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Platelet monoamine oxidase type B (MAO-B) activity in psychopathy Gretton, Heather Margaret 1991

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PLATELET MONOAMINE OXIDASE TYPE B (MAO-B) ACTIVITY IN PSYCHOPATHY by HEATHER MARGARET GRETTON .Sc. (Honours), The University of Calgary, 198 A, THESIS SUBMITTED IN PARTIAL FULFILLMENT OF . THE REQUIREMENTS FOR THE DEGREE OF MASTER OF ARTS in THE FACULTY OF GRADUATE STUDIES (Department of Psychology) We accept t h i s thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA August 1991 c Heather Margaret Gretton, 1991 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 of The University of British Columbia Vancouver, Canada Date Q r A * \ M _ _ DE-6 (2/88) Abstract Studies of p l a t e l e t MAO-B a c t i v i t y have revealed a l i n k between low p l a t e l e t a c t i v i t y and psyc h i a t r i c syndromes characterized by an i n a b i l i t y to control impulses and to anticipate future consequences of behavior (Oreland, 1980; G o t t f r i e s , von Knorring, & Oreland, 1980). These c h a r a c t e r i s t i c s are fundamental to the construct of psychopathy, and we might therefore expect that psychopathy i s associated with low MAO a c t i v i t y . Indeed, some investigators have suggested that low p l a t e l e t MAO-B a c t i v i t y i s a potential marker f o r v u l n e r a b i l i t y to psychopathy (Schalling, Asberg, Edman, & Oreland, 1987). However, no study to date has d i r e c t l y examined the association between p l a t e l e t MAO a c t i v i t y and psychometrically-sound indices of psychopathy. The present study measured p l a t e l e t MAO-B a c t i v i t y i n a sample of 54 male offenders, assessed with the Psychopathy Checklist-Revised (PCL-R; Hare, 1991). PCL-R scores were not s i g n i f i c a n t l y related to l e v e l of p l a t e l e t MAO a c t i v i t y . The re s u l t s are discussed i n terms of methodological issues involved i n conducting biochemical research. i i i TABLE OF CONTENTS Abstract i i . L i s t of Tables v. Acknowledgements v i . I. Introduction I II . P l a t e l e t MAO-B as a Marker Enzyme for P s y c h i a t r i c Disorder 3 II I . Methodological Considerations 5 A. Alcoholism 6 B. Smoking 7 C. Pharmacological Treatment 8 D. Age 10 E. Sex 10 F. Diet 10 G. Race 11 IV. P l a t e l e t MAO-B A c t i v i t y and Psychopathy 12 V. The Revised Psychopathy Checklist (PCL-R) 15 VI. Purpose of the Present Study 19 VII. Method 19 A. Subjects 19 B. Procedure 20 1. Assessment of Psychopathy 21 2. Biochemical Assays 22 3. Alcohol Use Ratings 24 i v 4. Substance Use Ratings 24 5. Other L i f e s t y l e Factors 25 6. Data Analyses 26 VIII. Results 28 A. PCL-R, Demographic, and L i f e s t y l e Factors .. 28 B. PCL-R and P l a t e l e t MAO A c t i v i t y 2 8 1. Correlational Analyses 28 2. Multiple Regression 29 Analyses IX. Discussion 32 References 38 Appendix A 48 Appendix B 52 V L i s t of Tables Table 1. Group Comparisons on Demographic/Lifestyle Measures 27 Table 2. Correlations for PCL-R, Factor 1, Factor 2, Demographic/Lifestyle Variables and P l a t e l e t MAO a c t i v i t y 3 0 Table 3. Multiple Regression - P l a t e l e t MAO A c t i v i t y 31 v i Acknowledgements I would l i k e to thank my supervisor, Dr. Robert Hare, for h i s guidance and support throughout t h i s project, and for i n s p i r i n g me with his enthusiasm for research. I would also l i k e to thank my committee members, Dr. B. Gorzalka and Dr. D. Papageorgis. Special thanks to my partner i n crime, Theresa Newlove, for her labour and commitment to t h i s project. I g r a t e f u l l y acknowledge the collaborative e f f o r t s of Dr. Peter Yu, Dr. Bruce Davis, and Dr. A. Boulton from Neuropsychiatry Research Unit (NRU) at the University of Saskatchewan, who served as expert consultants to the project, and who assisted i n the biochemical analyses. Thanks to Adelle Forth, Steve Hart, E l s i e DeVita, and Susan Nurse for t h e i r assistance. Special thanks to a l l of my family, Andrew, and Marcy, f o r t h e i r steadfast support and encouragement. 1 I. Introduction Recent research has focussed on gaining a better understanding of the neurochemical bases of p s y c h i a t r i c disorder. Monoamine Oxidase (MAO), a mitochondrial enzyme responsible for the oxidative deaminatiori of endogenous neurotransmitter amines as well as oxidative monoamines, seems to be la r g e l y under genetic control and stable over time. Human blood p l a t e l e t MAO a c t i v i t y i s more accessible f o r measurement than brain MAO. Because of i t s a c c e s s i b i l i t y and r e l a t i v e s t a b i l i t y over time, i t has been studied extensively as a possible peripheral marker for c o n s t i t u t i o n a l v u l n e r a b i l i t y to psychopathology. Two c a t a l y t i c a l l y active forms of MAO a c t i v i t y have been distinguished, d i f f e r i n g i n t h e i r substrate s p e c i f i c i t y and i n h i b i t o r s e n s i t i v i t y . MAO-A displays greater a f f i n i t y for amine neurotransmitters 5-hydroxytryptamine (5-HT) and norepinephrine, and i s se n s i t i v e to i n h i b i t i o n by c l o r g y l i n e . MAO-B oxidizes tryptamine, phenylethylamine and benzylamine, and i s s e n s i t i v e to i n h i b i t i o n by deprenyl and pargyline. Tyramine and dopamine are substrates for both forms (Brown, Powell, & Craig, 1980; Murphy, 1978, Edwards, 1980 for review). Human l i v e r and brain express high l e v e l s of both MAO-A and MAO-B. MAO-B i s l o c a l i z e d i n neuronal c e l l bodies i n regions containing serotonergic neurons, including the raphe complex and the nucleus c e n t r a l i s superior. MAO-A i s found i n catecholamine-containing neurons 2 such as the nucleus locus coeruleus and c e l l s scattered i n the commissural and s o l i t a r y n u c l e i . P l a t e l e t s , lymphocytes and mononuclear leukocytes, a l l appear to contain MAG—B but no detectable MAO-A. Human p l a t e l e t MAO, l i k e other tissue monoamine oxidases, appears to be primarily located i n the mitochondria. Because of findings of an association between serotonin turnover and MAO a c t i v i t y i n ce r t a i n parts of the brain (Adolfsson et a l , 1978), i t has been speculated that both brain and p l a t e l e t MAO a c t i v i t y , as well as serotonin turnover i n the ce n t r a l nervous system (CNS), r e f l e c t some stable c h a r a c t e r i s t i c of the serotonin system, and that low serotonin turnover might be relat e d to v u l n e r a b i l i t y to psychopathology. Some further support for a connection between p l a t e l e t MAO a c t i v i t y and serotonergic turnover i n the CNS comes from findings of p o s i t i v e c o r r e l a t i o n s between p l a t e l e t MAO a c t i v i t y and sp i n a l f l u i d concentrations of dopamine and seratonin metabolites, homovanillic acid (HVA) and 5-HIAA, i n normals (Oreland et a l , 1981). The r e l a t i o n between p l a t e l e t MAO a c t i v i t y and MAO a c t i v i t y i n the mammalian brain has not been established (Fowler et a l , 1982). I t has been hypothesized that p l a t e l e t and brain MAO a c t i v i t y and part of the central monoaminergic system i s regulated by a common, possibly genetic factor (Oreland & Fowler, 1982) . Several studies have indicated that p l a t e l e t MAO a c t i v i t y i s at lea s t i n part under genetic control. V a r i a t i o n i n a c t i v i t y 3 per unit p l a t e l e t from blood samples taken from the same ind i v i d u a l s over time appears to be r e l a t i v e l y small and stable over short periods (1-2 weeks), and long periods (8-10 weeks) (Murphy et a l , 1976; Fowler et a l , 1982). Evidence from family (Pandey, Dorus, Shaughnessy, & Davis, 1979) and twin (Hussein, Sindarto, & Goedde, 1980) studies indicates that much of the s t a b i l i t y i n monoamine oxidase a c t i v i t y within i n d i v i d u a l s i s gen e t i c a l l y determined. L i t t l e i s known about the genetics of MAO; however recent evidence indicates that the genes encoding monoamine oxidases-A and B are located i n close proximity on the X chromosome (Pintar, 1981; Kochersperger, Parker, S i c i l i a n o , Darlington, & Denney, 1986) . I I . P l a t e l e t MAO as a Marker Enzyme for P s y c h i a t r i c Disorder In humans, extremes i n p l a t e l e t MAO a c t i v i t y have been found i n patterns of personality and behavior considered high r i s k f o r p s y c h i a t r i c dysfunction. S p e c i f i c a l l y , low p l a t e l e t MAO a c t i v i t y may r e f l e c t some co n s t i t u t i o n a l weakness of monoamine systems i n the brain (Oreland, 1980). Studies of deviant p l a t e l e t MAO-B a c t i v i t y have revealed a l i n k between low p l a t e l e t a c t i v i t y and psychiatric syndromes characterized by an i n a b i l i t y to control impulses and to anticipate future consequences of behavior. Low level s of p l a t e l e t MAO-B a c t i v i t y have been associated with: v i o l e n t suicide attempts (Gottfries, von Knorring, & Oreland, 1980); attention d e f i c i t disorder and hyperactivity (Shekim et a l , 1986); drug abuse i n teenage boys (von Knorring et a l , 1987); conduct disorder-undersocialized 4 type (Bowden, Deutsch, & Swanson, 1988); and "Type I I " alcoholism (characterized by early age of onset, signs of s o c i a l complications, aggressiveness when intoxicated, and tendency to abuse i l l e g a l drugs) (von