . (1979a, 1982). The width of the t h i r d v e n t r i c l e was measured at the widest p o i n t that a continuous v e n t r i c l e w a l l c o u l d be seen. The degree of c o r t i c a l atrophy was assessed u s i n g the t h r e e - p o i n t r a t i n g s c a l e d e s c r i b e d p r e v i o u s l y . One i n d i c a t e d t h at no s u l c i were v i s i b l e , two i n d i c a t e d t h at s u l c i were v i s i b l e but not e x t e n s i v e , and three denoted s u l c i t h a t were c l e a r l y v i s i b l e and e x t e n s i v e . Interview Data. The n e g a t i v e symptom r a t i n g was made by t a b u l a t i n g items from the PSE t h a t i n d i c a t e d the presence of n e g a t i v e symptoms. The r e s u l t i n g score ranged from zero to 13. Zero i n d i c a t e s t h a t no n e g a t i v e symptoms were judged to be present while 13 i n d i c a t e s severe i n c a p a c i t a t i o n with negative symptoms. The A b b r e v i a t e d P h i l l i p s S c a l e r a t i n g s range from one (very poor premorbid adjustment) to 70 (very good premorbid adjustment) f o r each of the s u b s c a l e s ( s o c i a l and h e t e r o s e x u a l adjustment). A r a t i n g of premorbid 113 adjustment was made by adding the s u b s c a l e s c o r e s . The t o t a l s core ranges from two to 140. Two independent r a t e r s d e r i v e d t h i s s c o r e from i n f o r m a t i o n c o l l e c t e d d u r i n g a s t a n d a r d i z e d i n t e r v i e w (see Appendix B). The average of these two r a t i n g s was used i n the a n a l y s e s of r e s u l t s . Eye Movement Data. Taped EOG and t a r g e t channels from the smooth p u r s u i t e y e - t r a c k i n g t a s k s were f e d i n t o a D i g i t a l Equipment C o r p o r a t i o n LSI 11/23 d i g i t a l computer. The computer was programmed to a l i g n the channels f o r phase d i f f e r e n c e s and to set channels equal with r e s p e c t to amplitude d i f f e r e n c e s . The computer was a l s o programmed to compute root-mean-square (RMS) e r r o r d e v i a t i o n of the EOG data channel from the t a r g e t channel. T h i s procedure i n v o l v e s the c a l c u l a t i o n of d i f f e r e n c e s , i n standard d e v i a t i o n u n i t s , between the t a r g e t s i g n a l and the s u b j e c t ' s eye movements. C o n c e p t u a l l y , t h i s measure r e p r e s e n t s the degree of f i t between the t a r g e t s i g n a l and t r a c k i n g performance. The mean of the t h r e e o b t a i n e d RMS v a l u e s (one f o r each of the .4, .8, and 1.2Hz t r a c k i n g tasks) was o b t a i n e d f o r each s u b j e c t . T h i s procedure p r o v i d e s a h i g h l y r e l i a b l e e s t imate of t r a c k i n g i n t e g r i t y (Iacono & Lykken, 1981). Because the d i s t r i b u t i o n of these data was p o s i t i v e l y skewed, the l o g of t h i s v alue was used i n the a n a l y s i s of the d a t a . R e s u l t s The r e s u l t s of t h i s r e s e a r c h are d i v i d e d i n t o three s e c t i o n s . The f i r s t , e n t i t l e d " R e l i a b i l i t y of Measures and 114 R a t i n g s " , p r e s e n t s the i n t e r j u d g e r e l i a b i l i t y f o r the measures used i n t h i s study. The second s e c t i o n , e n t i t l e d "Subject C h a r a c t e r i s t i c s " , i s d i v i d e d i n t o f o u r s u b s e c t i o n s : "Sex of S u b j e c t s " , "Age of S u b j e c t s " , " P a r t i c i p a n t s and N o n p a r t i c i p a n t s " and "Medical C o n t r o l Group". The i s s u e s of age and sex d i f f e r e n c e s a c r o s s p a t i e n t and c o n t r o l groups i s addressed. In a d d i t i o n , t h i s s e c t i o n a l s o d e a l s with comparisons between s u b j e c t s who d i d not r e c e i v e a CT scan and those who consented t o p a r t i c i p a t e i n t h i s study. The f o u r t h s u b s e c t i o n d e a l s w i t h the d i f f e r e n c e s between those medical p a t i e n t s who had CT scans w i t h a c o n t r a s t medium and those who, l i k e a l l other s u b j e c t s i n t h i s study, r e c e i v e d a CT scan without c o n t r a s t medium. A c o n t r a s t medium i s i n j e c t e d i n t o p a t i e n t s i n order t o make s o f t t i s s u e such as tumors more v i s i b l e on an X-ray scan. The t h i r d s e c t i o n of the r e s u l t s , " A n a l y s i s of CT F i n d i n g s " , i s concerned with t e s t i n g the r e s e a r c h hypotheses. T h i s s e c t i o n i s d i v i d e d i n t o f o u r s u b s e c t i o n s : " L a t e r a l V e n t r i c l e s " , " T h i r d V e n t r i c l e " , " C o r t i c a l Atrophy" and " R e l a t i o n s h i p s Between M o r p h o l o g i c a l Measures". Between group d i f f e r e n c e s are a ssessed f o r each m o r p h o l o g i c a l measure. The groups are s c h i z o p h r e n i a , s c h i z o p h r e n i f o r m , b i p o l a r , and major d e p r e s s i o n (diagnosed a c c o r d i n g to DSM-III c r i t e r i a ) , and v o l u n t e e r and medical c o n t r o l groups. R e l i a b i l i t y of Measures and R atings Pearson c o r r e l a t i o n c o e f f i c i e n t s were computed i n the f o l l o w i n g a n a l y s e s except where i n d i c a t e d . In o r d e r to assess 115 the concurrent v a l i d i t y of VBR measures, g l o b a l r a t i n g s of v e n t r i c u l a r d i l a t i o n were compared w i t h p l a n i m e t r y measures. The scans of 20 randomly s e l e c t e d s u b j e c t s were rank ordered a c c o r d i n g t o l a t e r a l v e n t r i c u l a r s i z e by a n e u r o r a d i o l o g i s t . P l a n i m e t r y measures were completed on the same scans by a second r a t e r and the rankings and measurements were compared. The Spearman rank c o r r e l a t i o n f o r t h i s comparison was h i g h ( r = .80). Interjudge r e l i a b i l i t y was a s s e s s e d by comparing the p l a n i m e t r y measures of two independent r a t e r s f o r 25 s u b j e c t s . T h i s measure of r e l i a b i l i t y was h i g h (r = .93). The width of the t h i r d v e n t r i c l e f o r 20 s u b j e c t s was measured by two independent r a t e r s . The l e v e l o f agreement between the two r a t e r s was very h i g h ( r = .97). The r a t i n g s of c o r t i c a l atrophy f o r a l l 166 s u b j e c t s were done by two independent r a t e r s . There was f u l l agreement on 150 (90%) of the 166 r a t i n g s . D i s c r e p a n t r a t i n g s were r e s o l v e d through mutual agreement. Two independent r a t e r s reviewed the i n f o r m a t i o n r e l e v a n t t o premorbid f u n c t i o n i n g and each a s s i g n e d a s c o r e f o r each p a t i e n t . The i n t e r j u d g e r e l i a b i l i t y f o r both the premorbid s o c i a l adjustment s c a l e and the premorbid s e x u a l adjustment s c a l e were h i g h ( r = .97, and r_ = .99 r e s p e c t i v e l y ) . Group v a l u e s f o r premorbid adjustment, n e g a t i v e symptoms and SPEM are g i v e n i n Appendix J . Subject C h a r a c t e r i s t i c s A number of s t a t i s t i c a l t e s t s were computed i n o r d e r t o p r o v i d e a c l e a r d e f i n i t i o n of the s u b j e c t samples and were not used t o t e s t r e s e a r c h hypotheses. In o r d e r t o determine whether there were any s y s t e m a t i c b i a s e s due t o age, sex, or 116 a t t r i t i o n , l i b e r a l t e s t s were used and a p r o b a b i l i t y value of .05 was employed as a c u t - o f f . Age of S u b j e c t s . The mean age of the i n d i v i d u a l s who p a r t i c i p a t e d i n the present study was s i m i l a r f o r the t o t a l p s y c h i a t r i c p a t i e n t sample and both of the c o n t r o l groups (Table 3, p. 104). There was a s i g n i f i c a n t c o r r e l a t i o n between age and each CT measure f o r the s c h i z o p h r e n i f o r m p a t i e n t s . However, one i n d i v i d u a l with l a r g e v e n t r i c l e s was s u b s t a n t i a l l y o l d e r than the mean of t h i s p a t i e n t group (33 years versus M = 20.6 Y e a r s ) . With t h i s s u b j e c t o u t l i e r removed from the c a l c u l a t i o n s , no CT measure was s i g n i f i c a n t l y r e l a t e d to age f o r any p a t i e n t or c o n t r o l groups (see Appendix H). Sex of S u b j e c t s . As Table 3 shows, th e r e are more males than females i n both the t o t a l p a t i e n t sample and the v o l u n t e e r c o n t r o l group. The predominance of males i s a l s o r e f l e c t e d i n the sex r a t i o of s c h i z o p h r e n i c , s c h i z o p r e n i f o r m , and depressed p a t i e n t groups. However, both sexes are e q u a l l y r e p r e s e n t e d i n the b i p o l a r p a t i e n t s and the medical c o n t r o l group has more females than males. Because the three major r e s e a r c h hypotheses d e a l with the p s y c h i a t r i c p a t i e n t groups and the v o l u n t e e r c o n t r o l group, a c h i square a n a l y s i s was computed to determine i f t h e r e were s i g n i f i c a n t d i f f e r e n c e s i n sex r a t i o a c r o s s these samples. In order to compensate f o r the s m a l l number of females i n each p a t i e n t group, Y a t e s 1 c o r r e c t i o n was a p p l i e d to t h i s a n a l y s i s . T h i s t e s t f a i l e d t o d e t e c t a s i g n i f i c a n t d i f f e r e n c e i n the 117 2. p of males to females over these groups, x (4, N = 129) = 7.11, p > .05. The f i n a l r e s e a r c h h y p o t h e s i s d e a l s w i t h the medical c o n t r o l group and the v o l u n t e e r c o n t r o l s u b j e c t s . In order to t e s t whether t h e r e are s i g n i f i c a n t d i f f e r e n c e s i n the r a t i o o f males to females a c r o s s these groups, a c h i square a n a l y s i s was computed over sex and type of c o n t r o l 2 group. T h i s a n a l y s i s was not s i g n i f i c a n t , x (1, N = 74) = 2.79, p>.05 (Because there i s one degree of freedom i n t h i s c h i square a n a l a s i s , Yates' c o r r e c t i o n was a p p l i e d , Hays, 1973). There were too few females i n each d i a g n o s t i c group t o a l l o w an a c c u r a t e assessment of sex d i f f e r e n c e s i n v e n t r i c l e or s u l c a l s i z e f o r each d i a g n o s i s . However, an a n a l y s i s of sex d i f f e r e n c e s over the s i z e of each of the CT measures ( t h i r d and l a t e r a l v e n t r i c l e s i z e and c o r t i c a l atrophy) f a i l e d t o d e t e c t a s i g n i f i c a n t e f f e c t f o r the t o t a l p a t i e n t sample, range of t s ( 8 9 ) = 0.12 t o 0.74, a l l ps>.l, the v o l u n t e e r c o n t r o l group, range of Jbs(42) = 0.16 t o 1.84, a l l ps>.05, and the medical c o n t r o l group, range of t s ( 2 8 ) = 0.47 to 1.72, a l l ps>.l. A l l t e s t s were two t a i l e d . In summary, whereas t h e r e are d i f f e r e n c e s i n the r a t i o of males t o females over the p a t i e n t and c o n t r o l groups, no s i g n i f i c a n t sex d i f f e r e n c e s were d e t e c t e d over the s i z e of the t h r e e CT measures ( l a t e r a l v e n t r i c l e , t h i r d v e n t r i c l e , c o r t i c a l s u l c i ) . Males and females were combined f o r a l l f u r t h e r a n a l y s e s . 118 P a r t i c i p a n t s and Nonparticipants,. Of the 176 p a t i e n t s who were i n i t i a l l y r e c r u i t e d , CT scans were not obtained on 85 i n d i v i d u a l s (see Table 4 ) . More males than females were i d e n t i f i e d i n i t i a l l y and t h i s d i f f e r e n c e i s a l s o r e f l e c t e d i n the p a t i e n t s who p a r t i c i p a t e d i n the CT scanning procedure. There were however, s l i g h t l y more female n o n p a r t i c i p a n t s (26/50, 52%) than males (59/126, 47%). The mean age of the p a t i e n t s who who d i d not r e c e i v e a CT scan (M + SD ^ 28.4 + 5.8 year s ) was s i g n i f i c a n t l y g r e a t e r than t h a t of the p a r t i c i p a n t s (M + SD = 23.5 + 6.5 y e a r s ) , t(175) - 5.26, p<.001. A number of p a t i e n t s who d i d not p a r t i c i p a t e i n the CT scanning procedure were r e l a t i v e l y advanced i n age. Seven p a t i e n t s with p a r a n o i d d i s o r d e r (M = 44.4 year s ) and one of the p a t i e n t s with major d e p r e s s i o n (aged 50) were no t a b l y o l d e r than the average age of the s u b j e c t s who r e c e i v e d a CT scan. There were some d i f f e r e n c e s i n the number of n o n p a r t i c i p a n t s between d i a g n o s t i c groups (Table 4 ) . P r o p o r t i o n a t e l y fewer p a t i e n t s with a f f e c t i v e d i s o r d e r s ( b i p o l a r or major d e p r e s s i o n ) r e c e i v e d a CT scan than d i d i n d i v i d u a l s with s c h i z o p h r e n i a or s c h i z o p h r e n i f o r m d i s o r d e r s . A c h i square a n a l y s i s a c r o s s s u b j e c t s ( p a r t i c i p a n t s , n o n p a r t i c i p a n t s ) and major p a t i e n t groups ( s c h i z o p h r e n i c , schzophreniform, b i p o l a r , depressed) f a i l e d t o d e t e c t a 2 s t a t i s t i c a l l y s i g n i f i c a n t d i f f e r e n c e , x (3, N = 160) = 4.38, p>.l. Of the 85 i n d i v i d u a l s who d i d not r e c e i v e a CT scan 63 (74%) r e f u s e d , 16 (19%) moved r e s i d e n c e and/or c o u l d not be l o c a t e d , 4 (5%) d i e d b e f o r e they c o u l d be scanned, and 2 (2%) 119 Table 4 Demographic C h a r a c t e r i s t i c s of N o n p a r t i c i p a n t s Number of Su b j e c t s Not a P a r t i c i p a t i n g (N) and T o t a l (T) Age of Male Female T o t a l Not N o n p a r t i c i p a n t s DSM I I I Diagnoses N T N T N T Scanned M SD Range S c h i z o p h r e n i a 15 41 5 10 20 51 (39%) 23. 1 5. .6 17--36 Sc h i z o p h r e n i f o r m 8 25 5 8 13 33 (39%) 25. 0 3. .6 18--29 B i p o l a r 14 23 7 16 21 39 (54%) 28. 4 7. ,8 19--46 Major Depression 16 27 5 10 21 37 (57%) 28. 7 7. ,5 19--50 Paranoid D i s o r d e r 4 5 3 5 7 10 (70%) 44. 4 6. .3 37--51 S c h i z o a f f e c t i v e 2 5 1 1 3 6 (50%) 28. 0 7. .0 19--45 T o t a l P a t i e n t s 59 126 26 50 85 176 (48%) 28. 4 5. .8 17--51 a T o t a l number of p a t i e n t s who were r e c r u i t e d i n the e p i d e m i o l o g i c a l study. 120 c o u l d not be r e l e a s e d from h o s p i t a l f o r the CT scan. In summary, approximately 50% of the s u b j e c t s r e c r u i t e d f o r the i n i t i a l e p i d e m i o l o g i c a l study d i d not p a r t i c i p a t e i n the CT scanning procedure. The r a t e of n o n p a r t i c i p a t i o n was very s i m i l a r a c r o s s males and females. However, the n o n p a r t i c i p a n t s tended to be o l d e r than the p a r t i c i p a n t s and there was a n o n s i g n i f i c a n t t r e n d towards p r o p o r t i o n a t e l y fewer p a r t i c i p a n t s with a f f e c t i v e d i s o r d e r s to p a r t i c i p a t e than f o r s c h i z o p h r e n i c or s c h i z o p h r e n i f o r m d i s o r d e r p a t i e n t s . Most i n d i v i d u a l s d i d not r e c e i v e a CT scan because they r e f u s e d or because they c o u l d not be l o c a t e d a f t e r they were r e l e a s e d from h o s p i t a l . M e dical C o n t r o l Group. A comparison was made over the three CT measures ( l a t e r a l v e n t r i c l e s , t h i r d v e n t r i c l e , c o r t e x ) between medical p a t i e n t s who were i n j e c t e d with a c o n t r a s t medium and those who, l i k e the other s u b j e c t s i n t h i s study, had noncontrast CT scans. There were no s i g n i f i c a n t d i f f e r e n c e s between these two groups over l a t e r a l v e n t r i c l e s i z e (M + SD = 5.84 + 2.44 Vs 5.56 + 2.83), t( 2 8 ) = .14, p>.l, t h i r d v e n t r i c l e width (M + SD - 2.93 + 0.68 Vs 2.94 + 0.93), t( 2 8 ) = .04, p>.1, or c o r t i c a l atrophy (M + SD = 1.54 + 0.78 Vs 1.30 + 0.47), t( 2 8 ) = 1.07, p>.1. A n a l y s i s of CT F i n d i n g s The f i r s t s e c t i o n of the r e s u l t s ( " R e l i a b i l i t y of Measures and Ratings") i n d i c a t e s t h a t the data were r e l i a b l y c o l l e c t e d . The second s e c t i o n ("Subject C h a r a c t e r i s t i c s " ) suggests t h a t although there are d i f f e r e n c e s i n the r a t i o of 121 males to females between groups there i s no i n d i c a t i o n t h a t t h i s d i s p a r i t y i n f l u e n c e d the r e s u l t s . In a d d i t i o n , a l a r g e number of p a t i e n t s who were i d e n t i f i e d i n the e p i d e m i o l o g i c a l study d i d not p a r t i c i p a t e i n the CT study. Whereas t h i s c o u l d have b i a s e d the ssample, t h e r e i s no evidence of d i f f e r e n t i a l a t t r i t i o n over sex or d i a g n o s i s . Subsequent an a l y s e s w i l l focus on t e s t i n g the r e s e a r c h hypotheses of the present study. Because the m a j o r i t y of p r e v i o u s r e s e a r c h e r s diagnosed p a t i e n t s a c c o r d i n g to DSM-III c r i t e r i a , t h i s d i a g n o s t i c system i s used to c l a s s i f y p a t i e n t s i n the present study. Numerous CT s t u d i e s have used RDC diagnoses and, i n order to e x p l o r e the p o s s i b i l i t y of the d i a g n o s t i c system having an a f f e c t on the o b t a i n e d r e s u l t s , the major hypotheses were a l s o t e s t e d with p a t i e n t s c l a s s i f i e d a c c o r d i n g t o RDC c r i t e r i a (see Appendix I ) . The major hypotheses p r e d i c t t h at p s y c h o t i c p a t i e n t groups w i l l have enlargement of the l a t e r a l v e n t r i c l e s , t h i r d v e n t r i c l e , and c o r t i c a l s u l c i . Furthermore, these m o r p h o l o g i c a l b r a i n changes should be r e l a t e d to poor premorbid adjustment, number of n e g a t i v e symptoms, and d i s r u p t e d smooth p u r s u i t eye movements. A f u r t h e r h y p o t h e s i s based on p r e v i o u s r e s e a r c h p r e d i c t s t h a t s i g n i f i c a n t r e s u l t s are l i k e l y t o be obtained i f the c o n t r o l group i s comprised of medical p a t i e n t s who are s e l e c t e d from r a d i o l o g y r e c o r d s . L a t e r a l V e n t r i c l e . In order t o a n a l y s e l a t e r a l v e n t r i c l e s i z e , a one-way ANOVA was performed to compare VBR r a t i n g s a c r o s s groups ( s c h i z o p h r e n i a , s c h i z o p h r e n i f o r m , 122 b i p o l a r , depressed, v o l u n t e e r c o n t r o l , and medical c o n t r o l ) . P s y c h i a t r i c p a t i e n t s were diagnosed a c c o r d i n g to DSM-III c r i t e r i a f o r t h i s a n a l y s i s . The s i z e and d i s t r i b u t i o n of the l a t e r a l v e n t r i c l e s were very s i m i l a r a c r o s s groups (Table 5, F i g u r e 2 ) . No s i g n i f i c a n t group d i f f e r e n c e was found, F(5, 153) = 0.51, p > .1. Only one p s y c h i a t r i c p a t i e n t (3%) exceeded the v o l u n t e e r c o n t r o l mean p l u s two standard d e v i a t i o n s (VBR > 11.90). Two v o l u n t e e r c o n t r o l s u b j e c t s (4%) exceeded t h i s v a l u e . I f the medical c o n t r o l group were used to determine the standard f o r normal v e n t r i c u l a r s i z e , two s c h i z o p h r e n i c ( 6 % ) , one s c h i z o p h r e n i f o r m ( 5 % ) , and two v o l u n t e e r c o n t r o l s u b j e c t s (4%) had s i g n i f i c a n t l y e nlarged l a t e r a l v e n t r i c l e s (VBR > 10.87). A n e g a t i v e f i n d i n g may be the r e s u l t of type II e r r o r . In order t o assess t h i s p o s s i b i l i t y , a power a n a l y s i s was computed. There i s a wide range i n the s i z e of the e f f e c t s t h a t have been r e p o r t e d i n the l i t e r a t u r e . These range from a h i g h of 1.92 SD (Johnstone et a l . , 1976) to a low of 0.4 SD (Andreasen et a l . , 1982) with a median of approximately 0.7 SD. I f t r u e d i f f e r e n c e s i n the p r e s e n t study are as l a r g e as the median of p r e v i o u s l y r e p o r t e d s t u d i e s then t h e r e i s a p r o b a b i l i t y of .95 t h a t i t would be d e t e c t e d i n the present study. I f , however, the p o p u l a t i o n d i f f e r e n c e i s as s m a l l as t h a t r e p o r t e d by Andreasen et a l . (1982), then there i s a p r o b a b i l i t y of 0.5 t h a t i t would have been d e t e c t e d i n the p r e s e n t study. Thus, while moderate d i f f e r e n c e s would probably be d e t e c t e d , small group d i f f e r e n c e s c o u l d have been 123 T a b l e 5 Mean Values f o r V e n t r i c l e and Cortex Measures f o r Each Group Group L a t e r a l Vent (VBR) T h i r d Vent (mm) Cortex (Rating) S c h i z o p h r e n i a M 6.74 4.05 2.06 N = 31 SD 2.59 1.50 0.85 S c h i z o p h r e n i f o r m M 5.74 3.28 1.95 N = 20 SD 2.44 0.83 0.76 B i p o l a r M 6.20 3.33 1.89 N = 18 SD 1.95 1.01 0.83 Depression M 6.36 3.63 2.00 N = 16 SD 2.96 0.88 0.89 T o t a l P a t i e n t s M 6.45 3.62 2.05 N - 91 SD 2.51 1.18 0.83 V o l u n t e e r C o n t r o l M 6.39 3.49 1.82 N - 44 SD 2.76 1.13 0.76 M e d i c a l C o n t r o l M 5.77 3.01 1.39 N = 30 SD 2.55 0.90 0.61 a A r a t i n g of 1 = no v i s i b l e s u l c i , 2 = s u l c i are v i s i b l e but not e x t e n s i v e , 3 = s u l c i are v i s i b l e and e x t e n s i v e . 124 14--13--12-_ l i -ft; to. > 10-CU N •H cn cu r H O -rH u +J C 9-8-7-5-4+ (0 cu +> ^ 3+ 2 -1--+-Sz Szm B i p o l a r Dep V o l C Med C (n=31) (n=20) (n=18) (n=16) (n=44) (n=30) F i g u r e 2. D i s t r i b u t i o n of V e n t r i c l e t o B r a i n R a t i o s i n Each P a t i e n t and C o n t r o l Group. Note 1. L i n e s above and below each bar denote the standard e r r o r o f measurement. Note 2. Sz = s c h i z o p h r e n i c , Szm = s c h i z o p h r e n i f o r m , Dep = d e p r e s s i o n , V o l C = v o l u n t e e r c o n t r o l , Med C = medical c o n t r o l . 