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.

Intermittent explosive disorder.

Intermittent explosive disorder (IED) may best be thought of as a categoric expression of recurrent, problematic impulsive aggressive behavior. Although diagnostic criteria issues have made systematic research in IED difficult, recent work with new research criteria may allow for important empiric work to take place. Given that previous research in the area of impulsive aggression has been highly informative concerning the genetics, biology, and pharmacologic treatment of this behavior, application and extension of this work to IED is crucial. This paper reviews several important aspects of IED including its history in the Diagnostic and Statistical Manual of Mental Disorders, the formation of new research criteria, and the phenomenologic, epidemiologic, genetic, biologic, and treatment correlates of this disorder.

Identifying personality disorders: towards the development of a clinical screening instrument.

The study objective was to identify a set of personality disorder (PD) criteria from the DSM PD diagnostic sets that can be used to detect subjects with an increased likelihood of having a PD diagnosis. In a series of outpatients evaluated systematically in two waves for every criteria item for 12 DSM-III-R PDs, stepwise logistic regression identified 45 criteria as discriminative for their specific PDs, which are selected for further analysis to assess their ability to discriminate for any PD. Receiver operating characteristic (ROC) analysis is used to evaluate their discriminative power in an independent conjoined sample (N = 1,342) from six centers that assessed every PD criteria item by structured instrument (Structured Clinical Interview for DSM-III-R PDs [SCID-II, Personality Disorder Examination [PDE], and Structured Interview for DSM-III-R PDs [SIDP-R]). The cutoff that maximizes information gain is used to determine the diagnostic threshold (DT). Initially, 15 of 45 criteria are identified. At the 0.43 PD prevalence, a DT of 2 or more of the 15 PD criteria across samples is optimal. The maximum information gain (MIG) is .42 bits, and the AUR is 0.94+/-.007. Other performance indices at this cutoff are .90 sensitivity, .84 specificity, .81 positive predictive power (PPP), .91 negative predictive power (NPP), and .86 hit rate (HR). Taken collectively, the 15 PD criteria selected by the data reduction techniques suggest a narrowed set to be assessed in screening for the presence or absence of any PD with comparable or better psychometric properties than other tests routinely used for diagnosing medical and psychiatric disorders. If specific PD categorization is needed, a second-step comprehensive assessment should follow.

Etiology of the impulsivity/aggression relationship: genes or environment?

Genetic and environmental influences on the phenotypic relationship between the Barratt Impulsiveness Scale and the aggression scales from the Buss-Durkee Hostility Inventory in adult males were examined. This study used 182 pairs of male MZ twins and 118 pairs of male DZ twins from the Vietnam Era Twin Registry. Phenotypic relationships between the measure of impulsivity and subscales of the measure of aggression (direct assault, verbal assault, indirect assault, and irritability) ranged from 0.22 to 0.51. Genetic and environmental mediation of the phenotypic relationship between impulsivity and aggression were approximately the same for all four models. Multivariate model-fitting analysis indicated that irritability and impulsivity had a larger phenotypic relationship, as well as a greater portion of shared genes and environment than the other three subscales of aggression. This suggests, for example, that there are more overlapping genetic and environmental influences accounting for the relationship between irritability and impulsivity than between direct assault and impulsivity. The effects of such findings on our understanding of impulsive aggression are discussed.

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 relationship between personality psychopathology and aggressive behavior in research volunteers.

Theorists and clinicians have long believed that personality psychopathology is a risk factor for aggressive behavior. Previous investigations in this area, however, have provided mixed results. In this study, the relationship between personality psychopathology and aggressive behavior was examined in 137 research volunteers. The influences of gender and coexisting major mental disorders were statistically controlled. Aggressive behavior was associated with criteria for 7 of the 11 personality disorders listed in the Diagnostic and Statistical Manual of Mental Disorders (3rd ed., rev.). Except for schizoid criteria, all relationships with aggressive behavior were in the positive direction. When all personality disorders were considered simultaneously, paranoid and passive-aggressive criteria were significant predictors of aggressive behavior.

Intermittent explosive disorder-revised: development, reliability, and validity of research criteria.

The study of human aggression has been hindered by the lack of reliable and valid diagnostic categories that specifically identify individuals with clinically significant displays of impulsive aggressive behavior. DSM intermittent explosive disorder (IED) ostensibly identifies one such group of individuals. In its current form, IED suffers from significant theoretical and psychometric shortcomings that limit its use in clinical or research settings. This study was designed to develop a revised criteria set for IED and present initial evidence supporting its reliability and validity in a well characterized group of personality disordered subjects. Accordingly, research criteria for IED-Revised (IED-R) were developed. Clinical, phenomenologic, and diagnostic data from 188 personality disordered individuals were reviewed. IED-R diagnoses were assigned using a best-estimate process. The reliability and construct validity of IED-R were examined. IED-R diagnoses had high interrater reliability (kappa = .92). Subjects meeting IED-R criteria had higher scores on dimensional measures of aggression and impulsivity, and had lower global functioning scores than non-IED-R subjects, even when related variables were controlled. IED-R criteria were more sensitive than DSM-IV IED criteria in identifying subjects with significant impulsive-aggressive behavior by a factor of four. We conclude that in personality disordered subjects, IED-R criteria can be reliably applied and appear to have sufficient validity to warrant further evaluation in field trials and in phenomenologic, epidemiologic, biologic, and treatment-outcome research.