Knorring et a l , 1985). Low MAO a c t i v i t y i s associated with sensation seeking (Murphy et a l , 1977) and with several dimensions measured by the Karolinska Scales of Personality (KSP): impulsivity, monotony avoidance, verbal aggression, and i n d i r e c t aggression (Klinteberg et a l , 1987; A. von Knorring, Bohman, L. von Knorring, & Oreland, 1985; Pe r r i s , Eisemann, von Knorring, Oreland, & P e r r i s , 1984) . Mattsson et a l (1980) have also observed, i n young male delinquents, a pattern consisting of a high testosterone l e v e l , low MAO a c t i v i t y , and high sensation seeking. In high-risk studies of male college students, low MAO a c t i v i t y i s associated with a high frequency of p s y c h i a t r i c counselling, many convictions for legal offenses, and a high rate of suicides, and suicide attempts i n t h e i r r e l a t i v e s (Murphy et a l , 1977; Buchsbaum, Coursey, & Murphy, 1976). T r a i t s that appear common to the above studies include monotony avoidance, sensation seeking, and impulsivity. When measured against lev e l s of MAO a c t i v i t y , the general f i n d i n g i s that i n d i v i d u a l s who high on these t r a i t s show a common pattern of low MAO a c t i v i t y (von Knorring et a l , 1987, Shekim et a l , 1986, Schalling et a l , 1987, Schalling et a l , 1983). While the pattern of findings described above appears to be impressive, i t i s d i f f i c u l t to evaluate the consistency of the 5 obtained r e l a t i o n s h i p s . For example, i n two studies P l i s z k a et a l (1988a, 1988b) reported no differences i n p l a t e l e t MAO a c t i v i t y i n conduct disordered youth. There were s t i l l no differences when the subjects were further subtyped as v i o l e n t or nonviolent according to t h e i r arrest record. They did, however f i n d an inverse relationship between MAO a c t i v i t y and score on the Lie Scale of the Revised Children's Manifest Anxiety Scale (RCMAS). From these findings i t i s assumed that inconsistencies do exis t within the l i t e r a t u r e . Inconsistencies, however, are d i f f i c u l t to assess since negative findings are not usually published except i n conjunction with other s i g n i f i c a n t findings. Considering the r e l a t i v e l y stable patterns of a c t i v i t y observed within individuals, MAO a c t i v i t y has been suggested as a b i o l o g i c a l marker, useful i n i d e n t i f y i n g v u l n e r a b i l i t y to some forms of psychopathology (Schalling et a l , 1987). I I I . Methodological Considerations There are non-genetic factors that may a f f e c t p l a t e l e t MAO a c t i v i t y . Factors that are known or suspected to influence measured p l a t e l e t MAO a c t i v i t y l e v e l s include alcoholism, pharmacological treatment, smoking, hormones, d i e t , age, sex, race, p l a t e l e t preparation, and assay methodology. P r a c t i c a l considerations may prohibit the a b i l i t y of researchers to control for a l l of the p o t e n t i a l l y confounding variables that may a f f e c t p l a t e l e t MAO a c t i v i t y . These factors require consideration, however, when researchers construct and inte r p r e t studies l i n k i n g p l a t e l e t MAO-B a c t i v i t y to psychopathology. Some 6 of the demographic/lifestyle factors known to a f f e c t p l a t e l e t MAO-B a c t i v i t y w i l l be discussed below. A. Alcoholism: Most investigators confirm a l i n k between low p l a t e l e t MAO a c t i v i t y and alcoholism (Ghanshyam, et a l , 1988, von Knorring et a l , 1985, Wiberg, G o t t f r i e s , & Oreland, 1977) that i s not related to iron deficiency. A stable l e v e l of reduced p l a t e l e t MAO a c t i v i t y has been found i n chronic a l c o h o l i c s over a twelve month period (Sullivan, S t a n f i e l d , Schanberg, & Cavenar, 1978). Alcoholic patients studied acutely or months a f t e r abstinence showed s i g n i f i c a n t l y lower MAO a c t i v i t y than age and sex matched controls (Wiberg, G o t t f r i e s , & Oreland, 1977). Whether alcohol i t s e l f a l t e r s p l a t e l e t MAO a c t i v i t y i s s t i l l unclear. Robinson and Nies (1980) found no s i g n i f i c a n t changes i n plasma or p l a t e l e t MAO a f t e r acute ethanol administration. In contrast, Tabakoff et a l (1988) found i n h i b i t i o n of MAO a c t i v i t y i n alcoholics when saturating concentrations of substrate were used i n assaying enzyme a c t i v i t y . This e f f e c t i n alcoholics may r e f l e c t a long term response to ethanol consumption or an inherent c h a r a c t e r i s t i c of persons with alcoholism. Given the strong and consistent l i n k that has been drawn between low MAO a c t i v i t y and long term alcohol use, i t i s obviously an important factor to be accounted for i n studies attempting to draw associations between MAO a c t i v i t y and psychopathology. However, i n spite of the evidence, i t appears to be a factor that has largely been ignored. For example, Zureick & Meltzer (1988) found that i n approximately 7 ha l f of studies investigating p l a t e l e t MAO a c t i v i t y i n schizophrenia, history or evidence of alcohol use was not reported. B. Smoking Several studies suggest that smoking i s associated with low MAO a c t i v i t y (Yu & Boulton, 1987; Norman et a l , 1986; Oreland et a l , 1981a). Whether smoking produces an i n h i b i t o r of MAO a c t i v i t y , decreases the synthesis of the enzyme, or whether individuals who have lower MAO a c t i v i t y are more l i k e l y to smoke, remains to be answered. Most authors ascribe findings of lowered a c t i v i t y i n smokers to personality c h a r a c t e r i s t i c s (e.g. Oreland et a l , 1981a). The few studies that looked for changes i n p l a t e l e t MAO a c t i v i t y upon cessation of smoking have demonstrated mixed r e s u l t s . Oreland et a l (1981a) found that p l a t e l e t MAO a c t i v i t y for ex-smokers was not s i g n i f i c a n t l y d i f f e r e n t than MAO a c t i v i t y f o r smokers, while Norman, Chamberlain, and French (1986) found that one month a f t e r cessation of smoking MAO a c t i v i t y rose s i g n i f i c a n t l y . These d i f f e r i n g r e s u l t s have been attributed to differences i n d e f i n i t i o n s used to describe smoking behavior.-Whereas i n Oreland et a l ' s (1981a) study s e l f report data were used, Norman et a l (1986) used plasma thiocyanate as an index of exposure to cig a r e t t e smoke. Whether cigarette smoke d i r e c t l y i n h i b i t s MAO a c t i v i t y , or MAO i s a marker for pe r s o n a l i t i e s prone towards smoking behavior, cigarette smoking i s c l e a r l y a factor that should be controlled i n studies investigating the r o l e of MAO a c t i v i t y i n psychopathology. 8 C. Pharmacological Treatment The p o s s i b i l i t y that low p l a t e l e t MAO a c t i v i t y might be an a r t i f a c t of pharmacological treatment requires consideration. T r i c y c l i c antidepressant drugs act as weak reversib l e i n h i b i t o r s of the enzyme MAO i n human cerebral cortex and p l a t e l e t s , with more potent i n h i b i t o r y actions on MAO B than MAO A (Reid, H i l l , & Murphy, 1988) . Fluoxetine, desmethylclomipramine, desipramine, a m i t r i p t y l i n e , and clomipramine a l l i n h i b i t MAO B i n human brain cortex and human p l a t e l e t . Each drug appears to be a more potent i n h i b i t o r of human p l a t e l e t than human cortex preparations (p_<.05) (Reid, H i l l & Murphy, 1988). An atypical biphasic response occurs i n human p l a t e l e t preparations with 10 -4 M clomipramine and imipramine (Reid et a l , 1988) when benzylamine, but not phenylethylamine i s used as a substrate. Considering the d i f f e r e n t drug e f f e c t s observed on MAO a c t i v i t y , depending on the substrate used i n analysis, caution i s recommended when comparing MAO B data using benzylamine versus phenylethylamine as substrates. There i s evidence that neuroleptic treatment can be associated with a drop i n p l a t e l e t MAO a c t i v i t y . This drop appears s u f f i c i e n t enough to produce a s i g n i f i c a n t e f f e c t when comparisons are made between the p l a t e l e t MAO a c t i v i t y of patient groups and normal controls. In a study that examined the ef f e c t s of neuroleptic treatment on p l a t e l e t MAO a c t i v i t y , Chojnacki et a l (1981) found that mean MAO a c t i v i t y (as measured with both tryptamine and phenylethylamine substrates) was 9 decreased by an average of about 15% i n schizophrenic patients re c e i v i n g 3 weeks of treatment with haloperidol. The extent of decrease i n p l a t e l e t MAO a c t i v i t y i n chronic patients treated with haloperidol was p o s i t i v e l y related to the mean plasma l e v e l of haloperidol. In patients receiving butaperazine, the decrease averaged 38.9% for both substrates (Chojnhacki et a l , 1981). S i m i l a r i l y , Meltzer et a l , 1982 found that p l a t e l e t MAO a c t i v i t y s i g n i f i c a n t l y decreased i n both men and women a f t e r treatment with eit h e r haloperidol or chlorpromazine. Patients with highest i n i t i a l p l a t e l e t MAO a c t i v i t y tend to have the largest decreases i n p l a t e l e t MAO a c t i v i t y during neuroleptic treatment (Meltzer et a l , 1982). I t has been suggested that at l e a s t some of the differences i n p l a t e l e t MAO a c t i v i t y reported i n r e l a t i o n to the use of some drugs might be explained by changes i n the rates of p l a t e l e t formation, release, or degradation, which could i n turn a f f e c t the average density of p l a t e l e t populations sampled (Murphy, Costa, Shafer, & Corash, 1978) . However, regardless of the mechanism by which these changes of a c t i v i t y occur, these findings underline the importance of monitoring h i s t o r y of pharmacological treatment i n patients and controls. These r e s u l t s suggest that at least part of the decrease i n MAO a c t i v i t y that has been observed i n chronic schizophrenic patients (Wyatt et a l , 1979) may be due to treatment with neuroleptic drugs. Findings of differences i n p l a t e l e t MAO a c t i v i t y based on subjects who have been treated pharmacologically must be interpreted with caution. 