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UBC Theses and Dissertations

Mood disorders and alcoholism Kirkham, Marion Lynn 1996

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MOOD DISORDERS AND ALCOHOLISM by MARION.LYNN KIRKHAM B.Sc, The U n i v e r s i t y of B r i t i s h Columbia, 1991 A THESIS SUBMITTED IN PARTIAL FULFILLMENT- OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE i n THE FACULTY OF GRADUATE STUDIES (Department of Medical Genetics) We accept t h i s t h e s i s as conforming to the re q u i r e d standard THE UNIVERSITY OF BRITISH COLUMBIA AUGUST 1996 /©Marion Lynn Kirkham, 1996 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 it 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 The University of British Columbia Vancouver, Canada DE-6 (2/88) ABSTRACT Age of onset data and pedigree information on 691 mood d i s o r d e r probands and 4040 of t h e i r f i r s t degree r e l a t i v e s were compared on the ba s i s of mood di s o r d e r subtype, gender of proband and r e l a t i v e , and presence or absence of alc o h o l i s m i n the proband or r e l a t i v e . Comparisons were undertaken to determine i f an a s s o c i a t i o n , suggested by the l i t e r a t u r e , e x i s t s between mood di s o r d e r s and al c o h o l i s m w i t h i n f a m i l i e s . Excess a l c o h o l i s m was observed i n the male, as compared to female, f i r s t degree r e l a t i v e s of the f o l l o w i n g proband groups: (i) Unipolar (Single Episode and Recurrent) (p=0.0005 f o r males; p<0.0001 f o r females); ( i i ) female B i p o l a r (I+II) probands (p<0.0001); ( i i i ) U n i p o l a r - S i n g l e Episode probands (p=0.0001 f o r males; p=0.0014 f o r females); (iv) female Unipolar-Recurrent probands (p<0.0001); and (v) female B i p o l a r I probands (p<0.0001). Excess a l c o h o l i s m was observed i n the male, as compared to female, second degree r e l a t i v e s of the f o l l o w i n g proband groups: (a) female U n i p o l a r - S i n g l e Episode probands (p=0.0002); female Unipolar-Recurrent probands (p=0.0002); and female B i p o l a r I probands (p=0.0014). However, when the gender p r o p o r t i o n of a l c o h o l i c s i n the general population was taken i n t o account, these s i g n i f i c a n t d i f f e r e n c e s were not observed. Neither a fa m i l y h i s t o r y of alcoholism, s u i c i d e nor co-morbid alc o h o l i s m i n mood di s o r d e r proband had a s i g n i f i c a n t e f f e c t on the average ages of onset i n the proband groups. The r e s u l t s of these comparisons i n d i c a t e that there i s no common genetic e t i o l o g y between a l c o h o l i s m and mood di s o r d e r s i n t h i s proband group. i i TABLE OF CONTENTS Abstract . • i i Table of Contents i i i L i s t of Tables v i i i L i s t of Figures x i i Acknowledgments x i i i Chapter 1 INTRODUCTION 1 1.1 Thesis Objectives 1 1.2 Background 1 1.21 Overview of C r i t e r i a f o r Unipolar Disorder 2 1.22 Overview of C r i t e r i a f o r B i p o l a r Disorder 3 1.23 Overview of C r i t e r i a f o r A l c o h o l Abuse 3 1.3 I n t r o d u c t i o n Overview 4 1.31 Family Studies 4 1.32 Twin Studies 5 1.33 Adoption Studies 5 1.4 Family Studies 6 1.41 U n i p o l a r - S i n g l e Episode Versus Unipolar-Recurrent ... 6 1.41.1 Studies of Unipolar Disorder Subdivided i n t o S i n g l e Episode and Recurrent Forms 7 1.41.2 Summary of Results of Studies on Unipolar-S i n g l e Episode and Unipolar-Recurrent 10 1.42 Family Studies-Unipolar Disorder and Alcoholism 11 1.42.1 Depression Spectrum Disease and Pure Depressive Disease 12 1.42.2 Support f o r A Common Genetic E t i o l o g y Between Depression and Alcoholism 16 i i i 1.42.3 Studies That Do Not Support A Common Genetic E t i o l o g y Between Depression and Alcoholism 18 1.43 B i p o l a r I Disorder Versus B i p o l a r I I Disorder 22 1.44 Family S t u d i e s - B i p o l a r Disorder and Alcoholism 23 1.44 1 Studies That Support A Common Genetic E t i o l o g y Between B i p o l a r Disorder and Alcoholism 24 1.4 4 2 Studies That Do Not Support A Common Genetic E t i o l o g y Between B i p o l a r Disorder and Alcoholism .... 25 1.44.3 Linkage Studies and B i p o l a r Disorder 30 1.44.3i B i p o l a r Disorder Studies of Old Order Amish 30 1.45 Alcoholism and Other P s y c h i a t r i c Disorders 32 1.45.1 Diagnostic C r i t e r i a f o r Seasonal A f f e c t i v e Disorder 32 1.45.2 Diagnostic C r i t e r i a f o r B o r d e r l i n e P e r s o n a l i t y Disorder 33 1.45.3 Diagnostic C r i t e r i a f o r Anxiety Disorders 33 1.45.4 Studies P e r t a i n i n g to Alcoholism and Other P s y c h i a t r i c Disorders 34 1.4 6 Mood Disorders and Substance Abuse 36 1.47 A s s o r t a t i v e Mating 40 1.48 Problems with Family Studies 41 1.5 Twin Studies 42 1.6 Adoption Studies 4 6 1.7 Summary 51 i v Chapter 2 MATERIALS AND METHODS 52 2.1 Probands 52 2.11 Diagnostic and S t a t i s t i c a l Manual I l l - R e v i s e d (DSM III-R) C r i t e r i a 53 2.11.1 U n i p o l a r - S i n g l e Episode and Unipolar-Recurrent 53 2.11.2 B i p o l a r I and B i p o l a r I I 54 2.11.3 A l c o h o l Abuse or Dependence 55 2.12 Research Diagnostic C r i t e r i a (RDC) 56 2.12.1 Major Depressive Disorder 57 2.12.2 Manic Disorder 58 2.12.3 Alcoholism 60 2.13 Age of Onset i n Mood Disorder Probands 61 2.2 F i r s t and Second Degree R e l a t i v e s of Probands 61 2.3 A n a l y s i s 64 2.31 Overview 64 2.32 Chi-Square Test A n a l y s i s Computational Formulae 70 2.33 SAS LIFETEST Computational Formulae 72 2.34 Z Test and Student's t Test Computational Formulae .. 75 2.35 Formula f o r 95% Confidence I n t e r v a l s 76 2.36 Z Test Formula f o r Comparisons of Gender Diff e r e n c e s 77 2.37 Gender S p e c i f i c Z Test Comparisons to General Population Rates 78 2.38 A n a l y s i s of Variance 80 2.39 Tukey Test 83 Chapter 3 RESULTS 8 6 3.1 Sample Analyzed 8 6 3.2 Results of Analyses 96 v 3.21 Frequency of A l c o h o l i c s i n F i r s t Degree R e l a t i v e s of Unipolar Probands 96 3.22 Frequency of A l c o h o l i c s i n F i r s t Degree R e l a t i v e s of B i p o l a r I and B i p o l a r I I Probands 100 3.23 Age of Onset Comparisons Between Probands 101 3.24 Comparisons of Age of Onset and Current Age of Unipolar - S i n g l e Episode Versus Unipolar-Recurrent Probands 106 3.25 Age of Onset Comparisons Between Probands With A Family H i s t o r y of Alcoholism Versus Those Without A Family H i s t o r y 109 3.2 6 Age of Onset Comparisons Between Probands With A Family H i s t o r y of Su i c i d e Versus Those Without A Family H i s t o r y 113 3.27 Case Studies of Probands with A Heavy Loading of Alcoholism i n Their F i r s t and Second Degree R e l a t i v e s ... 118 3.3 Summary of Results 119 Chapter 4 DISCUSSION 123 4.1 Comparison with Other Studies 123 4.2 Proband and R e l a t i v e F a m i l i a l Gender Ratios 124 4.3 Diagnosis and Gender S p e c i f i c F a m i l i a l Rates of Alcoholism 127 4.4 Age of Onset Comparisons Between Proband Groups 128 4.5 E f f e c t of Co-morbid Alcoholism on the Average Ages of Onset i n Probands 129 4.6 Age Comparisons Between U n i p o l a r - S i n g l e Episode and Unipolar-Recurrent Probands 132 4.7 E f f e c t of A Family H i s t o r y of Alcoholism on the Average Ages of Onset of A Mood Disorder i n Probands 134 v i 4.8 E f f e c t of A Family H i s t o r y of Suicid e on the Average Ages of Onset of A Mood Disorder i n Probands 136 4.9 C h a r a c t e r i s t i c s of Fa m i l i e s Loaded with Alcoholism 137 Chapter 5 CONCLUSION 138 REFERENCES 141 APPENDIX A 151 APPENDIX B 155 v i i LIST OF TABLES From Chapter 1-INTRODUCTION: TABLE 1.1 Summary of Studies on Un i p o l a r - S i n g l e Episode Versus Unipolar-Recurrent 9 TABLE 1.2 S i g n i f i c a n t Phenotypic Differences Observed Between Un i p o l a r - S i n g l e Episode and Unipolar-Recurrent.in Cassano et a l . (1989) and Merikangas et a l . (1994) 11 TABLE 1.3 D e s c r i p t i o n of Depression Spectrum Disease (DSD) versus Pure Depressive Disease (PDD) 13 TABLE 1.4 Summary of Studies on the V a l i d i t y of the Depression Spectrum Disease (DSD) versus Pure Depressive Disease (PDD) Su b d i v i s i o n 15 TABLE 1.5 Summary of Studies That Support an A s s o c i a t i o n Between Alcoholism and Mood Disorders Within F a m i l i e s 17 TABLE 1.6 Studies That Do Not Support A Common Genetic E t i o l o g y f o r A l c oholism and Unipolar Disorder 21 TABLE 1.7 Studies i n Support of A Common Genetic E t i o l o g y f o r Alcoholism and B i p o l a r Disorder 25 TABLE 1.8 Studies That Do Not Support A Common Genetic E t i o l o g y f o r Alcoholism and B i p o l a r Disorder 29 TABLE 1.9 Studies of A Common Genetic E t i o l o g y f o r Alcoholism and Other P s y c h i a t r i c Disorders 34 TABLE 1.10 Studies of Substance Abuse and Mood Disorders 39 TABLE 1.11 Summary of Results of Twin Studies on Alcoholism, Unipolar Disorder and B i p o l a r Disorder 45 TABLE 1.12 Summary of Results of Adoption Studies on Mood Disorder and Alcoholism A f f e c t e d I n d i v i d u a l s 4 9 v i i i From Chapter 2 MATERIALS AND METHODS TABLE 2.1 DSM II I - R C r i t e r i a f o r Unipolar Disorder 54 TABLE 2.2 DSM II I - R C r i t e r i a f o r B i p o l a r I and B i p o l a r I I Disorder 55 TABLE 2.3 DSM II I - R f o r A l c o h o l Dependence 56 TABLE 2.4 RDC f o r A Major Depressive Episode 58 TABLE 2.5 RDC f o r Mania 59 TABLE 2.6 RDC f o r Hypomania 59 TABLE 2.7 RDC f o r Alcoholism 60 TABLE 2.8 Proband Subgroups Used i n Analyses 64 TABLE 2.9 Age of Onset Comparisons Between Proband Groups . . . 66 TABLE 2.10 Summary of Studies Reporting Gender S p e c i f i c Ratios of. Alcoholism i n the General Population 79 From Chapter 3 RESULTS TABLE 3.1 D i s t r i b u t i o n of Probands By Gender and Diagnosis 86 TABLE 3.2 Summary of Comparisons of Proportions of Male versus Female A l c o h o l i c s i n Proband Groups Versus the General Population .88 TABLE 3.3 D i s t r i b u t i o n of F i r s t Degree R e l a t i v e s by Their A l c o h o l i c Status 89 TABLE 3.4 Summary of Comparisons of Proportions of A l c o h o l i c s i n F i r s t Degree R e l a t i v e s of Proband Groups Versus the General Population 91 TABLE 3.5 Average Ages at the Time Of Genetic Interview f o r F i r s t Degree R e l a t i v e s of Probands 92 TABLE 3.6 D i s t r i b u t i o n of Second Degree R e l a t i v e s By Their A l c o h o l i c Status 94 i x TABLE 3.7 Summary of Comparisons of Proportions of A l c o h o l i c s i n Second Degree R e l a t i v e s of Proband Groups Versus the General Population 95 TABLE 3.8 Summary of Chi-Square Comparisons of Gender Ratios of A l c o h o l i c R e l a t i v e s of Mood Disorder Probands 97 TABLE 3.9 Gender Ratio of Mood Disorder Probands With At Least One A l c o h o l i c F i r s t Degree R e l a t i v e 99 TABLE 3.10 Gender Ratio of A l c o h o l i c R e l a t i v e s of Mood Disorder Probands 100 TABLE 3.11 Average Ages of Onset of UP and BP Probands by Their A l c o h o l i c Status 103 TABLE 3.12 Summary of Comparisons of Average Ages of Onset of A l c o h o l i c Versus non-Alcoholic UP and BP Probands 103 TABLE 3.13 Average Ages of Onset of UP-SE, UP-R, BP I and BP I I Probands by Their A l c o h o l i c Status 104 TABLE 3.14 Summary of Comparisons of Average Ages of Onset of A l c o h o l i c Versus non-Alcoholic UP-SE, UP-R, BP I and BP I I Probands 105 TABLE 3.15 Mean Age of Onset of U n i p o l a r - S i n g l e Episode Versus Unipolar-Recurrent Probands 106 TABLE 3.16 Mean Current Age of U n i p o l a r - S i n g l e Episode Versus Unipolar-Recurrent Probands 107 TABLE 3.17 Mean Difference Between the Age of Onset and The Current Age of U n i p o l a r - S i n g l e Episode Versus Unipolar-Recurrent Probands 107 TABLE 3.18 Summary of Comparisons Between the Age of Onset, the Age at Interview and the Age Dif f e r e n c e of U n i p o l a r - S i n g l e Episode Versus Unipolar-Recurrent Probands 108 TABLE 3.19 Average Ages of Onset of UP-SE, UP-R, BP I and BP I I Probands with Versus without A l c o h o l i c F i r s t Degree R e l a t i v e s .... 110 x TABLE 3.20 Summary of Comparisons of Average Ages of Onset of UP-SE, UP-R, BP I and BP I I Probands with Versus without A l c o h o l i c •Firs t Degree R e l a t i v e s I l l TABLE 3.21 Average Ages of Onset of UP and BP Probands with Versus without A l c o h o l i c F i r s t Degree R e l a t i v e s 112 TABLE 3.22 Summary of Comparisons of Average Ages of Onset of UP and BP Probands with Versus without A l c o h o l i c F i r s t Degree R e l a t i v e s 112 TABLE 3.23 D i s t r i b u t i o n of F i r s t and Second Degree R e l a t i v e s Who Committed S u i c i d e : Subdivided by Gender and Diagnosis of Proband Group 114 TABLE 3.24 Average Ages of Onset of UP and BP Probands with Versus without F i r s t or Second Degree R e l a t i v e s who Committed Su i c i d e 115 TABLE 3.25 Summary of Comparisons of Average Ages of Onset of UP and BP Probands with Versus without F i r s t Degree or Second Degree R e l a t i v e s who Committed Suici d e 115 TABLE 3.2 6 Average Ages of Onset of UP-SE, UP-R, BP I and BP I I Probands with Versus without F i r s t or Second Degree R e l a t i v e s who Committed S u i c i d e 116 TABLE 3.27 Summary of Comparisons of Average Ages of Onset of UP-SE, UP-R, BP I and BP I I Probands with Versus without F i r s t Degree or Second Degree R e l a t i v e s who Committed S u i c i d e 117 TABLE 3.28 D i s t r i b u t i o n of Mood Disorder Probands with Greater than Two, Three, Four or Five A l c o h o l i c F i r s t or Second Degree R e l a t i v e s 119 x i LIST OF FIGURES FIGURE 2.1 Sample 2X2 Contingency Table x i i ACKNOWLEDGMENTS I would l i k e to thank and acknowledge the f o l l o w i n g people f o r t h e i r support and comments: Nancy Greig, Dr. R. Remick, Dr. M. H a r r i s , Dr. M a c G i l l i v r a y , Dr. R. Lam. I would l i k e to thank Irene Yee f o r a l l her support and guidance i n the analyses undertaken i n t h i s t h e s i s , without who's help t h i s p r o j e c t would not been p o s s i b l e . I would a l s o l i k e to thank Dr. A. D. Sadovnick, without who's as s i s t a n c e and support, t h i s p r o j e c t would not have been s t a r t e d , l e t alone completed. x i i i 1 INTRODUCTION 1.1 Thesis Object ives (1) To determine whether the d i s t r i b u t i o n by gender of a l c o h o l i c f i r s t degree r e l a t i v e s i s as s o c i a t e d with the gender and/or s p e c i f i c mood d i s o r d e r diagnosis of the proband i n the Mood Disorders Service Genetic Database. (2) To s p e c i f i c a l l y i n v e s t i g a t e the hypothesis that females with a diagnosis of Unipolar depression have a s i g n i f i c a n t l y higher p r o p o r t i o n of a l c o h o l i c male, as compared to female, f i r s t degree r e l a t i v e s , when compared to the f i r s t degree r e l a t i v e s of probands with various other mood di s o r d e r diagnoses. (3) To determine whether a fa m i l y h i s t o r y of alc o h o l i s m i s as s o c i a t e d with the age of onset of the mood di s o r d e r i n the p a t i e n t s i n the MDS Genetic Database. (4) To determine whether or not a f a m i l y h i s t o r y of s u i c i d e i n the f i r s t or second degree r e l a t i v e s a f f e c t s the age of onset of the mood di s o r d e r i n the probands. (5) To review i n d e t a i l "loaded" f a m i l i e s (presented as case reports) to i d e n t i f y any obvious b i o l o g i c a l p a t t e r n s . 1.2 Background The f a m i l i a l aggregation of alcoholism and of mood dis o r d e r s have each been thought to have a genetic 'component. Many studies have shown that the pa t t e r n of trans m i s s i o n of mood dis o r d e r s and alc o h o l i s m seen w i t h i n a f a m i l y suggests an a s s o c i a t i o n between these two d i s o r d e r s . This t h e s i s p r o j e c t was designed to determine i f an a s s o c i a t i o n does indeed e x i s t between mood dis o r d e r s and alcoholism w i t h i n f a m i l i e s , using data from the Mood Disorders Service Genetic Database (MDS genetic database), Department of Ps y c h i a t r y , 1 U n i v e r s i t y of B r i t i s h Columbia. The MDS genetic database c o n s i s t s of f a m i l y h i s t o r y and c l i n i c a l i n f o r m a t i o n f o r a l l i n p a t i e n t s and outp a t i e n t s r e f e r r e d to the Mood Disorders Service from January 1987 to May 1990. A l l i n p a t i e n t s and o u t p a t i e n t s , with or without a co-morbid diagnosis of alcoholism (Diagnostic and S t a t i s t i c a l Manual I l l - R e v i s e d , 1987 (DSM I I I - R ) ) , were included i f they a l s o were (1) Un i p o l a r - S i n g l e Episode, (2) Unipolar-Recurrent Episodes, (3) B i p o l a r I Disorder or (4) B i p o l a r I I Disorder. DSM II I - R and Research Diagnostic C r i t e r i a (RDC) ( S p i t z e r et a l . , 1978) were used to diagnose the probands. ("Proband" r e f e r s to the a f f e c t e d f a m i l y member through whom the fa m i l y i s ascertained, i n t h i s case the i n p a t i e n t s and outpa t i e n t s r e f e r r e d to above.) These c r i t e r i a are presented below i n synoptic form. See Section 2.11 f o r complete DSM I I I - R c r i t e r i a and Section 2.12 f o r d e t a i l e d RDC c r i t e r i a . The l i t e r a t u r e on the genetics of alc o h o l i s m and mood di s o r d e r s w i l l be overviewed i n Section 1.3, and discussed more thoroughly i n the se c t i o n s on fam i l y studies (Section 1.4), twin s t u d i e s (Section 1.5), and adoption s t u d i e s (Section 1.6). The I n t r o d u c t i o n s e c t i o n w i l l be followed by a s e c t i o n on the M a t e r i a l s and Methods used to analyze the data contained i n the Mood Disorders Service Database. The analyses are presented i n the Results s e c t i o n and t h e i r i n t e r p r e t a t i o n i n the Discussion s e c t i o n . 1.21 Overview of C r i t e r i a f o r Unipolar Disorder Unipolar d i s o r d e r (depression) p a t i e n t s g e n e r a l l y d i s p l a y a depressed mood or l o s s of i n t e r e s t or pleasure i n ne a r l y a l l usual d a i l y a c t i v i t i e s , weight l o s s (or ga i n ) , increase (or decrease) i n a p p e t i t e , insomnia (or hypersomnia), psychomotor r e t a r d a t i o n (or a g i t a t i o n ) , f a t i g u e or l o s s of energy, f e e l i n g s of worthlessness or excessive g u i l t , i n d e c i s i v e n e s s or decreased a b i l i t y to concentrate, and/or recurrent thoughts of death. (See 2 Section 2.11.1, TABLE 2.1 f o r f u l l DSM II I - R c r i t e r i a and Section 2.12.1, TABLE 2.4 f o r d e t a i l e d RDC c r i t e r i a . ) The c l a s s i f i c a t i o n " U n i p o l a r - S i n g l e Episode" a p p l i e s i f only one depressive episode has occurred by the time of assessment. "Unipolar-Recurrent" r e f e r s to i n d i v i d u a l s who are depressed at the time of t h e i r assessment and have had at l e a s t one previous episode of depression from which recovery was complete. 1.22 Overview of C r i t e r i a f o r B ipo la r Disorder B i p o l a r I d i s o r d e r r e f e r s to persons who- have periods of major depression i n t e r s p e r s e d with periods of mania (e.g.: expansive, i r r i t a b l e or elevated moods; decreased need f o r sleep; i n f l a t e d s e l f esteem or g r a n d i o s i t y ; pressure of speech; f l i g h t of ideas; d i s t r a c t i b i l i t y ; excessive involvement i n pleasurable a c t i v i t i e s which have a high p o t e n t i a l f o r bad consequences; and/or psychomotor a g i t a t i o n ) . B i p o l a r I I d i s o r d e r r e f e r s to major depression i n t e r s p e r s e d with periods of hypomania. Hypomania symptoms resemble those described f o r mania, but they are l e s s severe and thus do not impair r e l a t i o n s h i p s , work and s o c i a l a c t i v i t i e s or re q u i r e p r o t e c t i v e ( s e l f , others) h o s p i t a l i z a t i o n . (See Section 2.11.2, TABLE 2.2 f o r f u l l DSM II I - R c r i t e r i a and Section 2.12.2, TABLE 2.5 and TABLE 2.6 f o r d e t a i l e d RDC c r i t e r i a . ) 1.23 Overview of C r i t e r i a f o r A l coho l Abuse Diagnostic c r i t e r i a f o r a l c o h o l abuse i n c l u d e : 1) re g u l a r d a i l y i n t a k e of l a r g e amounts of a l c o h o l , 2) regu l a r heavy d r i n k i n g u s u a l l y l i m i t e d to weekends or h o l i d a y s , or 3) long periods of abstinence i n t e r s p e r s e d with binges of d a i l y heavy d r i n k i n g , l a s t i n g weeks or months. (See Section 2.11.3 3 and TABLE 2.3 f o r DSM II I - R c r i t e r i a and Section 2.12.3, TABLE 2.7 f o r d e t a i l e d RDC c r i t e r i a . ) 1.3 Introduct ion Overview There are many d i f f e r e n t methods that have been used to study mood dis o r d e r s and alc o h o l i s m and t h e i r p o s s i b l e common genetic e t i o l o g y . These i n c l u d e : (1) fa m i l y s t u d i e s ; (2) twin s t u d i e s ; (3) adoption s t u d i e s ; (4) genetic modelling s t u d i e s ; (5) animal modelling s t u d i e s ; (6) genetic (e.g.: linkage) s t u d i e s ; and (7) b i o l o g i c a l (e.g.: neurochemical l e v e l ) s t u d i e s . This t h e s i s w i l l focus on family, adoption and twin s t u d i e s . A b r i e f synopsis of the l i t e r a t u r e p e r t a i n i n g to these three types of studies w i l l be followed by a more d e t a i l e d review. 1.31 Family Studies Family studies r e f e r to the i n v e s t i g a t i o n of the patterns of c e r t a i n d i s o r d e r s w i t h i n the f a m i l i e s of probands with p a r t i c u l a r medical or p s y c h i a t r i c c o n d i t i o n s . Family studies are c r i t i c a l to f i n d i n g patterns of f a c t o r s w i t h i n f a m i l i e s , which can help to e l u c i d a t e genetic and/or environmental causes of d i s o r d e r s . However, fa m i l y studies are prone to sev e r a l biases which could confound r e s u l t s , i n c l u d i n g : (1) the method of ascertainment; (2) the category of r e l a t i v e (parent, c h i l d , aunt, cousin, e t c . ) ; and (3) the accuracy of diagnoses i n probands and t h e i r r e l a t i v e s . Studies of mood diso r d e r s and alc o h o l i s m have not been exempt from these f a c t o r s and as a r e s u l t , f i n d i n g s have not been c o n s i s t e n t . The r e s u l t s of the many fa m i l y studies of mood d i s o r d e r probands suggest an a s s o c i a t i o n w i t h i n f a m i l i e s between mood di s o r d e r s and alc o h o l i s m (e.g.: Winokur and P i t t s (1965); Winokur et a l . (1971); Winokur et a l . (1972); Rosenthal (1975); Winokur et a l • (1975); VanValkenburg et a l . (1977); Powell 4 et a l . (1982); Leckman et a l . (1983); Woods et a l . (1986); Winokur and C o r y e l l (1991); Winokur and C o r y e l l (1992); Kendler et a l . (1993a); Reich (1993); Clark et a l . (1994)). However, t h i s observation i s not u n i v e r s a l i n that other studies have not supported t h i s hypothesis (e.g.: Cadoret and Winokur (1973); Goodwin et a l . (1977a); Hensel et a l . (1979); Rice et a l . (1987); Schuckit (1994)). 1.32 Twin Studies Twin studies i n v e s t i g a t e the occurrence of a given d i s o r d e r among monozygotic (100% g e n e t i c a l l y i d e n t i c a l ) and d i z y g o t i c (50% of genes i n common) co-twins, i . e . : concordance or discordance. (For more d e t a i l on twin studies r e f e r to Section 1.5.) Twin studies have a l s o shown c o n t r a d i c t o r y r e s u l t s about the p o s s i b l e a s s o c i a t i o n , between a l c o h o l i s m and mood d i s o r d e r s . Few studies have i n v e s t i g a t e d both mood d i s o r d e r s and alc o h o l i s m i n twins. However of those that have, some have concluded an a s s o c i a t i o n between mood dis o r d e r s and alcoholism (e.g.: Pickens et a l . , 1991; Kendler et a l . , 1993a), whereas one other has not (Kendler et a l . , 1995a). (Refer to Section 1.5.) 1.33 Adoption Studies Adoption studies are a type of fa m i l y study which help e l u c i d a t e the r e l a t i v e r o l e s of genetic versus environmental (non-genetic) f a c t o r s i n dis o r d e r causation or s u s c e p t i b i l i t y . (For more d e t a i l s , r e f e r to Section 1.6.) As with other types of fa m i l y s t u d i e s , adoption s t u d i e s i n mood dis o r d e r s and alc o h o l i s m have a l s o produced i n c o n s i s t e n t r e s u l t s . For example, the Goodwin et a l . adoption study s e r i e s (1973, 1977a, 1977b) concluded that (1) a l c o h o l i s m i s genetic and (2) Unipolar d i s o r d e r i s elevated i n females, 5 but ( i n general) only i f they were r a i s e d by t h e i r b i o l o g i c a l a l c o h o l i c f a t h e r s . Several other studies have found evidence of a genetic a s s o c i a t i o n between alcoholism and mood di s o r d e r s between adoptive c h i l d r e n and t h e i r b i o l o g i c a l r e l a t i v e s (Ingraham and Wender, 1992; Cadoret et a l . , 1994). However, s e v e r a l studies have not seen t h i s p a t t e r n (Cadoret et a l . , 1994-M u l t i - c e n t e r study). (Refer to Section 1.6.) 1.4 Family Studies I t i s g e n e r a l l y accepted that Unipolar (both U n i p o l a r - S i n g l e Episode and Unipolar-Recurrent) and B i p o l a r (both B i p o l a r I and B i p o l a r II) d i s o r d e r s are two separate c o n d i t i o n s with at l e a s t p a r t i a l l y separate genetic e t i o l o g i e s (e.g.: Winokur et a l . , 1995b). Therefore, t h i s t h e s i s w i l l be s t r u c t u r e d throughout so that Unipolar disease + alcoholism and B i p o l a r disease + alcoholism w i l l be presented as separate subheadings. The s t u d i e s reviewed i n the f o l l o w i n g s e c t i o n s i n v e s t i g a t e d patterns of alco h o l i s m and mood d i s o r d e r s . The a l c o h o l i c probands were u s u a l l y d i v i d e d on the basis of whether the onset of the alcoholism was before (primary) or a f t e r (secondary) the onset of the p s y c h i a t r i c c o n d i t i o n under c o n s i d e r a t i o n . This d i f f e r e n c e i s important because heavy a l c o h o l intake can mimic depressive symptoms and thereby complicate diagnosis of mood di s o r d e r probands. 1.41 Unipolar-S ingle Episode versus Unipolar-Recurrent Unipolar d i s o r d e r p a t i e n t s d i s p l a y a depressed mood or l o s s of i n t e r e s t or pleasure i n ne a r l y a l l usual d a i l y a c t i v i t i e s , as w e l l as a number of other symptoms ( o u t l i n e d i n Sectio n 1.21 and Section 2.11). A diagnosis of Unip o l a r -S i n g l e Episode occurs i n the absence of any previous episode of depression. Over time, U n i p o l a r - S i n g l e Episode may evolve i n t o Unipolar-Recurrent i f a depressive episode recurs. Unipolar-Recurrent r e q u i r e s at l e a s t one previous 6 episode of depression, and f u l l recovery before the onset of the present episode. The separation of Unipolar d i s o r d e r i n t o recurrent and s i n g l e episode forms i s a r e l a t i v e l y new s u b d i v i s i o n (DSM III-R, 1987; RDC, 1978). Consequently, r e l a t i v e l y few studies have been done to date to determine i f these are: (1) two d i s t i n c t d i s o r d e r s , (2) v a r i a b l e expressions of the same dis o r d e r , or (3) i n r e a l i t y , a l l cases represent Unipolar-Recurrent with i n s u f f i c i e n t lag-time to i d e n t i f y the recurrent episode. Studies that have i n v e s t i g a t e d these questions w i l l be reviewed i n the f o l l o w i n g paragraphs and are summarized i n TABLE 1.1. 1.41.1 Studies of Unipolar Disorder Subdivided in to S ing le Episode and Recurrent Forms Bland et a l . , 1986 were among the f i r s t to study the s u b d i v i s i o n of Unipolar d i s o r d e r d i v i d e d i n t o recurrent and s i n g l e episode forms (see TABLE 1.1). The study was a 12 to 18 year l o n g i t u d i n a l i n v e s t i g a t i o n of 763 r e l a t i v e s of 75 probands, who were separated according to a diagnosis of Uni p o l a r - S i n g l e Episode or Unipolar-Recurrent and e a r l y or l a t e onset depression. Late onset was defined as the age of onset of depression being older than 51.2 years, the mean age of onset of the study group. Bland et a l . (1983) found that the average age of onset was highest f o r U n i p o l a r - S i n g l e Episode probands and lowest f o r Unipolar-Recurrent probands. (This f i n d i n g would be expected i f a l l cases of U n i p o l a r - S i n g l e Episode, i n r e a l i t y , represented Unipolar-Recurrent that had not had s u f f i c i e n t lag-time to recur.) Morbid r i s k s i n f i r s t - d e g r e e r e l a t i v e s of the probands ranged as f o l l o w s : (1) l a t e onset U n i p o l a r - S i n g l e Episode probands'-3.39%; (2) e a r l y onset Unipolar-S i n g l e Episode probands'-7.45%; (3) l a t e onset Unipolar-Recurrent probands'-8.17%; and (4) e a r l y onset Unipolar-Recurrent probands'-17.43%. Factors such 7 as the sex of the r e l a t i v e and proband, the generation or b i r t h cohort of the r e l a t i v e ( i . e . : parent, s i b l i n g , c h i l d ) , and the b i r t h order p o s i t i o n of the proband d i d not a l t e r the f i n d i n g s . The study found that a " s u b s t a n t i a l " but n o n - s i g n i f i c a n t p r o p o r t i o n of the e a r l y onset U n i p o l a r - S i n g l e Episode probands' depressive episodes recurred over the course of the study, emphasizing that Unipolar probands must be followed over time before a d e f i n i t e diagnoses of U n i p o l a r - S i n g l e Episode versus Unipolar-Recurrent can be given. Bland et a l . (1986) concluded that Unipolar-Recurrent and Unipolar-S i n g l e Episode have d i f f e r e n t e t i o l o g i e s . Bland et a l . (1986) are l i k e l y c o r r e c t i n t h e i r suggestion that U n i p o l a r - S i n g l e Episode probands should be followed up l o n g i t u d i n a l l y to screen f o r recurrence of depression (and the e v o l u t i o n of the proband's di s o r d e r i n t o a recurrent form). However, the conclusion by Bland et a l . that the recurrent and s i n g l e episode forms have d i f f e r e n t genetic e t i o l o g i e s i s premature. The conclusion was based p r i m a r i l y on suggestive age of onset d i f f e r e n c e s observed between the proband groups and d i d not i n c l u d e any i n d i c a t i o n of d i f f e r e n c e s i n the t r a n s m i s s i o n patterns i n the f a m i l i e s of U n i p o l a r - S i n g l e Episode versus Unipolar-Recurrent probands. The conclusion that these r e s u l t s i n d i c a t e a d i f f e r e n t genetic e t i o l o g y f o r s i n g l e episode versus recurrent forms of depression should be considered p r e l i m i n a r y . Cassano et a l . (1989) i n v e s t i g a t e d the d i f f e r e n c e s i n the phenotypes of U n i p o l a r - S i n g l e Episode and Unipolar-Recurrent probands (see TABLE 1.2). In the study of 405 depressed i n p a t i e n t s and o u t p a t i e n t s seen at various p s y c h i a t r i c centres i n I t a l y over an 18 month peri o d , s i g n i f i c a n t d i f f e r e n c e s were observed between the proband groups. Based on the r e s u l t s of the study, shown i n TABLE 1.2, the authors suggested that the e t i o l o g y of U n i p o l a r - S i n g l e Episode was e n t i r e l y due to non-genetic f a c t o r s of a " d i f f i c u l t l i f e " , whereas Unipolar-Recurrent was at l e a s t i n part the r e s u l t of genetic f a c t o r s . 8 In a l a t e r study done on a l a r g e r proband group by the same authors (Cassano et a l . , 1993), s i m i l a r r e s u l t s were found. The 1993 study by Cassano et a l . found an i n t e r e s t i n g p a t t e r n : the c h a r a c t e r i s t i c s of the e a r l y onset U n i p o l a r - S i n g l e Episode probands mimicked those of the Unipolar-Recurrent proband group. The c h a r a c t e r i s t i c s of the l a t e onset U n i p o l a r - S i n g l e Episode probands mimicked those seen i n the c o n t r o l group. The authors concluded that a high p r o p o r t i o n of Un i p o l a r - S i n g l e Episode probands i n r e a l i t y w i l l become Unipolar-Recurrent over time. This conclusion was e s p e c i a l l y strong i f the Uni p o l a r - S i n g l e Episode was e a r l y onset. The authors a l s o suggested that l a t e onset U n i p o l a r - S i n g l e Episode was l i k e l y due to environmental causes, or even could be e a r l y signs of other c o n d i t i o n s , e.g.: A l z h e i m e r - l i k e Dementia, without n e c e s s a r i l y being r e l a t e d to Unipolar-Recurrent. TABLE 1.1: SUMMARY OF STUDIES ON UNIPOLAR-SINGLE EPISODE VERSUS UNIPOLAR-RECURRENT Author(s) and Year of Study Sample Size Follow Up Conclusions Bland et a l . (1986) 75 UP probands 763 1st degree r e l a t i v e s 12-18 years Morbid Risk of UP i n r e l a t i v e s of probands lowest f o r l a t e onset UP-SE (3.39%),highest f o r e a r l y onset UP-R (17.43%). D i f f e r e n t d i s o r d e r s Cassano et a l . (1989) 405 UP probands None Differences seen between UP-R & UP-SE phenotypes (see TABLE 1.2). No genetic b a s i s to UP-SE Cassano et a l . (1993) 213 UP-SE; 473 UP-R probands None Differences seen between l a t e and e a r l y onset UP-SE versus UP-R phenotypes Merikangas et a l . (1994) 591 UP probands parents & s i b s 10 years D i r e c t r e l a t i o n s h i p between s e v e r i t y of UP and the dur a t i o n and recurrence of depressive episodes over time (see TABLE 1.2) Where s i b s = S i b l i n g s ; UP=Unipolar d i s o r d e r ; UP-SE=Unipolar-Single Episode; UP-R=Unipolar-Recurrent; l s t = F i r s t 9 In an e p i d e m i o l o g i c a l , l o n g i t u d i n a l study, Merikangas et a l . (1994) studi e d 591 young a d u l t s s e l e c t e d f o r t h e i r high score on a census of depressive symptoms. A fa m i l y h i s t o r y was taken f o r the probands' f i r s t -degree r e l a t i v e s and a random s e l e c t i o n of low sc o r i n g census takers was se l e c t e d as a c o n t r o l group f o r comparison. The d i f f e r e n c e s seen between the proband groups who were e v e n t u a l l y diagnosed with U n i p o l a r - S i n g l e Episode or Unipolar-Recurrent are presented i n TABLE 1.2. The r e s u l t s i n TABLE 1.2 i n d i c a t e that d i f f e r e n c e s between the types of Unipolar d i s o r d e r e x i s t . However, because 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 the tra n s m i s s i o n patterns i n the f a m i l i e s of the probands were seen, the authors concluded that Unipolar-Sing l e Episode and Unipolar-Recurrent were not g e n e t i c a l l y d i s t i n c t d i s o r d e r s 1.41.2 Summary of Results of Studies on Unipolar-S ingle Episode and Unipolar Recurrent In summary, the data to date suggest: (1) an excess of female Unipolar Recurrent probands versus the equal sex r a t i o seen with U n i p o l a r - S i n g l e Episode probands; (2) a higher morbid r i s k of mood di s o r d e r s i n the f a m i l i e s of Unipolar-Recurrent probands than that seen i n the r e l a t i v e s of Unipolar -Single Episode probands; and (3) Un i p o l a r - S i n g l e Episode probands have a l a t e average age of onset than Unipolar-Recurrent probands. The c o n s i s t e n t l y observed d i f f e r e n c e s between U n i p o l a r - S i n g l e Episode and Unipolar-Recurrent probands suggest that there may be d i f f e r e n t genetic f a c t o r s r e s p o n s i b l e f o r the type of depression seen. However, although morbid r i s k s of depressive d i s o r d e r s were higher f o r the f i r s t - d e g r e e r e l a t i v e s of Unipolar-Recurrent versus U n i p o l a r - S i n g l e Episode probands, the patterns of trans m i s s i o n w i t h i n f a m i l i e s were not d i f f e r e n t . Further research must be done before any conclusions can be made about whether U n i p o l a r - S i n g l e Episode and Unipolar-10 Recurrent represent d i f f e r e n t manifestations of the same genetic defect or have d i f f e r e n t e t i o l o g i e s . TABLE 1.2: SIGNIFICANT PHENOTYPIC DIFFERENCES OBSERVED BETWEEN UNIPOLAR-SINGLE EPISODE AND UNIPOLAR-RECURRENT IN Cassano et a l • (1989) AND Merikangas et a l . (1994) Unipolar S i n g l e Episode Unipolar Recurrent S i g n i f i c a n t D i f f e r e n c e Study Sex D i s t r i b u t i o n Male=33.0% Male=45.5% Male=22.4% Male=32.8% p<0 p<0 001 01 C M Age of Onset 48.7 years 19.2 years 36.6 years 17.6 years p<0 p<0 001 01 C M MR i n R e l a t i v e s 30.9% 37 . 9% no C Duration of I l l n e s s * 1.7 years 3.9 years chronic 15.7 years 6.6 years i n t e r m i t t e n t p<0 p<0 001 001 C M H i s t o r y of Inpatient Treatment 0% 8.2% p<0 001 M S u i c i d e Attempts 3.0% 19.7% p<0 01 M Parent or Sib with Depression 41.4% 53. 9% R<0 001 M Where C=Cassano et a l . (1989); M=Merikangas et a l . (1994); MR=Morbid Risk; S t a t i s t i c a l f i n d i n g s based on Chi-Squared t e s t s ; No confidence l i m i t s given. * • as p r e d i c t e d by d e f i n i t i o n s of UP-R versus UP-SE 1.42 Family Studies-Unipolar Disorder and Alcohol ism E x i s t i n g f a m i l y data have been c o n t r o v e r s i a l with respect to the p o s s i b l e r e l a t i o n s h i p between Unipolar d i s o r d e r (both S i n g l e Episode and Recurrent) and alcoholism. For example, there i s no consensus on whether or not (1) genetic f a c t o r s have r o l e s i n the t r a n s m i s s i o n of Unipolar d i s o r d e r and alcoholism, and (2) a l c o h o l i s m and Unipolar d i s o r d e r share a common e t i o l o g y . There are s e v e r a l p o s s i b l e explanations f o r the i n c o n s i s t e n t r e s u l t s found, such as (1) i n c o n s i s t e n t study design, (2) d i f f e r e n t methods of 11 case ascertainment, (3) changes over time i n d i a g n o s t i c t e c h n i q u e s / c r i t e r i a , and (4) r a t e r r e l i a b i l i t y . Due to una v a i l a b l e d i a g n o s t i c c r i t e r i a and procedures, e a r l y studies often were imprecise with respect to diag n o s i s ; e.g.: h o s p i t a l i z e d depressed probands were not separated according to whether or not manic episodes occurred (Rosanoff et a l . , 1935; Cassidy et a l . , 1957). In general, i t i s theref o r e very d i f f i c u l t to compare r e s u l t s of these e a r l y studies with present day work. Nevertheless, e a r l y work of Rosanoff et a l . (1935) and Cassidy et a l . (1957) warrant f u r t h e r d i s c u s s i o n i n Sections 1.5 and 1.42, r e s p e c t i v e l y . As w e l l , very few studies have i n v e s t i g a t e d Unipolar d i s o r d e r probands that were d i v i d e d i n t o subgroups dependent on the type of t h e i r depression (See TABLE 1.1, TABLE 1.3 to 1.6). For these reasons, the l i t e r a t u r e on Unipolar d i s o r d e r and alcoholism w i l l be reviewed i n temporal order. 