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.

Neurobiologic correlates of violence: relevance to criminal responsibility.

Studies addressing the relationship between neurotransmitter functioning and violent crime are reviewed. A rich literature exists to support the notion that monoamine (i.e., serotonin, dopamine, and norepinephrine) neurotransmitter functioning is related to human aggressive behaviour. Results from these studies provide, at best, indirect evidence that neurotransmitter abnormalities are involved in violent criminal behavior. Few studies have specifically addressed the role of neurotransmitter functioning in violent crime. To illustrate how current knowledge in this area has been applied in forensic settings, a case study in which neurotransmitter functioning was introduced as evidence to support an insanity defense is presented. Potential problems associated with such defenses are discussed.

Prolactin response to D-fenfluramine in outpatients with major depression.

There is much indirect evidence of serotonin abnormalities in patients with major depression. Unfortunately, previous reports of serotonin challenge studies in depressed patients have yielded conflicting results. In order to test the serotonin hypothesis of depression, the authors compared 20 outpatients with major depressive disorder to 20 normal control subjects using prolactin response to D-fenfluramine as a measure of central serotonergic (5-HT) functioning. Patients were free of histories of suicidal behavior and had no Axis II disorders. There were no significant differences in prolactin responses between depressed patients and control subjects to challenge with D-fenfluramine at a dose of 0.5 mg/kg. The possible implications of these findings are discussed with respect to theories regarding biological vulnerabilities to major depression.

Acute tryptophan depletion attenuates the prolactin response to d-fenfluramine challenge in healthy human subjects.

Prolactin responses to d-fenfluramine (d-FEN) Challenge (0.5 mg/kg PO) were examined after pretreatment with and without acute tryptophan depletion (ATD) in six physically healthy male volunteers. Compared to pretreatment with SHAM-ATD, ATD pretreatment attenuated the PRL response to d-FEN Challenge in all subjects. These data suggest that PRL responses to cl-FEN challenge reflect to a substantial degree the activity of newly synthesized 5-HT.

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.

Clinical outcome of psychopharmacologic treatment of borderline and schizotypal personality disordered subjects.

This paper reviews the biological and psychopharmacologic nature of personality disordered subjects, specifically those with borderline (BPD) and schizotypal (ScPD) personality disorder. Generally speaking, there is no agent of choice for the treatment of either BPD or ScPD. Many agents of different classes appear to offer some benefit to selected subjects depending upon their symptom presentation. For example, ScPD or BPD subjects with prominent cognitive/perceptual distortion may respond to neuroleptic agents, while some BPD subjects with depressed mood may respond best to antidepressants. The hypothesis that biological and behavioral dimensions underlie the psychopharmacologic response to treatment in personality disordered subjects, proposed over the past decade, is now being tested. The most salient example of this is the testing of serotonin-specific agents (e.g., fluoxetine) for potential antiaggressive efficacy in personality disordered subjects with prominent histories of impulsive aggressive behavior and putative reduced serotonin system function.

Divalproex sodium for impulsive aggressive behavior in patients with personality disorder.

OBJECTIVE: Divalproex sodium, an anticonvulsant and antimanic agent, has recently been studied for its antiaggressive effects in patients with brain injuries, dementia, and borderline personality disorder. Since patients with other personality disorders also exhibit impulsive aggressive behavior, we conducted a preliminary open-label trial of divalproex sodium as a treatment for irritability and aggression in patients with a variety of personality disorders. METHOD: Ten patients meeting DSM-IV criteria for at least one personality disorder were treated with divalproex sodium in an 8-week open clinical trial. All patients had failed a trial of a selective serotonin reuptake inhibitor (SSRI). Divalproex sodium was increased as tolerated using a flexible dosing schedule. Clinician ratings for impulsive aggressive behavior and irritability were made every 2 weeks using the modified Overt Aggression Scale (OAS-M). RESULTS: Six of 8 completers reported significant decreases in irritability (p = .003) and impulsive aggressive behavior (p = .019). For the entire sample, improvement on OAS-M irritability and overt aggression scores was noted by the end of 4 weeks and continued to occur through week 8. CONCLUSION: This study suggests that divalproex sodium is an effective treatment for impulsive aggressive behavior in some patients with personality disorder who fail to respond to other antiaggressive agents (i.e., SSRIs). Controlled studies are needed to determine which patients are most likely to benefit from divalproex sodium and to evaluate the differential effectiveness of various agents in reducing impulsive aggressive behavior.

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.

Neuroendocrine challenge studies of suicidal behavior.

This article reviews the research data regarding human neuroendocrine systems and suicidal behavior. Special emphasis is placed on pharmacochallenge studies. Such studies uniquely allow for functional assessment of neuroendocrine parameters in living subjects. Serotonergic mechanisms have been the most fruitful areas of research. While discussing the major areas of controversy, theoretical approaches to integration are offered.