Serotonergic responsivity and behavioral dimensions in antisocial personality disorder with...

BIOL PSYCHIATRY 325 1990;28:325-338

Serotonergic Responsivity and Behavioral Dimensions in Antisocial Personality Disorder with Substance Abuse

Howard B. Moss, Jeffrey K. Yao, and George L. Panzak

In order to assess the possibility of altered serotonergic responsivity in antisocial personality disorder with substance abuse (ASP), 15 men with ASP and 12 controls were challenged with the serotonin agonist, m-chlorophenylpiperazine ( m-CPP), and prolactin and cortisol responses were evaluated. Psychometric measures of hostility and aggression, impulsivity, cogitative tempo, and various aspects of sociopathy were also obtained. ASP subjects had a significantly reduced prolactin response to m-CPP compared with coptrols, and a significantly greater cortisol response. The prolactin responses showed a significant inverse correlation with measures of assaultive aggression, hypophoria (negative affects), and increased needs. There was no significant correlation found between cortisol responses and any of the psychometric measures, lmpulsivity as characterized either by behavioral self-report or measurement of cognitive tempo did not correlate with either prolactin or cortisol responses. A discriminant function analysis depicted ASP subjects as displaying resentment towards others and having poor test-tLking efficiency, heightened irritability, and diminished prolactin response to m-CPP. Using these four criteria, nearly 93% of subjects were successfully classified. These results suggest that altered serotonergic function is associated with assaultiveness and dysphoria but not impulsivity in individuals with ASP.

Antisocial personality disorder (ASP) is depicted as a pattern of irresponsible and antisocial behavior beginning before age 15 years and continuing into adulthood (DSM-III-R criteria). ASP is more common among men, and is thought to be transmitted through an interaction between genetic and environmental factors (Crowe 1974). Individuals with ASP tend to be irritable, physically aggressive, impulsive, behave recklessly, are sexually promiscuous, and have high rates of psychoactive substance abuse (Cleckley 1964; Robins 1966; Schuckit 1973; Virkkunen 1979; Cadoret et al. 1985). ASP has been identified as an etiological factor for both alcoholism (Robins 1966; Cloninger et al. 1978) and other chemical dependencies (Yost 1954; Kosten et al. 1982). Genetic studies of the familial transmission of alcoholism suggest that sociopathy and criminality may be linked to a

"male-limited" form of the disorder (Bohman et al. 1984; Cloningcr 1988). Hesselbrock

From the Comprehensive Alcohol and Drug Abuse Program, Western Psychiatric Institute and Clinic, Department of Psychiatry, University of Pittsburgh School of Medicine (H.B.M., G.L.P.); and Department of Psychiatry, University of Pittsburgh School of Medicine, Department of Veterans Affairs Medical Center-Highland Drive (J.K.Y.), Pittsburgh, PA.

Address reprint requests to Dr. Howard B. Moss, Westerp Psychiatric Institute 3~i i ~'X~ra St., Pittsburgh, PA 15213-2593. Supported in part by NIDA Center P50-DA5605. Received November 2, 1989; revised January 16, 1990.

© 1990 S~iety of Biological Psychiatry 0006-3223/90/$03.50

326 BIOL PSYCHIATRY 1990;28:325-338

H.B. Moss et al.

et al. (1985) reported that nearly 50¢:~ of hospitalized alcoholic men at their center had additional psychopathology in the form of ASP, further supporting the association between ASP and substance abuse disorders.

Previous investigations have suggested that reduced serotdnergic (5-HTergic) neurotransmission is implicated in the imp~ ~ive and aggressive behavior of personality-disordered military men (Brown et al., ~ ~'~; Brown et al. 1982), violent criminal offenders (Linnoila et al., 1983), and alcoholic ~ (Ballenger et al. 1979; Kent et al. 1985), as well as in depressed and suicidal pa~ :~:s (van Praag 1977; Asberg et al. 1976; Agren 1980; Siever et al. 1984). Increased ~ ~dTergic activity, on the other hand, has been implicated in more ruminative and behaviorally inhibited conditions such as obsessive- compulsive disorder (Zohar et al. 1987) and anorexia nervosa (Kaye et al. 1984).