1.42.1 Depression Spectrum Disease and Pure Depressive Disease Winokur and P i t t s (1965) were among the f i r s t to separate depressed probands according to whether or not mania (or a fa m i l y h i s t o r y of mania) was present. (NB: Today-if a f i r s t degree r e l a t i v e has B i p o l a r d i s o r d e r and the proband has Unipolar d i s o r d e r , the f a m i l y can be inc l u d e d i n B i p o l a r linkage studies.) O v e r a l l , they found s i g n i f i c a n t l y elevated rates of mania and/or depression i n the r e l a t i v e s of 366 probands with any type of mood d i s o r d e r versus the r e l a t i v e s of 180 p h y s i c a l l y i l l age, sex and m a r i t a l status matched c o n t r o l s . There was als o a f i v e times higher r a t e of alc o h o l i s m i n the fath e r s of the mood d i s o r d e r probands versus the fat h e r s of the c o n t r o l s . Winokur and P i t t s thus hypothesized that depression should be separated i n t o two d i s t i n c t d i s o r d e r s , "Depression Spectrum Disease" (or DSD), i . e . : the depressed proband had a f a m i l y h i s t o r y of alc o h o l i s m or a n t i s o c i a l p e r s o n a l i t y 12 d i s o r d e r , as w e l l as depression, and "Pure Depressive Disease" (or PDD), i . e . : the depressed proband had a fa m i l y h i s t o r y of depression only. In summary, Winokur and P i t t s (1965) concluded that depressive probands should be subdivided on the basis of t h e i r f a m i l y h i s t o r i e s . (Winokur and P i t t s suggest t h a t , at the time of admission, a l l probands and at l e a s t one of t h e i r f i r s t degree r e l a t i v e s be interviewed regarding the f a m i l y h i s t o r y of the proband. The information gleaned may then be used to assign p s y c h i a t r i c diagnoses w i t h i n the f a m i l i e s of the probands.) For a more d e t a i l e d d e s c r i p t i o n of the p r o t o t y p i c a l proband f o r each of these " d i s o r d e r s " , see TABLE 1.3. TABLE 1.3: DESCRIPTION OF DEPRESSION SPECTRUM DISEASE (DSD) VERSUS PURE DEPRESSIVE DISEASE (PDD) DSD PDD Onset of Unipolar Depression e a r l y l a t e Gender Ratio i n Probands Female>Male Female=Male Rates of Depression i n Re l a t i v e s Increased rates i n females only Increased rates i n males and females Rates of Alcoholism and A n t i s o c i a l P e r s o n a l i t y Disorder i n R e l a t i v e s Increased rates i n male r e l a t i v e s , but popula t i o n rates i n females Rates i n R e l a t i v e s equal to population rates f o r both genders Where "Increased r a t e s " r e f e r to rates above those seen i n the population Source: Paraphrased from Winokur et a l . , 1972a Some subsequent work has supported the existence of Depression Spectrum Disease and Pure Depressive Disease (Winokur, 1972a; Winokur 1972b; Winokur et a l . , 1975; Winokur et a l . , 1978; Winokur, 1982). For d e t a i l s on these s t u d i e s , r e f e r to TABLE 1.4. In explanation, a n t i s o c i a l p e r s o n a l i t y d i s o r d e r , beginning before age f i f t e e n and continu i n g i n t o adulthood, i s "chronic a n t i s o c i a l behaviour" 13 c h a r a c t e r i z e d by at l e a s t three of the f o l l o w i n g : frequent job changes, s i g n i f i c a n t unemployment, serious absenteeism, poor academic performance, s e v e r a l a r r e s t s f o r serious offenses, m a r i t a l i n s t a b i l i t y , f i g h t i n g , excessive d r i n k i n g , debt d e f a u l t , no permanent residence, impaired a b i l i t y to s u s t a i n r e l a t i o n s h i p s with f a m i l y , f r i e n d s or sexual partners ( S p i t z e r et a l . ,1978). The p o s s i b i l i t y of an a s s o c i a t i o n between alcoholism, depression and a n t i s o c i a l p e r s o n a l i t y d i s o r d e r was i n v e s t i g a t e d i n s e v e r a l s t u d i e s , as shown i n TABLE 1.4 and discussed below (Section 1.42.2). The use of the Depression Spectrum Disease and Pure Depressive Disease s u b d i v i s i o n decreased s u b s t a n t i a l l y a f t e r a paper by Winokur and C o r y e l l (1991) f o r s e v e r a l reasons. (Rush et a l • (1995) i s one of the few recent papers that uses the Depression Spectrum Disease and Pure Depressive Disease s u b d i v i s i o n ) . F i r s t l y , Winokur and colleagues were not c o n s i s t e n t l y f i n d i n g support f o r t h e i r s u b d i v i s i o n of depression. Secondly, few other authors used Winokur and P i t t s ' (1965) d i a g n o s t i c c a t e g o r i e s . Several studies that support an a s s o c i a t i o n between al c o h o l i s m and mood d i s o r d e r s , but do not use Winokur and P i t t s ' (1965) d i a g n o s t i c c r i t e r i a f o r Depression Spectrum Disease and Pure Depressive Disease, are summarized i n TABLE 1.5 and discussed i n more d e t a i l below (Section 1.42.2). 14 TABLE 1 .4: SUMMARY OF STUDIES ON THE VALIDITY OF THE DEPRESSION SPECTRUM DISEASE (DSD) VERSUS PURE DEPRESSIVE DISEASE (PDD) SUBDIVISION Author(s) Sample Conclusions and Year Size of Study Winokur and 366 MD probands;180 Excess MD i n r e l a t i v e s of probands P i t t s (1965) P h y s i c a l l y i l l c o n t r o l s e s p e c i a l l y A l c oholism i n fathers Winokur (1972a) Winokur (1972b) Winokur et a l . (1975) Winokur et a l . (19.78) Winokur (1982) Dorzab et a l . (1971) Marten et a l . (1972) Kupfer et a l . (1989) Winokur & C o r y e l l (1991) Rush et a l . (1995) DSD:PDD v a l i d s u b d i v i s i o n 526 depressed probands DSD:PDD v a l i d s u b d i v i s i o n 259 a l e probands; 1st degree r e l a t i v e s 100 depressed probands, t h e i r s i b s & parents 216 depressed probands and t h e i r f a m i l i e s review of 6 studies with 1255 probands 100 UP, Ale,manic or drug abusers; 400 1st-degree r e l a t i v e s 204 UP probands, s i b s and parents 1st r e l a t i v e s of 179 UP-R probands 326 UP probands; 723 1st,2nd & 3rd-degree r e l a t i v e s DSD:PDD v a l i d s u b d i v i s i o n DSD:PDD v a l i d s u b d i v i s i o n DSD:PDD v a l i d as long as include "Sporadic Depression" f o r probands with no f a m i l y h i s t o r y 25% of female r e l a t i v e s had UP; 19% of male r e l a t i v e s had UP; 11% of male r e l a t i v e s had a l e or ASP PDD transmits i n pure form; DSD transmits heterogeneously. DSD and PDD d i f f e r g e n e t i c a l l y Excess r i s k of a l e i n male r e l a t i v e s , depression i n female r e l a t i v e s Excess a l e i n r e l a t i v e s of female UP probands only, DSD:PDD patterns seen DSD with FH of Ale:22 Probands with FH of a l e and UP had male,86 female. DSD with the lowest age of onset and were more FH of A l e and UP:28 male, s i m i l a r to PDD probands than to 75 female. PDD:46 male, probands with a FH of a l e only. 116 female. Where alc=alcoholism; ASP=Antisocial P e r s o n a l i t y Disorder; DSD=Depression Spectrum Disease; MD=Mood Disorders; PDD=Pure Depressive Disease; SDD=Sporadic Depressive Disease; UP=Unipolar d i s o r d e r ; UP-R=Unipolar-Recurrent d i s o r d e r ; l s t = F i r s t ; 2nd=Second; 3rd=Third. 15 1.42.2 Support f o r A Common Genetic E t i o logy Between Depression and Alcohol ism Powell et a l . (1982) supported an alcoholism:depression a s s o c i a t i o n i n t h e i r study based on 565 male a l c o h o l i c United States veteran i n p a t i e n t s . The probands were given a two hour s t r u c t u r e d p s y c h i a t r i c i n t e r v i e w to diagnose primary a l c o h o l i s m as w e l l as co-morbid, secondary, B i p o l a r d i s o r d e r , Unipolar d i s o r d e r and/or a n t i s o c i a l p e r s o n a l i t y d i s o r d e r . Unipolar d i s o r d e r (not subdivided as to recurrent or s i n g l e episode types) was seen co-morbidly with a l c o h o l i s m more f r e q u e n t l y than expected by chance and more f r e q u e n t l y than al c o h o l i s m was seen with a n t i s o c i a l p e r s o n a l i t y d i s o r d e r or B i p o l a r d i s o r d e r . No s t a t i s t i c a l t e s t s were shown other than the r e s u l t s shown i n TABLE 1.5. The authors concluded that t h e i r f i n d i n g s supported .an a s s o c i a t i o n between alcoholism and mood di s o r d e r s (Unipolar d i s o r d e r e s p e c i a l l y ) , the ba s i s of which was not obvious from the study. A study by Finn et a l . (1990) found support f o r an a s s o c i a t i o n between Unipolar d i s o r d e r and alc o h o l i s m using data on probands a s c e r t a i n e d from volunteers who responded to a census given at c o l l e g e s and h o s p i t a l s . Fourteen n o n - a l c o h o l i c male respondents with a strong f a m i l y h i s t o r y of alcoholism were compared to eleven n o n - a l c o h o l i c male respondents with no fam i l y h i s t o r y of alcoholism. The respondents and at l e a s t one of t h e i r f i r s t - d e g r e e r e l a t i v e s were interviewed. 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 diagnosed the respondents and t h e i r r e l a t i v e s using RDC (S p i t z e r et a l . , 1978) as w e l l as DSM II I - R (1987) c r i t e r i a . The study found a s t a t i s t i c a l l y s i g n i f i c a n t increase i n the rates of Unipolar d i s o r d e r and anxiety d i s o r d e r s i n the males from the a l c o h o l i c f a m i l i e s . (Anxiety d i s o r d e r s can be l o o s e l y defined as over exaggerated nervous responses to various, u s u a l l y innocuous, f a c t o r s . ) The authors concluded that a l c o h o l i s m and Unipolar d i s o r d e r were co-segregating i n these f a m i l i e s and that t h e i r data supported a genetic a s s o c i a t i o n between al c o h o l i s m and depressive 16 d i s o r d e r s . The small s i z e of t h i s study decreases the strength of the authors' conclusions, but the r e s u l t s are suggestive of an a s s o c i a t i o n between alc o h o l i s m and depression. A more recent study by Mathew et a l . (1993), supported an a s s o c i a t i o n between al c o h o l i s m and Unipolar d i s o r d e r s (TABLE 1.5). A community sample of probands, o u t l i n e d i n TABLE 1.5, were compared on the ba s i s of t h e i r own p s y c h i a t r i c diagnoses and whether or not they had a f a m i l y h i s t o r y of alcoholism. Excess alcoholism was observed i n the males with a f a m i l y h i s t o r y of alcoholism, compared to the males without such a f a m i l y h i s t o r y . As w e l l , elevated rates of anxiety d i s o r d e r s and Unipolar d i s o r d e r were observed i n the adult females with a l c o h o l i c f a t h e r s . Mathew et a l • (1993) concluded that a f a m i l i a l a s s o c i a t i o n between Unipolar d i s o r d e r and alc o h o l i s m e x i s t s . TABLE 1.5: SUMMARY OF STUDIES THAT SUPPORT AN ASSOCIATION BETWEEN ALCOHOLISM AND MOOD DISORDERS WITHIN FAMILIES Author(s) and Year of Study Sample Size Conclusions Powell et 565 male a l e and/or MD a l . (1982) and/or ASP probands (1990) Mathew et a l . (1993) 42% co-morbid UP; 20% co-morbid ASP; 20% co-morbid BP; 37% a l e only. UP and al e seen co-morbidly more oft e n than expected by chance Finn et a l . 25 non-ale males with or Excess UP & anxi e t y d i s o r d e r s i n males without a FH of A l e ; >1 1st r e l a t i v e 144 males & 264 females with, and 538 males & 939 females without a FH of a l e with a FH of Ale versus those without a FH of a l e (p<0.025) Excess anxiety d i s o r d e r s i n r e l a t i v e s with a FH of a l e (p<0.003); excess a l e i n males with a FH of a l e (p<0.007) Where alc=Alcoholism; ASP=Antisocial P e r s o n a l i t y Disorder; FH=Family H i s t o r y ; MD= Mood Disorders; UP=Unipolar Disorder; UP-R=Unipolar-Recurrent; l s t = F i r s t ; >=Greater than or Equal To The studies o u t l i n e d i n TABLE 1.4 and TABLE 1.5 provide support f o r an a s s o c i a t i o n between al c o h o l i s m and Unipolar d i s o r d e r , but the nature of the 17 common f a c t o r remains ambiguous. In con t r a s t , other s t u d i e s have not reported such a commonality-see TABLE 1.6. 1.42.3 Studies That Do Not Support A Common Genetic E t i o logy Between Alcohol ism and Depression Three studies by Winokur and colleagues (Winokur et a l . , 1970; Winokur et a l . , 1971b; Cadoret and Winokur, 1973) looked at d i f f e r e n t combinations of one group of probands from two p r i v a t e a l c o h o l treatment h o s p i t a l s . A l l three studies used the f o l l o w i n g p r o t o c o l : short s t r u c t u r e d i n t e r v i e w s , based on the c r i t e r i a used i n Cassidy et a l . (1957), were used to gather information and diagnose 103 female a l c o h o l i c s and 156 male a l c o h o l i c s . At l e a s t one (us u a l l y more) of t h e i r f i r s t - d e g r e e r e l a t i v e s were interviewed i n order to c o l l e c t p s y c h i a t r i c f a m i l y h i s t o r y data. Female probands were s e l e c t i v e l y a s c e r t a i n e d by i n c r e a s i n g the geographic area from they were drawn ( i . e . : males from St. Louis and B l i s s were included, while females from these areas as w e l l as the surrounding areas were i n c l u d e d ) . The probands were not screened f o r primary versus secondary a l c o h o l i s m and many had co-morbid dis o r d e r s (primary versus secondary r e f e r s to the temporal sequence of onset of the diso r d e r s i n question, with primary being f i r s t and secondary being second to another d i s o r d e r ) . P s y c h i a t r i c diagnoses f o r probands and t h e i r r e l a t i v e s were: (i) no mental i l l n e s s , ( i i ) schizophrenia, ( i i i ) mood disor d e r s (depression i n a l l but f i v e r e l a t i v e s , who had B i p o l a r d i s o r d e r (out of 77 who had mood d i s o r d e r s ) ) , (iv) alcoholism or (v) a n t i s o c i a l p e r s o n a l i t y d i s o r d e r . Any f i r s t degree r e l a t i v e who could not be reached f o r an in t e r v i e w , but was known to have been h o s p i t a l i z e d f o r a mental d i s o r d e r without obvious a f f e c t i v e symptoms, was c l a s s i f i e d as schizophrenic unless documentation to the contrary was obtainable. (This method may not be a v a l i d one: a p r e f e r r e d technique would have been to exclude those r e l a t i v e s on whom 18 no accurate i n f o r m a t i o n could be gathered.) No c o n t r o l groups were used f o r comparison. The studies r e f e r r e d to i n the previous paragraph (Winokur et a l • , 1970; Winokur et a l . , 1971b; Cadoret and Winokur, 1973) concluded that alcoholism, a n t i s o c i a l p e r s o n a l i t y d i s o r d e r , and depressive d i s o r d e r s are t r a n s m i t t e d i n a manner i n d i c a t i v e of separate genetic e t i o l o g i e s . The stu d i e s based these conclusions on the f o l l o w i n g patterns observed ( r e f e r to TABLE 1.6): (1) the highest rates of alc o h o l i s m were observed i n the r e l a t i v e s of probands whose only diagnosis was alcoholism; (2) the highest rates of depression were observed i n the r e l a t i v e s of the probands with diagnoses of both alcoholism and depression. However, s e v e r a l patterns could not be explained by the hypothesis of separate genetic e t i o l o g i e s : (1) female r e l a t i v e s of a l c o h o l i c probands tended to have increased rates of mood di s o r d e r s ( u s u a l l y depression), while male r e l a t i v e s had increased rates of alc o h o l i s m ; (2) a l c o h o l i c probands had higher rates of co-morbid depression and/or a n t i s o c i a l d i s o r d e r than expected by co-incidence, i . e . : the rat e s of co-morbidity were higher than expected by the general population rates of the three d i s o r d e r s alone. Zisook and Schuckit (1987) looked at the s e v e r i t y and symptoms of alco h o l i s m i n 361 male a l c o h o l i c s according to whether or not there was a h i s t o r y i n t h e i r f i r s t - d e g r e e r e l a t i v e s of any type of mood d i s o r d e r and/or alcoholism. The probands were interviewed using Schedule f o r A f f e c t i v e Disorders and Schizophrenia (Endicott et a l . , 1978) seventy-two hours a f t e r admission to an a l c o h o l treatment centre. No c o n t r o l s were used. A l c o h o l i c s with a fa m i l y h i s t o r y of mood di s o r d e r s and/or a l c o h o l i s m had s i g n i f i c a n t l y increased rates of a l c o h o l r e l a t e d problems and secondary depression compared to a l c o h o l i c s with no such f a m i l y h i s t o r y . A l l probands were re - i n t e r v i e w e d one year l a t e r using a short s t r u c t u r e d i n t e r v i e w . I f the probands had 19 abstained from a l c o h o l f o r the previous year, the increase i n rates of secondary depression was no longer observed. The authors concluded tha t , i n these probands, depression was a symptom of the a l c o h o l i s m and thus there was no evidence of a common genetic b a s i s f o r mood di s o r d e r s and alcoholism. This conclusion i s premature as the study only looked at probands with primary al c o h o l i s m and secondary depression. The f a m i l i e s of a l l combinations of probands with these two d i s o r d e r s ( i . e . : with regard to primary versus secondary status) should be i n v e s t i g a t e d before such a c o n c l u s i o n i s drawn. In a d d i t i o n to these four studies described i n d e t a i l , s e v e r a l others f a i l e d to support a common genetic e t i o l o g y f o r a l c o h o l i s m and depressive d i s o r d e r s based on (1) the f i n d i n g that the highest l e v e l s of alcoholism were seen i n the f a m i l i e s of a l c o h o l i c probands; and (2) the f i n d i n g that the highest rates of depression were seen i n the f a m i l i e s of Unipolar d i s o r d e r probands (Hensel et a l . , 1979; Behar et a l . , 1980; G a l d i and Bonato, 1981; Spring and Rothgery, 1984; Merikangas et al.,1985; Hesselbrock, 1991). Another i n t e r e s t i n g , yet unexplained, observation from some of these studies (Hensel et a l . , 1979; Behar et a l . , 1980; Merikangas et al.,1985) was that female r e l a t i v e s of a l c o h o l i c probands and/or Unipolar probands had excess ( i . e . : higher than expected by chance alone) rates of depression, while the male r e l a t i v e s had excess rates of alcoholism. This p a t t e r n supports a popular hypothesis that phenotypic expression of a genetic v u l n e r a b i l i t y to depression i s d i f f e r e n t i n males and females based on c u l t u r a l f a c t o r s - i . e . : males dr i n k when they become depressed ( e x t e r n a l i s e ) and thus present as a l c o h o l i c s whereas females become depressed ( i n t e r n a l i s e ) and seek help. See TABLE 1.6 f o r f u r t h e r d e t a i l s . In conclusion, the s t u d i e s presented above and summarized i n TABLE 1.6, i d e n t i f i e d the f o l l o w i n g p a t t e r n s : (1) the highest rates of a l c o h o l i s m were c o n s i s t e n t l y found i n the r e l a t i v e s of a l c o h o l i c s ; (2) the highest rates of 20 Unipolar d i s o r d e r were c o n s i s t e n t l y found i n the r e l a t i v e s of Unipolar probands. These patterns do not support a common genetic e t i o l o g y f o r a l c o h o l i s m and depressive d i s o r d e r s . TABLE 1.6: STUDIES THAT DO NOT SUPPORT A COMMON GENETIC ETIOLOGY FOR ALCOHOLISM AND UNIPOLAR DISORDER Author (s) and Year of Study Sample Size Conclusions Winokur et a l . (1970,1971) Cadoret & Winokur (1973) Zisook & Schuckit (1987) Henzel et a l . (1979) Behar et a l . (1980) G a l d i & Bonato (1981) SpringsRothgery (1984) Merikangas et a l . (1985) Hesselbrock (1991) 103 a l e females, 156 al e males; co-morbid MD, ASP, a l e . > 1 1st-degree r e l a t i v e s 361 male a l e with or without a FH of a l e and/or MD males: 53 BP,13 BP/alc* 11 UP,1 UP/alc.Females: 73 BP, 5 BP/alc, 12 UP. 787 1st deg. r e l a t i v e s 238 female UP probands with or without a FH of a l e , UP or ASP 39 o r i e n t a l & 62 Jewish Schizophrenics, 4088 controls,79 UP probands 156 MD probands with or without a FH of ale 133 UP probands, 82 community c o n t r o l s 197 male and 69 female a l e with ASP, UP a l l found an excess a l e i n male r e l a t i v e s ; excess MD i n female r e l a t i v e s . Separate genetic e t i o l o g i e s f o r MD, ASP and a l e Excess a l c o h o l problems and depression i n probands with a FH of ale or MD; not seen on follow-up Separate e t i o l o g y f o r MD, a l e and ASP. Separate e t i o l o g y f o r UP, a l e and ASP. Excess a l e i n male r e l a t i v e s ; Excess MD i n female r e l a t i v e s Separate e t i o l o g y f o r UP, ale and ASP as no increase i n MD or ASP with c u l t u r a l decrease i n Ale Separate e t i o l o g y f o r MD and a l e Separate e t i o l o g y f o r UP and a l e Separate e t i o l o g y f o r UP and a l e Where alc=alcoholism; ASP=Antisocial P e r s o n a l i t y Disorder; FH=Family H i s t o r y ; UP=Unipolar d i s o r d e r ; l s t = F i r s t ; deg.=Degree * order of the l i s t e d d i s o r d e r s r e f e r s to t h e i r temporal occurrence i n the proband group under c o n s i d e r a t i o n , e.g.: BP/alc r e f e r s to primary BP and secondary alcoholism. 21 Conclusions, however, may be confounded by problems i n the study designs and execution. A major flaw of a l l of the studies p r e v i o u s l y discussed i s that the c r i t e r i a f o r diagnosis of the probands and t h e i r r e l a t i v e s were of t e n based on informat i o n obtained only by s t r u c t u r e d i n t e r v i e w s , with l i t t l e or no a d d i t i o n a l supportive data. Another common problem was that the d i a g n o s t i c c r i t e r i a were not s t r i c t and d i f f e r e d between s t u d i e s . Further, most of the studies d i d not compare t h e i r study group to a c o n t r o l group, making any conclusions d i f f i c u l t to r e f e r back to the general population These r e s u l t s , t h e r e f o r e , cannot be viewed as d e f i n i t i v e . The c o n f l i c t i n g r e s u l t s seen i n the various s t u d i e s are d i f f i c u l t to e x p l a i n . At t h i s point no conclusions can be drawn. The need f o r f u r t h e r study i s evident, e s p e c i a l l y r e p l i c a t i o n s of the previous s t u d i e s with d i f f e r e n t proband groups, using c o n s i s t e n t d i a g n o s t i c c r i t e r i a and co n s i s t e n t ascertainment techniques. Attempts must be made to e l u c i d a t e whether or not the p u t a t i v e Unipolar d i s o r d e r and alc o h o l i s m a s s o c i a t i o n i s based on genetic causes, environmental causes, or both. As w e l l , attempts must be made to determine the cause of the sex s p e c i f i c t r a n s m i s s i o n patterns observed i n some f a m i l i e s a f f e c t e d with depressive d i s o r d e r s and/or al c o h o l i s m . 1.43 B ipo la r I D isorder Versus B ipo la r II D isorder B i p o l a r d i s o r d e r has only r e c e n t l y been subdivided i n t o Type I and Type I I ( B i p o l a r I I inc l u d e d as a subtype of B i p o l a r d i s o r d e r i n DSM I I I - R (1987) and i n c l u d e d as a separate d i s o r d e r i n DSM IV (1994)), depending on the s e v e r i t y of the manic s t a t e , ( i . e . : B i p o l a r I probands experience f u l l blown mania while B i p o l a r I I experience hypomania.) Consequently, few studies have i n v e s t i g a t e d probands separated i n t o B i p o l a r I and B i p o l a r I I subtypes (see Section 1.44 f o r more d e t a i l ) . Gershon et a l . (1982) and Sadovnick et a l . (1994) found that B i p o l a r I probands had more f i r s t degree r e l a t i v e s with mood 22 d i s o r d e r s than d i d B i p o l a r I I probands. Huen and Maier (1993) d i d not observe a d i f f e r e n c e . , More stu d i e s need to be done to determine whether or not B i p o l a r I and B i p o l a r I I are d i s t i n c t d i s o r d e r s with separate genetic e t i o l o g i e s . No studies could be found that compared patterns of a l c o h o l abuse i n the f a m i l i e s of B i p o l a r I versus B i p o l a r I I probands. As a consequence, Section 1.44 does not review the l i t e r a t u r e on B i p o l a r d i s o r d e r and alc o h o l i s m with B i p o l a r d i s o r d e r separated i n t o Type I and Type I I forms. 1.44 Family Studies-Bipolar Disorder and Alcohol ism B i p o l a r d i s o r d e r r e f e r s to i n d i v i d u a l s with episodes of major depression that c y c l e with episodes of mania (B i p o l a r I disorder) or hypomania (Bipolar I I d i s o r d e r ) . Probands are u s u a l l y r e f e r r e d to as a l c o h o l i c s i f they d r i n k e x c e s s i v e l y d a i l y , on weekends, or i n binges, to the poin t of a f f e c t i n g t h e i r work or t h e i r r e l a t i o n s h i p s . Alcoholism and B i p o l a r d i s o r d e r are defined i n more d e t a i l i n the Background Section (1.22 and 1.23); c r i t e r i a f o r t h e i r diagnosis are presented i n the M a t e r i a l s and Methods Secti o n (Sections 2.11.2, 2.11.3, 2.12.2, 2.12.3). To date there i s l i t t l e evidence f o r a common genetic e t i o l o g y f o r B i p o l a r d i s o r d e r and alcoholism. Most studies on the f a m i l i a l t ransmission patterns of B i p o l a r d i s o r d e r and alc o h o l i s m have concluded that the two dis o r d e r s are oft e n co-morbid, but not g e n e t i c a l l y associated. A b r i e f d i s c u s s i o n of studies that suggest an a s s o c i a t i o n between alcoholism and B i p o l a r d i s o r d e r (Cassidy et a l . (1957) and Winokur and Reich (1970)) w i l l be followed by a d i s c u s s i o n of the studies that do not support such an a s s o c i a t i o n (Andreason et a l . , 1987; Dunner et a l . , 1979; Hensel and Dunner, 1979; Merikangas and Gelernter, 1990; Winokur et a l . , 1994). The two 23 supportive studies are presented i n the Section 1.44.1 i n some d e t a i l , as w e l l as i n summary form i n TABLE 1.7. 1.44.1 Studies that Support A Common Genetic E t i o logy Between B ipo l a r Disorder and Alcohol ism Cassidy et a l . (1957) found a small excess of a l c o h o l i c s i n the f a m i l i e s of probands diagnosed with "common p s y c h i a t r i c d i s o r d e r s " , such as "manic depressive disease" compared to p h y s i c a l l y i l l , age and gender matched c o n t r o l s ( r e f e r to TABLE 1.7). Unfortunately, s e v e r a l f a c t o r s make the r e s u l t s of t h i s study d i f f i c u l t to compare to more recent ones. F i r s t l y , B i p o l a r d i s o r d e r was not defined at the time. Secondly, the d i a g n o s t i c c r i t e r i a used f o r "manic depressive disease" were not defined w i t h i n the study. Further, the probands were not subdivided i n t o manic versus depressive subgroups. The study by Winokur and Reich (1970) provides support f o r a p u t a t i v e common genetic e t i o l o g y f o r a l c o h o l i s m and B i p o l a r d i s o r d e r ( r e f e r to TABLE 1.7) using data from a small group of severe, h o s p i t a l i z e d B i p o l a r probands. A small excess of a l c o h o l i c s i n the male r e l a t i v e s of B i p o l a r probands of e i t h e r gender was found. Winokur and Reich (1970) concluded that a l c o h o l i s m and B i p o l a r d i s o r d e r were as s o c i a t e d i n a gender s p e c i f i c manner. In contrast to the study by Cassidy et a l . (1957.), the l a t e r one by Winokur and Reich (1970) used w e l l defined B i p o l a r probands and t h e i r r e l a t i v e s r a t h e r than "manic depressive" probands with u n s p e c i f i e d mood di s o r d e r diagnoses. Unfortunately, Winokur and Reich (1970) d i d not look at d i f f e r e n c e s i n the rates of alc o h o l i s m and mania i n the f i r s t degree r e l a t i v e s of male versus 24 female probands, t h e r e f o r e , any gender s p e c i f i c f a c t o r s common to alcoholism and B i p o l a r d i s o r d e r were not i n v e s t i g a t e d . There are se v e r a l s t u d i e s i n the l i t e r a t u r e that provide support f o r the hypothesis of separate genetic t r a n s m i s s i o n patterns f o r a l c o h o l i s m and B i p o l a r d i s o r d e r . These studies are reviewed i n the f o l l o w i n g s e c t i o n and are summarized i n TABLE 1.8. TABLE 1.7: STUDIES IN SUPPORT OF A COMMON GENETIC ETIOLOGY FOR ALCOHOLISM AND BIPOLAR DISORDER Author(s) Sample Conclusions and Year Size of Study Cassidy et manic:34 males,66 females Excess a l e i n f a m i l i e s of manic a l . (1957) p h y s i c a l l y i l l c o n t r o l s : probands vs f a m i l i e s of c o n t r o l s -21 males,29 females R a t i o ^ . 01 to 3.12 Winokur & 35 female BP; 26 male BP 16% of male r e l a t i v e s of e i t h e r sex Reich (1970) 167 lst-degree r e l a t i v e s of BP proband had a l e Where alc=alcoholism; BP=Bipolar d i s o r d e r ; l s t = F i r s t ; "manic"=at the time of Cassidy et a l . (1957), t h i s term r e f e r r e d to a l l types of mood d i s o r d e r s ; vs=Versus 1 .44.2 Studies that Do Not Support A Common Genetic E t i o logy Between B ipo la r Disorder and Alcohol ism Studies by Dunner et a l . (1979) and Hensel and Dunner (1979) were among the f i r s t to suggest that B i p o l a r d i s o r d e r and alcoholism are tra n s m i t t e d through f a m i l i e s i n a manner i n d i c a t i v e of separate genetic e t i o l o g i e s (see TABLE 1.8). The two studies were s i m i l a r i n that they (i) i d e n t i f i e d subjects from l i t h i u m treatment c l i n i c s (a drug often used to t r e a t mania); ( i i ) used very s t r i c t c r i t e r i a f o r diagnosis of alc o h o l i s m and B i p o l a r d i s o r d e r ; and ( i i i ) i nterviewed probands and t h e i r r e l a t i v e s using a questionnaire based on Schedule f o r A f f e c t i v e Disorders and Schizophrenia-Lifetime Version (Endicott 25 et a l . , 1978). Each study concluded that B i p o l a r d i s o r d e r was tr a n s m i t t e d through f a m i l i e s , but alc o h o l i s m was tr a n s m i t t e d only i f the B i p o l a r proband was a l s o a l c o h o l i c and t h e r e f o r e , a l c o h o l i s m was not g e n e t i c a l l y a s s o c i a t e d with B i p o l a r d i s o r d e r . A study by Andreason et a l . (1987) d i d not support a p u t a t i v e common genetic e t i o l o g y between B i p o l a r d i s o r d e r and alc o h o l i s m (see TABLE 1.8). The study was part of the N a t i o n a l I n s t i t u t e of Mental Health C o l l a b o r a t i o n Study. A t o t a l of 955 Caucasian probands and t h e i r f i r s t - d e g r e e r e l a t i v e s were evaluated. 151 of the probands (15.8%) were r i g o r o u s l y diagnosed as B i p o l a r I. There was no evidence f o r an excess.of a l c o h o l i s m i n the r e l a t i v e s of the B i p o l a r I probands compared to rates expected f o r the general population. A major flaw with t h i s study Was that the d i a g n o s t i c c r i t e r i a used f o r the r e l a t i v e s of the probands were very s t r i c t , and as a consequence, some a l c o h o l i c r e l a t i v e s may have had f a l s e negative diagnoses. In contrast to the s t r i c t c r i t e r i a used to diagnose probands i n t h i s study, the c r i t e r i a used to diagnose r e l a t i v e s should have been r e l a t i v e l y l e s s s t r i c t because complete medical and p s y c h i a t r i c h i s t o r i e s of r e l a t i v e s are often d i f f i c u l t to ob t a i n . For t h i s reason, the r e s u l t s of Andreason et a l . (1987) may be f a l s e l y negative. A review of the l i t e r a t u r e by Merikangas and Gelernter (1990) compared the r e s u l t s of many studies d e a l i n g with mood di s o r d e r s and alcoholism. Merikangas and Gelernter (1990) concluded that a l c o h o l i s m was often a consequence of B i p o l a r d i s o r d e r , but that the two dis o r d e r s were not associated g e n e t i c a l l y . Recently, Winokur et a l • (1994) reported on a ten-year follow-up of 131 B i p o l a r I probands a s c e r t a i n e d from p s y c h i a t r i c h o s p i t a l s (National I n s t i t u t e of Mental Health C o l l a b o r a t i o n ) , interviewed using Schedule f o r A f f e c t i v e Disorders and Schizophrenia (Endicott and S p i t z e r , 1978) and diagnosed using 26 RDC ( S p i t z e r et a l . , 1978) (see TABLE 1.8). The probands were re - i n t e r v i e w e d b i - a n n u a l l y f o r the f i r s t f i v e years and then annually f o r the remaining f i v e years. Probands were excluded i f B i p o l a r I I or primary a l c o h o l i s m were present at the time of ascertainment. The r e s u l t s of the study suggested that B i p o l a r I symptoms l e d probands to dri n k e x c e s s i v e l y , which r e s u l t e d i n alcoholism. Further, the r e s u l t s i n d i c a t e d that a l c o h o l i c symptomatology developed over the course of the study decreased with treatment of the B i p o l a r I symptoms. The authors concluded that , although t h i r t y percent of the probands showed a l c o h o l i c symptoms over the course of the study, alcoholism and BP I di s o r d e r d i d not have a common genetic e t i o l o g y . However, t h i s c o nclusion i s premature. The f i n d i n g s of t h i s study i n d i c a t e that alcoholism and B i p o l a r d i s o r d e r are ass o c i a t e d i n that B i p o l a r d i s o r d e r appears to cause a l c o h o l i c symptoms to develop, however, the r e s u l t s do not allow conclusions to be drawn with regard to the source ( i . e . : genetic or non-genetic basis) of the observed a s s o c i a t i o n . Very r e c e n t l y , Winokur et a l . (1995a), using the same group of probands asc e r t a i n e d through the N a t i o n a l I n s t i t u t e of Mental Health C o l l a b o r a t i o n , found 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 the p s y c h i a t r i c h i s t o r i e s of the f i r s t -degree r e l a t i v e s of: (1) 30 B i p o l a r I probands with secondary alcoholism; (2) 34 a l c o h o l i c s with secondary B i p o l a r I ; (3) 161 probands with B i p o l a r I alone ( r e f e r to TABLE 1.8). The d i s t i n c t i o n between primary and secondary di s o r d e r s i s important because i f B i p o l a r d i s o r d e r and alcoholism have a common genetic e t i o l o g y , there w i l l not be a d i f f e r e n c e between the f a m i l i e s of primary a l c o h o l i c s with secondary B i p o l a r d i s o r d e r versus the f a m i l i e s of primary B i p o l a r d i s o r d e r probands with secondary alcoholism. Further, the d i s t i n c t i o n i s important because, f o r example, primary B i p o l a r d i s o r d e r may cause secondary alcoholism due to the proband d r i n k i n g e x c e s s i v e l y to s e l f - t r e a t the mania symptoms. Conversely, excessive d r i n k i n g ( i . e . : primary alcoholism) may 27 cause symptoms that mimic mania, lea d i n g to an erroneous diagnosis of secondary B i p o l a r d i s o r d e r . The p s y c h i a t r i c h i s t o r i e s of the probands' f i r s t -degree r e l a t i v e s and 4 69 of the r e l a t i v e s ' acquaintances were compared using Kaplan-Meier (Kaplan and Meier, 1958) estimates of l i f e t i m e f a m i l i a l r i s k f o r a lcoholism or B i p o l a r I d i s o r d e r . The authors suggested that t h e i r f i n d i n g s confirm t h e i r e a r l i e r c onclusion (Winokur et a l . , 1994) that the excess al c o h o l i s m probably r e s u l t e d from s e l f treatment of B i p o l a r symptoms with a l c o h o l . As with t h e i r e a r l i e r study, the authors concluded that a l c o h o l i s m and B i p o l a r I di s o r d e r do not have a common • genetic e t i o l o g y . A study by Maier et a l . (1995) compared the rates of alc o h o l i s m and B i p o l a r d i s o r d e r i n the f i r s t degree r e l a t i v e s of probands with B i p o l a r d i s o r d e r , a l c o h o l i s m and co-morbid B i p o l a r d i s o r d e r and al c o h o l i s m (disorders not s p e c i f i e d as to primary versus secondary) to the rates observed i n the r e l a t i v e s of a group of gender, age and socio-economically matched c o n t r o l s (see TABLE 1.8). When the f i r s t degree r e l a t i v e s of the proband groups were compared to those of the c o n t r o l s , s e v e r a l r e l a t i v e r i s k s were s i g n i f i c a n t l y elevated i n the r e l a t i v e s of the probands: (1) increased r i s k of B i p o l a r d i s o r d e r i n the r e l a t i v e s of probands that had B i p o l a r d i s o r d e r , regardless of whether or not the proband a l s o had co-morbid alcoholism; (2) increased r i s k of a l c o h o l i s m i n the r e l a t i v e s of probands with alcoholism. The study concluded two t h i n g s : (1) that both alcoholism and B i p o l a r d i s o r d e r are f a m i l i a l d i s o r d e r s and (2) that the patterns observed i n the r e l a t i v e s of t h e i r study group i n d i c a t e d that a l c o h o l i s m and B i p o l a r d i s o r d e r do not have a common genetic e t i o l o g y . 28 TABLE 1.8: STUDIES THAT DO NOT SUPPORT A COMMON GENETIC ETIOLOGY FOR ALCOHOLISM AND BIPOLAR DISORDER Author(s) and Year of Study Sample Size Conclusions Dunner et a l , (1979) Hensel et a l . (1979) Andreason et a l . (1987) Merikangas & Gelernter (1990) Winokur et a l . (19947 Winokur et a l . (1995a) Maier et a l . (1995) 7 male BP/alc;30 male BP; 36 female BP; 371 parents and s i b s males:53 BP,13 BP/alc* 11 UP,1 UP/alc.Females: 73 BP, 5 BP/alc, 12 UP 787 1st deg. r e l a t i v e s 82 female & 69 male BP I probands;569 l s t -degree r e l a t i v e s Review of Mood Disorder studies 10 year study of 48 male & 83 female BP I probands w/out a l e males:50 BP I/alc*;60 BP I. Females:20 a l e / BP I; 101 BP I.1st deg r e l a t i v e s and 469 of t h e i r acquaintances males:18 BP+alc;23 BP; 47 ale.Females:11 BP+ alc;30 BP;26 a l e . 109 c o n t r o l s . 