Moderating effects of childhood maltreatment on associations between social information processing and adult aggression.

BACKGROUND: Associations between early life maltreatment, social information processing (SIP) and aggression in childhood and adolescence have been widely documented. Few studies have examined the importance of childhood maltreatment independent of SIP in the etiology of adult aggression. Furthermore, moderating effects of childhood maltreatment on the SIP-aggression links have not been explored. METHOD: Hierarchical, multi-level models were fitted to data from n=2752 twins aged 20-55 years from the PennTwins Cohort. Adult aggression was assessed with the Life History of Aggression questionnaire. Childhood maltreatment was measured using the Childhood Trauma Questionnaire. Two aspects of SIP were examined: hostile attribution biases (HAB); negative emotional responses (NER). RESULTS: Childhood maltreatment was positively correlated with adult aggression, independently of HAB and NER. In addition, childhood maltreatment moderated the relationships between both aspects of SIP and adult aggression. Specifically, the relationship between NER and aggression was stronger among individuals with higher levels of childhood maltreatment and NER was not associated with aggression for adults who experienced low levels of childhood maltreatment. Moderating effects of childhood maltreatment on the NER-aggression link were supported for total childhood maltreatment, emotional neglect and emotional abuse. In contrast, HAB was more strongly associated with adult aggression at lower levels of emotional abuse and physical neglect. CONCLUSIONS: The current study provides insight into the mechanisms by which early life experiences influence adult aggression. Our findings suggest that childhood maltreatment may not only lead to increased levels of aggression in adulthood but may also modify the associations between SIP and adult aggression.

Fluoxetine and impulsive aggressive behavior in personality-disordered subjects.

BACKGROUND: Evidence of an inverse relationship between central serotonergic (serotonin [5-hydroxytryptamine]) system function and impulsive aggressive behavior has been accumulating for more than 2 decades. If so, pharmacological enhancement of serotonin activity should be expected to reduce impulsive aggressive behavior in subjects in whom this behavior is prominent. METHODS: A double-blind, placebo-controlled trial of the selective serotonin-uptake inhibitor fluoxetine hydrochloride was conducted in 40 nonmajor-depressed, nonbipolar or schizophrenic, DSM-III-R personality-disordered individuals with current histories of impulsive aggressive behavior and irritability. Measures included the Overt Aggression Scale-Modified for Outpatients, Clinical Global Impression Rating of Improvement, and several secondary measures of aggression, depression, and anxiety. RESULTS: Fluoxetine, but not placebo, treatment resulted in a sustained reduction in scores on the Irritability and Aggression subscales of the Overt Aggression Scale-Modified for Outpatients that was first apparent during months 2 and 3 of treatment, respectively. Fluoxetine was superior to placebo in the proportion of "responders" on the Clinical Global Impression Rating of Improvement: first at the end of month 1, and then finally demonstrating a sustained drug-placebo difference from the end of month 2 through the end of month 3 of treatment. These results were not influenced by secondary measures of depression, anxiety, or alcohol use. CONCLUSION: Fluoxetine treatment has an antiaggressive effect on impulsive aggressive individuals with DSM-III-R personality disorder.

Impulsive aggression in personality disorder correlates with tritiated paroxetine binding in the platelet.

BACKGROUND: To examine the relationship between binding parameters of the platelet central serotonergic (5-HT) transporter and measures of aggression and impulsivity in adult human subjects. METHODS: Maximal number of platelet tritiated paroxetine binding sites (Bmax) and dissociation constant (Kd) values were measured in patients with personality disorder (n = 24) and healthy volunteers (n = 12). Measures of aggression and impulsivity included the total score and aggression subscale of the Life History of Aggression, the Motor Aggression factor and the assault subscale of the Buss-Durkee Hostility Inventory, and the total score and motor impulsivity subscale of the Barratt Impulsiveness Scale. RESULTS: The Bmax, but not Kd, values of platelet tritiated paroxetine binding was inversely correlated with the Life History of Aggression total score and aggression score and with the Buss-Durkee Hostility Inventory assault score in patients with personality disorder but not in healthy volunteer subjects. This relationship was independent of influences of factors related to depression, global function, or history of alcoholism or drug abuse. CONCLUSIONS: Reduced numbers of platelet 5-HT transporter sites may covary with life history of aggressive behavior in patients with personality disorder. This may represent another abnormality in 5-HT function in individuals with personality disorder and aggressive behavior.