Neuroendocrine evidence of altered 5-HTergic function has also been recently reported in personality-disordered patients (Coccaro et al. 1989), and in impulsive and aggressive substance abusers (Fishbein et al. 1989). These investigations utilized a pharmacological challenge with d,/-fenfluramine (a presynaptic 5-HT releaser), and the measurement of prolactin and cortisol responses as an ndex of serotonergic function.

The initial purpose of this investigation was to test the hypothesis that altered 5- HTergic functioning is implicated in t~e DSM-HI-R syndrome of ASP based on a differential prolactin and cortisol response to the "selective" postsynaptic 5-HT agonist, m- chlorophenylpiperazine (m-CPP) relative to controls. Furthermore, '-,he hormonal responses to m-CPP were evaluated with respect to associations with personality dimensions such as impulsivity (measured both by ~spositional self-report, and evaluation of cognitive tempo), aggression and hostility, a~,:i ~he characteristics of sociopathy that have been hypothesized to contribute to substa~ ~:~ abuse.

Although the pharmacological sp~ ~ i:~city of m-CPP in humans has recently become controversial (Hamik and Peroutka 1 ~ ~9), our results are consistent with the hypothesis of altered 5-HT responsivity in ASP individuals, and that an association may exist between dimensions of assaultive aggression, dysphoric mood, increased needs, and central 5- HTergic functioning.

Methods

Subjects The experimental group consisted of i5 men with ASP (mean age 30.3 years) according to DSM-III-R clinical diagnostic criteria (APA 1987) referred from the inpatient units or outpatient clinics of Western Psychiatric institute and Clinic. All ASP subjects also met diagnostic criteria for a past or current psychoactive substance abuse disorder in addition to ASP; 13 had multiple substance dependence and 2 met criteria solely for alcohol dependence. Among the multiple substance abusers, 8 abused alcohol, 8 abused cocaine, 7 abused marijuana, 5 abused opiates, l abused amphetamine, and 3 abused LSD and/or mescaline. Prest~dy abstinence intervals ranged from 2 weeks to 5 years 7 months prior to participation i- the study, and were confirmed by urine toxicological testing and determination of serum gamma-glutamyl transaminase conce atrations. Eleven of the 15 sociopaths studied had a father who was an alcoholic according to Family History Research Diagnostic Criteria (FH-RDC) (Andreasen et al. 1977). All experimental and control subjects underwent a physical exam and laboratory biochemical evaluation to assure the absence of any active medical disorder including liver disease.

Serotonin and Behavior in Antisocial Addicts BIOL PSYCHIATRY 327 1990;27:325-338

Twelve healthy control men (mean age 28.5 years) who were without past or current DSM-III-R psychiatric diagnoses (including any psychoactive substance use disorders, or ASP) ~vere recruited to participate in this study. No control subject had a first or second degree family member who met FH-RDC criteria for alcoholism or drug use disorders. None currently used illicit drugs nor smoked cigarettes. No subjects had a subthreshold history of antisocial behavior. All control subjects admitted to occasional use of alcoholic beverages.

This protocol was approved by the Institutional Review Board of the University of Pittsburgh School of Medicine. All subjects provided informed consent prior to participation in this research. Subjects from both the experimental and control groups were paid for participation in this research protocol.

Assessment of Psychological Dimensions of ASP

Prior to the study day, all subjects completed the Psychopathic States Inventory (PSI) (Haertzen et al. 1980), an instrument designed to evaluate various dimensions of sociopathy that are hypothesized to underlie substance abuse. It is a 90-item self-administered questionnaire comprised of six sub,tales. The subscales (and their respective dimenJ sions) are (1) "search for highs" (motivation to use substances to alter consciousness); (2) impulsivity (self-report of impulsive behaviors); (3) egocentricity (self-centered attitudes); (4) increased needs; (5) hypophoria (negative affects); and (6) sociopathic behavior (self-report of antisocial activities). The inventory was developed by '.he authors utilizing rewritten scales from the MMPI, the California Psychological Inventory, and the Addiction Research Center Inventory.