10 Low MAO a c t i v i t y has been associated with heavy marijuana use (Stillman, Wyatt, & Murphy, 1978). Benzodiazepines and barbituates do not appear to have a s i g n i f i c a n t e f f e c t on MAO a c t i v i t y . Amphetamines appear to a f f e c t MAO a c t i v i t y only i n extreme concentrations. Reports on the e f f e c t of lithium carbonate on MAO a c t i v i t y are contradictory (for review see S u l l i v a n et a l , 1980). D. Age and P l a t e l e t MAO A c t i v i t y The e f f e c t of age on MAO a c t i v i t y i s disputed. A number of studies have found a s i g n i f i c a n t p o s i t i v e c o r r e l a t i o n between age and MAO a c t i v i t y (Fowler, Wiberg, Oreland, Marcusson, & Winblad, 1980; Robinson & Nies, 1980). In these studies males tend to show a small, l i n e a r increase i n MAO a c t i v i t y with age beginning at age 20. Females show a d i f f e r e n t trend, tending to be stable from the second u n t i l the f i f t h decade, with a sudden r i s e occurring a f t e r age 60 (Robinson, & Nies, 1980). In contrast, Murphy et a l (1976) found no s i g n i f i c a n t changes i n p l a t e l e t MAO a c t i v i t y i n either males or females between the ages of 10 and 70 when MAO a c t i v i t y was measured per unit p l a t e l e t . Sandler et a l (1981) confirm t h i s f i n d i n g of no s i g n i f i c a n t change with age. E. Sex Differences i n Mao A c t i v i t y Studies have consistently shown that women have s i g n i f i c a n t l y higher mean p l a t e l e t and plasma MAO a c t i v i t y than men (Robinson & Nies, 1980, Robinson et a l , 1971; Murphy et a l , 1976). F. Diet Riboflavin deficiency i s associated with decreased MAO a c t i v i t y (Sullivan et a l , 1980; Sourkes, 1983). This decrease i n a c t i v i t y can be reversed by the introduction of r i b o f l a v i n into the d e f i c i e n t d i e t . Iron d e f i c i e n c i e s have been reported to r e s u l t i n a decrease i n MAO a c t i v i t y (Sourkes, 1983). However, p l a t e l e t MAO a c t i v i t y apparently returns to normal when i r o n - d e f i c i e n t subjects are treated with iron. Youdim et a l (1975) have shown that serum iron l e v e l s are p o s i t i v e l y related to MAO a c t i v i t y . I t i s unclear to what extent moderate variati o n s i n the intake of these n u t r i t i o n a l factors a f f e c t MAO a c t i v i t y . The influence of caffeine i s a factor that has been larg e l y neglected i n the l i t e r a t u r e . In a single study that addressed caffe i n e as a potential confound, G i l l e r et a l (1984) found no s i g n i f i c a n t c o r r e l a t i o n between p l a t e l e t MAO and number of cups of coffee consumed per day. G. Race Although r a c i a l e f f e c t s would appear to be an important factor to consider i n studies of p l a t e l e t MAO a c t i v i t y i n psychopathology, the influence of race on MAO a c t i v i t y has been la r g e l y neglected i n l i t e r a t u r e . Groshong et a l (1978) found p l a t e l e t MAO a c t i v i t y to be s i g n i f i c a n t l y lower i n blacks than whites. Meltzer (1988) reports a complex i n t e r a c t i o n between race, subtype of schizophrenia, symptoms, and p l a t e l e t MAO a c t i v i t y , whereby black paranoid schizophrenics with auditory hallucinations had lower p l a t e l e t MAO a c t i v i t y than white patients of the same type. No studies to date have addressed differences i n MAO a c t i v i t y between white, Asian, or native Indian populations. 12 IV. P l a t e l e t MAO A c t i v i t y and Psychopathy The emerging relationships between p l a t e l e t MAO-B a c t i v i t y and v u l n e r a b i l i t y to psychopathology, are of considerable i n t e r e s t to the study of the p s y c h i a t r i c syndrome of psychopathy. Psychopathy i s a personality disorder. Like a l l personality disorders, i t has an early onset and characterizes the i n d i v i d u a l ' s long-term functioning, r e s u l t i n g i n s o c i a l and interpersonal dysfunction (American P s y c h i a t r i c Association, 1987; M i l l o n , 1981). Symptoms of psychopathy are usually evident by middle to late childhood, and can be assessed r e l i a b l y i n adolescence (Forth, Hart, & Hare, 1990; Robins, 1966). The disorder i s chronic and pe r s i s t s well into adulthood, although there may be some changes i n i t s symptom pattern a f t e r age 45 or so (Cleckley, 1976; Hare, McPherson, & Forth, 1988; Harpur & Hare, 1990b; Robins, 1966). The pattern of personality variables associated with low MAO a c t i v i t y i n the current l i t e r a t u r e , shows s t r i k i n g s i m i l a r i t i e s to the psychopathic personality. Impulsivity, u n r e l i a b i l i t y , proneness to boredom, lack of insi g h t , i r r e s p o n s i b i l i t y , violence, and aggressive behaviour are personality and behavioural c h a r a c t e r i s t i c s considered to be core elements of the psychopathic personality (Cleckley, 1976; Hare & McPherson, 1984a). Psychopathy i s associated with unstable interpersonal r e l a t i o n s , poor occupational functioning, and increased r i s k of involvement i n criminal a c t i v i t y (Cleckley, 1976; Hare et a l . , 1988; Hart, Kropp, & Hare, 1988; Kosson, Smith, & Newman, 1990; Woodruff, Guze, & Clayton, 1980). Psychopathy can be d i f f e r e n t i a t e d from other personality disorders on the basis of i t s c h a r a c t e r i s t i c pattern of interpersonal, a f f e c t i v e , and behavioral symptoms. Interpersonally, psychopaths are grandiose, egocentric, manipulative, dominant, f o r c e f u l , and cold-hearted. A f f e c t i v e l y , they display shallow and l a b i l e emotions, are unable to form long-lasting bonds to people, p r i n c i p l e s , or goals, and are lacking i n empathy, anxiety, and genuine g u i l t or remorse. Behaviorally, psychopaths are impulsive and sensation-seeking, and tend to v i o l a t e s o c i a l norms; the most obvious expressions of these predispositions involve c r i m i n a l i t y , substance abuse, and a f a i l u r e to f u l f i l l s o c i a l obligations and r e s p o n s i b i l i t i e s . I t i s t h e i r disproportionate involvement i n crime, p a r t i c u l a r l y v i o l e n t crime, that makes them of p a r t i c u l a r concern to the criminal j u s t i c e system, and to society i n general. While the concept of psychopathy has long held a prominent p o s i t i o n i n psychiatry and c l i n i c a l research, there i s a dearth of l i t e r a t u r e addressing possible l i n k s between biochemistry and psychopathy. Only two studies to date have attempted to examine the r e l a t i o n s h i p between psychopathy and p l a t e l e t MAO a c t i v i t y . Lidberg, Modin. Oreland, Tuck and G i l l n e r (1985) Lidberg et a l . (1985) examined MAO l e v e l s i n a sample of 37 men admitted to a Forensic Psychiatric C l i n i c for p s y c h i a t r i c examination by court appointment. Patients were diagnosed as eith e r schizophrenic, psychopathic (according to global ratings based on descriptions by Cleckley [1976]), or "other" ( i . e . no schizophrenic or psychopathic diagnosis). Two control groups were included; they were a group of construction workers and male s t a f f i n the c l i n i c . Substance use was assessed v i a blood assay and reported to be n e g l i g i b l e . Smoking habits did not d i f f e r between the groups. There was a tendency for the "psychopathic" group to have low MAO a c t i v i t y . While t h i s f i n d i n g of differences between the groups i s i n t e r e s t i n g , these r e s u l t s should be interpreted with caution. The method for diagnosing psychopathy was inadequate: Information on how the diagnoses were made, and evidence for the r e l i a b i l i t y and v a l i d i t y of the diagnoses, was absent. Yu. Davis. Gordon. Reid, Green, and Boulton (1985) Yu et a l (1985) examined MAO lev e l s i n 125 male inmates i n a Canadian Federal Penitentiary. Inmates were categorized into v i o l e n t , semi- violent, and non- vi o l e n t groups according to court records and i n s t i t u t i o n a l behavior. They were also assessed for verbal and non-verbal aggression. MAO a c t i v i t y varied inversely and s i g n i f i c a n t l y with dimensions of anger, h o s t i l i t y , and depression proneness. P l a t e l e t MAO a c t i v i t y was not 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 i n "aggressive psychopaths". Details concerning t h e i r procedures f o r c l a s s i f y i n g psychopaths were not given. I t appears that psychopathy was not formally assessed, but rather i