125 missed. Because of methodological d i f f e r e n c e s between s t u d i e s , the p r a c t i c e of u s i n g a predetermined c u t - o f f should i d e a l l y be avoided. However, Weinberger et a l . (1982) have recommended a VBR value of ten as a c o n s e r v a t i v e c u t - o f f p o i n t t h a t may be used t o d e f i n e l a t e r a l v e n t r i c u l a r enlargement. S i x of 91 p s y c h i a t r i c p a t i e n t s (7%) i n the present study had VBR s c o r e s g r e a t e r than t e n . Four of these s u b j e c t s were diagnosed s c h i z o p h r e n i c (13%), one s c h i z o p h r e n i f o r m ( 5 % ) , and one p a r a n o i d , a c c o r d i n g to DSM-III d i a g n o s t i c c r i t e r i a . Three of the s i x were male and t h r e e were female. Four were l e s s than 30 years of age. There were a l s o f i v e of 44 v o l u n t e e r c o n t r o l s u b j e c t s (11%) and one of 30 medical c o n t r o l p a t i e n t s (3%) who had VBR v a l u e s g r e a t e r than t e n . The f i v e v o l u n t e e r s u b j e c t s with e n l a r g e d v e n t r i c l e s appeared t o be no d i f f e r e n t from the remaining v o l u n t e e r s . There were thr e e males and two females and a l l were working, i n hi g h s c h o o l , or i n c o l l e g e . Four were under 30 years of age and a l l r e p o r t e d a c t i v e s o c i a l l i v e s . The medical p a t i e n t with a VBR v a l u e g r e a t e r than ten was a 24 year o l d female. She was r e f e r r e d f o r a CT scan t o i n v e s t i g a t e an aneurism. Because the premorbid R a t i n g s are measured on an o r d i n a l s c a l e , the r e l a t i o n s h i p between premorbid adjustment and l a t e r a l v e n t r i c l e s i z e was assessed u s i n g Spearman rank c o r r e l a t i o n s . The r e l a t i o n s h i p s between l a t e r a l v e n t r i c l e s i z e and both n e g a t i v e symptoms and smooth-pursuit eye 126 movements were asse s s e d u s i n g Pearson c o r r e l a t i o n s . In order t o i n c r e a s e the s t a t i s t i c a l power of these a n a l y s e s , b i p o l a r and depressed p a t i e n t s were combined i n one group. There were no s i g n i f i c a n t r e l a t i o n s h i p s between l a t e r a l v e n t r i c l e s i z e and premorbid adjustment, smooth p u r s u i t eye-movements or n e g a t i v e symptoms f o r any d i a g n o s t i c groups (Table 6 ) . In a d d i t i o n , no d i f f e r e n c e s were o b t a i n e d by d i v i d i n g the p a t i e n t s a t the median VBR and examining the mean d i f f e r e n c e between the two groups over the t h r e e c l i n i c a l - p s y c h o p h y s i o l o g i c a l v a r i a b l e s , range of t s ( 7 9 to 87) = -1.52 t o 0.83, a l l £S>.1. Q u a r t i l e s p l i t s ( e q u i v a l e n t t o comparing the group below the 25th w i t h t h a t above the 75th p e r c e n t i l e ) l i k e w i s e f a i l e d to show s i g n i f i c a n t d i f f e r e n c e s between p a t i e n t s w i t h s m a l l and those w i t h l a r g e v e n t r i c l e s a c r o s s premorbid adjustment, n e g a t i v e symptoms, and smooth p u r s u i t eye-movements, range of J t s(44) = -0.47 t o 1.30, a l l ps>.1. T h i r d V e n t r i c l e . Table 5 and F i g u r e 3 show t h a t the mean wid t h o f the t h i r d v e n t r i c l e i n both the s c h i z o p h r e n i c and depressed p a t i e n t groups appears g r e a t e r than t h a t of the v o l u n t e e r c o n t r o l group. In a d d i t i o n , the mean v e n t r i c l e width of the v o l u n t e e r c o n t r o l group appears g r e a t e r than the m e d i c a l c o n t r o l group. In o r d e r to determine i f these d i f f e r e n c e s are s t a t i s t i c a l l y s i g n i f i c a n t , a one-way ANOVA was c a l c u l a t e d a c r o s s groups ( s c h i z o p h r e n i a , s c h i z o p h r e n i f o r m , b i p o l a r , depressed, v o l u n t e e r c o n t r o l , and m e d i c a l c o n t r o l ) . w i t h p a t i e n t s diagnosed a c c o r d i n g t o DSM-III c r i t e r i a , a 127 Table 6 C o r r e l a t i o n s Between VBR and Premorbid Adjustment, Negative  Symptoms, and Smooth-Pursuit Eye Movements DSM I I I Diagnosed Poor Negative Eye Movement a b b Groups Premorbid Symptoms Impai rment S c h i z o p h r e n i a rho = .11 r = -.15 r = -.02 (n= 28) (n= 31) (n= 30) S c h i z o p h r e n i f o r m rho = -.08 r = -.02 r = -.13 (n= 19) (n= 20) (n= 18) A f f e c t i v e ( B i p o l a r rho = .15 r = -.28 r = .16 and Depressed) (n= 29) (n= •34 ) (n= 34) T o t a l P a t i e n t s rho = .06 r = -.15 r = -.18 (n= 81) (n= 89) (n= 88) Note. No c o r r e l a t i o n was s t a t i s t i c a l l y s i g n i f i c a n t at p<.05 o n e - t a i l e d . a b Spearman c o r r e l a t i o n s . Pearson c o r r e l a t i o n s . c The t o t a l p a t i e n t group i n c l u d e s p aranoid d i s o r d e r and s c h i z o a f f e c t i v e d i s o r d e r p a t i e n t s i n a d d i t i o n t o the th r e e major d i a g n o s t i c groups l i s t e d i n t h i s t a b l e . 128 8t 7-6--H X -P TJ •H & CU rH O -H -P c cu > T3 S-l •H X! 4-3-2-1-Sz Szm B i p o l a r Dep V o l C Med C (n=31) (n=20) (n=18) (n=16) (n=44) (n=30) F i g u r e 3. D i s t r i b u t i o n of T h i r d V e n t r i c l e Width i n Each P a t i e n t and C o n t r o l Group. Note 1. L i n e s above and below the bars i n d i c a t e the standard e r r o r o f measurement. Note 2. Sz = s c h i z o p h r e n i c , Szm = s c h i z o p h r e n i f o r m , Dep = depressed, V o l C = v o l u n t e e r c o n t r o l , Med C = medical c o n t r o l . 129 s i g n i f i c a n t group e f f e c t was obtained over t h i r d v e n t r i c l e width F(5, 153) = 2.97, p = .014. In order t o maintain an experiment-wise alpha l e v e l of .05, the l e v e l of s i g i f i c a n c e f o r each of the t h r e e one-way ANOVAs ( l a t e r a l v e n t r i c l e s , t h i r d v e n t r i c l e and c o r t e x ) should be a d j u s t e d to p = .017. The between groups a n a l y s i s o f t h i r d v e n t r i c l e width a c h i e v e s t h i s l e v e l o f s i g n i f i c a n c e . However, the B a r t l e t t - B o x t e s t i n d i c a t e d t h a t group v a r i a n c e s were s i g n i f i c a n t l y heterogeneous, F = 2.88, p = .01. T h i s v i o l a t e s an assumption of ANOVA and, wit h unequal numbers of s u b j e c t s i n the groups, can s e r i o u s l y a f f e c t the l e v e l of al p h a t h a t i s obt a i n e d ( G l a s s , Pedcham, & Sanders, 1974). An examination o f the group v a r i a n c e s i n d i c a t e d t h a t l a r g e r v a r i a n c e s tended to be a s s o c i a t e d with l a r g e r groups. A Spearman c o r r e l a t i o n between group s i z e and v a r i a n c e i n d i c a t e d a moderately s t r o n g p o s i t i v e r e l a t i o n s h i p , rho = .66. Under these circumstances, the l e v e l o f alpha i s l i k e l y t o be underestimated by the ANOVA t e s t (Myers, 1979, p69) and the s t a t i s t i c a l s i g n i f i c a n c e o f t h i s ANOVA i s t h e r e f o r e accepted. An h y p o t h e s i s of the present study, based on p r e v i o u s r e s e a r c h f i n d i n g s (see I n t r o d u c t i o n ) , p r e d i c t s t h a t s c h i z o p h r e n i c , s c h i z o p h r e n i f o r m , b i p o l a r and depressed p a t i e n t s w i l l have l a r g e r v e n t r i c l e s than normal i n d i v i d u a l s . In o r d e r t o t e s t t h i s h y p o t h e s i s , planned orthogonal c o n t r a s t s were computed between the v o l u n t e e r c o n t r o l group and each of the p a t i e n t groups i n t h i s study. The width of the t h i r d v e n t r i c l e was s i g n i f i c a n t l y g r e a t e r f o r the 130 s c h i z o p h r e n i c group than f o r the v o l u n t e e r c o n t r o l group, t(73) = 2.12, p<.05 one t a i l e d t e s t . No other p a t i e n t groups had s i g n i f i c a n t enlargement of the t h i r d v e n t r i c l e . P r e v i o u s r e s e a r c h a l s o suggests that medical p a t i e n t s tend to have s m a l l e r v e n t r i c l e s than normal i n d i v i d u a l s . In order t o t e s t t h i s h y p o t h e s i s , a planned o r t h o g o n a l c o n t r a s t was computed between the two c o n t r o l groups. The mean width of the t h i r d v e n t r i c l e i n the v o l u n t e e r c o n t r o l group was s i g n i f i c a n t l y g r e a t e r than t h a t of the medical p a t i e n t s , t (72) = 1.80, p<.05 one t a i l e d t e s t . U s i n g an upper l i m i t of 5.75mm as a c u t - o f f (the normal c o n t r o l mean p l u s two standard d e v i a t i o n s ) , t h e r e were t h r e e o f 31 s c h i z o p h r e n i c s (10%) w i t h s i g n i f i c a n t enlargement of the t h i r d v e n t r i c l e . No oth e r p a t i e n t s had s i g n i f i c a n t enlargement ( F i g u r e 3 ) . There were a l s o t h r e e of 44 normal c o n t r o l s u b j e c t s (7%) with a s i g n i f i c a n t l y wide t h i r d v e n t r i c l e . I f the medical c o n t r o l group i s used as a b a s i s t o d e f i n e normal v e n t r i c l e s , then e i g h t s c h i z o p h r e n i c s (26%), one s c h i z o p h r e n i f o r m ( 5 % ) , one b i p o l a r ( 6 % ) , and one depressed p a t i e n t (6%) have an en l a r g e d t h i r d v e n t r i c l e (M + 2SD = 4.81mm). S i x normal c o n t r o l s u b j e c t s (14%) and one medical p a t i e n t (3%) a l s o have a s i g n i f i c a n t l y e n l a r g e d t h i r d v e n t r i c l e i f the medical c o n t r o l group i s used as a standard. Because premorbid adjustment was measured u s i n g an o r d i n a l s c a l e , the r e l a t i o n s h i p between t h i r d v e n t r i c l e width and l e v e l o f premorbid f u n c t i o n i n g was assessed u s i n g Spearman rank c o r r e l a t i o n s . The r e l a t i o n s h i p s between t h i r d 131 v e n t r i c l e width and both n e g a t i v e symptoms and smooth-p u r s u i t eye movements were assessed u s i n g Pearson c o r r e l a t i o n s . The b i p o l a r and depressed p a t i e n t groups were combined to i n c r e a s e the power of t h i s a n a l y s i s . T h i r d v e n t r i c l e width was not s i g n i f i c a n t l y r e l a t e d to premorbid adjustment, smooth-pursuit eye movements (SPEM), or n e g a t i v e symptoms (Table 7 ) . A median s p l i t f a i l e d to f i n d any d i f f e r e n c e s between p a t i e n t s with l a r g e t h i r d v e n t r i c l e s and those with s m a l l t h i r d v e n t r i c l e s on premorbid adjustment, SPEM, or n e g a t i v e symptoms, range of t_s(79 t o 87) = -1.86 to -0.50, a l l p>.05. A q u a r t i l e s p l i t a l s o f a i l e d to d e t e c t any d i f f e r e n c e s , range of t s ( 4 4 ) = 0.16 to 1.50, a l l p>. 1. C o r t i c a l S u l c i . C o r t i c a l atrophy was r a t e d on a t h r e e p o i n t o r d i n a l s c a l e . There has been some c o n f u s i o n i n the l i t e r a t u r e r e g a r d i n g whether ANOVA i s a p p r o p r i a t e f o r t h i s type of data (Gato, 1980). I f the assumptions of n o r m a l i t y , independence, and homogeneity of v a r i a n c e are met, ANOVA i s an a p p r o p r i a t e s t a t i s t i c a l method r e g a r d l e s s of the s c a l e of measurement (Gato, 1980). A one-way ANOVA a c r o s s DSM-III diagnosed p a t i e n t and c o n t r o l groups was s i g n i f i c a n t , F(5, 153) = 2.95, p = .014. The B a r t l e t t - B o x t e s t i n d i c a t e d t h a t group v a r i a n c e s were homogeneous, F = .925, p = .46. I t can be seen from Table 5 and F i g u r e 4 t h a t the mean c o r t i c a l atrophy r a t i n g s are very s i m i l a r a c r o s s a l l groups except f o r the medical c o n t r o l . Planned o r t h o g o n a l c o n t r a s t s were computed between the 132 Table 7 C o r r e l a t i o n s Between T h i r d V e n t r i c l e S i z e and Premorbid Adjustment, Negative Symptoms and Smooth-Pursuit Eye Movements Premorbid Negative Smooth-Pursuit a b b DSM I I I Diagnoses Adjustment Symptoms Eye Movements S c h i z o p h r e n i a rho = -.16 r = ' .23 r = .17 (n= 28) (n= -31) (n= 30) S c h i z o p h r e n i f o r m rho = -.15 r = -.04 r = -.37 (n= 19) (n= 20) (n= 18) A f f e c t i v e ( B i p o l a r r = .10 r = -.01 r = .19 and Depressed) (n= 29) (n= 34) (n= 34) Is T o t a l P a t i e n t s rho = .01 r = ' .14 r = .14 (n= 81) (n= 89) (n= 88) Note. No c o r r e l a t i o n was s t a t i s t i c a l l y s i g n i f i c a n t a t p<.05 o n e - t a i l e d t e s t . a b Spearman rank c o r r e l a t i o n s . Pearson c o r r e l a t i o n s . c The t o t a l p a t i e n t group i n c l u d e s p aranoid d i s o r d e r and s c h i z o a f f e c t i v e d i s o r d e r p a t i e n t s i n a d d i t i o n t o the three major d i a g n o s t i c groups l i s t e d i n t h i s t a b l e . 133 3t en a -P a > i O 2" M -P < rH o • H +J O u 1-Sz Szm B i p o l a r Dep V o l C Med C (n=31) (n=20) (n=18) (n=16) (n=44) (n=30) F i g u r e 4. D i s t r i b u t i o n of C o r t i c a l Atrophy R a t i n g s i n Each P a t i e n t and C o n t r o l Group. Note 1. The l i n e s above and below the bars denote the standard e r r o r o f e s t i m a t e . Note 2. Sz = s c h i z o p h r e n i c , Szm = s c h i z o p h r e n i f o r m , Dep = depressed, V o l C = V o l u n t e e r c o n t r o l , Med C » medical c o n t r o l . 134 v o l u n t e e r c o n t r o l group and each of the p a t i e n t groups and between the v o l u n t e e r c o n t r o l group and the medical c o n t r o l group. These a n a l y s e s i n d i c a t e d that no p a t i e n t group showed more c o r t i c a l atrophy than the v o l u n t e e r c o n t r o l group but t h a t s i g n i f i c a n t l y l e s s atrophy was observed i n the medical p a t i e n t s than i n the v o l u n t e e r c o n t r o l s u b j e c t s , t(72) = 2.35, p<.05 one t a i l e d . C o r t i c a l atrophy r a t i n g s r e p r e s e n t an o r d i n a l s c a l e with a h i g h p r o p o r t i o n of t i e d ranks. In t h i s s i t u a t i o n , K e n d a l l ' s tau i s an a p p r o p r i a t e measure of a s s o c i a t i o n and was used i n the f o l l o w i n g a n a l y s e s . There were no s i g n i f i c a n t r e l a t i o n s h i p s between c o r t i c a l atrophy and l e v e l of premorbid adjustment, SPEM i n t e g r i t y , or number of n e g a t i v e symptoms (Table 8 ) . T h i s was a l s o the case when p a t i e n t s were d i v i d e d i n t o a t r o p h i c ( r a t i n g s of 2 or 3) or n o n a t r o p h i c (a r a t i n g o f 1) groups and compared a c r o s s the t h r e e c l i n i c a l - p s y c h o p h y s i o l o g i c a l v a r i a b l e s ; range of t s ( 7 9 to 87) = -1.21 t o 0.63, a i l ps>.l. R e l a t i o n s h i p s between M o r p h o l o g i c a l Measures. In order to a s sess whether l a t e r a l and t h i r d v e n t r i c l e s i z e and c o r t i c a l s u l c i d i l a t i o n are i n t e r r e l a t e d phenomena or whether they are independent m o r p h o l o g i c a l c h a r a c t e r i s t i c s , c o r r e l a t i o n c o e f f i c i e n t s were computed between these measures f o r each group. Pearson c o r r e l a t i o n s were used to measure the a s s o c i a t i o n between l a t e r a l and t h i r d v e n t r i c l e s i z e , and K e n d a l l ' s t a u t o compare the r e l a t i o n s h i p between c o r t i c a l atrophy and both t h i r d and l a t e r a l v e n t r i c u l a r s i z e . A 135 Table 8 C o r r e l a t i o n s Between C o r t i c a l Atrophy and Premorbid Adjustment, a Negative Symptoms, and Smooth-Pursuit Eye Movements DSM I I I Diagnosed Premorbid Negative Smooth-Pursuit Groups Adjustment Symptoms Eye Movements S c h i z o p h r e n i a 7--.19 7 = -.01 Y = .01 (n- 28) (n= 31) (n= 30) S c h i z o p h r e n i f o r m 4 = -.11 7 = .31 7 = -.02 (n= 19) (n= 20) (n= 18) A f f e c t i v e ( B i p o l a r 7 = .15 -.17 -r = .13 and Depressed) K (n= 29) (n= 34) (n= 34) U T o t a l P a t i e n t s 7 = -.05 r- .04 r = .07 (n= 81) (n= 89) (n= 88) Note. No c o r r e l a t i o n was s t a t i s t i c a l l y s i g n i f i c a n t at p<.05 one t a i l e d , a K e n d a l l c o r r e l a t i o n c o e f i c i e n t s were used. b The t o t a l p a t i e n t group i n c l u d e s p a r a n o i d d i s o r d e r and s c h i z o a f f e c t i v e d i s o r d e r p a t i e n t s i n a d d i t i o n t o the th r e e major d i a g n o s t i c groups l i s t e d i n t h i s t a b l e . 136 s i g n i f i c a n t p o s i t i v e c o r r e l a t i o n was found between the s i z e of the l a t e r a l v e n t r i c l e s (VBR) and the width of the t h i r d v e n t r i c l e f o r both the v o l u n t e e r ( r = .48, p<.01) and medical ( r = .47, p<.01) c o n t r o l groups (Table 9 ) . A s m a l l e r s i g n i f i c a n t c o r r e l a t i o n was found f o r the p s y c h i a t r i c p a t i e n t s ( r = .24, p<.05). In order t o compare the two c o r r e l a t i o n s , each was changed a c c o r d i n g to F i s h e r ' s Z t r a n s f o r m a t i o n s and a t - t e s t was computed between the two v a l u e s . The d i f f e r e n c e between the t o t a l p a t i e n t and v o l u n t e e r c o n t r o l group c o r r e l a t i o n s was assessed and found to be n o n s i g n i f i c a n t , t(134) = 1.52, p>.05. The r e l a t i o n s h i p between l a t e r a l and t h i r d v e n t r i c l e s i z e was a l s o e x p l o r e d f o r t h r e e DSM-III diagnosed p a t i e n t groups ( s c h i z o p h r e n i c , s c h i z o p h r e n i f o r m , and combined b i p o l a r and depressed p a t i e n t s ) . A l l t h r e e groups showed p o s i t i v e n o n s i g n i f i c a n t c o r r e l a t i o n s t h a t were s i m i l a r i n s i z e t o t h a t of the t o t a l p a t i e n t sample (Table 9 ) . These f i n d i n g s suggest t h a t l a r g e l a t e r a l v e n t r i c l e s tend t o be a s s o c i a t e d with a l a r g e t h i r d v e n t r i c l e i n normal i n d i v i d u a l s but t h i s r e l a t i o n s h i p may be weaker i n p s y c h o t i c p a t i e n t s . The r e l a t i o n s h i p between the s i z e of the l a t e r a l v e n t r i c l e s and c o r t i c a l atrophy was c o n s i s t e n t l y low f o r a l l groups (Table 9 ) . Using K e n d a l l c o r r e l a t i o n c o e f f i c i e n t s , a low, s i g n i f i c a n t l y p o s i t i v e c o r r e l a t i o n was obtained f o r the medical s u b j e c t s and the a f f e c t i v e d i s o r d e r p a t i e n t s . No s i g n i f i c a n t c o r r e l a t i o n s were ob t a i n e d f o r the v o l u n t e e r s u b j e c t s or s c h i z o p h r e n i c or s c h i z o p h r e n i f o r m p a t i e n t s . 137 Table 9 C o r r e l a t i o n s Between L a t e r a l V e n t r i c l e S i z e (VBR), T h i r d  V e n t r i c l e Width, and C o r t i c a l Atrophy L a t e r a l by L a t e r a l by T h i r d by a b b Groups T h i r d Cortex Cortex S c h i z o p h r e n i a r = .22 7" =-.23 7- .06 N = 31 S c h i z o p h r e n i f o r m r = .36 7* = .21 t = .10 N = 20 c A f f e c t i v e r = .21 T = .25 y = ** .37 N = 34 d T o t a l P a t i e n t s r = * .24 7* = .02 -r = * .16 N = 91 V o l u n t e e r C o n t r o l r = ** .48 T' = .06 -f = * .29 N = 44 M e d i c a l C o n t r o l r = ** .47 * T' = .25 .20 N = 30 a Pearson c o r r e l a t i o n s . b K e n d a l l c o r r e l a t i o n s c A f f e c t i v e d i s o r d e r p a t i e n t s i n c l u d e i n d i v i d u a l s with b i p o l a r d i s o r d e r or major d e p r e s s i o n , d The t o t a l p a t i e n t group i n c l u d e s p aranoid d i s o r d e r and s c h i z o a f f e c t i v e d i s o r d e r p a t i e n t s i n a d d i t i o n t o the three major d i a g n o s t i c groups l i s t e d i n t h i s t a b l e . * ** p<.05 p<.01 two t a i l e d . 138 The r e l a t i o n s h i p s between t h i r d v e n t r i c l e width and c o r t i c a l atrophy were a l s o assessed u s i n g K e n d a l l c o r r e l a t i o n c o e f f i c i e n t s . Low s i g n i f i c a n t l y p o s i t i v e c o r r e l a t i o n s were ob t a i n e d f o r the v o l u n t e e r c o n t r o l group, the a f f e c t i v e d i s o r d e r p a t i e n t s , and the t o t a l group of p s y c h i a t r i c p a t i e n t s (Table 9 ) . The c o r r e l a t i o n s between t h i r d v e n t r i c l e width and s u l c a l d i l a t i o n t h a t were ob t a i n e d f o r the medical c o n t r o l group, the s c h i z o p h r e n i c , and s c h i z o p h r e n i f o r m groups i n d i c a t e d low n o n s i g n i f i c a n t c o r r e l a t i o n s . Summary of R e s u l t s The r e s u l t s o f t h i s study i n d i c a t e t h a t a l l data were r e l i a b l y c o l l e c t e d and no b i a s e s due to age or sex were d e t e c t e d . The f i r s t r e s e a r c h h y p o t h e s i s was not confirmed. The mean s i z e of the l a t e r a l v e n t r i c l e s was not g r e a t e r i n the p a t i e n t groups than i n the v o l u n t e e r c o n t r o l group. The second h y p o t h e s i s was confirmed f o r the s c h i z o p h r e n i c p a t i e n t s . There was a s i g n i f i c a n t d i f f e r e n c e between the s c h i z o p h r e n i c p a t i e n t s and the v o l u n t e e r c o n t r o l s u b j e c t s over t h i r d v e n t r i c l e width. No other p a t i e n t groups had s i g n i f i c a n t enlargement of the t h i r d v e n t r i c l e . The t h i r d r e s e a r c h h y p o t h e s i s was not confirmed. None of the p a t i e n t groups had s i g n i f i c a n t l y more c o r t i c a l atrophy than d i d the v o l u n t e e r c o n t r o l group. The f o u r t h r e s e a r c h h y p o t h e s i s was not confirmed. L a t e r a l v e n t r i c l e s i z e , t h i r d v e n t r i c l e width, and atrophy of the c e r e b r a l c o r t e x were not s i g n i f i c a n t l y r e l a t e d to the l e v e l o f premorbid adjustment, smooth-pursuit eye movement i n t e g r i t y , 139 or number of n e g a t i v e symptoms f o r any p a t i e n t group. The f i f t h h y p o t h e s i s was confirmed over t h i r d v e n t r i c l e width and c o r t i c a l atrophy. Both the t h i r d v e n t r i c l e and c o r t i c a l s u l c i were s i g n i f i c a n t l y s m a l l e r i n the medical p a t i e n t s than i n the v o l u n t e e r c o n t r o l group. The s i z e of the l a t e r a l v e n t r i c l e s was p o s i t i v e l y r e l a t e d to the width of the t h i r d v e n t r i c l e i n the t o t a l p a t i e n t sample and i n each of the two c o n t r o l groups. Whereas t h i s c o r r e l a t i o n was s i g n i f i c a n t f o r the t o t a l p a t i e n t sample, none of the i n d i v i d u a l p a t i e n t groups showed a s i g n i f i c a n t r e l a t i o n s h i p between these v a r i a b l e s . C o n s i s t e n t l y low c o r r e l a t i o n s were o b t a i n e d between c o r t i c a l atrophy and both l a t e r a l and t h i r d v e n t r i c l e s i z e f o r a l l p a t i e n t and c o n t r o l samples. D i s c u s s i o n The primary purpose of the present study was t o t e s t t h r e e major r e s e a r c h hypotheses. Each of these hypotheses i s supported to v a r y i n g degrees by a l a r g e body of r e s e a r c h l i t e r a t u r e . Two a d d i t i o n a l hypotheses, based on p r e l i m i n a r y f i n d i n g s , were a l s o t e s t e d . In p a r t i a l support of one h y p o t h e s i s , the major s i g n i f i c a n t f i n d i n g of t h i s study was i n c r e a s e d t h i r d v e n t r i c l e width i n s c h i z o p h r e n i c p a t i e n t s . T h i s r e s u l t i s c o n s i s t e n t w i t h e i g h t of ten p r e v i o u s s t u d i e s t h a t have i n v e s t i g a t e d t h i s phenomenon. The f i n d i n g of no enlargement of the t h i r d v e n t r i c l e i n s c h i z o p h r e n i f o r m , b i p o l a r , and depressed p a t i e n t s , because no p r e v i o u s r e s e a r c h has addressed t h i s q u e s t i o n , r e p r e s e n t s a p r e l i m i n a r y r e s u l t and r e q u i r e s r e p l i c a t i o n . The two other major hypotheses 140 (those concerning l a t e r a l v e n t r i c u l a r enlargement and enlargement of the c o r t i c a l s u l c i ) were not supported i n the present study d e s p i t e the f a c t t h a t t h e r e was s u f f i c i e n t s t a t i s t i c a l power. Given the i n c o n s i s t e n c i e s i n the l i t e r a t u r e surrounding these two hypotheses (see Summary of the L i t e r a t u r e above), the present f i n d i n g i s not unexpected. The f o u r t h h y p o t h e s i s p r e d i c t e d s i g n i f i c a n t r e l a t i o n s h i p s between mor p h o l o g i c a l b r a i n anomalies (enlargement of the t h i r d v e n t r i c l e , l a t e r a l v e n t r i c l e , or c o r t i c a l s u l c i ) and c l i n i c a l / p s y c h o p h y s i o l o g i c a l f a c t o r s (smooth-pursuit eye movements, premorbid adjustment, and n e g a t i v e symptoms). T h i s h y p o t h e s i s was not supported i n the present study d e s p i t e the use of a l a r g e number of t e s t s with l i b e r a l l e v e l s of alpha and the i n c l u s i o n of median and q u a r t i l e s p l i t s . T h i s f i n d i n g was not unexpected over the l a t e r a l v e n t r i c l e s and c o r t i c a l s u l c i g iven the f a i l u r e t o f i n d s i g n i f i c a n t d i l a t i o n of e i t h e r o f these s t r u c t u r e s . A l s o , because no r e s e a r c h l i t e r a t u r e t o date has addressed the i s s u e of an a s s o c i a t i o n between t h i r d v e n t r i c u l a r enlargement and SPEM, premorbid adjustment, and n e g a t i v e symptoms, the present f i n d i n g i s not i n c o n s i s t e n t w i t h past r e s e a r c h . In p a r t i a l support of the f i f t h h y p o t h e s i s , the mean s i z e of the t h i r d v e n t r i c l e and c o r t i c a l s u l c i were found to be s m a l l e r i n the medical group than i n the normal group. Other s t a t i s t i c a l t e s t s under the "Subject C h a r a c t e r i s t i c s " p a r t of the R e s u l t s s e c t i o n were designed t o p r o v i d e a c l e a r d e f i n i t i o n of the sample used i n t h i s study 141 and do not t e s t hypotheses. Those s t a t i s t i c a l t e s t s under the s e c t i o n " R e l a t i o n s h i p s between Measures" are a l s o d e s c r i p t i v e r a t h e r than h y p o t h e s i s t e s t i n g . Some e x p l o r a t o r y a n a l y s e s are presented i n Appendix H and t e s t the f i r s t t h ree hypotheses when RDC diagnoses were used t o c l a s s i f y p a t i e n t s . L a t e r a l V e n t r i c l e s . The s c h i z o p h r e n i c group had l a r g e r l a t e r a l v e n t r i c l e s than d i d the normal c o n t r o l group but t h i s d i f f e r e n c e f a i l e d t o reach s t a t i s t i c a l s i g n i f i c a n c e . L a t e r a l v e n t r i c l e s i z e was very s i m i l a r a c r o s s the remaining p a t i e n t groups and the normal c o n t r o l group. The f i n d i n g of no enlargement i s c o n t r a r y t o most of the p r e v i o u s r e p o r t s of l a t e r a l v e n t r i c l e s i z e i n p s y c h o t i c p a t i e n t s . I t i s noteworthy, however, t h a t the mean VBR f o r the s c h i z o p h r e n i c p a t i e n t s i n the present study (6.74) i s very s i m i l a r t o t h a t of the p a t i e n t s from the seven p r e v i o u s s t u d i e s t h a t r e p o r t no LVE (6.75) and to t h a t of the p a t i e n t s from the 14 s t u d i e s t h a t found LVE (6.86). T h i s f i n d i n g suggests t h a t the present group of s c h i z o p h r e n i c p a t i e n t s i s comparable t o those of p r e v i o u s s t u d i e s r e g a r d l e s s of the outcome of these s t u d i e s . The mean VBR of the c o n t r o l s u b j e c t s i n the present study (6.39), although s i m i l a r t o t h a t of the s t u d i e s that r e p o r t no LVE (6.34), i s very d i f f e r e n t from that of the s t u d i e s t h a t r e p o r t v e n t r i c u l a r enlargement (3.95). T h i s f i n d i n g supports the r e s u l t s from p r e v i o u s r e s e a r c h and suggests t h a t the i n t e r p r e t a t i o n of CT r e s u l t s r e g a r d i n g l a t e r a l v e n t r i c l e s i z e depends on the s i z e of the v e n t r i c l e s i n the c o n t r o l s u b j e c t s but not i n s c h i z o p h r e n i c p a t i e n t s . 