Assessment of Cognitive Tempo as a Determinant of lmpulsivity

The hypothesis that cognitive tempo is a detenninant of impulsivity (Kagan 1966) is based on the observation that children and adults solved problems in two general ways. Some individuals select and report solutions to problems quickly with minimal reflection about their probable accuracy, whereas others take more, time to decide about the validity of their solutions. In this construct, the: former cognitive style is referred to as impulsivity, and the latter style is called reflection. The discriminant appears to be cognitive tempo rather than intelligence. The Matchin[~ Familiar Figures Test (MFFT) is a performance measure designed to differentiate between reflective versus impulsive cognitive styles (Kagan 1966). The test requires the sabject to select from among eight pictorial stimuli the one picture that is identical to the standard. Twelve trials are given and latency to first response (latency score) and the numbers of errors (up to 5 errors) before a correct match are recorded (error score). Although this instrument was originally developed to reliably evaluate dimensions of impulsivity in children (reviewed by Messer 1976), it has been demonstrated to be useful and valid for evaluation of these dimensions in adults as well (Kendall et al. 1980). All subjects completed the MFFT prior to the m-CPP study day.

Assessment of Hostility and Aggression The Buss-Durkee Hostility Inventory (BDI) is a self-rating scale of 75 true or false items. This instrument has been demonstrated to discriminate between violent and nonviolent alcohol abusers (Renson et al. 1978). The questionnaire is based on the rationale that


H.B. Moss et al.

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Figure 1. Serum prolactin responses to m-CPP. When prolactin concentrations at each time point were covaried with basal pmlactin concentrations (time = 0 min), ASP subjects were found to have significantly reduced prolactin concentrations at 30 min (F(2,22) = 95.18, p < 0.001); 60 min (F(2,22) = 14.57, p < 0.001); 90 min (F(2,22) = 7.44, p < 0.005); 120 rain (F(2,22) = 6.79, p < 0.01); 150 min (F(2,22) = 15.55, p < 0.001); 210 min (F(2,24) = 4.63, p < 0.05); and 240 min (F(2,24) = 8.9, p < 0.005).

hostility can be empirically divided into the following seven subgroups or scales (Buss and Durkee 1957): assault, indirect aggression, irritability, negativism, resentment (angry alienation), suspicion, and verbal aggression. Validity and reliability have been established for this instrument (Buss and Durkee 1957). All subjects completed the BDI prior to the m-CPP study day.

m-CPP Challenge

Subjects were instructed not to consume food or drink after midnight on the protocol day. On arrival at the study site, sabjects assumed a supine position, remained awake, and continued to fast until termination of the procedure. At approximately 9:00 AM on the protocol day, an intravenous catheter was inserted into an antecubital vein and kept patent with a saline infusion. After I hr of adaptation, three baseline 6 cc blood specimens were sampled 15 min apart through a two-way stopcock in the i.v. line. Im_~.,ediately after the last baseline blood sample was obtained, gelatin capsules containing m-CPP (0.5 mg/kg body weight) were ingested by the subjects followed by a drink of water. Serial 6 cc blood san~ples were then obtained at half-hour intervals for the next 4 hr. Se l l rat;ngs of side effects and mood state were obtained at baseline ( - 30 min) and at hourly intervals using a modified version of the NIMH Self Rating Scale (Van Kammen and Murphy 1975). Oral temperature, pulse, and blood pressure were also obtained at hourly intervals.

Samples were collected in commercial glass serum separation tubes (Becton Dickinson, Rutherford, N J) and kept on wet ice. After 20 min centrifugation at 4°C, serum was pipetted off and transferred to polypropylene storage tubes. Serum samples were stored at -80°C until assayed.


Assay Methods

Serum cortisol and prolactin concentrations were measured by a dissociation-enhanced lanthanide fluoroimmunoassay (DELFIA) method (Electro-Nucleonics, Inc., Columbia, MD). This is a solid phase, two-side fluoroimmunometric assay which is based on the "direct sandwich technique" in which there is competition between immobilized prolactin (or cortisol) and sample prolactin (or cortisol) for europium-labeled polyclonal antipro- lactin (or anticortisol) antibodies. Standard control and subject samples containing hormone inhibit the binding of the europium-labeled antibodies tc the immobilized hormone molecules.