1135 1st r e l a t i v e s . BP elevated i n r e l a t i v e s of BP probands (MR=6.4 to 68.8, p>0.05); a l e elevated i f proband a l s o a l e (MR=24.9,p<0.01) BP elevated i n r e l a t i v e s of BP probands (MR=7.3 to 15.8); a l e elevated only i f BP proband a l s o a l e (MR=13.3 to 25). BP and a l e not g e n e t i c a l l y r e l a t e d No excess a l e i n r e l a t i v e s of BP I probands (12.5%) compared to population l e v e l s at the time UP of t e n a r e s u l t of a l e while a l e often a r e s u l t of BP; no genetic r e l a t i o n s h i p between the diso r d e r s BP I leads to excess d r i n k i n g as s e l f treatment, l e d to excess a l e over 10 years (37% a l e ) . A l e & BP I r e l a t e d symptomatically, not g e n e t i c a l l y No s i g n i f i c a n t d i f f e r e n c e s seen between the r e l a t i v e s of the proband groups. Al e and BP I do not have a common genetic e t i o l o g y i n t h i s group Excess BP i n r e l a t i v e s of BP probands w/ or w/o a l e (RR=0.6 to 12.6 versus c o n t r o l s , p<0.01). Excess a l e i n r e l a t i v e s of a l e probands (RR=1.1 to 4.5 versus c o n t r o l s , p<0.01). Where alc=alcoholism; BP 1= B i p o l a r I Disorder; BP=Bipolar Disorder; UP=Unipolar d i s o r d e r ; l s t = F i r s t ; deg.=Degree; MR=Morbid Risk, or the Risk of Becoming 111 With the Disorder i n Question w i t h i n A L i f e s p a n ; RR=Relative Risk. * order of the l i s t e d d i s o r d e r s r e f e r s to t h e i r temporal occurrence i n the proband group under c o n s i d e r a t i o n , e.g.: BP I / a l c r e f e r s to primary BP I and secondary alcoholism. Most of the p r e v i o u s l y discussed s t u d i e s , summarized i n TABLE 1.7 and TABLE 1.8, do not support the hypothesis that B i p o l a r d i s o r d e r has a common genetic e t i o l o g y with alcoholism. Nevertheless, there i s a f a i r l y c o n s i s t e n t 29 f i n d i n g of excessive a l c o h o l i s m i n B i p o l a r I probands. Further studies need to be done to determine whether or not the excess a l c o h o l i s m seen i n B i p o l a r probands i s due to genetic causes, or a m a n i f e s t a t i o n of B i p o l a r symptomatology. As w e l l , studies should be done on l a r g e r , more a c c u r a t e l y and more c o n s i s t e n t l y diagnosed B i p o l a r probands and t h e i r f a m i l i e s . 1.44.3 Linkage Studies and B ipo la r Disorder This s e c t i o n has been included f o r i n t e r e s t s sake because, u n l i k e Unipolar d i s o r d e r , B i p o l a r d i s o r d e r has been i n c o n s i s t e n t l y l i n k e d to chromosome 11 and the X chromosome i n the human genome. This s e c t i o n does not deal with l i n k a g e s t u d i e s and Unipolar d i s o r d e r , but r a t h e r s p e c i f i c a l l y reviews linkage studies that use B i p o l a r pedigrees from the Old Order Amish. The Old Order Amish studies have not held up to s c r u t i n y over time (see f o l l o w i n g Section) but i f there was f i r m linkage f i n d i n g s between B i p o l a r d i s o r d e r (or alcoholism, or Unipolar disorder) and some genetic l o c u s / l o c i then the p o s s i b i l i t y of an a s s o c i a t i o n between al c o h o l i s m and B i p o l a r d i s o r d e r (for example) could be determined. I f a l c o h o l i s m and B i p o l a r d i s o r d e r had a common genetic e t i o l o g y , then we would expect that some f a m i l i e s that showed linkage of B i p o l a r d i s o r d e r to a genetic locus would show al c o h o l i s m l i n k e d to the same s i t e . 1.44.3i B ipo la r Disorder Studies of Old Order Amish Old Order Amish have been used i n linkage studies i n B i p o l a r d i s o r d e r f o r s e v e r a l reasons: (1) Members of the pedigrees are a l l r a i s e d i n s i m i l a r environments, thereby decreasing v a r i a b i l i t y due to non-genetic f a c t o r s ; (2) the pedigrees tend to have m u l t i p l e f a m i l y members a f f e c t e d with c o n s i s t e n t and d e f i n a b l e B i p o l a r d i s o r d e r phenotypes; and (3) the Amish have increased genetic homogeneity due to t h e i r closed, small genetic pool (Egeland and 30 Hostetter, 1983; Hostetter et a l . , 1983). These f a c t o r s help to reduce u n c e r t a i n t i e s i n linkage analyses due to f a c t o r s such as genetic heterogeneity, v a r i a b l e mode of i n h e r i t a n c e , phenocopies, penetrance and/or environmental v a r i a b i l i t y (Pauls et a l . , 1995). Egeland et a l . i n 1979, found evidence f o r linkage of B i p o l a r Disorder to chromosome l l p l 5 i n a l a r g e , m u l t i g e n e r a t i o n a l Old Order Amish pedigree. This f i n d i n g set o f f a number of s t u d i e s of the Amish i n an attempt to confirm or disprove these f i n d i n g s and to c l a r i f y the i n c o n s i s t e n t reports of l i n k a g e of B i p o l a r d i s o r d e r to the X chromosome (For a l i s t of p e r t i n e n t references, see Pauls et a l . , 1995). When more of the members of the o r i g i n a l Amish pedigree were in c l u d e d i n f u r t h e r s t u d i e s , using m u l t i p l e genetic markers throughout the human genome, the f i n d i n g s of Egeland et a l . (1979) were not supported (e.g.: Kidd et a l . , 1984; Kidd et a l . , 1987; Kelsoe et a l . , 1989; P a k s t i s et a l . , 1991; Pauls et a l . , 1991; Law et a l . , 1992; Ginns et a l . , 1992; Gerhard et a l . , 1994; Ewald et a l . , 1995). At present, there i s l i t t l e d i r e c t , l i n k a g e based support f o r genetic f a c t o r s i n v o l v e d i n B i p o l a r d i s o r d e r that are l o c a t e d on chromosome 11 or the X chromosome (Kidd et a l . , 1987; Mendelbaum et a l . , 1995; Pauls et a l . , 1995) . In contrast to the linkage study f i n d i n g s , there are two b i o l o g i c a l l y based f a c t o r s that support a r o l e of chromosome l.lpl5 i n B i p o l a r d i s o r d e r : (1) t y r o s i n e hydroxylase, the r a t e l i m i t i n g enzyme i n catecholamine b i o s y n t h e s i s , i s l o c a t e d on chromosome l l p l 5 ; (2) the D2 Receptor gene i s l o c a t e d on chromosome l l q ; and (3) there i s some evidence that catecholamine l e v e l s are a f f e c t e d i n i n d i v i d u a l s with mood d i s o r d e r s . There have been se v e r a l studies that have i n d i r e c t l y excluded l i n k a g e of B i p o l a r d i s o r d e r to t y r o s i n e hydroxylase by excluding linkage to the region i n which the gene i s l o c a t e d (see Pauls et a l . , 1995 f o r d e t a i l e d r e f e r e n c e s ) . A study by Kelsoe et a l . (1993) used s e v e r a l Amish and I c e l a n d i c pedigrees to s t r o n g l y exclude 31 l i n k a g e of B i p o l a r d i s o r d e r to the D2 Receptor gene on chromosome l l q i n the pedigree studi e d . At present, the l i k e l i h o o d of genetic f a c t o r s l i n k e d to chromosome 11 in v o l v e d i n B i p o l a r d i s o r d e r i s small, however, there i s s t i l l a great deal to be i n v e s t i g a t e d i n the realm of lin k a g e and b i o l o g i c a l studies of B i p o l a r d i s o r d e r . 1.45 Alcohol ism and Other P sych i a t r i c Disorders Findings of excess a l c o h o l i s m i n the r e l a t i v e s of probands with Unipolar d i s o r d e r , as w e l l as with anxiety d i s o r d e r s (see TABLE 1.7), b o r d e r l i n e p e r s o n a l i t y d i s o r d e r (Loranger and T u l l s , 1985), and seasonal a f f e c t i v e d i s o r d e r ( A l l e n et a l . , 1993), lea d to the suggestion that a l c o h o l i s m may be ass o c i a t e d with p s y c h i a t r i c i l l n e s s e s i n general, rather than with mood di s o r d e r s , i n p a r t i c u l a r . These st u d i e s are reviewed below i n d e t a i l and summarized i n TABLE 1.7. F i r s t l y , i n explanation, a b r i e f d e s c r i p t i o n of the c r i t e r i a f o r seasonal a f f e c t i v e d i s o r d e r , b o r d e r l i n e p e r s o n a l i t y d i s o r d e r and anxiety d i s o r d e r s w i l l be presented. 1.45.1 Diagnost ic C r i t e r i a f o r Seasonal A f f e c t i v e Disorder "Seasonal A f f e c t i v e Disorder" i s a subtype of recurrent major depression that tends to worsen at p a r t i c u l a r times of the year. The depressive symptoms must remit and then recur seasonally f o r two to three years before a diagnosis of "Recurrent Unipolar Disorder-Seasonal Onset" i s given (Paraphrased from A l l e n et a l . , 1993). The v a l i d i t y of a seasonal subtype of depression i s s t i l l c o n t r o v e r s i a l , although support i s i n c r e a s i n g (Sakamoto et a l . , 1995). 32 1.45.2 Diagnost ic C r i t e r i a f o r Border l ine Persona l i t y Disorder The DSM II I - R (1987) req u i r e s at l e a s t three of the f o l l o w i n g symptoms or behaviours to be manifested before a diagnosis of B o r d e r l i n e p e r s o n a l i t y d i s o r d e r i s given: s h o p l i f t i n g , s e l f m u t i l a t i o n , marked s h i f t s i n a t t i t u d e , s u i c i d a l gestures, recurrent accidents or f i g h t s , s e l f - d e v a l u a t i o n , i d e n t i t y disturbance, i m p u l s i v i t y or u n p r e d i c t a b i l i t y (paraphrased from Loranger and T u l l s (1985)). 1.45.3 Diagnost ic C r i t e r i a f o r Anxiety Disorders Anxiety d i s o r d e r s represent a "mixed-bag" as they r e f e r to a large number of d i f f e r e n t d i s o r d e r s . Leckman et a l . (1983b), Finn et a l . (1990), and Mathew et a l . (1993 found high f a m i l i a l rates of alc o h o l i s m associated with g e n e r a l i z e d anxiety d i s o r d e r and panic d i s o r d e r . These p a r t i c u l a r anxiety d i s o r d e r s w i l l be described more f u l l y . The RDC manual ( S p i t z e r et a l . , 1978) sta t e s that g e n e r a l i z e d a n x i e t y d i s o r d e r p a t i e n t s must have a predominantly anxious, nervous, j i t t e r y , tense, r e s t l e s s or uptight mood f o r at l e a s t two weeks. As w e l l , the p a t i e n t must have at l e a s t one of the f o l l o w i n g symptoms: d i f f i c u l t y f a l l i n g asleep, sweating, b l u s h i n g , d i z z i n e s s , shortness of breath, muscular tension, p e r s i s t e n t worrying about future events, or i n a b i l i t y to s i t s t i l l . Panic d i s o r d e r p a t i e n t s must have experienced at l e a s t 6 "panic" attacks w i t h i n a s i x week peri o d , c h a r a c t e r i z e d by at l e a s t three of the f o l l o w i n g : d i f f i c u l t y breathing, p a l p i t a t i o n s , chest pain, choking sensations, d i z z i n e s s , t i n g l i n g , sweating, f a i n t n e s s , trembling, fear of dying, f e a r of going crazy, fear of l o s i n g c o n t r o l during the attack. Panic d i s o r d e r can be diagnosed co-morbidly with major depressive d i s o r d e r i f the f o l l o w i n g c r i t e r i u m i s met: the panic attacks must have occurred i n a p e r i o d outside of the time i n which 33 the depressive 1978) . episode was experienced (paraphrased from S p i t z e r et a l . , 1.45.4 Studies Per ta in ing to Alcohol ism and Other P sych i a t r i c Disorders From Section 1.42, TABLE 1.3 and TABLE 1.4 i t can be seen that s e v e r a l d i f f e r e n t studies have found that mood di s o r d e r s and alc o h o l i s m may be asso c i a t e d with one another, as w e l l as with a n t i s o c i a l p e r s o n a l i t y d i s o r d e r . However, as discussed (See Section 1.42, TABLE 1.6), most studies d i d not f i n d that alcoholism, mood di s o r d e r s and a n t i s o c i a l p e r s o n a l i t y d i s o r d e r were tra n s m i t t e d through f a m i l i e s i n a manner i n d i c a t i v e of a common genetic e t i o l o g y . TABLE 1.9: STUDIES OF A COMMON GENETIC ETIOLOGY FOR ALCOHOLISM AND OTHER PSYCHIATRIC DISORDERS Author(s) Sample Conclusions and Year Size of Study Leckman et 77 UP+Panic Dis.;56 a l . (1983b) UP probands;82 normal c o n t r o l s ; lst-degree r e l a t i v e s Finn et a l . 25 non-ale males with (1990) or w/out a FH of a l e & > 1 lst-degree r e l a t i v e Mathew et 144 males&264 females a l . (1993) with, and 538 males & 939 females without, a FH of a l e . Loranger and parents&sibs of 100 BPD T u l l s (1985) 100 schizophrenics 100 BP probands Familie s of UP+Panic Dis. probands had 2 times higher rates of Ale,UP,Anxiety d i s . vs the f a m i l i e s of UP only probands excess UP and anxiety d i s . i n males with a FH of a l e vs. those w/out a a FH of a l e . excess a n x i e t y d i s . i n probands with a FH of a l e (p<0.003);excess a l e i n males with a FH of a l e (p<0.007) highest r i s k of a l e i n f a m i l i e s of BPD probands (MR=18.5%). Separate genetic e t i o l o g y f o r a l l three d i s o r d e r s A l l e n et a l . 34 SAD, 34 matched Ale seen i n 41% of the lst-degree (1993) non-seasonal MD r e l a t i v e s of MD probands with SAD vs probands those w/out a seasonal onset (18%) Where alc=alcoholism; BP 1= B i p o l a r I Disorder; BP=Bipolar Disorder; BPD=Borderline P e r s o n a l i t y Disorder; Deg=Degree; Dis.=Disorder; FH=Family H i s t o r y ; MR=Morbid Risk; MD=mood d i s o r d e r ; SAD=Seasonal A f f e c t i v e Disorder; s i b s = s i b l i n g s ; UP=Unipolar d i s o r d e r ; l s t = F i r s t 34 As p r e v i o u s l y mentioned, Leckman et a l . (1983b), Finn et a l . (1990) and Mathew et a l . (1993) found that i n d i v i d u a l s with f a m i l y h i s t o r i e s of alco h o l i s m tended to have s t a t i s t i c a l l y s i g n i f i c a n t l y increased rates of depression and anxiety d i s o r d e r s , e s p e c i a l l y g e n e r a l i z e d a n x i e t y d i s o r d e r and panic d i s o r d e r (See TABLE 1.5 and TABLE 1.9 f o r more d e t a i l s ) . These studies suggest three p o s s i b l e r e l a t i o n s h i p s between alcoholism, depression and anxiety d i s o r d e r s : (1) they are g e n e t i c a l l y r e l a t e d ; (2) they are r e l a t e d through a common non-genetic f a c t o r ( s ) ; (3) they have common genetic and non-genetic s u s c e p t i b i l i t y f a c t o r s . Which of the previous three scenarios i s true i s d i f f i c u l t to i n t e r p r e t f o r s e v e r a l reasons. F i r s t l y , a n x i e t y symptoms are commonly observed with depression and are u s u a l l y considered part of the depressive episode. Secondly, depression and alc o h o l i s m appear to be asso c i a t e d with one another i n f a m i l i e s and are fr e q u e n t l y seen co-morbidly. Together, these f a c t o r s suggest that a l c o h o l i s m and anxiety d i s o r d e r s may be each g e n e t i c a l l y and/or n o n - g e n e t i c a l l y a s s o c i a t e d with depression, but a l l three d i s o r d e r s may not be ass o c i a t e d with one another. . Another p o s s i b i l i t y i s that alcoholism, depression and anxiety d i s o r d e r s l i e on a continuum of m u l t i p l e genetic and non-genetic s u s c e p t i b i l i t y f a c t o r s . According to t h i s " M u l t i f a c t o r i a l " hypothesis, which of the three d i s o r d e r s manifests i t s e l f i n a proband depends on the genetic loading the proband possesses and on the non-genetic f a c t o r s w i t h i n the proband's l i f e . A study by Loranger and T u l l s (1985) compared the f a m i l i e s of 83 h o s p i t a l i z e d female b o r d e r l i n e p e r s o n a l i t y disordered probands to the f a m i l i e s of 100 female schizophrenic and 100 female B i p o l a r probands. DSM I I I (1979) c r i t e r i a were used to diagnose the probands. Parents and s i b l i n g s of the bo r d e r l i n e p e r s o n a l i t y disordered probands showed a two to three f o l d increase i n the rate of alc o h o l i s m compared to the r e l a t i v e s of the other two proband groups. Loranger and T u l l s (1985) concluded that a l c o h o l i s m and b o r d e r l i n e 35 p e r s o n a l i t y d i s o r d e r appeared to be asso c i a t e d . However, the p o s s i b i l i t y of an a s s o c i a t i o n must be considered p r e l i m i n a r y because the probands used i n t h i s study were not screened f o r a h i s t o r y of alcoholism. In a study by A l l e n et a l . (1993), f i r s t - d e g r e e r e l a t i v e s of 34 r i g o r o u s l y diagnosed mood di s o r d e r probands with a seasonal onset and 34 age, gender, and diagnosis matched mood di s o r d e r probands with a non-seasonal onset were compared. F i r s t - d e g r e e r e l a t i v e s of the seasonal onset probands had higher rates of alcoholism, suggesting that mood di s o r d e r s with a seasonal onset may be ass o c i a t e d with higher l e v e l s of alc o h o l i s m i n f a m i l i e s . A l l the s t u d i e s , summarized i n TABLE 1.9, share the major flaw that the probands were not screened f o r e i t h e r a p r i o r diagnosis of alc o h o l i s m or of mood d i s o r d e r s . Thus, despite some evidence that a l c o h o l i s m may be ass o c i a t e d with s e v e r a l d i f f e r e n t p s y c h i a t r i c d i s o r d e r s , the preponderance of evidence i n d i c a t e s that mood di s o r d e r s and alcoholism, s p e c i f i c a l l y , may share a common genetic e t i o l o g y r a t h e r than a l c o h o l i s m being a s s o c i a t e d with p s y c h i a t r i c d i s o r d e r s i n general. 1.46 Mood Disorders and Substance Abuse Several studies have i n d i c a t e d that substance abuse (e.g.: opiates, cocaine) and sedative-hypnotics (e.g.: valium)) i n mood d i s o r d e r probands i s observed more often that expected by general population rates alone, e s p e c i a l l y i n B i p o l a r probands ( R u s s e l l et a l . , 1994; Sonne et a l . , 1994; Strakowski et a l . , 1994; Brady and Sonne, 1995). (Substance abuse i n t h i s S ection r e f e r s to n a r c o t i c s , not alcohol.) Conversely, studies of substance abusing populations have i n d i c a t e d an excess number of probands with co-morbid mood di s o r d e r s ( M i r i n et a l . , 1991; Weiss et a l . , 1992). A s e l e c t i o n of studies on the patterns of drug abuse and mood di s o r d e r s i n probands and t h e i r r e l a t i v e s are summarized i n TABLE 1.10. 36 S i m i l a r to the h i s t o r y regarding a l c o h o l i s m and B i p o l a r d i s o r d e r (Sections 1.44.1 and 1.44.2), one theory suggests that probands with mood disor d e r s self-medicate themselves with drugs, which e v e n t u a l l y leads to a substance abuse d i s o r d e r (Weiss et a l . , 1992; Sonne et a l . , 1994). This " s e l f - m e d i c a t i o n " theory suggests that the use of n a r c o t i c s to s e l f - t r e a t depressive or manic symptoms may lead to f u l l blown Unipolar or B i p o l a r d i s o r d e r . At t h i s p o i n t , i t i s d i f f i c u l t to d i s c e r n between s e v e r a l p o s s i b l e pathways to the high co-morbidity r a t e between mood di s o r d e r s and substance abuse: (1) the use of n a r c o t i c s may l e a d to depressive or manic symptoms; or (2) the presence of depressive or manic symptoms may l e a d to excessive drug use i n an attempt to self-medicate. Most l i k e l y , both of these patterns may lead to an excess number of substance abusers with mood di s o r d e r s as w e l l as an excess number of mood di s o r d e r probands with substance abuse d i s o r d e r s . Another theory suggests that l o s s of impulse c o n t r o l seen i n B i p o l a r d i s o r d e r leads to excessive n a r c o t i c use, and eventual substance abuse (Strakowski et a l . (1994)). According to t h i s theory, two p o s s i b l e pathways may lead to the abuse of n a r c o t i c s : (1) the pleasure seeking behaviour observed i n some cases of B i p o l a r d i s o r d e r may l e a d probands to use n a r c o t i c s to heighten t h e i r manic mood; or (2) l o s s of impulse c o n t r o l may lead to n a r c o t i c use i n B i p o l a r probands who o r d i n a r i l y would not use n a r c o t i c s . Again, i t appears l i k e l y that both of these pathways may l e a d to the observed excess number of probands with co-morbid substance abuse d i s o r d e r and B i p o l a r d i s o r d e r . From TABLE 1.10, i t can be seen that Ingraham and Wender (1992) found evidence of a f a m i l i a l ( p o s s i b l y genetic) r e l a t i o n s h i p between mood diso r d e r s and substance abuse. However, i n t h i s study most of the "substance abuse" seen i n the r e l a t i v e s of the probands was a l c o h o l abuse ra t h e r than n a r c o t i c abuse. No r e l a t i o n s h i p was observed between mood di s o r d e r s and n a r c o t i c abuse 37 w i t h i n these f a m i l i e s a f t e r the e x c l u s i o n of the a l c o h o l i c s . This r e s u l t may be due to the f a c t that very few of the r e l a t i v e s abused n a r c o t i c s (or admitted to such abuse). Cadoret et a l . (1995) found evidence of a genetic "pathway" between alc o h o l i s m i n b i o l o g i c a l r e l a t i v e s and drug abuse i n male adoptees. (TABLE 1.10). However, t h i s study had a major defect i n that i t used probands and b i o l o g i c a l r e l a t i v e s a s c e r t a i n e d through p r i s o n , h o s p i t a l and adoption records i n the 1930's. As w e l l , the whole treatment of adoption i n the 1930's was d i f f e r e n t from the present. This group of probands and b i o l o g i c a l r e l a t i v e s can not be assumed to be complete due to the u n l i k e l i h o o d that a l l of the adopted probands' r e l a t i v e s with a l c o h o l i s m or other p s y c h i a t r i c d i s o r d e r s would have gone to p r i s o n or to a h o s p i t a l . Due to the u n l i k e l i h o o d that a l l or even many of the adoptees' b i o l o g i c a l r e l a t i v e s were ascertained, t h i s study needs to be confirmed with a d i f f e r e n t , more recent group of adoptees along with t h e i r more thoroughly a s c e r t a i n e d r e l a t i v e s . Within the studies o u t l i n e d i n TABLE 1.10 there i s l i t t l e evidence of a genetic r e l a t i o n s h i p between substance (narcotic) abuse and B i p o l a r or Unipolar d i s o r d e r (Kosten et a l . , 1991; M i r i n et a l . , 1991). I t seems more l i k e l y that s e v e r a l f a c t o r s may lead to the excess use of n a r c o t i c s i n mood d i s o r d e r a f f e c t e d probands: (1). intake of n a r c o t i c s to self-medicate manic or depressive symptoms; (2) intake of n a r c o t i c s to heighten manic symptoms; or (3) intake of n a r c o t i c s with l o s s of impulse c o n t r o l i n Bipolar.probands. Any or a l l of these f a c t o r s may lead to the excess number of mood d i s o r d e r probands with substance abuse d i s o r d e r s (or the excess number of substance abusers with mood disorders) observed i n the studies o u t l i n e d i n TABLE 1.10. 38 TABLE 1.10: STUDIES OF SUBSTANCE ABUSE AND MOOD DISORDERS Author(s) and Year of Study Sample Size Conclusions Kosten et a l . (1991) M i r i n et a l . (1991) Ingraham and Wender (1992) Weiss et a l . (1992) Sonne et a l . (1994) Strakowski et a l . (1994) Cadoret et a l . (1995) 201 Opiate abusers; 877 1st degree r e l a t i v e s 186 Opiate abusers; 120 Cocaine abusers;44 Sed-Hyp abusers. 1478 1st Degree R e l a t i v e s Increased rates of a l e . and UP only r e l a t e d proband a l e or UP,respectively 45.5-55.6% of drug abusers were al s o a l e . 9.2-13.6% were UP. 2.3-5.0% were BP. Patterns of UP,BP,Ale and drug abuse i n r e l a t i v e s i n d i c a t e d no genetic r e l a t i o n s h i p between them. Adoptees:27 UP;10 BP;34 Increased ra t e of MD i n female B i o l with other MD; matched r e l . Increased r a t e of substance abuse c o n t r o l s . B i o l R e l : 194 (esp. Ale) i n male B i o l r e l . Not seen male;193 female.Adoptive i n Adoptive r e l or B i o l r e l of rel:191 male;153 female, c o n t r o l Adoptees. 229 Opiate abusers; 202 Cocaine abusers;63 Sed-Hyp abusers. BP probands:30 drug abusers (24 a l e ) ; 14 Non-users. Review of l i t e r a t u r e r e l a t e d to BP 95 male adoptees-1/2 with alc/ASP b i o l parents, 1/2 c o n t r o l adoptees Co-morbid d i s o r d e r s seen: 10% UP, 6% anxiety d i s o r d e r s , 5% BP I I , 4% BP I I Many more females had UP than males. Many probands reported use of drugs to s e l f medicate MD symptoms. BP probands that abused drugs had an e a r l i e r age of onset of BP, more severe symptoms. Many had other co-morbid a n x i e t y d i s o r d e r s . S e l f medication of BP symptoms common. Rates of co-morbid a l e 20-60%;drug abuse 8-60%. In c o n s i s t e n t f i n d i n g s of s e l f - t r e a t of BP l e a d i n g to drug a b u s e : l i k e l y due to l o s s of impulse c o n t r o l . No evidence of a s s o c i a t i o n between alc/drug abuse and BP. Pathways to drug abuse d i r e c t from a l e b i o l parent to adoptee or from ASP b i o l parent through ASP adoptee to drug abuse i n adoptee. Where A l c = A l c o h o l i c ; ASP=Antisocial P e r s o n a l i t y Disorder; B i o l = B i o l o g i c a l ; BP=Bipolar; BP I=Bipolar I; BP' II=Bipolar I I ; MD=Mood Disorders; Rel=Relatives; Sed-Hyp=Sedative-Hypnotic; UP=Unipolar; l s t = F i r s t ; Co-morbidity between t r a i t s t e l l s l i t t l e about the genetics of pre-d i s p o s i t i o n to the di s o r d e r s under question. Family studies would be more 39 u s e f u l i n determining whether a genetic r e l a t i o n s h i p between mood diso r d e r s and n a r c o t i c s abuse e x i s t s by t e s t i n g whether or not the presence of one t r a i t (e.g.: B i p o l a r disorder) i n a proband puts his / h e r f i r s t degree r e l a t i v e s at r i s k f o r the other t r a i t (e.g.: n a r c o t i c s dependence). Nevertheless, from the r e s u l t s of the stu d i e s summarized i n TABLE 1.10, i t appears that i t would be prudent to counsel 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 that they have an increased r i s k of developing a substance abuse d i s o r d e r . 1.47 Assor ta t i ve Mating A s s o r t a t i v e mating i s the " s e l e c t i o n of a mate with preference f o r a p a r t i c u l a r genotype; that i s , non-random mating" . The s e l e c t i o n of a mate may be towards s i m i l a r genotypes ( p o s i t i v e a s s o r t a t i v e mating), or towards d i s s i m i l a r genotypes (negative a s s o r t a t i v e mating). Random mating i s " s e l e c t i o n of a mate without regard to the genotype of the mate. In a randomly mating population the frequencies of the various matings are determined s o l e l y by the frequencies of the genes concerned" (Thompson et a l . , 1991) . A s s o r t a t i v e mating a f f e c t s the r e s u l t s of f a m i l y s t u d i e s , which assume random mating. In a randomly mating population, the frequency of matings between a l c o h o l i c s and persons with mood di s o r d e r s should approximate the product of the population frequency of alc o h o l i s m and mood d i s o r d e r s . However, s e v e r a l small s t u d i e s have found excess matings between a l c o h o l i c s and persons with mood d i s o r d e r s , suggestive that a s s o r t a t i v e mating may be occ u r r i n g . The studies found the f o l l o w i n g : (1) a higher than expected p r o p o r t i o n of B i p o l a r : U n i p o l a r marriages (Waters et a l . , 1983), (2) a s i g n i f i c a n t increase i n the rates of mood di s o r d e r s i n wives, but not husbands, of mood dis o r d e r p a t i e n t s (Dunner et a l . , 1976) and (3) s i m i l a r f a m i l y h i s t o r i e s of 40 p s y c h i a t r i c i l l n e s s e s i n the spouses of mood d i s o r d e r probands and the probands themselves (Rimmer and Winokur, 1972; Kendler et a l . , 1994). The r e s u l t s of these s t u d i e s seem to i n d i c a t e that a s s o r t a t i v e mating may be occ u r r i n g , perhaps as the r e s u l t of s o c i e t a l pressures. Therefore, the e f f e c t s of a s s o r t a t i v e mating must be taken i n t o c o n s i d e r a t i o n when e v a l u a t i n g f a m i l y studies on mood di s o r d e r s and alcoholism. 1.48 Problems with Family Studies In summary, s e v e r a l of the p r e v i o u s l y discussed s t u d i e s (Sections 1.42 to 1.44) i n d i c a t e d that (i) a l c o h o l i s m appears to be over represented i n the f i r s t - d e g r e e r e l a t i v e s of mood d i s o r d e r p a t i e n t s , and ( i i ) mood dis o r d e r s are over represented i n the f i r s t - d e g r e e r e l a t i v e s of a l c o h o l i c p a t i e n t s . However, the nature of these f a m i l i a l aggregations has been d i f f i c u l t to determine f o r se v e r a l reasons. A major problem has been that, to date, i t has been very d i f f i c u l t to determine whether the observed f a m i l i a l aggregations are genetic, environmental (non-genetic) or a combination of the two. Other confounding f a c t o r s i n f a m i l y studies have included: (1) probands were not asce r t a i n e d uniformly among s t u d i e s ; (2) d i a g n o s t i c c r i t e r i a and accuracy d i f f e r e d among s t u d i e s ; (3) there have been temporal changes i n d i a g n o s t i c c r i t e r i a ; 4) diagnoses of mood dis o r d e r s and alc o h o l i s m may have s o c i a l stigma, these diagnoses may be " s e c r e t i v e " and thus f a m i l y informants may be unaware of the diagnosis, or not forthcoming; and (5) mating may be a s s o r t a t i v e . While f a m i l y studies i n general are w e l l done and provide researchers with valuable information, i n t e r study comparisons, nevertheless, are d i f f i c u l t (see previous paragraph). Despite t h i s problem, f a m i l y studies are e s s e n t i a l i n the e l u c i d a t i o n of the r o l e of genetics i n the e t i o l o g y of mood dis o r d e r s and alcoholism. Family studies l e a d research i n c e r t a i n d i r e c t i o n s 41 based on the r e l a t i o n s h i p s between f a c t o r s observed w i t h i n f a m i l i e s and the informati o n gleaned i s e s s e n t i a l to the process of mapping genes. Well designed, r e p r e s e n t a t i v e f a m i l y studies can enable a search f o r the r e l a t i v e r o l e s of genetic and environmental f a c t o r s i n disease e t i o l o g y using the t o o l s of genetic epidemiology. Also, r e s u l t s of f a m i l y s t u d i e s can be used f o r modelling-e.g.: Gershon et a l . (1982); Gandini (1992); Devor (1993); Petronis and Kennedy (1995). Well documented f a m i l i e s are e s s e n t i a l f o r genome screens, a s s o c i a t i o n and lin k a g e s t u d i e s . 1.5 Twin Studies Twin st u d i e s are a type of f a m i l y study i n which comparisons are made between monozygotic (100% genes i n common) and d i z y g o t i c (50% genes i n common) twin concordance r a t e s . In twin studies c e r t a i n environmental f a c t o r s are c o n t r o l l e d f o r ( i . e . : age, u t e r i n e environment, maternal environment). Unfortunately, twin s t u d i e s tend to have a bias i n that excess monozygotic twins tend to be asc e r t a i n e d (Sadovnick et a l . , 1993). Most twin studies attempt to draw popu l a t i o n based proband groups, u n f o r t u n a t e l y , many of them s t i l l have over-representations of monozygotic twins, and th e r e f o r e under-re p r e s e n t a t i o n of d i z y g o t i c twins. However, the most common source of bias i n twin studies occurs i f monozygotic twins concordant f o r the d i s o r d e r i n question are more l i k e l y to be asc e r t a i n e d than monozygotic discordant or d i z y g o t i c twins. These f a c t o r s a f f e c t study r e s u l t s because the d i z y g o t i c twin concordance rate i s compared with the concordance rates of monozygotic twins and s i b l i n g s , to estimate genetic and environmental c o n t r i b u t i o n s to the di s o r d e r i n question. Twin studies of alc o h o l i s m and/or mood di s o r d e r s have c o n s i s t e n t l y shown an increase i n monozygotic twin concordance rates versus d i z y g o t i c twin concordance rates (Rosanoff et a l . , 1935; A l l e n et a l . , 1974; Pickens et a l . , 42 1991; Kendler et a l . , 1993; Kendler et a l . , 1994). The higher concordance rates i n monozygotic twins versus d i z y g o t i c twins suggests that Unipolar d i s o r d e r , B i p o l a r d i s o r d e r , and al c o h o l i s m have genetic f a c t o r s i n v o l v e d i n t h e i r separate e t i o l o g i e s . Only Kendler et a l . (1993) has looked at concordance rates f o r these d i s o r d e r s i n combination. A l l of these studies are discussed i n the f o l l o w i n g paragraphs and are summarized i n TABLE 1.11. Results of twin studies by Rosanoff et a l . (1935) and A l l e n et a l . (1974) concluded that mood d i s o r d e r s were i n h e r i t e d . These e a r l y studies are summarized i n TABLE 1.11. Support f o r a genetic b a s i s to the trans m i s s i o n of al c o h o l i s m was found i n a study by Pickens et a l . (1991) i n which monozygotic twin concordance rates were s t a t i s t i c a l l y s i g n i f i c a n t l y higher than same-sexed d i z y g o t i c twin concordance r a t e s . This e f f e c t was seen f o r male twins, but not f o r female twins ( r e f e r to TABLE 1.11). Based on the gender s p e c i f i c concordance rates observed, the authors concluded that-males had a stronger genetic s u s c e p t i b i l i t y to al c o h o l i s m than females. The small h e r i t a b i l i t y estimate c a l c u l a t e d f o r both genders of twins i n d i c a t e d that genetic f a c t o r s had only a modest i n f l u e n c e on r i s k f o r alcoholism i n e i t h e r gender. Another p e r t i n e n t study (Kendler et a l . , 1993a) a s c e r t a i n e d female twins from a popu l a t i o n based twin r e g i s t r y . The female twins were diagnosed with alcoholism and/or depression using a s t r u c t u r e d i n t e r v i e w based on DSM I I I - R (1987) c r i t e r i a . Under the hypothesis that depressive d i s o r d e r s and alc o h o l i s m were d i f f e r e n t expressions of the same genetic defect, the authors found a s i g n i f i c a n t l y higher r a t e of concordance of al c o h o l i s m and/or major depression i n monozygotic twins versus d i z y g o t i c twins. A high r a t e of co-morbid a l c o h o l i s m and major depression was a l s o seen. The authors concluded that genetic s u s c e p t i b i l i t y f a c t o r s e x i s t that predispose women to alcoholism, to depression, or to both. 43 In a second study, Kendler et a l . (1994) used the same twin r e g i s t r y and techniques to study 1030 a l c o h o l i c female twins (1.34 monozygotic:1 d i z y g o t i c ) and 1468 of t h e i r parents. A h e r i t a b i l i t y estimate of a l c o h o l i s m i n the female twins of 51% to 59% was found ( r e f e r to TABLE 1.11). Based on the high h e r i t a b i l i t y estimate and the "best f i t " of the data to an a d d i t i v e genetic model, the authors concluded that alcoholism was h i g h l y h e r i t a b l e . The authors cautioned that they d i d not screen the probands or the parents f o r co-morbid p s y c h i a t r i c d i s o r d e r s so they could not estimate the e f f e c t of other p s y c h i a t r i c i l l n e s s e s on the transmission of alcoholism. The data from Kendler et a l . (1994) were re-examined using complex m u l t i v a r i a t e twin analyses (Kendler et a l . , 1995a). In the female twin proband group, the r e l a t i v e e f f e c t s of genetic f a c t o r s , f a m i l y environment and i n d i v i d u a l - s p e c i f i c environment were i n v e s t i g a t e d f o r alcoholism, major depression, and s e v e r a l a n x i e t y d i s o r d e r s . Many d i f f e r e n t combinations of models, and a myriad of genetic and non-genetic numerical f a c t o r s ( i . e . : d i d the model f i t the data b e t t e r i f one environmental (unknown/un-named) f a c t o r was included, versus two, versus none, etc.) were t e s t e d f o r the "best f i t " of the data to a model. Several r e s u l t s were found that i n d i c a t e d the f o l l o w i n g : (1) of the genetic i n f l u e n c e s on alcoholism, 79% were s p e c i f i c to alcoholism; (2) f a m i l i a l environment had a small e f f e c t on l i a b i l i t y to a l c o h o l i s m or major depression; (3) an i n d i v i d u a l , unknown environmental f a c t o r increased l i a b i l i t y to major depression, a l c o h o l i s m and s e v e r a l anxiety d i s o r d e r s ; and (4) a l c o h o l i s m was more c l o s e l y a s s o c i a t e d with major depression than any anxiety-based d i s o r d e r . Based on these r e s u l t s , the study concluded: (i) genetic i n f l u e n c e s on the d i s o r d e r s were n e i t h e r h i g h l y s p e c i f i c to each d i s o r d e r , nor h i g h l y n o n - s p e c i f i c ; and ( i i ) genetic f a c t o r s , f a m i l y environment, and i n d i v i d u a l s p e c i f i c environment a l l i n f l u e n c e s u s c e p t i b i l i t y to co-morbidity to alcoholism, major depression and s e v e r a l anxiety d i s o r d e r s . 44 TABLE 1.11: SUMMARY OF RESULTS OF TWIN STUDIES ON ALCOHOLISM, UNIPOLAR DISORDER AND BIPOLAR DISORDER Author(s) and Year of Study Sample Size Conclusions Rosanoff et a l . (1935) A l l e n et a l . (1974) Pickens et a l . (1991) Kendler et a l . (1993a) Kendler et a l . (1994) Kendler et a l . (1995a) Kendler et a l . (1995b) 67 DZ and 23 MZ with "Manic Depression" 24 MZ, 58 DZ U.S.A. Veterans with UP or BP males:50 MZ,64 DZ females:31 MZ,24 DZ. a l l A l e 590 MZ & 440 DZ female p a i r s . 3 1 % UP, 6.2-17% a l e 1030 a l e female twin p a i r s & 1468 of t h e i r parents (1.74 MZ:1 DZ) 1030 a l e female twins p a i r s ; 1 s t degree r e l a t i v e s (1.74 MZ:1 DZ) 1030 a l e female twin p a i r s Concordance rates f o r Manic Depression:16.4% fo r same-sex DZ, 69.6% f o r MZ. Same-sex s i b s 4x lower concordance than same-sex DZ. Concordance rates f o r any MD: DZ: UP. MZ:40% f o r UP and 20% f o r BP. h e r e d i t a r y 0% f o r BP or MD are Concordance f o r a l e s i g n i f i c a n t l y higher f o r male MZ vs DZ twins only (p<0.04). H e r i t a b i l i t y estimates of 0.35 i n a l e . Higher r a t e of concordance (10 to 65%) and co-morbidity (2.68 to 4.19) f o r a l e and/or UP i n MZ vs DZ twins H e r i t a b i l i t y estimate f o r alc=51-59%. A l e t r a n s m i t t e d e q u a l l y from mother or f a t h e r to female twin. Transmission of v u l n e r a b i l i t y to al e i n daughters i s h i g h l y genetic. Ale more c l o s e l y a s s o c i a t e d with UP than with anxiety d i s o r d e r s . 