142 The present c o n t r o l group i s comprised of 44 h e a l t h y v o l u n t e e r s who were screened f o r c h r o n i c i l l n e s s , a l c o h o l and drug abuse, and f o r p e r s o n a l or f a m i l i a l p s y c h i a t r i c problems. The l a r g e s i z e of t h i s group and the absence of medical or p s y c h i a t r i c problems suggests t h a t these i n d i v i d u a l s should approximate the d i s t r i b u t i o n of v e n t r i c l e s i z e s found i n the normal p o p u l a t i o n . In a d d i t i o n , the f a c t t h a t mean v e n t r i c l e s i z e i n the present normal group i s very s i m i l a r t o t h a t of the s t u d i e s t h a t r e p o r t no LVE and s i g n i f i c a n t l y d i f f e r e n t from that of the s t u d i e s r e p o r t i n g LVE (Smith & Iacono, 1986) s t r o n g l y suggest b i a s e s i n the c o n t r o l groups of s t u d i e s t h a t r e p o r t s i g n i f i c a n t v e n t r i c u l a r enlargement. Even though there i s s t r o n g evidence t o suggest c o n t r o l group b i a s i n some p r e v i o u s r e s e a r c h s t u d i e s , i t i s p o s s i b l e t h a t f a i l u r e t o o b t a i n a s i g n i f i c a n t e f f e c t i n the present study c o u l d have r e s u l t e d from type II e r r o r or from m e t h o d o l o g i c a l problems. The power f o r d e t e c t i n g a s i g n i f i c a n t l a t e r a l v e n t r i c l e e f f e c t e q u i v a l e n t to the s m a l l e s t s i g n i f i c a n t r e s u l t that has been r e p o r t e d (0.4 SD, Andreasen et a l . , 1982) i s r e l a t i v e l y low (50%) i n the present study. However, the chances of o b t a i n i n g a more t y p i c a l e f f e c t s i z e (0.7 SD, Weinberger et a l . , 1982) i s h i g h (95%). Thus, u n l e s s there i s minimal enlargement, i t i s u n l i k e l y t h a t the present r e s u l t s are a t t r i b u t a b l e to type II e r r o r . I t i s a l s o u n l i k e l y t h a t m e t h o d o l o g i c a l d i f f i c u l t i e s are 143 r e s p o n s i b l e f o r the present r e s u l t s . The CT scanning procedure and methods of a s s e s s i n g the v e n t r i c l e s and s u l c i were s t a n d a r d i z e d f o r a l l s u b j e c t s and were comparable to those used i n most p r e v i o u s s t u d i e s . High i n t e r j u d g e r e l i a b i l i t y was obtained f o r a l l CT measures and these measures corresponded w e l l to g l o b a l r a t i n g s made by a n e u r o r a d i o l o g i s t . The p a t i e n t groups comprised a wide c r o s s s e c t i o n of f i r s t e pisode p s y c h o t i c i n d i v i d u a l s . P a t i e n t s were r e c r u i t e d from a l l h o s p i t a l s and community agencies as p a r t of an e x t e n s i v e study to determine the i n c i d e n c e of f i r s t episode p s y c h o s i s i n the Vancouver a r e a . T h i s sample i s as r e p r e s e n t a t i v e as i s p o s s i b l e w i t h i n the l i m i t s of informed consent. N e v e r t h e l e s s , a l a r g e number of p a t i e n t s who were i d e n t i f i e d i n the e p i d e m i o l o g i c a l study d i d not p a r t i c i p a t e i n the CT study. An a n a l y s i s of n o n p a r t i c i p a n t s f a i l e d to d e t e c t d i f f e r e n t i a l a t t r i t i o n over sex or d i a g n o s i s . However, the g r e a t e r number of males i d e n t i f i e d i n i t i a l l y c o u l d r e f l e c t a s e l e c t i o n b i a s i n the e p i d e m i o l o g i c a l study. S e v e r a l s t u d i e s have i n d i c a t e d t h a t the i n c i d e n c e of s c h i z o p h r e n i a i s the same f o r both males and females ( F l o r -Henry, 1985). However, i n a review of the l i t e r a t u r e on sex d i f f e r e n c e s i n s c h i z o p h r e n i a , F l o r - H e n r y (1985) noted that the sex r a t i o of males t o females f o r onset under 40 years of age i s approximately 2:1. The r a t i o f o r onset before 20 years i s f a r g r e a t e r (4:1) whereas there i s an excess of females i n those s t u d i e s t h a t i n c l u d e d onset a f t e r 45 years 144 (Flor-Henry, 1 9 8 5 ) . Although an attempt was made t o r e c r u i t p a t i e n t s o f a l l ages, d i s p r o p o r t i o n a t e l y more young people have f i r s t break p s y c h o s i s . Because most of the p a t i e n t s i n the p r e s e n t study are young (M = 2 3 . 5 ) the r a t i o o f male t o female s c h i z o p h r e n i c s ( 5 : 1 ) i s s i m i l a r t o the expected r a t i o . The s u b j e c t s who r e c e i v e d a CT scan were s i g n i f i c a n t l y younger than the t o t a l group of s u b j e c t s r e c r u i t e d i n the e p i d e m i o l o g i c a l study. T h i s d i f f e r e n c e r e p r e s e n t s a p o t e n t i a l b i a s i n the present study. However, p r e v i o u s r e s e a r c h i n d i c a t e s t h a t the p r o g n o s i s f o r e a r l y onset s c h i z o p h r e n i a tends t o be worse than that f o r l a t e onset ( N e i l e & Oltmanns, 1981, pp 343-388). Thus i f the present sample i s b i a s e d , i t i s most l i k e l y to be b i a s e d towards e x c l u d i n g good p r o g n o s i s i n d i v i d u a l s . Because t h e r e i s some evidence t o i n d i c a t e t h a t LVE i s most common i n s e v e r e l y impaired p a t i e n t s , and e a r l y onset i n d i v i d u a l s tend to have poor p r o g n o s i s , then any b i a s t h a t may have o c c u r r e d i n the p r e s e n t study should exaggerate the s i z e of the l a t e r a l v e n t r i c l e s i n the p o p u l a t i o n of p s y c h o t i c p a t i e n t s and would not account f o r the f a i l u r e to f i n d LVE. In a d d i t i o n , because p a t i e n t s were r e c r u i t e d from treatment c e n t r e s , any i n d i v i d u a l s who were f u n c t i o n i n g s u f f i c i e n t l y w e l l to a v o i d p r o f e s s i o n a l c o n t a c t would be missed by the present study. T h i s f a c t o r would a l s o tend to b i a s the present sample i n the d i r e c t i o n of more severe impairment. Thus, the present f a i l u r e t o d e t e c t LVE i s u n l i k e l y to be due t o s e l e c t i o n b i a s . F i n a l l y , the f a c t t h a t e x p l o r a t o r y analyses i n d i c a t e d t h a t the same r e s u l t s are obtained whether DSM I I I or RDC diagnoses are used suggests that t h i s r e s u l t i s not due to 145 the method of d i a g n o s i s that was used. In summary, f a i l u r e t o o b t a i n s i g n i f i c a n t r e s u l t s c o u l d r e s u l t from type I I e r r o r or from a number of methodological problems. The sample s i z e used i n the present study makes type II e r r o r s u n l i k e l y . M e t h o d o l o g i c a l f a c t o r s t h a t c o u l d a f f e c t r e s u l t s i n c l u d e the scanning procedure, the methods used i n e s t i m a t i n g b r a i n c h a r a c t e r i s t i c s , the s e l e c t i o n of a c o n t r o l group, and the s e l e c t i o n and d e f i n i t i o n of a p a t i e n t sample. A l l of these f a c t o r s were r i g o r o u s l y c o n t r o l l e d i n the present study and are u n l i k e l y t o account f o r the n e g a t i v e r e s u l t s . The present r e s u l t s i n d i c a t e t h a t l a r g e l a t e r a l v e n t r i c l e s are n e i t h e r a marker of v u n e r a b i l i t y t o p s y c h o s i s nor the r e s u l t of an a t r o p h i c process t h a t occurs b e f o r e the onset of i l l n e s s . In o r d e r f o r a p a r t i c u l a r c h a r a c t e r i s t i c t o q u a l i f y as a marker of v u n e r a b i l i t y , i t should be found more i n i n d i v i d u a l s with a p a r t i c u l a r i l l n e s s than i n the g e n e r a l p o p u l a t i o n (Iacono, 1983). T h i s should be the case r e g a r d l e s s of the d u r a t i o n of i l l n e s s . The present r e s u l t s i n d i c a t e t h a t no p a t i e n t group has s i g n i f i c a n t l y l a r g e r l a t e r a l v e n t r i c l e s than the v o l u n t e e r c o n t r o l group. L i k e w i s e , i f atrophy o c c u r r e d b e f o r e the onset of p s y c h o s i s i n a s i g n i f i c a n t p r o p o r t i o n of i n d i v i d u a l s , some p a t i e n t s should show more v e n t i c u l a r enlargement than the c o n t r o l s u b j e c t s . T h i s i s c l e a r l y not the case. An a t r o p h i c process t h a t o c c u r r e d b e f o r e the onset of p s y c h o s i s would a l s o be l i k e l y t o a f f e c t the l e v e l of 146 premorbid f u n c t i o n i n g . Premorbid f u n c t i o n i n g should be the worst i n those i n d i v i d u a l s with the l a r g e s t v e n t r i c l e s ; i . e . , f o r those i n d i v i d u a l s who have s u f f e r e d the most atrophy. The r e s u l t s of the present study i n d i c a t e t h a t the s i z e of the l a t e r a l v e n t r i c l e s i s not s i g n i f i c a n t l y r e l a t e d to l e v e l of premorbid f u n c t i o n i n g . F i n a l l y , i f v e n t r i c l e s i z e r e f l e c t s an e a r l y a t r o p h i c p r o c e s s , then other c h a r a c t e r i s i t c s t h a t tend to appear more f r e q u e n t l y i n s e v e r e l y a f f l i c t e d persons might be expected to be found more i n i n d i v i d u a l s who d i s p l a y the g r e a t e s t s i g n s of atrophy. The f a c t t h a t no s i g n i f i c a n t r e l a t i o n s h i p s were ob t a i n e d between l a t e r a l v e n t r i c l e s i z e and e i t h e r n e g a t i v e symptoms or smooth-pursuit eye movements f u r t h e r supports the c o n t e n t i o n t h a t the s i z e of the l a t e r a l v e n t r i c l e s probably does not r e f l e c t the extent of an e a r l y a t r o p h i c process or that v e n t r i c l e s i z e does not a f f e c t the l e v e l of f u n c t i o n i n g a t the time of or b e f o r e the f i r s t p s y c h o t i c e p i s o d e . I t i s p o s s i b l e t h a t some of the i n c o n s i s t e n c i e s i n the CT l i t e r a t u r e r e s u l t from an o v e r s i m p l i f i e d view of LVE. The use of c u t - o f f s to d i s t i n g u i s h e n l a r g e d v e n t r i c l e s from normal s i z e d v e n t r i c l e s i s based on the assumption t h a t i t i s the a b s o l u t e s i z e r a t h e r than the amount of enlargement that has taken p l a c e t h a t i s the most a p p r o p r i a t e measure of LVE. T h i s would be the case i f the o b t a i n e d d i f f e r e n c e i n the s i z e of the v e n t r i c l e s between p a t i e n t s and c o n t r o l s u b j e c t s was u s u a l l y great or i f normal v a r i a b i l i t y i n v e n t r i c l e s i z e were s m a l l . 147 There i s , however, c o n s i d e r a b l e v a r i a b i l i t y i n CT re s e a r c h f i n d i n g s c o n cerning the preva l e n c e and magnitude of v e n t r i c u l a r d i l a t i o n i n p s y c h o t i c p a t i e n t s . The median e f f e c t s i z e i s 1.7 VBR u n i t s (approximately 0.7 SD) and there i s a l a r g e normal range i n the s i z e of l a t e r a l v e n t r i c l e s w i t h i n s t u d i e s ( e i g h t to 11 VBR u n i t s i n the nine s t u d i e s t h a t r e p o r t the range). T h i s l a r g e normal range and sm a l l e f f e c t s i z e suggests t h a t , f o r any i n d i v i d u a l p a t i e n t , moderate enlargement of the l a t e r a l v e n t r i c l e s would go unnoticed i f the v e n t r i c l e s were smal l b e f o r e the onset of p s y c h o s i s . T h i s c o n t e n t i o n i s supported by the f i n d i n g s of three s t u d i e s i n which s i b l i n g s , d i s c o r d a n t f o r s c h i z o p h r e n i a , were i n v e s t i g a t e d ( D e L l s i et a l . , 1986; Revely et a l . , 1982; Weinberger e t a l . , 1981). In each of these s t u d i e s , s c h i z o p h r e n i c p a t i e n t s tended t o have l a r g e r v e n t r i c l e s than t h e i r s i b l i n g s but v e n t r i c u l a r s i z e i n most of these p a t i e n t s was not c o n s i d e r e d e n l a r g e d a c c o r d i n g to the u s u a l d e f i n i t i o n o f enlargement ( i . e . , g r e a t e r than the c o n t r o l mean p l u s two standard d e v i a t i o n s ) . Small e f f e c t s i z e s and l a r g e normal v a r i a b i l i t y i n d i c a t e t h a t enlargement would be l i k e l y t o appear as an o v e r a l l s h i f t i n the d i s t r i b u t i o n o f v e n t r i c l e s i z e r a t h e r than a c l u s t e r i n g of i n d i v i d u a l s i n the en l a r g e d v e n t r i c l e range. The present f i n d i n g s p r o v i d e t e n t a t i v e support f o r t h i s n o t i o n and i n d i c a t e a s h i f t away from s m a l l l a t e r a l v e n t r i c l e s i n s c h i z o p h r e n i c p a t i e n t s . Those s t u d i e s i n which the d i s t r i b u t i o n of VBR v a l u e s was p r o v i d e d (e.g. Andreasen 148 et a l . , 1982b; Schulz et a l . , 1983; Weinberger et a l . , 1982) a l s o i n d i c a t e a r e l a t i v e l y s m a l l o v e r a l l s h i f t i n the d i s t r i b u t i o n of v e n t r i c l e s i z e s . The present f i n d i n g s of c o n s i s t e n t l y low c o r r e l a t i o n s between any m o r p h o l o g i c a l anomaly ( t h i r d or l a t e r a l v e n t r i c l e s i z e , or s u l c a l d i l a t i o n ) and premorbid adjustment, n e g a t i v e symptoms or d i s r u p t e d SPEM i s a l s o c o n s i s t e n t with t h i s h y p o t h e s i s . That i s to say, a c l i n i c a l measure a s s o c i a t e d with neuropathology would be more l i k e l y t o be r e l a t e d to the amount of v e n t r i c u l a r enlargement t h a t has o c c u r r e d r a t h e r than a c t u a l v e n t r i c l e s i z e . T h i s c o n t e n t i o n was supported i n a recent study by B i r d , Levy and Jacoby (1986). In t h i s study, a group of 50 normal i n d i v i d u a l s over the age of 60 r e c e i v e d two CT scans over a two year p e r i o d . A h i g h l y s i g n i f i c a n t n e g a t i v e r e l a t i o n s h i p was o b t a i n e d between l e v e l o f c o g n i t i v e f u n c t i o n i n g and the amount of v e n t r i c u l a r enlargement t h a t o c c u r r e d between the time of the f i r s t and second scans. In summary, the magnitude of v e n t r i c u l a r enlargement r e p o r t e d i n most p r e v i o u s s t u d i e s i s s m a l l . H a l f of the p r e v i o u s s t u d i e s r e p o r t a d i f f e r e n c e of l e s s than 0.7 SD between the p a t i e n t and c o n t r o l group. There i s a l s o a r e l a t i v e l y l a r g e range i n v e n t r i c l e s i z e a c r o s s both p a t i e n t and c o n t r o l s u b j e c t s . Because LVE i n s c h i z o p h r e n i c p a t i e n t s tends t o be s m a l l and v a r i a b i l i t y i n v e n t r i c l e s i z e i s normally l a r g e , l a r g e samples w i l l be u s u a l l y needed to o b t a i n s i g n i f i c a n t group d i f f e r e n c e s . Enlargement f o r any 149 i n d i v i d u a l i s l i k e l y t o be i n the form of a small s h i f t i n v e n t r i c l e s i z e . R e p o r t i n g on c l u s t e r s of p a t i e n t s i n the e n l a r g e d v e n t r i c l e range and u s i n g a b s o l u t e v e n t r i c l e s i z e (VBR) as an index of v e n t r i c u l a r enlargement i s l i k e l y t o o v e r s i m p l i f y t h i s complex i s s u e . T h i r d V e n t r i c l e The present r e s u l t s support the f i n d i n g s of e i g h t of the ten p r e v i o u s s t u d i e s and i n d i c a t e s i g n i f i c a n t enlargement of the t h i r d v e n t r i c l e i n the s c h i z o p h r e n i c p a t i e n t group. T h i r d v e n t r i c l e s i z e was very s i m i l a r a c r o s s the remaining p a t i e n t groups and the v o l u n t e e r c o n t r o l group. T h i s r e s u l t suggests t h a t enlargement of the t h i r d v e n t r i c l e r e f l e c t s a marker o f s u s c e p t i b i l i t y t o s c h i z o p h r e n i a and/or i s a s s o c i a t e d w i t h e t i o l o g l c a l l y s i g n i f i c a n t f a c t o r s . The absence of d i l a t i o n i n the other p a t i e n t groups ( s c h i z o p h r e n i f o r m , b i p o l a r , depressed) suggests that enlargement of the t h i r d v e n t r i c l e may be s p e c i f i c t o s c h i z o p h r e n i a i n f i r s t episode p s y c h o t i c p a t i e n t s . I t i s u n l i k e l y that the f i n d i n g of enlargement i n the s c h i z o p h r e n i c group i s due to a b i a s e d p a t i e n t sample. The f a c t t h a t no enlargement of the l a t e r a l v e n t r i c l e s or c o r t i c a l s u l c i was d e t e c t e d i n these p a t i e n t s suggests that t h i s group d i d not have e x t e n s i v e atrophy. In a d d i t i o n , whereas t h e r e was a moderately h i g h c o r r e l a t i o n between t h i r d and l a t e r a l v e n t r i c l e s f o r both c o n t r o l groups, t h i s r e l a t i o n s h i p was a t t e n u a t e d i n the p a t i e n t groups. T h i s r e s u l t suggests t h a t t h e r e may be l o c a l r a t h e r than d i f f u s e 150 b r a i n changes. Furthermore, a wide range i n l e v e l of premorbid adjustment, d u r a t i o n of f i r s t h o s p i t a l i z a t i o n , and age a t onset suggests that these p a t i e n t s r e p r e s e n t a wide c r o s s s e c t i o n o f s c h i z o p h r e n i c s . The f i n d i n g of enlargement of the t h i r d v e n t r i c l e i s a l s o probably not due to a s p u r i o u s l y low mean v e n t r i c l e s i z e i n the c o n t r o l sample. The v o l u n t e e r c o n t r o l group comprised h e a l t h y i n d i v i d u a l s with no i n d i c a t i o n of p s y c h i a t r i c d i s t u r b a n c e , d r u g / a l c o h o l abuse, or c h r o n i c medical problems. The scanning procedures were i d e n t i c a l f o r a l l p a r t i c i p a n t s and a l l CT measures were taken with the r a t e r b l i n d t o the s u b j e c t s ' i d e n t i t y or group membership. F i n a l l y , h i g h i n t e r r a t e r r e l i a b i l i t y was o b t a i n e d f o r a l l CT measures. The s t u d i e s of Nyback et a l . (1982), Smith and Maser (1983), and Boronow et a l . (1985) a l l i n c l u d e c h r o n i c p a t i e n t groups and r e p o r t e f f e c t s i z e s very s i m i l a r t o t h a t o b t a i n e d i n the present study. In a d d i t i o n , the s c h i z o p h r e n i f o r m and b i p o l a r and depressed groups i n the present study had s i m i l a r s i z e d or s l i g h t l y s m a l l e r mean t h i r d v e n t r i c l e widths than the v o l u n t e e r c o n t r o l group. These f i n d i n g s suggest that the b r a i n changes t h a t r e s u l t i n t h i r d v e n t r i c u l a r enlargement i n s c h i z o p h r e n i a occur b e f o r e the onset of p s y c h o t i c symptoms. However, i t i s p o s s i b l e t h a t a r a p i d change i n v e n t r i c l e s i z e o c c u r s with the onset of s c h i z o p h r e n i a or with the a d m i n i s t r a t i o n of n e u r o l e p t i c m e d i c a t i o n . Enlargement i n o t h e r p s y c h o t i c p a t i e n t groups, i f i t o c c u r s , i s more l i k e l y t o r e s u l t from the i l l n e s s p rocess or long term treatment 151 e f f e c t s . F u r t h e r r e s e a r c h , u s i n g repeated CT scans i s needed to t e s t these hypotheses. In a d d i t i o n , because no p r e v i o u s study has assessed t h i r d v e n t r i c l e s i z e i n f i r s t episode p s y c h o t i c p a t i e n t s , the present f i n d i n g s r e q u i r e r e p l i c a t i o n b e f o r e any f i r m c o n c l u s i o n s can be drawn. C o r t i c a l S u l c i No d i l a t i o n of the c o r t i c a l s u l c i was e v i d e n t i n any p a t i e n t group r e l a t i v e t o the v o l u n t e e r c o n t r o l group. However, because few medical p a t i e n t s had any v i s i b l e s u l c i , the v o l u n t e e r c o n t r o l group showed s u l c a l d i l a t i o n r e l a t i v e to the medical c o n t r o l group. The i n t e r p r e t a t i o n of p r e v i o u s r e p o r t s of c o r t i c a l atrophy i n p s y c h o t i c p a t i e n t s has been made d i f f i c u l t by a l a c k of consensus r e g a r d i n g the method of a s s e s s i n g s u l c a l d i l a t i o n , and by i n s u f f i c i e n t p r o c e d u r a l i n f o r m a t i o n . W i t h i n these l i m i t a t i o n s , most s t u d i e s (10/13) i n d i c a t e t h a t c o r t i c a l atrophy i s present i n s c h i z o p h r e n i c p a t i e n t s . Of the ten s t u d i e s i n which s i g n i f i c a n t f i n d i n g s were r e p o r t e d , e i g h t used medical p a t i e n t s as c o n t r o l s u b j e c t s . The present f i n d i n g s i n d i c a t e t h a t these r e s u l t s should be i n t e r p r e t e d with c a u t i o n . N e v e r t h e l e s s , the c o n s i s t e n c y of r e p o r t e d atrophy and the f a c t t h a t two i n v e s t i g a t i o n s i n which normal c o n t r o l s u b j e c t s were used r e p o r t atrophy, suggests t h a t a p r o p o r t i o n of s c h i z o p h r e n i c p a t i e n t s have s u l c a l d i l a t i o n . The present f i n d i n g s suggest t h a t t h i s atrophy probably occurs a f t e r the onset of p s y c h o s i s . 