The sensitivity of the DELFIA cortisol assay is approximately 5 nmol/liter. Intraassay precision is 5%-7% coefficient of variation (C.V.) within run and 4%-7% C.V. between run. Recoveries from spiked serum samples are 98.6% 4- 7.4% (n = 15). The cross reactivities (at the 50% inhibition level) of the DELFIA cortisol kit with other steroids are reported to be as follows: prednisolone 21.9%, 1 l-deoxycortisol 14.2%, prednisone 5.2%, 17-hydroxyprogesterone 4.6%, cortisone 4.3%, dexamethasone 2.4%, corticos- terone 1.2%, deoxycorticosterone 1.1%, and 1 l-dehydrocorticosterone 1.2%.

The sensitivity of the prolactin assay is 0.04 ng/ml. Intraassay precision is 2%-3% C.V. and interassay C.V. is 3%-6%. Recoveries from spiked serum samples are 100.4% ± 1.6% (n = 9). The cross reactivity of the DELFIA hPRL kit with other hormones (hGH, hFSH, hLH, hTSH, HCG) are reported to be less than 0.005%.

Statistical Analysis Following graphic representation and calculation of descriptive statistics, standard scores (Z-scores) were calculated for all psychometric test results in order to describe the relative position of these values within the subject distribution.

Mean basal prolactin and cortisoi concentrations were calculated using the three baseline serum samples ( - 3 0 min, - 1 5 min, and 0 time) prior to ingestion of m-CPP. Between-group differences in mean basal prolactin and cortisol concentrations, as well as psychometric test results, were tested by one-way analysis of variance (ANOVA). Post-m-CP? responses wcrc -:.valuated at each time point, and the integrated hormonal output over time was determined by calculation of prolactin and cortisol areas-under-the- curve (AUC) using Simpson's Rule (Tallarida and Murray 1981). Between-group differences in hormonal responses to m-CPP were tested using analysis of covariance (AN- COVA) with the mean basal prolactin and cortisol concentrations as covariates, respectively. Evaluations of linear associations between variables were performed using the Pearson correlation coefficient (r).

In order to establish which four of the psychometric and hormonal response variables were most important in distinguishing between ASP and control subjects, a stepwise discriminant analysis was performed using the minimizatlc , of Wilk's Lambda for variable selection (Lackenbruch 1975).

Psychological Characteristics of ASP Presumed to Underlay Substance Abuse

As noted in Table 1, significantly elevated scores for ASP versus control subjects were found with respect to "search for highs" (F(I,25) = 6.32, p < 0.02); impulsivi~y


H.B. Moss et al.

Table 1. Mean Psychometric Test Scores: ASP vs. Control Subjects

ASP Controls

Instrument (n = 15) (n = 12) //i

Psychopathic States Inventory "Search for highs" 3.40 ± 2.16 b !.75 .4- 0.75 0.02 Impulsivity 6.93 ± 3.67 4.17 .4- 2.79 0.04 Egocentricity 7.C-7 .4- 2.37 4.25 - 2.22 0.004 Increased needs 6.20.4- 2.68 3.50 ± 1.31 0.004 Hypophoria (Dysphoria) 7.40 ± 2.75 5.33 ± 1.87 0.04 Sociopathic attitudes 4.60 ± 2.69 1.33 ± 1.50 <0.001 Total psychopathy 35.60 ± 13.88 20.33 ± 9.26 0.003

Buss Durkee Hostility Inventory Assault 5.67 ± 2.50 2.83 ± 0.94 0.001 Indirect aggression 4.13 ± 1.9b 2.58 ± 1.73 0.04 Irritability 5.80 ± 2.54 3.08 ± 1.24 0.002 Negativism 2.73 ± 1.44 2.00 ± 1.21 n.s. Resentment 4.13 ± 1.77 1.58 _+ i.56 <0.001 Suspicion 4.87 ± 1.92 2.75 ± 2.26 0.01 Verbal Aggression 7.60 ± 2.67 4.92 ± 2.61 0.01 Guilt 4.21 ± 2.49 2.42 ± 2.78 0.09 Total hostility/aggression 39.20 ± 13.15 22.17 ± 7.44 <0.001

Matching familiar figures test Response latency (see) 29.68 ± 13.80 28.26 ± 13.81 n.s. Errors 17.92 ± 8.28 I! .00 ± 7.58 0.04

q3ne way ANOVA.

bValues are _+ SD.