n f e r r e d based upon court records and i n s t i t u t i o n a l behavior. They did, however f i n d an inverse relationship between MAO a c t i v i t y and anger and 15 h o s t i l i t y , consistent with previous patterns that have been observed. However, without v a l i d psychopathy assessments, the findings are d i f f i c u l t to interpret i n r e l a t i o n to the concept of psychopathy. These findings suggest that further i n v e s t i g a t i o n i n p l a t e l e t MAG—B a c t i v i t y , i n search of a better biochemical understanding of psychopathy, may be f r u i t f u l . However, r e l i a b l e and v a l i d assessment procedures are e s s e n t i a l i f neurochemical correlates of psychopathy are to be uncovered. Most importantly, investigations concerning biochemical underpinnings of psychopathy have long term implications i n terms of diagnosis and treatment of psychopaths i n the mental health and criminal j u s t i c e system. These p r a c t i c a l implications underscore the need f o r v a l i d and r e l i a b l e assessment of psychopathy, i f biochemical studies of psychopathy are to be useful. V. The R e v i s e d P s y c h o p a t h y C h e c k l i s t (PCL-R) The Revised Psychopathy Checklist (PCL-R; Hare, 1991; Hare et a l . , 1990) i s a 20-item rating scale designed to assess the t r a d i t i o n a l c l i n i c a l construct of psychopathy, perhaps best exemplified i n the work of Cleckley (1976). The PCL-R i s the basis for one of the four c r i t e r i a sets being evaluated i n the DSM-IV f i e l d t r i a l s for a n t i s o c i a l personality disorder (Hare, Hart, & Harpur, 1991). The PCL-R measures behaviors and infe r r e d personality t r a i t s considered fundamental to the c l i n i c a l construct of psychopathy. Each item i s scored on a 3-point scale, where 0 16 indicates that i t d e f i n i t e l y does not apply, 1 that i t applies somewhat or only i n a limited sense, and 2 that i t d e f i n i t e l y does apply, to the i n d i v i d u a l . The information needed to score the items i s obtained from a semi-structured interview and i n s t i t u t i o n a l f i l e s . Detailed instructions for scoring the items are contained i n the manual for the PCL-R (Hare, 1990). Although c l i n i c a l judgment and inference are required, the items are not d i f f i c u l t to score. PCL-R Total scores can range from 0 to 40. In most samples, the d i s t r i b u t i o n of scores i s approximately normal, with a s l i g h t negative skew. Although the Total scores are dimensional, they have been used to provide a categorical diagnosis of psychopathy. A cutoff score of 30 has proven useful f o r t h i s purpose. Mean Total scores are r e l a t i v e l y consistent across samples of prison inmates, and across forensic patients, from d i f f e r e n t i n s t i t u t i o n s and countries. Hare et a l . (in press) reported that the mean Total score for six samples of male prison inmates (N = 1065) was 23.37 (SD = 7.96), and that the mean score for four samples of male forensic patients (N = 440) was 20.56 (SD = 7.79). Total scores i n these samples had high i n t e r r a t e r r e l i a b i l i t y and int e r n a l consistency. Thus, for the prison and forensic psychiatric samples pooled, the i n t r a c l a s s c o r r e l a t i o n was .83 for a single rating and .92 f o r the average of two ratings. C o e f f i c i e n t alpha was .87, and the mean i n t e r -item c o r r e l a t i o n was .25. Although i t meets the s t a t i s t i c a l c r i t e r i a f o r a homogeneous, unidimensional scale, there i s very strong evidence that two oblique factors underlie the PCL-R (Hare et a l . , i n press; Harpur et a l . , 1988). The c o r r e l a t i o n between the factors i s about the same i n samples of prison inmates (.56 on average) as i t i s i n samples of forensic patients (.53 on average). Factor 1 r e f l e c t s interpersonal and a f f e c t i v e c h a r a c t e r i s t i c s , such as egocentricity, lack of remorse, and callousness, considered fundamental to c l i n i c a l conceptions of psychopathy. In s p i t e of the r e l a t i v e l y small number (8) of items involved, Factor 1 scores, obtained by summing the i n d i v i d u a l item scores, are r e l i a b l e i n samples of prison inmates and forensic patients. Evidence presented elsewhere (Hare, 1990; Harpur et a l . , 1989; Hart & Hare, 1989) indicates that Factor 1 i s most c l o s e l y correlated with c l a s s i c c l i n i c a l descriptions of psychopathy, p r o t o t y p i c a l i t y ratings of n a r c i s s i s t i c personality disorder, and with s e l f - r e p o r t measures of machiavellianism, narcissism, empathy, and anxiety. Factor 2 r e f l e c t s those aspects of psychopathy related to impulsivity, a n t i s o c i a l behavior, and an unstable l i f e s t y l e . Factor 2 i s most strongly correlated with diagnoses of A n t i s o c i a l Personality Disorder, criminal behaviors, socioeconomic background, and s e l f - r e p o r t measures of s o c i a l i z a t i o n and a n t i s o c i a l behavior. In addition, recent evidence indicates that Factor 2 i s much more strongly r e l a t e d to substance abuse than i s Factor 1 (Hart & Hare, 1989; Smith & Newman, 1990). The r e l i a b i l i t y and the v a l i d i t y of the PCL-R are well established. With respect to concurrent v a l i d i t y , the PCL i s p o s i t i v e l y correlated with p r o t o t y p i c a l i t y ratings of psychopathy and a n t i s o c i a l personality disorder and with diagnoses of a n t i s o c i a l personality disorder (APD) made according to DSM-III c r i t e r i a (Hare, 1985b; Harpur et a l . , 1989; Hart & Hare, 1989). Second, with respect to convergent and discriminant v a l i d i t y , Hart and Hare (1989) found that PCL ratings were either uncorrelated or negatively correlated with most DSM-III Axis I disorders; p o s i t i v e l y correlated with h i s t r i o n i c , n a r c i s s i s t i c , and antisocal personality disorder; and e i t h e r uncorrelated or negatively correlated with the remaining personality disorders. Several studies indicate that the PCL i s p o s i t i v e l y associated with both symptoms and diagnoses of substance use disorders (Hart & Hare, 1989; Hemphill, Hart, & Hare, 1990; Smith & Newman, i n press). Third, with respect to predictive v a l i d i t y , PCL scores are rela t e d to conditional release v i o l a t i o n s (Hart, Kropp, & Hare, 1988; Serin, Barbaree, & Peters, 1987), poor response i n i n s t i t u t i o n a l treatment programs (Ogloff & Wong, i n press; Rice & Harris, 1988), and v i o l e n t recidivism (Forth, Hart, & Hare", i n press; Rice & Harris, 1988). F i n a l l y , with respect to other aspects of construct v a l i d i t y , PCL scores are related i n t h e o r e t i c a l l y meaningful ways to performance on a variety of psychophysiological, cognitive, and l i n g u i s t i c tasks (Gillstrom & Hare, 1988; Hare, Williamson, & Harpur, 1988) and to criminal behaviors (Hare & McPherson, 1984; Hare, McPherson, & Forth, 1989; Williamson, Hare, & Wong, 1987). 19 VI. Purpose of the Present Study To date, no study has measured p l a t e l e t MAG—B a c t i v i t y i n well-defined groups of psychopaths under c a r e f u l l y c o n t r o l l e d conditions. In t h i s study, differences i n p l a t e l e t MAO a c t i v i t y were examined i n a group of male offenders, assessed f o r psychopathy according to Hare's Psychopathy Checklist (PCL, Hare, 1991). The Psychopathy Checklist (PCL), scored from interview and case-history information, i s an e x p l i c i t , r e l i a b l e , and v a l i d procedure for the assessment of psychopathy i n prison populations. F i n a l l y , as previously discussed, there i s some evidence that p l a t e l e t MAO-B a c t i v i t y may be influenced by a number of variables, including age (Persky, Smith, & Basu, 1971), alcoholism (Pandey et a l , 1988, von Knorring et a l , 1985, Wiberg, G o t t f r i e s , & Oreland, 1977), smoking (eg. Yu & Boulton, 1987); heavy marijuana use (Stillman, Wyatt, & Murphy, 1978); and pharmacological treatment (Reid, H i l l & Murphy, 1988). These factors were determined v i a self-reports and i n s t i t u t i o n a l f i l e s ; the ef f e c t s of these variables were s t a t i s t i c a l l y c o n t r o l l e d through regression analyses. I f psychopathy i s negatively associated with p l a t e l e t MAO-B a c t i v i t y , as suggested i n the l i t e r a t u r e thus far, i t may be expected that high PCL scores, would correlate negatively with l e v e l s of MAO a c t i v i t y . VII. Method A. Subjects Subjects were male inmates from Matsqui I n s t i t u t i o n , a medium security Canadian federal i n s t i t u t i o n i n Abbotsford, 20 B.C., who volunteered to pa r t i c i p a t e i n the present study. A l l were serving sentences for two years or longer, mostly for v i o l e n t crimes. Participants provided informed consent and permission to inspect t h e i r i n s t i t u t i o n a l f i l e s . Anonymity was assured through a data coding system, and the inmates were assured that study r e s u l t s would not be released to the s t a f f or administration of the i n s t i t u t i o n . Subjects were assured that blood analyses were not performed for the purposes of AIDS te s t i n g . Subjects were paid a t o t a l of $25.00, deposited d i r e c t l y into t h e i r i n s t i t u t i o n a l accounts, for p a r t i c i p a t i o n . E t h i c a l approval