BIOL PSYCHIATRY 1990;28:325-338
325
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 obsessivecompulsive 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 5HTergic 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, mchlorophenylpiperazine (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:~cityof 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 5HTergic 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 1990;27:325-338
327
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) ~vererecruited 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
328
H.B. Moss et al.
BIOL PSYCHIATRY 1990;28:325-338
10
1 E E
8
/
C
o O_
oT-To
T/
6t
0
E
l
O
O ~
J,~
1
©
.
d3 &
O I
0
30
60
90 120 time (rain.)
ASP O Controls &
I
I
1
150
180
210
240
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. S e 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 - 8 0 ° C until assayed.
Serotonin and Behavior in Antisocial Addicts
BIOL PSYCHIATRY 1990;27:325-338
329
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 antiprolactin (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%, 1l-deoxycortisol 14.2%, prednisone 5.2%, 17-hydroxyprogesterone 4.6%, cortisone 4.3%, dexamethasone 2.4%, corticosterone 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-thecurve (AUC) using Simpson's Rule (Tallarida and Murray 1981). Between-group differences in hormonal responses to m-CPP were tested using analysis of covariance (ANCOVA) 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
330
H.B. Moss et al.
BIOL PSYCHIATRY 1990;28:325-338
Table 1. Mean Psychometric Test Scores: ASP vs. Control Subjects Instrument Psychopathic States Inventory "Search for highs" Impulsivity Egocentricity Increased needs Hypophoria (Dysphoria) Sociopathic attitudes Total psychopathy Buss Durkee Hostility Inventory Assault Indirect aggression Irritability Negativism Resentment Suspicion Verbal Aggression Guilt Total hostility/aggression Matching familiar figures test Response latency (see) Errors
ASP (n = 15)
Controls
(n = 12)
//i
3.40 ± 6.93 ± 7.C-7 .46.20.47.40 ± 4.60 ± 35.60 ±
2.16 b 3.67 2.37 2.68 2.75 2.69 13.88
!.75 4.17 4.25 3.50 5.33 1.33 20.33
.4.4± ± ± ±
0.75 2.79 2.22 1.31 1.87 1.50 9.26
0.02 0.04 0.004 0.004 0.04
325
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 obsessivecompulsive 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 5HTergic 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, mchlorophenylpiperazine (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:~cityof 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 5HTergic 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 1990;27:325-338
327
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) ~vererecruited 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
328
H.B. Moss et al.
BIOL PSYCHIATRY 1990;28:325-338
10
1 E E
8
/
C
o O_
oT-To
T/
6t
0
E
l
O
O ~
J,~
1
©
.
d3 &
O I
0
30
60
90 120 time (rain.)
ASP O Controls &
I
I
1
150
180
210
240
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. S e 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 - 8 0 ° C until assayed.
Serotonin and Behavior in Antisocial Addicts
BIOL PSYCHIATRY 1990;27:325-338
329
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 antiprolactin (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%, 1l-deoxycortisol 14.2%, prednisone 5.2%, 17-hydroxyprogesterone 4.6%, cortisone 4.3%, dexamethasone 2.4%, corticosterone 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-thecurve (AUC) using Simpson's Rule (Tallarida and Murray 1981). Between-group differences in hormonal responses to m-CPP were tested using analysis of covariance (ANCOVA) 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
330
H.B. Moss et al.
BIOL PSYCHIATRY 1990;28:325-338
Table 1. Mean Psychometric Test Scores: ASP vs. Control Subjects Instrument Psychopathic States Inventory "Search for highs" Impulsivity Egocentricity Increased needs Hypophoria (Dysphoria) Sociopathic attitudes Total psychopathy Buss Durkee Hostility Inventory Assault Indirect aggression Irritability Negativism Resentment Suspicion Verbal Aggression Guilt Total hostility/aggression Matching familiar figures test Response latency (see) Errors
ASP (n = 15)
Controls
(n = 12)
//i
3.40 ± 6.93 ± 7.C-7 .46.20.47.40 ± 4.60 ± 35.60 ±
2.16 b 3.67 2.37 2.68 2.75 2.69 13.88
!.75 4.17 4.25 3.50 5.33 1.33 20.33
.4.4± ± ± ±
0.75 2.79 2.22 1.31 1.87 1.50 9.26
0.02 0.04 0.004 0.004 0.04