(F(1,25) = 4.65, p < 0.05); egocentficity (F(1,25) = 9.93, p < 0.005); increased needs (F(1,25) = 10.18, p < 0.005); hypophoria (F(1,25) = 4.93, p < 0.05); sociopathic behavior (F(1,25) = 14.09, p < 0.001); and the sun~lmary psychopathy scores (F(1,25) = 10.67, p < 0.005). Thus, the experimental group scored significantly higher on all the dimensions of sociopathy underlying substance abuse as assessed with the PSI.

Conceptual Tempo as a Determinant of lmpulsivity

Significant between-group differences were not found for latency scores on the MFFT (F(1,23) = 0.07, n.s.). However, ASP subjects were found to have significantly higher error scores than controls (F(1,23) = 4.73, p < 0.05) suggesting reduced test-taking efficiency among sociopathic subjects. Mean latency and error scores by group are shown in Table 1.

In order to test the dimensional relationship between self-reports of dispositional impulsive behavior from the PSI impulsivity scale, and the cognitive tempo performance scores i;om the M..~T_~ correlations were performed with pooled data from both groups. A modest positive correlation was ,,,,... . . . . . . . . . . . . . . . . . . . . . . . . and PSI impulsivity self-report scores (r = 0 .41 , n = 25, p < 0 .05) . N o such correlation was found between MFFT errors and PSI impulsivity scores (r ~ 0~05, n = 25, n.s.).

Serotonin and Behavior in Antisocial Addicts nlot. PS¥CHP,'mV 33 i 1990;27:325-338

Assessment of Hostility and Aggression

Hostility/aggression scores from the BDI are shown in Table 1. ASP subjects had significantly higher assaultiveness scores than controls (F(1,25) = 13.79, p = 0.001). ASP subjects also had significantly higher indirect aggression scores (F(1,25) = 4.62, p < 0.05) than controls. Irritability scores were also significantly higher among the ASP group (F(1,25) = 11.46, p < 0.005). However, negativism scores showed no between-group differences (F(1,25) = 1.99, n.s.). Resentment scores (F(1,25 = 15.33, p < 0.001), suspicion scores (F(1,25 = 6.91, p < 0.05), verbal aggression scores (F(1,25) = 6.88, p < 0.05), and the total BDI summary scores (F(1,25) = 15.95, p = 0.0005) were significantly higher among ASP subjects than controls. There was a trend toward higher guilt scores among ASP subjects than controls (F(1,25) = 3.03, p = 0.09).

Hormonal Responses to m-CPP

Prolactin responses. The prolactin time-concentration curves are shown in Figure 1. Basal prolactin concentrations were not found to differ between ASP and control subjects (F(1,25) = 0.0004, n.s.). Following ingestion of m-CPP, ASP subjects demonstrated a blunted prolactin response relative to controls across most of the 240 min of the procedure. When covaried with basal prolactin concentrations, ASP subjects were found to have significantly reduced prolactin responses at +30 min (F(2,22) = 95.18, p < 0.001), +60 min (F(2,22) = 14.57, p < 0.001), +90 min (F(2,22) = 7.44, p < 0.005), + 120 min (F(2,22) = 6.79, p < 0.01), + 150 min (F(2,22) = 15.55, p < 0.001), + 180 rain (F(2,24) = 2.9, p = 0.07) (trend), +210 rain (F(2,24) =.4.63, p < 0.02), and at + 240 min (F(2,24) = 8.9, p < 0.005). Post m-CPP prolactin AUCs (Figure 3), when corrected for basal prolactin, were also significantly less among ASP subjects than controls (F(2,24) = 23.8, p < 0.001).