was obtained from the University of B r i t i s h Columbia Ethics Committee. The study was approved by both the research committee and the inmate committee at Matsqui I n s t i t u t i o n . Information regarding age, race, h i s t o r y of alcohol and substance abuse, smoking, and pharmacological treatment was coded according to f i l e information and s e l f report. Blood samples were obtained from s i x t y inmates. Of these, s i x were excluded for the following reasons: two subjects were transferred before psychopathy assessments could be made, one subject ate p r i o r to the blood draw, and three samples were dropped due to d i f f i c u l t i e s with biochemical assays. Data from the remaining 54 male subjects, ranging from ages 18-53 years (M = 27.35, SD = 6.18) were used to complete the study. The r a c i a l composition of the sample was 74% White, 22% Native American Indian, and 4% other. B. Procedure 21 1. Assessment of Psychopathy: A c r u c i a l requirement of research with psychopathological populations i s that the procedures for the diagnosis and se l e c t i o n of subjects have demonstrated r e l i a b i l i t y and v a l i d i t y . The assessment procedure that was used i n the present study was the Revised Psychopathy Checklist (PCL-R; Hare, 1990; Hare et a l . , 1990), an instrument that has proven remarkably successful i n generating a consistent body of findings on psychopathy. B r i e f l y , the PCL-R i s a 20-item r a t i n g scale designed to assess the t r a d i t i o n a l c l i n i c a l construct of psychopathy, perhaps best exemplified i n the work of Cleckley (197 6). The PCL-R measures both personality- and behavior-r e l a t e d c h a r a c t e r i s t i c s of psychopathy; i t can be used to obtain both dimensional and categorical scores; i t i s scored on the basis of both present-state and h i s t o r i c a l information. PCL ratings are usually made on the basis of both f i l e and interview information, although they can be made on the basis of f i l e information alone i f the f i l e s are s u f f i c i e n t l y d e t a i l e d (Hart, 1987; Wong, 1988). The information needed to score the items i s obtained from a 90-180 minute semi-structured interview and i n s t i t u t i o n a l f i l e s . Each item i s scored on a 3 point scale: 2 indicates that the item d e f i n i t e l y applies, 1 that i t may or may not apply, and 0 that i t d e f i n i t e l y does not apply, to the subject. Items are summed to y i e l d a t o t a l score that can range from 0 to 40. Factor 1 scores are obtained by summing the scores on items 1, 2, 4, 5, 6, 7, 8, and 16; Factor 2 scores by summing the scores on items 3, 9, 10, 12, 13, 14, 15, 18, and 19. Interrater r e l i a b i l i t y ( intraclass c o r r e l a t i o n c o e f f i c i e n t , or ICC1) for the PCL-R was determined on twenty subjects by independent raters, using the videotaped interviews and i n s t i t u t i o n a l f i l e s . The ICC for PCL-R ratings was .83. The t o t a l mean chec k l i s t score sample was 26.5 (SD = 6.71), a score that i s s l i g h t l y higher that obtained with much larger samples of inmates (Hare, 1991). The Total scores were used to form groups of Psychopaths (Total score > 30; n=20, M=33.3, SD=2.6), and Nonpsychopaths (Total score < 30, n=34, M=22.5 SD=5.8). 2. Biochemical Assays Preparation of the Blood At least two measurements on d i f f e r e n t days are required fo r data to be r e l i a b l e (Davis, 1989). Two blood samples were taken per subject (one week apart), between 0700 and 0900 hrs, before breakfast. Blood was coll e c t e d into 4.5 ml vacuum blood c o l l e c t i o n tubes containing sodium c i t r a t e as anticoagulant. P l a t e l e t s and plasma levels were prepared by d i f f e r e n t i a l c entrifugation. The l i t e r a t u r e indicates that time and gravity force should be held constant for a l l samples so that the type and density of the p l a t e l e t obtained i n the f i n a l p e l l e t i s constant (for review, see Wise et a l , 1980). B r i e f l y , a registered medical technician co l l e c t e d 20 ml blood samples from each of s i x t y subjects. Blood was then transferred into two 12-15 ml p l a s t i c tubes. Blood was centrifuged at 2000 g f o r t h i r t y minutes. Red blood c e l l s were discarded, and the p l a t e l e t r i c h 23 plasma was transferred to a clean p l a s t i c tube and centrifuged again at 2 000 g for 10 minutes. The p l a t e l e t p e l l e t was suspended i n cold .32 M sucrose solution and centrifuged again at 2000 to 3000 g for ten minutes. Supernatant was discarded. The washed p l a t e l e t preparations were la b e l l e d , packed i n dry ic e , and sent to a -70 C freezer outside of the i n s t i t u t i o n , and within one week was sent packed i n dry ice i n a l i g h t proof box for a i r f r e i g h t to the Neuropsychiatry Research Unit (NRU) at the University of Saskatchewan, where they were analyzed under the d i r e c t i o n of Dr. A. Boulton, dir e c t o r of NRU Saskatchewan, Dr. B. Davis, and Dr. P. Yu. A l l biochemical determinations were performed by personnel who were bl i n d to c l i n i c a l data, and a l l c l i n i c a l interviewing and ratings were done b l i n d to biochemistry. Assay of P l a t e l e t MAO-B A c t i v i t y MAO a c t i v i t y was determined radioenzymatically as described i n Yu (1986; see appendix a), using 14C l a b e l l e d p - [ l - C] tyramine (1 10 -4 M), as the substrate, and toluene: ethylacetate (1:1) as the extraction solvent. I n t r a i n d i v i d u a l s t a b i l i t y of p l a t e l e t MAO-B a c t i v i t y i n t r a c l a s s c o r r e l a t i o n c o e f f i c i e n t (ICC), established i n the present study for the average of the two samples taken one week apart, was .79. R e l i a b i l i t y between two assays, using p-tyramine as a substrate, has previously been reported to be somewhat higher (r = .88, p < .01, Yu. et a l , 1982) i n healthly controls. Mean p l a t e l e t MAO-B a c t i v i t y for the entire sample was 17.27 nmol/hr/mg protein, SD = 8.31. Mean p l a t e l e t MAO-B a c t i v i t y for the psychopathic group was 16.3, SD=7.2. Mean p l a t e l e t a c t i v i t y f o r the nonpsychopathic group was 17.8, SD=8.9. 3. Alcohol Use Ratings Information regarding alcohol, substance abuse, and smoking habits was coded according to f i l e information and s e l f report. A f i v e - p o i n t global rating for history of alcohol abuse was made for each subject (l=No Use, 5=Chronic Problematic Use). Each alcohol abuse ra t i n g was made according to (a) descriptions obtained according to DSM-III-R c r i t e r i a (b) medical and f i l e information i n d i c a t i n g history of alcohol abuse (c) s e l f report information regarding history of alcohol use. Interrater r e l i a b i l i t y was established for history of alcohol use on a sample of twenty subjects. Characteristics of the present sample i n terms of alcohol and substance use are de t a i l e d i n Table 1. Interrater r e l i a b i l i t y was determined on twenty subjects by independent raters using i n s t i t u t i o n a l f i l e information along with s e l f report. The ICC-1 for alcohol abuse ratings was .85. 4. Substance Use Ratings A f i v e - p o i n t global rating for history of substance abuse was made using the same five-point scale. Ratings were made based on information obtained from (a) descriptions according to DSM-III-R c r i t e r i a (b) medical and f i l e information i n d i c a t i n g h i s t o r y of alcohol abuse (c) s e l f report information. Interrater r e l i a b i l i t y was established for history of substance abuse on a sample of twenty subjects. The ICC-1 for substance use ratings was .85. Self report, f i l e , and interview information indicated that a wide variety of prescription and non-prescription drugs was currently being used and transferred among inmates. In l i g h t of the v a r i e t y of drugs used by the present sample, and i n view of the p r a c t i c a l d i f f i c u l t y of estimating amount of drug intake without the aid of blood assay or u r i n a l y s i s to detect the presence of s p e c i f i c drugs, a mixed substance use r a t i n g was made. For the mixed substance use rating, inmates were rated according to the types of drugs taken over the l a s t one month period. Subjects were given one point for each category of drug reported to have been taken over the l a s t month. Total number of points was used as a rating for the mixed substance use category. The categories were: Narcotics (heroin, morphine, demerol); Amphetamine l i k e substances; Cocaine; Sedatives, hypnotics, t r a n q u i l i z e r s , valium, Cannabis derivatives (marijuana, hashish); Hallucinogens (LSD, Mescaline); Solvents; Non p r e s c r i p t i o n drugs, antipsychotic and antidepressant medication, and alcohol. F i n a l l y , subjects were separated according to h i s t o r y of alcohol and/or substance use, to investigate the proportion of subjects with either a substance use history, alcohol history, or both. 5. Other L i f e s t y l e Factors Information on several l i f e s t y l e variables was obtained using the PCL-R interview, as well as a questionnaire that was constructed s p e c i f i c a l l y for the present study. These included: smoking, coffee consumption, and exercise habits over the previous 24 hours, two week, and one month period (see appendix b). Using t h i s information, d a i l y and monthly l i f e s t y l e habits were estimated on each of the variables. 