Cerebrospinal fluid vasopressin levels: correlates with aggression and serotonin function in personality-disordered subjects.

BACKGROUND: Animal studies suggest that central vasopressin plays a facilitatory role in aggressive behavior. To examine this possibility in humans, the relationship between cerebrospinal fluid (CSF) arginine vasopressin (AVP) and indices of aggression and central serotonin system function was examined in personality-disordered subjects. METHODS: We used CSF (AVP), CSF 5-hydroxyindoleacetic acid, and the prolactin response to d-fenfluramine challenge (PRL[d-FEN]) as central indices of vasopressin and serotonergic system function, respectively, in 26 subjects who met the DSM-IV criteria for personality disorder. Measures of aggression and impulsivity included the Life History of Aggression assessment and the Barratt Impulsiveness Scales. RESULTS: The CSF AVP level was correlated directly with life history of general aggression and aggression against persons and inversely with PRL[d-FEN] responses (but not with CSF 5-hydroxyindoleacetic acid), which in turn was correlated inversely with these 2 measures of life history of aggression. The positive relationship between CSF AVP and life history of aggression remained even when the variance associated with PRL[d-FEN] responses in these subjects was accounted for. CONCLUSION: Central AVP may play a role in enhancing, while serotonin plays a role in inhibiting, aggressive behavior in personality-disordered individuals. In addition to the possibility of central AVP and serotonin interacting to influence human aggression, central AVP may also influence human aggressive behavior through a mechanism independent of central serotonin in personality-disordered subjects.

Familial correlates of reduced central serotonergic system function in patients with personality disorders.

BACKGROUND: To test the hypothesis that evidence of reduced central serotonergic (5-HT) system function in probands with personality disorders is associated with an elevated morbid risk of psychopathological conditions putatively associated with 5-HT dysfunction in first-degree relatives of these probands. METHODS: Data were collected during a study of the 5-HT correlates of behavior in male patients with DSM-III personality disorders conducted at a Veterans Affairs medical center. Probands in this study were selected from those patients who had undergone both a fenfluramine hydrochloride challenge and a family history assessment. Axis II diagnosis were made according to DSM-III criteria after a structured interview of the proband, using the Structured Interview for Diagnosing Personality Disorders, given by two raters and a similar interview with a knowledgeable informant by another rater. RESULTS: Reduced prolactin responses to the 5-HT releasing/uptake inhibiting agent fenfluramine was associated with an elevated morbid risk of impulsive personality disorder traits in the first-degree relatives of patients with a primary DSM-III diagnosis of a personality disorder. Quantitative scores on assessments of impulsive aggression in the probands were not correlated with an increased morbid risk for impulsive personality disorder traits. A trend in the same direction was noted for affective personality disorder traits and alcoholism. CONCLUSIONS: These results suggest that a central 5-HT system abnormality in probands is associated with an increased risk of impulsive aggression in their first-degree relatives, and that assessment of central 5-HT system function in probands may be a more sensitive parameter for identification of this familial trait than the presence of impulsive aggressive behaviors in the proband.

Prostaglandin receptor sensitivity in psychiatric disorders.

The cyclic adenosine monophosphate (cAMP) responses to prostaglandin E1 (PGE1) in platelets and leukocytes from drug-free schizophrenic patients, depressive patients, and normal controls have been compared. Both schizophrenic and depressive patients had a significantly lower platelet cAMP response to PGE1 than controls. The platelet cAMP response to PGE1 did not discriminate among exacerbated, remitted, and poor-prognosis schizophrenic patients, or between exacerbated and remitted depressive patients. The cAMP response to PGE1 was negatively correlated with global symptom severity in actively ill schizophrenic patients, but was not correlated with symptom severity in exacerbated depressive patients. The leukocyte cAMP response to PGE1 did not differ among normal controls, schizophrenic patients, and depressive patients. These data indicate that a diminished platelet cAMP response to PGE1 may be a marker common to both schizophrenia and depression but that this effect does not extend to a cAMP-linked PGE1 receptor on another blood cell type.

Serotonergic studies in patients with affective and personality disorders. Correlates with suicidal and impulsive aggressive behavior.