Cortisol responses. Cortisol concentration-t:~me curves are shown in Figure 2. No differences in basal cortisol concentrations were found between ASP and control subjects (F(1,25) = 0.24, n.s.). When basal cortisol was covaried with cortisol levels at each post-m-CPP time point, significant differences between ASP subjects and controls were found such that ASP subjects had greater cortisol concentrations at + 30 min (F(2,24) = 20.66, p < 0.001), a trend at +90 rain (F(2,24) = 2.88, p < 0.08), and at + 120 min (F(2,24) = 7.37, p < 0.005). When post-m-CPP cortisol AUCs were covaried with basal cortisol levels (Figure 4), significantly higher cortisc! AUCs were found among the ASP subjects (F(2,24) = 4.4, p < 0.03).

Associations Between Measures of Saciopathy, Aggressivity, Cognitive Tempo, and Hormonal Responses Correlations between the integrated post-m-CPP prolactin concentrations over time (prolactin AUC), the integrated corfisol responses (cortisol AUC), and the various measures of sociopathy, aggressivity, and cognitive tempo are shown in Table 2. Significant, but modest, negative correlations were found between projacth~ AUC apd a~-sau!tiveness (r = - 0 . 4 3 , p = 0.03), prolactin AUC and hypophoria (dysphoria) (r = -0 .39 , p < 0.05), and for prolactin AUC and increased needs (r = -0 .38 , p = 0.05). Modest trends were noted for prolactin AUC and "search for highs" (r = -0 .35 , p = 0.08),


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Figure 2. Serum cortisol responses to m-CPP. When serum cortisol concentrations were covaried with basal concentrations (time = 0 min), ASP subjects were found to have greater cortisol concentrations at 30 min (F(2,24) = 20.66, p < 0.001), a trend toward greater cortisol at 90 min (F(2,24) = 2.88, p < 0.08), and significantly greater concentrations at 120 min (F(2,24) = 7.37, p < 0.005).

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Figure 3. Prolactin responses to m-CPP integrated over time. Post :n-CPP prolactin AUCs, corrected for basal prolactin, were significantly less for ASP subjects than for controls (F(2,24) = 23 8, p < 0.001).

Serotonin and Behavicr in Antisocial Addicts BIOL PSYCW~ATRY 333 1990;27:32A -338

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Figure 4. Cortisol responses to m-CPP integrated over time. Post-m-CPP cortisol AUCs, correlated for basal cortisol levels, were significantly higher for ASP subjects than for controls (F(2,24) = 4.4, p < 0.03).

Table 2. Correlation Coefficients for Hormonal Responses to m-CPP and Psychometric Measures of Sociopathy, Aggression, and Cognitive Tempo

Instrument Prolactin AUC Cortisol AUC

Psychopathic States Inventory ':Search for high" - 0 . 3 5 07 = 0.08) - 0 . 3 2 (n.s.) Impulsivity - 0.20 (n. s.) - 0.21 (n.s.) Egocentricity - 0 . 3 3 07 = 0.09) - 0 . 2 3 (n.s.) Increased needs - 0 . 3 8 (p = 0.05) - 0 . 1 7 (n.s.) Hypophoria (Dysphoria) - 0 . 3 9 07 = 0.05) - 0 . 1 4 (n.s.) Sociopath~c attitudes - 0.24 (n.s.) - 0.14 (n.s.) Total psychopathy - 0 . 3 4 07 < 0.09) - 0 . 2 2 (n.s.)

Buss-Durkee Hostility Inventory Assault - 0 . 4 3 07 < 0.03) - 0 . 0 7 (n.s.) Indirect aggression - 0 . 2 2 (n.s.) 0.26 (n.s.) Irritability - 0 . 1 6 (n.s.) 0.02 (n.s.) Negativism - 0.14 (n.s.) - 0.12 (n.s.) Resentment - 0 .25 (n.s.) - 0. ! ~ (n.s.) Suspicion - 0 . 2 4 (n.s.) - 0 . 1 2 (n.s.) Guilt - 0 . 1 4 (n.s.) - 0 . 3 3 07 = Total hostility/aggression - 0.29 (n.s.) - 0.08 (n.s.)

Matching familiar figures test Response latency 0.07 (n.s.) - 0 . 1 0 (n.s.) Errors 0.11 (n.s.) 0..04 (n.s.)

0.09)

Significant correlations appear in bold. AUC = post-m-CPP "area-under-the-curve as calculated by Simpson's rule.


H.B. Moss et al.