6. Data Analysis. The key data analyses included: (a) c a l c u l a t i o n of cor r e l a t i o n s between PCL-R scores and biochemical variables, (b) h i e r a r c h i c a l multiple regression procedures i n order to s t a t i s t i c a l l y control for history and current substance use, smoking, age, and race. TABLE 1 Group Comparisons on Demographic/Lifestyle Measures Group NonPsychopaths (N=34) Psychopaths (N=20) History Chronic 27% 74% Alcohol Abuse History Chronic 41% 59% Substance Abuse History Alcohol 85% 94% &/or Substance Abuse # Cigarettes** M=17.7 M=17.6 Per Day SD=17.6 SD=8.9 # Days aerobic** M=3.l M=2.2 exercise/week SD=2.6 SD=2.8 # Cups coffee/ M=ll.1 M=7.9 Day* SD=16.9 SD=7.6 **estimated over month p r i o r to f i r s t blood sample None of the differences between groups was s i g n i f i c a n t 28 VIII. Results A. PCL-R, Demographic, and L i f e s t y l e Factors There were no s i g n i f i c a n t differences between psychopaths and nonpsychopaths with respect to age, smoking and exercise habits, coffee consumption, history of problematic and chronic alcohol and/or drug abuse, or i n the variety of drugs used (see Table 1). There was a s i g n i f i c a n t between-groups difference i n r a c i a l composition: 91.5% of psychopaths were white, compared to 65% of nonpsychopaths, X 2 = 4.20, p_ < .05. Thirty-one percent of the nonpsychopaths were Natives, and because there are no data on MAO l e v e l s i n Natives the p r a c t i c a l s i g n i f i c a n c e , for MAO l e v e l s , of a high proportion of Natives i n the nonpsychopathic group i s unknown. The disproportionate number of Natives i n the nonpsychopathic group i s unusual; i n most samples obtained from Canadian prison populations there i s l i t t l e d i fference i n the r a c i a l composition of psychopathic and nonpsychopathic groups (Hare, 1991). In any case, the confound between psychopathy and race was taken into account i n the regression analyses described below. B. PCL-R and P l a te l e t MAO A c t i v i t y 1. Correlational Analyses Both p l a t e l e t MAO a c t i v i t y and PCL-R scores were normally d i s t r i b u t e d i n the present sample. Pearson c o r r e l a t i o n s were computed as a l i b e r a l approach towards examining the rel a t i o n s h i p s among p l a t e l e t MAO a c t i v i t y , PCL-R ratings, and demographic/lifestyle variables. The r e s u l t s are presented i n Table 2; none of the correlations was s i g n i f i c a n t . 2. Multiple Regression Analyses Multiple regression analyses were also used i n order to s t a t i s t i c a l l y control for p o t e n t i a l l y confounding demographic/lifestyle variables and to determine i f combinations of variables were related to MAO a c t i v i t y . In each analysis, the dependent variable was p l a t e l e t MAO-B a c t i v i t y and the predictor variables were demographic/lifestyle measures (current use and h i s t o r y of alcohol, substance abuse smoking, age, race) and psychopathy measures (see table 3). In one analysis, demographic/lifestyle variables were forced into the p r e d i c t i v e equation and psychopathy measures were allowed to enter only i f they had s i g n i f i c a n t incremental v a l i d i t y ( i . e . , i f they s i g n i f i c a n t l y improved the R 2 of the regression equation). In a second analysis, the psychopathy measures were forced i n f i r s t , and demographic/lifestyle measures allowed to enter only i f they have s i g n i f i c a n t incremental v a l i d i t y . An a d d i t i o n a l set of regression analyses evaluated the influence on MAO a c t i v i t y of other demographic/lifestyle v a r i a b l e s : estimated coffee consumption and days of aerobic exercise over the l a s t month. Nothing of s i g n i f i c a n c e emerged from these analyses. 30 T a b l e 2 Correlations Among PCL-R Total Scores, Factor 1 Scores, Factor 2 Scores, Demographic/Lifestyle Variables, and P l a t e l e t MAO A c t i v i t y Variables: MAOl Alcohol Use Substance Use Mixed Drug Use2 Cigarette /Day 2 Age PCL-R -.13 .01 .17 .00 .01 .04 FACTOR 1 .03 -.02 -.01 -.12 . 10 -.02 FACTOR 2 -.15 .03 . 19 .10 -.07 .04 MAO 1.00 -.07 .11 .03 .12 -.01 1 MAO a c t i v i t y (expressed i n nmol/hr/mg protein); p-tyramine as substrate 2 estimated over one month p r i o r to blood c o l l e c t i o n * E < .05 31 Table 3 Multiple Regression/ Stepwise P l a t e l e t MAO A c t i v i t y Betal PCL-R -.153 Alcohol Use -.067 Substance Use . 132 Mixed Substance Use -.005 Age -.003 Cigarettes/day .118 Race .169 1 none of the values are s i g n i f i c a n t 32 IX. Discussion The c o r r e l a t i o n a l analyses did not reveal a s i g n i f i c a n t r e l a t i o n s h i p between p l a t e l e t MAO a c t i v i t y and psychopathy. This r e s u l t does not appear to be due to low s t a t i s t i c a l power. Previous studies investigating the association between p l a t e l e t MAO a c t i v i t y , extraversion, monotony avoidance, and verbal aggression, have obtained correlations within the -.17 to -.38 range (Perris et a l , 1984; af Klinteberg et a l , 1988). With a sample s i z e of 54, a c o r r e l a t i o n of only -.2 3 i s required for s i g n i f i c a n c e at the .05 l e v e l . Variables known or strongly suspected to influence MAO a c t i v i t y were recorded. None of these variables, including alcoholism, history of substance use, estimated mixed drug use over the l a s t month, age, smoking, race, or estimates of aerobic a c t i v i t y , were associated with MAO a c t i v i t y . Dietary variables, including r i b o f l a v i n and iron deficiency, are associated with decreased p l a t e l e t MAO a c t i v i t y (Sullivan et a l , 1980; Sourkes, 1983; Murphy et a l , 1976). It was not possible to monitor these variables, and they may have had a confounding e f f e c t on the r e s u l t s . However, there i s no reason to suspect that dietary d e f i c i e n c i e s related to MAO a c t i v i t y are also r e l a t e d to psychopathy. The lack of relationship between p l a t e l e t MAO and alcohol or substance abuse was somewhat surprising; previous research indicates that p l a t e l e t MAO a c t i v i t y and alcohol abuse, are consistently related to one another (e.g. Wiberg, 1979; Ghanshyam, 1988; G i l l e r et a l , 1984). One possible explanation fo r t h i s negative finding may have been the high l e v e l of both alcohol and substance use i n the present sample: 94% of the psychopaths and 85% of nonpsychopaths had a prominent h i s t o r y of one year or more of severe alcohol and/or substance use. Group differences i n MAO a c t i v i t y may have been overwhelmed by the high base rate for substance use. Previous research investigating p l a t e l e t MAO a c t i v i t y i n p s y c h i a t r i c disorders has been plagued by un r e l i a b l e p s y c h i a t r i c assessment. This does not appear to have been a problem i n the present study. The r e l i a b i l i t y and the v a l i d i t y of the PCL-R are well established. Similarly, a standard method fo r the estimation of p l a t e l e t MAO a c t i v i t y (Yu, 1986) was used. Enzyme a c t i v i t e s were expressed r e l a t i v e to protein per sample (nnmol/hr/mg protein). Using t h i s method, values should not be affected by t o t a l p l a t e l e t count because r e l a t i v e recoveries of plasma protein and MAO a c t i v i t y should remain constant across subjects. An alternative method would be to express p l a t e l e t MAO a c t i v i t y i n terms of p l a t e l e t count. Estimations of p l a t e l e t MAO a c t i v i t y using the p l a t e l e t count are highly correlated with estimations using the p l a t e l e t protein method (r =.85, p<.001; Murphy, 1978). Previous studies have used a variety of substrates i n t h e i r determinations of p l a t e l e t MAO a c t i v i t y (e.g. p-tyramine, B-phenylethylamine, and tryptamine). P l a t e l e t MAO a c t i v i t y determinations, based on these substrates are highly correlated i n healthy individuals (Yu et a l , 1982). I t appears, therefore that substrate s p e c i f i c i t y for healthy subjects i s quite homogenous. In chronic schizophrenics, however, c o r r e l a t i o n s among substrates are somewhat lower (ranging from r = .64 to .81, p_ < .05), possibly due to long-term administration of neuroleptic drugs (Yu et a l , 1982). Whether or not substrate s p e c i f i c i t y was compromized by the high base rate of drug and alcohol use i n the present sample cannot be determined. This may l i m i t the extent to which the present r e s u l t s can be compared to r e s u l t s obtained i n other studies which, l i k e t h i s one, use tyramine as a substrate. Extraction e f f i c i e n c y depends on the substrates and solvents employed. Approximate recoveries, using 14C l a b e l l e d p - [ l - C] tyramine (1 10 -4 M) and toluene: ethylacetate (1:1), i s high, estimated at 96% (Yu, 1986). Overall, i n t r a - i n d i v i d u a l r e l i a b i l i t y and extraction e f f i c i e n c y , using radioenzymatic method of assay and p-tyramine as substrate, appear to be high r e l a t i v e to other methods employed for the determination of p l a t e l e t MAO-B a c t i v i t y . A l l blood samples were treated and analyzed i n the same manner. There i s no obvious reason why assay methodology should have had d i f f e r e n t i a l e f f e c t s on individual subjects or groups i n t h i s study. P l a t e l e t MAO a c t i v i t