Dysfunction of the central serotonergic system has been variously associated with depression and with suicidal and/or impulsive aggressive behavior. To evaluate central serotonergic function in relation to these variables, prolactin responses to a single-dose challenge with fenfluramine hydrochloride (60 mg orally), a serotonin releasing/uptake-inhibiting agent, were examined in 45 male patients with clearly defined major affective (n = 25) and/or personality disorder (n = 20) and in 18 normal male control patients. Prolactin responses to fenfluramine among all patients were reduced compared with responses of controls. Reduced prolactin responses to fenfluramine were correlated with history of suicide attempt in all patients but with clinician and self-reported ratings of impulsive aggression in patients with personality disorder only; there was no correlation with depression. These results suggest that reduced central serotonergic function is present in a subgroup of patients with major affective and/or personality disorder and is associated with history of suicide attempt in patients with either disorder, but with impulsive aggression in patients with personality disorder only.

Serotonin function and antiaggressive response to fluoxetine: a pilot study.

BACKGROUND: The reported inverse relationship between indices of central serotonin (5-HT) function and indices of impulsive aggression in human subjects suggests the possibility that enhancement of 5-HT activity will reduce impulsive aggressive behavior. Although evidence for this hypothesis is emerging, the relationship between baseline central 5-HT system function and antiaggressive responses to treatment with 5-HT agents has not yet been examined in human subjects. METHODS: In this pilot study, we examined the relationship between: a) pretreatment prolactin responses to d-fenfluramine (PRL[d-FEN]) challenge; and b) antiaggressive responses to 12 weeks of treatment with either fluoxetine or placebo in 15 impulsively aggressive personality disordered subjects as observed in a 12-week, double-blind, placebo-controlled trial. RESULTS: Among all subjects there were positive correlations between the pretreatment PRL[d-FEN] response and the percent improvement in Overt Aggression Scale-Modified scores for "Aggression" and "Irritability." These correlations were present in the fluoxetine (n = 10), but not in the placebo (n = 5), treated subjects. CONCLUSIONS: These data suggest the possibility that the antiaggressive response to fluoxetine is directly, rather than inversely, dependent on the responsiveness of central 5-HT synapses in the brain of impulsive aggressive personality disordered subjects.

Prolactin response to d-fenfluramine in major depression before and after treatment with serotonin reuptake inhibitors.

BACKGROUND: Central serotonin dysfunction is thought to be involved in the etiology of major depression. Serotonergic challenge studies before and after treatment of depressed patients have yielded conflicting results; however, these studies have not focused on the effect of antidepressant treatment with selective serotonin reuptake inhibitors (SSRIs) on serotonergic challenge studies. METHODS: The authors studied 19 outpatients with major depressive disorder using prolactin response to d-fenfluramine as a measure of central serotonergic functioning. Testing of patients was conducted just before and right after 8 weeks of treatment with either fluoxetine (n = 10) or fluvoxamine (n = 9) as part of a randomized, double-blind treatment trial. Blood samples for prolactin were collected prior to administration of d-fenfluramine (0.5 mg/kg) and then over the next 5 hours. RESULTS: Unlike previous studies in which antidepressant treatment produced an enhanced prolactin response to fenfluramine, in this study there was no increase in prolactin response to d-fenfluramine following SSRI treatment. In fact, prolactin response to d-fenfluramine was significantly diminished after treatment with fluvoxamine but not fluoxetine. CONCLUSIONS: The implications of these findings are discussed with regard to possible mechanisms of action of SSRI treatment.

The cortisol response to clonidine in acute and remitted depressed men.

To assess the relationship between the hypothalamo-pituitary-adrenal (HPA) axis and the noradrenergic system in patients with major depression, 26 normal controls, 32 acutely depressed patients, and 21 patients with remitted depression, all men, were administered intravenous clonidine (2 micrograms/kg) or placebo. Acute, but not remitted, depressed patients had a greater plasma cortisol baseline than did normal controls (t = 2.0, p < 0.03). Only acutely depressed patients had a greater decrease in plasma cortisol in response to clonidine than to placebo (t = 2.5, p < 0.02). Statistically controlling for both diurnal variation and baseline cortisol, acute, but not remitted, depressed patients had a greater decrease in plasma cortisol in response to clonidine than did the controls (analysis of covariance: F[1,35] = 4.26, p < 0.05). These results support a state-dependent noradrenergic-HPA axis regulatory disturbance in depressed patients, suggesting that clonidine inhibits the elevated plasma cortisol in acute depression but not the normal concentrations observed in remitted depression or healthy controls.