Table 3. Discriminant Function Analysis

Standardized canonical discriminant function coefficients BDl-resentment 0.53 MFFT-errors score 0.58 BDl-irritability 0.60 Prolactin AUC - 0.52

Canonical discriminant functions at group means Antisocial personality disorder (ASP) Con~'ols

Classification results

1.07 - ! . 1 6

Actual group Predicted group ASP Control

ASP (n = 15) 14 (93.3%) 1(6.7%) Controls (n = 12) ! (8.3%) !1 (91.7%)

Percentage of cases directly classified = 92.6%.

prolactin AUC and egocentficity (r = -0 .33 , p = 0 . 0 9 ) , and prolactin AUC enid total PSI score (r = -0 .34 , p < 0.09).

No significant correlations between cortisol AUC and psychometric measures were found, although a trend suggested an inverse association between cortisol AUC and guilt (r = -0 .33 , p = 0.09). Measures of cognitive tempo obtained from the MFFT did not significantly correlate with either hormonal output signal.

Discriminanl Analys~5

The four predictor variables derived from the discriminant analysis procedure were BDI resentment, MFFT errors, BDI irritability, and prolactin AUC. The standardized canonical discriminant function coefficients, and the canonical discriminant functiorps at group mem~ls are shown in Table 3. The results of classification of subjects base~ on a priori group membership (ASP versus controls) compared to the predicted grouping using the discriminant function are also shown in Table 3. The percent of correctly classified subjects based on this discriminant function using the four predictor variables was 92.6%.

Discussion

As previously noted, alterations in serotonergic neurotransmission have been implicated in disorders characterized by impulsivity, aggression, low mood, and substance abuse. ASP is a syndromal disorder that typifies these disinhibitory attributes. The preliminary observation of a blunted prolactin response, and a modestly elevated cortisol response to the 5-HT agonist, m-CPP among ASP subjects supports the notion of altered serotonergic neurotransmission in these individuals. Ho~vever, recent evidence concerning the pharmacological specificity of ..,n-CPP in humans has made this interpretation somewhat more controversial.

A recent report concerning the affinity of m-CPP at various neurotransmitter receptor binding sites in the postmortem human frontal cortex suggests that the drug has equipotent affinities not only at all serotonergic receptors, but also at alphaz-adrenergic, and to a lesser extent at alphar and beta-adrenergic receptors, as well as dopaminergic and musu

Serotonin and Behavior in Antisocial Addicts BIOL PSYCHIATRY 335 1990:27:325-338

carinic receptor sites (Hamik and Peroutka 1989). Thus, what was originally thought to be a highly specific 5-HT~B agonist in animal models (Sills et al. 1984) now appears to have broader activity and less pharmacological specificity in man. However, the observation that the nonspecific 5-HT antagonist metergoline almost totally blocks the hormonal response to m-CPP in humans (Meuller et al. 1986) supports the initial theoretical con- tcntion that 5-HTergic function is implicated in this hormonal output signal, and therefore the reduced prolactin responses noted in our ASP subjects is probably due to functional differences in this neurotransmitter system. There are also numerous other neurochemical factors that modulate prolactin secretion, and could therefore be involved in this differential response (Tuomisto and Mannisto 1985).

The observation that ASP individuals have an enhanced cortisol response compared with controls is also difficult to interpret given the various modulatory factors present along the hypothalamic-pituitary-adrenal axis. Future measurement of the ACTH responses to m-CPP in these subjects may clarify at what level of biological organization this response is occurring.

An additional methodological problem is interpretation of these results stems from the absence of m-CPF pharmacokinetic data from all subjects. Between-group differences in hormonal responses may be due to the differential absorption, distribution, and elimination of the dose of oral m-CPP administered. Similarly, abuse of specific drugs by ASP subjects may bias the hormonal responses to m-CPP. For example, cocaine abuse may cause a persistent perturbation of the dopaminergic prolactin regulatory system (Mendelson et al. 1988). However, the ASP sample size is insufficient to test this hypothesis.