y i s measured i n terms of rate of reaction per minute, rather than i n absolute terms. Within laboratories, researchers standardize t h e i r techniques for measuring MAO a c t i v i t y , thereby reducing intra-laboratory noise i n p l a t e l e t preparation and assay procedures. However, there i s no u n i v e r s a l l y accepted procedure for measuring p l a t e l e t MAO a c t i v i t y . Because of t h i s , there i s a wide range of enzyme rates reported among researchers and studies. Due to the lack of standardized procedures across researchers, there i s a lack of normative data against which to compare observed r e s u l t s . Studies conducted from the same biochemical laboratory have yielded estimations of p l a t e l e t MAO a c t i v i t y ranging from 1.68 nmol/mg/hr for schizophrenic group to 3.17 nmol/mg/hour for i n s t i t u t i o n a l controls (Davis, Yu, Carlson, O'Sullivan, & Boulton, 1982). The large discrepency between these r e s u l t s and the present findings (the mean p l a t e l e t MAO a c t i v i t y for the present sample was 17.27 nmol/hr/mg protein, SD = 8.31) i s d i f f i c u l t to interpret. While i t i s not generally meaningful to compare the rates of p l a t e l e t MAO a c t i v i t y among samples i n which there are even minor variations i n procedures, i n l i g h t of the large differences i n estimated p l a t e l e t MAO a c t i v i t y between these two studies, conclusions based upon these findings should be made with caution. There are several steps i n p l a t e l e t preparation and assay where v a r i a b i l i t y may be introduced. Some of the steps that might contribute to v a r i a b i l i t y include: (1) The determination of p l a t e l e t protein concentration when estimating MAO a c t i v i t y per mg protein, when other plasma protein and non-protein substances are included i n the p l a t e l e t p e l l e t during the centrifugation of p l a t e l e t r i c h plasma; (2) Choice of 36 anticoagulant and substrate; and (3) Factors such as temperature, plasma proteins, gravity force, and v a r i a b i l i t y i n the d i s t r i b u t i o n and p l a t e l e t density between in d i v i d u a l s that i n t e r a c t with d i f f e r e n t i a l centrifugation methods to y i e l d v a r i a b l e r e s u l t s (for reviews see Jackman & Meltzer, 1980; Murphy, Costa, Shafer & Corash, 1978; Wise et a l , 1980; Brown, Powell, & Craig, 1980). Procedures were standardized i n order to minimize these potential sources of a r t i f a c t . Samples were c o l l e c t e d from psychopaths and nonpsychopaths i n random fashion, using the same centrifuge, and holding constant the gr a v i t y force and time factor. The r e l i a b i l i t y of the p l a t e l e t MAO samples was somewhat lower than has been previously reported using s i m i l a r methods— .79 averaged across samples i n the present study versus .88 previously reported (Yu, 1982). Due to lack of f a c i l i t i e s , samples were shipped on dry ice from the i n s t i t u t i o n to a minus 70-degree freezer i n a Vancouver hos p i t a l . When a l l samples had been c o l l e c t e d , over a two-week period, they were shipped to Saskatoon for analysis. I t i s possible that during transportation there was some decomposition of the samples, r e s u l t i n g i n an increase i n error associated with the assays; t h i s would have compromized the v a l i d i t y of the measurements of p l a t e l e t MAO a c t i v i t y . The r e s u l t s of the present study lend no support to the hypothesis of low p l a t e l e t MAO a c t i v i t y i n criminal psychopaths. This i s an i n t e r e s t i n g finding i n i t s own r i g h t , p a r t i c u l a r i l y because of previous findings of s i g n i f i c a n t r e l a t i o n s h i p s between p l a t e l e t MAO a c t i v i t y and personality t r a i t s commonly associated with the construct of psychopathy (eg. Schalling, Edman, & Asberg, 1983; Lidberg et a l , 1985; Schalling et a l , 1987) . These personality t r a i t s were not assessed i n t h i s study. I t i s possible that p l a t e l e t MAO i s more strongly r e l a t e d to s p e c i f i c personality t r a i t s (e.g impulsivity, extraversion, monotony avoidance) than to the c o n s t e l l a t i o n of symptoms that form the construct of psychopathy. 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Markers for v u l n e r a b i l i t y to psychopathology: temperament t r a i t s associated with p l a t e l e t MAO a c t i v i t y . Acta.  Psychiatr. Scand., 76, 172-182. Schalling, D., Edman, G., & Asberg, M. (1983). Impulsive Cognitive Style and I n a b i l i t y to t o l e r a t e boredom: psychobiological studies of temperamental v u l n e r a b i l i t y . In M. Zuckerman (Ed.), B i o l o g i c a l Bases of Sensation Seeking.  Impulsivity. and Anxiety (pp. 123-145). H i l l s d a l e New Jersey: Erlbaum Assoc. Serin, R., Barbaree, H., & Peters, R. (1987, June). Psychopathy  and recidivism i n prisoners. Paper presented at the Annual General Meeting of the Canadian Psychological Association, Toronto, Canada. Shekim, W.O., Bylund, D.B., Alexson, J., Glaser, R.D., Jones, S.B., Hodges, K., & Perdue, S. (1986). P l a t e l e t MAO and measures of attention and impulsivity i n boys with attention d e f i c i t disorder and hyperactivity. Psychiatry  Research, 18, 179-188. 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Su l l i v a n , J.L., Stanfield, C.N., Schanberg, S., Cavenar, J . (1978). P l a t e l e t monoamine oxidase and serum dopamine-B-hydroxylase a c t i v i t y i n chronic a l c o h o l i c s . Archives of  General Psychiatry. 35, 1209-1213. Tabakoff, B., Hoffman, P.L., Lee, J.M., Saito, T., Willard, B., & De Leon-Jones, F. (1988). Differences i n p l a t e l e t enzyme a c t i v i t y between alcoholics and nonalcoholics. New England  Journal of Medicine. 318, 134-139. Wiberg, A. (1979). Increase i n p l a t e l e t monamine oxidase a c t i v i t y during controlled abstinence a f t e r alcohol abuse. Medical Biology. 57, 133-134. Wiberg, A., Go t t f r i e s , C-G., & Oreland, L. (1977). Low p l a t e l e t MAO a c t i v i t y i n human alcoho l i c s . Medical Biology. 55, 181. Williamson, S.E., Hare, R.D., Se Wong, S. (1987). Violence: Criminal psychopaths and t h e i r victims. Canadian Journal of  Behavioral Science. 19, 454-462. Wise, CD., Potkin, S.G., Bridge, P.T., Phelps, T.P., Cannon-Spoor, H.E., & Wyatt, R.J. (1980). Sources of error i n the determination of p l a t e l e t monoamine oxidase: a review of methods. Schizophrenia B u l l e t i n . 6, 245-253. Wong, S. (1988). Is Hare's Psychopathy Checklist r e l i a b l e without the interview? Psychological Reports. 62., 931-934. Woodruff, R.A., Guze, S.B., abd Clayton, P.J. (1980). The medical and psyc h i a t r i c implications of a n t i s o c i a l personality (sociopathy). In H.J. Vetter and R.W. Rieber (Eds.), The psychological foundations of criminal j u s t i c e . Vol. II (pp. 307-312). New York: John Jay Press. Wyatt, R.J., Potkin, S.G., & Murphy, D.L. (1979). P l a t e l e t monoamine oxidase a c t i v i t y i n schizophrenia: A review of the data. American Journal of Psychiatry. 136, 377-385. 47 Youdim, M.B., Woods, H.D., M i t c h e l l , B., Grahame-Smith, D.G., & Callender, S. (1975). Human p l a t e l e t MAO a c t i v i t y i n i r o n -deficiency anaemia. C l i n i c a l Science and Molecular  Medicine, 48, 289. Youdim, M.B. (1988). P l a t e l e t monoamine oxidase, use and misuse. Experientia. 44, 137-141. Yu., P.H. (1986). Monoamine oxidase. In A. Boulton, G. Baker, & P. Yu (Eds.), Neuromethods. Vol. 5 (pp. 235-272). New Jersey: Humana Press Inc. Yu, P. H. & Boulton, A. A. (1987). I r r e v e r s i b l e i n h i b i t i o n of monoamine oxidase by some components of cig a r e t t e smoke. L i f e Sciences, 41/ (6), 675-682. Yu, P.H., Bowen, R., Carlson, K., O'Sullivan, K., & Boulton, A. (1982). In: Kamijo, K, Usdin, E. and Nagatsu, T (eds.) Monoamine Oxidase: Basic and C l i n i c a l Frontiers. 87-99. Exerpta Medica, Amsterdam. Yu. P.H., Davis, B.A., Gordon, A., Reid, D.M., Green, C., & Boulton, A. (1985). Biochemical l i n k s to aggressive psyhopathy. B i o l o g i c a l Psychiatry. 170. 341-343. Zureick, J.L. & Meltzer, H.Y. (1988) . P l a t e l e t mao a c t i v i t y i n ha l l u c i n a t i n g and paranoid schizophrenics: a review and meta-analysis. B i o l o g i c a l Psychiatry. 