Bupropion sustained release (SR) for the treatment of hypoactive sexual desire disorder (HSDD) in nondepressed women.

This article describes the results of the first report of bupropion sustained release (SR) in nondepressed females with hypoactive sexual desire disorder (HSDD). Eligible females entered a 4-week, single-blind, placebo baseline phase. Subjects, all of whom did not respond to placebo, continued in a single-blind active treatment phase where they received bupropion SR for up to 8 additional weeks. We assessed HSDD by using investigator ratings of sexual desire and sexual functioning. Of the 51 evaluable subjects who entered the active treatment phase, 29% responded to treatment with bupropion SR. Bupropion SR was generally well tolerated. Pending the results of further study, bupropion SR may offer a treatment option for women with HSDD.

Evaluation of sexual functioning in depressed outpatients: a double-blind comparison of sustained-release bupropion and sertraline treatment.

Sexual dysfunction is a frequently reported side effect of many antidepressants, including serotonin reuptake inhibitors. Bupropion, an antidepressant of the aminoketone class, is relatively free of adverse sexual effects. In a randomized, double-blind, multicenter trial, sustained-release bupropion (bupropion SR) and sertraline, a selective serotonin reuptake inhibitor, were found to be similarly efficacious in the treatment of outpatients with moderate to severe depression. This report describes the results of a double-blind comparison of the sexual side effect profiles of bupropion SR and sertraline. Two hundred forty-eight patients who had received a diagnosis of moderate to severe major depression were randomly assigned to receive treatment with bupropion SR (100-300 mg/day) or sertraline (50-200 mg/day) for 16 weeks. Eligible patients were required to be in a stable relationship and to have normal sexual functioning. Sexual functioning was assessed by the investigator at each clinic visit using investigator-rated structured interviews. A significantly greater percentage of sertraline-treated patients (63% and 41% of men and women, respectively) developed sexual dysfunction compared with bupropion SR-treated patients (15% and 7%, respectively). Sexual dysfunction was noted as early as day 7 in sertraline-treated patients at a dose of 50 mg/day and persisted until the end of the 16-week treatment phase. Four patients, all of whom were treated with sertraline, discontinued from the study prematurely because of sexual dysfunction. Given the similar efficacy of the two drugs in treating depression, bupropion SR may be a more appropriate antidepressant choice than sertraline in patients for whom sexual dysfunction is a concern.

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.

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.

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.

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.

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 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.

The neurobiology of impulsive aggression.

As noted previously, it is likely that the tendency to lash out verbally or physically at others is influenced by an interaction among multiple complex biologic factors. We need to investigate how these systems interact with each other to develop a more thorough understanding of the brain's influence over aggressive behavior. We are at a very early stage in our understanding of the neurobiology of aggression. There are no simple tools for studying the complex neurophysiology of the human brain. The studies cited in this article include techniques limited in their utility. As our technologies improve, discovering a more thorough picture of the brain's influence over aggressive behavior may be possible. For example, functional neuroimaging may help to localize abnormal neurotransmitter functioning in the brains of individuals with impulsive aggressive behavior. Our technologies are beginning to reveal the differential effects of subsystems of neurotransmitter regulation. Subtypes of serotonin receptors may differentially mediate impulsive aggressive behaviors. Animal studies suggest that 5-HT 1A receptor stimulation results in a decrease in aggressive behavior. As noted previously, aggressive personality-disordered patients show a blunted prolactin response to the 5-HT1A agonist buspirone. Antagonism of 5-HT 2 receptors appears to decrease aggression, and this effect may explain the ability of newer antipsychotic agents (which, unlike older antipsychotic medications, block 5-HT 2 receptors) to produce a dramatic reduction in aggression and agitation independent of effects on psychotic symptoms. Neglecting psychosocial factors in the causes of aggressive behavior would also be naive. Although environmental factors account for much of the predisposition to aggression, there have been few systematic studies to explore the relationship between life experiences and aggression. In addition, there have been no well-designed studies of the interaction between biology and an individual's environment in the genesis of aggressive behavior. There is some evidence of an association between childhood abuse and neglect and adult antisocial personality disorder, but this relationship might be merely an artifact of the genetic relationship between parental and offspring antisocial personality disorder. As we discussed in the introduction, one of the biggest hurdles in the study of the neurobiology of aggression is the lack of a consensus on definitions. "Intermittent Explosive Disorder" is the only category in DSM-IV that directly addresses individuals with problems with aggression, but the criteria are vague and only focus on a handful of the many patients who exhibit problems with aggressive behavior. It is our hope that investigators in this field can work together toward developing more precise and encompassing diagnostic criteria to study effectively both the neurobiology and treatment of these disorders.

Impulsive aggression in personality disorder correlates with platelet 5-HT2A receptor binding.

The purpose of this study was to examine the relationship between platelet 5-HT2A receptor binding and aggressive behavior. 125I-LSD Bmax and Kd values were measured for 22 subjects meeting DMS-III-R criteria for one or more personality disorders and 12 healthy volunteer subjects. Aggression and impulsivity were assessed using the Buss-Durkee Hostility Inventory (BDHI) Assault scale, Life History of Aggression (LHA) scale, and the Barratt-11 Impulsiveness scale (BIS-11). Bmax and Kd values did not differ between personality disordered subjects and healthy volunteers. However, both Bmax and Kd values correlated positively with BDHI Assault scores in personality-disordered subjects but not in healthy volunteer subjects. These results suggest that assaultiveness in personality-disordered subjects may covary with increasing numbers, but decreasing affinity, of platelet 5-HT2A receptor sites labeled by 125I-LSD.