The strongest as,:,ociations between the prolactin response and dimensional dispositional characteristics were in the areas of physical aggression, dysphoric mood, and increased needs. Our results confirm the previously noted observations of a relationship among altered 5oHTergL,;: fun,:tion, physical aggressivity, and low mood. However, they bring into question the association between impulsivity and altered 5-HT neurou'ansmission. Neither self-reports of impulsive behavior nor impulsive cognitive style (as defined by short latencies to erroneous responses on the MFFT) correlated with either prolactin or cortisol responses to m-CPP.

Impulsivity (as measured by either behavioral self report or cognitive tempo) was not found to be a discriminant of ASP group membership nor did it correlate with prolactin or cortisol responses to m-CPP. Perhaps this is due to the fact that the construct of "impulsivity" suffers from a lack of universally accepted operational criteria. Our performance and self-report measures of impulsivity correlated only weakly. Others have also noted this lack of association between different impulsivity measures, and their underlying theoretical constructs (Paulsen and Johnson 1980; Gerbing et al. 1987). Despite the importance of the concept of impulsivity to contemporary psychiatry (e.g., substance abuse, eating disorders, pathological gambling, explosive disorders), disparate constructs and methods of quantification hinder systematic research.

Our results further conf,,-n the observations of Haerzten et al. (1980) concerning the presence of dispositional characteristics of sociopaths which may either predispose them to or coexist with substance abuse. ASP subjects demonstrated greater motivation to alter consciousness with substances; greater self-reported impulsive behavior, egocena'icity, dysphoria, and antisocial attitudes; physical assaultiveness, irritability, resentment, suspicion, and indirect aggression; and poorer test-taking efficiency due either to diminished motivation or an inherent cognitive incapacity. Given these dispositional characteristics,


H.B. Moss et al.

it is hardly surprising that ASP individuals have a relatively poor outcome in substance abuse treatment (Cadoret et al. 1984; Woody et al. 1985; RounsaviUe et al. 1987).

Recently, Coccaro et al. (1989) and Fishbein et al° (1989) have reported on the effects of pharmacological chMlenges using fenfluramine (a presynaptic 5-HT releaser and ~eup- take inhibitor) on prolactin and cortisol secretion in personality-disordered mtd sub~,ta~ce- abuse populations, respectively. Fishbein et al. found that aggressive and impulsive substance abusers had greater prolactin concentrations at baseline and following admin- istration of fenfluramine, but Coccaro et al. found that among a mixed group of impulsive and aggressive personality-disordered and affective-disordered patients, prolactin responses were inversely related to severity of assaultiveness and impulsivity and a history of suicide attempts. Our findings, using the 5-HT agonist m-CPP rather than fenfluramine, are consistent with the latter report on an inverse association between assaultive aggression and prolactin response to 5-HT stimulation, but do not support the former group's observation of an elevated baseline prolactin or a direct linear association between the prolactin response to 5-HT stimulation and the magnitude of aggression and impulsivity present in substance-abusing subjects. Perhaps differences in diagnostic groups account for this discrepancy.

It is unclea~, whether our results are indicative of the features of "pure" ASP, the substrate or consequences of substance abuse among ASP subjects, or characteristic of sociopathic substance abusers as a unique entity. The high proportion of ASP subjects with a positive family history of substance abuse disorders further begs the question of whether ASP substance abusers are a unique taxonomic category [such as Cloninger's (1988) type 2 alcoholic] or whether they represent a comorbid diagnostic condition. The diagnostic confusion over the relationship between s~iopathy and substance abuse, first noted by Schuckit (1973), seriously hampers precise intet+vretation of these data.

The elucidation of putative serotonergic mechanisms underlying ASP, substance abuse disorders, and their psychological attributes clearly requires further research utilizing more specific 5-HT agonists, and involves challenges with both presynaptic and Imst- synaptic drugs within each carefully ascertained st~bject. Longitudinal investigations into the psychobiology of conduct-disordered adolescents (initiated prior to the onset of substance abuse), may yield some clarification as to whether altered 5-HTergic function is a result or a consequence of substar++ee abuse, or is associated with the dispositional characteristics of ASP.

The authors wish to thank Ralph Tarter, Ph.D., for his statistical consultation and advice in the preparation of this manuscript, and Jules Rosen, M.D. for his useful comments concerning the manuscript.

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