152 C o n t r o l Groups A review of p r e v i o u s CT s t u d i e s (see Summary of CT S t u d i e s above) i n d i c a t e s t h a t v a r i a b i l i t y i n the s i z e of the v e n t r i c l e s i n c o n t r o l s u b j e c t s accounts f o r many of the i n c o n s i s t e n c i e s i n r e s e a r c h f i n d i n g s . Some of t h i s i n c o n s i s t e n c y i s accounted f o r by the f a c t t h a t medical c o n t r o l groups tend to have s m a l l e r v e n t r i c l e s than do groups of normal i n d i v i d u a l s . The r e s u l t s of the present study support t h i s f i n d i n g and c l e a r l y i n d i c a t e the mean s i z e o f the t h i r d v e n t r i c l e and c o r t i c a l s u l c i i s l e s s i n the medical c o n t r o l group than i n the normal c o n t r o l group. I f the medical p a t i e n t s are used as a standard of normal m o r p h o l o g i c a l b r a i n measures, then the depressed p a t i e n t s , i n a d d i t i o n t o the s c h i z o p h r e n i c i n d i v i d u a l s would have enlargement of the t h i r d v e n t r i c l e and a l l p a t i e n t groups would appear t o have c o r t i c a l atrophy. Whereas th e r e i s no s i g n i f i c a n t enlargement of the l a t e r a l v e n t r i c l e s i n any group r e l a t i v e t o the medical p a t i e n t s , the d i f f e r e n c e between the s c h i z o p h r e n i c and medical group approaches s i g n i f i c a n c e , t ( 5 9 ) = 1.46, .l>p>.05. There are a number of p o t e n t i a l problems with medical c o n t r o l groups. Some medical d i s o r d e r s , i n c l u d i n g head trauma, hematoma, astrocytomas, and vasospasms, can r e s u l t i n edema and decreased v e n t r i c l e s i z e (Schneider et a l . , 1982). The f a c t t h a t head trauma can r e s u l t i n decreased v e n t r i c l e s i z e i s p a r t i c u l a r l y noteworthy because a number of i n v e s t i g a t o r s i n c l u d e a c c i d e n t v i c t i m s i n t h e i r medical 153 c o n t r o l sample (e.g., Schulz et a l . , 1983; N a s r a l l a h et a l . , 1982a, 1984). B i a s e s i n medical c o n t r o l groups may a l s o stem from the method of choosing "normal" scans. I f scans t h a t are d e s c r i b e d as showing l a r g e v e n t r i c l e s are excluded, an i n v e s t i g a t o r may be r e j e c t i n g those i n d i v i d u a l s who have normal but l a r g e v e n t r i c l e s . For example, t h r e e medical p a t i e n t s i n the present study were d e s c r i b e d as having normal scans but having l a t e r a l v e n t r i c l e s t h a t were l a r g e f o r the person's age. L a t e r a l and t h i r d v e n t r i c l e s i z e f o r these t h r e e p a t i e n t s were w i t h i n the range observed i n the v o l u n t e e r s u b j e c t s . I t i s a l s o noteworthy t h a t the d i s t r i b u t i o n of VBR v a l u e s i n the medical c o n t r o l groups of most p r e v i o u s s t u d i e s i n which the s u b j e c t d i s t r i b u t i o n was p r o v i d e d are p o s i t i v e l y skewed. T h i s i s n o t a b l y so i n the two s t u d i e s i n which f i r s t e pisode s c h i z o p h r e n i c p a t i e n t s were s t u d i e d ( S c h u l z et a l . , 1983; Weinberger et a l . , 1982). The present study and one p r e v i o u s i n v e s t i g a t i o n ( P e a r l s o n et a l . , 1984a) used h e a l t h y v o l u n t e e r s and found a normal d i s t r i b u t i o n i n v e n t r i c l e s i z e . T h i s f i n d i n g t e n t a t i v e l y suggests t h a t medical p a t i e n t groups may be b i a s e d towards sma l l l a t e r a l v e n t r i c l e s . The p r a c t i c e of u s i n g CT scans from r e g u l a r s i z e d X-ray f i l m when t a k i n g p l a n i m e t r y measures can p o t e n t i a l l y r e s u l t i n measurement e r r o r . P l a n i m e t r y r e a d i n g s are taken from a v e r n i e r s c a l e and are read to t h r e e decimal p l a c e s . In the present study the range of area measurements of i n d i v i d u a l 154 l a t e r a l v e n t r i c l e s from r e g u l a r ( s m a l l ) s i z e d CT f i l m i s 0.001 t o 0.019 (These measures are i n a r b i t r a r y u n i t s of a r e a ) . Normal v a r i a b i l i t y i n t r a c i n g s m a l l f i g u r e s such as a s i n g l e l a t e r a l v e n t r i c l e i s g r e a t e r than v e n t r i c l e s i z e f o r sma l l v e n t r i c l e s (approximately + 0.003). Because of the measurement v a r i a b i l i t y a s s o c i a t e d with e s t i m a t i n g the s i z e of small v e n t r i c l e s from s m a l l s i z e d scans, a number of i n v e s t i g a t o r s (Andreasen et a l . , 1982; Targum e t a l . , 1983; Weinberger et a l . , 1979a, 1982) have c l a s s i f i e d some small v e n t r i c l e s as too small t o measure and a s c r i b e d v a l u e s o f zer o or 0.5 VBR u n i t s t o them. However, a s c r i b i n g low numbers t o small v e n t r i c l e s i s l i k e l y to underestimate the a c t u a l s i z e . T h i s c o u l d l e a d to s p u r i o u s l y low e s t i m a t e s of mean v e n t r i c l e s i z e . The t h i r d v e n t r i c l e i s a l s o s u s c e p t i b l e t o measurement e r r o r . Because the t h i r d v e n t r i c l e i s normally sma l l (approximately 1mm to 7.5mm i n the present s t u d y ) , and the image on r e g u l a r s i z e d CT f i l m i s reduced by a f a c t o r of approximately t h r e e , t h i s measure i s d i f f i c u l t t o take a c c u r a t e l y without some m a g n i f i c a t i o n . Incomplete r e p o r t s of methodology i n many of the s t u d i e s of the t h i r d v e n t r i c l e make i t d i f f i c u l t t o as s e s s the i n f l u e n c e o f measurement e r r o r f o r t h i s aspect of the b r a i n . E i g h t of the ten p r e v i o u s s t u d i e s of t h i r d v e n t r i c l e s i z e i n s c h i z o p h r e n i a r e p o r t s i g n i f i c a n t enlargement. I t i s noteworthy that seven of the e i g h t used medical p a t i e n t s as c o n t r o l s u b j e c t s . The one study i n which normal i n d i v i d u a l s 155 were used as c o n t r o l s u b j e c t s (Nyback et a l . , 1982) r e p o r t e d the second l a r g e s t mean t h i r d v e n t r i c l e width and, when RDC diagnoses were used to d e f i n e s c h i z o p h r e n i c p a t i e n t s , the r e s u l t s were not s i g n i f i c a n t . The present f i n d i n g s a l s o i n d i c a t e g r e a t e r mean t h i r d v e n t r i c l e width i n the normal c o n t r o l group than those of the c o n t r o l s of e i g h t of the ten p r e v i o u s s t u d i e s and no enlargement when RDC diagnoses were used. T h i s r e s u l t , together with the present f i n d i n g of a s i g n i f i c a n t d i f f e r e n c e between medical p a t i e n t s and normal c o n t r o l s u b j e c t s over t h i r d v e n t r i c l e width suggests t h a t the t h i r d v e n t r i c l e i n medical c o n t r o l p a t i e n t s may be s m a l l e r than those i n h e a l t h y v o l u n t e e r s . I f t h i s i s the case, then t h i s f a c t o r c o u l d s y s t e m a t i c a l l y b i a s r e s u l t s i n f a v o r of o v e r e s t i m a t i n g the preva l e n c e of t h i r d v e n t r i c u l a r enlargement i n p s y c h o t i c p a t i e n t groups. F u r t h e r s t u d i e s are c l e a r l y needed to examine t h i s p o s s i b i l i t y . The c l e a r e s t d i f f e r e n c e between the medical and normal c o n t r o l groups was ob t a i n e d over r a t i n g s of c o r t i c a l atrophy. An a n a l y s i s of the data i n d i c a t e d t h a t the absence o f v i s i b l e s u l c i i n the medical p a t i e n t s was not due t o the f a c t t h at some of these i n d i v i d u a l s r e c e i v e d an i n j e c t i o n o f c o n t r a s t medium before r e c e i v i n g a CT scan. S p e c i f i e d CT procedures (angle and width of CT cut and window and l e v e l s e t t i n g s on the CT scanner) were the same f o r the medical p a t i e n t s as they were f o r the oth e r s u b j e c t s i n t h i s study. N e v e r t h e l e s s , minor adjustments made t o a CT scanner i n order to i n c r e a s e the r e s o l u t i o n of an area of i n t e r e s t can a f f e c t 156 CT f i n d i n g s with medical p a t i e n t s (Boronow e t a l . , 1985). The c o r t i c a l s u l c i , because they are s m a l l , are more l i k e l y t o be obscured by v a r i a b l e scanning procedures than are l a r g e r b r a i n s t r u c t u r e s . In a d d i t i o n , the f a c t that the v o l u n t e e r c o n t r o l group does not show a s i m i l a r p a t t e r n of r a t i n g s suggests t h a t the f i n d i n g s from the medical c o n t r o l group do not a c c u r a t e l y r e f l e c t the u sual d i s t r i b u t i o n of s u l c a l d i l a t i o n i n the normal p o p u l a t i o n . I t i s , however, u n c l e a r what accounts f o r the d earth of v i s i b l e s u l c i i n the medical p a t i e n t s used i n t h i s study. In summary, the present r e s u l t s i n d i c a t e that medical c o n t r o l groups are p o t e n t i a l l y b i a s e d towards a sm a l l mean s i z e of the t h i r d v e n t r i c l e and fewer v i s i b l e s u l c i . An a n a l y s i s of p r e v i o u s s t u d i e s of the l a t e r a l v e n t r i c l e s t o g e t h e r with the present f i n d i n g s a l s o suggests t h a t l a t e r a l v e n t r i c l e s i z e may be s m a l l e r i n medical c o n t r o l groups than i n normal i n d i v i d u a l s . P o s s i b l e causes of s m a l l v e n t r i c l e s i n medical p a t i e n t s are p a t h o l o g i c a l l y s m a l l v e n t r i c l e s , s u b j e c t s e l e c t i o n b i a s e s , measurement e r r o r a s s o c i a t e d with e s t i m a t i n g s m a l l s t r u c t u r e s , and d i f f e r e n c e s i n CT scanning procedures between r e s e a r c h s u b j e c t s and medical p a t i e n t s . Together the present r e s u l t s and the f i n d i n g s of p r e v i o u s i n v e s t i g a t i o n s suggest that the p r e v a l e n c e of v e n t r i c l e and s u l c a l enlargement i n p s y c h o t i c p a t i e n t s i s exagerated by abnormally sma l l v e n t r i c l e s and s u l c i i n medical c o n t r o l p a t i e n t s . There are no c l e a r standards of normal v e n t r i c u l a r and s u l c a l s i z e at the present time (Maser & K e i t h , 1983). 157 U n t i l normal v a r i a b i l i t y i s d e f i n e d , r e s e a r c h e r s must be c o g n i z a n t of the problems a s s o c i a t e d with u s i n g medical p a t i e n t s . C o n c l u s i o n The present f a i l u r e t o d e t e c t l a t e r a l v e n t r i c u l a r enlargement i n p s y c h o t i c p a t i e n t s i s i n c o n f l i c t with the m a j o r i t y of p r e v i o u s r e s u l t s . Because measures i n the present study were ob t a i n e d from a unique p a t i e n t sample (a r e p r e s e n t a t i v e cros& s e c t i o n of f i r s t episode p a t i e n t s ) and two independent c o n t r o l groups were used, i t p r o v i d e s s t r o n g evidence t h a t a s i g n i f i c a n t p r o p o r t i o n of p a t i e n t s do not have enlargement of the l a t e r a l v e n t r i c l e s a t the onset of p s y c h o s i s . In a d d i t i o n , the present r e s u l t i s i n agreement with a number of recent s t u d i e s i n which no l a t e r a l v e n t r i c u l a r enlargement was found. Together these n e g a t i v e f i n d i n g s emphasize a need f o r c a u t i o n i n drawing c o n c l u s i o n s i n t h i s r e s e a r c h area and s t r o n g l y suggest t h a t i t i s premature t o conclude t h a t a s i g n i f i c a n t p r o p o r t i o n of a l l s c h i z o p h r e n i c p a t i e n t s have LVE. The present r e s u l t s a l s o suggest t h a t any changes i n l a t e r a l v e n t r i c l e s i z e t h a t do occur may f o l l o w r a t h e r than precede the onset of p s y c h o s i s . The f i n d i n g of s i g n i f i c a n t enlargement of the t h i r d v e n t r i c l e i n the p r e s e n t study p r o v i d e s s t r o n g evidence f o r b r a i n anomalies at the onset of p s y c h o s i s i n a s i g n i f i c a n t p r o p o r t i o n of a l l s c h i z o p h r e n i c p a t i e n t s . Because t h i s f i n d i n g was o b t a i n e d i n f i r s t episode p a t i e n t s , these r e s u l t s suggest that changes i n the area of the t h i r d v e n t r i c l e may 158 be a marker of s u s c e p t i b i l i t y t o s c h i z o p h r e n i a , have e t i o l o g i c a l s i g n i f i c a n c e , or t h a t changes occur r a p i d l y with the onset of p s y c h o s i s . No m o r p h o l o g i c a l anomalies i n n o n s c h i z o p h r e n i c p s y c h o t i c p a t i e n t s , on the other hand, suggest t h a t p r e v i o u s l y r e p o r t e d b r a i n anomalies i n c h r o n i c n o n s c h i z o p h r e n i c p a t i e n t s may r e s u l t from the i l l n e s s p r ocess or from long term treatment. The f a c t t h a t t h i s f i n d i n g was o b t a i n e d whether a normal or medical c o n t r o l group was used, adds c o n f i d e n c e to the a s s e r t i o n t h a t b r a i n changes occur i n some s c h i z o p h r e n i c p a t i e n t s b e f o r e the onset of p s y c h o t i c symptoms. The s u g g e s t i o n of atrophy i n the d i e n c e p h a l i c r e g i o n of the b r a i n i s i n t r i g u i n g because the surrounding s t r u c t u r e s are c e n t r a l t o p r e v a i l i n g t h e o r i e s of n e u r a l f u n c t i o n i n g i n s c h i z o p h r e n i a (Neale & Oltmanns, 1981, pp 217-252). The present f i n d i n g s support the c o n t e n t i o n t h a t s t r u c t u r a l b r a i n changes i n the midbrain are c e n t r a l t o the s c h i z o p h r e n i c d e f i c i t . However, i n order to v e r i f y t h i s h y p o t h e s i s , i t w i l l be necessary t o estimate the amount of v e n t r i c u l a r enlargement t h a t has o c c u r r e d r a t h e r than use a measure of a c t u a l v e n t r i c l e s i z e . I f t h i s can be achieved, then r e s e a r c h i n t o the c o r r e l a t e s of b r a i n anomalies i s l i k e l y to advance our knowledge about s c h i z o p h r e n i a s u b s t a n t i a l l y . The present study c l e a r l y i n d i c a t e s t h a t no p a t i e n t group has s i g n i f i c a n t c o r t i c a l atrophy. M e t h o d o l o g i c a l problems and i n s u f f i c i e n t p r o c e d u r a l d e s c r i p t i o n s a s s o c i a t e d with p r e v i o u s s t u d i e s make i t d i f f i c u l t t o compare f i n d i n g s . 159 However, the present r e s u l t s suggest t h a t the s u l c a l d i l a t i o n t h a t was o b t a i n e d i n other s t u d i e s may have r e s u l t e d from the i l l n e s s p r ocess or treatment e f f e c t s or may r e s u l t from b i a s e d c o n t r o l samples. An important f i n d i n g of the present study together with an a n a l y s i s of past s t u d i e s i n d i c a t e t h a t c o n t r o l groups chosen from r a d i o l o g y r e c o r d s may be b i a s e d towards sma l l l a t e r a l and t h i r d v e n t r i c l e s and fewer v i s i b l e s u l c i . I f t h i s i s the case, many p r e v i o u s CT s t u d i e s have overestimated the p r e v a l e n c e of m o r p h o l o g i c a l b r a i n anomalies i n p s y c h o t i c p a t i e n t s . The present r e s u l t s c l e a r l y i n d i c a t e t h a t t h e r e i s an immediate need f o r r e s e a r c h i n t o t h i s problem. The present f i n d i n g s b r i n g i n t o sharp focus both the e x c i t i n g p o s s i b i l i t i e s t h a t t h i s l i n e of r e s e a r c h holds and a c l e a r warning that c a u t i o n i s needed i n drawing c o n c l u s i o n s at the present time. The complexity of r e s e a r c h f i n d i n g s i n d i c a t e a need f o r consensus on the methodology t h a t i s used and f o r more d e t a i l e d s u b j e c t and p r o c e d u r a l i n f o r m a t i o n . As Boronow et a l . (1985) noted, t h e r e i s a growing need f o r a c o l l a b o r a t i v e e f f o r t i n the CT r e s e a r c h of s c h i z o p h r e n i a . In o r d e r to r e s o l v e some of the c o n t r a d i c t i o n s i n the present l i t e r a t u r e , a c o - o p e r a t i v e e f f o r t i s needed to conduct l o n g t i t u d i n a l r e s e a r c h , i n v o l v i n g repeated CT scans, a number of d i f f e r e n t p a t i e n t groups, and c a r e f u l m o n i t o r i n g of c l i n i c a l s t a t u s . T h i s r e s e a r c h must i n c l u d e normal i n d i v i d u a l s f o r comparison with the p s y c h i a t r i c p a t i e n t s and comparisons between medical and normal c o n t r o l groups. 160 References American P s y c h i a t r i c A s s o c i a t i o n (1980). D i a g n o s t i c and s t a t i s t i c a l manual of mental d i s o r d e r s (3rd ed.). Washington, D.C: American P s y c h i a t r i c A s s o c i a t i o n . Andreasen, N. C. (1982). Negative symptoms i n s c h i z o p h r e n i a : D e f i n i t i o n and r e l i a b i l i t y . A r c h i v e s of General P s y c h i a t r y , 39, 784-788. Andreasen, N. C , & Olsen, S. (1982). Negative and p o s i t i v e s c h i z o p h r e n i a . A r c h i v e s of General P s y c h i a t r y , 39, 789-794. Andreasen, N. C., Olsen, S. A., Dennert, J . W., & Smith, M. R. (1982a). V e n t r i c u l a r enlargement i n s c h i z o p h r e n i a : R e l a t i o n s h i p t o p o s i t i v e and n e g a t i v e symptoms. American J o u r n a l of P s y c h i a t r y , 139, 297-302. Andreasen, N. C , Smith, M. R., Jacoby, C. G., Dennert, J . W., & Olsen, S. A. (1982b). V e n t r i c u l a r enlargement i n s c h i z o p h r e n i a : D e f i n i t i o n and p r e v a l e n c e . American J o u r n a l of P s y c h i a t r y , 139, 292-296. A n g r i s t , B. M., Retrosen, J . , & Gershon, S. (1980). D i f f e r e n t i a l e f f e c t s of amphetamine and n e u r o l e p t i c s on n e g a t i v e vs p o s i t i v e symptoms i n s c h i z o p h r e n i a . Psychopharmacology, 72, 17-19. Barron, S. A., Jacobs, L., & K i n k e l , W. R. (1976). Changes i n s i z e of normal l a t e r a l v e n t r i c l e s d u r i n g aging determined by computerized tomography. Neurology, 26, 1011-1013. B a r t f a i , A., Levender, S. E., Nyback, H., Berggren, B., & S c h a l l i n g , D. (1985). Smooth p u r s u i t eye t r a c k i n g , neuro-161 p s y c h o l o g i c a l t e s t performance, and computed tomography i n s c h i z o p h r e n i a . P s y c h i a t r y Research, 15, 49-62. Benes, F., Pearson, S., Jones, B. D., LeMay, M., Cohen, B. M., & L i p i n s k i , J . F. (1982). Normal v e n t r i c l e s i n young s c h i z o p h r e n i c s . B r i t i s h J o u r n a l of P s y c h i a t r y , 141, 90-93. Bentson, J . , Reza, M., Winter, J . , & Wilson, G. (1978). S t e r o i d s and apparent c e r e b r a l atrophy on computer tomography scans. J o u r n a l of Computer A s s i s t e d Tomography, 2, 16-23. B i r d , J . M. (1982). Computerized tomography, atrophy and dementia: A review. Progress i n Neurobiology, 19, 91-115. B i r d , J . M., Levy, R., & Jacoby, R. J . (1986). Computed tomography i n the e l d e r l y : Changes over time i n a normal p o p u l a t i o n . B r i t i s h J o u r n a l of P s y c h i a t r y , 148, 80-85. Boronow, J . , P i c k a r , D., Ninan, P. T., Roy, A., Hommer, D., L i n n o i l a , M., & P a u l , S. M. (1985). Atrophy l i m i t e d to the t h i r d v e n t r i c l e i n c h r o n i c s c h i z o p h r e n i c p a t i e n t s : Report of a c o n t r o l l e d s e r i e s . A r c h i v e s of General  P s y c h i a t r y , 42, 266-270. C a r l e n , P. L., W i l k i n s o n , D. A., Wortzman, G., 8s Holgate, R. (1984). P a r t i a l l y r e v e r s i b l e c e r e b r a l atrophy and f u n c t i o n a l improvement i n r e c e n t l y a b s t i n e n t a l c o h o l i c s . Le J o u r n a l Canadien Des S c i e n c e s Nurologiques, 11, 441-446. Carpenter, W. T., Bartko, J . J . , Carpenter, C. L., & S t r a u s s , J . S. (1976). Another view of s c h i z o p h r e n i a subtypes. 162 A r c h i v e s of General P s y c h i a t r y , 33, 508-516. Crow, T. J . (1980). M o l e c u l a r pathology of s c h i z o p h r e n i a : More than one d i s e a s e process? B r i t i s h M e d i c a l J o u r n a l , 280, 66-68. Crow, T. J . (1981). P o s i t i v e and neg a t i v e s c h i z o p h r e n i a symptoms and the r o l e of dopamine. B r i t i s h J o u r n a l of  P s y c h i a t r y , 139, 251-254. Crow, T. J . , Bloxham, C , Cross, A. J . , F e r r i e r , I. N., Johnstone, E. C , Owen, F., & ©Owens, D. G. (1982a). Is ther e a neurochemical b a s i s f o r the type II syndrome i n s c h i z o p h r e n i a ? B r i t i s h J o u r n a l of P s y c h i a t r y , 140, 205-206. Crow, T. J . , C r o s s , A. J . , Johnstone, E. C , & Owen, F. (1982b). Two syndromes i n s c h i z o p h r e n i a and t h e i r p a t h o g e n i s i s . In F. A. Henn & H. A. N a s r a l l a h , ( E d s . ) , S c h i z o p h r e n i a as a b r a i n d i s e a s e . New York: Oxford U n i v e r s i t y P r e s s . D a r o f f , R. B., & T r o o s t , B. T. (1978). Supranuclear d i s o r d e r s of eye movements. In J . S. G l a s s e r (Ed.), N e u r - ophthalmology. New York: Harper & Row P u b l i s h e r s . Davidson, K., & Bagley, C. R. (1969). S c h i z o p h r e n i a - l i k e psychoses a s s o c i a t e d with o r g a n i c d i s o r d e r s of the c e n t r a l nervous system: A review of the l i t e r a t u r e . In R. N. H e r r i n g t o n (Ed.), Current problems i n n e u r o p s y c h i a t r y :  S c h i z o p h r e n i a , e p i l e p s y , the temporal lobe. ( B r i t i s h J o u r n a l o f P s y c h i a t r y S p e c i a l P u b l i c a t i o n No 4 ) . Ashford, Kent: Headley B r o t h e r s L t d . 163 deLeon, M. J . , George, A. E., F e r r i s , S. H., Christman, D. R., Fowler, J . S., Gentes, C. I., B r o d i e , J . , Rei s b e r g , B., & Wolf, A. P. (1984). P o s i t r o n e m i s s i o n tomography and computed tomography assessments of the ag i n g human b r a i n . J o u r n a l of Computer A s s i s s t e d Tomography, 8, 88-94. D e L i s i , L. E., G o l d i n , L. R., Hamovit, J . R., Maxwell, M. E., Ku r t z , D., & Gershon, E. S. (1986). A f a m i l y study of the a s s o c i a t i o n o f i n c r e a s e d v e n t r i c u l a r s i z e with s c h i z o -p h r e n i a . A r c h i v e s of General P s y c h i a t r y , 43, 148-156. DeMeyer, M. K., Gilmor, R., DeMeyer, W. E., Hendrie, H., Edwards, M., & Franco, J . N. (1984). T h i r d v e n t r i c l e s i z e and v e n t r i c u l a r b r a i n r a t i o i n treatment r e s i s t a n t p s y c h i a t r i c p a t i e n t s . J o u r n a l of O p e r a t i o n a l P s y c h i a t r y , 15, 2-8. Dewan, M. J . , Pandurangi, A. K., Lee, S. H., Ramachandran, T., Levy, B. F., Boucher, M., Yozawitz, A., & Major, L. (1983). C e r e b e l l a r morphology i n c h r o n i c s c h i z o p h r e n i c p a t i e n t s : A c o n t r o l l e d computed tomography study. P s y c h i a t r y Research, 10, 97-103. DeWolf, A.S. (1968). S e l f r e p o r t s and case h i s t o r i e s of s c h i z o p h r e n i c p a t i e n t s : R e l i a b i l i t y and v a l i d i t y of P h i l l i p s S c a l e r a t i n g s . J o u r n a l of C l i n i c a l Psychology, 24, 415-418. Evans, W. A. (1942). An encephalographic r a t i o f o r e s t i m a t i n g v e n t r i c u l a r enlargement and c e r e b r a l atrophy. A r c h i v e s of  N e u r o l o g i c a l P s y c h i a t r y , 47, 931-931. Famuyiwa, 0. 