79% of genetic e t i o l o g y of al e s p e c i f i c to a l e . Ale and UP separate d i s o r d e r s with weak genetic r e l a t i o n s h i p . S t r e s s f u l l i f e events increased r i s k of UP, e s p e c i a l l y f o r twins concordant f o r a l e . Where A l c = A l c o h o l i c ; BP=Bipolar Disorder; DZ=Dizygotic Twins; MD=Mood Disorders; MZ=Monozygotic Twins; s i b s = s i b l i n g s ; UP=Unipolar d i s o r d e r ; vs=Versus; l s t = F i r s t "Manic Depression" at the time of Rosanoff et a l . (1935) r e f e r r e d to a l l mood dis o r d e r s A very recent study by Kendler et a l . (1995b) i n v e s t i g a t e d the onset of depression i n the same 1030 female twin p a i r s with a l c o h o l i s m used i n previous studies (see TABLE 1.11). The r e s u l t s of the study i n d i c a t e d that s t r e s s f u l l i f e events, such as divorce or a death i n the f a m i l y , were s i g n i f i c a n t l y 45 a s s o c i a t e d with the onset of a major, depressive episode. This e f f e c t was seen to a strong extent i n twins concordant f o r major depression. In summary, the four studies by Kendler et a l . (1993a, 1994, 1995a, 1995b) concluded that depression and a l c o h o l i s m are d i s t i n c t d i s o r d e r s which show a weak genetic a s s o c i a t i o n . . The four Kendler et a l . studies on female twins need to be r e p l i c a t e d using male twins, and using independent samples. A review of the l i t e r a t u r e on the genetics of a f f e c t i v e d i s o r d e r s by Craddock and McGuffin (1993) found reports of monozygotic twin p a i r s were one twin had Unipolar d i s o r d e r and one twin had B i p o l a r d i s o r d e r . There are a l s o examples (e.g.: Kendler et a l . , 1993a) of monozygotic twins were one twin had Unipolar d i s o r d e r and the other twin had alcoholism. Together, these observations suggest that Unipolar d i s o r d e r , B i p o l a r d i s o r d e r and alcoholism may have a genetic r e l a t i o n s h i p , the phenotype being determined by environmental f a c t o r s . These r e s u l t s must be confirmed. Well designed, population-based twin s t u d i e s of mood diso r d e r s and/or alc o h o l i s m are r e l a t i v e l y r a r e . More i n v e s t i g a t i o n s are needed before any conclusions can be drawn regarding the h e r i t a b i l i t y of the p u t a t i v e mood di s o r d e r : a l c o h o l i s m a s s o c i a t i o n . 1.6 Adoption Studies Adoption studies are another type of " f a m i l y study" which enable the separation of genetic and non-genetic f a c t o r s . Adoption studies allow comparisons of morbid r i s k s f o r b i o l o g i c a l and n o n - b i o l o g i c a l (e.g.: adopting parents, adopted/adoptive s i b l i n g s , adopted c h i l d r e n ) r e l a t i v e s of probands. The r a t i o n a l e f o r adoption studies i s as f o l l o w s : (1) i f f a m i l i a l aggregation i s genetic the r i s k f o r b i o l o g i c a l r e l a t i v e s i s s i g n i f i c a n t l y higher than that f o r n o n - b i o l o g i c a l r e l a t i v e s , which approaches population prevalence; (2) i f f a m i l i a l aggregation i s non-genetic the r i s k i s 46 approximately the same f o r b i o l o g i c a l and n o n - b i o l o g i c a l r e l a t i v e s ; (3) i f f a m i l i a l aggregation i s a mixture of genetic and non-genetic f a c t o r s the r i s k f o r n o n - b i o l o g i c a l r e l a t i v e s i s intermediate between the r i s k f o r b i o l o g i c a l r e l a t i v e s and the general p o p u l a t i o n . Most adoption studies use i n d i v i d u a l s who were adopted out i n e a r l y i n f a n c y to ensure that environmental f a c t o r s r e l e v a n t to the "adopted-out" i n d i v i d u a l ' s h i s t o r y are r e l a t e d to t h e i r adoptive f a m i l y , not t h e i r b i o l o g i c a l f a m i l y . To date, the m a j o r i t y of adoption s t u d i e s have focused on the rate of a l c o h o l i s m i n adults who were "adopted-out" as c h i l d r e n , and who had a l c o h o l i c b i o l o g i c a l parents (Goodwin et a l • , 1973; Goodwin et a l . , 1977a; Goodwin et a l . , 1977b; Cadoret et a l . , 1994; Cutrona et a l . , 1994; Cadoret et a l . , 1995). One study i n v e s t i g a t e d s i m i l a r f a c t o r s i n the adopted out adult c h i l d r e n of mood di s o r d e r a f f e c t e d parents (Ingraham and Wender, 1992). These studies w i l l be reviewed i n the f o l l o w i n g paragraphs and are summarized i n TABLE 1.12. The Goodwin et a l . s e r i e s (Goodwin et a l . , 1973; Goodwin et a l . , 1977a; Goodwin et a l . , 1977b) were based on probands a s c e r t a i n e d through Danish adoption records. The adopted probands were cross referenced to h o s p i t a l records to gather i n f o r m a t i o n on adopted c h i l d r e n who's b i o l o g i c a l parents were h o s p i t a l i z e d f o r alcoholism. C o n t r o l groups were formed by s e l e c t i n g from h o s p i t a l records, parents with a l c o h o l i s m who had r a i s e d t h e i r own c h i l d r e n . The r e s u l t s of a l l three studies are summarized i n TABLE 1.12. The Goodwin et a l . s e r i e s (1973, 1977a, 1977b) i n d i c a t e d that alcoholism was s i g n i f i c a n t l y elevated i n the b i o l o g i c a l adult male c h i l d r e n of a l c o h o l i c s whether they were adopted out or not. As w e l l , t h i s e f f e c t was seen to a non-s i g n i f i c a n t extent i n adult females who were adopted out as c h i l d r e n , and who had b i o l o g i c a l parents with alcoholism. The s e r i e s a l s o showed that depression was s i g n i f i c a n t l y elevated i n the daughters of a l c o h o l i c s , but only 47 i f the daughters were r a i s e d by t h e i r a l c o h o l i c b i o l o g i c a l parent(s) (77% of the a l c o h o l i c b i o l o g i c a l parents were f a t h e r s ) . Unfortunately, Goodwin et a l • d i d not d i f f e r e n t i a t e between the e f f e c t of an a l c o h o l i c b i o l o g i c a l mother versus an a l c o h o l i c b i o l o g i c a l f a t h e r on the r i s k of depression i n the female adoptees. The Goodwin et a l . s e r i e s (1973, 1977a, 1977b) suggests that there may be strong genetic f a c t o r s r e s p o n s i b l e f o r the t r a n s m i s s i o n of alcoholism i n males and to a l e s s o r extent, depressive d i s o r d e r s i n females. The data do not demonstrate a strong r e l a t i o n s h i p between al c o h o l i s m and depression. Results may have been confounded by some study flaws. For example, the method of proband ascertainment l i k e l y produced f a l s e l y low numbers of a l c o h o l i c parents i n that the f a t h e r s of many of the adoptees were not on record and t h e r e f o r e could not be i n c l u d e d i n the study. Secondly, h o s p i t a l i z a t i o n f o r a lcoholism was not common i n 1947 and consequently, there may have been ascertainment bias towards b i o l o g i c a l parents with severe a l c o h o l i s m or a more severe spectrum of a l c o h o l i s m with (perhaps) a heavier loading of a l c o h o l i s m s u s c e p t i b i l i t y genes. Ingraham and Wender (1992) used the adoption r e g i s t r i e s and ascertainment techniques of the Goodwin et a l . s e r i e s (1973, 1977a, 1977b). The r e s u l t s of t h e i r study suggested a gender s p e c i f i c p a t t e r n of d i s o r d e r s i n the b i o l o g i c a l r e l a t i v e s of probands who were adopted-out as i n f a n t s i n t o non-r e l a t e d f a m i l i e s . The patterns observed were: (1) the rate of a l c o h o l i s m was elevated i n the male b i o l o g i c a l r e l a t i v e s of the adopted-out probands; and (2) the rate of depression was elevated i n the female b i o l o g i c a l r e l a t i v e s of the adopted-out probands (see TABLE 1.12). Based on the patterns observed, Ingraham and Wender (1992) concluded that the p u t a t i v e a s s o c i a t i o n between Unipolar d i s o r d e r and a l c o h o l i s m i s based on both genetic and non-genetic f a c t o r s . 48 TABLE 1.12: SUMMARY OF RESULTS OF ADOPTION STUDIES ON MOOD DISORDER AND ALCOHOLISM AFFECTED INDIVIDUALS Author(s) Sample and Year Size of Study Conclusions Goodwin et a l . (1973) Goodwin et a l . (1977a) Goodwin et a l . (1977b) IngrahamS Wender (1992) Cutrona et a l . (1994) Cadoret et a l . 55 male adoptees* with a l e parent(s) vs matched c o n t r o l adoptees Female adoptees:49 with a l e f a t h e r s ; 47 without a l e f a t h e r s . 66 female .adoptees and 47 t h e i r s i s t e r s who were r a i s e d by t h e i r a l e fat h e r 48 female,23 male adoptees with MD; 67 matched c o n t r o l s . 1st degree b i o l and adoptive r e l a t i v e s of both groups Adoptees with a l e . parent: 45 female,48 male.Adoptees without a l e parent:107 female,75 male 95 male adoptees, 50% al e p a r e n t ( s ) . (1995) Adoptees with a l e parents had elevated a l e and psych problems vs c o n t r o l s . Genetic f a c t o r s i n v o l v e d i n a l e . Adoptees with a l e fa t h e r s had no more UP than c o n t r o l s . A l e i n fathers does not increase r i s k of UP i n adopted out females r a i s e d by f o s t e r parents. Daughters l i v i n g with a l e fathers had more UP than daughters adopted-out. Excess a l e i n both groups of daughters No s i g n i f i c a n t r e s u l t s . Excess MD i n female b i o l r e l a t i v e s , Excess a l e i n male b i o l r e l a t i v e s of MD vs normal adoptees. Not seen i n adoptive r e l a t i v e s . No d i r e c t s i g n i f i c a n t genetic or environmental f a c t o r s i n transmission of a l e . Rates of a l e d i d not d i f f e r between proband groups Ale i n B i o l parents and psych problems i n adoptive parents a s s o c i a t e d with increased drug abuse i n male adoptees. Where A l c = A l c o h o l i c ; b i o l = B i o l o g i c a l ; MD=Mood Disorders; Psych=Psychiatric; UP=Unipolar d i s o r d e r ; l s t = F i r s t ; * In every study, adoptions occurred to n o n - r e l a t i v e s before the adoptee was two years of age. Cutrona et a l . (1994) used male and female adoptees to i n v e s t i g a t e d i f f e r e n c e s i n r i s k f o r al c o h o l i s m i n adoptees, c o n t r o l l i n g f o r whether or not they had a b i o l o g i c a l parent with a l c o h o l i s m (see TABLE 1.12). A l l probands were given a numerical r a t i n g on each of the f a c t o r s under i n v e s t i g a t i o n and probands were then compared on the ba s i s of t h e i r score, t h e i r b i o l o g i c a l f a m i l y h i s t o r y and t h e i r own p s y c h i a t r i c h i s t o r y . No d i f f e r e n c e s i n r i s k f o r 49 a l c o h o l i s m were observed between the proband groups. Cutrona et a l . (1994) als o t e s t e d f o r genetic and environmental f a c t o r s that may have had a r o l e i n the adoptees' r i s k f o r alcoholism. Factors such as adoptive parent d i v o r c e , adoptive parent alcoholism, and adoptive f a m i l y coherence were found to have no s t a t i s t i c a l l y s i g n i f i c a n t e f f e c t on the r i s k f o r a l c o h o l i s m i n males. For females, suggestive genetic/environment i n t e r a c t i o n s were observed i n that an a l c o h o l i c b i o l o g i c a l parent and c o n f l i c t or psychopathology i n an adoptive parent g r e a t l y increased the female adoptee's r i s k f o r alcoholism. The authors concluded that the f i n d i n g s i n d i c a t e d gene/environment i n t e r a c t i o n s i n v o l v e d i n a l c o h o l i s m i n women only. This f i n d i n g does not agree with s e v e r a l previous f i n d i n g s i n which a l c o h o l i s m was found to have a stronger genetic b a s i s i n males versus females (Refer to TABLE 1.12). For t h i s reason, t h i s study should be re-done or re-evaluated before any conclusions are drawn. Cadoret et a l • (1995) used adoption records cross referenced with h o s p i t a l and p r i s o n records to i n v e s t i g a t e a l c o h o l and drug dependency i n male adoptees + a l c o h o l i c b i o l o g i c a l parents ( r e f e r to TABLE 1.12 f o r more d e t a i l s ) . While the study p r i m a r i l y i n v e s t i g a t e d patterns of drug abuse, two aspects were p e r t i n e n t to t h i s t h e s i s : (1) a l c o h o l i s m i n b i o l o g i c a l parents was r e l a t e d to an increase i n drug abuse i n t h e i r adopted out male o f f s p r i n g ; and (2) psychopathology i n adoptive parents increased the r i s k of substance abuse i n adopted out male o f f s p r i n g . Adoption studies have the p o t e n t i a l to be very h e l p f u l but are d i f f i c u l t to execute. They r e q u i r e a l a r g e , p o p u l a t i o n - a s c e r t a i n e d , w e l l documented study group. As adoption i s r e l a t i v e l y rare, a very large p o p u l a t i o n must be screened. Together, these f a c t o r s r e s u l t i n d i f f i c u l t y i n doing f u r t h e r adoption studies or r e p l i c a t i n g the studies summarized i n TABLE 1.12. Cross-r e f e r e n c i n g i n d i v i d u a l s adopted-out, with b i o l o g i c a l parents, can a l s o be confounded by the accuracy of r e p o r t i n g . 50 1.7 Summary Family h i s t o r y s t u d i e s , twin s t u d i e s , and adoption s t u d i e s i n c o n s i s t e n t l y suggest that s u s c e p t i b i l i t y to mood di s o r d e r s and alc o h o l i s m are g e n e t i c a l l y r e l a t e d . The f a m i l i a l patterns of trans m i s s i o n of mood dis o r d e r s and alc o h o l i s m suggest that each d i s o r d e r has s p e c i f i c genetic s u s c e p t i b i l i t y f a c t o r s that overlap with one another. The genetic components of mood di s o r d e r s and alc o h o l i s m s u s c e p t i b i l i t y are l i k e l y complicated, but i t may be p o s s i b l e to e l u c i d a t e some, or a l l , of them. The MDS Genetic Data Base at the U n i v e r s i t y of B r i t i s h Columbia provides a l a r g e database of i n d i v i d u a l s with diagnoses of mood d i s o r d e r s . Family h i s t o r y information has al s o been documented f o r a l l these i n d i v i d u a l s . This data can be used to study the p u t a t i v e mood d i s o r d e r and alc o h o l i s m a s s o c i a t i o n . The o b j e c t i v e s of t h i s t h e s i s are to explore the f a m i l i a l r e l a t i o n s h i p between mood di s o r d e r s and alc o h o l i s m using the data contained i n the MDS genetic database. ( S p e c i f i c t h e s i s o b j e c t i v e s are o u t l i n e d i n Section 1.1. ) 51 2 MATERIALS AND METHODS 2.1 Probands This t h e s i s i n v o l v e d a n a l y s i s of data p r e v i o u s l y c o l l e c t e d and v e r i f i e d i n the Mood Disorders Service Genetic Database. See Sadovnick et a l . (1994) f o r more d e t a i l s and references f o r the f o l l o w i n g summary. The a c t u a l data c o l l e c t i o n and v a l i d a t i o n were thus not a part of the present study. Nevertheless, the methodology f o r data c o l l e c t i o n and v a l i d a t i o n are summarized because of assumptions needed f o r the analyses. The Mood Disorders Service (MDS) Genetic Database at the U n i v e r s i t y of B r i t i s h Columbia was e s t a b l i s h e d using data c o l l e c t e d on a l l consecutive unrelated i n p a t i e n t s and out p a t i e n t s (probands) seen at the MDS from January 1987 to May 1990, i n c l u s i v e . The MDS Genetic Database contains demographic informat i o n and medical and p s y c h i a t r i c diagnoses on each proband. For each proband, the pedigree was extended to f i r s t , second and t h i r d degree r e l a t i v e s , provided that accurate demographic, medical and p s y c h i a t r i c i nformation could be obtained from m u l t i p l e f a m i l y informants. A c o n s u l t i n g p s y c h i a t r i s t from the MDS completed two d i a g n o s t i c summaries on each proband, one using Diagnostic and S t a t i s t i c a l Manual I l l -Revised (DSM III-R) (1987) c r i t e r i a , and the second based on Research Diagnostic C r i t e r i a (RDC) (S p i t z e r et a l . , 1978). (The DSM I I I - R c r i t e r i a and the RDC w i l l be described i n Section 2.11 and Section 2.12, r e s p e c t i v e l y . ) The RDC were used to maintain consistency i n diagnoses with the r e l a t i v e s of the probands, who were diagnosed using Family H i s t o r y Research Diagnostic C r i t e r i a , (FHRDC) (Endicott et a l . , 1975). This t h e s i s focused on mood di s o r d e r probands aged over ten years who had e i t h e r of the f o l l o w i n g diagnoses: (i) U n i p o l a r - S i n g l e Episode, ( i i ) Unipolar-Recurrent, ( i i i ) B i p o l a r I or (iv) B i p o l a r I I . 52 Information on the R e l i a b i l i t y and accuracy of the proband diagnoses, are presented i n d e t a i l i n Sadovnick et a l • (1994) and are summarized below. Cohen's kappa s t a t i s t i c ( F l e i s s , 1981) measured the i n t e r - r a t e r d i a g n o s t i c consistency ( i . e . : between diagnosing p s y c h i a t r i s t s ) while a l l o w i n g f o r agreement due to chance. P s y c h i a t r i c data on 34 randomly chosen probands were reviewed by two c l i n i c i a n s , b l i n d e d to the diagnosis of the proband as w e l l as the i d e n t i t y of the c o n s u l t i n g p s y c h i a t r i s t who gave the o r i g i n a l d iagnosis. The diagnoses given to each proband by two d i f f e r e n t c l i n i c i a n s had an o v e r a l l i n t e r - r a t e r agreement that was e x c e l l e n t [kappa=0.8, 95% Confidence I n t e r v a l (0.59, 1.00)], suggesting that the diagnoses of the probands were very r e l i a b l e (Sadovnick et al.,1994). 2.11 Diagnost ic and S t a t i s t i c a l Manual I l l -Rev ised (DSM III-R) C r i t e r i a As mentioned i n Section 2.1, probands from the MDS Genetic Database were each assigned a.DSM II I - R diagnosis(es) . The c r i t e r i a o u t l i n e d i n Sections 2.11.1, 2.11.2 and 2.11.3 were taken i n paraphrased form from the DSM II I - R manual (1987). The c u r r e n t l y used v e r s i o n of the c r i t e r i a , the Diagnostic and S t a t i s t i c a l Manual f o r Mental Disorders IV (DSM IV, 1994) was not used because the DSM II I - R was the only format a v a i l a b l e at the time the diagnoses were assigned to the MDS Genetic Database probands. I t was not f e a s i b l e , as part of t h i s t h e s i s , to rea s s i g n diagnoses according to DSM IV. Changes i n di a g n o s t i c c r i t e r i a f o r the categories needed f o r t h i s t h e s i s were e s s e n t i a l l y n e g l i g i b l e between DSM I I I - R and DSM IV. 2.11.1 Unipolar-S ingle Episode and Unipolar-Recurrent DSM I I I - R c r i t e r i a f o r Unipolar d i s o r d e r are given i n TABLE 2.1. 53 TABLE 2.1: DSM III-R DIAGNOSTIC CRITERIA FOR UNIPOLAR DISORDER1 (A) A Un ipolar Disorder-S ingle Episode diagnosis r e q u i r e s t h a t : 1) the proband meets the c r i t e r i a f o r a depressive episode and 2) has not had a previous episode of depression (B) I f the proband has experienced at l e a s t one previous episode of depression and f u l l y recovered before the onset of the current episode, a diagnosis of Unipolar Disorder-Recurrent may be assigned. (C) The c r i t e r i a f o r a depressive episode i n c l u d e : 1) f o r a p e r i o d of at l e a s t two weeks, the proband must have had at l e a s t f i v e of the f o l l o w i n g symptoms, one of which must be e i t h e r (i) or ( i i ) : (i) depressed mood, ( i i ) l o s s of i n t e r e s t or pleasure i n ne a r l y a l l usual d a i l y a c t i v i t i e s , ( i i i ) weight l o s s or gain, (iv) increase or decrease i n ap p e t i t e , (v) insomnia or hypersomnia, (vi) psychomotor r e t a r d a t i o n or a g i t a t i o n n o t i c e a b l e to others, ( v i i ) f a t i g u e or l o s s of energy, ( v i i i ) f e e l i n g s of worthlessness or excessive g u i l t , (ix) i n d e c i s i v e n e s s or decreased a b i l i t y to concentrate, (x) recurrent thoughts of death (D) the symptoms must be severe enough to a f f e c t work, s o c i a l a c t i v i t i e s or r e l a t i o n s h i p s or re q u i r e h o s p i t a l i z a t i o n to prevent harm to the proband or others (E) a l l organic causes f o r the depression must be r u l e d out (F) the depression must not be due to g r i e v i n g . - Paraphrased from Diagnostic and S t a t i s t i c a l Manual of Mental Disorders, T h i r d E d i t i o n - R e v i s e d , 1987 2.11.2 B ipo la r I and B ipo la r II For a DSM II I - R diagnosis of B i p o l a r I d i s o r d e r , MDS probands were req u i r e d to have had depressive episodes which met the c r i t e r i a o u t l i n e d i n TABLE 2.1, as w e l l as a manic episode(s) according to the DSM II I - R c r i t e r i a -see TABLE 2.2. For a DSM I I I - R diagnosis of B i p o l a r I I di s o r d e r , MDS probands were re q u i r e d to have had at l e a s t one depressive episode (TABLE 2.1) as w e l l as a DSM II I - R diagnosis of "hypomania", as described i n TABLE 2.2. 54 TABLE 2.2: DSM III-R CRITERIA FOR BIPOLAR I AND BIPOLAR II DISORDERS1 (A) Both B i p o l a r I and B i p o l a r I I di s o r d e r s diagnoses r e q u i r e the proband to have had at l e a s t one depressive episode (see TABLE 2.1) (B) A diagnosis of B ipo la r I . r e q u i r e s that the symptoms of the manic episode are severe enough to a f f e c t work, s o c i a l a c t i v i t i e s or r e l a t i o n s h i p s or re q u i r e h o s p i t a l i z a t i o n to prevent harm to the proband or others (C) A B ipo la r II d i s o r d e r diagnosis r e q u i r e s that c r i t e r i a (A) and (D) are met, but the proband must not meet c r i t e r i u m . (B) . (D) The c r i t e r i a f o r a manic episode: (1) the main mood i s expansive, i r r i t a b l e or elevated (2) at l e a s t three of the f o l l o w i n g symptoms, four i f the main mood i s i r r i t a b l e : (i) decreased need f o r sleep, ( i i ) i n f l a t e d s e l f esteem or gr a n d i o s i t y , ( i i i ) pressure of speech, (iv) f l i g h t of ideas, (v) d i s t r a c t i b i l i t y , (vi) excessive involvement i n pleasurable a c t i v i t i e s which have a high p o t e n t i a l f o r bad consequences, ( v i i ) psychomotor a g i t a t i o n (3) organic causes of the mania must have been r u l e d out, as w e l l as any other d e l u s i o n a l type p s y c h i a t r i c d i s o r d e r s (schizophrenia, s c h i z o a f f e c t i v e d i s o r d e r ) . - Paraphrased from Diagnostic and S t a t i s t i c a l Manual of Mental Disorders, T h i r d E d i t i o n - R e v i s e d , 1987 2.11.3 A l coho l Abuse or Dependence DSM I I I - R (1987) l i s t s c r i t e r i a f o r "psychoactive substance use di s o r d e r s " , which includes abuse/dependence of nine c l a s s e s of substances, i n c l u d i n g a l c o h o l . The DSM II I - R c r i t e r i a f o r a l c o h o l dependence are paraphrased i n TABLE 2.3. According to DSM III-R, the three main patterns of a l c o h o l abuse/dependence are as f o l l o w s 1 : 1) re g u l a r d a i l y i n t a k e of la r g e amounts of a l c o h o l , 2) re g u l a r heavy d r i n k i n g l i m i t e d to weekends or h o l i d a y s , and 3) long periods of abstinence i n t e r s p e r s e d with binges of d a i l y heavy d r i n k i n g l a s t i n g weeks or months. DSM II I - R mentions that a l c o h o l dependence i s chronic and u s u a l l y s t a r t s i n the l a t e teens or e a r l y twenties. Within the 55 MDS Genetic Database, probands were considered a l c o h o l i c i f they met c r i t e r i a f o r a l c o h o l dependence, and at l e a s t one f a m i l y informant supported the contention that the proband was an a l c o h o l i c TABLE 2.3: DSM III-R CRITERIA FOR ALCOHOL DEPENDANCE1 (A) At l e a s t three of the f o l l o w i n g symptoms: (i) a l c o h o l taken i n l a r g e r amounts than proband intended, ( i i ) p e r s i s t e n t d e s i r e or one or more attempts to decrease consumption, ( i i i ) great deal of time spent i n g e t t i n g , d r i n k i n g or recovering from the e f f e c t s of a l c o h o l , (iv) frequent i n t o x i c a t i o n or withdrawal symptoms when expected to f u l f i l o b l i g a t i o n s at school, home or work or drunk when p h y s i c a l l y dangerous, (v) important s o c i a l , occupational or r e c r e a t i o n a l a c t i v i t i e s given up or decreased due to d r i n k i n g , (vi) continued d r i n k i n g despite known, negative, s o c i a l , p h y s i c a l or p s y c h o l o g i c a l consequences, ( v i i ) marked tolerance or markedly diminished e f f e c t with continued use of s i m i l a r amounts of a l c o h o l , ( v i i i ) withdrawal symptoms, (ix) d r i n k i n g to decrease or avoid withdrawal symptoms. (B) Some symptoms must have p e r s i s t e d f o r at l e a s t one month, or have occurred repeatedly over a longer p e r i o d of time. 1 Paraphrased from Diagnostic and S t a t i s t i c a l Manual of Mental Disorders, T h i r d E d i t i o n - R e v i s e d , 1987. 2.12 Research Diagnost ic C r i t e r i a (RDC) The f u l l p s y c h i a t r i c assessment given to each proband i n c l u d e d a diagnosis based on DSM II I - R c r i t e r i a as w e l l as a diagnosis based on RDC (Sp i t z e r et a l . , 1978). The RDC diagnoses were assigned to allow comparisons ' between the probands and t h e i r r e l a t i v e s , who were diagnosed using Family H i s t o r y Research Diagnostic C r i t e r i a (Endicott et a l . , 1975). Refer to Section 2.1 f o r more d e t a i l . The probands were rated depending on the type and s e v e r i t y of t h e i r d i s o r d e r , as D e f i n i t e , Probable or P o s s i b l e . However, only probands with d e f i n i t e diagnoses were considered i n t h i s t h e s i s , and th e r e f o r e , the c r i t e r i a 56 r e q u i r e d to assign a "Probable or P o s s i b l e " diagnosis are not given. See Sadovnick et a l . (1994) f o r d e t a i l s of these c a t e g o r i e s . A d i a g n o s t i c c l a s s i f i c a t i o n of " D e f i n i t e " r e q u i r e d that probands meet the c r i t e r i a l i s t e d below f o r major depressive d i s o r d e r , manic d i s o r d e r and/or alcoholism. 2.12.1 Major Depressive Disorder To have rece i v e d a RDC diagnosis of " D e f i n i t e " Major Depressive Disorder, the proband must have d i s p l a y e d the symptoms o u t l i n e d i h TABLE 2.4. Several subtypes of Major Depressive Disorder e x i s t f o r RDC, i n c l u d i n g primary versus secondary depression. The primary versus secondary Major Depressive Disorder d i s t i n c t i o n i s based on the temporal sequencing of the depression when compared to the onset of any other co-morbid d i s o r d e r s the proband may have di s p l a y e d . Only probands with primary Major Depressive Disorder were considered i n t h i s t hes i s . Of the se v e r a l other subtypes of Major Depressive Disorder included i n RDC, only S i n g l e Episode Major Depressive Disorder versus Recurrent Major Depressive Disorder were p e r t i n e n t to t h i s t h e s i s . Recurrent Major Depressive Disorder was diagnosed i f the proband had experienced at l e a s t two previous depressive episodes, each separated by at l e a s t two months of more or l e s s normal functioning.. S i n g l e Episode Major Depressive Disorder was diagnosed i f the proband had never had a previous episode of depression. By comparing the c r i t e r i a o u t l i n e d i n TABLE 2.1 and i n TABLE 2.4 s e v e r a l s i m i l a r i t i e s between the DSM III-R and the RDC can be seen, i n that, f o r the most p a r t , the symptoms o u t l i n e d i n both sets of c r i t e r i a are qu i t e s i m i l a r . DSM I I I - R and RDC c r i t e r i a d i f f e r s u b s t a n t i a l l y i n that the RDC are more d i f f i c u l t to meet symptom-wise, but l e s s d i f f i c u l t to meet duration-wise. Further, the RDC f o r recurrent versus s i n g l e episode depression are much more s t r i c t than the c r i t e r i a o u t l i n e d i n the DSM III- R . 57 TABLE 2.4: RDC FOR A MAJOR DEPRESSIVE EPISODE2 (1) dysphoric mood or pervasive l o s s of i n t e r e s t or pleasure, (2) at l e a s t f i v e of the f o l l o w i n g : (i) increased or decreased a p p e t i t e , ( i i ) weight l o s s or gain, ( i i i ) insomnia or hypersomnia, (iv) decreased energy or t i r e d n e s s , (v) psychomotor a g i t a t i o n or r e t a r d a t i o n , (vi) f e e l i n g s of s e l f c r i t i c i s m or g u i l t , ( v i i ) decreased a b i l i t y to t h i n k or concentrate, ( v i i i ) thoughts of death or s u i c i d e , (ix) s u i c i d e attempts (3) the dur a t i o n of symptoms must have been at l e a s t one week (4) the proband sought help f o r the depression, was medicated f o r symptoms or the depression a f f e c t e d work or home r e l a t i o n s h i p s , (5) schizophrenia was excluded (6) mania and/or hypomania was never evident. - Paraphrased from "Research Diagnostic C r i t e r i a " by S p i t z e r et a l • , 1978 2.12.2 Manic Disorder RDC subdivides Manic Disorder i n t o two separate d i s o r d e r s , as f o l l o w s : (i) B i p o l a r I d i s o r d e r , where the proband meets the c r i t e r i a f o r Manic Disorder and f o r Major depression, and ( i i ) B i p o l a r I I d i s o r d e r , where the proband meets the c r i t e r i a f o r Major Depression and Hypomania. The c r i t e r i a f o r Major Depression are as o u t l i n e d i n Section 2.12.1. The c r i t e r i a f o r Mania are o u t l i n e d i n TABLE 2.5, while the c r i t e r i a f o r Hypomania are o u t l i n e d i n TABLE 2.6. The c r i t e r i a o u t l i n e d i n TABLE 2.2, TABLE 2.5 and TABLE 2.6 rev e a l s e v e r a l s i m i l a r i t i e s between the DSM II I - R and the RDC f o r mania. F i r s t l y , both l i s t s i m i l a r symptoms and a s i m i l a r s e v e r i t y of mania i s req u i r e d to meet both c r i t e r i a . RDC and DSM III-R d i f f e r i n that the RDC inclu d e s an exc l u s i o n a r y clause f o r symptoms caused by a l c o h o l or drug abuse, whereas the DSM II I - R does not. As w e l l , the RDC inclu d e s the c r i t e r i o n of "the manic 58 symptoms are severe enough to make conversation impossible" (TABLE 2.5), a u s e f u l , non-medical symptom that i s not included i n the DSM III- R . TABLE 2 . 5 : RDC FOR MANIA 2 1) The proband must have met the f o l l o w i n g c r i t e r i a on at l e a s t one occasion f o r a du r a t i o n of at l e a s t one week: 2) predominantly elevated, i r r i t a b l e or expansive mood 3) and at l e a s t three of the f o l l o w i n g symptoms: (i) more a c t i v e than usual at work, play, or s e x u a l l y or p h y s i c a l l y r e s t l e s s , ( i i ) more t a l k a t i v e than usual or pressure of speech, ( i i i ) f l i g h t of ideas or r a c i n g thoughts, (iv) g r a n d i o s i t y , (v) decreased need f o r sleep, (vi) d i s t r a c t i b i l i t y , ( v i i ) excessive involvement i n a c t i v i t i e s without r e c o g n i t i o n of t h e i r p o s s i b l y harmful consequences 4) the manic symptoms are severe enough to make conversation impossible, to a f f e c t the p a t i e n t s ' home or work r e l a t i o n s h i p s or to r e q u i r e h o s p i t a l i z a t i o n 5) schizophrenia i s excluded 6) the symptoms are not due to drug or a l c o h o l abuse. - Paraphrased from "Research Diagnostic C r i t e r i a " by S p i t z e r et a l , 1 9 7 8 TABLE 2 . 6 : RDC FOR HYPOMANIA 2 The f o l l o w i n g requirements from TABLE 2.4 must be met hypomania: to assign a diagnosis of 1) c r i t e r i u m (2) 2) at l e a s t two of the symptoms l i s t e d i n c r i t e r i u m (3) 3) c r i t e r i u m (5) 4) c r i t e r i u m (6) 5) the symptoms must have l a s t e d at l e a s t two days - Paraphrased from "Research Diagnostic C r i t e r i a " by S p i t z e r et a l , 1978 59 2.12.3 Alcohol ism The .RDC includes s p e c i f i c d i a g n o s t i c c r i t e r i a f o r alcoholism, which are l i s t e d i n TABLE 2.7. Within the MDS Genetic Database, i n contrast to the d i a g n o s t i c r a t i n g s f o r Unipolar d i s o r d e r and B i p o l a r d i s o r d e r , probands were considered a l c o h o l i c i f t h e i r RDC d i a g n o s t i c r a t i n g was D e f i n i t e , or Probable. This was done to c o r r e c t f o r the inherent under-reporting and under-diagnosis of alcoholism. TABLE 2.7: RDC FOR ALCOHOLISM2 (A) The p a t t e r n of d r i n k i n g must be e i t h e r at l e a s t one month of recurrent binge d r i n k i n g or n e a r l y d a i l y d r i n k i n g (B) At l e a s t two f o r a "Probable" dia g n o s i s , or three f o r a " D e f i n i t e " diagnosis, of the f o l l o w i n g manifestations must occur simultaneously with c r i t e r i u m (A): (1) proband t h i n k s he d r i n k s e x c e s s i v e l y , (2) others t h i n k he d r i n k s too much, (3) admits he can't stop d r i n k i n g when he wants to , (4) frequent d r i n k i n g before break f a s t , (5) d r i n k i n g a f f e c t s job performance, (6) d r i n k i n g caused l o s s of job, (7) problems with f a m i l y r e l a t i o n s h i p s caused by d r i n k i n g , (8) d r i n k i n g caused divorce or separation, (9) a l c o h o l i c benders l a s t i n g three or more days, (10) p h y s i c a l v i o l e n c e caused by d r i n k i n g , (11) t r a f f i c v i o l a t i o n s caused by d r i n k i n g , (12) problems with p o l i c e as a r e s u l t of d r i n k i n g , (13) blackouts, (14) d e l i r i u m tremens, (15) h a l l u c i n a t i o n s on withdrawal of a l c o h o l , (16) withdrawal s e i z u r e s , (17) c i r r h o s i s of the l i v e r , p a n c r e a t i t i s or g a s t r i t i s caused by the d r i n k i n g , (18) polyneuropathy l i k e l y due to d r i n k i n g . - Paraphrased from "Research Diagnostic C r i t e r i a " by S p i t z e r et a l , 1 9 7 8 The RDC and DSM I I I - R c r i t e r i a are s i m i l a r i n that both l i s t binge d r i n k i n g and d a i l y d r i n k i n g as p o s s i b l e patterns of alcoholism. An important d i f f e r e n c e between the two c r i t e r i a i s that DSM I I I - R c r i t e r i a are much more s u b j e c t i v e and open to i n t e r p r e t a t i o n , whereas the RDC l i s t very s p e c i f i c 60 " r e a l l i f e " symptoms. The l a r g e , s p e c i f i c l i s t of symptoms i n the RDC allow a more o b j e c t i v e diagnoses to be given. Although DSM I I I - R c r i t e r i a are more open to s u b j e c t i v e i n t e r p r e t a t i o n , they i n c l u d e important c r i t e r i a not l i s t e d i n the RDC, such as "a l a r g e amount of time spent g e t t i n g , d r i n k i n g or recovering from a l c o h o l consumption" (see TABLE 2.3). 2.13 Age of Onset i n Mood Disorder Probands The age of onset of the mood di s o r d e r f o r each proband was defined as e i t h e r the age at which the proband sought medical help f o r the mood di s o r d e r , or the age at which the proband had considerable p s y c h o s o c i a l impairment from the mood d i s o r d e r . I f the proband was unsure of e i t h e r of these ages (e.g.: "mid-twenties"), a middle estimate was given (e.g.: 25). (Sadovnick et a l . , 1994) . 