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.

Serotonin function in human subjects: intercorrelations among central 5-HT indices and aggressiveness.

Three central indices of serotonin (5-HT) system activity in human subjects were examined to: (a) estimate intercorrelations among 5-HT indices and (b) compare correlations of these indices with a measure of assaultiveness (Buss-Durkee 'Assault') in personality-disordered individuals. Cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) concentration and prolactin responses to m-chlorophenylpiperazine (m-CPP) m-CPP (PRL[m-CPP]) and fenfluramine (PRL[FEN]), served as indices of pre-, post- and 'net'-synaptic central 5-HT activity, respectively. PRL[D,L-FEN] responses were inversely related to CSF 5-HIAA concentration and positively correlated with PRL[m-CPP] responses. Both PRL[D,L-FEN] and PRL[m-CPP] response data correlated equally, and inversely, with BD Buss-Durkee Assault when the same subjects were examined. Basal CSF 5-HIAA concentration did not correlate with Buss-Durkee 'Assault'. PRL responses to challenge probes which involve activation of 5-HT post-synaptic receptors may correlate better than a basal measure of pre-synaptic 5-HT function with a tendency to assaultive behavior in non-criminally aggressive personality-disordered individuals.

Assessment of life history of aggression: development and psychometric characteristics.

The Life History of Aggression (LHA) assessment was administered to up to 252 subjects. In addition to a total LHA score, subscale scores for Aggression, Social Consequences and Antisocial Behavior, and Self-directed Aggression were calculated. Test-retest stability, interrater agreement, and internal consistency reliability were excellent both for the LHA Total score and the LHA Aggression subscore. There were moderately strong correlations between these scores and both self-reports of aggressive tendency (Buss-Durkee Hostility Inventory: n = 214) and recent overt aggression (Overt Aggression Scale-Modified for Out-patients: n = 61). LHA Total scores were highest among subjects with Antisocial or Borderline Personality Disorder. These results support the use of the LHA assessment, and especially the LHA Aggression subscore, as a measure of life history of aggressive behavior.

Double-blind comparison of bupropion sustained release and sertraline in depressed outpatients.

BACKGROUND: A sustained-release formulation of bupropion (bupropion SR), developed with an improved pharmacokinetic profile to permit less frequent dosing than the immediate-release form, has not been evaluated in active comparator trials. This randomized, double-blind, parallel-group trial was conducted to compare the efficacy and safety of bupropion SR and sertraline. METHOD: Outpatients with moderate to severe major depressive disorder (DSM-IV) received bupropion SR (100-300 mg/day) or sertraline (50-200 mg/day) for 16 weeks. Psychiatric evaluations, including the Hamilton Rating Scale for Depression (HAM-D), the Hamilton Rating Scale for Anxiety (HAM-A), the Clinical Global Impressions scale for Severity of Illness (CGI-S), and for Improvement (CGI-I) were completed, and adverse events were assessed in the clinic periodically throughout treatment. Patients' orgasm function was also assessed. RESULTS: Mean HAM-D, HAM-A, CGI-I, and CGI-S scores improved over the course of treatment in both the bupropion SR group and the sertraline group; no between-group differences were observed on any of the scales. Orgasm dysfunction was significantly (p < .001) more common in sertraline-treated patients compared with bupropion SR-treated patients. The adverse events of nausea, diarrhea, somnolence, and sweating were also experienced more frequently (p < .05) in sertraline-treated patients. No differences were noted between the two treatments for vital signs and weight. CONCLUSION: This double-blind comparison of bupropion SR and sertraline demonstrates that bupropion and sertraline are similarly effective for the treatment of depression. Both compounds were relatively well tolerated, and orgasm dysfunction, nausea, diarrhea, somnolence, and sweating were reported more frequently in sertraline-treated patients.

Hormonal responses to d- and d,l-fenfluramine in healthy human subjects.

Two different doses of d-fenfluramine HCl and d,l-fenfluramine HCl (0.5 mg/kg and 1.0 mg/kg) were administered to 11 healthy male volunteers to compare the neuroendocrine responses to these two forms of fenfluramine in human subjects. Prolactin (PRL) responses to d- and d,l-fenfluramine were significantly greater than those to placebo and were equivalent at both dose levels. Adrenocortiatrophic-releasing hormone (ACTH) and cortisol (CORT) responses to d-fenfluramine at both dose levels were also significantly greater than those to placebo. In contrast, the higher dose of d,l-fenfluramine was associated only with a significant CORT response in comparison to placebo. PRL responses to d-fenfluramine were higher than the PRL response to d,l-fenfluramine at either dose level. The PRL response to d-fenfluramine at 0.5 mg/kg was very highly correlated with the PRL responses to d,l-fenfluramine at 1.0 mg/kg (r = 0.97, n = 10). Homovanillic acid (HVA) were not altered by either d, or d,l-fenfluramine at either dose in a subsample of subjects (n = 4). ACTH/CORT responses to d- and d,l-fenfluramine were modestly intercorrelated. These data suggest that the PRL response evoked by d-fenfluramine is quantitatively very similar to that evoked by d,l-fenfluramine.

5-HT3 receptor antagonism by ondansetron does not attenuate 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 pre-treatment with and without the 5-HT3 receptor antagonist ondansetron (16 mg PO) in 11 physically healthy male volunteers. Compared to pretreatment with placebo, pre-treatment with ondansetron did not significantly attenuate the PRL response to d-FEN challenge. These data are consistent with other data suggesting little role for 5-HT3 receptors in the PRL response to 5-HT agonist challenge in human subjects.

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.