0., E c c l e s t o n , D., Donaldson, A. A., & G a r s i d e , 164 R. F. (1979). T a r d i v e d y s k i n e s i a and dementia. B r i t i s h J o u r n a l of P s y c h i a t r y , 135, 500-504. Flor-Henry, P. (1985). S c h i z o p h r e n i a : Sex d i f f e r e n c e s . Canadian J o u r n a l of P s y c h i a t r y , 30, 319-322. Gato, J . (1980). Measurement s c a l e s and s t a t i s t i c s : Resurgence of an o l d misconception. P s y c h o l o g i c a l B u l l e t i n , 87, 564-567. G i t t l e m a n - K l e i n , R., & K l e i n , D. F. (1969). Premorbid a s o c i a l adjustment and pr o g n o s i s i n s c h i z o p h r e n i a . J o u r n a l of P s y c h i a t r i c Research, 7, 35-53. G l a s s , G. V., Peckham, P. D., & Sanders, J . R. (1974). Consequences of f a i l u r e t o meet assumptions u n d e r l y i n g the f i x e d e f f e c t s a n a l y s i s o f v a r i a n c e and c o v a r i a n c e . Review of E d u c a t i o n a l Research, 42, 237-288. Gluck, E., Radu, E. W., Mundt, C., & Gerhardt, P. A. (1980). A computed tomographic p r o l e c t i v e trohoc study of c h r o n i c s c h i z o p h r e n i c s . Neuroradiology, 20, 167-171. Golden, C. J . , Moses, J . A., Zelazowski, R., Graber, R., Zatz, L. M., Horvath, T. B., & Berger, P. A. (1980). C e r e b r a l v e n t r i c u l a r s i z e and n e u r o p s y c h o l o g i c a l impairment i n young c h r o n i c s c h i z o p h r e n i c s . A r c h i v e s of General P s y c h i a t r y , 37, 619-623. Gottesman, I. I., & S h i e l d s , J . (1982). S c h i z o p h r e n i a : The e p i g e n e t i c p u z z l e . Cambridge: Cambridge U n i v e r s i t y P r e s s . Gyldensted, C. (1977). Measurements of the normal v e n t r i c u l a r system and hemispheric s u l c i o f 100 a d u l t s with computed tomography. Neuroradiology, 14, 183-192. 165 H a r r i s , J . G. (1975). An a b b r e v i a t e d form of the P h i l l i p s R a t i n g S c a l e of Premorbid Adjustment i n s c h i z o p h r e n i a . J o u r n a l of Abnormal Psychology, 84, 129-137. Haug, J . 0. (1962). Pneumoencephalographic s t u d i e s i n mental d i s e a s e . A c t a P s y c h i a t r i c a S c a n d i n a v i a , 3 8 ( s u p p l . ) , 1-114. Hauser, S. L., DeLong, G. R., & Roseman, N. P. (1975). Pneumographic f i n d i n g s i n the i n f a n t i l e autism syndrome. B r a i n , 98, 667-688. Hays, W. L. (1973). S t a t i s t i c s f o r the s o c i a l s c i e n c e s . Toronto: H o l t , R i n e h a r t & Winston, Inc. Holzman, P. S., K r i n g l e n , E., Levy, D. H., P r o c t o r , L. R., & Haberman, S. (1978). Smooth p u r s u i t eye movements i n twins d i s c o r d a n t f o r s c h i z o p h r e n i a . J o u r n a l of P s y c h i a t r i c Research, 14, 111-120. Holzman, P. S., Levy, D. L., Uhlenhuth, E. H., P r o c t o r , L. R., & Freedman, D. X. (1975). Smooth p u r s u i t eye movements and diazepam, C.P.Z., and s e c o b a r b i t a l . Psychopharmacologia, 44, 111-115. Holzman, P. S., P r o c t o r , L. R., & Hughes, D. W. (1973). Eye-t r a c k i n g p a t t e r n s i n s c h i z o p h r e n i a . S c i e n c e , 181, 179-182. Holzman, P. S., P r o c t o r , L. R., Levy, D. L., Y a s i l l o , N. J . , M e l t z e r , H. Y., & Hurt, S. W. (1974). Eye t r a c k i n g d y s f u n c t i o n s i n s c h i z o p h r e n i c p a t i e n t s and t h e i r r e l a t i v e s . A r c h i v e s of General P s y c h i a t r y , 31, 143-149. Holzman, P. S., Soloman, C. M., L e v i n , S., & Waternaux, C. S. (1984). P u r s u i t eye movement d y s f u n c t i o n s i n s c h i z o p h r e n i a . A r c h i v e s of General P s y c h i a t r y , 41, 136-139. 166 Hungerford, G. D., duBoulay, G. H., & Z i l k h a , K. J . (1976). Computerized a x i a l tomography i n p a t i e n t s with severe migraine: A p r e l i m i n a r y r e p o r t . J o u r n a l of Neurology  and N e u r o s u r g i c a l P s y c h i a t r y , 39, 990-1114. Iacono, W. G. (1983). The g e n e t i c s of psychopathology as a t o o l f o r understanding the b r a i n : The search f o r a g e n e t i c marker of s c h i z o p h r e n i a . In I. L i e b l i c h (Ed.), G e n e t i c s of the b r a i n . Amsterdam: E l s e v i e r / N o r t h H o l l a n d B i o m e d i c a l P r e s s . Iacono, W. G., & Koenig, W. G. (1983). Features t h a t d i s t i n g u i s h smooth p u r s u i t eye t r a c k i n g performance of s c h i z o p h r e n i c , a f f e c t i v e d i s o r d e r , and normal i n d i v i d u a l s . J o u r n a l of Abnormal Psychology, 92, 29-41. Iacono, W. G., P e l o q u i n , L. J . , Lumry, A. E., V a l e n t i n e , R. H., & Tuason, V. B. (1982). Eye t r a c k i n g i n p a t i e n t s with u n i p o l a r and b i p o l a r a f f e c t i v e d i s o r d e r s i n r e m i s s i o n . J o u r n a l of Abnormal Psychology, 91, 35-44. Iacono, W. G., Tuason, V. B., & Johnson, R. A. (1981). D i s s o c i a t i o n of smooth p u r s u i t and s a c c a d i c t r a c k i n g performance of s c h i z o p h r e n i c s i n r e m i s s i o n : An o c u l a r r e a c t i o n time task s c h i z o p h r e n i c s perform w e l l . A r c h i v e s  of General P s y c h i a t r y , 38, 991-996. Jacobs, L., K i n k e l , W. R., & H e f f n e r , R. R. (1976). Autopsy c o r r e l a t i o n of computerized tomography: Experience with 6000 CT scans. Neurology, 26, 1111-1118. Jacobs, L., K i n k e l , W. R., & P a i n t e r , F. (1978). Computerized tomography i n dementia with s p e c i a l r e f e r e n c e to changes i n s i z e of normal v e n t r i c l e s d u r i n g aging and normal p r e s s u r e hydrocephalus. In R. Katzman, R. D. T e r r y , & K. L. B i c k s ( E d s . ) . Alzheimer's d i s e a s e s e n i l e dementia  and r e l a t e d d i s o r d e r s , (pp241-260). New York: Raven P r e s s . Jacoby, R. J . , Levy, R., & Dawson, J . M. (1980). Computed tomography i n the e l d e r l y : 1. The normal p o p u l a t i o n . B r i t i s h J o u r n a l of P s y c h i a t r y , 136, 249-255. J e l l i n e k , E. H., (1976). C e r e b r a l atrophy and c o g n i t i v e impairment i n c h r o n i c s c h i z o p h r e n i a . Lancet, 2, 1202-1203. J e l l i n g e r , K. (1977). Neuropathologic f i n d i n g s a f t e r n e u r o l e p t i c long term therapy. In L. R o i z i n , H. S h i r a k i & N. G r c e v i c ( E d s . ) , N e u r o t o x i c i t y . New York: Raven P r e s s . J e r n i g a n , T. L., Zatz, L. M., Moses, J . A., & Berger, P. A. (1982). Computed tomography i n s c h i z o p h r e n i c s and normal v o l u n t e e r s : F l u i d Volume. A r c h i v e s of General P s y c h i a t r y , 39, 765-770. J e s t e , D. V., Kleinman, J . E., P o t k i n , S. G., L u c h i n s , D. J . , & Weinberger, D. R. (1982). Ex uno m u l t i : Subtyping the s c h i z o p h r e n i c syndrome. B i o l o g i c a l P s y c h i a t r y , 17, 199-222. Johnstone, E. C , Crow, T. J . , F r i t h , C. D., Carney, M. W., & P r i c e , J . S. (1978a). Mechanism of the a n t i p s y c h o t i c e f f e c t i n the treatment of acute s c h i z o p h r e n i a . Lancet, 1, 848-851. Johnstone, E. C., Crow, T. J . , F r i t h , C. D., Husband, J . , & 168 K r e e l , L. (1976). C e r e b r a l v e n t r i c u l a r s i z e and c o g n i t i v e c h r o n i c s c h i z o p h r e n i a . Lancet, 2, 924-926. Johnstone, E. C., Crow, T. J . , F r i t h , C. D., Stephens, M., K r e e l , L., & Husband, J . (1978b). The dementia of dementia praecox. Acta P s y c h i a t r i c a S c a n d i n a v i a , 57, 305-324. Johnstone, E. C., Owens, D. G. C , Crow, T. J . , & Jagoe, R. (1981). A CT study of 188 p a t i e n t s with s c h i z o p h r e n i a , a f f e c t i v e p s y c h o s i s , and n e u r o t i c i l l n e s s . In C. P e r r i s , G. Struwe & B. Jansson ( E d s . ) , B i o l o g i c a l p s y c h i a t r y ,  1981, (pp237-240). New York: E l s e v i e r / N o r t h H o l l a n d Bi o m e d i c a l P r e s s . Karson, C. N., Berman, K. F., & LeWitt, P. A. (1983). Neuropharmocological and c l i n i c a l evidence of dopaminergic c o n t r o l . Psychopharmacology B u l l e t i n , 19, 620-622. Kleinman, J . E., Karson, C. N., Weinberger, D. R., Freed, W. J . , Berman, K. F., & Wyatt, R. J . (1984). Eye b l i n k i n g and c e r e b r a l v e n t r i c u l a r s i z e i n c h r o n i c s c h i z o p h r e n i c p a t i e n t s . American J o u r n a l of P s y c h i a t r y , 141, 1430-1432. K l l n g , A. S., K u r t z , N., T a c h i k i , K., & Orzeck, A. (1982/83). CT scans i n subgroups of c h r o n i c s c h i z o p h r e n i c s . J o u r n a l  of P s y c h i a t r i c Research, 17, 375-384. Kokes, R. F., S t r a u s s , J . S., & Klorman, R. (1977). Premorbid adjustment i n s c h i z o p h r e n i a : I I . Measuring premorbid adjustment. S c h i z o p h r e n i a B u l l e t i n , 3, 186-213. Kuechenmeister, C. A., L i n t o n , P. H., & M u e l l e r , T. V. (1977). Eye t r a c k i n g i n r e l a t i o n t o age, sex and i l l n e s s . A r c h i v e s of General P s y c h i a t r y , 130, 59-63. 169 Largen, J . W. , Smith, R. C., Calderon, M., Baumgartner, R., Lu, R., Schoolar, J . C., & Ravichandran, G. K. (1984). A b n o r m a l i t i e s of b r a i n s t r u c t u r e and d e n s i t y i n s c h i z o p h r e n i a . B i o l o g i c a l P s y c h i a t r y , 19, 991-1013. L a r g e n s t e i n , I., W i l l i g , R. P., & Kuhne, D. (1979). R e v e r s i b l e c e r e b r a l atrophy caused by c o r t i c o t r o p h i n . Lancet, 1_, 1246. LeMay, M. & Kido, D. K. (1978). Asymmetries of the c e r e b r a l hemispheres on computed tomograms. J o u r n a l of Computer A s s i s t e d Tomography, 2, 471-476. L i p t o n , R. B., F r o s t , L. A., & Holzman, P. S. (1980). Smooth p u r s u i t eye movements, s c h i z o p h r e n i a and d i s t r a c t i o n . P e r c e p t u a l and Motor S k i l l s , 50, 159-167. L u c h i n s , D. J . (1982). Computed tomography i n s c h i z o p h r e n i a : D i s p a r i t i e s i n the p r e v a l e n c e of a b n o r m a l i t i e s . A r c h i v e s of General P s y c h i a t r y , 39, 859-860. Lu c h i n s , D. J . , Lewine, R. R. J . , & Melzer, H. Y. (1984). L a t e r a l v e n t r i c u l a r s i z e psychopathology and medication response i n the psychoses. B i o l o g i c a l P s y c h i a t r y , 19, 29-44. Lu c h i n s , D. J . , & Melzer, H. Y. (1986). A comparison of CT f i n d i n g s i n acute and c h r o n i c ward s c h i z o p h r e n i c s . Psych- i a t r y Research, 17, 7-14. McNeil, T. F., & K a i j , L. (1978). O b s t e t r i c f a c t o r s i n the development of s c h i z o p h r e n i a . In L. C. Wynne, R. L. Cromwell & S. Matthysse ( E d s . ) , The nature of s c h i z o p h r e n i a , (401-429). 170 Marsden, C. D. (1976). C e r e b r a l atrophy and c o g n i t i v e impairment i n c h r o n i c s c h i z o p h r e n i a . Lancet, 2^ , 1072. Maser, J . , & K e i t h , R. (1983). CT scans and s c h i z o p h r e n i a : Report on a workshop. S c h i z o p h r e n i a B u l l e t i n , 9, 265-283 Mednick, S. A., & S c h u l s i n g e r , F. (1965). A l o n g t i t u d i n a l study of c h i l d r e n with a h i g h r i s k f o r s c h i z o p h r e n i a : A p r e l i m i n a r y r e p o r t . In S. Vandenberg ( E d . ) . Methods and  g o a l s i n human behavior g e n e t i c s , (255-296). New York: Academic P r e s s . M e l t z e r , H. Y. (1979). B i o l o g y of s c h i z o p h r e n i a subtypes: A review and p r o p o s a l f o r methods of study. S c h i z o p h r e n i a  B u l l e t i n , 5, 460-479. Messert, B., Wannamaker, B. B., & Dudley, A. W. (1982). Re-e v a l u a t i o n of the s i z e of the l a t e r a l v e n t r i c l e s of the b r a i n : Postmortem study of an a d u l t p o p u l a t i o n . Neurology, 22, 941-951. M i a l e t , J . P., & P i c h o t , P. (1981). Eye t r a c k i n g p a t t e r n s i n s c h i z o p h r e n i a . A r c h i v e s of General P s y c h i a t r y , 38, 183-186. Myers, J . L. (1979). Fundamentals of experimental design, Toronto: A l l y n and Bacon Inc.. N a s r a l l a h , H. A., Jacoby, C. G., Chapman, S., & McCalley-W h i t t e r s , M. (1985). T h i r d v e n t r i c u l a r enlargement on CT scans i n s c h i z o p h r e n i a : A s s o c i a t i o n w i t h c e r e b e l l a r atrophy. B i o l o g i c a l P s y c h i a t r y , 20, 443-450. N a s r a l l a h , H. A., Jacoby, C. G., M c C a l l e y - W h i t t e r s , M., & Kuperman, S. (1982a). C e r e b r a l v e n t r i c u l a r enlargement i n 171 subtypes of c h r o n i c s c h i z o p h r e n i a . A r c h i v e s of General  P s y c h i a t r y , 39, 774-777. N a s r a l l a h , H. A., Kuperman, S., Hamra, B. J . , & McCalley-W h i t t e r s , M. (1983). C l i n i c a l d i f f e r e n c e s between s c h i z o p h r e n i c p a t i e n t s with and without l a r g e c e r e b r a l v e n t r i c l e s . J o u r n a l of C l i n i c a l P s y c h i a t r y , 44, 407-409. N a s r a l l a h , H. A., M c C a l l e y - W h i t t e r s , M., & Jacoby, C. G. (1982b). C e r e b r a l v e n t r i c u l a r enlargement i n young manic males: A c o n t r o l l e d CT study. J o u r n a l of A f f e c t i v e  D i s o r d e r s , 4, 15-19. N a s r a l l a h , H. A., M c C a l l e y - W h i t t e r s , M., & P f o h l , B. (1984). C l i n i c a l s i g n i f i c a n c e of l a r g e c e r e b r a l v e n t r i c l e s i n manic males. P s y c h i a t r y Research, 13, 151-156. N a s r a l l a h , H. A., Olsen, S. C , M c C a l l e y - W h i t t e r s , M., Chapman, S., & Jacoby, C. G. (1986). C e r e b r a l v e n t r i c u l a r enlargement i n s c h i z o p h r e n i a : A p r e l i m i n a r y follow-up study. A r c h i v e s of General P s y c h i a t r y , 43, 157-159. Neale, J . M., & Oltmanns, T. J . (1980). S c h i z o p h r e n i a • New York: John Wiley & Sons. Nyback, H., W i e s e l , F. A., Berggren, B. M., & Hindmarsh, T. (1982). Computed tomography of the b r a i n i n p a t i e n t s with acute p s y c h o s i s and i n h e a l t h y v o l u n t e e r s . A c t a  P s y c h i a t r i c a S c a n d i n a v i a , 65, 403-414. Okasha, A., Madkour, 0., & Abol Mago, F. (1981). C o r t i c a l and c e n t r a l atrophy i n c h r o n i c s c h i z o p h r e n i a : A c o n t r o l l e d study. In C. P e r r i s , G. Struwe, & B. Jansson ( E d s . ) . B i o l o g i c a l P s y c h i a t r y , 1981, PP. 241-245. New 172 York: E l s e v i e r / H o l l a n d Biomedical P r e s s . Okasha, A., & Madkour, 0. (1982). C o r t i c a l and c e n t r a l atrophy i n c h r o n i c s c h i z o p h r e n i a . Acta P s y c h i a t r i c a S c a n d i n a v i a , 65, 29-34. Okuna, T., I t o , M., K o n i s h i , Y., Yoshioka, M., & Nakano, Y. (1980). C e r e b r a l atrophy f o l l o w i n g ACTH therapy. J o u r n a l of Computer A s s i s t e d Tomography, 4, 20-23. Owens, D. G. C., Johnstone, E. C , Crow, T. J . , F r i t h , C. D., Jagoe, J . R., & K r e e l , L. (1985). L a t e r a l v e n t r i c u l a r s i z e i n s c h i z o p h r e n i a : R e l a t i o n t o the d i s e a s e process and i t s c l i n i c a l m a n i f e s t a t i o n s . P s y c h o l o g i c a l Medicine, 15, 27-41. Pandurangi, A. K., Dewan, M. J . , Lee, S. H., Ramachandran, T., Levy, B. F., Boucher, M., Yozawltz, A., & Major, L. (1984). The v e n t r i c u l a r system i n c h r o n i c s c h i z o p h r e n i c p a t i e n t s : A c o n t r o l l e d computed tomography study. B r i t i s h J o u r n a l of P s y c h i a t r y , 144, 172-176. Parnas, J . , S c h u l s i n g e r , F., S c h u l s i n g e r , H., Mednick, S. A., & Teasdale, T. W. (1982). B e h a v i o r a l p r e c u r s o r s o f s c h i z o p h r e n i a spectrum: A p r o s p e c t i v e study. A r c h i v e s of  General P s y c h i a t r y , 39, 658-664. Parnas, J . , S c h u l s i n g e r , F., Teasdale, T. W., S c h u l s i n g e r , H., Feldman, P. M., & Mednick, S. A. (1982). P e r i n a t a l c o m p l i c a t i o n s and c l i n i c a l outcome w i t h i n the s c h i z o p h r e n i a spectrum. B r i t i s h J o u r n a l of P s y c h i a t r y , 140, 416-420. Pass, H. L., Salzman, L. F., Klorman, R., Kaskey, G. B., & 173 K l e i n , R. H. (1978). The e f f e c t s of d i s t r a c t i o n on acute s c h i z o p h r e n i c s ' v i s u a l t r a c k i n g . B i o l o g i c a l P s y c h i a t r y , 13, 587-593. P e a r l s o n , G. D., Garbacz, D. J . , Breaky, W. R., Ahn, H. S., DePaulo, J . R. (1984). L a t e r a l v e n t r i c u l a r enlargement a s s o c i a t e d with p e r s i s t e n t unemployment and n e g a t i v e symptoms i n both s c h i z o p h r e n i a and b i p o l a r d i s o r d e r . P s y c h i a t r y Research, 12, 1-9. P e a r l s o n , G. D., Garbacz, D. J . , Moberg, P. J . , Ahn, H. S., & DePaulo, J . R. (1985). Symptomatic, f a m i l i a l , p e r i n a t a l and s o c i a l c o r r e l a t e s of computerized a x i a l tomography (CAT) changes i n s c h i z o p h r e n i c s and b i p o l a r s . J o u r n a l of  Nervous and Mental Disease, 173, 42-50. P e a r l s o n , G. D., Garbacz, D. J . , Tomkins, R. H., Ahn, H. S., Gutterman, D. E., V e r o f f , A. E., & DePaulo, J . R. (1984). C l i n i c a l c o r r e l a t e s of l a t e r a l v e n t r i c u l a r enlargement i n b i p o l a r a f f e c t i v e d i s o r d e r . American J o u r n a l of P s y c h i a t r y , 141, 253-256. P e a r l s o n , G. D., & V e r o f f , A. E. (1981). Computerized tomographic scan changes i n manic d e p r e s s i v e i l l n e s s . Lancet, 2, 470. P e a r l s o n , G. D., V e r o f f , A. E., & McHugh, P. R. (1981). The use of computed tomography i n p s y c h i a t r y : Recent a p p l i c a t i o n s t o s c h i z o p h r e n i a , manic d e p r e s s i v e i l l n e s s and dementia syndromes. Johns Hopkins M e d i c a l J o u r n a l , 149, 194-202. Penn, R. D., Belanger, M. G., & Y a s n o f f , W. A. (1978). 174 V e n t r i c u l a r volume i n man computed from CAT scans. Annals  of Neurology, 3, 216-223. P e r r i s , C., Struwe, G., & Jansson, B. (1981). B i o l o g i c a l  P s y c h i a r t y 1981: Proceedings of the I I I world congress of  b i o l o g i c a l p s y c h i a t r y h e l d from June 28th t o J u l y 3rd,  1981 i n Stockholm. New York: E l s e v i e r / N o r t h H o l l a n d B i o m e d i c a l P r e s s . Reveley, M. A. (1985). Ct scans i n s c h i z o p h r e n i a . B r i t i s h  J o u r n a l of P s y c h i a t r y , 146, 367-371. Reveley, A. M., Reveley, M. A., C l i f f o r d , C. A., & Murray, R. M. (1982). C e r e b r a l v e n t r i c u l a r s i z e i n twins d i s c o r d a n t f o r s c h i z o p h r e n i a . Lancet, 1_, 540-541. Reveley, A. M., Reveley, M. A., & Murray, R. M. (1984). C e r e b r a l v e n t r i c u l a r enlargement i n non-genetic s c h i z o p h r e n i a : A c o n t r o l l e d twin study. B r i t i s h J o u r n a l  of P s y c h i a t r y , 144, 89-93. R i e d e r , R. 0., Broman, S. H. , SE Rosenthal, D. (1977). The o f f s p r i n g of s c h i z o p h r e n i c s : I I . P e r i n a t a l f a c t o r s and I. Q.. A r c h i v e s of General P s y c h i a t r y , 34, 789-799. R i e d e r , R. 0., Donnelly, E. F., Herdt, J . R., & Waldman, I. N. (1979). S u l c a l prominence i n young c h r o n i c s c h i z o p h r e n i c p a t i e n t s : CT scan f i n d i n g s a s s o c i a t e d with impairment on n e u r o p s y c h o l o g i c a l t e s t s . P s y c h i a t r y  Research, 1, 1-8. R i e d e r , R. 0., Mann, L. S., Weinberger, D. R., vanKammel, D. P., & Post, R. M. (1983). CAT scans i n p a t i e n t s with s c h i z o p h r e n i a , s c h i z o a f f e c t i v e and a f f e c t i v e d i s o r d e r s . 175 A r c h i v e s of General P s y c h i a t r y , 40, 735-739. Salzman, L. F., K l e i n , R. H., & S t r a u s s , J . S. (1978). Pendulum e y e - t r a c k i n g i n r e m i t t e d p s y c h i a t r i c p a t i e n t s . J o u r n a l of P s y c h i a t r i c Research, 14, 121-126. Schneider, R. C., Kahn, E. A., Crosby, E. C , & Taren, J . A. ( E d s . ) . (1982). C o r r e l a t i v e Neurosurgery (3rd ed.). S p r i n g f i e l d , I l l i n o i s : C h a r l e s C. Thomas. S c h u l s i n g e r , F., Parnas, J . , P e t e r s e n , E. T., S c h u l s i n g e r , H., Teasdale, T. W., Mednick, S. A., M o l l e r , L., & S i l v e r t o n , L. (1984). C e r e b r a l v e n t r i c u l a r s i z e i n the o f f s p r i n g of s c h i z o p h r e n i c mothers: A p r e l i m i n a r y study. A r c h i v e s of General P s y c h i a t r y , 41, 602-606. Sc h u l z , S. C , R o l l e r , M. M. , K i s h o r e , P. R. , Hamer, R. M., Gehl, J . J . , & F r e i d e l , R. 0. (1983). V e n t r i c u l a r enlargement i n teenage p a t i e n t s w i t h s c h i z o p h r e n i a spectrum d i s o r d e r . American J o u r n a l of P s y c h i a t r y , 140, 1592-1595. S c o t t , M. L., Golden, C. J . , Ruedrich, S. L., & Bishop, R. J . (1983). V e n t r i c u l a r enlargement i n major d e p r e s s i o n . P s y c h i a t r i c Research, 8, 91-93. Seidman, L. J . (1983). S c h i z o p h r e n i a and b r a i n d y s f u n c t i o n : An i n t e g r a t i o n of recent n e u r o d i a g n o s t i c f i n d i n g s . P s y c h o l o g i c a l B u l l e t i n , 94, 195-238. Shaglass, C , Amadeo, M., & Overton, D. (1974). E y e - t r a c k i n g performance i n p s y c h i a t r i c p a t i e n t s . B i o l o g i c a l P s y c h i a t r y , 9, 245-260. Shima, S., Kanba, S., Masuda, Y., Tsukumo, T., Kitamura, T., 176 & A s a i , M. (1985). Normal v e n t r i c l e s i n c h r o n i c s c h i z o p h r e n i c s . Acta P s y c h o l o g i c a S c a n d i n a v i a , 71, 25-29. Smith, G. N. (1983). The p r e d i c t i o n of s h o r t term adjustment i n p s y c h o t i c p a t i e n t s . Unpublished master's t h e s i s . U n i v e r s i t y of B r i t i s h Columbia, Vancouver, B. C . Smith, G. N., & Iacono, W. G. (1986). L a t e r a l v e n t r i c l e s i z e i n s c h i z o p h r e n i a and c h o i c e of c o n t r o l group. Lancet, i n p r e s s . Smith, R. C., Baumgartner, R., Ravichandran, G. K., Mauldin, M., Burd, A., V r o u l i s , G., Gordon, J . , & Calderon, M. (1985). L a t e r a l v e n t r i c u l a r enlargement and c l i n i c a l response i n s c h i z o p h r e n i a . P s y c h i a t r y Research, 14, 241-253. Smith, R. C., & Maser, J . (1983). M o r p h o l o g i c a l and neuro-p s y c h o l o g i c a l a b n o r m a l i t i e s as p r e d i c t o r s of c l i n i c a l reponse t o p s y c h o t r o p i c drugs. Psychopharmocology  B u l l e t i n , 19, 505-509. S o i n i n e n , H., Puranen, M., & R l e k k i n e n , P. J . (1982). Computed tomography f i n d i n g s i n s e n i l e dementia and i n normal aging. J o u r n a l of Neurology, Neurosurgery, and  P s y c h i a t r y , 45, 50-54. Sommers, A. A. (1985). Negative symptoms: Conceptual and m e t h o d o l o g i c a l problems. S c h i z o p h r e n i a B u l l e t i n , 11, 364-379. S p i t z e r , R. L., E n d i c o t t , J . , & Robins, E. (1978). Research  d i a g n o s t i c c r i t e r i a (RDC) f o r a s e l e c t e d group of function-a l d i s o r d e r s (3rd Ed.). New York: B i o m e t r i c s Research, New 177 York S t a t e P s y c h i a t r i c I n s t i t u t e . S t a n d i s h - B a r r y , H. M., Bouras, N. , B r i d g e s , P. K., & B a r t l e t t , J . R. (1982). Pneumoencephalographic and computerized a x i a l tomography scan changes i n a f f e c t i v e d i s o r d e r . B r i t i s h J o u r n a l of P s y c h i a t r y , 141, 614-617. Stevens, J . R. (1978). Eye b l i n k and s c h i z o p h r e n i a : P s y c h o s i s or t a r d i v e d y s k i n e s i a ? American J o u r n a l of P s y c h i a t r y , 135, 223-226. Synek, V., & Reuben, J . R. (1976). The v e n t r i c u l a r - b r a i n r a t i o u s i n g p l a n i m e t r i c measurement of EMI scans. B r i t i s h  J o u r n a l of Radiology, 49, 233-237. Tanaka, Y., Hazama, H., Kawahara, R., & Kobayashi, K. (1981). Computerized tomography of the b r a i n i n s c h i z o p h r e n i c p a t i e n t s . A c t a P s y c h i a t r i c a S c a n d i n a v i a , 63, 191-197. Targum, S. D., Rosen, L. N., D e L i s i , L. E., Weinberger, D. L., & C i t r i n , C. M. (1983). C e r e b r a l v e n t r i c u l a r s i z e i n major d e p r e s s i v e d i s o r d e r : A s s o c i a t i o n with d e l u s i o n a l symptoms. B i o l o g i c a l P s y c h i a t r y , 18, 329-336. TerBrugge, K. G., & Rao, K. C. (1983). Hydrocephalus and atrophy. In S. H. Lee & Rao, K. C. ( E d s . ) , C r a n i a l  computed tomography. Toronto: McGraw-Hill Book Co. T r i m b l e , M., & K i n g s l e y , D. (1978). C e r e b r a l v e n t r i c u l a r s i z e i n c h r o n i c s c h i z o p h r e n i a . Lancet, 1, 278-279. Weinberger, D. R. (1984). Computed tomography f i n d i n g s i n s c h i z o p h r e n i a : S p e c u l a t i o n on the meaning of i t a l l . J o u r n a l of P s y c h i a t r i c Research, 18, 477-490. Weinberger, D. R., Bigelow, L. B., & Kleinman, J . E. 178 (1980a). C e r e b r a l v e n t r i c u l a r enlargement i n c h r o n i c s c h i z o p h r e n i a : I t s a s s o c i a t i o n with poor response to treatment. A r c h i v e s of General P s y c h i a t r y , 37, 11-13. Weinberger, D. R., Cannon-Spoor, E., & P o t k i n , S. G. (1980b). Poor premorbid adjustment and CT scan a b n o r m a l i t i e s i n c h r o n i c s c h i z o p h r e n i a . American J o u r n a l of P s y c h i a t r y , 137, 1410-1413. Weinberger, D. R., D e L i s l , L. E., Neophytides, A. N., & Wyatt, R. J . (1981). F a m i l i a l a s p e c t s of CT scan a b n o r m a l i t i e s i n c h r o n i c s c h i z o p h r e n i c p a t i e n t s . P s y c h i a t r y Research, 4, 65-71. Weinberger, D. R., D e L i s i , L. E., Perman, G. P., Targum, S., & Wyatt, R. J . (1982). Computed tomography i n s c h i z o p h r e n i f o r m d i s o r d e r and other acute p s y c h i a t r i c d i s o r d e r s . A r c h i v e s of General P s y c h i a t r y , 39, 778-783. Weinberger, D. R., Torrey, E. F., Neophytides, A., & Wyatt, R. J . (1979). L a t e r a l c e r e b r a l v e n t r i c u l a r enlargement i n c h r o n i c s c h i z o p h r e n i a . A r c h i v e s of General P s y c h i a t r y , 36, 735-739. Weinberger, D. R., Torrey, E. F., Neophytides, A. N., & Wyatt, R. J . (1979b). S t r u c t u r a l a b n o r m a l i t i e s i n the c e r e b r a l c o r t e x of c h r o n i c s c h i z o p h r e n i c s . A r c h i v e s of General  P s y c h i a t r y , 36, 935-939. Weinberger, D. R., Wagner, R. L., & Wyatt, R. J . (1983). n e u r o p a t h o l o g i c a l s t u d i e s of s c h i z o p h r e n i a : A s e l e c t e d review. S c h i z o p r e n i a B u l l e t i n , 9, 193-212. Weinberger, D. R., & Wyatt, R. J . (1982a). B r a i n morphology 179 i n s c h i z o p h r e n i a : In v i v o s t u d i e s . In F. A. Henn & H. A. N a s r a l l a h ( E d s . ) , S c h i z o p h r e n i a as a b r a i n d i s e a s e . New York: Oxford U n i v e r s i t y P r e s s . Weinberger, D. R., & Wyatt, R. J . (1982b). C e r e b r a l v e n t r i c u l a r s i z e : A b i o l o g i c a l marker f o r subtyping c h r o n i c s c h i z o p h r e n i a . In E. Usdin & I. Hasdin ( E d s . ) , B i o l o g i c a l markers i n p s y c h i a t r y and neurology, (pp505-512). New York: Pergamon P r e s s . W i l l i a m s , A. 0., Revely, M. A., Kolakowska, T., Arden, M., & Mandelbrote, B. M. (1985). S c h i z o p h r e n i a with good and poor outcome. I I , C e r e b r a l v e n t r i c u l a r s i z e and i t s c l i n i c a l s i g n i f i c a n c e . B r i t i s h J o u r n a l of P s y c h i a t r y , 146, 239-246. Wing, J . K., Cooper, J . E., & S a r t o r i u s , N. (1974). The  measurement and c l a s s i f i c a t i o n of p s y c h i a t r i c symptoms. London: Cambridge U n i v e r s i t y P r e s s . Woods, B. T., & Wolf, J . (1983). A r e c o n s i d e r a t i o n of the r e l a t i o n of v e n t r i c u l a r enlargement to d u r a t i o n of i l l n e s s i n s c h i z o p h r e n i a . American J o u r n a l of P s y c h i a t r y , 140, 1564-1570. Wyatt, R. J . , P o t k i n , S. G., Kleinman, J . E., Weinberger, D. R., L u c h i n s , D. J . , & J e s t e , D. V. (1981). The s c h i z o p h r e n i a syndrome: Examples of b i o l o g i c a l t o o l s f o r s u b c l a s s i f i c a t i o n . J o u r n a l of Nervous and Mental Diseas e . 169, 100-112. 180 Appendix A Linear Measures of the L a t e r a l V e n t r i c l e s 1. Evan's Ratio i s the width of the greatest span o f the f r o n t a l horns di v i d e d by the greatest width o f the i n t e r n a l diameter of the s k u l l (AB/KL). 2. C e l l a Media Ratio i s the narrowest width of the bodies of the l a t e r a l v e n t r i c l e s d ivided by the greatest i n t e r n a l diameter of the s k u l l (IJ/KL). 3. Bicaudate Ratio i s the width of the v e n t r i c l e s l y i n g between the caudate n u c l e i d ivided by the i n t e r n a l diameter of the s k u l l at the same l e v e l (GB/EE). 4 . Frontal Horn Ratio i s the width o f the f r o n t a l horns divided by the i n t e r n a l diameter o f the s k u l l a t the same l e v e l (AB/CD) Horizontal sections o f the b r a i n at the l e v e l of the t h i r d ( l e f t ) and l a t e r a l (right) v e n t r i c l e s . Arrows i n d i c a t e l i n e a r measurements as described above. 181 APPENDIX B Premorbid S t a t u s Interview and S c a l e s Interview 1. Did you belong t o any groups, c l u b s , o r g a n i z a t i o n s , or a t h l e t i c teams, i n c l u d i n g s c h o o l o r g a n i z a t i o n s , while you were a teenager? Yes (ask i ) No (ask i v ) ( i ) What type of o r g a n i z a t i o n or group d i d you belong to? How long were you a member? Did you hold an o f f i c e or p o s i t i o n of l e a d e r s h i p i n (any o f ) the group(s)? Yes (ask i i ) No (ask i i i ) ( i i ) What p o s i t i o n ( s ) d i d you hold? How long d i d you h o l d t h i s (these) p o s i t i o n ( s ) ? ( i i i ) Would you d e s c r i b e y o u r s e l f as an a c t i v e and i n t e r e s t e d member or were you not very a c t i v e i n t h i s (any of these) o r g a n l z a t i o n ( s ) ? A c t i v e / i n t e r e s t e d Not a c t i v e ( i v ) While you were a teenager, d i d you belong to a group of f r i e n d s who d i d t h i n g s t o g e t h e r ? Yes (ask v) No (ask v i ) 182 (v) Would you d e s c r i b e y o u r s e l f as an a c t i v e and i n t e r e s t e d member? Yes No ._ ( v i ) D id you have any f r i e n d s w h i l e you were a teenager? (ALLOW SUBJECTS TO USE THEIR OWN DEFINITION OF FRIEND) Yes (ask v i i ) No (ask v i i i ) ( v i i ) When you were a teenager, how many f r i e n d s d i d you have? How many of these people were c l o s e f r i e n d s you c o u l d r e a l l y t r u s t or count on? ( v i i i ) Would you d e s c r i b e y o u r s e l f as g e n e r a l l y p r e f e r i n g t o be by y o u r s e l f d u r i n g your teenage years or d i d you p r e f e r t o be with o t h e r people? With o t h e r s Alone ( i x ) D i d you p r e f e r t o be alone i n the years b e f o r e your teens? Yes No 2. Are you p r e s e n t l y married or are you widowed, separated, d i v o r c e d , or have you never been married? married (ASK A & B) widowed (ASK A) When d i d your husband/wife d i e ? separated (ASK A) When d i d you and your husband/wife 183 d i v o r c e d (ASK A) When d i d you and your husband/wife separate? never married (SKIP TO 5) A. When were you married? B. Are you p r e s e n t l y l i v i n g with your husband/wife? 3. How many times have you been l e g a l l y married? (IF MORE THAN ONCE ASK A) A. How long were you married the f i r s t (second) time? 4. (So you've never been/How many times have you been) Divorced? 5. Have you ever l i v e d with someone f o r at l e a s t a year as though you were married? 6. Did you date as a teenager? Yes (ASK A) No (ASK B) 7. How many times d i d you date i n an average month between the ages of 16 and ? 8. D i d you ever get engaged t o be married when you were a teenager? 9. What i s the longest p e r i o d of time you have been i n one r e l a t i o n s h i p s i n c e you were a teenager? A. How o l d were you then? B. How o f t e n d i d you see t h i s person i n an average month? 10. Have you ever been engaged to be married s i n c e you were a teenager? 184 11. Have you ever had sexual r e l a t i o n s with a man/woman (SAME SEX AS EXAMINEE)? Yes (ASK A) No A. Would you say you have had sexual r e l a t i o n s more with men or more with women? 12. Have you been s e x u a l l y a t t r a c t e d to both men and women, or o n l y men or onl y women? Not a t t r a c t e d t o e i t h e r Opposite sex only Both sexes Same sex only 13. (IF NOT MARRIED) Are you l i v i n g w i t h someone now as though you were married? Yes For how long? No 185 Abbrev i a t e d Form of P h i l l i p s Premorbid Adjustment S c a l e ( H a r r i s , 1975). 1. Premorbid S o c i a l - P e r s o n a l Adjustment 61-70 A l e a d e r or o f f i c e r i n f o r m a l l y d e s i g n a t e d groups, c l u b s , or a t h l e t i c teams i n s e n i o r h i g h s c h o o l , v o c a t i o n a l s c h o o l , c o l l e g e , or i n young adulthood. 51-60 An a c t i v e and i n t e r e s t e d p a r t i c i p a n t , but d i d not p l a y a l e a d i n g r o l e i n groups of f r i e n d s , c l u b s , o r g a n i z a t i o n s , or a t h l e t i c teams i n s e n i o r high s c h o o l , v o c a t i o n a l s c h o o l , c o l l e g e or i n young adulthood. 41-50 A nominal member, but had no involvement i n , or commitment t o , groups of f r i e n d s , c l u b s , o r g a n i z -a t i o n s , or a t h l e t i c teams i n s e n i o r high s c h o o l , v o c a t i o n a l s c h o o l , c o l l e g e or i n young adulthood. 31-40 From adolescence through e a r l y adulthood, had onl y a few c a s u a l o r c l o s e f r i e n d s . 21-30 From adolescence through e a r l y adulthood, had no r e a l f r i e n d s , o n l y a few s u p e r f i c i a l r e l a t i o n s h i p s or attachments to o t h e r s . 11-20 From adolescence through e a r l y adulthood, q u i e t , s e c l u s i v e , p r e f e r e d t o be by s e l f ; minimal e f f o r t s t o maintain any c o n t a c t at a l l w i t h o t h e r s . 1-10 No d e s i r e t o be wit h playmates, peers, or o t h e r s , from e a r l y c h i l d h o o d . E i t h e r a s o c i a l or a n t i s o c i a l . 186 2. Premorbid Sexual Adjustment A. M a r r i e d P r e s e n t l y or Formally 61-70 M a r r i e d , o n l y one marriage (or remar r i e d o n l y once as a consequence of death of spouse), l i v i n g as a u n i t . 51-60 M a r r i e d more than one time, maintained a home i n one marriage f o r at l e a s t f i v e y e a r s . 41-50 M a r r i e d and a p p a r e n t l y permanently separated or d i v o r c e d without remarriage but maintained a home i n one marriage f o r a t l e a s t f i v e y e a r s . 31-40 Same as (41-50) but maintained a home i n one marriage f o r l e s s than f i v e y e a r s . B. S i n g l e (30 years or over) 41-50 Has been engaged one or more times or has had a long term r e l a t i o n s h i p ( at l e a s t 2 years ) i n v o l v i n g h e t e r o -sexual r e l a t i o n s or apparent evidence f o r a "l o v e a f f a i r " with one person, but unable t o achieve marriage. 31-40 B r i e f or short-term h e t e r o s e x u a l or s o c i a l d a t i n g experiences with one or more p a r t n e r s , but no long l a s t i n g sexual e x p e r i e n c e s with a s i n g l e p a r t n e r . 21-30 Sexual and/or s o c i a l r e l a t i o n s h i p s p r i m a r i l y with the same sex, but may have had o c c a s i o n a l h e t e r o -sexual c o n t a c t s or d a t i n g e x p e r i e n c e s . 11-21 Minimal sexual or s o c i a l i n t e r e s t i n e i t h e r men or women. 187 C. S i n g l e (under 30 y e a r s ) 61-70 Has had at l e a s t one long-term " l o v e a f f a i r " (minimum of s i x months to one year) or engagement, even though r e l i g i o u s or other p r o h i b i t i o n s or i n h i b i t i o n s may have prevented a c t u a l sexual union. 51-60 B r i e f or s h o r t - t e r m h e t e r o s e x u a l or d a t i n g exper-i e n c e s , " l o v e a f f a i r s " , with one or more p a r t n e r s , but no long l a s t i n g sexual e x p e r i e n c e s with a s i n g l e p a r t n e r . 41-50 Casual sexual or s o c i a l r e l a t i o n s h i p s with persons of e i t h e r sex, with no deep emotional meaning. 31-40 Sexual and/or s o c i a l r e l a t i o n s h i p s p r i m a r i l y with the same sex, w i t h no deep emotional meaning. 21-30 Minimal sexual or s o c i a l i n t e r e s t i n e i t h e r men or women. 188 Question 7 from G i t t l e m a n - K l e i n R a t i n g s of Premorbid  A s o c i a l i t y ( G i t t l e m a n - K l e i n & K l e i n , 1969) S o c i o s e x u a l Adjustment from 16 t o 20 Years of Age. 61-70 Healthy i n t e r e s t i n g i r l s / b o y s ; steady c l o s e r e l a t i o n -s h i p with sexual i n t e r c o u r s e or sexual p l a y . Went out with g i r l s / b o y s r e g u l a r l y ; steady c l o s e r e l a t i o n s h i p with l i t t l e or no sexual p l a y . 51-60 Went out with g i r l s / b o y s r e g u l a r l y ; steady c a s u a l r e l a t i o n s h i p with or without sexual p l a y or i n t e r c o u r s e . 41-50 Went out with g i r l s / b o y s r e g u l a r l y ; p a s s i n g c a s u a l r e l a t i o n s h i p with or without sexual i n t e r c o u r s e . 31-40 Casual o c c a s i o n a l c o n t a c t with g i r l s / b o y s with or without sexual i n t e r c o u r s e or se x u a l p l a y . 21-30 I n t e r e s t e d i n g i r l s / b o y s , but never went out on dates. 11-20 Homosexual involvement o n l y . 1-10 No sexual i n t e r e s t i n e i t h e r sex. 189 Appendix C Symptom C h e c k l i s t s S c h i z o p h r e n i a I n c l u s i o n C r i t e r i a DSM-III RDC A. Phenomenology YES NO YES NO DSM-III: At l e a s t one of 1 t o 6. RDC: A l e a s t 1 of 1 t o 8 f o r probable, 2 f o r d e f i n i t e . a. Somatic, grandiose, r e l i g i o u s , n i h i l i s t i c or o t h e r d e l u s i o n s without p e r s e c u t o r y or j e a l o u s content. 1 1 b. A u d i t o r y h a l l u c i n a t i o n s , running comment-any on p a t i e n t or 2 or more v o i c e s c o n v e r s i n g with each o t h e r . 2_ c. A u d i t o r y h a l l u c i n a t i o n s w i t h no apparent r e l a t i o n t o d e p r e s s i o n or e l a t i o n . DSM-III: More than 1 time & more than 1 or 2 words. 3 RDC: Spoken t o the p a t i e n t . 3_ d. Incoherence, loose a s s o c i a t i o n s , i l l o g i c a l t h i n k i n g or marked poverty of content of speech with b l u n t e d or i n a p p r o p r i a t e a f f e c t 4a 4a_ d e l u s i o n s or h a l l u c i n a t i o n s (or) 4b 4b_ g r o s s l y d i s o r g a n i z e d / c a t a t o n i c behav 4c 4c_ e. D e l u s i o n i f accompanied by h a l l u c i n a t i o n s DSM-III: D e l u s i o n s must have p e r s e c u t o r y or j e a l o u s content. 5 RDC: D e l u s i o n s of any type f o r a t l e a s t one week. 5_ Thought i n s e r t i o n , b l o c k i n g or withdrawal 6a 6 190 Yes No Yes No g. B i z a r r e d e l u s i o n s , or d e l u s i o n s of c o n t r o l or i n f l u e n c e , or other m u l t i p l e d e l u s i o n s . 6b 7 h. H a l l u c i n a t i o n s of any type throughout the day f o r s e v e r a l days or i n t e r m i t t e n t f o r one month 8 B. D u r a t i o n : weeks DSM-III: Prodromal + a c t i v e phase + r e s i d u a l i s at l e a s t 2 weeks. RDC: A c t i v e phase i s at l e a s t 2 weeks. C. D e t e r i o r a t i o n from p r e v i o u s l e v e l of f u n c t i o n i n g i n work, s o c i a l r e l a t i o n s or s e l f - c a r e . D. Check YES i f f u l l (probable f o r RDC) d e p r e s s i v e or manic syndrome i s e i t h e r NOT present or, f o r DSM-III, developed a f t e r any p s y c h o t i c symptoms, or was b r i e f i n d u r a t i o n r e l a t i v e t o the d u r a t i o n of p s y c h o t i c symptoms. E. Onset (prodromal or a c t i v e ) b e f o r e age 45. F. Not due to OBD or MR Prodromal/Residual Symptoms (DSM-III) number of Weeks Prodromal R e s i d u a l a. S o c i a l i s o l a t i o n or withdrawl b. Marked impairment of r o l e f u n c t i o n i n g c. Markedly p e c u l i a r behavior d. Marked impairment of p e r s o n a l hygene e. B l u n t e d , f l a t or i n a p p r o p r i a t e a f f e c t f . D i g r e s s i v e , vague, o v e r e l a b o r a t e , circum-s t a n t i a l , or m e t a p h o r i c a l speech g. Odd or b i z a r r e i d e a t i o n , magical t h i n k i n g 191 S c h i z o p h r e n i a Subtypes DSM-III RDC l e s No Yes No 1. Paranoid: P e r s i s t e n c e or p r e o c c u p a t i o n with one or more of a. P e r s e c u t o r y d e l u s i o n s b. Grandiose d e l u s i o n s c. D e l u s i o n s of j e a l o u s y d. H a l l u c i n a t i o n s with p e r s e c u t o r y or grandiose content 2. D i s o r g a n i z e d (Hebephrenic) RDC: a., b. or c. , and d. are r e q u i r e d . a. RDC: Marked formal thought d i s o r d e r (incoherence, loose a s s o c i a t i o n , i l l o g i c a l t h i n k i n g , poverty of content of speech, neologisms) DSM-III: Frequent incoherence b. RDC: A f f e c t t h a t i s shallow, s i l l y or incongruous DSM-III: Blunted, i n a p p r o p r i a t e or s i l l y a f f e c t c. Fragmentary d e l u s i o n s or h a l l u c i n a t i o n s with content not o r g a n i z e d i n t o a coherent theme d. Not a s s o c i a t e d with marked emotional t u r m o i l exept d u r i n g e x a c e r b a t i o n 3. C a t a t o n i c : C l i n i c a l p i c t u r e i s dominated by any of a. C a t a t o n i c stupor b. C a t a t o n i c n e g a t i v i s m c. C a t a t o n i c r i g i d i t y d. Waxy f l e x i b i l i t y e. C a t a t o n i c excitement 192 Yes No Yes No 4. Undifferentiated (or Mixed): Illness mee+~ --"iteria for more than one subtype or for none 5. Residual 193 S c h i z o a f f e c t i v e D i s o r d e r : RDC T h i s category i n c l u d e s forms i n which the s c h i z o p h r e n i c symptoms are b r i e f i n d u r a t i o n compared to the a f f e c t i v e symptoms or the converse. 1. D i a g n o s t i c C r i t e r i a YES NO A. a) Subject must f u l f i l l the c r i t e r i a f o r probable or d e f i n i t e manic or d e p r e s s i v e syndrome (symptoms A, B, and C from the r e s p e c t i v e c h e c k l i s t s ) b) Signs of i l l n e s s must l a s t at l e a s t one week from the onset of a n o t i c e a b l e change i n the p a t i e n t ' s u s u a l c o n d i t i o n c) A f f e c t i v e symptoms o v e r l a p t e m p o r a r i l y to some degree with the a c t i v e p e r i o d of s c h i z o p h r e n i c -l i k e symptoms ( d e l u s i o n s , h a l l u c i n a t i o n s , thought d i s o r d e r , b i z a r r e b e h a v i o r . B. At l e a s t one of the f o l l o w i n g symptoms s u g g e s t i v e of s c h i z -ophrenia i s present d u r i n g the a c t i v e phase of i l l n e s s . Mania Dep a) D e l u s i o n s of c o n t r o l or i n f l u e n c e , or thought b r o a d c a s t i n g , i n s e r t i o n , or withdrawal. b) N o n a f f e c t i v e h a l l u c i n a t i o n s of any type throughout the day f o r s e v e r a l days or i n t e r -m i t t e n t l y throughout a one week p e r i o d . c) A u d i t o r y h a l u c i n a t i o n s i n which e i t h e r a v o i c e keeps up a running comentary on the s u b j e c t ' s behavior or thoughts, or two or more v o i c e s converse with each o t h e r . d) At sometime d u r i n g the p e r i o d of i l l n e s s , more than one week with no prominent d e p r e s s i v e or manic symptoms but had d e l u s i o n s or h a l l u -c i n a t i o n s ( t y p i c a l d e p r e s s i v e d e l u s i o n s such as d e l u s i o n s of g u i l t , s i n , poverty, n i h i l i s m , s e l f - d e p r e c i a t i o n or h a l l u c i n a t i o n s of s i m i l a r content are not i n c l u d e d ) . e) S e v e r a l d e f i n i t e i n s t a n c e s of marked formal thought d i s o r d e r accompanied by e i t h e r b l u n t e d or i n a p p r o p r i a t e a f f e c t , d e l u s i o n s or h a l l u -c i n a t i o n s of any type, or g r o s s l y d i s o r g a n i z e d b e h a v i o r . For mania on l y , t h i s must occur d u r i n g a one week i n t e r v a l when no prominent 194 Mania Dep f ) P r e o c c u p a t i o n with a d e l u s i o n or h a l l u c i n a t i o n to the r e l a t i v e e x c l u s i o n of other symptoms or concerns (other than t y p i c a l d e p r e s s i v e d e l u s i o n s and h a l l u c i n a t i o n s . 2. Mainly S c h i z o p h r e n i c i f e i t h e r A or B. YES NO A. Core s c h i z o p h r e n i c symptoms l i s t e d under l . B . above were present f o r a t l e a s t one week i n the absence of manic or d e p r e s s i v e f e a t u r e s . B. P r i o r to the onset of d e p r e s s i v e f e a t u r e s , the p a t i e n t e x h i b i t e d the f o l l o w i n g f e a t u r e s which are o f t e n a s s o c i a t e d with s c h i z o p h r e n i a : S o c i a l withdrawal, impairment of o c c u p a t i o n a l f u n c t i o n -i n g , e c c e n t r i c behavior, emotional b l u n t i n g , or unusual thoughts or p e r c e p t u a l e x p e r i e n c e s . 3. Ma i n l y a f f e c t i v e i f both A and B. A. S c h i z o p h r e n i c - l i k e symptoms l i s t e d under l . B . above f o l l o w e d manic or d e p r e s s i v e symptoms and were never present f o r at l e a s t one week i n the absence of manic or d e p r e s s i v symptoms. B. Good premorbid s o c i a l and o c c u p a t i o n a l f u n c t i o n i n g 4. Other, does not c l e a r l y f i t 2 or 3. 195 Manic Episode I n c l u s i o n DSM-III RDC YES NO YES NO A. E l e v a t e d , expansive or i r r i t a b l e mood t h a t i s prominent and p e r s i s t a n t . B. D u r a t i o n : weeks, YES = 1 week or more. C. DSM-III and RDC: 3/7 symptoms needed i f mood i s expansive 4/7 i f i r r i t a b l e . 1. Increased s o c i a l or sexual a c t i v i t y or r e s t l e s s n e s s . 2. Increased t a l k a t i v e n e s s or p r e s s u r e t o t a l k . 3. F l i g h t o f idea s or r a c i n g thoughts. 4. I n f l a t e d s e l f - e s t e e m . 5. Decreased need f o r s l e e p . 6. D i s t r a c t i b l e . 7. E x c e s s i v e involvement i n a c t i v i t i e s without r e c o g n i z i n g the h i g h p o t e n t i a l f o r p a i n f u l consequences. D. DSM-III: Check YES i f b e f o r e the episode developed o r a f t e r i t r e m i t t e d t h e r e were NO mood incongruent d e l u s i o n s or h a l l u -c i n a t i o n s or b i z a r r e b e h a v i o r . RDC: Check YES i f c r i t e r i a f o r s c h i z o -a f f e c t i v e d i s o r d e r are NOT met. E. Check YES i f d i s o r d e r i s NOT superimposed on s c h i z o p h r e n i a , p a r a n o i d d i s o r d e r , or o r g a n i c mental d i s o r d e r . 196 Mania wi t h P s y c h o t i c F e a t u r e s : DSM-III 1. Mood Congruent YES NO a. D e l u s i o n s or h a l l u c i n a t i o n s whose content i s e n t i r e l y c o n s i s t e n t w i t h themes of i n f l a t e d worth, power, knowledge, i d e n t i t y or s p e c i a l r e l a t i o n s h i p to a d e i t y or famous person. b. F l i g h t of ide a s without apparent awareness by the i n d i v i d u a l that the speech i s not understandable. 2. Mood Incongruent ( e i t h e r a or b below) a. D e l u s i o n or h a l l u c i n a t i o n s whose content does not i n v o l v e themes of e i t h e r i n f l a t e d worth, power, knowledge, i d e n t i t y , or s p e c i a l r e l a t i o n s h i p t o a d e i t y or famous person. Included are p e r s e c u t o r y d e l u s i o n s , thought i n s e r t i o n , and d e l u s i o n s of c o n t r o l , whose content has no apparent r e l a t i o n -s h i p t o the themes noted above. b. Any of the f o l l o w i n g c a t o t o n i c sy ptoms: stupor, mutism, neg a t i v i s m , p o s t u r i n g . 197 Major Depressive Episode I n c l u s i o n C r i t e r i a DSM-III RDC YES NO YES NO A. Prominent p e r s i s t e n t d y s p h o r i c mood or l o s s of i n t e r e s t or p l e a s u r e . B. D u r a t i o n weeks. DSM-III: 2 weeks or more. RDC: 2 weeks or more f o r d e f i n i t e , 1 week f o r probable. C. DSM-III: 4/8 symptoms needed. RDC: 5/8 symptoms f o r d e f i n i t e , 4/8 f o r probable. 