2.2 F i r s t and Second Degree Re la t i ves of Probands The fa m i l y data i n the MDS Genetic Database were c o l l e c t e d using the "Family H i s t o r y " method, which uses personal i n t e r v i e w s with m u l t i p l e f a m i l y informants to gather inform a t i o n on a l l remaining f a m i l y members. The fa m i l y h i s t o r y method has been shown to be a v a l i d means of c o l l e c t i n g data provided that m u l t i p l e f a m i l y informants are interviewed and s t r i c t c r i t e r i a f o r diagnoses are used (Thompson et a l . , 1982; Kendler et a l • , 1991; Horwath, 1992; Remick et a l . , 1993; Norden et a l . , 1995). The fa m i l y h i s t o r y method has a l s o been shown to be a r e l i a b l e method of data c o l l e c t i o n f o r the w e l l recognized genetic database f o r the M u l t i p l e S c l e r o s i s C l i n i c at the U n i v e r s i t y H o s p i t a l - U n i v e r s i t y of B r i t i s h Columbia S i t e (Sadovnick et a l . , 1992; Sadovnick and Ebers, 1995). The "Family Study" method was not used i n e s t a b l i s h i n g the MDS Genetic Database as t h i s method requ i r e s personal i n t e r v i e w s of a l l f a m i l y members. I t 61 i s p r o h i b i t i v e l y labour and cost i n t e n s i v e to use t h i s method i n many s t u d i e s , i n c l u d i n g the Mood Disorders Service study (Sadovnick et a l . , 1994). A Masters of Science l e v e l Genetic c o u n s e l l o r with s p e c i a l t r a i n i n g i n p s y c h i a t r i c d i s o r d e r s undertook the c o l l e c t i o n of the f a m i l y h i s t o r y data f o r the Mood Disorders S e r v i c e . The Genetic c o u n s e l l o r was chosen because of her t r a i n i n g i n methods of e l i c i t i n g s e n s i t i v e i n f o r m a t i o n from h e s i t a n t or u n w i l l i n g informants. As w e l l , the genetic c o u n s e l l o r had s u f f i c i e n t medical t r a i n i n g to allow her to e l i c i t as much p e r t i n e n t medical and p s y c h i a t r i c i n f o r m a t i o n as p o s s i b l e from each f a m i l y informant. The "Family H i s t o r y " method was used to c o l l e c t data on the probands' r e l a t i v e s using personal i n t e r v i e w s with m u l t i p l e f a m i l y informants. For each purportedly " a f f e c t e d " f a m i l y member, the genetic c o u n s e l l o r completed a Family H i s t o r y Research Diagnostic C r i t e r i a (FHRDC) questionnaire (Endicott et a l . , 1975; Andreasen et a l . , 1977) during the genetic i n t e r v i e w with the fami l y informant (see Appendix A f o r examples). The purportedly " a f f e c t e d " r e l a t i v e was then contacted so that he (or she) could be p e r s o n a l l y interviewed and permission gained to obtain relevant supportive medical and/or p s y c h i a t r i c records. A l l a v a i l a b l e information was reviewed by a MDS p s y c h i a t r i s t (R.A. Remick) and a "Best Estimate" diagnosis was given. The r e l a t i v e s ' diagnoses were cat e g o r i z e d as " d e f i n i t e " , "probable", " p o s s i b l e " or "no" using the f o l l o w i n g c r i t e r i a 1 : T a k e n f r o m S a d o v n i c k e t a l . , 1994 62 DEFINITE: The FHRDC diagnosis was supported by both d e s c r i p t i v e (FHRDC questionnaires) data and appropriate m e d i c a l / p s y c h i a t r i c documentation. PROBABLE: The r e l a t i v e r e c e i v e d medical treatment f o r the reported p s y c h i a t r i c c o n d i t i o n , but s u f f i c i e n t w r i t t e n documentation (e.g., d e t a i l e d p s y c h i a t r i c reports) could not be obtained. However, s u f f i c i e n t d e s c r i p t i v e data using FHRDC questionnaires were a v a i l a b l e to c l e a r l y f u l f i l FHRDC f o r a mood or non-mood p s y c h i a t r i c d i a g n o s i s . The analyses presented i n t h i s t h e s i s consider only f i r s t and second degree r e l a t i v e s with d i a g n o s t i c c e r t a i n t y r a t i n g s of "no", d e f i n i t e or probable. FHRDC do not allow separation i n t o B i p o l a r I versus B i p o l a r I I di s o r d e r s . Thus b i p o l a r r e l a t i v e s could not be sub-categorized. I n t e r - r a t e r agreement t e s t s were performed (Sadovnick et a l . , 1994) to ensure the accuracy of the r e l a t i v e s ' diagnoses using Cohen's kappa s t a t i s t i c ( F l e i s s , 1981). The kappa s t a t i s t i c was c a l c u l a t e d using the r e l a t i v e s ' data, which were independently reviewed by two MDS c l i n i c i a n s , b l i n d e d to the f o l l o w i n g : (1) the diagnosis of the proband, (2) the i n i t i a l diagnosis of the " a f f e c t e d " r e l a t i v e and (3) the i d e n t i t y of the p s y c h i a t r i s t who i n i t i a l l y diagnosed the r e l a t i v e . The o v e r a l l i n t e r - r a t e r agreement on 39 f i r s t degree r e l a t i v e s of 33 randomly chosen mood di s o r d e r probands was e x c e l l e n t (kappa=0.89, 95% Confidence I n t e r v a l s (0.77, 1.00)) (Sadovnick et a l . (1994)). POSSIBLE: The r e l a t i v e appeared to meet FHRDC based on d e s c r i p t i v e information only. Medical treatment ( i n p a t i e n t / o u t p a t i e n t ; f a m i l y d o c t o r / p s y c h i a t r i s t , etc.) was never obtained. NO: No h i s t o r y of the di s o r d e r under question 63 2.3 Analyses 2.31 Overview The analyses presented i n t h i s t h e s i s focus on probands with the f o l l o w i n g s i n g l e mood d i s o r d e r s : (i) U n i p o l a r - S i n g l e Episode, ( i i ) U nipolar-Recurrent, ( i i ) B i p o l a r I and (iv) B i p o l a r I I . For each subcategory, the probands were separated according to whether or not there was co-morbid alcoholism. The groups used i n the analyses were thus subdivided according to the diagnosis and gender of the proband. See TABLE 2.8 f o r a summary of the types of proband groups and TABLE 3.1 f o r the number of probands i n each group. The data on the f i r s t degree r e l a t i v e s of each proband subgroup were used to determine the f o l l o w i n g : Do the rates of a l c o h o l i s m i n r e l a t i v e s of mood d i s o r d e r probands depend on the gender and diagnosis of the proband ? These comparisons were performed using Chi-Square 2X2 contingency t a b l e s (see Section 2.32 f o r d e t a i l s ) . TABLE 2.8: PROBAND SUBGROUPS USED IN ANALYSES (1) Male and female Unipolar-Recurrent probands (2) Male and female Unipolar-Recurrent probands with co-morbid alcoholism (3) Male and female U n i p o l a r - S i n g l e Episode probands (4) Male and female U n i p o l a r - S i n g l e Episode probands with co-morbid al c o h o l i s m (5) Male and female B i p o l a r I probands (6) Male and female B i p o l a r I probands with co-morbid al c o h o l i s m (7) Male and female B i p o l a r I I probands (8) Male and female B i p o l a r I I probands with co-morbid alcoholism The average ages of onset of the various proband groups were considered to be a gauge of mood d i s o r d e r s e v e r i t y i n that an a s s o c i a t i o n has been shown between a younger age of onset and i n c r e a s i n g s e v e r i t y of a mood di s o r d e r (Cook and Winokur, 1985). The f i n d i n g s of Cook and Winokur (1985) suggest that the average ages of onset in'proband subgroups can be used as a gauge of the 64 e f f e c t of a f a m i l y h i s t o r y of alc o h o l i s m by comparing the ages of onset of mood di s o r d e r probands with versus without a f a m i l y h i s t o r y of alcoholism. This suggestion a l s o leads to the f o l l o w i n g hypothesis: i f a l c o h o l i s m and mood dis o r d e r s share a common genetic e t i o l o g y , then the genetic f a c t o r s r e s p o n s i b l e f o r these d i s o r d e r s would be tr a n s m i t t e d together through f a m i l i e s . I f t h i s were true, then we would expect that f a m i l i e s that d i s p l a y alcoholism, as w e l l as mood d i s o r d e r s , w i l l transmit a heavier load of the mood di s o r d e r and alc o h o l i s m genes, and th e r e f o r e have an increased s e v e r i t y of mood di s o r d e r which occurs at a younger age, when compared to f a m i l i e s i n which a l c o h o l i s m or mood di s o r d e r s segregate alone. From t h i s we expect that mood d i s o r d e r probands with co-morbid a l c o h o l i s m w i l l have the youngest average age of onset, as, under t h i s hypothesis, they are expected to have the heaviest l o a d i n g of mood di s o r d e r and alcoholism genes. The LIFETEST procedure from the S t a t i s t i c a l A n a l y s i s Software (SAS, 1985) package, which uses the Kaplan-Meier (Kaplan and Meier, 1958) method, was used to analyze the ages of onset (see Section 2.33 f o r d e t a i l s ) . The age of onset comparisons were c a r r i e d out on the probands' data when the probands were subdivided i n t o Unipolar and B i p o l a r groups, as w e l l as when the probands were subdivided i n t o U n i p o l a r - S i n g l e Episode, Unipolar-Recurrent, B i p o l a r I, and B i p o l a r I I groups. For a summary of the comparisons c a r r i e d out, see TABLE 2.9. Z-tests or Student's t - t e s t s were used to compare the average ages of onset of the various proband groups to determine whether or not there were 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 s . The d e t a i l s and computational formulae are presented i n Section 2.34. 65 TABLE 2.9: AGES OF ONSET COMPARISONS BETWEEN PROBAND GROUPS (A) 1) Average of onset of male versus female n o n - a l c o h o l i c Unipolar d i s o r d e r probands. 2) Average of onset of male versus female n o n - a l c o h o l i c B i p o l a r d i s o r d e r probands. 3) Average of onset of male versus female a l c o h o l i c Unipolar d i s o r d e r probands. 4) Average of onset of m a l e . a l c o h o l i c versus n o n - a l c o h o l i c Unipolar d i s o r d e r probands. 5) Average of onset of female a l c o h o l i c versus n o n - a l c o h o l i c Unipolar d i s o r d e r probands. 6) Average of onset of female a l c o h o l i c versus n o n - a l c o h o l i c B i p o l a r d i s o r d e r probands. (B) 1) Average of onset of male n o n - a l c o h o l i c Unipolar-Recurrent versus Unipolar-Sing l e Episode probands. 2) Average of onset of female n o n - a l c o h o l i c Unipolar-Recurrent versus U n i p o l a r - S i n g l e Episode probands. 3) Average of onset of female a l c o h o l i c Unipolar-Recurrent versus Unipolar-S i n g l e Episode probands. 4) Average of onset of male n o n - a l c o h o l i c versus a l c o h o l i c Unipolar-Recurrent probands. 5) Average of onset of female n o n - a l c o h o l i c versus a l c o h o l i c U nipolar-Recurrent probands. 6) Average of onset of female n o n - a l c o h o l i c versus a l c o h o l i c U n i p o l a r - S i n g l e Episode probands. 7) Average of onset of male n o n - a l c o h o l i c B i p o l a r I versus B i p o l a r I I probands. 8) Average of onset of female n o n - a l c o h o l i c B i p o l a r I versus B i p o l a r I I probands. 9) Average of onset of female n o n - a l c o h o l i c versus a l c o h o l i c B i p o l a r I probands. (C) 1) Average of age of onset of male Unipolar probands with versus without a l c o h o l i c r e l a t i v e s . 66 TABLE 2.9 Continued: 2) Average of age of onset of female Unipolar probands with versus without a l c o h o l i c r e l a t i v e s . 3) Average of age of onset of male B i p o l a r probands with versus without a l c o h o l i c r e l a t i v e s . 4) Average of age of onset of female B i p o l a r probands with versus without a l c o h o l i c r e l a t i v e s . (D) 1) Average of age of onset of male Unipolar-Recurrent probands with versus without a l c o h o l i c r e l a t i v e s . 2) Average of age of onset of male U n i p o l a r - S i n g l e Episode probands with versus without a l c o h o l i c r e l a t i v e s . 3) Average of age of onset of female Unipolar-Recurrent probands with versus without a l c o h o l i c r e l a t i v e s . 4) Average of age of onset of female U n i p o l a r - S i n g l e Episode probands with versus without a l c o h o l i c r e l a t i v e s . 5) Average of age of onset of male B i p o l a r I probands with versus without a l c o h o l i c r e l a t i v e s . 6) Average of age of onset of male B i p o l a r I I probands with versus without a l c o h o l i c r e l a t i v e s . 7) Average of age of onset of female B i p o l a r I probands with versus without a l c o h o l i c r e l a t i v e s . 8) Average of age of onset of female B i p o l a r I I probands with versus without a l c o h o l i c r e l a t i v e s . (E) 1) Average of age of onset of male Unipolar probands with versus without r e l a t i v e s who committed s u i c i d e . 2) Average of age of onset of female Unipolar probands with versus without r e l a t i v e s who committed s u i c i d e . 3) Average of age of onset of male B i p o l a r probands with versus without r e l a t i v e s who committed s u i c i d e . 4) Average of age of onset of female B i p o l a r probands with versus without r e l a t i v e s who committed s u i c i d e . (F) 1) Average of age of onset of male Unipolar-Recurrent probands with versus without r e l a t i v e s who committed s u i c i d e . 67 TABLE 2.9 Continued: 2) Average of age of onset of female Unipolar-Recurrent probands with versus without r e l a t i v e s who committed s u i c i d e . 3) Average of age of onset of male U n i p o l a r - S i n g l e Episode probands with versus without r e l a t i v e s who committed s u i c i d e . 4) Average of age of onset of female U n i p o l a r - S i n g l e Episode probands with versus without r e l a t i v e s who committed s u i c i d e . 5) Average of age of onset of male B i p o l a r I probands with versus without r e l a t i v e s who committed s u i c i d e . 6) Average of age of onset of female B i p o l a r I probands with versus without r e l a t i v e s who committed s u i c i d e . 7) Average of age of onset of female B i p o l a r I I probands with versus without r e l a t i v e s who committed s u i c i d e . Where Unipolar=Unipolar-Single Episode and Recurrent; B i p o l a r = B i p o l a r I and B i p o l a r I I . Average ages of onset of mood dis o r d e r s i n the proband groups were compared to answer the f o l l o w i n g questions, where probands were considered p o s i t i v e f o r a f a m i l y h i s t o r y i f at l e a s t one f i r s t degree r e l a t i v e was " a f f e c t e d " : (1) Does a f a m i l y h i s t o r y of alc o h o l i s m i n f i r s t degree r e l a t i v e s a f f e c t the age of onset i n mood d i s o r d e r probands ? (2) Does a fa m i l y h i s t o r y of s u i c i d e i n f i r s t or second degree r e l a t i v e s a f f e c t the age of onset i n mood di s o r d e r probands ? These comparisons were c a r r i e d out using Z t e s t s and Student's t t e s t s (see Section 2.34 f o r d e t a i l s ) . The age d i s t r i b u t i o n , the gender d i s t r i b u t i o n and the d i s t r i b u t i o n of the d i f f e r e n c e s between the age of onset of the mood d i s o r d e r and the age at the time of the genetic i n t e r v i e w were a l l compared f o r U n i p o l a r - S i n g l e Episode versus Unipolar-Recurrent probands. These t e s t s were done to determine i f the d i f f e r e n c e s seen between the U n i p o l a r - S i n g l e Episode and the Unipolar-68 Recurrent subgroups were an a r t i f a c t of ascertainment or represented a " t r u e " d i f f e r e n c e . The p r o p o r t i o n of a l c o h o l i c s was c a l c u l a t e d f o r each proband group and fo r each group of f i r s t degree r e l a t i v e s . N i n e t y - f i v e percent confidence i n t e r v a l s were c a l c u l a t e d f o r a l l of the proportions using the formula presented i n Section 2.35. P r o p o r t i o n a l Z t e s t s were used to compare the gender r a t i o s of the various groups of probands, as w e l l as t h e i r f i r s t and second degree r e l a t i v e s . The computational formulae are presented i n Section 2.36. The gender r a t i o s of the probands and t h e i r f i r s t and second degree r e l a t i v e s were compared to the general population rates using a modified Z t e s t . See Section 2.37 f o r d e t a i l s and formulae. The average ages at the time of the genetic i n t e r v i e w were c a l c u l a t e d f o r the f i r s t degree r e l a t i v e s of each proband subgroup using SAS MEANS procedure. The r e l a t i v e s ' age demographics were then compared using A n a l y s i s of Variance and Tukey t e s t s (See Section 2.38 and 2.39, r e s p e c t i v e l y , f o r formulae). Probands, subdivided as to whether or not they had co-morbid alcoholism, were screened f o r "heavy l o a d i n g " of a l c o h o l i s m i n t h e i r f i r s t and second degree r e l a t i v e s . These subgroups were f u r t h e r d i v i d e d i n t o those with no a l c o h o l i c r e l a t i v e s , and those with >2, >3, >4, or >5 a l c o h o l i c r e l a t i v e s . In explanation, the group c o n t a i n i n g probands with at l e a s t two a l c o h o l i c r e l a t i v e s , contained those probands that had two, or three, or four, or at l e a s t f i v e , a l c o h o l i c f i r s t or second degree r e l a t i v e s . The data on probands with at l e a s t four a l c o h o l i c r e l a t i v e s were used as the b a s i s f o r a small case study (See Appendix B f o r more d e t a i l ) . The case study was done to d i s c e r n i f there were any obvious patterns of p s y c h i a t r i c 69 d i s o r d e r s , n o n - p s y c h i a t r i c d i s o r d e r s or relatedness between the a l c o h o l i c s i n the probands' f a m i l i e s . 2.32 Chi-Square Test Ana lys i s Computational Formulae The chi-square t e s t i s used to t e s t how f a r a sample taken from a population deviates from the t h e o r e t i c a l d i s t r i b u t i o n of that population under the n u l l hypothesis of no d i f f e r e n c e . Or, i n other words, the chi-square t e s t i s used to f i n d i f the data observed could have been found by chance. For most of the chi-square t e s t s performed i n t h i s t h e s i s , the n u l l hypothesis was that the d i s t r i b u t i o n of subgroups of r e l a t i v e s d i d not d i f f e r between proband groups. Chi-square contingency t a b l e s were used to t e s t m u l t i p l e proband groups i n a t a b u l a r format. A sample contingency t a b l e i s shown i n FIGURE 2.1 and explained i n more d e t a i l i n the f o l l o w i n g paragraph. In the 2X2 contingency t a b l e s , the probands under c o n s i d e r a t i o n were d i v i d e d i n t o four " c e l l s " , X n, X 1 2, X 2 1 and X 2 2, u s u a l l y on the ba s i s of gender and d i a g n o s i s . Each c e l l i n the 2X2 t a b l e had a corresponding row t o t a l , Ri or R2, and a corresponding column t o t a l , Ci or C2 (see FIGURE 2.1). FIGURE 2.1: SAMPLE 2X2 CONTINGENCY TABLE Diagnosis A of the Gender of Male Xu the R e l a t i v e Female X 1 2 Row Totals Ri Proband B X 2 1 X 2 2 R2 Column Totals Ci c 2 Grand T o t a l T 70 The number of probands expected i n each c e l l under the n u l l hypothesis was c a l c u l a t e d using the f o l l o w i n g equation: (Rj ) ( C J ) where: / ' f i j i s the expected number i n c e l l X-^  i = l , 2 , j = l , 2 ; Ri i s the t o t a l of row i ; i = l , 2 ; Cj i s the t o t a l of column j ; j = l , 2 ; T i s the grand t o t a l . The expected and observed numbers of probands i n each c e l l were t e s t e d f o r s i g n i f i c a n t d i f f e r e n c e s from the n u l l hypothesis, using the f o l l o w i n g formula: I - 0.05) where: i and j l a b e l the rows and columns of each t a b l e ; f i j i s the observed number of subjects i n row ± and column j ; f i j i s the expected number i n row t and column j under the n u l l hypothesis; -0.05 i s Yates c o r r e c t i o n f o r c o n t i n u i t y (Zar, 1984); summation i s performed f o r each c e l l i n the t a b l e . Yates c o r r e c t i o n f o r c o n t i n u i t y was used to c o r r e c t f o r the f a c t that the chi-square d i s t r i b u t i o n i s a continuous one, whereas the data being t e s t e d are counts. The t h e o r e t i c a l chi-square d i s t r i b u t i o n , to which the c a l c u l a t e d values were compared, i s a continuous one, which allows f o r a l l values of c h i -square f o r a given degree of freedom. The chi-square values c a l c u l a t e d using counts are ther e f o r e only approximations to the t h e o r e t i c a l d i s t r i b u t i o n . The 71 approximation i s a good one unless the degree of freedom i s one. Yates c o r r e c t i o n f o r c o n t i n u i t y i s used when the degree of freedom i s one (v=l) (as i n 2x2 contingency tables) to d e f l a t e the chi-square value and thereby decrease the p r o b a b i l i t y of Type I e r r o r (Zar,1984). Type I I e r r o r , or the p r o b a b i l i t y that you have a f a l s e l y p o s i t i v e r e s u l t , i s not a f f e c t e d by the c o r r e c t i o n f o r c o n t i n u i t y . As both types of e r r o r are decreased with i n c r e a s i n g sample s i z e , the p r o b a b i l i t y of e i t h e r type of e r r o r i s small due to the l a r g e study group used i n t h i s t h e s i s . . Due to the large number of chi-square comparisons ( i . e . : 20, see TABLE 3.4), the c r i t i c a l l e v e l of s i g n i f i c a n c e was c o r r e c t e d using the Bonferroni method (Elston and Johnson, 1994). A c r i t i c a l s i g n i f i c a n c e l e v e l of p=0.05 was d i v i d e d by the number of t e s t s performed (20) to give a c o r r e c t e d c r i t i c a l s i g n i f i c a n c e l e v e l of p=0.0025, to which the chi-square t e s t r e s u l t s were compared. 2.33 SAS LIFETEST Computational Formulae The SAS LIFETEST was used to c a l c u l a t e the average and standard e r r o r of the ages of onset of probands i n each d i a g n o s t i c subgroup. These values were then used as a means of comparing proband groups under the i n f l u e n c e of co-morbid a l c o h o l i s m or various f a m i l y h i s t o r i e s of p s y c h i a t r i c d i s o r d e r s . For each diagnosis, a small number of the probands' records were incomplete or the probands were unsure of the age of onset of t h e i r mood d i s o r d e r and, consequently, these probands had to be excluded from the age of onset s t a t i s t i c a l analyses. The SAS LIFETEST procedure uses the Kaplan-Meier (Kaplan and Meier, 1958) method, a non-parametric method of c a l c u l a t i n g the " S u r v i v a l Function", or the d i s t r i b u t i o n of probands that " s u r v i v e " a disease w i t h i n a study. This method req u i r e s no p r i o r i n f o r m a t i o n on the age of onset d i s t r i b u t i o n among 72 the a f f e c t e d i n d i v i d u a l s (Lee, 1992). Kaplan-Meier estimates (product l i m i t estimates) of s u r v i v a l d i s t r i b u t i o n are c a l c u l a t e d using the f o l l o w i n g formula: Sk = Pi x p 2 x p 3 . . . x p k , where: k =the year under c o n s i d e r a t i o n i n the c a l c u l a t i o n of the s u r v i v a l d i s t r i b u t i o n ; Sk =the s u r v i v a l d i s t r i b u t i o n ; Pi =the p r o p o r t i o n of probands that survive at l e a s t one year w i t h i n the study; p 2 =the p r o p o r t i o n of probands that s u r v i v e the second year given that they s u r v i v e the f i r s t year; p 3 =the p r o p o r t i o n of probands that survive the t h i r d year given that they survive the f i r s t and second years; p k =the p r o p o r t i o n of probands that survive to the Kth year ( l a s t year under study) given that they survive a l l of the previous (K-l) years. The product l i m i t estimate can be thought of as f o l l o w s : the estimate Sk i s a product of s e v e r a l "terms" and each term i n the product i s an estimate of the p r o b a b i l i t y of a proband s u r v i v i n g past time i n t e r v a l t j , given that they have survived t i l l j u s t p r i o r to that time i n t e r v a l (Lawless, 1982). For the purpose of t h i s t h e s i s , the " s u r v i v a l " of a proband r e f e r s to the age up u n t i l when one i s a f f e c t e d by a mood d i s o r d e r . For example, i f a proband's mood di s o r d e r s t a r t e d at age 25, the proband would be considered to have "surv i v e d " u n t i l age 25 i n the Kaplan-Meier c a l c u l a t i o n s . The product l i m i t estimate would be the product of a l l of the p r o b a b i l i t i e s of the proband " s u r v i v i n g " to age 25, given that he/she survived to the previous age. The SAS LIFETEST procedure c a l c u l a t e s the product l i m i t estimate, S ( t j ) of the s u r v i v a l d i s t r i b u t i o n f u n c t i o n using the f o l l o w i n g formula: 73 S(tj) = where: j i s the l a b e l of the time i n t e r v a l under c o n s i d e r a t i o n , e.g.: f o r the f i r s t year of the study, j = l ; t j i s the l i m i t i n the j t h time i n t e r v a l , i n t h i s case the age of onset of the probands. In explanation, t i i s the f i r s t age of onset considered ( i . e . : 10 years of age), t 2 i s the second age of onset considered ( i . e . : 11 years of age), and so on u n t i l t i . t i i s the age of onset of the person a f f e c t e d at the ol d e s t age i n the subgroup under c o n s i d e r a t i o n . The highest t i f o r a l l of the subgroups compared was f o r a male with Unipolar Diso r d e r - S i n g l e Episode who had an age of onset of 78, so t i f o r that p a r t i c u l a r proband group would have been 68 (since t i was f o r an age of onset of 10); nj i s the t o t a l number of probands i n the subgroup who are at r i s k of becoming a f f e c t e d by age t j . For example, i f there were 10 people at tx and 3 people became a f f e c t e d by age t 2 , then ^=10 and n2=7; dj i s the number of probands who become a f f e c t e d w i t h i n a time span l a b e l l e d by t j ( i . e . : i f 5 probands became a f f e c t e d at age t j then The product l i m i t estimate was used to determine the mean of the s u r v i v a l d i s t r i b u t i o n , or the cor r e c t e d average age of onset. The SAS LIFETEST procedure used the f o l l o w i n g formula: to=0, which r e f e r s to the assumption that a l l probands are considered unaffected at the e a r l i e s t age of onset being considered w i t h i n the study ( i . e . : at age 10). The variance of the average age of onset, a l s o known as the variance of the estimated s u r v i v a l f u n c t i o n , was c a l c u l a t e d by SAS LIFETEST using the f o l l o w i n g formula: dj=5) . where: 74 where: n and S(t j ) ( t j + 1 - t-j ) The standard d e v i a t i o n was c a l c u l a t e d by t a k i n g the square root of the variance. The SAS LIFETEST computed the average age of onset of the mood di s o r d e r of the various subgroups along with the standard e r r o r of these averages. These values were used as the ba s i s of comparison between various groups of The Z t e s t was used to compare the average ages of onset of two of the proband groups when both sample s i z e s were l a r g e r than n=50. The Z t e s t was used because, as the sample s i z e , n, gets l a r g e r , the d i s t r i b u t i o n of measured values approach those i n a normal d i s t r i b u t i o n , thereby a l l o w i n g f o r comparison of the Z t e s t r e s u l t s to the c r i t i c a l values i n a normal d i s t r i b u t i o n t a b l e (Zar, 1984). For sample s i z e s under n=50, the Student's t t e s t was used, since the t d i s t r i b u t i o n allows f o r the l a r g e r variances i n smaller samples. The computational formula f o r the Z t e s t s was as f o l l o w s : i n t e r e s t using Z t e s t s and Student's t t e s t s . 2 . 3 4 Z Test and Student 's t Test Computational Formulae Z = where: Xi i s the mean of sample i ; SE i s the standard e r r o r ; i = l , 2 . 75 Standard e r r o r s of X1 and X 2 were computed by the SAS LIFETEST, along with the average age of onset, or the "mean". The r e s u l t i n g Z values were t e s t e d f o r s i g n i f i c a n c e by comparison to the c r i t i c a l values l i s t e d on a normal d i s t r i b u t i o n t a b l e (Zar, 1984). The formula used f o r c a l c u l a t i n g the Student's t t e s t s t a t i s t i c was as fo l l o w s : SE (X7 - "X7) The degrees of freedom f o r the Student's t t e s t s were c a l c u l a t e d using the f o l l o w i n g formula: v = ( n x + n 2 ) - 2 , where: ni i s the sample s i z e i n group one; n 2 i s the sample s i z e i n group two. The r e s u l t i n g Student's t values were t e s t e d f o r s i g n i f i c a n c e by comparison to the c r i t i c a l values l i s t e d on a t d i s t r i b u t i o n t a b l e (Zar, 1984) fo r the appropriate degrees of freedom. The Z t e s t s and the Student's t t e s t s were two sided t e s t s , a l l o w i n g f o r d i f f e r e n c e s from the t h e o r e t i c a l mean i n e i t h e r d i r e c t i o n . The c r i t i c a l s i g n i f i c a n c e l e v e l used f o r the two sided Z t e s t s and Student's t t e s t s was alpha=0.025. 2.35 Formula f o r 95% Confidence Interva ls Confidence i n t e r v a l s were c a l c u l a t e d f o r the percentage of a l c o h o l i c probands compared to the t o t a l number of each proband type. As w e l l , 76 confidence i n t e r v a l s were c a l c u l a t e d f o r the percentage of a l c o h o l i c f i r s t degree r e l a t i v e s of the proband groups compared to the number of r e l a t i v e s i n t o t a l f o r each proband group. The 95% confidence i n t e r v a l s were c a l c u l a t e d using the f o l l o w i n g formula: P =Percentage of A l c o h o l i c s n =Total Number of Probands (or R e l a t i v e s ) q =1 - p Z0.025=1 - 96 (Zar, 1984) 2.36 Z t e s t Formula f o r Comparisons of Gender D i f fe rences Comparisons of gender d i f f e r e n c e s were done using a Z t e s t f o r comparisons of proportions (Zar, 1984). The computational formulae f o r the Z t e s t comparisons of the gender proportions were as f o l l o w s : P + where: Z = P i ~ where: p = X , + X X q = 1 - p n ( + n j . P i = X - 0.5 X. + 0.5 and where: 77 Xi=the number of alcoholic.probands (or r e l a t i v e s ) i n sample group i ; n =the t o t a l number of probands (or r e l a t i v e s ) i n sample group i ; i =1,2 where the data p e r t a i n i n g to the smaller of the two percentages are always l a b e l l e d as group 1; 0.5 =continuity c o r r e c t i o n ( u s u a l l y used i n comparisons of proportions (Zar, 1984)) ; Pi =the c o n t i n u i t y c o r r e c t e d percentage of a l c o h o l i c s i n the l a r g e r of the two groups under c o n s i d e r a t i o n (see above equation); P2 =the c o n t i n u i t y c o r r e c t e d percentage of a l c o h o l i c s i n the smaller of the two groups under c o n s i d e r a t i o n (see above equation). 2.37 Gender S p e c i f i c Z Test Comparisons to General Populat ion Rates The proportions of male versus female probands were compared to the gender r a t i o s observed i n the general p o p u l a t i o n . According to the w e l l accepted DSM II I - R (1987), there are f i v e male a l c o h o l i c s f o r every one female a l c o h o l i c i n the United States general population. Many stu d i e s were reviewed i n an attempt to f i n d accurate rates of alc o h o l i s m i n the general population. Several s t u d i e s , o u t l i n e d i n TABLE 2.10, found rates of alc o h o l i s m ranging from 3% to 29.3% i n males and 0.1% to 6.7% i n females. The gender s p e c i f i c rates of alc o h o l i s m from the DSM I I I - R were used f o r s e v e r a l reasons: (1) the rate was based on a la r g e community based sample of the American general population, (2) the DSM I I I - R i s a w e l l accepted manual that has been i n general use f o r s e v e r a l years, and (3) the DSM II I - R was a main source of d i a g n o s t i c c r i t e r i a during the time p e r i o d i n which the probands from t h i s study were ascertained. The DSM I I I - R - r a t e s of alcoholism are not the i d e a l ones to use with the present study group f o r one main reason: the study group used i n t h i s t h e s i s was drawn from the population i n B r i t i s h Columbia while the DSM II I - R i s based on the American general population. The rates between the two countries should not vary widely due to s i m i l a r s o c i a l s t r u c t u r e s . Using the 5:1 r a t i o given i n the DSM III-R, the gender s p e c i f i c r a t e of alco h o l i s m i n the general population was determined to be 83.3% male (compared 78 to the pr o p o r t i o n of female a l c o h o l i c s ) . The rates of alcoholism i n the proband groups were compared to -the general population rates using the above mentioned r a t i o . TABLE 2.10: SUMMARY OF STUDIES REPORTING GENDER S P E C I F I C RATIOS OF ALCOHOLISM IN THE GENERAL POPULATION Author and Year Population Gender Ratio Reported Goodwin (1971) Review of stu d i e s from f i v e European co u n t r i e s 3-5% Males 0.1-1% i n Females DSM II I - R (1987) American General Population (no s p e c i f i c s given) Males 5:1 Females Bland et (1988) a l . 3258 randomly s e l e c t e d households surveyed i n Edmonton, AB L i f e t i m e prevalence Males 29.3+1.3% Females 6.7+0.6% Helzer et (1990) a l . Data gathered from household surveys from f i v e c o u n t r i e s i n North America and A s i a L i f e t i m e prevalence Edmonton: Males 18.5% Females 3.9% Canadian (1994) P r o f i l e Data gathered from law enforcement and various r e g u l a t o r y bodies No gender s p e c i f i c r a t e s given In a d d i t i o n to the comparisons made between the proband groups, the proportions of male (versus female) f i r s t and second degree r e l a t i v e s of the probands were compared to the general population r a t e s . The computational formula f o r the Z t e s t comparisons was as f o l l o w s : 79 where p =Corrected Proportion of A l c o h o l i c s i n the Proband Group of I n t e r e s t (Compared to the pr o p o r t i o n of Female A l c o h o l i c s ) ; PD =Proportion of male A l c o h o l i c s i n the General Population (Compared to the Proportion of Female A l c o h o l i c s ) ; Q o = 1 - P D ; n =Corrected Sample S i z e ; l/2n = C o r r e c t i o n f o r C o n t i n u i t y . The c o r r e c t i o n f o r c o n t i n u i t y (l/2ri). c o r r e c t s f o r the f a c t that' the normal d i s t r i b u t i o n , to which the Z t e s t r e s u l t s were compared, i s a continuous one while the data analysed were i n the form of d i s c r e t e counts. P Q r e f e r s to two cl a s s e s of data ( i . e . : Binomial d i s t r i b u t i o n , male and female), but Z t e s t r e s u l t s are compared to a normal d i s t r i b u t i o n . The estimate provided by the Z t e s t of the standard d e v i a t i o n of the data from the t h e o r e t i c a l Binomial d i s t r i b u t i o n of P Q i s e x c e l l e n t , i f a c o r r e c t i o n f o r c o n t i n u i t y i s included ( i . e . : l/2n) ( F l e i s s , 1 9 8 1 ) . The sample s i z e (n) and the p r o p o r t i o n of male a l c o h o l i c s i n each group of i n t e r e s t (p) were co r r e c t e d f o r unequal sample s i z e s . This c o r r e c t i o n was done to ensure that the number of male a l c o h o l i c s observed i n the sample groups were accurate representations of the number expected to have been observed i f the groups were of equal s i z e . 2.38 Ana lys i s of Var iance The average ages of the f i r s t degree r e l a t i v e s of the various proband subgroups at the time of the genetic i n t e r v i e w were compared using S t a t i s t i c a l A n a l y s i s Software-Analysis of Variance, or SAS-ANOVA procedure. The average ages of f i r s t degree r e l a t i v e s of the various proband groups were compared to 80 determine whether or not d i f f e r e n c e s i n the ages of the f i r s t degree r e l a t i v e s might have had an e f f e c t on the patterns seen i n the f a m i l i e s of the proband groups. In explanation, i f one p a r t i c u l a r proband group had, on average, younger . f i r s t degree r e l a t i v e s , then we would expect fewer p s y c h i a t r i c d i s o r d e r s when compared to the older f i r s t degree r e l a t i v e s of another proband group. The SAS-ANOVA procedure t e s t s the n u l l hypothesis of e q u a l i t y of m u l t i p l e sample means, i . e . : the hypothesis of equal average ages at the time of genetic i n t e r v i e w f o r the f i r s t degree r e l a t i v e s of a l l of the proband subgroups. ANOVA i s based on the s t a t i s t i c a l property that each d e v i a t i o n of an observed datum from the grand ( t o t a l ) mean of a l l data c o l l e c t e d i s equal to the d e v i a t i o n of that datum from i t s group mean and the d e v i a t i o n of the group mean from the grand mean (Zar, 1984). In other words, ANOVA c a l c u l a t e s three sources of v a r i a t i o n between the average ages of f i r s t degree r e l a t i v e s at the time of genetic i n t e r v i e w : (1) the d i f f e r e n c e between each r e l a t i v e ' s age and the average age of the group of r e l a t i v e s as a whole, (2) the d i f f e r e n c e between each group of r e l a t i v e s ' average ages compared to the t o t a l average age of the r e l a t i v e s i n t o t a l and (3) the t o t a l v a r i a t i o n among a l l ages of r e l a t i v e s . These sources of v a r i a t i o n are used to c a l c u l a t e a F value s t a t i s t i c . The SAS-ANOVA procedure uses the f o l l o w i n g formulae: Groups Sum of Squares = Err o r Sum of Squares = T o t a l Sum of Squares Groups Sum of Squares 81 where: i= group of r e l a t i v e s , e.g.: the f i r s t degree r e l a t i v e s of male B i p o l a r I probands; j= p a r t i c u l a r data p o i n t , i . e . : r e l a t i v e number j i n group number i , r\i= sample s i z e of each c l a s s , or group of r e l a t i v e s ; N= t o t a l sample s i z e , or t o t a l number of r e l a t i v e s f o r a l l proband types. The degrees of freedom (DF) are c a l c u l a t e d d i f f e r e n t l y f o r each type of Sum of Squares, as f o l l o w s : DF f o r T o t a l Sum of Squares (Total DF) = N - 1 DF f o r Groups Sum of Squares (Groups DF) = k - 1 DF f o r e r r o r Sum of Squares (Error DF) = N - k where: k = t o t a l number of groups considered (8). The Mean Squares (MS) of the E r r o r Sum of Squares and the Groups Sum of Squares are c a l c u l a t e d as f o l l o w s : Groups MS= Groups Sum of Squares Groups DF Er r o r MS = E r r o r Sum of Squares E r r o r DF The F s t a t i s t i c i s c a l c u l a t e d using the f o l l o w i n g formula: 82 F = Groups MS E r r o r MS The F s t a t i s t i c i s compared to a t a b l e of a F d i s t r i b u t i o n using the f o l l o w i n g c r i t i c a l value: F (0.05)(1)(Groups DF)(Error DF) where: 0.05 = chosen s i g n i f i c a n c e l e v e l , 1 = s i n g l e v a r i a b l e c a l c u l a t i o n . 2.39 Tukey Test I f the r e s u l t s of an ANOVA comparison r e s u l t i n the r e j e c t i o n of a n u l l hypothesis, i t i s of t e n of i n t e r e s t to determine which of the m u l t i p l e means compared i n the ANOVA t e s t d i f f e r from the others. There are s e v e r a l m u l t i p l e comparison procedures which allow m u l t i p l e means to be compared on a p a i r w i s e b a s i s , but one of the most commonly used and r e a d i l y accepted (Zar, 1984) i s the Tukey t e s t (Tukey, 1953)(also known as the wholly s i g n i f i c a n t d i f f e r e n c e t e s t ) . The Tukey t e s t procedure t e s t s whether or not the mean of group A equals the mean of group B, where A and B r e f e r to any number of groups compared i n p a i r s ( a l l p a i r w i s e comparisons). The ANOVA t e s t f o r average ages at the time of the genetic i n t e r v i e w f o r the f i r s t degree r e l a t i v e s of the various proband groups r e s u l t e d i n the r e j e c t i o n of the n u l l hypothesis of no d i f f e r e n c e . A Tukey t e s t was performed on the various combinations of average ages of r e l a t i v e s to determine which groups of r e l a t i v e s were younger (or older) than the others. 83 The average ages of each of the groups of f i r s t degree r e l a t i v e s at the time of the genetic i n t e r v i e w were determined using the MEANS sub-procedure of SAS-ANOVA. The r e s u l t s of the ANOVA and MEANS procedures were used i n the TUKEY sub-procedure of the SAS-ANOVA package. The Tukey t e s t s t a t i s t i c , q, i s c a l c u l a t e d f o r each p a i r wise comparison using the f o l l o w i n g formula: SE where: q = Tukey t e s t s t a t i s t i c ; X B = mean of s p e c i f i c group B (or A); X B> X A f o r every p a i r w i s e comparison. SE / s f f 1 + 1 \ J 2 \ n A n B J where: SE = Standard E r r o r (approximation due to unequal sample s i z e s (Zar, 1984)); s 2 = E r r o r Mean Square from ANOVA procedure (see Section 2.38); n = sample s i z e A, B = group reference. The Tukey t e s t s t a t i s t i c , q, i s compared to a t a b l e of studentized s t a t i s t i c s f o r the f o l l o w i n g c r i t i c a l value: q(0.05)(v)(k) where: 0.5 = chosen s i g n i f i c a n c e l e v e l ; v = E r r o r Degrees of Freedom =N - K; k = number of groups under comparison. 