The TRH-stimulation test in DSM-III personality disorder.

The authors examined thyrotropin-releasing hormone (TRH) stimulation testing in the neuroendocrine evaluation of DSM-III major depressive disorder in 26 consecutive medication-free, medically healthy patients meeting a primary DSM-III diagnosis of axis II personality disorder. Thyroid-stimulating hormone (TSH) responses to TRH challenge were not significantly different between patients with or without major depression at time of study, or between patients with or without a life history of major affective disorder. Further, TSH responses to TRH among 11 healthy male nonpsychiatric controls were not significantly different from those in patients with personality disorders. Comparison of those patients with blunted TSH responses (< 7.0 microU/ml) versus those without blunted response (< or = 7.0 microU/ml) also did not reveal a significant difference. In addition, the TSH response to TRH did not correlate with dimensional assessments of state or trait depression, anxiety, or with past history of suicide attempt or alcohol abuse. These data suggest that TRH stimulation testing has limited utility in the evaluation of major depression or other relevant affective states/traits in personality-disordered patients. Affective symptoms in personality-disordered patients do not seem to be associated with dysregulation of the hypothalamic-pituitary-thyroid axis.

Platelet [3H]imipramine binding in psychiatric disorders.

The Bmax and Kd values for [3H]imipramine binding were measured in platelets from drug-free normal controls and schizophrenic and depressive patients. No differences among groups were found. Exacerbated and remitted patients with either schizophrenia or depression did not differ in platelet [3H]imipramine binding parameters. No correlations were observed between platelet [3H]imipramine binding parameters and measures of symptom severity among actively ill patients with either schizophrenia or depression.

Relationship of prolactin response to d-fenfluramine to behavioral and questionnaire assessments of aggression in personality-disordered men.

Prolactin (PRL) responses to acute challenge with the serotonin (5-HT) releaser/uptake inhibitor, d-fenfluramine (PRL[d-FEN]), were correlated with three different measures of aggression in 14 male personality-disordered subjects. Consistent with previous work, PRL[d-FEN] responses were inversely correlated with scores on the Buss-Durkee Hostility Inventory-Assault scale (BDHI-Assault) and with the Brown-Goodwin Aggression-Revised (BGA-R) Aggression scale. In addition, PRL[d-FEN] responses were inversely correlated with a direct laboratory measure of aggressive behavior (Point-Subtraction Aggression Paradigm: PSAP). Although all measures of aggression correlated with PRL[d-FEN] response, differences among the intercorrelations of these measures were found. Specifically, BGA-R Aggression scores correlated with both BDHI-Assault and PSAP scores, but no relation was found between BDHI-Assault and PSAP scores. The results suggest that central 5-HT function may be associated with both self-report and behavioral measures of aggressive behavior, which may represent somewhat separate aspects of aggressive behavior.

Heritability of aggression and irritability: a twin study of the Buss-Durkee aggression scales in adult male subjects.

To determine the degree of genetic and environmental influences on assessments of aggression and irritability in male subjects, the "Motor Aggression" subscales of the Buss-Durkee Hostility Inventory (BDHI) were mailed to 1208 male twins in the Vietnam Era Twin Registry. Data from monozygotic 182 and 118 dizygotic twin pairs were available and were analyzed using model-fitting procedures. Three of the four BDHI subscales demonstrated significant heritability of a nonadditive nature: 40% for Indirect Assault, 37% for Irritability, and 28% for Verbal Assault. Additive genetic variance accounted for 47% of the individual differences for Direct Assault. Nonshared, but not shared, environmental influences contributed to explaining the variance in the model, with estimates ranging from 53% (Direct Assault) to 72% (Verbal Assault). Because some of these BDHI scales have been shown to correlate with indices of central serotonin function, it is possible that impulsive aggression, as reflected by these scales, is heritable in men.

Cyclic-AMP production by polymorphonuclear leukocytes in psychiatric disorders.