1. P o o r / i n c r e a s e d a p p e t i t e with weight l o s s or g a i n ( l i b per week or 101b i n a year) 2. Insomnia or hypersomnia 3. Loss of energy or f a t i g u e . 4. Loss of i n t e r e s t , p l e a s u r e or sex d r i v e . 5. F e e l i n g s of w o r t h l e s s n e s s , g u i l t or s e l f r e p r o a c h f u l . 6. Diminished a b i l i t y t o t h i n k , c o n c e n t r a t e or i n d e c i s i v e n e s s . 7. Recurrent thoughts of death, s u i c i d e or s u i c i d a l b e h a v i o r . 8. A g i t a t i o n or r e t a r d a t i o n . D. DSM-III: Check YES i f b e f o r e the episode developed or a f t e r i t r e m i t t e d there were NO mood incongruent d e l u s i o n s or h a l l u c -i n a t i o n s or b i z a r r e b e h a v i o r . RDC: Check YES i f c r i t e r i a f o r s c h i z o -a f f e c t i v e d i s o r d e r i s NOT met. F. Check YES i f the d i s o r d e r i s NOT super-imposed on s c h i z o p h r e n i a p a r a n o i d d i s o r d e r , OBD, or uncomplicated bereavement. G. P a t i e n t s sought help;took medications or was d y s f u n c t i o n a l d u r i n g episode. 198 S u b c l a s s i f i c a t i o n of Major Depressive Episode 1. P s y c h o t i c DSM-III YES NO Gross impairment i n r e a l i t y t e s t i n g (e.g. d e l u s i o n s or h a l l u c i n a t i o n s ) or D e p r e s s i v e stupor (mute or unresponsive) a. Mood congruent p s y c h o t i c f e a t u r e s : D e l u s i o n s or h a l l u c i n a t i o n s whose content i s e n t i r e l y c o n s i s t e n t with themes of p e r s o n a l inadequacy, g u i l t , d i s e a s e , death, n i h i l i s m , or deserved punishment. De p r e s s i v e s t u p o r . b. Mood incongruent p s y c h o t i c f e a t u r e s : D e l u s i o n s or h a l l u c i n a t i o n s with themes other than the above (e.g. p e r s e c u t o r y d e l u s i o n s , thought i n s e r t i o n , thought b r o a d c a s t i n g , and d e l u s i o n s of c o n t r o l ) . 2. P s y c h o t i c RDC a. C r i t e r i a f o r s c h i z o a f f e c t i v e d i s o r d e r are not met. b. One of the f o l l o w i n g : D e l u s i o n s H a l l u c i n a t i o n s D e p r e s s i v e stupor (mute or unresponsive) 3. M e l a n c h o l i c DSM-III Loss of p l e a s u r e i n almost a l l a c t i v i t i e s Lack of r e a c t i v i t y t o u s u a l l y p l e a s u r a b l e a c t i v i t i e s . Three of the f o l l o w i n g : a. Depressed mood d i s t i n c t l y d i f f e r e n t from that a s s o c i a t e d with the death of a loved one. b. Depression worse i n the morning. c. E a r l y morning wakening (2 hours e a r l y ) d. Marked psychomotor r e t a r d a t i o n or a g i t a t i o n . e. S i g n i f i c a n t a n o r e x i a or weight l o s s . ±99 4. Endogenous RDC Yes No One symptome from a. p l u s f o u r symptoms from a. and b. f o r probable, s i x f o r d e f i n i t e . a. Depressed mood d i s t i n c t l y d i f f e r e n t from that a s s o c i a t e d with the death of a loved one. Lack of r e a c t i v i t y t o environmental changes. Mood worse i n the morning. P e r v a s i v e l o s s of i n t e r e s t or p l e a s u r e . b. S e l f reproach or e x c e s s i v e / i n a p p r o p r i a t e g u i l t . E a r l y morning wakening or middle insomnia. Psychomotor r e t a r d a t i o n or a g i t a t i o n . Poor a p p e t i t e . Weight l o s s (21b/week f o r s e v e r a l weeks or 201b year when not d i e t i n g ) Loss of i n t e r e s t / p l e a s u r e or decreased sex d r i v e . 5. Primary RDC Episode NOT preceded by other n o n a f f e c t i v e p s y c h i a t r i c d i s o r d e r , s e r i o u s p h y s i c a l i l l n e s s or p h y s i c a l i l l n e s s o f t e n a s s o c i a t e d with psycho-l o g i c a l symptoms. 6. Secondary RDC Episode preceded by one of the above. 7. I n c a p a c i t a t i n g RDC , One of the f o l l o w i n g ; a. Unable to f u n c t i o n at work or s c h o o l , or t o take care of the house f o r at l e a s t one week . ( o r , . i f was h o s p i t a l i z e d , was so impaired t h a t o b v i o u s l y c o u l d not work). b. Unable t o feed or c l o t h e h i m s e l f or maintain minimal p e r s o n a l hygiene without h e l p . 8. A g i t a t e d RDC Yes Two of the f o l l o w i n g symptoms are present f o r at l e a s t s e v e r a l days; a. P a c i n g b. Handwringing c. Unable t o s i t s t i l l d. P u l l i n g or rubbing on h a i r , s k i n , c l o t h i n g , or oth e r o b j e c t s e. Outbursts of complaining or s h o u t i n g f . T a l k s on and on or cannot seem to stop t a l k i n g 9. Retarded RDC Two of the f o l l o w i n g symptoms are present f o r a t l e a s t one week; a. Slowed speech b. Increased pauses b e f o r answering c. Low or monotonous speech d. Mute or markedly decreased amount of speech e. Slowed body movements 10. S i t u a t i o n a l RDC An event or s i t u a t i o n seems l i k e l y t o have c o n t r i b u t e d t o the d e p r e s s i v e episode. 11. Simple RDC No s i g n i f i c a n t s i g n s of p s y c h i a t r i c d i s t u r b a n c e i n the p r e v i o u s year, other than those a s s o c i a t e d with the a f f e c t i v e i l l n e s s . O f ten begins with phobias, p a n i c a t t a c k s , or e x c e s s i v e somatic concern. 201 DSM-III D i a g n o s i s  A x i s I. C l i n i c a l syndromes: A x i s I I . P e r s o n a l i t y d i s o r d e r s : A x i s I I I . P h y s i c a l d i s o r d e r s : A x i s IV. S e v e r i t y of p s y c h o s o c i a l s t r e s s o r s : T h i s r a t i n g shoud be based on the c l i n i c i a n ' s assessment of the s t r e s s an average person i n s i m i l a r circumstances with s i m i l a r s o c i o c u l t u r a l v a l u e s would experience from the p a r t i c u l a r p s y c h o s o c i a l s t r e s s o r s . Consider a. the amount of change i n the i n d i v i d u a l s l i f e caused by the s t r e s s o r . b. the degree t o which the event i s d e s i r e d . c. the degree to which the event i s under the i n d i v i d u a l ' s c o n t r o l . d. the number of s t r e s s o r s . The r a t i n g should not be based on the i n d i v i d u a l ' s vuner-a b i l i t y t o the p a r t i c u l a r s t r e s o r . In most cases the s t r e s s o r w i l l have o c c u r r e d w i t h i n the year p r i o r t o the onset of the c u r r e n t episode. In some i n s t a n c e s i t c o u l d be the a n t i c i p a t i o n of a f u t u r e event, e.g., r e t i r e m e n t . Code Term A d u l t Example 1 None No apparent s t r e s s o r 2 Minimal Minor v i o l a t i o n s of the law; s m a l l bank loan 3 M i l d Argument with neighbor, change i n work hours 4 Moderate New c a r e e r , death of a c l o s e f r i e n d , pregnancy 5 Severe S e r i o u s i l l n e s s i n s e l f or f a m i l y , major f i n a n t i a l l o s s , m a r r i t a l s e p a r a t i o n , b i r t h of a c h i l d 6 Extreme Death of a c l o s e r e l a t i v e , d i v o r c e 7 C a t a s t r o p h i c C o n c e n t r a t i o n camp experi e n c e , d e v a s t a t i n g n a t u r a l d i s a s t e r 8 U n s p e c i f i e d No i n f o r m a t i o n or not a p p l i c a b l e •Z02 A x i s V. Highest l e v e l of ad a p t i v e f u n c t i o n i n g i n the past year Adaptive f u n c t i o n i n g i s a composite of three major areas: s o c i a l r e l a t i o n s , o c c u p a t i o n a l f u n c t i o n i n g , and use of l e i s u r e time. In making the r a t i n g , s p e c i a l a t t e n t i o n should be p a i d t o s o c i a l r e l a t i o n s . Code Term 1 S u p e r i o r D e s c r i p t i o n Unusually e f f e c t i v e f u n c t i o n i n g i n a l l three areas 2 3 Very good B e t t e r than average f u n c t i o n i n g i n a l l three areas Good F a i r Poor No more than s l i g h t impairment i n e i t h e r s o c i a l or o c c u p a t i o n a l f u n c t i o n i n g Moderate impairment i n e i t h e r s o c i a l or o c c u p a t i o n a l f u n c t i o n i n g , or some impairment i n both Marked impairment i n e i t h e r s o c i a l r e l a t i o n s or o c c u p a t i o n a l f u n c t i o n i n g , or moderate impairment i n both 6 Very poor Marked impairment i n both s o c i a l r e l a t i o n s and o c c u p a t i o n a l f u n c t i o n i n g 7 G r o s s l y Gross impairment i n v i r t u a l l y a l l areas of impaired f u n c t i o n i n g 8 No i n f o r m a t i o n RDC D i a g n o s i s RDC d i a g n o s i s Notes: Use the space below f o r any q u a l i f y i n g i n f o r m a t i o n or important d e t a i l s . 2 0 3 P o s s i b l e Diagnoses DSM-III S c h i z o p h r e n i a : Paranoid, D i s o r g a n i z e d , C a t a t o n i c , U n d i f f -e r e n t i a t e d , R e s i d u a l , A t y p i c a l , S c h i z o p h r e n i f o r m . B r i e f r e a c t i v e p s y c h o s i s . B i p o l a r d i s o r d e r : Manic, Depressed, Mixed, A t y p i c a l . Major d e p r e s s i v e d i s o r d e r , A t y p i c a l d e p r e s s i o n . P a r a n o i a : Shared paranoid d i s o r d e r , Acute paranoid d i s o r d e r , RDC (Note: Diagnoses can be probable or d e f i n i t e . ) S c h i z o p h r e n i a : Paranoid, D i s o r g a n i z e d , C a t a t o n i c , U n d i f f e r e n t -i a t e d , R e s i d u a l . S c h i z o a f f e c t i v e D i s o r d e r : Manic, Depressed. Depressive syndrome superimposed on r e s i d u a l s c h i z o p h r e n i a . Manic D i s o r d e r . Major Depressive D i s o r d e r : Primary, Secondary, Recurrent u n i p o l a r , P s y c h o t i c , I n c a p a c i t a t i n g , Endogenous, A g i t a t e d , Retarded, S i t u a t i o n a l , Simple. U n s p e c i f i e d F u n c t i o n a l D i s o r d e r . 2 0 4 Appendix D Consent Forms Consent Form 1_ Name I agree t o p a r t i c i p a t e i n t h i s study of h e a l t h and s o c i a l problems. I understand t h a t my involvement w i l l i n c l u d e i n t e r v i e w s , the completion of q u e s t i o n a i r e s , and the review of my h e a l t h r e c o r d s . I a l s o understand that I may be asked to p a r t i c i p a t e a g a i n i n t h i s study i n 9 months and i n 18 months and th a t I may be i n v i t e d to p a r t i c i p a t e i n another p a r t of t h i s study i n which my p h y s i c a l r e a c t i o n s t o simple tones and l i g h t s w i l l be measured. T h i s separate s e c t i o n of the study, d e a l i n g with p h y s i c a l r e a c t i o n s , w i l l be e x p l a i n e d i n more d e t a i l l a t e r and I can decide at th a t time whether or not I wish t o take p a r t i n i t . I understand that i n f o r m a t i o n t h a t w i l l be h e l p f u l t o my care or treatment w i l l be conveyed t o my ( p a t i e n t ' s name: ) t h e r a p i s t . I understand that p u b l i c a t i o n s that are the products of t h i s study w i l l c o n t a i n r e p o r t s about groups of persons and that no i n d i v i d u a l w i l l be i d e n t i f i a b l e . F i n a l l y , I understand that I am ( o r [ p a t i e n t ' s name] i s ) f r e e t o withdraw from t h i s p r o j e c t at any time; t h i s w i l l i n no way a f f e c t any h e a l t h or s o c i a l s e r v i c e s t h a t I am (or [ p a t i e n t ' s name] i s ) r e c e i v i n g . S i g n a t u r e : (Parent or guardian must s i g n i f i n d i v i d u a l i s under 16 or i f unable t o g i v e v a l i d consent) 205 Consent Form 2 ( P s y c h o p h y s i o l o g i c a l T e s t i n g ) I have been asked t o p a r t i c i p a t e i n a study i n which my body's responses w i l l be recorded w h i l e I perform s e v e r a l simple t a s k s . These t a s k s i n c l u d e comfortably r e l a x i n g w h ile l i s t e n i n g t o b r i e f tones, watching b r i e f f l a s h e s of l i g h t , and watching a spot of l i g h t move back and f o r t h on a screen and attempting t o produce s i m i l a r movements by t u r n i n g a knob back and f o r t h . The responses of my body that w i l l be recorded i n c l u d e my eye movements, heart beat, b r a i n waves, and the a c t i v i t y of my sweat glands. To make these r e c o r d i n g s , sensors w i l l be a t t a c h e d to my arms, l e g s and head, but no danger or d i s c o m f o r t t o myself i s i n v o l v e d . In another p a r t o f t h i s study, a drop o f o i l , s i m i l a r t o cooking o i l , w i l l be p l a c e d on my s k i n near each of my f i n g e r n a i l s and a photograph of my s k i n w i l l be made. I understand that these t e s t s w i l l not i n f l u e n c e my medical care or treatment, and that a l l the i n f o r m a t i o n o b t a i n e d i n t h i s p r o j e c t w i l l be kept c o n f i d e n t i a l and used o n l y f o r the purposes of t h i s study. By s i g n i n g t h i s form, I agree t o p a r t i c i p a t e , a lthough I r e a l i z e t h a t I am f r e e t o withdraw from t h i s study at any time without p r e d j u d i c e t o c u r r e n t and f u t u r e care and treatment. S i g n i t u r e Witness P r i n t name Date I.D. number 206 Consent Form 3a (CAT Scan; P a t i e n t ) You have been asked to p a r t i c i p a t e i n a study i n which p i c t u r e s of your head w i l l be made with a machine c a l l e d a CAT scanner or body image scanner. A CAT scan i s very much l i k e an X-ray and makes i t p o s s i b l e t o look at the s t r u c t u r e or organs i n s i d e a person's body. Having a CAT scan made i s a r o u t i n e h o s p i t a l procedure t h a t takes about 20 minutes. There i s nothi n g unpleasant about a CAT scan; a l l you have to do i s l i e s t i l l on a bed while the machine takes the p i c t u r e . L i k e an X-ray, a CAT scan i n v o l v e s exposure t o some r a d i a t i o n . The purpose of our study i s to determine i f th e r e are f e a t u r e s of the b r a i n t h a t are r e l a t e d t o the k i n d s of problems t h a t you have been having or t h a t are r e l a t e d t o the measures of eye-movement, sweat gland, and b r a i n wave a c t i v i t y that we have recorded from you e a r l i e r i n the MAP study. Information t h a t w i l l be h e l p f u l t o your care or treatment may be conveyed to your t h e r a p i s t (or to ). Otherwise, a l l the i n f o r m a t i o n o b tained i n t h i s p r o j e c t w i l l be kept c o n f i d e n t i a l and used o n l y f o r the purposes of t h i s study. You are f r e e to ask q u e s t i o n s about the procedure a t any time. By s i g n i n g t h i s form, you agree to p a r t i c i p a t e , although you are f r e e t o withdraw from t h i s study at any time without predudice t o c u r r e n t and f u t u r e care and treatment. Witness S i g n a t u r e Date ID Number 207 Consent Form 3b (CAT Scan; C o n t r o l ) You have been asked t o p a r t i c i p a t e i n a study i n which p i c t u r e s of your head w i l l be made with a machine c a l l e d a CAT scanner or body image scanner. A CAT scan i s very much l i k e an X-ray and makes i t p o s s i b l e t o look at the s t r u c t u r e or organs i n s i d e a person's body. Having a CAT scan made i s a r o u t i n e h o s p i t a l procedure that takes about 20 minutes. There i s nothing unpleasant about a CAT scan; a l l you have t o do i s l i e s t i l l on a bed w h i l e the machine takes the p i c t u r e . L i k e an X-ray, a CAT scan i n v o l v e s exposure t o some r a d i a t i o n . The purpose of our study i s t o determine i f t h e r e are f e a t u r e s of the b r a i n s t r u c t u r e t h a t are r e l a t e d t o d i f f e r e n t k i n d s of p s y c h i a t r i c d i s o r d e r and to the f i n d i n g s from the eye-movement, sweat gland, and b r a i n wave ta s k s you completed e a r l i e r i n the study. Of course, we need people who do not have p s y c h i a t r i c d i s o r d e r s , such as y o u r s e l f , i n our study f o r comparison w i t h those who do. Information t h a t may be h e l p f u l t o your h e a l t h may be conveyed t o your p e r s o n a l p h y s i c i a n , (or t o ). Otherwise, a l l the i n f o r m a t i o n o b t a i n e d i n t h i s p r o j e c t w i l l be kept c o n f i d e n t i a l and used o n l y f o r the purposes of t h i s s t u y. You are f r e e t o ask q u e s t i o n s about the procedure at any time. You have the r i g h t t o r e f u s e t o p a r t i c i p a t e or withdraw from the study a t any time. Witness S i g n a t u r e Date ID Number 208 Appendix E S c r e e n i n g Schedule f o r P a t i e n t s WHO c o l a b o r a t i v e study on determinants of outcome of severe mental d i s o r d e r . Name of F a c i l i t y : Person who made t h i s assessment: Name: P o s i t i o n : P a t i e n t ' s r e s e a r c h number ( t o be completed by r e s e a r c h team): / / Date when t h i s form was f i l l e d i n : / / Sex of p a t i e n t (1 = male, 2 = female): A. 1) Is t h i s p a t i e n t ' s age below 15 or above 54? Yes No 2) Does t h i s p a t i e n t at present l i v e o u t s i d e the catchment area d e f i n e d f o r t h i s study? Yes No B. Is t h e r e evidence t h a t t h i s p a t i e n t has any of the f o l l o w i n g problems? (see g u i d l i n e s ) 1) C l i n i c a l l y manifest o r g a n i c c e r e b r a l d i s o r d e r (e.g., i n f e c t i o u s , p a r a s i t i c , c e r b r o v a s c u l a r , t o x i c , e p i l e p s y , b r a i n i n j u r y , e t c . ) Yes No 2) Severe mental r e t a r d a t i o n ( i . e . , IQ l e s s than 50, or c l i n i c a l l y m a n ifest as such) Yes No 3) Severe a l c o h o l dependence manifest i n : Presence of marked withdrawal symptoms Yes No Presence of a l c o h o l encephalopathy or Korsakov's p s y c h o s i s Yes No H i s t o r y of acute a l c o h o l p s y c h o s i s ( d e l i r i u m tremens or h a l l u c i n o s i s ) w i t h i n the l a s t year Yes No 4) Demonstrable dependence on e i t h e r : 1) Opium or d e r i v a t i v e s or i i ) B a r b i t u r a t e s Yes No 209 C. During the past one year has the p a t i e n t presented any of the f o l l o w i n g ? 1) H a l l u c i n a t i o n s or p s e u d o h a l l u c i n a t i o n s i n any m o d a l i t y . 2) D e l u s i o n s . 3) Marked thought and speech d i s o r d e r (e.g., incoherence, i r r e l e v a n c e , thought b l o c k i n g , neologisms, i n c o m p r e h e n s i b i l i t y of speech) other than simple r e t a r d a t i o n or a c c e l e r a t i o n . 4) Marked psychomotor d i s o r d e r (e.g., n e g a t i v i s m mutism or stupor; c a t a t o n i c exitement; c o n s t r a i n e d a t t i t u d e s or u n n a t u r a l postures maintained f o r long p e r i o d s ) other than simple r e t a r d a t i o n or a c c e l e r a t i o n . 5) Emergence or marked e x a c e r b a t i o n of b i z a r r e and g r o s s l y i n a p p r o p r i a t e behavior (e.g., t a l k i n g or g i g g l i n g to s e l f , a c t s incomprehensible t o o t h e r s , l o s s of s o c i a l c o n s t r a i n t s , e t c . ) Yes No D. During the past one year, has the p a t i e n t presented a d e f i n i t e change of p e r s o n a l i t y and behavior manifested i n any of the f o l l o w i n g ? 1) Marked r e d u c t i o n or l o s s of i n t e r e s t s , i n i t i a t i v e an r i v e , l e a d i n g to s e r i o u s d e t e r i o r a t i o n of the performance u s u a l a c t i v i t i e s and t a s k s . 2) Emergence of or marked e x a c e r b a t i o n of s o c i a l wlthdrawl ( a c t i v e avoidance of communication with other p e o p l e ) . 3) Severe excitement, p u r p o s l e s s d e s t r u c t i v e n e s s or a g g r e s s i o n . 4) E p i s o d i c or p e r s i s t e n t s t a t e s of overwhelming f e a r or severe a n x i e t y . 5) Gross and p e r s i s t e n t s e l f n e g l e c t . E. Has the p a t i e n t been admitted to any h o s p i t a l , or otherwise diagnosed or t r e a t e d f o r a p s y c h o t i c d i s o r d e r , s i m i l a r t o or continuous with the present i l l n e s s , at any time b e f o r the c u r r e n t c o n t a c t or s p e l l of treatment f o r p s y c h i a t r i c d i s o r d e r ? (Do not c o n s i d e r c o n t a c t s f o r minor problems long ago, l i k e attendence t o a c h i l d guidance c l i n i c f o r conduct or emotional d i s o r d e r s d i s o r d e r , e t c . ) Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No yes No zlO F. D i a g n o s i s of the p a t i e n t made at the f a c i l i t y . / / / / . . I I I I G. C o n d i t i o n s f o r i n c l u s i o n i n the study: 1) A l l r e p l i e s to q u e s t i o n s i n s e c t i o n A, B l , B2, and E must be "No" and there should be at l e a s t one "Yes" i n s e c t i o n C or two "Yes"s i n s e c t i o n D. OR 2) I f the p a t i e n t does not meet the c r i t e r i a s p e c i f i e d i n 1) the p a t i e n t may s t i l l be i n c l u d e d i f the r a t e r has other reasons t o b e l i e v e t h a t he/she may be s u f f e r i n g from a s c h i z o p h r e n i c d i s o r d e r . Such reasons should be s p e c i f i e d below: Other reasons f o r i n c l u s i o n TO BE COMPLETED BY RESEARCH TEAM: CONCLUSION: T h i s p a t i e n t i s INCLUDED ( r i n g as a p p r o p r i a t e ) EXCLUDED 2 1 1 G u i d l i n e s f o r Use of the Screening Schedule General The s c r e e n i n g schedule should be f i l l e d i n by a p s y c h i a t r i s t or by another i n v e s t i g a t o r with r e l e v a n t e x p e r i e n c e q u a l i f y i n g him to apply r e l i a b l y the s c r e e n i n g c r i t e r i a . Any user of the schedule, whether a member of the p r o j e c t team or not, should be g i v e n b r i e f but adequate t r a i n i n g i n the use of the instrument. The c h i e f i n v e s t i g a t o r should check the adequacy of such t r a i n i n g by d i s c u s s i o n and by a j o i n t s c r e e n i n g e x e r c i s e on a few c a s e s . The s c r e e n i n g schedule w i l l be f i l l e d i n on the b a s i s of i n f o r m a t i o n from: ( i ) a b r i e f i n t e r v i e w with the p a t i e n t , ( i i ) a b r i e f i n t e r v i e w with the informant, ( i i i ) admission or o u t p a t i e n t notes, ( i v ) any combination of these. C o n s i d e r i n g the l i m i t e d access t o some k i n d s of i n f o r m a t i o n at the s c r e e n i n g stage, the i n v e s t i g a t o r should p r e f e r a b l y e r r on the o v e r i n c l u s i v e s i d e and not exclude cases which r a i s e doubts or cannot be adequately assessed with the s c r e e n i n g c r i t e r i a . Such p p a t i e n t s can be excluded, i f necessary, a f t e r a more d e t a i l e d assessment with the PSE and the P s y c h i a t r i c H i s t o r y Schedule. Organic c e r e b r a l d i s o r d e r i s c o n s i d e r e d to be p r e s e n t i f t h e r e i s c l e a r evidence at the time of examination or i n the  l a s t t h r e e months of any of the f o l l o w i n g : ( i ) marked d i s t u r b a n c e of memory, ( i i ) episodes of c l o u d i n g of consciousness or c o n f u s i o n manifested i n impaired o r i e n t a t i o n i n p l a c e and/or time, ( i i i ) f o c a l symptoms l i k e a p h a s i a . 212 Organic c e r e b r a l d i s o r d e r i s a l s o c o n s i d e r e d present i f i n  the l a s t one year t h e r e was: ( i ) a h i s t o r y of head i n j u r y f o l l o w e d by coma l a s t i n g f o r e i g h t hours or more, or by p o s t -t r a u m a t i c amnesia l a s t i n g f o r 72 hours or more, ( i i ) two or more e p i l e p t i c f i t s , or evidence t h a t the p a t i e n t has been on a n t i - c o n v u l s a n t m edication f o r more than s i x months. Severe a l c o h o l dependence i s presumed to be present i f with regard t o the l a s t 12 months th e r e i s evidence o f e x c e s s i v e a l c o h o l i n t a k e and any of the f o l l o w i n g : ( i ) withdrawl symptoms (tremor, sweating, p a l p a t a t i o n s , insomnia, i r r i t a b i l i t y ) on c e s s a t i o n o f d r i n k i n g , ( i i ) h i s t o r y of a l c o h o l p s y c h o s i s i n the past year, ( i i i ) symptoms of a l c o h o l encephalopathy or p o l y n e u r i t i s . C a u t i o n should be e x e r c i s e d i n cases of suspected a l c o h o l h a l l u c i n o s i s accompanied by c l e a r c o n s c i o u s n e s s : such p a t i e n t s should be p r o v i s i o n a l l y i n c l u d e d . The d i a g n o s i s t o be entered i s the one made at the f a c i l i t y p r i o r t o the assessment of the p a t i e n t by the p r o j e c t team. The p r o j e c t d i a g n o s i s made a f t e r the assessment should be recorded on the Present S t a t e Exam (PSE). 