84 The s i g n i f i c a n c e l e v e l (0.05) i s the p r o b a b i l i t y of encountering at l e a s t one Type I e r r o r during the course of the m u l t i p l e comparisons undertaken i n the Tukey t e s t . I t i s not the p r o b a b i l i t y of committing a Type I e r r o r f o r a s i n g l e comparison. In other words, f o r the Tukey t e s t , the 0.05 s i g n i f i c a n c e l e v e l i s the experiment-wise e r r o r r a t e r a t h e r than the comparison-wise e r r o r r a t e (Zar, 1984). The type I I e r r o r r a t e i s unknown f o r the Tukey t e s t but i s higher than f o r ANOVA. In both types of t e s t s , Type I I e r r o r decreases as sample s i z e increases (Zar, 1984). •' 85 3 RESULTS 3.1 Sample Analyzed Of 1045 probands i n the Mood Disorders Service Database, 691 met the e l i g i b i l i t y c r i t e r i a f o r t h i s t h e s i s . TABLE 3.1 summarizes the a l c o h o l i c and mood d i s o r d e r status of the 691 e l i g i b l e probands. TABLE 3.3 gives the a l c o h o l i c status of 4040 f i r s t degree r e l a t i v e s of each subgroup of i n t e r e s t . TABLE 3.1: DISTRIBUTION OF PROBANDS BY GENDER AND DIAGNOSES Dx of Sex of Tot a l # of Ale o •6 of Ale To t a l A l e Z t e s t Proband Proband # i n Probands Probands Sex Sex Result ++, Group Group Proband i n Group in Group Ratio Ratio p value Group . (with = D (M: F) (M: F) UP Male 176 8 4 . 55 + 3 .09 1: 1 .81 1.33:1 Z=1.371, (SE+R) Female 310 6 1. 94 + 1 . 53 p=0.0853 UP-SE Male 69 1 1. 45 + 2 .82 1: 1 .24 1:2 Z=0.183, Female 85 2 2. 35 + 3 .22 p=0.4286 UP-R Male 107 7 6. 52 + 4 . 08 1: 2 .21 1.75:1 Z=1.937, * Female 225 4 * 1. 78 + 1 . 73 p=0.0262 BP Male 66 1 1. 52+2 . 95 1: 2 .06 1:5 Z=0.401, (I+II) Female 139 5 3. 60 + 3 . 10 p=0.3446 BP I Male 47 1 2. 13+4 . 13 1: 2 . 02 1:4 Z=0.129, Female 97 4 4 . 12 + 3 . 96 p=0.4483 BP I I Male 19 0 0 1: 2 .16 n/a n/a Female 42 1 2. 38 + 4 . 61 Where Alc=probands r a t e d as d e f i n i t e or probable a l c o h o l i c s ; BP(I+II)=Bipolar I and B i p o l a r I I ; BP I=Bipolar I; BP II=Bipolar I I ; CI=95% Confidence I n t e r v a l s ; Dx=Diagnosis; #=Number; Sex Ratio=refers to the r a t i o of the t o t a l number of probands or the r a t i o of the number of a l c o h o l i c probands; UP(SE+R)=Unipolar-Single Episode and Unipolar -Recurrent; UP-SE=Unipolar-Si n g l e Episode; UP-R=Unipolar-Recurrent. * = S i g n i f i c a n t Result; ++=Z t e s t comparisons of proportions of male versus female a l c o h o l i c s . 86 The proportions of male versus female a l c o h o l i c s f o r each mood di s o r d e r proband subgroup were compared using Z t e s t s . Although not d i r e c t l y r e levant to the t h e s i s o b j e c t i v e s (see Section 1.1), the p a t t e r n of gender and diagnosis s p e c i f i c proportions of a l c o h o l i c s was of i n t e r e s t . The r e s u l t s of comparing the proportions of male versus female a l c o h o l i c s f o r each proband subgroup are shown i n TABLE 3.1. The r e s u l t s of the p r o p o r t i o n a l Z t e s t s showed s i g n i f i c a n t d i f f e rences f o r the a l c o h o l i c Unipolar-Recurrent probands only (Z=1.937, p=0.0262). Since there was a 1:2.21 r a t i o of male to female Unipolar-Recurrent probands i n t o t a l , i t was expected that there would be an excess of female a l c o h o l i c s i n t h i s proband group. However, there was an excess of male a l c o h o l i c s (1.75:1, males to females).. This p a t t e r n was not observed f o r any of the other proband groups. The proportions of male and female mood di s o r d e r probands with co-morbid al c o h o l i s m were compared to the general population r a t e s . The general p o p u l a t i o n r a t e f o r a l c o h o l i s m was taken as a r a t i o of f i v e males to every female (see Section 2.37 and TABLE 2.10 f o r more d e t a i l , and j u s t i f i c a t i o n f o r t h i s r a t i o ) . When the proportions of a l c o h o l i c males and females f o r each proband group were compared to the proportions observed i n the general population, the f o l l o w i n g r e s u l t s were observed (see TABLE 3.2): the only proband group that had a d i f f e r e n t p r o p o r t i o n of a l c o h o l i c s from that expected i n the general p o p u l a t i o n was the male B i p o l a r I group, i n that there were s i g n i f i c a n t l y fewer a l c o h o l i c male B ipo la r I probands than expected (Z=2.706, p=0.0034). The low number of male B i p o l a r I probands with a l c o h o l i s m may be r e p r e s e n t a t i v e of the p o s s i b i l i t y that probands with a l c o h o l i s m and mood dis o r d e r s may be more i n c l i n e d to seek help at an a l c o h o l treatment center rather than at a p s y c h i a t r i c c l i n i c (Sadovnick et a l . , 1994). 87 TABLE 3.2: SUMMARY OF COMPARISONS OF PROPORTIONS OF MALE AND FEMALE ALCOHOLICS IN PROBAND GROUPS VERSUS THE GENERAL POPULATION Dx of Proband Group Z Test Result p Value Unipolar (SE+R) 1.286 p=0.0985 Un i p o l a r - S i n g l e Episode 1.431 p=0.0764 Unipolar-Recurrent 0.224 p=0.4129 B i p o l a r (I & II) 1.163 p=0.1230 B i p o l a r I 2.706 p=0.0034 * B i p o l a r I I n/a + Where Dx=Diagnosis; * = S i g n i f i c a n t Result; (SE+R)=Single Episode & Recurrent; +=Comparison could not be done as no a l c o h o l i c male B i p o l a r I I probands. One of the o b j e c t i v e s of t h i s t h e s i s was to determine whether or not the d i s t r i b u t i o n of al c o h o l i s m i n the r e l a t i v e s of the proband groups was dependent on the mood d i s o r d e r diagnosis or the gender of the proband subgroup to which the r e l a t i v e s were r e l a t e d . The comparisons made were dependent on the d i a g n o s t i c subtype and the gender of the proband to whom the r e l a t i v e s were r e l a t e d . Z t e s t s were used to compare the gender r a t i o s of the a l c o h o l i c f i r s t degree r e l a t i v e s of the proband groups (TABLE 3.3). Several s i g n i f i c a n t d i f f e r e n c e s were found: (a) There was a 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 rence i n the gender r a t i o of f i r s t degree r e l a t i v e s of male Unipolar-S ing le Episode probands. The r a t i o of t o t a l number of r e l a t i v e s of the male U n i p o l a r - S i n g l e Episode probands was 1:1.02 (males to females), while the r a t i o of a l c o h o l i c r e l a t i v e s was 17:1 (males to females) (Z=3.655, p=0.0001). The gender r a t i o of the t o t a l number of r e l a t i v e s was almost equal, while the number of male a l c o h o l i c r e l a t i v e s was much.higher than the number of female a l c o h o l i c r e l a t i v e s f o r the male U n i p o l a r - S i n g l e Episode probands. 88 TABLE 3.3: DISTRIBUTION OF FIRST DEGREE RELATIVES BY THEIR ALCOHOLIC STATUS Dx of Sex of Sex of To t a l # of o "5 of Ale To t a l A l e Z t e s t Proband Proband Rel # of Ale Rel Sex Sex Result, Group Group Rel Rel (with Ratio Ratio p value CI) (M: F) (M: F) UP-SE Male Male 201 ' 17 8 .46+3 85 1:1.02 17 :1 Z=3.655, * (n=69) Female 205 1 0 .49+0 96 p=0.0001 Female Male 270 23 8 . 52 + 3 33 1.13:1 4.6:1 Z=2.981, * (n=85) Female 240 5 2 .08 + 1 81 p=0.0014 UP-R Male Male 301 20 6 . 64 + 2 81 1.02:1 1.67:1 Z=1.214, (n=107) Female 295 12 4 . 07 + 2 25 p=0.1131 Female Male 728 70 9 . 62 + 2 14 1:1.08 5:1 Z=5.825, * (n=225) Female 672 14 2 . 08 + 0 11 p<0.0001 BP I Male Male 131 6 4 .58 + 3 58 1.13:1 2 : 1 Z=0.493, (n=47) Female 116 3 2 .5 9+2 89 p=0.3121 Female Male 260 31 11 . 92 + 3 94 1:1.05 6.2:1 Z=4.475, * (n=97) Female 273 5 1 . 83 + 1 59 p<0.0001 BP I I Male Male 73 4 5 .48 + 5 22 1.33:1 4 :1 Z=0.,595, (n=19) Female 55 1 1 . 82 + 3 33 p=0".'277 6 Female Male 114 9 7 .89+4 95 1.08:1 2.25:1 Z=1.009, (n=42) Female 106 4 3 . 77 + 3 63 p=0.1562 Where A l c = A l c o h o l i c , R e l a t i v e s were Considered A l c o h o l i c i f They Met Research Diagnostic C r i t e r i a f o r D e f i n i t e or Probable Alcoholism; BP I=Bipolar I; BP II=Bipolar I I ; CI=95% Confidence I n t e r v a l s Dx=Diagnosis; #=Number; *= S i g n i f i c a n t Result; Rel=Relatives, f i r s t degree only; Sex Ratio=refers to the r a t i o of the t o t a l number of R e l a t i v e s or the r a t i o of the number of a l c o h o l i c R e l a t i v e s ; UP-SE=Unipolar-Single Episode; UP-R=Unipolar-Recurrent. (b) There was a 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 rence i n the gender r a t i o of f i r s t degree r e l a t i v e s of female Unipolar-S ingle Episode probands. The r a t i o of t o t a l number of r e l a t i v e s of the female U n i p o l a r - S i n g l e Episode probands was 1.13:1 (males to females), while the r a t i o of a l c o h o l i c r e l a t i v e s was 4.6:1 (males to females) (Z=2.981, p=0.0014). The gender r a t i o of the t o t a l number of r e l a t i v e s was almost equal, while the number of male a l c o h o l i c r e l a t i v e s was much higher than the number of female a l c o h o l i c r e l a t i v e s f o r the female U n i p o l a r - S i n g l e Episode probands. 89 (c) There was a 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 rence i n the gender r a t i o of f i r s t degree r e l a t i v e s of female Unipolar-Recurrent probands. The r a t i o of t o t a l number of r e l a t i v e s of the female Unipolar-Recurrent probands was 1.08:1 (males to females), while the r a t i o of a l c o h o l i c r e l a t i v e s was 5:1 (males to females) (Z=5.825, p<0.0001). The t o t a l number of male r e l a t i v e s and the number of male a l c o h o l i c r e l a t i v e s were both higher than the number of female r e l a t i v e s of female Unipolar-Recurrent probands. (d) There was a 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 rence i n the gender r a t i o of f i r s t degree r e l a t i v e s of female B ipo la r I probands. The r a t i o of t o t a l number of r e l a t i v e s of female B i p o l a r I probands was 1:1.05 (males to females), while the r a t i o of a l c o h o l i c r e l a t i v e s was 6.2:1 (males to females) (Z=4.475, p<0.0001). The t o t a l number of male r e l a t i v e s was s l i g h t l y lower than the number of female r e l a t i v e s , while the number of male a l c o h o l i c r e l a t i v e s was much higher f o r the female B i p o l a r I probands. The r e s u l t s of comparisons presented i n TABLE 3.3 i n d i c a t e that there i s an excess of male a l c o h o l i c s i n the f i r s t degree r e l a t i v e s of probands. The r e s u l t s are e s p e c i a l l y strong f o r female probands and e s p e c i a l l y f o r the female Unipolar-Recurrent group. The Unipolar-Recurrent group i s w e l l defined whereas, the U n i p o l a r - S i n g l e Episode group i s more heterogeneous i n that some probands w i l l stay as U n i p o l a r - S i n g l e Episode, but s e v e r a l w i l l e v e n t u a l l y convert to Unipolar-Recurrent. For t h i s reason there i s more emphasis or confidence i n the r e s u l t s of the comparisons of the r e l a t i v e s of the Unipolar-Recurrent proband group. The p r o p o r t i o n of a l c o h o l i c s i n the f i r s t degree r e l a t i v e s of probands were compared to the proportions i n the general p o p u l a t i o n (general population rates according to the DSM III-R, 1987, see Section 2.37 and TABLE 2.10). These comparisons were done to determine i f the excess male a l c o h o l i c s , seen i n the f i r s t degree r e l a t i v e s of various proband groups, was simply an e f f e c t 90 of the excess male a l c o h o l i c s i n the general p o p u l a t i o n as a whole. The r e s u l t s of the Z t e s t comparisons between the genders of the f i r s t degree r e l a t i v e s of the various proband groups are presented i n TABLE 3.4. The only s i g n i f i c a n t d i f f e r e n c e observed was that t h e r e was a s i g n i f i c a n t l y l o w e r p r o p o r t i o n o f male a l c o h o l i c f i r s t d e g r e e r e l a t i v e s o f male U n i p o l a r - R e c u r r e n t p r o b a n d s t h e n e x p e c t e d f r o m t h e g e n e r a l p o p u l a t i o n r a t e s (Z=2.969, p=0.0015). TABLE 3.4: SUMMARY OF COMPARISONS OF PROPORTIONS OF ALCOHOLICS IN THE FIRST DEGREE RELATIVES OF PROBAND GROUPS VERSUS THE GENERAL POPULATION Diagnosis of Gender of Z Test p Value Proband Group Proband Group Result U n i p o l a r - S i n g l e Male 0 972 p=0 1660 Episode Female 0 135 p=0 4443 Unipolar -Recurrent • Male 2 969 p=0 0015 * Female 0 109 p=0 4562 B i p o l a r I Male 1 028 p=0 1515 Female 0 345 p=0 3632 B i p o l a r I I Male 0 226 p=0 4090 Female 1 094 p=0 1379 Where * = S i g n i f i c a n t Result. Along with the gender p r o p o r t i o n comparisons between the f i r s t degree r e l a t i v e s , and comparisons to the general population, the average ages at the time of the genetic i n t e r v i e w were compared between the various groups of r e l a t i v e s . These comparisons, although not d i r e c t l y r e l e v a n t to the t h e s i s o b j e c t i v e s , were undertaken to ensure that any patterns seen i n l a t e r analyses were not simply due to d i f f e r e n c e s between the average ages of the f i r s t 91 degree r e l a t i v e s of the probands. The average ages of the f i r s t degree r e l a t i v e s are presented i n TABLE 3.5. The average ages of the f i r s t degree r e l a t i v e s at the time of the genetic i n t e r v i e w were compared using SAS-ANOVA (see Section 2.38 f o r d e t a i l ) . A s t a t i s t i c a l l y s i g n i f i c a n t r e s u l t of d i f f e rences between the average ages at the time of genet ic interv iew f o r the f i r s t degree r e l a t i v e s of the proband groups was found (Fg.osd) (7) (3093)=4 • 67, p<0.0001). TABLE 3.5: AVERAGE AGES AT THE TIME OF GENETIC INTERVIEW FOR FIRST DEGREE RELATIVES OF PROBANDS Diagnosis of Proband Group Gender of Proband Group Average Ages of R e l a t i v e s (+/-F i r s t Degree Standard Deviation) U n i p o l a r - S i n g l e Male 50. 92 + 16 . 13 Episode Female 48 . 03 + 16 .73 Unipolar-Recurrent Male 50. 09 + 15 .79 Female 51. 51 + 16 . 62 B i p o l a r I Male 47 . 44 + 17 .27 Female 48 . 55 + 16 .31 B i p o l a r I I Male 47 . 79 + 14 .19 Female 46. 56 + 16 .75 The average ages of the f i r s t degree r e l a t i v e s at the time of the genetic i n t e r v i e w were compared on a p a i r wise b a s i s using the Tukey t e s t . The Tukey t e s t i s a m u l t i p l e comparison t e s t that allows one to determine which of the average ages of the f i r s t degree r e l a t i v e s d i f f e r e d from the others. The f i r s t degree r e l a t i v e s of Unipolar-Recurrent females were found to be s i g n i f i c a n t l y o lder than the f i r s t degree r e l a t i v e s of : (a) Unipolar-S ing le Episode females [p<0.05]; (b) B ipo la r I females [p<0.05]; (c) B ipo la r I males [p<0.05]; and (d) B ipo l a r II females [p<0.05]. Only the s i g n i f i c a n t l y 92 d i f f e r e n t comparisons are presented here due to the la r g e number of comparisons preformed. This r e s u l t i s not due to the average ages of the proband groups themselves as the average ages of the Unipolar-Recurrent females are not s i g n i f i c a n t l y o l d e r than any of the other proband groups. In f a c t , Unipolar-Recurrent females were found to be s i g n i f i c a n t l y younger than Unipolar males and U n i p o l a r - S i n g l e Episode females (see Section 3.23, TABLE 3.13). The older average age of the f i r s t degree r e l a t i v e s of the Unipolar-Recurrent female probands may have had an e f f e c t on the patterns seen i n the analyses presented l a t e r i n t h i s t h e s i s i n that fewer p s y c h i a t r i c d i s o r d e r s may be present i n the "younger" r e l a t i v e s simply due to t h e i r , on average, l e s s exposure time, rat h e r than due to any genetic or non-genetic e f f e c t . S i m i l a r to the analyses preformed on the f i r s t degree r e l a t i v e s of the probands, the gender r a t i o s were compared between the various groups of second degree r e l a t i v e s of the probands. These comparisons were done to determine whether or not the gender r a t i o patterns i n the second degree r e l a t i v e s were dependent on the gender or d i a g n o s t i c subtype of the proband to which the r e l a t i v e s were r e l a t e d . The same degree of care that was used i n the ascertainment and pedigree a n a l y s i s of the f i r s t degree r e l a t i v e s of the proband groups was a l s o used i n the c o l l e c t i o n of informat i o n on the second degree r e l a t i v e s . The d i s t r i b u t i o n of the 6299 e l i g i b l e second degree r e l a t i v e s of the various proband groups i s shown i n TABLE 3.6. The gender r a t i o s of second degree r e l a t i v e s with versus without al c o h o l i s m were compared f o r the various groups of second degree r e l a t i v e s of the probands. There were s e v e r a l s i g n i f i c a n t d i f f e r e n c e s observed: (a) There was a 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 rence i n the gender r a t i o of a l c o h o l i c second degree r e l a t i v e s of female Unipolar-S ing le Episode 93 probands. The r a t i o of t o t a l number of r e l a t i v e s of female U n i p o l a r - S i n g l e Episode probands was 1.05:1 (males to females), while the r a t i o of a l c o h o l i c r e l a t i v e s was 7.3:1 (males to females) (Z=3.534, p=0.0002). The t o t a l number of male r e l a t i v e s and the number of male a l c o h o l i c r e l a t i v e s were both higher than the number of female r e l a t i v e s f o r female U n i p o l a r - S i n g l e Episode probands. TABLE 3 . 6 : DISTRIBUTION OF SECOND DEGREE RELATIVES BY THEIR ALCOHOLIC STATUS Dx of Proband Group Sex of Proband Group Sex of Rel T o t a l # of Rel # of Ale Rel % of A l e Rel (with CI) T o t a l Sex Ratio (M:F) Ale Sex Ratio (M:F) Z t e s t Result, p value UP-SE Male Male 316 11 3 .48+2 02 1:1.02 n/a n/a (n=69) Female 322 0 n/a Female Male 465 22 4 .73+1 93 1.05:1 7.3:1 Z=3.534, * (n=85) Female 444 3 0 . 68 + 0 76 p=0.0002 UP-R Male Male 485 5 0 . 63+0 70 1:1.01 2.5:1 Z=0.778, (n=107) Female 490 2 0 .41 + 0 57 p=0.2217 Female Male 1127 33 2 . 93 + 0 98 1:1.00 3.7:1 Z=3.554, * (n=225) Female 1129 9 0 .80 + 0 52 p=0.0002 BP I Male Male 169 4 2 .37+2 29 1.11:1 4 :1 Z=0.779, (n=47) Female 152 1 0 . 66+1 29 p=0.2177 Female Male 423 20 4 .73+2 02 1.37:1 10:1 Z=2.977, * (n=97) Female 309 2 0 . 65+0 90 p=0.0014 BP I I Male Male 69 4 5 . 80 + 5 52 1:1.32 n/a n/a (n=19) Female 91 0 n /a Female Male 149 3 2 .01+2 25 1:1.07 n/a n/a (n=42) Female 159 0 n/a Where A l c = A l c o h o l i c ; BP I=Bipolar I; BP II=Bipolar I I ; CI=95% Confidence I n t e r v a l s Dx=Diagnosis; #=Number; Rel=Second Degree R e l a t i v e s ; UP-SE=Unipolar-Si n g l e Episode; UP-R=Unipolar-Recurrent. (b) There was a 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 rence i n the gender r a t i o of a l c o h o l i c second degree r e l a t i v e s of female Unipolar-Recurrent 94 probands. The r a t i o of t o t a l number of r e l a t i v e s of female Unipolar-Recurrent probands was ne a r l y equal, while the r a t i o of a l c o h o l i c r e l a t i v e s was 3.7:1 (males to females) (Z=3.554, p=0.0002). In the r e l a t i v e s of the female Unipolar-Recurrent probands, the number of male a l c o h o l i c r e l a t i v e s was s i g n i f i c a n t l y higher than the number of female a l c o h o l i c r e l a t i v e s despite the nea r l y equal gender r e p r e s e n t a t i o n of the r e l a t i v e s i n t o t a l . (c) There was a 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 ence i n the gender r a t i o of a l c o h o l i c second degree r e l a t i v e s of female B ipo la r I probands. The r a t i o of t o t a l number of r e l a t i v e s of female B i p o l a r I probands was 1.37:1 (males to females), while the r a t i o of a l c o h o l i c r e l a t i v e s was 10:1 (males to females) (Z=2.977, p=0.0014). For the female B i p o l a r I probands, the t o t a l number of male r e l a t i v e s and the number of male a l c o h o l i c r e l a t i v e s were both higher than the number of female r e l a t i v e s . TABLE 3.7: SUMMARY OF COMPARISONS OF PROPORTIONS OF ALCOHOLICS IN THE SECOND DEGREE RELATIVES OF PROBANDS VERSUS IN THE GENERAL POPULATION Diagnosis of Proband Group Gender of Proband Group Z Test Result p Value U n i p o l a r - S i n g l e Male n/a + Episode Female 0.278 p=0.3897 Unipolar-Recurrent Male 0.328 p=0.3707 Female 0.609 p=0.2709 B i p o l a r I Male 0.339 p=0.3669 Female 0.174 p=0.4325 B i p o l a r I I Male n/a + Female n/a + Where +=Comparisons not performed as no female second degree r e l a t i v e s with alcoholism. The proportions of a l c o h o l i c s i n the second degree r e l a t i v e s of the probands were compared to the proportions observed i n the general population 95 (rates according to the DSM III-R, 1987, see Section 2.37 f o r d e t a i l s ) . The r e s u l t s of the Z t e s t comparisons are shown i n TABLE 3.7. 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 observed i n the gender proportions of the second degree r e l a t i v e s when they were compared to the general p o p u l a t i o n . 3.2 Results of Analyses 3.21 Frequency of A l coho l i c s i n F i r s t Degree Re la t i ves of Unipolar Probands One of the o b j e c t i v e s of t h i s t h e s i s i s to determine whether or not any patterns e x i s t i n the f i r s t degree r e l a t i v e s of the proband groups with respect to gender of the r e l a t i v e , a l c o h o l i s m i n the r e l a t i v e , mood di s o r d e r diagnosis of the proband and gender of the proband. P r e v i o u s l y , gender r a t i o comparisons were presented. Another form of t e s t s were done using chi-square comparisons of "counts", as opposed to pro p o r t i o n s . In explanation, the p r e v i o u s l y described comparisons were based on proportions of r e l a t i v e s i n various groups while the chi-square comparisons r e l a t e to a c t u a l numbers of the r e l a t i v e s . Chi-square t e s t comparisons between the genders of a l c o h o l i c f i r s t degree r e l a t i v e s of both Unipolar and B i p o l a r d i s o r d e r probands are summarized i n TABLE 3.8 (see Section 3.22 f o r the r e s u l t s of the comparisons between the B i p o l a r proband groups). A c r i t i c a l s i g n i f i c a n c e l e v e l of p=0.0025 was used due to the large number of chi-square t e s t s performed (see Section 2.32). In TABLE 3.8, comparisons 1, 17 and 18 s p e c i f i c a l l y address the question of whether or not there are d i f f e r e n c e s i n the gender frequency of a l c o h o l i c f i r s t degree r e l a t i v e s between Unipolar proband groups. No s i g n i f i c a n t d i f f e r e n c e was found between the gender r a t i o s of the a l c o h o l i c r e l a t i v e s of male versus female Unipolar probands (comparison 1). When the u n i p o l a r proband group was d i v i d e d i n t o U n i p o l a r - S i n g l e Episode and Unipolar-Recurrent 96 subgroups (comparisons 17 and 18, r e s p e c t i v e l y ) , 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. TABLE 3.8: SUMMARY OF CHI-SQUARE COMPARISONS OF GENDER RATIOS OF ALCOHOLIC RELATIVES OF MOOD DISORDER PROBANDS Group Comparison Chi-Square S t a t i s t i c df p value 1) Sex versus r a t i o of a l c o h o l i c female UP probands. r e l a t i v e s of male 1. 256 1 p>0 50 2) Sex r a t i o of a l c o h o l i c versus female BP probands. r e l a t i v e s of male 0. 209 1 p>0 50 3) Sex versus r a t i o of a l c o h o l i c BP probands. r e l a t i v e s of UP 0. 001 1 p>0 50 4) Sex versus r a t i o s of a l c o h o l i c BP female probands. r e l a t i v e s of UP 0. 000 1 p>0 50 5) Sex versus r a t i o of a l c o h o l i c BP male probands. r e l a t i v e s of UP 0. 000 1 p>0 50 6) Sex versus r a t i o of a l c o h o l i c BP I probands. r e l a t i v e s of UP- R 0, 186 1 p>0 50 7) Sex versus r a t i o of a l c o h o l i c BP I I probands. r e l a t i v e s of UP- R 0. 041 1 p>0 50 8) Sex versus r a t i o of a l c o h o l i c BP I probands. r e l a t i v e s of UP- SE 0. 112 1 p>0 50 9) Sex versus r a t i o of a l c o h o l i c BP I I probands. r e l a t i v e s of UP- SE 1. 329 1 0.10<p<0 25 10) Sex versus r a t i o of a l c o h o l i c BP I I probands. r e l a t i v e s of. BP I 0. 293 1 p>0 50 11) Sex versus r a t i o of a l c o h o l i c r e l a t i v e s BP I female probands. of UP- R 0. 012 1 p>0 50 12) Sex versus r a t i o of a l c o h o l i c BP I male probands. r e l a t i v e s of UP- R 0 052 1 p>0 50 13) Sex versus r a t i o of a l c o h o l i c r e l a t i v e s BP I female probands. of UP- SE 0 008 1 p>0 50 14) Sex versus r a t i o of a l c o h o l i c BP I male probands. r e l a t i v e s of UP- SE 1 799 1 0.10<p<0 25 9 7 TABLE 3 8 Continued: 15) Sex versus r a t i o of a l c o h o l i c r e l a t i v e s BP I I female probands. of BP I 2 412 1 0.10<p<0.25 16) Sex versus r a t i o of a l c o h o l i c r e l a t i v e s BP I I male probands. of BP I 0 008 1 p>0.50 17) Sex versus r a t i o of a l c o h o l i c r e l a t i v e s female UP-R probands. of male 4 648 1 0.025<p<0.05 18) Sex versus r a t i o of a l c o h o l i c r e l a t i v e s female UP-SE probands. of male 0 579 1 p>0.50 19) Sex versus r a t i o of a l c o h o l i c r e l a t i v e s female BP I probands. of male 0 77 1 p>0.50 20) Sex versus r a t i o of a l c o h o l i c r e l a t i v e s female BP I I probands. of male 0 017 1 p>0.50 Where BP=Bipolar I and B i p o l a r I I ; BP I=Bipolar I; BP II=Bipolar I I ; UP=Unipolar-Single Episode and Unipolar-Recurrent; UP-R=Unipolar-Recurrent; UP-SE=Unipolar S i n g l e Episode. When comparing the o v e r a l l gender r a t i o of a l c o h o l i c f i r s t degree r e l a t i v e s of a l l Unipolar probands with that of a l l B i p o l a r probands, no 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 s were found. None of the chi-square comparisons made between the gender s p e c i f i c groups of a l c o h o l i c f i r s t degree r e l a t i v e s of probands were found to be s i g n i f i c a n t l y d i f f e r e n t from one another. In other words, there was no i n d i c a t i o n that any type of proband had more male versus female f i r s t degree r e l a t i v e s with a lcoho l i sm, when compared to any other group of r e l a t i v e s . The d i s t r i b u t i o n and proband gender r a t i o s of B i p o l a r (I and II) and Unipolar (Single Episode and Recurrent) probands with at l e a s t one a l c o h o l i c f i r s t degree r e l a t i v e are shown i n TABLE 3.9. Although not d i r e c t l y r e levant to any of the t h e s i s o b j e c t i v e s , comparisons of the proportions of probands with at l e a s t one f i r s t degree r e l a t i v e with a l c o h o l i s m were thought to be of i n t e r e s t . The gender r a t i o of probands with at l e a s t one a l c o h o l i c f i r s t degree r e l a t i v e was 1:2.17 f o r Unipolar females to males and 1:3.27 f o r 98 B i p o l a r females to males. There was a s i g n i f i c a n t d i f f e rence i n the r a t i o of female Unipolar probands with at l e a s t one a l c o h o l i c f i r s t degree r e l a t i v e compared to the r a t i o of Unipolar probands as a whole [Z=7.938, p<0.0001]. 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 the B i p o l a r probands. TABLE 3.9: GENDER RATIO OF MOOD DISORDER PROBANDS WITH AT LEAST ONE ALCOHOLIC FIRST DEGREE RELATIVE Gender of the Ratio T o t a l # of Z Test Result, Proband Group (M: F) Probands p Value Male Female Male Female Unipolar (SE+R) 35 76 1:2.17 176 310 Z=7.938, p<0. 0001 * B i p o l a r (I+II) 11 36 1:3.27 66 139 Z=1.292, p=0. 0985 Where (SE+R)= U n i p o l a r - S i n g l e Episode and Unipolar-Recurrent; (I+II)= B i p o l a r I and B i p o l a r I I ; * = S i g n i f i c a n t Result. The gender r a t i o s of a l c o h o l i c r e l a t i v e s and the comparisons between them are presented i n TABLE 3.10. Several s i g n i f i c a n t d i f f e r e n c e s were seen i n the number of male versus female a l c o h o l i c r e l a t i v e s of the various proband groups: (1) An excess of male a l c o h o l i c f i r s t degree r e l a t i v e s i n the f am i l i e s of Unipolar (Single Episode and Recurrent) males (Z=3.319; p=0.0005); (2) an excess of male a l c o h o l i c f i r s t degree r e l a t i v e s i n the f am i l i e s of Unipolar (Single Episode and Recurrent) females (Z=6.627; p<0.0001); (3) an excess of male a l c o h o l i c f i r s t degree r e l a t i v e s i n the f am i l i e s of B ipo la r (I and II) females (Z=4.477; p<0.0001). No such d i f f e r e n c e was found between the r e l a t i v e s of the male B i p o l a r probands. This f i n d i n g supports the suggestion that there are an excess of male a l c o h o l i c s i n the r e l a t i v e s of mood di s o r d e r probands. However, the proportions of a l c o h o l i c f i r s t degree r e l a t i v e s of the various proband groups 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 the proportions seen i n the general population (see TABLE 3.4). 99 TABLE 3.10: GENDER RATIO OF ALCOHOLIC RELATIVES OF MOOD DISORDER PROBANDS Dx of Sex of Sex of Tot a l # of Gender Z t e s t Proband Proband 1st Deg # of Ale Ratio of Result, Group Rel Rel Rel A l e Rel p value (M:F) Unipolar Male Male 502 37 2.. 85:1 Z=3.319, p=0 0005 * (SE+R) Female 500 13 Female Male 998 93 4.90:1 Z=6.627, p<0 0001 * Female 912 19 B i p o l a r Male Male 204 10 2.5:1 Z=1.033, p=0 1515 (I+II) Female 171 4 Female Male 374 40 4.4:1 Z=4.477, p<0 0001 * Female 379 9 Where (SE+R)= U n i p o l a r - S i n g l e Episode and Unipolar-Recurrent; (I+II)= B i p o l a r I and B i p o l a r I I . These r e s u l t s , presented i n TABLES 3.8, 3.9 and 3.10, support the suggestion that there i s an excess of alc o h o l i s m i n the male r e l a t i v e s of female probands with mood d i s o r d e r s , e s p e c i a l l y with Unipolar d i s o r d e r , not subdivided i n t o S i n g l e Episode and Recurrent forms. However, when the gender p r o p o r t i o n a l rates of a l c o h o l i c s i n the general p o p u l a t i o n were compared to the rates i n the f i r s t degree r e l a t i v e s of the probands, no excess male a l c o h o l i c r e l a t i v e s were observed (see Section 3.1). 3.22 Frequency of A l coho l i c s i n the F i r s t Degree Re la t i ves of B ipo la r I versus B ipo la r II Probands In the process of determining whether or not there e x i s t s a gender and mood di s o r d e r diagnosis s p e c i f i c p a t t e r n of alc o h o l i s m i n the r e l a t i v e s of mood di s o r d e r probands, i t was discovered that there were no 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 s between the gender r a t i o s of the a l c o h o l i c r e l a t i v e s of male and female B i p o l a r (I and II) probands. Nor were there any d i s c e r n i b l e d i f f e r e n c e s between the sex r a t i o s of the a l c o h o l i c r e l a t i v e s of 100 B i p o l a r I versus B i p o l a r I I probands (TABLE 3.8, comparisons 10, 15, 16, 19 and 20). TABLE 3.10 shows a s i g n i f i c a n t l y excessive number of male versus female a l c o h o l i c r e l a t i v e s of female B i p o l a r probands ( p r e v i o u s l y reported as Z=4.477, p<0.0001). The r a t i o s found are not strong evidence, but are suggestive of an excess of male a l c o h o l i c r e l a t i v e s i n the f a m i l i e s of female B i p o l a r probands. (There were no female a l c o h o l i c r e l a t i v e s of B i p o l a r I I probands, and consequently, t h e i r gender r a t i o s could not be c a l c u l a t e d and compared with the r e l a t i v e s of the B i p o l a r I probands (see TABLE 3.6)). There were no d i f f e r e n c e s observed when the gender proportions of a l c o h o l i c f i r s t and second degree r e l a t i v e s of the B i p o l a r probands were compared to the gender proportions of a l c o h o l i c s i n the general population (see TABLE 3.4 and 3.7). 3.23 Age of Onset Comparisons Between Probands One of the o b j e c t i v e s of t h i s t h e s i s i s to determine whether or not a f a m i l y h i s t o r y of a l c o h o l i s m (or s u i c i d e ) has an e f f e c t on the average ages of onset of mood di s o r d e r s i n probands with versus without such a f a m i l y h i s t o r y . Although not d i r e c t l y r elevant to the t h e s i s o b j e c t i v e s , the average ages of onset of the various proband groups were i n v e s t i g a t e d to determine i f they d i f f e r e d based on the mood d i s o r d e r type, gender, or on the presence or absence of co-morbid al c o h o l i s m i n the proband. Unipolar and B i p o l a r probands were subgrouped by t h e i r diagnosis and by whether or not they had a co-morbid diagnosis of a l c o h o l i s m (see TABLE 3.1). These subgroups were then used to c a l c u l a t e the average age of onset of t h e i r mood di s o r d e r using the S t a t i s t i c a l A n a l y s i s Software (SAS) LIFETEST procedure. The r e s u l t s are presented i n TABLE 3.11. These values were then 101 used to t e s t f o r d i f f e r e n c e s between the groups using the Z t e s t and the Student's t-Test. The r e s u l t s are summarized i n TABLE 3.12. The only 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 was the f o l l o w i n g : there was a s i g n i f i c a n t d i f f e rence between the average age of onset of female versus male non-alcohol ic Unipolar probands. Female Unipolar probands had a lower average age of onset (Z=2.876; p=0.0021). The analyses were repeated a f t e r f u r t h e r s u b d i v i d i n g a l c o h o l i c and non-a l c o h o l i c Unipolar and B i p o l a r probands i n t o U n i p o l a r - S i n g l e Episode, Unipolar-Recurrent, B i p o l a r I and B i p o l a r I I subgroups. The r e s u l t s of the SAS LIFETEST c a l c u l a t e d average ages of onset are presented i n TABLE 3.13. The r e s u l t s of d i f f e r e n t comparisons are summarized i n TABLE 3.14. 102 TABLE 3 . 1 1 : AVERAGE OF AGES OF ONSET OF UP AND BP PROBANDS BY THEIR ALCOHOLIC STATUS Diagnosis of Proband Group Sex of Proband Group T o t a l # of Probands # of Probands Tested Probands W/ unknown Age Onset LIFETEST Average age Onset + SE NO CO-MORBID ALCOHOLISM: Unipolar Male 168 161 7 37 93+1.18 (R+SE) Female 304 296 8 33 84+0.80 B i p o l a r Male 65 61 4 30 92+1.67 (I+II) Female 134 129 5 28 20+0.94 CO-MORBID ALCOHOLISM: Unipolar Male 8 6 2 29 50+4.22 (R+SE) Female 6 6 0 26 83+3.80 B i p o l a r Male 1 1 0 45 00 (I+II) Female 5 5 0 30 40+3.23 Where (SE+R)=Unipolar-Single Episode and Unipolar-Recurrent; (I+II)=Bipolar I and B i p o l a r I I ; A l c o h o l i c = D e f i n i t e or Probable a l c o h o l i c on the RDC s c a l e ; #=number; # of probands tested=the T o t a l Number of Probands - the Number of Probands with Unknown Age of Onset TABLE 3 . 1 2 : SUMMARY OF COMPARISONS OF AVERAGE AGES OF ONSET OF ALCOHOLIC VERSUS NON-ALCOHOLIC UP AND BP PROBANDS Group Comparisons t or Z t e s t df p value 1) Average of onset of male versus female no n - a l c o h o l i c Unipolar probands. Z=2 876 n/a p=0.0021 * 2) Average of onset of male versus female no n - a l c o h o l i c B i p o l a r probands. Z=l 413 n/a p=0.0793 3) Average of onset of male versus female a l c o h o l i c Unipolar probands. t=0 470 10 p>0.50 4) Average of onset of male a l c o h o l i c versus n o n - a l c o h o l i c Unipolar probands. t = l 926 165 0.10<p<0 20 5) Average of onset of female a l c o h o l i c versus n o n - a l c o h o l i c Unipolar probands. t = l 805 300 0.05<p<0 10 6) Average of onset of female a l c o h o l i c versus n o n - a l c o h o l i c B i p o l a r probands. t=0 653 132 p>0.50 Where Unipolar=Unipolar-Recurrent and U n i p o l a r - S i n g l e Episode; B i p o l a r = B i p o l a r I and B i p o l a r I I ; * = S i g n i f i c a n t Result. 103 TABLE 3.13: AVERAGE AGES OF ONSET OF UP-SE, UP-R, BP I AND BP 11 PROBANDS BY THEIR ALCOHOLIC STATUS Diagnosis Sex of To t a l # of Probands LIFETEST of Proband Proband # of Probands w/ Unknown Average age Group Group Probands Tested Age of Onset + SE Onset NO CO-MORBID ALCOHOLISM: UP-R Male 100 94 6 34 24+1.48 Female 221 214 7 32 28+0.89 UP-SE Male 68 67 1 43 10+1.74 Female 83 82 1 37 91+1.64 BP I Male 46 44 2 31 76+2.78 Female 93 91 2 27 4 4+0.95 BP I I Male 19 17 2 36 65+3.26 Female 41 38 3 30 03+2.27 CO-MORBID ALCOHOLISM: UP-R Male 7 5 2 31 60+4.48 Female 4 4 0 26 00+5.33 UP-SE Male 1 1 0 19 00 Female 2 2 0 28 50+6.50 BP I Male 1 1 0 45 00 Female 4 4 0 33 50+1.19 BP I I Male 0 0 0 Female 1 0 0 18 00 Where UP-R=Unipolar-Recurrent; UP-SE=Unipolar-Single Episode; BP I=Bipolar I; BP II=Bipolar I I ; A l c o h o l i c = D e f i n i t e or Probable a l c o h o l i c on the RDC s c a l e ; #=Number; # of Probands Tested=the Number of probands - the number of probands with an unknown age of onset. 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 s between the average ages of onset were found f o r the f o l l o w i n g comparisons: (a) Male, as wel l as female, Unipolar-S ingle Episode versus Unipolar-Recurrent non-alcohol ic probands had un-equal average ages of onset. In both the male (Z=3.875; p<0.0001) and the female (Z=3.028; p=0.0013) groups, the 104 probands with Unipolar-Recurrent had lower average ages of onset than probands with U n i p o l a r - S i n g l e Episode. (b) Female a l c o h o l i c versus non-alcohol ic B ipo la r I probands had un -equal average ages of onset. In t h i s case, the no n - a l c o h o l i c B i p o l a r I females had a lower average age of onset than the a l c o h o l i c B i p o l a r I females (t=3.985; df=93; p<0.001). TABLE 3.14: SUMMARY OF COMPARISONS OF SAS-LIFETEST AVERAGE AGES OF ONSET OF ALCOHOLIC VERSUS NON-ALCOHOLIC UP-SE, UP-R, BP I AND BP II PROBANDS Group Comparisons t or Z t e s t S t a t i s t i c df p value 1) Average of onset of male n o n - a l c o h o l i c UP-R versus UP-SE probands. Z=3. 875 n/a p<0.0001 * 2) Average of onset of female n o n - a l c o h o l i c UP-R versus UP-SE probands Z=3. 028 n/a p=0.0013 * 3) Average of onset of female a l c o h o l i c UP-R versus UP-SE probands. t=0. 298 4 p>0.50 4) Average of onset of male n o n - a l c o h o l i c versus a l c o h o l i c UP-R probands. t=0. 561 97 p>0.50 5) Average of onset of female n o n - a l c o h o l i c versus a l c o h o l i c UP-R probands. t = l . 163 216 0.20<p<0 50 6) Average of onset of female n o n - a l c o h o l i c versus a l c o h o l i c UP-SE probands. t = l . 405 82 0.10<p<0 20 7) Average of onset of male n o n - a l c o h o l i c BP I versus BP I I probands. t = l . 140 59 0.20<p<0 50 8) Average of onset of female n o n - a l c o h o l i c BP I versus BP I I probands. t = l . 054 127 0.20<p<0 50 9) Average of onset of female n o n - a l c o h o l i c versus a l c o h o l i c BP I probands. t=3. 985 93 p<0.001 Where UP-R=Unipolar-Recurrent; UP-SE=Unipolar-Single Episode; BP I=Bipolar I; BP II=Bipolar I I ; * = S i g n i f i c a n t Result. 