24., 63-78. /PPENDIX A Radioeruymatic Assay Procedure Enzyme Preparation Crude tissue homogenates (tissues homogenized in 0.32.M sucrose or 0.1IM KG), partially purified mitochondrial membrane fragments (see below), fractions prepared by solubilization in de-tergents, as well as enzymes that have been purified to different degrees of purity can all be used. Reagents 1. Phosphate buffer (0.2 mol/l) 2. Substrate solution: This depends on which subsjrate is being utilized and the purpose of the study (often the final concentration of the substrate can be set at twice its Km value) 3. nC-Labeled substrates: specific activity approximate-ly 50 mCi/mmol, concentration 100 u.Ci/mL 4. Citric acid, IN 5. Extraction solvent, i.e., toluene:ethylacetate (1:1) 6. Scintillation cocktail Assay Procedure The following incubation mixture (200 u.L) is prepared in con-ical glass centrifuge tubes in an icebath. Final Volume, |iL concentration Enzyme (suitably diluted) Phosphate buffer (0.2M, pH 7.4) Substrate (8-20 x ltr*M) ,4C-substrate (premixed with the nonlabeled substrate) H 2 0 50 — 50 5 x lfr JM 49 2-5 x l(r*M 1 0.1 jiCi 50 — In the incubation mixture used to obtain blank values, the M A O inhibitor pargyline (0.1 rruVf) is included. The incubation is carried out at 37>C for 30 min and terminated by adding 200 u.L 2N citric acid and 1 mL extraction solvent. After vigorous mixing on a Vortex mixer, the mixtures are centrifuged at 3000g for 5 min in a clinical centrifuge. An aliquot (0.5 mL) of the organic phase is then transferred to a counting vial, toluene-based scintillation fluid (10 mL) is added, and the mixture is subsequently counted in a liquid scintillation counter. Calculation If the scintillation counter is not equipped with automatic quenching compensation, the counting efficiency (%) (or quench-ing correction) must be determinedas described by Peng (1970). Specific M A O activity (nmoles/min/mg) = 1 1 (Exp-blank) dpm x — x Specific Time of radioactivity incubation (min) Extraction 1.0 1 coefficient x ^ x p r 0 t d n ( m g ) Extraction of Product It has generally been considered (although it may not be true for some substrates) that the aldehydes formed in the above in-cubation conditions are unstable and are rapidly oxidized in air to their corresponding acids or alcohols in the presence of aldehyde reductase and N A D H or N A D P H . The extraction conditions are such that the amine substrates remain associated with the aqueous phase and the acidic or neutral metabolites (i.e., acids, alcohols, or aldehydes) extract into the organic solvent phase. Ion-exchange resins and liquid ion exchangers have also been used to separate the reaction products from the substrates. Comparisons of these various methods indicate that they are all rather similar in their efficiency of extraction (Anderson, 1983), and it is a fact that they are relatively easy to perform and apparently suitable for measur-ing both low and high M A O activity. Unfortunately, extraction with solvents is never 100% effec-tive, and, indeed, the extraction efficiency depends on the sub-strates and solvents used (Tipton and Youdim, 1983). A number of different solvents have been employed (Wurtman and Axelrod, 1963; Otsuka and Kobayashi, 1964; McCaman et al., 1965; South-gate and Collins, 1969; Jain et al., 1973; Callingham and Laverty, 1973; Tipton and Youdim, 1976; Fowler and Oreland, 1980). To illustrate the point, approximate recoveries with different solvents for 5-HT, B-phenylethylamine, and p-TA are listed in Table 4. It is clear, therefore, that the extraction coefficients must be established for each substrate and solvent before proceeding to finalize any M A O activities. Validation of Method This radioenzymatic method is highly sensitive, specific, reproducible, relatively simple, and convenient because a wide variety of radioactively labeled amine substrates are commercially available. There are, however, several sources of error that may produce misleading results. Although tritium-labeled amine substrates are commercially available and offer much higher specific radioactivities, their use in the radioenzymatic assay for M A O is not recommended. First, the Table 4 Extraction of Different Amine Metabolites by Different Solvents* Recovery of metabolite (7c) Substrate Toluene:ethyl acetate Benzene:ethyl acetate used (1:1) (1:1) 5-Hydroxytryptamine 74 91 B-Phenylethylamine 92 — p-Tyramine 96 65 Dopamine 54 18 *Data from Otsuka and Kobayashi H964), Tipton and Youdim (1976), and Fowler and Oreland (1980). dpm values obtained after extraction are unreliable because of exchange of the isotope in water, even in the absence of enzyme (May, 1980). Second, it has recently been observed that when the label is on the a-carbon position, a significant isotope effect occurs during the enzyme reaction (Yu et al., 1981, 1982b). It has been shown, for example, that the rates of enzymatic deamination of those amines in which the a-side chain hydrogens had been re-placed by deuterium were much slower (approximately one-third) than those exhibited with unlabeled amines. Compounds labeled with tritium would probably exhibit an even more pronounced isotope effect since the carbon-tritium bond is even stronger. A further disadvantage of this method is the fact that it is a discontinuous procedure, i.e., incubation is carried out for 20-30 min and then the reaction is stopped. It is also necessary to es-tablish the time course in order to ensure that the reaction is linear. Often the linearity disappears when a proportion of substrate has been consumed. It is also dependent on the amount of substrate added and the amount of enzyme present in the incubation ma-ture. Finally, an additional criterion relates to substrate purity for both unlabeled and labeled substrates. Some contaminants are potent M A O inhibitors and frequently appear as substrate in-hibitors in kinetic studies. Impurities in the radioactive amines often cause high background errors in the calculation of enzyme activity. In such cases the substrate should be purified by recrystallization, extraction with solvents, or appropriate chroma-tography. Purification of MAO-B From Human Platelet Human platelets contain exclusively type B M A O . A pro-cedure has been developed to isolate homogenous MAO-B from them (Ansari et al., 1983). The washed platelet suspension is frozen at -20°C overnight, thawed, and centrifuged at 35,000g for 60 min. The pellets are then suspended in 0.05M phosphate buffer at pH 8.0 containing 0.1% Triton X-100 at 4°C for 60 min. They are then recentrifuged at 35,000g for 30 min. The pellets, after suspension in the same buffer containing 0.5% Triton, are stirred for 60 min at 4°C and centri-fuged at 150,000# for 60 min. The supernatant containing solubi-lized M A O is dialyzed against 0.01M phosphate buffer at pH 8.0. The M A O - B in the dialysate is then fractionated on a DEAE-Sephacel (Pharmacia) column that has been previously equili-brated with 0.01M phosphate buffer at pH 8.0. The column is developed by stepwise elution with 0.01M, 0.1M phosphate buffer (pH 8.0), and 0.1M phosphate buffer (pH 8.0) containing 0.25% Triton X-100. The collected enzyme fractions are precipitated by addition of ammonium sulfate to 50% saturation. The precipitate that floats to the surface is dissolved in 0.05M phosphate buffer (pH 8.0) containing 1% octylglucosideand dialyzed against 0.025M Tris-acetate buffer at pH 7.4. Solid octylglucoside is then added to the dialyzed solution to a final concentration of 1%. This prepara-tion is then further fractionated on a Polybuffer Exchanger 94 (Pharmacia) chromato-focusing column according to the in-structions provided by Pharmacia Fine Chemicals. Diluted (1:8) Polybuffer 7.4 (Pharmacia) pH 4 (adjusted with INHC1)containing 1% octylglucoside is used to elute the enzyme. Those fractions exhibiting high MAO-B activity (i.e., near pH 5.3) are pooled and concentratediby ammonium sulfate precipitation. The floating pre-cipitate is collected, dissolved in 0.05M pnosphate buffer at pH 7.4 containing 1% octylglucoside and dialyzed against pH 7.4 buffer, and then subjected to HPLC separation performed on a Syn-chropah AX-300 column in 0.1M phosphate buffer (pH 7.4), fol-lowed by a gradient (0-1%) of octylglucoside in the same buffer. The MAO-B active fractions are pooled, dialyzed, and lyophilized. This method yields a 43-fold purification, but only a 0.25% re-covery. 52 BIOCHEMICAL MEASURES OK BEHAVIOR DATE I SUBJECT I.D. These a re a few q u e s t i o n s about your a c t i v i t i e s i n t he l a s t 24 hours * * * * * * * * * * * * * * * * * * * * * * * A L L ANSWERS W i l l . BR KEPT STRICTLY C O N F I D E N T I A L * * * * * * * * * * * * 1. How many c i g a r e t t e s have you smoked i n t h e pas t 24 h o u r s ? 2. How many cups o f c o f f e e have you had i n t h e pas t 24 h o u r s ? 3. Have you consumed any a l c o h o l i n t he pa s t 24 hours? . I f s o , how much? 4. Have you t a k e n any p r e s c r i p t i o n drugs In t he p a s t 24 h o u r s ? I f s o , what k i n d o f m e d i c a t i o n ? 5. Have you t a k e n any n o n - p r e s c r i p t i o n drugs i n t h e p a s t 24 hour s ? I f s o , what k i n d o f drugs? 6. Have you had any p h y s i c a l f i g h t s i n t h e l a s t 24 hour s ? I f s o , when? 7. Have you had any arguments i n the l a s t 24 hours? I f s o , when? 8. Have you done any p h y s i c a l e x e r c i s e s i n t"he l a s t 24 h o u r s ? I f s o , when? 53 BIOCHEMICAL MEASURES OF BEHAVIOR DATE: SUBJECT I.D. These a r e a few q u e s t i o n s about your a c t i v i t i e s i n t h e l a s t 2 weeks and 1 month p e r i o d . ******************* ALL ANSWERS WILL BR KEPT STRICTLY CONFIDENTIAL************** 1. Over t h e l a s t 2 weekB how many c i g a r e t t e s / packages have you smoked p e r day? Over t h e l a s t month? 2. Over t h e l a s t 2 weeks, app rox ima te l y how many cups o f c o f f e e do you d r i n k p e r day? Over t h e l a s t month? 3. Over t h e l a s t 2 weeks, a p p r o x i m a t e l y how much a l c o h o l have you consumed? Over t h e l a s t month? 4. Over t h e l a s t 2 weeks have you t aken any p r e s c r i p t i o n drugs? I f s o , what . Over t h e l a s t month? when Over t h e l a s t month? 5. Over t h e l a s t 2 weeks have you t aken any n o n - p r e s c r i p t i o n d rugs ? I f s o , what Over t h e l a s t month? when Over t h e l a s t month? 6. Do you f o l l o w a r e g u l a r e x e r c i s e rou t ine?_ I f s o , what _ _ _ How o f t e n i n t h e l a s t two weeks? How o f t e n i n t h e l a s t month? 

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