213 Appendix F Scre e n i n g Schedule f o r V o l u n t e e r C o n t r o l S u b j e c t s Have you ever r e c e i v e d treatment f o r emotional or p s y c h i a t r i c i l l n e s s ? No Yes Nature of problem What k i n d of treatment ( i n c . meds or hosp) Have your mother, f a t h e r , b r o t h e r s , s i s t e r s , or c h i l d r e n ever r e c e i v e d treatment f o r emotional or p s y c h i a t r i c i l l n e s s ? No Yes Nature of r e l a t i v e ' s problem R e l a t i v e Treatment Have you ever had a d r i n k i n g problem or has anyone ever suggested that you had a d r i n k i n g problem? No Yes Treatment Have your mother, f a t h e r , b r o t h e r s , s i s t e r s , or c h i l d r e n ever had a d r i n k i n g problem? No Yes Who Extent Treatment Do you have any d i s o r d e r a f f e c t i n g your b r a i n or s p i n a l c o r d , long term p a i n d i s o r d e r , o r long term p h y s i c a l d i s o r d e r (e.g., e p i l e p s y , c h r o n i c back p a i n , a r t h r i t i s , d i a b e t e s , h y p e r t e n s i o n , m u l t i p l e s c l e r o s i s , s t r o k e , e t c ) No Yes S p e c i f y 214 G u i d l i n e s f o r Use of the S c r e e n i n g Schedule A. E x c l u s i o n C r i t e r i a 1. P a t i e n t s who have r e c e i v e d m e dication (other than minor t r a n q u i l i z e r s f o r p s y c h i a t r i c problems) or who have been h o s p i t a l i z e d because of an emotional or p s y c h i a t r i c  i l l n e s s . 2. P a t i e n t s who are a l c o h o l i c s or are recovered a l c o h o l i c s . 3. P a t i e n t s whose pa r e n t s , s i b l i n g s , or c h i l d r e n have r e c e i v e d medication or been h o s p i t a l i z e d because of emotional or p s y c h i a t r i c i l l n e s s , are a l c o h o l i c s or recovered a l c o h o l i c s , or are p e r c e i v e d as being i n need of treatment f o r a l c o h o l i s m . 4. P a t i e n t s with n e u r o l o g i c a l d i s o r d e r s such as e p i l e p s y , m u l t i p l e s c l e r o s i s , s t r o k e , v e s t i b u l a r d i s o r d e r s ( i n c -l u d i n g nystagmus), or dementia. 5. P a t i e n t s whose v i s i o n cannot be normalized with c o r r e c t i v e l e n s e s ; e.g., p a t i e n t s with c a t e r a c t s , glaucoma, or detached r e t i n a s . 6. P a t i e n t s who would have d i f f i c u l t y p a r t i c i p a t i n g i n the study because of c h r o n i c p a i n ; e.g., p a t i e n t s with c h r o n i c back p a i n , cancer, or a r t h r i t i s . 7. P a t i e n t s who are r e c e i v i n g treatment f o r pregnancy or postpartum c a r e . 8. P a t i e n t s w i t h c h r o n i c p h y s i c a l i l l n e s s such as d i a b e t e s , Crohn's d i s e a s e , c h r o n i c o b s t r u c t i v e lung d i s e a s e , hyper-t e n s i o n , e t c . B. I n c l u s i o n C r i t e r i a 1. Age: 15 t o 40 y ears of age. 2. Persons are permanent or temporary r e s i d e n t s of the c i t i e s of Richmond or Vancouver (minimum of s i x months r e s i d e n c y ) . 3. People who have sought treatment f o r p r e v e n t a t i v e s e r v i c e s such as i m u n i z a t i o n s ; w e l l baby check-up; annual pap smear; p h y s i c a l examination; f a m i l y p l a n n i n g ; and d i e t c o u n s e l l i n g ; or f o r medical management of a s h o r t episode of i l l n e s s or any acute c o n d i t i o n such as f l u . 4. Parents of c h i l d r e n brought i n t o treatment e i t h e r f o r 215 Appendix G Negative Symptom Ra t i n g s Present S t a t e Examination (PSE) items 36, 54, 58, 107, 110, 119, 128, 129, 130, 133, 134, and 138. 36. A n e r g i a Do you seem to be slowed down i n your movements, or have too l i t t l e energy r e c e n t l y ? How much has i t a f f e c t e d you? (Do t h i n g s seem to be moving too f a s t f o r you?) RATE SUBJECTIVE ANERGIA AND RETARDATION 0 = Symptom not present to a s i g n i f i c a n t degree. 1 = Marked s u b j e c t i v e l i s t l e s s n e s s and l a c k of energy. 2 = Marked r e t a r d a t i o n and u n d e r a c t i v i t y ( I r r e s p e c t i v e of time d u r i n g month) 54. L o s t Emotions Do you f e e l you have l o s t your emotions i n some way? (That you are empty of a l l f e e l i n g s , i n c a p a b l e of r e a c t i n g e m o t i o n a l l y ? ) ( I s t h i s a d e f i n i t e change, or have you always been l i k e t h a t ? ) (How do you e x p l a i n i t ? ) RATE LOST EMOTIONS: Rate on l y s u b j e c t i v e l o s s of a f f e c t , i . e . , s u b j e c t can remember being a b l e t o r e a c t e m o t i o n a l l y , though t h i s might have been months or even years ago. 0 = Symptom not present to a s i g n i f i c a n t degree. 1 = Symptom d e f i n i t e l y present d u r i n g the past month but l e s s than 50% of the time. 2 = Symptom present more than 50% d u r i n g the past month. 58. Thought Block Do you ever e x p e r i e n c e your thoughts s t o p p i n g q u i t e unexpectedly so t h a t t h e r e are none l e f t i n your mind, even when your thoughts were f l o w i n g f r e e y b e f o r e ? (What i s t h a t l i k e ? ) (How o f t e n does t h a t occur? What i s i t due to?) Do Your thoughts ever seem to be taken out of your head, as though some e x t e r n a l person or f o r c e was removing them? (Can you g i v e an example?) (How do you e x p l a i n i t ? ) 216 RATE THOUGHT BLOCK OR WITHDRAWAL. 1 = Thought b l o c k . Do not i n c l u d e i f due to a n x i e t y or lac k of c o n c e n t r a t i o n ; only i f i t o c c u r s t o t a l l y unexpectedly when thoughts are f l o w i n g f r e e l y . One s i n g l e o c c a s i o n i s not s u f f i c i e n t f o r a r a t i n g . Be  very c r i t i c a l i n r a t i n g t h i s symptom. 2 = D e l u s i o n a l e x p l a n a t i o n t h a t thoughts are withdrawn. 107. S o c i a l Impairment Of a l l the problems t h a t you have t o l d me about, which one a f f e c t s you the most? How much does i t i n t e r f e r e with your work or your r e l a t i o n s h i p s with o t h e r people? (Have you a c t u a l l y been out of work, or been unable t o do the houswork, or go shopping, t r a v e l l i n g , e t c . , d u r i n g the past month?) (Have the symptoms impaired your e f f i c i e n c y i n any other way?) RATE SOCIAL IMPAIRMENT DUE TO PSYCHOTIC CONDITION. 0 = No n e u r o t i c or p s y c h o t i c symptoms p r e s e n t . 1 = P s y c h o t i c symptoms present but l i t t l e d i m u n i t i o n o f s u b j e c t ' s e f f i c i e n c y or i n t e r f e r e n c e with everyday a c t i v i t i e s . 2 = P s y c h o t i c symptoms i n t e r f e r e with s u b j e c t ' s e f f i c i e n c y t o a moderate extent but are not i n c a p a c i t a t i n g , e.g., s u b j e c t n e g l e c t s housework or can't enjoy l e i s u r e a c t i v i t i e s or s o c i a l r e l a t i o n s h i p s , or f i n d s work-e f f i c i e n c y reduced. Subject does not, however, stop work a l t o g e t h e r or completely n e g l e c t the houshold. 3 = Subject s e v e r e l y i n c a p a c i t a t e d by p s y c h o t i c symptoms: had t o have at l e a s t a week o f f work d u r i n g the past month; was housbound f o r a week or more; was a c t i v e l y withdrawn from a l l s o c i a l r e l a t i o n s h i p s , e t c . The s u b j e c t does not have t o be t o t a l l y i n c a p a c i t a t e d f o r the whole month f o r t h i s r a t i n g to be made, but impairment has to be very severe. 108. S e l f N e g l e c t , ( d u r i n g the i n t e r v i e w ) C l e n l i n e s s , shaven, make-up, s t a t e of h a i r and c l o t h e s . RATE SELF NEGLECT. 0 = Normal 1 = F a i r l y severe. 2 = Very severe. 217 110. Slowness and U n d e r a c t i v i t y ( d u r i n g the i n t e r v i e w ) S i t s abnormally s t i l l , walks abnormally s l o w l y , delay i n performing movements. RATE SLOWNESS. 0 = Symptom absent 1 = Present i n f a i r l y severe degree, or very severe but i n t e r m i t t e n t duribng the i n t e r v i e w . 2 = Present i n very severe degree and almost continuous d u r i n g the i n t e r v i e w . 119. C a t a t o t o n i c Movements ( d u r i n g the i n t e r v i e w ) Negativism: does the o p p o s i t e of what i s asked. Ambitendence: begins to take p r o f f e r e d hand, then w i t h -draws e t c . Echopraxia: i m i t a t e s examiner's movement. F l e x i b i l i t a s c e r e a : arm remains where i t i s put f o r at l e a s t 15 seconds. Mitgehen: e x c e s s i v e c o o p e r a t i o n i n p a s s i v e movement. E c h o l a l i a : i m i t a t e s words and phrases with the same i n t o n a t i o n n and i n f l e c t i o n o f v o i c e . ) 0 = Symptom absent. 1 = Present i n f a i r l y severe degree, or very severe but i n t e r m i t t e n t d u r i n g i n t e r v i e w . 2 = Present i n very severe degree and almost continuous d u r i n g the i n t e r v i e w . 128. Blunted A f f e c t ( d u r i n g i n t e r v i e w ) E x p r e s s i o n l e s s f a c e and v o i c e , uniform b l u n t i n g whatever the t o p i c o f c o n v e r s a t i o n , i n d i f f e r e n c e t o d i s t r e s s i n g t o p i c s , whether d e l u s i o n a l or normal. 0 = Symptom absent. 1 = B l u n t i n g not uniform, e.g., at times responds a f f e c t -i v e l y but at other times i s markedly f l a t ; or responds with some evidence o f a f f e c t , but d e f i n i t e l y l e s s than expected. 2 = Severe and uniform b l u n t i n g . 129. I n c o n g r u i t y o f A f f e c t ( d u r i n g the i n t e r v i e w ) I n c o n g r u i t y of a f f e c t (emotion i s shown, but not congruent with t o p i c ) . 0 = Symptom absent. 1 = Present i n f a i r l y severe degree, or very severe but i n t e r m i t t e n t d u r i n g the i n t e r v i e w . 2 = Present i n very severe degree and almost continuous d u r i n g the i n t e r v i e w . 218 130. Slow Speech Slow speech ( l o n g pauses b e f o r e answering, long pauses between words). 0 = Symptom absent. 1 = Present i n f a i r l y severe degree, or very severe but i n t e r m i t t e n t d u r i n g the i n t e r v i e w . 2 = Present i n very severe degree and almost continuous d u r i n g the i n t e r v i e w . 133. Muteness 0 = Normal speech. 1 = Almost mute. 2 = T o t a l l y mute. 134. R e s t r i c t e d Q u a n t i t y of Speech Subject f r e q u e n t l y f a i l s t o answer, q u e s t i o n s have to be repeated, r e s t r i c t e d t o minimum necessary, no e x t r a sentences, no a d d i t i o n a l comments. 0 = Symptom absent. 1 = Present i n f a i r l y severe degree, or very severe but i n t e r m i t t e n t d u r i n g the i n t e r v i e w . 2 = Present i n very severe degree and almost continuous d u r i n g the i n t e r v i e w . 138. Poverty of Content of Speech The s u b j e c t t a l k s f r e e l y but so vaguely t h a t l i t t l e i n f o r m a t i o n i s g i v e n i n s p i t e of the number of words used: rambles on without coming to a p o i n t ; may wander f a r from o r i g i n a l theme. Exclude incoherence or f l i g h t of i d e a s . Rate o n l y i f severe and always g i v e w r i t t e n example. 0 = Symptom absent. 1 - Present i n f a i r l y severe degree, or very severe but i n t e r m i t t e n t d u r i n g the i n t e r v i e w . 2 = Present i n very severe degree and almost continuous d u r i n g the i n t e r v i e w . 219 Appendix H C o r r e l a t i o n s between Age and Each CT Measure D i a g n o s i s # L a t e r a l Vent T h i r d Vent Cortex S c h i z o p h r e n i a 31 r =-.14 r = .03 = .28 1 1 1 S c h i z o p h r e n i f o r m 20 r = .50 r = .55 = .48 B i p o l a r and Dep 34 r = .16 r =-.13 = .14 T o t a l 91 r = .14 r =-.13 = .08 V o l C o n t r o l 44 r = .18 r = .22 = .16 Med C o n t r o l 30 r =-.09 r = .04 = .14 1 A l l c o r r e l a t i o n s f o r s c h i z o p h r e n i f o r m p a t i e n t s were i n f l u e n c e d by one s u b j e c t o u t l i e r (age 33). With t h i s i n d i v i d u a l removed from the c a l c u l a t i o n s , the age c o r r e l a t i o n s f o r the s c h i z o p h r e n i f o r m p a t i e n t s were r =.26 over the l a t e r a l v e n t r i c l e s , r = .35 over the t h i r d v e n t r i c l e , and = .37 over the c o r t i c a l s u l c i . None of these c o r r e l a t i o n s was s t a t i s t i c a l l y s i g n i f i c a n t a t p <.05. 220 APPENDIX I The E f f e c t s o f Using RDC Diagnoses on the R e s u l t s Most r e s e a r c h e r s use e i t h e r RDC or DSM-III d i a g n o s t i c c r i t e r i a . There are a number of b a s i c d i f f e r e n c e s between these systems t h a t c o u l d i n f l u e n c e r e s e a r c h r e s u l t s ; e.g., s c h i z o p h r e n i f o r m d i s o r d e r and s c h i z o a f f e c t i v e d i s o r d e r are not used or are not used i n the same way i n both systems. As with the m a j o r i t y of p r e v i o u s s t u d i e s , the hypotheses i n the present study were t e s t e d with p a t i e n t s diagnosed a c c o r d i n g to DSM-III c r i t e r i a . The f o l l o w i n g e x p l o r a t o r y a n a l y s e s w i l l address the r e s e a r c h hypotheses with the p a t i e n t s diagnosed a c c o r d i n g t o RDC s p e c i f i c a t i o n s . The hypotheses of the present study p r e d i c t t h a t the p s y c h o t i c p a t i e n t s have en l a r g e d 1. l a t e r a l v e n t r i c l e s , 2. t h i r d v e n t r i c l e , and 3. c o r t i c a l s u l c i . A f o u r t h h y p o t h e s i s p r e d i c t s t h a t medical p a t i e n t s s e l e c t e d from r a d i o l o g y r e c o r d s have s m a l l e r v e n t r i c l e s and s u l c i than do h e a l t h y i n d i v i d u a l s . Table 1 shows the number and age of s u b j e c t s i n each RDC d e f i n e d p a t i e n t group and each c o n t r o l group. R e s u l t s There were no s i g n i f i c a n t group d i f f e r e n c e s i n l a t e r a l v e n t r i c l e s i z e when RDC diagnoses were used t o c l a s s i f y p a t i e n t s , F(5, 155) = 1.04 £=.40, Table 2. T h i s i s the same r e s u l t t h a t was ob t a i n e d when 1DSM-III diagnoses were used. F i v e p a t i e n t s with VBR v a l u e s g r e a t e r than ten were diagnosed s c h i z o p h r e n i c and one was diagnosed u n s p e c i f i e d f u n c t i o n a l p s y c h o s i s . T h i s compares to f o u r s c h i z o p h r e n i c , one 221 Table II Demographic C h a r a c t e r i s t i c s of Subjec t s Number of S u b j e c t s Age RDC Diagnosed Groups Male Female T o t a l M SD Range S c h i z o p h r e n i a 34 5 39 21.7 5.0 15-35 S c h i z o a f f e c t i v e 17 11 28 24.8 7.1 16-43 Mania 6 4 10 26.0 7.6 18-39 Depression 8 2 10 21.7 2.2 17-28 U n s p e c i f i e d Func. P s y c h o s i s 1 2 3 34.0 12.1 23-47 T o t a l P a t i e n t s 67 24 91 23.5 6.5 16-47 V o l u n t e e r C o n t r o l 29 15 44 23.2 5.6 15-42 Me d i c a l C o n t r o l 13 17 30 23.2 4.4 15-32 s c h i z o p h r e n i f o r m and one paranoid d i s o r d e r when p a t i e n t s were c l a s s i f i e d a c c o r d i n g t o DSM-III c r i t e r i a . As was the case when DSM-III c r i t e r i a were used, t h e r e were no s i g n i f i c a n t r e l a t i o n s h i p s between l a t e r a l v e n t r i c l e s i z e and premorbid adjustment, smooth-pursuit eye movements, or n e g a t i v e symptoms f o r any RDC d e f i n e d d i a g n o s t i c group. No s i g n i f i c a n t group d i f f e r e n c e s were o b t a i n e d over the width of the t h i r d v e n t r i c l e when Research D i a g n o s t i c C r i t e r i a were used t o c l a s s i f y p a t i e n t s , F(5, 155) = 1.69, p =.14. No s i g n i f i c a n t r e l a t i o n s h i p s were o b t a i n e d between t h i r d v e n t r i c l e s i z e and l e v e l of premorbid adjustment, n e g a t i v e symptoms, or smooth-pursuit eye movements. T h i s f i n d i n g d i f f e r s from that o b t a i n e d when DSM-III diagnoses 222 Table 12 Mean Values f o r V e n t r i c l e and Cortex f o r Each Group with P a t i e n t s Diagnosed A c c o r d i n g to Research D i a g n o s t i c C r i t e r i a L a t e r a l Vent T h i r d Vent Cortex a Groups (VBR) (mm) (Rating) S c h i z o p h r e n i a M 6.45 3.73 1.95 N = 39 SD 2.76 1.42 0.79 S c h i z o a f f e c t i v e M 6.10 3.40 2.07 N = 28 SD 2.29 0.83 0.86 Manic M 5.75 3.57 2.00 N = 10 SD 1.65 1.13 0.94 Depression M 7.82 3.77 2.10 N = 10 SD 2.11 0.92 0.88 T o t a l P a t i e n t s M 6.45 3.62 2.05 N = 91 SD 2.51 1.18 0.83 V o l u n t e e r C o n t r o l M 6.39 3.49 1.82 N = 44 SD 2.76 1.13 0.76 M e d i c a l C o n t r o l M 5.77 3.01 1.39 N = 30 SD 2.55 0.90 0.61 a A r a t i n g of 1 = no atrophy, 2 = moderate atrophy, and 3 = severe atrophy. 2 2 3 were used. As was the case when p a t i e n t s were c l a s s i f i e d a c c o r d i n g to DSM-III c r i t e r i a , s i g n i f i c a n t d i f f e r e n c e s were obtained between RDC diagnosed groups over the l e v e l o f c o r t i c a l atrophy, F(5, 155) = 3.15, p <.01. Planned orthogonal c o n t r a s t s i n d i c a t e d t hat RDC diagnosed s c h i z o p h r e n i c , s c h i z o a f f e c t i v e , and a f f e c t i v e d i s o r d e r p a t i e n t s d i d not show s i g n i f i c a n t l y more c o r t i c a l atrophy than the v o l u n t e e r c o n t r o l s u b j e c t s . However, l i k e the DSM-III f i n d i n g s , the v o l u n t e e r c o n t r o l group had more s u l c a l d i l a t i o n than the medical c o n t r o l group, t.(72) = 2.58, p<.01, o n e - t a i l e d . No s i g n i f i c a n t r e l a t i o n s h i p s were o b t a i n e d between c o r t i c a l atrophy and l e v e l of premorbid adjustment, n e g a t i v e symptoms or smooth-pursuit eye movements. These f i n d i n g s are e s s e n t i a l l y the same whether p a t i e n t s were c l a s s i f i e d a c c o r d i n g t o RDC or DSM-III c r i t e r i a . In summary, the r e s u l t s t h a t were ob t a i n e d when RDC c r i t e r i a were used to c l a s s i f y p a t i e n t s are e s s e n t i a l l y the same as when DSM-III c r i t e r i a were used over l a t e r a l v e n t r i c l e s i z e and c o r t i c a l atrophy. There i s , however, a d i s c r e p a n c y between the two d i a g n o s t i c systems over the width of the t h i r d v e n t r i c l e . The f i n d i n g s from the present study suggest t h a t s i g n i f i c a n t group d i f f e r e n c e s i n the s i z e of the t h i r d v e n t r i c l e a re more l i k e l y t o be o b t a i n e d i f DSM-III c r i t e r i a are used t o diagnose p a t i e n t s . 224 D i s c u s s i o n The present study suggests t h a t the method of d i a g n o s i s may i n f l u e n c e the r e s u l t s t h a t are o b t a i n e d . Whereas c l e a r d i l a t i o n of the t h i r d v e n t r i c l e was obtained i n the s c h i z o p h r e n i c p a t i e n t s when DSM-III diagnoses were used, no e f f e c t was found when RDC diagnoses were employed. The r e s u l t s over l a t e r a l v e n t r i c l e s i z e and s u l c a l d i l a t i o n were the same whether p a t i e n t s were diagnosed a c c o r d i n g to RDC or DSM-III c r i t e r i a . The r e s u l t s of p r e v i o u s i n v e s t i g a t i o n s suggest t h a t the method of d i a g n o s i s t h a t i s used does not a f f e c t the s i g n i f i c a n c e of ob t a i n e d r e s u l t s . Of the 28 s t u d i e s of l a t e r a l v e n t r i c l e s i z e i n which p a t i e n t s were diagnosed a c c o r d i n g t o e i t h e r RDC or DSM-III c r i t e r i a , 16 used DSM-III and 12 used RDC diagnoses. P o s i t i v e r e s u l t s were ob t a i n e d i n 81% (13/16) of DSM-III and 75% (9/12) of RDC diagnosed 2 p a t i e n t s . T h i s d i f f e r e n c e i s not s i g n i f i c a n t , x (1, N = 28) = .12, p>.l. The number of i n v e s t i g a t i o n s t h a t o b t a i n e d enlargement of the t h i r d v e n t r i c l e was the same whether p a t i e n t s were diagnosed a c c o r d i n g to RDC (3/4) or DSM-III (3/4) c r i t e r i a . A major d i f f e r e n c e between RDC and DSM-III diagnoses of s c h i z o p h r e n i a i s the minimum d u r a t i o n o f i l l n e s s t h a t i s r e q u i r e d . For a d i a g n o s i s of s c h i z o p h r e n i a u s i n g DSM-III c r i t e r i a , an i n d i v i d u a l must e x h i b i t some symptoms f o r at l e a s t s i x months. T h i s can i n c l u d e prodromal, a c t i v e , and r e s i d u a l symptoms. Because p a t i e n t s i n the present study 2 2 5 were r e c r u i t e d w i t h i n three months of t h e i r f i r s t p s y c h o t i c i l l n e s s , they must have had prodromal symptoms f o r a minimum of three months i n order to r e c e i v e a d i a g n o s i s of s c h i z o p h r e n i a . P a t i e n t s who had a r a p i d onset of p s y c h o t i c symptoms w i l l have r e c e i v e d a DSM-III d i a g n o s i s of s c h i z o -p h r e n i f o r m d i s o r d e r i n the present study. However, because an RDC d i a g n o s i s of s c h i z o p h r e n i a r e q u i r e s o n l y two weeks of a c t i v e p s y c h o t i c symptoms, t h i s method of c l a s s i f y i n g p a t i e n t s does not d i s c r i m i n a t e on the b a s i s of r a p i d or i n s i d i o u s onset i n the present study. Because of the d i f f e r e n c e s between DSM-III and RDC systems, i t i s p o s s i b l e t h a t the use of DSM-III c r i t e r i a has segregated p a t i e n t s with s c h i z o p h r e n i c - l i k e symptoms i n t o r a p i d onset ( s c h i z o p h r e n i f o r m ) v e r s u s i n s i d i o u s onset ( s c h i z o p h r e n i a ) . T h i s d i s t i n c t i o n i s s u g g e s t i v e of the p r o c e s s - r e a c t i v e dichotomy (Neale & Oltmanns, 1980) and may r e f l e c t good ve r s u s poor p r o g n o s i s i n these p a t i e n t s . An i n s p e c t i o n of the l e v e l of premorbid adjustment i n s c h i z o p h r e n i c and s c h i z o p h r e n i f o r m p a t i e n t groups f a i l s t o support t h i s h y p o t h e s i s . There were s i m i l a r l e v e l s and ranges of adjustment i n both groups ( s c h i z o p h r e n i c median = 106, range = 44 t o 140, s c h i z o p h r e n i f o r m median = 103, range = 46 to 140; n.b. premorbid adjustment was measured on a s c a l e of two to 140). T h i s r e s u l t suggests t h a t t h e r e are no d i f f e r e n c e s between these groups over l e v e l of adjustment d u r i n g s e v e r a l years b e f o r e the onset of p s y c h o s i s . In order t o r e s o l v e t h i s i s s u e , a f o l l o w - u p study i n c l u d i n g recent 226 onset p a t i e n t s needs to be conducted. I f i t were the case t h a t the DSM-III diagnosed s c h i z o p h r e n i c p a t i e n t s i n the present study had a poor p r o g n o s i s , then t h i s would suggest t h a t b r a i n changes may be a s s o c i a t e d with i l l n e s s s e v e r i t y . 227 Appendix J Mean Values f o r Scores o f Premorbid S t a t u s , N egative Symptoms Group Premorbid Negative D i a g n o s i s S t a t u s Symptoms SPEM S c h i z o p h r e n i a M 99.54 2.58 246.70 SD 26.32 1.43 24.66 Range 44-140 1-6 207-296 n 28 31 30 Schi z o p h r e n i f o r m M 101.74 2.55 234.33 SD 22.18 1.50 21 .56 Range 46-140 0-6 194-263 n 19 20 18 B i p o l a r M 107.8 0 1.29 245.94 SD 21.67 0.85 21 .62 Range 69-140 0-3 215-281 n 15 17 18 Depressed M 109.14 1.93 230.25 SD 16.15 1 .28 23.89 Range 77-128 1-5 205-286 n 14 15 16 

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