105 3.24 Comparisons of Age of Onset and Current Age of Unipolar-S ingle Episode Versus Unipolar-Recurrent Probands Comparisons between U n i p o l a r - S i n g l e Episode and Unipolar-Recurrent probands (and r e l a t i v e s ) have been made i n the recent l i t e r a t u r e (see Secti o n 1.41). The f o l l o w i n g comparisons, while not; d i r e c t l y a p p l i c a b l e to the t h e s i s o b j e c t i v e s , were in c l u d e d to determine i f d i f f e r e n c e s between the average ages of the two types of Unipolar probands, at various l i f e p o i n t s , may help to c l a r i f y whether or not Unipolar d i s o r d e r i s made up of two (at l e a s t ) g e n e t i c a l l y d i s t i n c t d i s o r d e r s . The range, mean, standard e r r o r , and minimum and maximum average ages of onset f o r U n i p o l a r - S i n g l e Episode versus Unipolar-Recurrent probands, c a l c u l a t e d using the SAS MEANS procedure, are presented i n TABLE 3.15. The average ages f o r the same groups at the time of t h e i r genetic i n t e r v i e w are presented i n TABLE 3.16. The average values f o r the d i f f e r e n c e s between the two ages are presented i n TABLE 3.17. A l l of the ages were compared using Z t e s t s , to determine i f there was a d i f f e r e n c e i n the time between the age at onset of the mood d i s o r d e r and the age at the time of the genetic i n t e r v i e w f o r U n i p o l a r - S i n g l e Episode versus Unipolar-Recurrent probands. The r e s u l t s of the t e s t s are presented i n TABLE 3.18. TABLE 3.15: MEAN AGE OF ONSET OF UNIPOLAR-SINGLE EPISODE VERSUS UNIPOLAR-RECURRENT PROBANDS Diagnosis Sex T o t a l Unknown Tested Mean Age of Onset of of # of # of # of Min-Max , (Range) Mean+SE Probands Prob Prob Prob Prob ( i n Years) UP-R Male 100 7 93 13-71, (58) 33.85+1 45 Female 222 9 213 9-81, (72) 32.2 9+0 90 UP-SE Male 68 1 67 11-78, (67) 43.10+1 74 Female 83 2 81 13-77, (64) 37.69+1 64 Where UP-R=Unipolar Disorder-Recurrent; UP-SE=Unipolar Diso r d e r - S i n g l e Episode; Dx=Diagnosis; Prob=Probands. 106 TABLE 3.16: MEAN AGE OF UNIPOLAR-SINGLE EPISODE VERSUS UNIPOLAR-RECURRENT PROBANDS Diagnosis Sex To t a l Unknown Tested Mean Age of of # of # of # of Min-Max, (Range) Mean+SE Probands Prob Prob Prob Prob (i n Years) UP-R Male 100 7 93 21-78, (57) 45.68+1 40 Female 222 9 213 20-87, (67) 46.18+0 97 UP-SE Male 68 1 67 19-83, (64) 46.43+1 67 Female 83 2 81 18-79, (61) 41.54+1 0 Where UP-R=Unipolar Disorder-Recurrent; UP-SE=Unipolar Diso r d e r - S i n g l e Episode; Dx=Diagnosis; Prob=Probands. TABLE 3.17: MEAN DIFFERENCE BETWEEN THE AGE OF ONSET AND THE CURRENT AGE OF UNIPOLAR-SINGLE EPISODE VERSUS UNIPOLAR-RECURRENT PROBANDS Diagnosis Sex T o t a l Unknown Tested Mean Dif f e r e n c e of of # of # of # of Min-Max, (Range) Mean+SE Probands Prob Prob Prob Prob (i n Years) UP-R Male 100 7 93 0-42, (42) 11.83+0.98 Female 222 9 213 0-52, (52) 13.89+0.74 UP-SE Male 68 1 67 0-31, (31) 3.33+0.62 Female 83 2 81 0-28, (28) 3.85+0.64 Where UP-R=Unipolar Disorder -Recurrent; UP-SE =Unipolar D i s o r d e r - S i n g l e Episode ; Dx=Diagnosis; Prob= Probands; Age Difference=Age at Time of Interview - Age at Time of Mood Disorder Onset; #=number. The f i n d i n g s from TABLE 3.18 were as f o l l o w s : 1) A 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 rence was found between the average ages of onset of Unipolar-S ingle Episode and Unipolar-Recurrent probands of e i t he r gender [Z=2.893, p=0.0019 f o r males; Z=4.092, p<0.0001 f o r females]. Probands with Unipolar-Recurrent had lower average ages of onset than probands with U n i p o l a r - S i n g l e Episode. 2) The average ages at the time of i n t e r v i e w were not s i g n i f i c a n t l y d i f f e r e n t f o r U n i p o l a r - S i n g l e Episode versus Unipolar-Recurrent f o r probands of e i t h e r gender. 107 3) A 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 rence between the average ages of onset and the average ages a t the time of the genet ic interv iew was found f o r both genders of Unipolar-S ingle Episode versus Unipolar-Recurrent probands [Z=10.509, p<0.0001 f o r males; Z=7.357, p<0.0001 f o r females]. For both males and females, there was a much longer time span between the onset of the mood di s o r d e r and the time at which a person sought s p e c i a l i z e d help f o r Unipolar-Recurrent d i s o r d e r than there was f o r someone with U n i p o l a r - S i n g l e Episode d i s o r d e r . TABLE 3.18: SUMMARY OF COMPARISONS BETWEEN THE AGE OF ONSET, THE AGE AT INTERVIEW AND THE AGE DIFFERENCE OF UNIPOLAR-SINGLE EPISODE VERSUS UNIPOLAR-RECURRENT PROBANDS Group Comparisons Z t e s t S t a t i s t i c p value 1) Average age of onset of male UP-R versus UP-SE probands. Z=2.893 p=0 0019 * 2) Current average age of male UP-R versus UP-SE probands. Z=2.522 p=0 0059 3) Comparison of the d i f f e r e n c e between the current average age and the average age of onset of male UP-R versus UP-SE probands. Z=10.509 p<0 0001 * 4) Average age of onset of female UP-R versus UP-SE probands. Z=4.092 p<0 0001 * 5) Current average age of female UP-R versus UP-SE probands. Z=0.3476 p=0 3632 6) Comparison of the d i f f e r e n c e between the current average age and the average age of onset of female UP-R versus UP-SE probands. Z=7.357 p<0 0001 * 108 3.25 Age of Onset Comparisons Between Probands With a Family H i s to ry of A lcohol ism Versus Those Without A Family H is to ry . The t h i r d o b j e c t i v e of t h i s t h e s i s i s to determine whether or not a fa m i l y h i s t o r y of alc o h o l i s m i n the f i r s t degree r e l a t i v e s has an e f f e c t on the average ages of onset of a mood di s o r d e r i n the probands. Un i p o l a r - S i n g l e Episode, Unipolar-Recurrent, B i p o l a r I and B i p o l a r I I probands were subdivided by sex, and f u r t h e r s t r a t i f i e d by whether or not they had a f i r s t degree r e l a t i v e with alcoholism. The average age of onset r e s u l t s , c a l c u l a t e d by SAS LIFETEST, are presented i n TABLE 3.19. The r e s u l t s of comparing d i f f e r e n t groups are summarized i n TABLE 3.20. 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 any of the groups. To t e s t whether or not the la c k of d i f f e r e n c e between the groups was due to t h e i r small s i z e , the U n i p o l a r - S i n g l e Episode and Unipolar-Recurrent probands were combined, as were the B i p o l a r I and B i p o l a r I I proband groups. The d i s t r i b u t i o n of the l a r g e r groups and the r e s u l t s of SAS LIFETEST average ages of onset are presented i n TABLE 3.21. The r e s u l t s of the Z t e s t s and Student's t t e s t s on the l a r g e r subgroups are summarized i n TABLE 3.22. Even fo r these l a r g e r c a t e g o r i 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 the groups. These r e s u l t s i n d i c a t e that a f a m i l y h i s t o r y of alc o h o l i s m i n f i r s t degree r e l a t i v e s does not have an e f f e c t on the average ages of onset of mood disor d e r s i n the probands i n t h i s study. 109 TABLE 3.19: AVERAGE AGES OF ONSET OF UP-SE, UP-R, BP I AND BP II PROBANDS WITH VERSUS WITHOUT ALCOHOLIC FIRST DEGREE RELATIVES Diagnosis of Proband Group Sex of Proband Group T o t a l # of Probands # of Probands Tested Probands w/ Unknown Age Onset LIFETEST Average age Onset + SE PROBANDS WITH NO ALCOHOLIC RELATIVES: UP-SE Male 55 54 1 42 .91+2.07 Female 62 61 1 39 .26+1.69 UP-R Male 79 76 3 34 .78+1.70 Female 166 161 5 34 .02+1.18 BP I Male 39 37 2 28 .73+2.10 Female 69 68 1 27 .93+1.16 BP I I Male 15 13 2 38 .38+3.26 Female 29 28 1 29 . 85+2.46 PROBANDS WITH ALCOHOLIC RELATIVES: UP-SE Male 13 13 0 43 .92+2.60 Female 22 22 0 35 .38+4.24 UP-R Male 21 18 3 39 .10+4.03 Female 54 52 2 32 .81+2.11 BP I Male 7 7 0 28 .57+4.12 Female 24 23 1 27 .7 9+1.88 BP I I Male 4 4 0 31. 00+9.42 Female 12 10 2 30. 50+5.41 Where BP I=Bipolar I; BP II=Bipolar I I ; UP-SE=Unipolar-Single Episode; UP-R=Unipolar-Recurrent; #=Number; # of Probands Tested= the T o t a l Number of Probands - the Number of Probands with Unknown Age of Onset. 110 TABLE 3.20: SUMMARY OF COMPARISONS OF AVERAGE AGE OF ONSET DATA OF UP-SE, UP-R, BP I AND BP II PROBANDS WITH VERSUS WITHOUT ALCOHOLIC FIRST DEGREE RELATIVES Group Comparisons t or Z t e s t S t a t i s t i c df p value 1) Average of age of with versus without onset of male UP-R probands a l c o h o l i c r e l a t i v e s t=0 986 92 0.20<p<0 50 2) Average of age of with versus without onset of male UP-SE probands a l c o h o l i c r e l a t i v e s . t=0 306 65 p>0.50 3) Average of age of probands with versus onset of female UP-R without a l c o h o l i c r e l a t i v e s . Z=0 501 n/a p=0.3085 4) Average of age of onset of female UP-SE probands with versus without a l c o h o l i c r e l a t i v e s t=0 849 78 0.20<p<0 50 5) Average of age of with versus without onset of male BP I probands a l c o h o l i c r e l a t i v e s . t=0 034 42 p>0.50 6) Average of age of with versus without onset of male BP I I probands a l c o h o l i c r e l a t i v e s . t=0 741 15 0.20<p<0 50 7) Average of age of probands with versus onset of female BP I without a l c o h o l i c r e l a t i v e s . t=0 061 89 p>0.50 8) Average of age of probands with versus onset of female BP I I without a l c o h o l i c r e l a t i v e s . t=0 108 36 p>0.50 Where UP-R=Unipolar-Recurrent; UP-SE=Unipolar-Single Episode; BP I=Bipolar I; BP II=Bipolar I I . I l l TABLE 3.21: AVERAGE AGES OF ONSET OF UP AND BP PROBANDS WITH VERSUS WITHOUT ALCOHOLIC FIRST DEGREE RELATIVES Diagnosis Sex of To t a l # of Probands LIFETEST of Proband Proband # of Probands w/ Unknown Average age Group Group Probands- Tested Age of Onset + SE Onset PROBANDS WITH NO ALCOHOLIC RELATIVES: Unipolar Male 134 130 4 38 39+1.41 (R+SE) Female 228 222 6 35 50+0.99 B i p o l a r Male 54 50 4 31 24+1.86 (I+II) Female 98 96 2 29 07+1.20 PROBANDS WITH ALCOHOLIC RELATIVES: Unipolar Male 34 31 3 41 48+2.57 (R+SE) Female 76 74 2 33 70+1.93 B i p o l a r Male 11 11 0 29 45+4.03 (I+II) Female 36 33 3 29 86+2.28 Where (SE+R)=Unipolar-Single Episode and Recurrent; (I + I I ) = B i p o l a r I and B i p o l a r I I ; A l c o h o l i c = D e f i n i t e or Probable a l c o h o l i c according to the RDC sc a l e ; #=Number; # of Probands Tested= the T o t a l Number of Probands - the Number of Probands with Unknown Age of Onset. TABLE 3.22: SUMMARY OF COMPARISONS OF AVERAGE AGES OF ONSET OF UP AND BP PROBANDS WITH VERSUS WITHOUT ALCOHOLIC FIRST DEGREE RELATIVES Group Comparisons t or Z t e s t S t a t i s t i c df p value 1) Average age of onset of male UP probands with versus without a l c o h o l i c r e l a t i v e s . t=1.056 159 0 . 20<p<0.50 2) Average age of onset of female UP probands with versus without a l c o h o l i c r e l a t i v e s . Z=0.831 n/a p=0.2033 3) Average age of onset of male BP probands with versus without a l c o h o l i c r e l a t i v e s . t=0.409 59 p>0.50 4) Average age of onset of female BP probands with versus without a l c o h o l i c r e l a t i v e s . t=0.305 127 p>0.50 Where UP=Unipolar (Single Episode and Recurrent); BP=Bipolar I and B i p o l a r I I . 112 3.26 Age of Onset Comparisons Between Probands with A Family H is tory of Su ic ide Versus Those Without A Family H is tory The f o u r t h o b j e c t i v e of t h i s t h e s i s ks to determine whether or not a fam i l y h i s t o r y of s u i c i d e i n the f i r s t or second degree r e l a t i v e s of the mood dis o r d e r probands has an e f f e c t on the average ages of onset of the mood dis o r d e r i n probands. Very few mood di s o r d e r probands had f i r s t or second degree r e l a t i v e s who had committed s u i c i d e . The d i s t r i b u t i o n of the s a i d r e l a t i v e s i s shown i n TABLE 3.23. The t o t a l number of f i r s t degree r e l a t i v e s who committed s u i c i d e was 20, while the t o t a l number of second degree r e l a t i v e s who committed s u i c i d e was 19. The small number of probands with f i r s t degree r e l a t i v e s who committed s u i c i d e made the analyses presented below u n f e a s i b l e unless probands with second degree r e l a t i v e s who committed s u i c i d e were a l s o included. The inherent lower degree of ascertainment accuracy f o r second degree r e l a t i v e data may make t h i s s e c t i o n l e s s accurate. A l s o , the use of second degree r e l a t i v e data excludes the p o s s i b i l i t y of comparisons between these r e s u l t s and the r e s u l t s of other papers which use f i r s t degree r e l a t i v e data only. The data on the Unipolar and B i p o l a r probands, s t r a t i f i e d as to whether or not they had f i r s t or second degree r e l a t i v e s who had committed s u i c i d e , were used to c a l c u l a t e the average ages of onset of each subgroup. The r e s u l t s of the SAS LIFETESTs are shown i n TABLE 3.24. The values were compared using Student's t t e s t s and the r e s u l t s are shown i n TABLE 3.25. No s i g n i f i c a n t d i f f e r e n c e s were observed between any of the groups. 113 TABLE 3.23: DISTRIBUTION OF FIRST AND SECOND DEGREE RELATIVES WHO COMMITTED SUICIDE: SUBDIVIDED BY GENDER AND DIAGNOSIS OF PROBAND GROUP Diagnosis Sex of Sex of Number of R e l a t i v e s T o t a l of Proband Proband R e l a t i v e Who Committed Sui c i d e Number of Group Group F i r s t Degree Second Degree R e l a t i v e s Unipolar- MALE MALE 2 4 786 Recurrent FEMALE 0 0 785 FEMALE MALE 5 1 1855 FEMALE 1 0 1801 Unipolar- MALE MALE 0 1 517 S i n g l e FEMALE 1 1 527 Episode FEMALE MALE 5 0 735 FEMALE 0 0 684 Unipolar- MALE MALE 2 5 1303 (Recurrent FEMALE 1 1 1312 & Single FEMALE MALE 10 0 2590 Episode) FEMALE 1 0 2485 B i p o l a r I MALE MALE 2 3 300 FEMALE 0 0 268 FEMALE MALE 2 4 683 FEMALE 1 3 582 B i p o l a r I I MALE MALE 0 0 142 FEMALE 0 0 146 FEMALE MALE 0 1 263 FEMALE 1 1 265 B i p o l a r MALE MALE 2 3 442 (I and II) FEMALE 0 0 414 FEMALE MALE 2 5 946 FEMALE 2 4 847 The same t e s t s were redone with the probands f u r t h e r subdivided i n t o U n i p o l a r - S i n g l e Episode, Unipolar-Recurrent, B i p o l a r I and B i p o l a r I I groups. The SAS LIFETEST values are presented i n TABLE 3.26. The proband groups were compared using Student's t t e s t s , the r e s u l t s of which are shown i n TABLE 114 TABLE 3.24: AVERAGE AGES OF ONSET OF UP AND BP PROBANDS WITH VERSUS WITHOUT FIRST OR SECOND DEGREE RELATIVES WHO COMMITTED SUICIDE Diagnosis Sex of Tot a l # of Probands LIFETEST of Proband Proband # of Probands w/ Unknown Average age Group Group Probands Tested Age of Onset + SE Onset PROBANDS WITH NO RELATIVES WHO COMMITTED SUICIDE: Unipolar Male 159 152 7 37 99+1.22 (R+SE) Female 292 284 8 33 89+0.80 B i p o l a r Male 60 56 4 30 96+1.80 d + II) Female 123 118 5 28 20+1.01 PROBANDS WITH RELATIVES WHO COMMITTED SUICIDE: Unipolar Male 9 9 •• 0 36 89+4.46 (R+SE) Female 12 12 0 34 50+6.05 B i p o l a r Male 5 5 0 30 40+3.70 (I+II) Female 11 11 ' 0 28 18+2.56 W h e r e ( S E + R ) = b o t h S i n g l e E p i s o d e a n d R e c u r r e n t p r o b a n d s ; ( I + I I ) = b o t h B i p o l a r I a n d B i p o l a r I I p r o b a n d s ; #=Number; # o f P r o b a n d s T e s t e d = t h e T o t a l N u m b e r o f P r o b a n d s - t h e N u m b e r o f P r o b a n d s w i t h U n k n o w n A g e o f O n s e t . TABLE 3.25: SUMMARY OF COMPARISONS OF AVERAGE AGE OF ONSET DATA OF UP AND BP PROBANDS WITH VERSUS WITHOUT FIRST OR SECOND DEGREE RELATIVES WHO COMMITTED SUICIDE Group Comparisons t t e s t S t a t i s t i c df p value 1) Average of age of onset of with versus without r e l a t i v e s male UP probands who committed s u i c i d e . t=0.239 159 p>0 50 2) Average of age of onset of with versus without r e l a t i v e s female UP probands who committed s u i c i d e . t=0.100 294 p>0 50 3) Average of age of onset of with versus without r e l a t i v e s male BP probands who committed s u i c i d e . t=0.137 59 p>0 50 4) Average of age of onset of with versus without r e l a t i v e s female BP probands who committed s u i c i d e . t=0.008 127 p>0 50 Where UP=Unipolar (Single Episode and Recurrent); BP=Bipolar I and B i p o l a r I I . 115 TABLE 3 . 2 6 : AVERAGE AGES OF ONSET OF U P - S E , U P - R , BP I AND BP I I PROBANDS WITH VERSUS WITHOUT FIRST OR SECOND DEGREE RELATIVES WHO COMMITTED SUICIDE Diagnosis Sex of To t a l # of Probands LIFETEST of Proband Proband # of Probands w/ Unknown Average age Group Group Probands Tested Age of Onset + SE Onset PROBANDS WITH NO RELATIVES WHO COMMITTED SUICIDE: UP-SE Male 65 64 1 43. 34+1.81 Female 78 77 1 37 35+1.64 UP-R Male 94 88 6 34 10+1.53 Female 214 207 7 32 4 9+0.8 9 BP I Male 41 39 2 28 49+2.06 Female 84 82 2 27 13+1.02 BP I I Male 19 17 2 36 64+3.26 Female 39 36 3 30 64+2.33 PROBANDS WITH RELATIVES WHO COMMITTED SUICIDE: UP-R Male 6 6 0 36 33+6.60 Female 7 7 0 25 8 6+6.76 UP-SE Male 3 3 0 38 00+4.51 Female 5 5 0 46 60+9.10 BP I Male 5 5 0 30 40+3.70 Female 9 9 0 30 22+2.41 BP I I Male 0 o • Female 2 2 0 19 00+7.00 Where BP I=Bipolar I Disorder; BP II=Bipolar I I Disorder; UP-R=Unipolar-Recurrent; UP-SE=Unipolar-Single episode; A l c o h o l i c = D e f i n i t e or Probable a l c o h o l i c on the Research Diagnostic C r i t e r i a s c a l e ; R e l a t i v e s = f i r s t or second degree r e l a t i v e s . 116 TABLE 3.27: SUMMARY OF COMPARISONS OF AVERAGE AGE OF ONSET DATA OF UP-SE, UP-R, BP I, AND BP II PROBANDS WITH VERSUS WITHOUT FIRST OR SECOND DEGREE RELATIVES WHO COMMITTED SUICIDE Group Comparisons t t e s t S t a t i s t i c df P value 1) Average of age of onset of male Unipolar-Recurrent probands with versus without r e l a t i v e s who committed s u i c i d e . t=0. 329 92 p>0.50 2) Average of age of onset of female Unipolar-Recurrent probands with versus without r e l a t i v e s who committed s u i c i d e . t=0. 973 212 ' 0 20<p<0. 50 3) Average of age of onset of male Unipolar-S i n g l e Episode probands with versus without r e l a t i v e s who committed s u i c i d e . t = l . 100 65 0 20<p<0 50 4) Average of age of onset of female Unipolar-S i n g l e Episode probands with versus without r e l a t i v e s who committed s u i c i d e . t = l . 001 80 0 20<p<0 50 5) Average of age of onset of male B i p o l a r I probands with versus without r e l a t i v e s who committed s u i c i d e . t=0. 452 42 p>0.50 6) Average of age of onset of female B i p o l a r I probands with versus without r e l a t i v e s who committed s u i c i d e . t = l . 179 89 0 20<p<0 50 7) Average of age of onset of female B i p o l a r I I probands with versus without r e l a t i v e s who committed s u i c i d e . t = l . 577 36 0 10<p<0 20 No 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 s were found between the average ages of onset of any of the groups. From these r e s u l t s , i t appears that a fa m i l y h i s t o r y of s u i c i d e does not a f f e c t the average age of onset i n mood di s o r d e r probands w i t h i n t h i s study group. Attempted s u i c i d e s were not recorded however, and t h i s may have caused an underestimate of the e f f e c t of a fa m i l y h i s t o r y of s u i c i d e . 117 3.27 Case Studies of Probands with A Heavy Loading of Alcohol i sm i n T h e i r F i r s t and Second Degree Re la t ive s The l a s t o b j e c t i v e of t h i s t h e s i s i s to review s e v e r a l f a m i l i e s loaded with a l c o h o l i s m to determine i f any obvious patterns of p h y s i c a l or p s y c h i a t r i c d i s o r d e r s are present, aside from the preponderance of alcoholism. The d i s t r i b u t i o n of probands with greater than two a l c o h o l i c f i r s t or second degree r e l a t i v e s , s t r a t i f i e d by whether or not the proband had co-morbid alcoholism, i s shown i n TABLE 3.28. Both the f i r s t and second degree r e l a t i v e s of the probands were considered. The higher degree of accuracy p o s s i b l e with the use of f i r s t degree r e l a t i v e s only was not necessary i n t h i s case as no s p e c i f i c t e s t s were performed. The accuracy of the ascertainment and diagnosis of the second degree r e l a t i v e s was s u f f i c i e n t f o r the purposes of i d e n t i f y i n g general patterns w i t h i n the f a m i l i e s . R e l a t i v e s were cate g o r i z e d as a f f e c t e d only i f t h e i r d i s o r d e r was rated as " d e f i n i t e " or "probable" i n the Mood Disorders Service Database. The itemized case reports are presented i n Appendix B. The f a m i l i e s were qu i t e d i v e r s e i n t h e i r h i s t o r i e s , making patterns d i f f i c u l t to d i s c e r n . There d i d , however, appear to be a p a t t e r n evident i n that nine out of eleven of the probands reviewed had an a l c o h o l i c f a t h e r and three probands had an a l c o h o l i c mother. Four out of nine of the probands were p h y s i c a l l y abused, three at the hands of t h e i r a l c o h o l i c f a t h e r . A l l of the probands reviewed had r e l a t i v e s with d i s o r d e r s aside from alcoholism. These d i s o r d e r s d i d not appear to f o l l o w a p a r t i c u l a r p a t t e r n but depression, a n t i s o c i a l p e r s o n a l i t y d i s o r d e r , and drug a d d i c t i o n were qu i t e prevalent. There were no s u i c i d e s on record f o r the f i r s t or second degree r e l a t i v e s of the probands. The rate of s u i c i d e attempts was high i n r e l a t i v e s , however most of these i n d i v i d u a l s had co-morbid diagnoses of 118 depression. These data suggest that s u i c i d e attempts may be more c l o s e l y a s s o c i a t e d with depression than with a l c o h o l i s m i n these f a m i l i e s . TABLE 3.28: DISTRIBUTION OF MOOD DISORDERED PROBANDS WITH GREATER THAN TWO, THREE, FOUR OR FIVE ALCOHOLIC FIRST OR SECOND DEGREE RELATIVES Diagnosis of Sex of Number of A l c o h o l i c R e l a t i v e s : Proband Proband >2 >3 >4 >5 NON-ALCOHOLIC PROBANDS: Unipolar- Male 9 3 1 0 Recurrent Female 23 10 5 1 Unipolar- Male 6 2 0 0 S i n g l e Episode Female 10 2 1 1 B i p o l a r I Male 2 1 1 0 Female 13 4 1 1 B i p o l a r I I Male 1 1 0 0 Female 2 0 0 0 ALCOHOLIC PROBANDS: Only those above zero shown. Unipolar-R Female 2 1 1 0 Unipolar-SE Female .2 1 1 0 B i p o l a r I Female 3 1 0 0 Where R=Recurrent; SE=Single Episode; A l c o h o l i c = R e l a t i v e s Considered A l c o h o l i c i f They Met the Research Diagnostic C r i t e r i a f o r D e f i n i t e or Probable Alcoholism. 3.3 Summary of Resul ts The s t a t i s t i c a l l y s i g n i f i c a n t f i n d i n g s of t h i s study were the f o l l o w i n g : (1) When the gender proportions of a l c o h o l i c versus t o t a l number of each proband group were compared to one another, there were s i g n i f i c a n t l y more a l c o h o l i c male Unipolar-Recurrent probands than expected. However, when the 119 gender p r o p o r t i o n of a l c o h o l i c probands were compared to the proportions observed i n the general p o p u l a t i o n , t h i s d i f f e r e n c e was not observed. (2) When the gender proportions of a l c o h o l i c versus t o t a l number of f i r s t degree r e l a t i v e s of probands were compared, there was an excess of male a l c o h o l i c r e l a t i v e s of the f o l l o w i n g proband groups: (a) male U n i p o l a r - S i n g l e Episode probands; (b) female U n i p o l a r - S i n g l e Episode probands; (c) female Unipolar-Recurrent probands; (d) female B i p o l a r I probands. However, when the gender proportions of a l c o h o l i c f i r s t degree r e l a t i v e s were compared to the proportions observed i n the general p o p u l a t i o n , there were s i g n i f i c a n t l y fewer male a l c o h o l i c f i r s t degree r e l a t i v e s of Unipolar-Recurrent males than expected (compared to the population p r o p o r t i o n s ) . (3) When the average ages of the f i r s t degree r e l a t i v e s at the time of the genetic i n t e r v i e w were compared f o r the various d i a g n o s t i c and gender subtypes of probands an o v e r a l l d i f f e r e n c e between the average ages was found. S p e c i f i c a l l y , the f i r s t degree r e l a t i v e s of female Unipolar-Recurrent probands were s i g n i f i c a n t l y o l d e r than: (a) the f i r s t degree r e l a t i v e s of female U n i p o l a r - S i n g l e Episode probands; (b) the f i r s t degree r e l a t i v e s of e i t h e r gender of B i p o l a r I probands; (c) the f i r s t degree r e l a t i v e s of female B i p o l a r I I probands. 120 (4) Chi square comparisons made between the number of male versus female f i r s t degree r e l a t i v e s of d i f f e r e n t types of probands i n d i c a t e d that there was no d i a g n o s t i c subgroup of probands that had more male versus female f i r s t degree r e l a t i v e s with alcoholism, when compared to any other group of probands' r e l a t i v e s . (5) When the gender proportions of a l c o h o l i c versus t o t a l number of second degree r e l a t i v e s of probands were compared, there was an excess of male a l c o h o l i c r e l a t i v e s of the f o l l o w i n g proband groups: (a) female U n i p o l a r - S i n g l e Episode probands; (b) female Unipolar-Recurrent probands; (c) female B i p o l a r I probands. However, when the gender proportions of a l c o h o l i c second degree r e l a t i v e s of the probands were compared to the proportions observed i n the general population, no s i g n i f i c a n t d i f f e r e n c e s were observed. (6) The average ages of onset of various combinations of Unipolar and B i p o l a r proband groups were compared based on gender and whether or not the proband had co-morbid alcoholism. Several groups had s i g n i f i c a n t l y d i f f e r e n t average ages of onset: (a) female Unipolar (Single Episode and Recurrent) probands without a l c o h o l i s m had s i g n i f i c a n t l y lower average ages of onset compared to Unipolar males without alcoholism; (b) male, as w e l l as female, U n i p o l a r - S i n g l e Episode probands without a l c o h o l i s m had s i g n i f i c a n t l y higher average ages of onset compared to analogous Unipolar-Recurrent probands without a l c o h o l i s m ; (c) female B i p o l a r I probands had s i g n i f i c a n t l y higher average 121 ages of onset i f they had co-morbid alcoholism. (7) There was a s i g n i f i c a n t d i f f e r e n c e observed between the average ages of onset and the average ages at the time of the genetic i n t e r v i e w f o r both genders of U n i p o l a r - S i n g l e Episode versus Unipolar-Recurrent probands i n that U n i p o l a r - S i n g l e Episode had s i g n i f i c a n t l y l e s s time'pass between onset of t h e i r mood d i s o r d e r and t h e i r genetic i n t e r v i e w . (8) A h i s t o r y of a l c o h o l i s m i n f i r s t degree r e l a t i v e s d i d not a f f e c t the average age of onset i n r e l a t e d probands. (9) A h i s t o r y of s u i c i d e i n f i r s t or second degree r e l a t i v e s d i d not have an a f f e c t on the average age of onset i n r e l a t e d probands. 122 4 DISCUSSION 4.1 Comparison with Other Studies The number of probands, f i r s t degree and second degree r e l a t i v e s used i n t h i s study i s qui t e large i n comparison to many other s i m i l a r mood di s o r d e r studies (see TABLE 1.1, 1.4, 1.5, 1.6, 1.7, 1.8 f o r s p e c i f i c numbers). In a d d i t i o n to i t s l a r g e s i z e , s e v e r a l other f a c t o r s give t h i s study advantages over many of the mood d i s o r d e r s t u d i e s to date. F i r s t l y , the probands used i n t h i s study were a s c e r t a i n e d from i n p a t i e n t s as w e l l as o u t p a t i e n t s ; a f a c t o r that may make the r e s u l t s of t h i s study more a p p l i c a b l e to the general p o p u l a t i o n than s t u d i e s that used h o s p i t a l i z e d probands only (e.g.: Winokur and P i t t s , 1965; Winokur et a l • , 1970, 1972, 1975, 1978; Powell et a l . , 1982). The use of i n p a t i e n t s and outpa t i e n t s a l s o allowed f o r a wider spectrum of mood di s o r d e r s e v e r i t i e s to be i n c l u d e d compared to studies which used an outpatient or community based sample (e.g.: Finn et a l . , 1990; Mathew et a l . , 1993; Merikangas et a l • , 1994) . Secondly, the probands were r i g o r o u s l y interviewed and diagnosed by p s y c h i a t r i s t s and a genetic c o u n s e l l o r . The probands were diagnosed using DSM III - R (1987) and RDC ( S p i t z e r et a l . , 1978) c r i t e r i a . The accuracy of the diagnoses were t e s t e d i n randomly chosen subjects using i n t e r - r a t e r kappa s t a t i s t i c s . Few of the stu d i e s reviewed i n the I n t r o d u c t i o n chapter used such s t r i n g e n t ascertainment and d i a g n o s t i c c r i t e r i a f o r t h e i r probands. Most of the studies used l e s s w e l l accepted c r i t e r i a f o r diagnosis (e.g.: Winokur et a l . , 1970 to 1975; Dorzab et a l . , 1971), or based diagnoses on data gleaned from i n t e r v i e w i n g the probands, with no attempt to gather supportive medical records (e.g.: Smith and Rothgery, 1984; Mathew et a l . , 1993). 123 T h i r d l y , the diagnoses of r e l a t i v e s i n t h i s study were very r i g o r o u s . Whenever p o s s i b l e , the r e l a t i v e was interviewed (and diagnosed) d i r e c t l y . I f not p o s s i b l e , a consensus of symptoms was gathered from i n t e r v i e w s with m u l t i p l e f a m i l y informants. Information sheets were f i l l e d out by the r e l a t i v e (see Appendix A f o r examples), and the data was used to gather medical records on the p u t a t i v e l y a f f e c t e d f a m i l y member. The f a m i l y member was considered " d e f i n i t e l y " a f f e c t e d only i f they met the s t r i n g e n t Family H i s t o r y Research Diagnostic C r i t e r i a (Endicott et a l . , 1975) and s u f f i c i e n t medical records could be obtained to confirm any diagnoses. In comparison, many studies used only one informant, often the proband (e.g.: Hasegawa et a l . , 1991; Rush et a l . , 1995), or m u l t i p l e f a m i l y informants with no attempt to gather medical records i n support of the i n t e r v i e w based diagnoses (e.g.: Henzel et a l . , 1979; Winokur et a l . , 1995a) . In summary, the amount of data on the probands and r e l a t i v e s used i n t h i s study i s unusually large and r e p r e s e n t a t i v e of i n p a t i e n t and o u t p a t i e n t s , compared with studies of i t s type. 4.2 Proband and Re la t i ve F a m i l i a l Gender Rat ios The data on the d i s t r i b u t i o n of probands, f i r s t degree r e l a t i v e s and second degree r e l a t i v e s are shown i n TABLE 3.1, TABLE 3.3, and TABLE 3.6, r e s p e c t i v e l y . The number of probands t o t a l l e d 691, the number of f i r s t degree r e l a t i v e s t o t a l l e d 4040 and the number of second degree r e l a t i v e s t o t a l l e d 6299. The d i s t r i b u t i o n s of the proband subgroups were compared on the ba s i s of the gender r a t i o s of the t o t a l number of i n d i v i d u a l s i n each group compared to the number of a l c o h o l i c i n d i v i d u a l s , using p r o p o r t i o n a l Z t e s t s . The gender d i s t r i b u t i o n s of probands were not s i g n i f i c a n t l y d i f f e r e n t , with the exception 124 of the s i g n i f i c a n t excess of male Unipolar-Recurrent probands with co-morbid alcoholism. When the p r o p o r t i o n a l gender r a t i o s of a l c o h o l i c probands were compared to the p r o p o r t i o n a l gender r a t i o s observed i n the general population, a lower than expected p r o p o r t i o n of B i p o l a r I males with a l c o h o l i s m was observed (see TABLE 3.2). No other s i g n i f i c a n t d i f f e r e n c e s were found. The low number of male B i p o l a r I probands with a l c o h o l i s m may be r e p r e s e n t a t i v e of the p o s s i b i l i t y that probands with a l c o h o l i s m and mood dis o r d e r s may be more i n c l i n e d to seek help at an a l c o h o l treatment center r a t h e r than at a p s y c h i a t r i c c l i n i c (Sadovnick et a l . , 1994). There i s no " g e n e r a l l y accepted" ra t e of co-morbidity of a l c o h o l i s m and mood diso r d e r s so i t i s d i f f i c u l t to determine i f t h i s study sample i s a f f e c t e d by t h i s source of ascertainment b i a s . On a review of the l i t e r a t u r e a range of co-morbidity rates from 2-53% have been reported, depending on the study po p u l a t i o n ( i . e . : h o s p i t a l i z e d versus community sample) (Merikangas and Gelernter, 1990; Merikangas et a l . , 1994; Winokur et a l . , 1994; Brady and Soone, 1995). None of the studies used an experimental population that i s comparable to the one used i n t h i s t h e s i s ( i . e . : i n p a t i e n t s and o u t p a t i e n t s ) , and none of the studies d i s t i n g u i s h e d between primary versus secondary alcoholism. For these reasons i t i s d i f f i c u l t to conclude whether or not t h i s study po p u l a t i o n has a u n r e a l i s t i c a l l y low r a t e of co-morbidity between al c o h o l i s m and mood di s o r d e r s . I t appears from these r e s u l t s that there are no gender or d i a g n o s t i c s p e c i f i c patterns of co-morbid alcoholism i n t h i s study group. No comparative studies could be found to support or r e f u t e t h i s f i n d i n g i n that no studies appeared to compare the gender proportions of a l c o h o l i c s i n t h e i r study group to those observed i n the general p o p u l a t i o n . The r e s u l t s of t h i s study must the r e f o r e be considered p r e l i m i n a r y . 125 The d i s t r i b u t i o n of f i r s t degree r e l a t i v e s was q u i t e d i f f e r e n t : f o r many of the subtypes of probands, there was an excess number of a l c o h o l i c male r e l a t i v e s , compared to the number of female a l c o h o l i c r e l a t i v e s and the number of r e l a t i v e s i n t o t a l f o r each proband type. This p a t t e r n of an excess of male a l c o h o l i c r e l a t i v e s was most f r e q u e n t l y observed i n the f i r s t degree r e l a t i v e s of female probands (see Sect i o n 3.1 f o r more d e t a i l ) . S i m i l a r patterns were observed i n the second degree r e l a t i v e s . However, when the gender proportions of a l c o h o l i c f i r s t degree (see TABLE 3.4) and second degree (see TABLE 3.7) r e l a t i v e s were compared to the gender proportions observed i n the general population, the only s i g n i f i c a n t d i f f e r e n c e observed was i n the lower than expected (compared to the general population) p r o p o r t i o n of male a l c o h o l i c f i r s t degree r e l a t i v e s of males with Unipolar-Recurrent d i s o r d e r . When the l i t e r a t u r e was reviewed, no studies could be found that preformed s i m i l a r comparisons. The conclusions based on the comparisons to the general p o p u l a t i o n must be considered p r e l i m i n a r y f o r s e v e r a l reasons: (1) t h i s study appears to be the f i r s t to do such comparisons, (2) the gender p r o p o r t i o n of a l c o h o l i c s i n the general population i s not d e f i n i t i v e , i n that a wide range of rates of al c o h o l i s m have been reported, and (3) the study pop u l a t i o n may not be s i m i l a r enough to the population from which the general p o p u l a t i o n gender proportions were c a l c u l a t e d to make the comparisons meaningful(see Sect i o n 2.37). The r e s u l t s of t h i s study must be considered p r e l i m i n a r y , however they do r a i s e an i n t e r e s t i n g i s s u e . Several p r e v i o u s l y discussed studies found an excess number of male a l c o h o l i c r e l a t i v e s i n the f i r s t degree r e l a t i v e s of mood d i s o r d e r probands (e.g.: Dorzab et a l • , 1971; Kupfer et a l . , 1989; Winokur and C o r y e l l , 1991). None of these studies compared the proportions i n t h e i r study group to the proportions observed i n the general p o p u l a t i o n . Dorzab et a l . (1971) and Kupfer et a l . (1989) d i d not use c o n t r o l groups at 126 a l l , but rat h e r compared t h e i r proband groups 'to one another. Winokur and C o r y e l l (1991) used two d i f f e r e n t c o n t r o l groups f o r comparison: (1) a group of " p s y c h o s o c i a l " c o n t r o l s from another study, and (2) a group of acquaintances of the r e l a t i v e s of the probands i n the study. This leads to the suggestion that the excess male r e l a t i v e s observed i n these studies may be erroneous and may simply represent the excess rat e of male a l c o h o l i c s observed i n the general population. The r e s u l t s of t h i s study i n d i c a t e that there are 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 the gender proportions of a l c o h o l i c f i r s t or second degree r e l a t i v e s of t h i s study's mood d i s o r d e r probands compared to the general population p r o p o r t i o n s . These r e s u l t s suggest that there are no gender s p e c i f i c genetic or non-genetic f a c t o r s common to the e t i o l o g y of mood disor d e r s and alc o h o l i s m w i t h i n these f a m i l i e s . 