The cyclic adenosine monophosphate (cAMP) responses to histamine, prostaglandin-E1, and isoproterenol in polymorphonuclear leukocytes from drug-free normal controls and patients with schizophrenia or major depressive disorder were compared. These three groups of subjects did not differ in their cAMP responses to receptor activation. Exacerbated and remitted patients with either schizophrenia or major depressive disorder did not differ in their cAMP responses. The data indicate that in polymorphonuclear leukocytes, the cAMP responses to activation of histamine H2, prostaglandin-E1, or beta-adrenergic receptors are neither state-independent nor state-dependent markers for schizophrenia or major depressive disorder.

Response of panic disorder and resistance of depression to imipramine.

The authors present the cases of two patients with panic disorder and major depression whose panic responded to imipramine but whose depression did not.

Effect of hospital admission on DST results.

The authors examined the dexamethasone suppression test (DST) responses of 41 patients with primary major depressive disorder and 40 patients with other psychiatric disorders who were tested within 2-6 days of hospital admission. Significantly more patients with primary depression who were tested on day 2 demonstrated abnormal cortisol suppression than those who were tested on days 3, 4, or 3-6 and than patients with other psychiatric disorders regardless of test day. These results suggest that patients with primary depression may be sensitive to psychophysiologic stresses associated with hospital admission and that the utility of the DST may require further evaluation vis-à-vis the day of DST administration.

Central serotonin activity and aggression: inverse relationship with prolactin response to d-fenfluramine, but not CSF 5-HIAA concentration, in human subjects.

OBJECTIVE: This study compared the nature and magnitude of the relationship between aggression and CSF 5-hydroxyindoleacetic acid (5-HIAA) concentration with that between aggression and the prolactin response to d-fenfluramine challenge in human subjects. METHOD: The Life History of Aggression assessment scores of 24 subjects with personality disorders were compared with their lumbar CSF 5-HIAA concentrations and with their prolactin responses to d-fenfluramine challenge. RESULTS: Aggression was significantly and inversely correlated with prolactin responses to d-fenfluramine challenge but not with lumbar CSF 5-HIAA concentrations in these subjects. CONCLUSIONS: Prolactin response to d-fenfluramine may be more sensitive than lumbar CSF 5-HIAA concentration in detecting a relationship between aggression and central serotonin activity in noncriminally violent human subjects.

Serotonin transporter protein gene polymorphism and personality measures in African American and European American subjects.

OBJECTIVE: The SLC6A4 locus encodes the serotonin transporter, which in turn mediates the synaptic inactivation of the neurotransmitter serotonin. A polymorphism located in the 5' promoter region of the gene is associated with altered transcriptional activity of SLC6A4; an earlier study reported an association of the polymorphism with anxiety- and depression-related traits, including harm avoidance and neuroticism. The authors attempted to replicate this finding. METHOD: They assessed genotype at the SLC6A4 promoter polymorphism, and an additional polymorphism in intron 2, in 322 American subjects of European and African ancestry, some with diagnoses of a personality disorder or substance dependence and some normal comparison subjects. Harm avoidance was measured by the Tridimensional Personality Questionnaire in all subjects, and neuroticism was measured by the NEO Five-Factor Inventory in 185 subjects. Allele frequencies in the groups were compared, and hierarchical multiple regression was used to examine the correlation of demographic features, psychiatric diagnostic group, and genotype with harm avoidance and neuroticism scores. RESULTS: Although the demographic factors and psychiatric diagnoses had effects on harm avoidance and neuroticism scores, there was no main effect of genotype on these personality measures. In the context of these overall negative findings, interactions were observed between sex and promoter system genotype and between race and promoter system genotype which suggest that the present findings are not wholly inconsistent with those of the earlier study. CONCLUSIONS: The authors were unable to replicate the association finding. The specific phenotypic composition of the groups studied with respect to other behaviors could have influenced ability to detect association of SLC6A4 polymorphisms with personality measures; population stratification for this locus is also of potential importance.

Structured interviews for borderline personality disorder.

The authors compared three instruments used to diagnose borderline personality disorder--the Diagnostic Interview for Borderline Patients (DIB), the Schedule for Interviewing Borderlines, and the Structured Interview for DSM-III Personality Disorders--in 56 patients with personality disorders. A borderline diagnosis was made according to the DIB in 30%, the Structured Interview for DSM-III Personality Disorders in 48%, and the Schedule for Interviewing Borderlines in 55% of the patients. Diagnostic agreement was only 52%, which has implications for the generalizability of results of validation studies of the borderline diagnosis. Improvement in diagnostic agreement requires modification of current criteria sets and/or the use of dimensional models.