4.3 Diagnosis and Gender S p e c i f i c F a m i l i a l Rates of A lcohol ism The data on the mood d i s o r d e r probands and t h e i r f i r s t degree r e l a t i v e s , contained i n TABLE 3.1 and TABLE 3.3, were compared using chi-square t e s t s . The r e s u l t s of the chi-square t e s t s , summarized i n TABLE 3.8, show no s i g n i f i c a n t d i f f e r e n c e s between any of the groups of r e l a t i v e s compared on the bas i s of mood di s o r d e r diagnosis and gender of proband to whom they were r e l a t e d . As p r e v i o u s l y mentioned, s e v e r a l studies have found an excess number of a l c o h o l i c male r e l a t i v e s of female (as opposed to male) Unipolar probands (Kupfer et a l . , 1989; Winokur and C o r y e l l , 1991). In co n t r a s t , Winokur- et a l . (1970 and 1971), and Cadoret and Winokur (1973), found an excess of male a l c o h o l i c r e l a t i v e s of Unipolar probands of e i t h e r gender, ra t h e r than s p e c i f i c a l l y i n the r e l a t i v e s of female Unipolar probands. The support f o r a 127 gender s p e c i f i c excess of a l c o h o l i c s i n the f a m i l i e s of Unipolar probands i s f u r t h e r confounded by two studies which observed no evidence of t h i s p a t t e r n (Spring and Rothgery, 1984; Merikangas et a l . , 1985). Support f o r the f i n d i n g of no s i g n i f i c a n t d i f f e r e n c e s between the gender d i s t r i b u t i o n s of a l c o h o l i c f i r s t degree r e l a t i v e s of e i t h e r gender of B i p o l a r proband can be seen i n the s i m i l a r r e s u l t s observed i n the f o l l o w i n g s t u d i e s : Dunner et a l . (1979), Hensel et a l . (1979), Andreason et a l . (1987), Winokur et a l . (1995a). In contrast to these s t u d i e s , Winokur and Reich (1970) found a s t a t i s t i c a l l y s i g n i f i c a n t excess of male a l c o h o l i c r e l a t i v e s of B i p o l a r probands of e i t h e r gender. The previous discussed s t u d i e s i n d i c a t e that the preponderance of evidence supports the hypothesis that the gender r a t i o of a l c o h o l i s m i n f i r s t degree r e l a t i v e s i s not dependent on the mood d i s o r d e r diagnoses or genders of the probands to whom the r e l a t i v e s are r e l a t e d . The f i n d i n g s of t h i s study support t h i s hypothesis and i n d i c a t e that there are not gender s p e c i f i c genetic or non-genetic f a c t o r s r e s p o n s i b l e f o r a common e t i o l o g y between alc o h o l i s m and mood di s o r d e r s w i t h i n these f a m i l i e s . 4.4 Age of Onset Comparisons Between Proband Groups The SAS LIFETEST c a l c u l a t e d average age of onset of the Unipolar (both Single Episode and Recurrent) and B i p o l a r (both I and II). groups are shown i n TABLE 3.11. The r e s u l t s of the Z t e s t and the Student's t-Test comparisons between the gender and diagnosis s t r a t i f i e d groups are summarized i n TABLE 3.12. Female Unipolar (Single Episode and Recurrent) probands had s t a t i s t i c a l l y s i g n i f i c a n t l y lower average ages of onset than male probands with s i m i l a r diagnoses (TABLE 3.12, comparison 1). This f i n d i n g was not s u r p r i s i n g as i t i s g e n e r a l l y accepted that female Unipolar probands tend to 128 have lower average ages of onset than male probands (DSM III-R, 1987; RDC, 1978). The n o n - a l c o h o l i c Unipolar and B i p o l a r probands were d i v i d e d i n t o U n i p o l a r - S i n g l e Episode, Unipolar-Recurrent, B i p o l a r I and B i p o l a r I I subgroups; the average ages of onset data are presented i n TABLE 3.13. The r e s u l t s of the Z t e s t and the Student's t t e s t comparisons of the new subgroups are summarized i n TABLE 3.14. Several d i f f e r e n c e s were found between the smaller subgroups. F i r s t l y , probands of both genders with Unipolar-Recurrent d i s o r d e r had s i g n i f i c a n t l y lower average ages of onset than probands with U n i p o l a r - S i n g l e Episode d i s o r d e r (TABLE 3.14, comparison 1 f o r males; comparison 2 f o r females). Due to the r e l a t i v e l y recent s u b d i v i s i o n of depression i n t o s i n g l e episode and recurrent forms, few stud i e s have compared them (summarized i n TABLE 1.8), so i t i 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 t h i s study i n l i g h t of the l i t e r a t u r e . However, Unipolar-Recurrent d i s o r d e r has been found to have a lower average age of onset than U n i p o l a r - S i n g l e Episode by se v e r a l d i f f e r e n t groups (DSM III-R, 1987; Bland et a l . , 1986; Cassano et a l . , 1993; Merikangas et a l . , 1994) . Secondly, no d i f f e r e n c e i n the average ages of onset were found f o r B i p o l a r I versus B i p o l a r I I probands of e i t h e r gender (TABLE 3.14, comparison 7 f o r males; comparison 8 f o r females). Despite the q u i t e recent s u b d i v i s i o n of B i p o l a r d i s o r d e r i n t o Type I and Type I I , there are s t u d i e s that support the f i n d i n g of s i m i l a r average ages of onset between the two types (Heun and Maier, 1993; McMahon et a l . , 1994). 4.5 E f f e c t of Co-morbid Alcohol i sm on Average Ages of Onset i n Probands TABLE 3.11 shows the average ages of onset, while TABLE 3.12 shows the Z t e s t and Student's t t e s t r e s u l t s f o r Unipolar (Single Episode and Recurrent) 129 and B i p o l a r (I and II) probands with versus without co-morbid alcoholism. No d i f f e r e n c e i n the average ages of onset were observed f o r any of the proband groups when compared on the ba s i s Of whether of not they had co-morbid alcoholism. This r e s u l t was s u r p r i s i n g , due to previous f i n d i n g s that co-morbid al c o h o l i s m may exacerbate or even cause a mood d i s o r d e r episode (Schuckit, 1986; Winokur et a l . , 1995). Unfortunately, n e i t h e r of these s t u d i e s i n v e s t i g a t e d average ages of onset data. No d i r e c t support of the f i n d i n g s of t h i s study could be found, so the r e s u l t s must be considered p r e l i m i n a r y . Despite the absence of support, these r e s u l t s suggest that a l c o h o l i s m and mood dis o r d e r s do not have a common genetic e t i o l o g y . When proband groups with versus without co-morbid a l c o h o l i s m were compared, dependent on gender and diagnosis of the proband, an i n t e r e s t i n g p a t t e r n was observed. When male and female Unipolar probands had co-morbid alcoholism, they no longer d i f f e r e d i n t h e i r average ages of onset (TABLE 3.12, comparison 3), i n contrast to the s i g n i f i c a n t d i f f e r e n c e s observed between the genders when co-morbid a l c o h o l i s m was not present. Further, there were no s i g n i f i c a n t d i f f e r e n c e observed i n the average ages of onset of female or male probands with U n i p o l a r - S i n g l e Episode versus Unipolar-Recurrent i f they were co-morbidly a l c o h o l i c , i n cont r a s t to the r e s u l t s seen between s i m i l a r proband groups without alcoholism. I t appears that co-morbid al c o h o l i s m may lower the age of onset of Unipolar d i s o r d e r , i n both genders, to the point where the average ages of onset no longer d i f f e r between genders. Neither supportive, nor unsupportive f i n d i n g s could be found i n the l i t e r a t u r e , so t h i s c onclusion must be considered p r e l i m i n a r y . The Unipolar and B i p o l a r proband groups were subdivided and re-compared. The average ages of onset and the Z t e s t and Student's t t e s t comparisons between U n i p o l a r - S i n g l e Episode, Unipolar-Recurrent, B i p o l a r I and B i p o l a r I I 130 subgroups are presented i n TABLE 3.13 and TABLE 3.14, r e s p e c t i v e l y . From TABLE 3.13 i t can be seen that some subgroups contained one, or l e s s , proband. Due to t h i s reason, there were no comparisons made that r e q u i r e d data on the f o l l o w i n g subgroups: male U n i p o l a r - S i n g l e Episode probands, male B i p o l a r I probands, male B i p o l a r I I probands or female B i p o l a r I I probands. The only 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 i n average ages of onset f o r probands with versus without co-morbid a l c o h o l i s m was observed f o r female B i p o l a r I probands (TABLE 3.14, comparison 9). This observation was s u r p r i s i n g because of the f i n d i n g of no d i f f e r e n c e between these groups when B i p o l a r I and B i p o l a r I I were combined (TABLE 3.12, comparison 6). Female B i p o l a r I probands with co-morbid a l c o h o l i s m were found to have higher average ages of onset than female B i p o l a r I probands without al c o h o l i s m . This observation can not be supported by any f i n d i n g s i n the l i t e r a t u r e due to the apparent absence of s i m i l a r s t u d i e s . From the r e s u l t s l i s t e d above, i t appears that co-morbid a l c o h o l i s m does not have a strong e f f e c t on the age of onset of mood d i s o r d e r s , except i n B i p o l a r I females. I t i s d i f f i c u l t to say at t h i s point why co-morbid al c o h o l i s m a f f e c t s the average ages of onset i n B i p o l a r I females only, r a t h e r than i n mood di s o r d e r probands i n general. One p o s s i b l e e x p lanation i s that B i p o l a r I may be g e n e t i c a l l y a s s o c i a t e d with a l c o h o l i s m to a greater extent than the other mood d i s o r d e r s . However, t h i s suggestion does not e x p l a i n the gender s p e c i f i c e f f e c t observed and i s not supported i n the l i t e r a t u r e (see Section 1.44). The stronger e f f e c t of co-morbid a l c o h o l i s m i n B i p o l a r I females could be due to s o c i e t a l f a c t o r s that r e s u l t i n females seeking help f o r a l c o h o l i s m r e l a t i v e l y sooner than males. This may r e s u l t i n an e a r l i e r , and more accurate estimate of the age of onset of B i p o l a r I d i s o r d e r and co-morbid a l c o h o l i s m i n these female probands. However, i f t h i s were t r u e , we would expect a "stronger e f f e c t " of co-morbid a l c o h o l i s m to be seen i n a l l 131 female probands. This r e s u l t i s unexplained at' t h i s point and may be erroneous or simply due to the small number of B i p o l a r I probands with co-morbid alcoholism. 4.6 Age Comparisons Between Unipolar-S ingle Episode and Unipolar-Recurrent Probands The range, mean, standard e r r o r , and minimum and maximum age f o r Un i p o l a r - S i n g l e Episode versus Unipolar-Recurrent probands were c a l c u l a t e d at se v e r a l d i f f e r e n t l i f e p o i n t s . These s t a t i s t i c s are shown f o r the f o l l o w i n g : (i) the average ages of onset of mood di s o r d e r , shown i n TABLE 3.15, ( i i ) the average ages at the time of the genetic i n t e r v i e w , shown i n TABLE 3.16, and ( i i i ) the average values f o r the d i f f e r e n c e s between the two ages, shown i n TABLE 3.17. A l l of the d i f f e r e n t ages were compared using Z t e s t s , the r e s u l t s of which are summarized i n TABLE 3.18. A l l of the t e s t s were done to determine whether or not a d i f f e r e n c e e x i s t e d between U n i p o l a r - S i n g l e Episode and Unipolar-Recurrent probands over the age s t r a t a mentioned i n the previous paragraph. Several things were found. F i r s t l y , as expected (see Table 3.14 and Section 4.5), the average ages of onset of Unipolar-Recurrent probands were found to be s t a t i s t i c a l l y s i g n i f i c a n t l y lower than the average ages of onset of U n i p o l a r - S i n g l e Episode probands, f o r both genders (TABLE 3.18, comparison 1 f o r males; comparison 4 f o r females). The second f i n d i n g was of no 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 i n the average ages at the time of i n t e r v i e w f o r e i t h e r Unipolar-S i n g l e Episode or Unipolar-Recurrent probands (TABLE 3.18, comparison 2 f o r male; comparison 5 f o r females). T h i r d l y , there was there was a s t a t i s t i c a l l s i g n i f i c a n t l y longer time span between the average ages of onset of the mood di s o r d e r and the average ages at which probands sought s p e c i a l i z e d help f o r 132 Unipolar-Recurrent d i s o r d e r , than there was f o r U n i p o l a r - S i n g l e Episode d i s o r d e r , f o r both genders of probands (TABLE 3.18, comparison 3 f o r males; comparison 6 f o r females). The s i g n i f i c a n t d i f f e r e n c e i n time between the average ages of onset and the average ages at the time of the genetic i n t e r v i e w f o r both genders and types of Unipolar probands r a i s e s an i s s u e . The s h o r t e r time span between the average ages of onset and the average ages at which the U n i p o l a r - S i n g l e Episode probands sought help i n d i c a t e s that some of the probands i d e n t i f i e d as having U n i p o l a r - S i n g l e Episode may a c t u a l l y have Unipolar-Recurrent that has not had time to recur. Any "Single Episode" probands that are a c t u a l l y "Recurrent" would, n a t u r a l l y , a f f e c t the r e s u l t s observed. This problem i s d i f f i c u l t to overcome unless l o n g i t u d i n a l s t u d i e s are undertaken. One such study by Merikangas et a l . (1994) found a s t a t i s t i c a l l y s i g n i f i c a n t p r o p o r t i o n of U n i p o l a r - S i n g l e Episode probands had a recurrence of t h e i r depression over the course of the ten year study. A study by Cassano et a l . (1993) f u r t h e r supports the contention that many probands diagnosed with U n i p o l a r - S i n g l e Episode may a c t u a l l y have Unipolar-Recurrent that has not had time to recur. The f i n d i n g s by Merikangas et a l . (1994), Cassano et a l . (1993) and t h i s study a l l suggest that comparisons between types of depression must consider p o s s i b l e changes i n diagnoses over time. This l i n e of t h i n k i n g could extend to the suggestion t h a t , given a s u f f i c i e n t amount of time, a l l U n i p o l a r - S i n g l e Episode diagnoses w i l l become Unipolar-Recurrent. I t i s u n l i k e l y , however, that there i s only one true type of Unipolar d i s o r d e r , due to the preponderance of evidence that depression i s made up of s e v e r a l d i f f e r e n t types (DSM III-R, 1987; RDC, 1978; Bland et a l . , 1986; Cassano et a l . , 1989; Cassano et a l . , 1993; Merikangas et a l . , 1994). However, any e f f e c t of i n c o r r e c t l y diagnosed U n i p o l a r - S i n g l e Episode probands, although d i f f i c u l t to detect over the span of most s t u d i e s , must be considered when drawing any 133 conclusions. Further, any U n i p o l a r - S i n g l e Episode proband group must be considered to be more heterogeneous when compared to an Unipolar-Recurrent proband group. This i s due to the p r o b a b i l i t y that s e v e r a l of the Unipolar-S i n g l e Episode probands w i l l experience another episode of depression and t h e i r Unipolar d i s o r d e r w i l l thereby evolve i n t o Unipolar-Recurrent. Despite these d i s c l a i m e r s , the r e s u l t s of t h i s study support the hypothesis that U n i p o l a r - S i n g l e Episode and Unipolar-Recurrent are s i g n i f i c a n t l y d i f f e r e n t c o n d i t i o n s with d i f f e r e n t l i f e p a t t e r n s , d i f f e r e n t ages of onset and d i f f e r e n t environmental and/or genetic f a c t o r s i n v o l v e d i n t h e i r t r a n s m i s s i o n . 4.7 E f f e c t of A Family H is tory of A lcohol ism on The Average Ages of Onset of A Mood Disorder i n Probands TABLE 3.19 contains the average ages of onset r e s u l t s of probands with U n i p o l a r - S i n g l e Episode, Unipolar-Recurrent, B i p o l a r I or B i p o l a r I I , s t r a t i f i e d by whether or not they had a f i r s t degree r e l a t i v e with a l c o h o l i s m . The r e s u l t s of the Z t e s t and Student's t t e s t comparisons of the proband groups based on t h e i r f a m i l y h i s t o r y are summarized i n TABLE 3.20. 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 any of the groups compared. To t e s t whether or not the la c k of d i f f e r e n c e between the groups was due to t h e i r small s i z e , the four proband groups were combined i n t o two, a Unipolar (Single Episode and Recurrent) group and a B i p o l a r (I and II) group. The average ages of onset of the new groups are shown i n TABLE 3.21, while the r e s u l t s of the Z t e s t and Student's t t e s t comparisons are summarized i n TABLE 3.22. Even with the new, l a r g e r proband groups, 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. The l a c k of any s i g n i f i c a n t d i f f e r e n c e between mood d i s o r d e r proband groups with versus without a l c o h o l i c f i r s t degree r e l a t i v e s i n d i c a t e s that 134 a l c o h o l i s m and mood di s o r d e r s may not be as s o c i a t e d w i t h i n f a m i l i e s . At the very l e a s t , t h i s r e s u l t i n d i c a t e s that a f a m i l y h i s t o r y of al c o h o l i s m does not a f f e c t mood d i s o r d e r probands' average ages of onset i n t h i s study group. No recent studies could be found to support these f i n d i n g s . However, t h i s f i n d i n g was ( i n d i r e c t l y ) not supported by s i m i l a r s t u d i e s which support a common genetic e t i o l o g y between mood di s o r d e r s and alc o h o l i s m (see TABLE 1.4 and 1.5). The l a c k of an e f f e c t of a f a m i l y h i s t o r y of alc o h o l i s m on the age of onset of a mood di s o r d e r may be due to se v e r a l t h i n g s . F i r s t l y , the la c k of d i f f e r e n c e may be because there i s no genetic r e l a t i o n s h i p between mood dis o r d e r s and alc o h o l i s m w i t h i n f a m i l i e s . Secondly, the r e s u l t s may have been d i l u t e d by the d i f f i c u l t i e s i m p l i c i t i n the i d e n t i f i c a t i o n of a l c o h o l i c s w i t h i n f a m i l i e s . A l c oholism i s a s e c r e t i v e disease and many f a m i l i e s may under report the extent of an a l c o h o l problem. As w e l l , most a l c o h o l i c s never rec e i v e treatment f o r t h e i r disease, making a RDC " d e f i n i t e " diagnosis impossible. These f a c t o r s , added together, may have l e d to probands erroneously c a t e g o r i z e d as having no a l c o h o l i c r e l a t i v e s . T h i r d l y , the average age of onset of a mood d i s o r d e r i n a proband group may not be a v a l i d means of i d e n t i f y i n g genetic f a c t o r s r e l a t e d to mood di s o r d e r s e v e r i t y , onset or f a m i l i a l t r a n s m i s s i o n . With these three d i s c l a i m e r s i n mind, the r e s u l t s of t h i s p r e l i m i n a r y study suggest that f a m i l i a l a l c o h o l i s m does not have a measurable e f f e c t on mood di s o r d e r s e v e r i t y , as measured by average ages of onset. 135 4.8 E f f e c t of A Family H i s t o r y of Su ic ide on the Average Ages of Onset of A Mood Disorder i n Probands The d i s t r i b u t i o n of the small number of f i r s t or second degree r e l a t i v e s who had committed s u i c i d e i s shown i n TABLE 3.23. Both f i r s t and second degree r e l a t i v e s were included i n t h i s s e c t i o n of the study due to the small number of r e l a t i v e s who completed committing s u i c i d e (see Section 3.26 f o r more d e t a i l ) . The average ages of onset of the Unipolar and B i p o l a r probands, s t r a t i f i e d as to whether or not they had f i r s t or second degree r e l a t i v e s who had committed s u i c i d e , are shown i n TABLE 3.24. The r e s u l t s of the Z t e s t and Student's t t e s t comparisons between the groups, based on the fa m i l y h i s t o r y of the proband group, are shown i n TABLE 3.25. No s i g n i f i c a n t d i f f e r e n c e s were observed between the groups. The same t e s t s were redone with the probands subdivided i n t o Unipolar-S i n g l e Episode, Unipolar-Recurrent, B i p o l a r I and B i p o l a r I I groups. The average ages of onset r e s u l t s are shown i n TABLE 3.26 and the Student's t t e s t comparisons are shown i n TABLE 3.27. Again, no 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 s were found. Upon a l i t e r a t u r e review, no studies were found that i n v e s t i g a t e d the e f f e c t s of a fam i l y h i s t o r y of s u i c i d e , so comparisons could not be made between the r e s u l t s of t h i s study and previous f i n d i n g s reported i n the l i t e r a t u r e . From the r e s u l t s i n TABLE 3.24 through 3.27, i t appears that a fa m i l y h i s t o r y of s u i c i d e i s not ass o c i a t e d with lower average ages of onset i n those probands with, versus those without, such a f a m i l y h i s t o r y . However, the nature of s u i c i d e may have caused f a l s e l y negative r e s u l t s . In t h i s study, r e l a t i v e s where counted as s u i c i d e v i c t i m s only i f they completed committing s u i c i d e , i . e . : s u i c i d e attempts were not considered. I f s u i c i d e s and s u i c i d e 136 attempts were considered i n t h i s s e c t i o n , the r e s u l t s may have been q u i t e d i f f e r e n t . C e r t a i n l y , at the very l e a s t , many more of the probands would have been considered to have a p o s i t i v e f a m i l y h i s t o r y of s u i c i d e (or attempted s u i c i d e ) . Consideration of r e l a t i v e s who attempted s u i c i d e was not done because many s u i c i d e attempts are " c r i e s f o r help" r a t h e r than true attempts to k i l l oneself. The i n c l u s i o n of r e l a t i v e s who attempted s u i c i d e was b e l i e v e d to introduce too high a f a c t o r of e r r o r to be considered. 4.9 Cha rac t e r i s t i c s of Fami l ies Loaded with A lcoho l i sm. A small case study was done to i d e n t i f y any f a m i l i a l patterns of mental or p h y s i c a l i l l n e s s i n the f a m i l i e s of mood di s o r d e r probands with a heavy loa d i n g of alc o h o l i s m i n t h e i r f i r s t and second degree r e l a t i v e s (see TABLE 3.28) . The f a m i l i e s were qu i t e diverse i n t h e i r h i s t o r i e s , making patterns d i f f i c u l t to d i s c e r n , however, s e v e r a l things were evident. F i r s t l y , there was a high number of probands with an a l c o h o l i c f a t h e r . Secondly, many of the probands were p h y s i c a l l y abused. T h i r d l y , depression, a n t i s o c i a l p e r s o n a l i t y d i s o r d e r , and drug a d d i c t i o n were q u i t e prevalent w i t h i n the f a m i l i e s . Fourthly, s u i c i d e was not prevalent i n that no f i r s t or second degree r e l a t i v e s of the probands completed committing s u i c i d e . I t appears from these observations that heavy lo a d i n g f o r a l c o h o l i s m i n f a m i l i e s helps to create an environment where many p s y c h i a t r i c d i s o r d e r s are fos t e r e d . In a d d i t i o n , i t appears that heavy lo a d i n g f o r a l c o h o l i s m w i t h i n these f a m i l i e s may r e s u l t i n males who are a l c o h o l i c and abusive to t h e i r c h i l d r e n and the c h i l d r e n i n t u r n become a l c o h o l i c or p s y c h i a t r i c a l l y i l l . 137 5 CONCLUSION The r e s u l t s presented i n t h i s study do not support the hypothesis that there i s an excess number of male a l c o h o l i c r e l a t i v e s i n the f a m i l i e s of mood di s o r d e r probands. When the gender proportions of a l c o h o l i c r e l a t i v e s of the various proband groups were compared to the gender proportions i n the general population, the only s i g n i f i c a n t d i f f e r e n c e observed was lower then expected p r o p o r t i o n of male r e l a t i v e s of male Unipolar-Recurrent probands. This study does not support the hypothesis that there i s a gender s p e c i f i c p a t t e r n of alc o h o l i s m i n the f i r s t degree r e l a t i v e s of mood di s o r d e r probands, dependent on the d i f f e r e n t d i a g n o s t i c and gender subtypes of probands to whom the r e l a t i v e s are r e l a t e d . A s i g n i f i c a n t l y excess number of male co-morbidly a l c o h o l i c Unipolar-Recurrent probands was observed i n the study group when the proband groups were compared to one another on the ba s i s of gender and mood di s o r d e r d i a g n o s i s . However, when the gender proportions of a l c o h o l i c s were compared to the gender proportions i n the general population, the only s i g n i f i c a n t d i f f e r e n c e observed was i n the lower than expected p r o p o r t i o n of male B i p o l a r I probands with co-morbid alcoholism. Together, the r e s u l t s of the previous two paragraphs i n d i c a t e that mood di s o r d e r s and alc o h o l i s m do not have a common genetic e t i o l o g y w i t h i n t h i s study group. Co-morbid al c o h o l i s m d i d not have a s i g n i f i c a n t e f f e c t on the average ages of onset i n any of the mood di s o r d e r proband groups, except f o r B i p o l a r I females. There was a higher average age of onset f o r female B i p o l a r I probands with alcoholism than there was f o r female B i p o l a r probands without alcoholism. This r e s u l t may be due to the small number of co-morbidly a l c o h o l i c B i p o l a r I probands. 138 Unipolar-Recurrent probands had s i g n i f i c a n t l y lower average ages of onset than U n i p o l a r - S i n g l e Episode probands f o r both genders. Female Unipolar probands had s i g n i f i c a n t l y lower average ages of onset than male Unipolar probands. B i p o l a r I and B i p o l a r I I d i d not have s i g n i f i c a n t l y d i f f e r e n t average ages of onset f o r e i t h e r gender. These r e s u l t s support the hypothesis that U n i p o l a r - S i n g l e Episode and Unipolar-Recurrent are d i f f e r e n t d i s o r d e r s . An a l t e r n a t e conclusion may be that U n i p o l a r - S i n g l e Episode i s a l e s s severe form of Unipolar-Recurrent d i s o r d e r , however the l i t e r a t u r e to date i n c o n s i s t e n t l y supports t h i s hypothesis. B i p o l a r I and B i p o l a r I I appear to be more s i m i l a r to one another i n terms of average ages of onset. This may i n d i c a t e that B i p o l a r I and B i p o l a r I I are not g e n e t i c a l l y d i s t i n c t d i s o r d e r s . A f a m i l y h i s t o r y of alc o h o l i s m i n f i r s t degree r e l a t i v e s d i d not have a s i g n i f i c a n t e f f e c t on the average ages of onset of the mood di s o r d e r probands. This r e s u l t i n d i c a t e s that a common genetic e t i o l o g y between al c o h o l i s m and mood di s o r d e r s may not be present i n these f a m i l i e s or may not be detectable using age of onset comparisons. A f a m i l y h i s t o r y of a f i r s t or second degree r e l a t i v e who had committed s u i c i d e d i d not have a s i g n i f i c a n t e f f e c t on the average ages of onset of mood dis o r d e r s i n any of the proband groups which were compared to analogous probands without such a fa m i l y h i s t o r y . This r e s u l t i n d i c a t e s that s u i c i d e , a l c o h o l i s m and mood di s o r d e r s do not have a common e t i o l o g y w i t h i n t h i s study group. A small case study of f a m i l i e s with at l e a s t four f i r s t or second degree r e l a t i v e s with a l c o h o l i s m revealed a heavy preponderance of p h y s i c a l abuse, a n t i s o c i a l p e r s o n a l i t y d i s o r d e r , depression and n a r c o t i c a d d i c t i o n . This study found l i t t l e evidence to support a hypothesis of a common genetic e t i o l o g y between al c o h o l i s m and mood d i s o r d e r s . This f i n d i n g i s 139 important due to the preponderance of these d i s o r d e r s i n the general p o p u l a t i o n . I t w i l l be a r e l i e f to f a m i l i e s seeking genetic c o u n s e l l i n g that a fa m i l y h i s t o r y of a l c o h o l i s m or mood di s o r d e r s does not n e c e s s a r i l y put them at increased r i s k f o r the other d i s o r d e r . 140 REFERENCES Alcoholism and A f f e c t i v e Disorders: C l i n i c a l , Genetic and Biochemical Studies, Ed. 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Did he/she ever have a period o t mors than 2 weeks of being depressed, sad, down in the dumps, not caring about anything, gui l ty , or some other bad mood l ike being anxious, irr i tanle or worried? (If yes, at what age?) 2. Did he/she have any problea with appetite, sleep (too much or too l i t t l e ) , loss of energy? 3. Did he/she lose or gain weight, pace or wring his hands, or move and speak slower than usual? 4. If yes: a) What was the nature of the mood and associated symptoas? b) Was he/she treated? c) What was the degree of impairment and course of the il lness? d) Describe other symptoms which might suggest Schizoaffective Disorder MEDICAL RECORDS yes / 'no/ pending CERTAINTY OF DIAGNOSIS possible / probable / definite 151 ID NUMBER: PROBAND LAST NAME: FIRST NAME: RELATIVE LAST NAME: FIRST NAME: RELATIONSHIP: YEAR BORN: MANIA 1. Did he/she ever have a period of f e e l i n g euphor ic , high, on top of the world , or impatient and i r r i t a b l e ? 2. Was he/she more a c t i v e , s o c i a b l e , or energet ic than usual? 3. Was he/she mor e t a l k a t i v e or jumping from one idea to another? -4. Did he/she have decreased need for s leep? 5. Did he/she fee l he/she had s p e c i a l a b i l i t i e s or powers, or could accomplish great things? h. Did he/she get involved in aany a c t i v i t i e s or become more s o c i a l l y , or sexual ly? act ive at work 7. Did he/she show poor judgement such as spending a lot of money or going in to bad business ventures? 152 It y e s : a) Hhat was the nature of the aood and assoc iated symptoms? a 1 c) What was the degree of impairment and course of the i 1 lness? d) Describe other symptoas which might suggest Schizo-Af fec t ive Di sorder . MEDICAL RECORDS yes / no / pending CERTAINTY OF DIAGNOSIS poss ib le / probable / d e f i n i t e 153 ID NUMBER: PROBAND LAST NAME: FIRST NAME: RELATIVE LAST NAME: FIRST NAME: RELATIONSHIP : . *EAR BORN: ALCOHOLISM 1. What was the nature of the d r i n k i n g problem? (How long, how often?) 2. Did he/she have any l e g a l problems Like being arrested or losing a driv e r ' s license? 3. Did he/she have any problems with health, such as DT's, blackouts, c i r r h o s i s , g a s t r i t i s ? 4. Were there problems with marriage cr. family? 5. Did i t cause any problems with work ( a b i l i t y to keep house)? 6. Did he/she lose jobs or have to give up some kind of work? 7. Was he/she ever treated for alcoholism, such as with ar.-abuse, h o s p i t a l i z e d or attending AA or some other support group? 8 . Did he/she have f i g h t s and/or lose friends? MEDICAL R E C O R D S y e s / no / p e n d i n g CERTAINTY OF D I A G N O S I S p o s s i b l e / p r o b a b l e / d e f i n i t e 154 APPENDIX B Summary of case reports on mood d isorder probands with a t l e a s t f i v e , or at l e a s t f ou r , a l c o h o l i c f i r s t or second degree r e l a t i v e s : Proband #01819: A female Unipolar-Recurrent outpatient with a p r i o r h i s t o r y of a l c o h o l abuse, an age of onset of 13 and an age at i n t e r v i e w of 21. This proband comes from a h i g h l y p h y s i c a l l y and mentally abusive f a m i l y and i s p r e s e n t l y p h y s i c a l l y abused by her partner. The a l c o h o l i c s i n her fa m i l y are her f a t h e r , two of her brothers and a l l of her mother's s i b l i n g s (two uncles and four aunts). Two of the proband's s i s t e r s were Unipolar-Recurrent; as w e l l , her mother was "depressed" and had "nerve problems". There was no fa m i l y h i s t o r y of s u i c i d e attempts, other medical c o n d i t i o n s , or other p s y c h i a t r i c d i s o r d e r s . Proband #02027: A female U n i p o l a r - S i n g l e Episode outpatient with an age of onset of 22 and an age at i n t e r v i e w of 30. The a l c o h o l i c s i n t h i s proband's f a m i l y were f i v e of her mother's s i b l i n g s (2 aunts who were al s o p o s s i b l y depressed and three uncles) and one p a t e r n a l uncle. In a d d i t i o n to the depression seen i n three maternal aunts, there was a p a t e r n a l aunt h o s p i t a l i z e d f o r U n i p o l a r - S i n g l e Episode and the proband's mother had dysthymia. There was no f a m i l y h i s t o r y of s u i c i d e s , other p s y c h i a t r i c d i s o r d e r s or medical d i s o r d e r s . Proband #01184: A female B i p o l a r I i n p a t i e n t with p r i o r h i s t o r y of a l c o h o l abuse and anxiety d i s o r d e r s and with an age of onset of 34 and an age at i n t e r v i e w of 37. The a l c o h o l i c s i n t h i s proband's f a m i l y were her f a t h e r , three brothers (one of whom was a drug a d d i c t ) , two s i s t e r s (one of whom was Unipolar-Recurrent and attempted s u i c i d e s e v e r a l times and the other of whom 155 was depressed), and two p a t e r n a l uncles. In a d d i t i o n to the two depressed, a l c o h o l i c s i s t e r s , t h i s proband a l s o had two depressed brothers. There was a fam i l y h i s t o r y of c o l i t i s , e p i l e p s y , j u v e n i l e diabetes and t h y r o i d dysfunction but no h i s t o r y of any other p s y c h i a t r i c d i s o r d e r s . Proband #02067: A female outpatient with Unipolar-Recurrent, panic d i s o r d e r and a p r i o r h i s t o r y of a l c o h o l abuse with an age of onset of 25 and an age at i n t e r v i e w of 35. The a l c o h o l i c s i n her f a m i l y were her fat h e r (who beat h i s w i f e ) , three brothers (one of whom a l s o had Unipolar-Recurrent and had made s e v e r a l s u i c i d e attempts) and a p a t e r n a l uncle. In a d d i t i o n to the depressed, a l c o h o l i c brother, the proband a l s o had three depressed s i s t e r s (one h o s p i t a l i z e d with U n i p o l a r - S i n g l e Episode, one with U n i p o l a r - S i n g l e Episode, co-morbid an x i e t y and panic d i s o r d e r and the t h i r d with depression concurrent with nervous breakdowns), and a depressed mother (who made m u l t i p l e s u i c i d e attempts). There was no fa m i l y h i s t o r y of p h y s i c a l d i s o r d e r s . F a m i l y h i s t o r i e s o f p r o b a n d s w i t h g r e a t e r t h a n f o u r a l c o h o l i c r e l a t i v e s : Proband #01722: A Unipolar-Recurrent male outpatient with an age of onset of 22 and an age at i n t e r v i e w of 45. This homosexual proband was the only one of h i s s i b l i n g s that experienced p h y s i c a l and mental abuse from h i s fa t h e r . The a l c o h o l i c s were h i s fa t h e r (who was al s o a convicted pedophile and had attempted s u i c i d e ) , two of h i s s i s t e r s (one of whom was depressed, had conduct d i s o r d e r as a c h i l d and attempted s u i c i d e many times) and h i s maternal uncle. In a d d i t i o n to the s i s t e r with a l c o h o l i s m and depression, t h i s proband had s e v e r a l other r e l a t i v e s with mood d i s o r d e r s : two s i s t e r s (one with B i p o l a r I and the other with depression, drug a d d i c t i o n and m u l t i p l e s u i c i d e attempts), and a p a t e r n a l uncle with depression. There was a fa m i l y h i s t o r y 156 of c l e f t l i p (mom and s i s t e r ) and diabetes, but no other mental or p h y s i c a l d i s o r d e r s . Proband #01074: A Unipolar-Recurrent female i n p a t i e n t with an age of onset of 34 and an age at i n t e r v i e w of 36. The a l c o h o l i c s were the proband's f a t h e r (who p h y s i c a l l y abused h i s w i f e ) , mother (who was a l s o agoraphobic and had s e v e r a l other phobias), maternal uncle, and p a t e r n a l uncle. The proband's son was diagnosed as a psychopath with a n t i s o c i a l p e r s o n a l i t y d i s o r d e r . There was no f a m i l y h i s t o r y of s u i c i d e attempts or any p h y s i c a l d i s o r d e r s . Proband #01665: A female Unipolar-Recurrent outpatient with a h i s t o r y of s u i c i d e attempts, an age of onset of 27 and an age at i n t e r v i e w of 36. This proband was r a i s e d with her s i b l i n g s i n a s e v e r e l y p h y s i c a l l y and mentally abusive and n e g l e c t f u l f o s t e r home. The a l c o h o l i c s i n her f a m i l y were her mother, her f a t h e r , and two brothers (one of whom was a l s o diagnosed with a n t i s o c i a l p e r s o n a l i t y d i s o r d e r ) . One of the proband's s i s t e r s was a drug abuser and depressed. There was no f a m i l y h i s t o r y of s u i c i d e , p h y s i c a l d i s o r d e r s or other p s y c h i a t r i c d i s o r d e r s . Proband #01252: A female Unipolar-Recurrent outpatient with a p r i o r h i s t o r y of panic d i s o r d e r and an age of onset of 36 and an age at i n t e r v i e w of 41. The a l c o h o l i c s i n t h i s proband's f a m i l y were her f a t h e r (also paranoid), her brother (who was a l s o a drug abuser), her s i s t e r and a p a t e r n a l aunt. As w e l l , the proband's mother was depressed. No other f a m i l y h i s t o r y of p h y s i c a l d i s o r d e r s , of other p s y c h i a t r i c d i s o r d e r s or of s u i c i d e attempts. Proband #01826: A female Unipolar-Recurrent outpatient with a p r i o r h i s t o r y of a n x i e t y d i s o r d e r , with an age of onset of 33 and an age at 157 i n t e r v i e w of 36. The a l c o h o l i c s i n t h i s proband's f a m i l y were two of her brothers (both of whom were a l s o drug abusers and one of whom had undiagnosed p s y c h i a t r i c problems), her pa t e r n a l uncle and her pa t e r n a l aunt (who was a l s o Unipolar-Recurrent). There was a f a m i l y h i s t o r y of diabetes (two uncles) and t h y r o i d d y s f u n c t ion (proband), but no fa m i l y h i s t o r y of s u i c i d e . Proband #11951: A male B i p o l a r I i n p a t i e n t with an age of onset of 16 and an age at i n t e r v i e w of 33. The a l c o h o l i c s i n the proband's f a m i l y were h i s f a t h e r , h i s mother, h i s brother (who was a l s o diagnosed with a n t i s o c i a l p e r s o n a l i t y disorder) and a pa t e r n a l uncle. There was no fam i l y h i s t o r y of s u i c i d e s or p h y s i c a l d i s o r d e r s . Proband #01129: A female outpatient with chronic U n i p o l a r - S i n g l e Episode and a p r i o r h i s t o r y of a l c o h o l abuse with an age of onset of 16 and an age at i n t e r v i e w of 20. The a l c o h o l i c s i n t h i s proband's f a m i l y were her fat h e r , her s i s t e r (who was a l s o depressed), her brother (who a l s o was a drug abuser), and a pa t e r n a l uncle. In a d d i t i o n to her depressed, a l c o h o l i c s i s t e r , t h i s proband had a depressed mother (who made m u l t i p l e s u i c i d e attempts), another depressed s i s t e r and a brother s e v e r e l y a f f e c t e d with b i p o l a r d i s o r d e r (also made m u l t i p l e s u i c i d e attempts). As w e l l as a drug abusing and a l c o h o l i c brother, t h i s proband a l s o had a drug abusing s i s t e r and her f a t h e r had adult onset diabetes. There was no fam i l y h i s t o r y of any other p h y s i c a l d i s o r d e r s and no h i s t o r y of nervous d i s o r d e r s . 158 

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