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Impulsive aggression is associated with central serotonergic dysfunction. Animal models particularly implicate the 5-HT(1A) receptor in this behavior. We tested the hypothesis that central 5-HT(1A) receptor function is impaired in impulsive aggressive personality disorder patients. A total of 52 individuals with DSM-III-R personality disorders, all medically healthy adult outpatients without concurrent psychiatric medication treatment, underwent serial plasma cortisol, prolactin, and temperature measurements before and after ipsapirone 20 mg oral administration. Subjects completed self-report measures of impulsivity, hostility, depression and anxiety, and childhood maltreatment. Stepwise regression analysis revealed impulsivity alone among symptom measures to be associated with significantly decreased peak cortisol and prolactin responses. Diagnoses of borderline personality disorder (BPD) and intermittent explosive disorder-revised (IED-R) were associated with significantly increased and decreased cortisol responses, respectively. However, post hoc analyses indicated that impulsivity was significantly negatively correlated with cortisol responses in the BPD group, and may mediate the association of both BPD and IED-R with altered cortisol responses. Temperature response was associated with neither diagnostic nor symptom measures. Neither diagnostic nor dimensional measures of depression or anxiety, nor severity of childhood maltreatment, were significantly associated with cortisol, prolactin, or temperature responses. Impulsivity is related to impaired function at (or downstream to) postsynaptic 5-HT(1A) receptors, and this relationship may be partly responsible for the association of impaired serotonergic function with diagnoses such as BPD and IED-R. In addition, D(2) receptor dysfunction may play a role in impulsivity, whereas 5-HT(1A) cell-body autoreceptor function may be spared in these disorders.

Objective: Schizotypal personality disorder (SPD) has many phenomenological, genetic, physiologic, and neuroanatomical commonalities with schizophrenia. Patients with the disorder often suffer from marked social and occupational impairment, yet they have been difficult to treat with medications because of their unusual sensitivity to side effects. This study was designed to determine whether low-dose risperidone treatment is acceptable to SPD patients and can reduce characteristic schizotypal symptoms. In addition, if SPD patients respond to an antipsychotic medication, this will provide support for the notion of a commonality in treatment response between SPD and schizophrenia. Method: Twenty-five patients with DSM-IV-defined SPD were entered into a 9-week randomized, double-blind, placebo-controlled study of low-dose risperidone (starting dose of 0.25 mg/day, titrated upward to 2 mg/day) in the treatment of SPD. Patients were rated with the Positive and Negative Syndrome Scale (PANSS), the Schizotypal Personality Disorder Questionnaire, the Hamilton Rating Scale for Depression, and the Clinical Global Impressions scale. Data were collected from 1995 to 2001. Results: The subjects had a low incidence of depression and of comorbid borderline personality disorder. Patients receiving active medication had significantly (p

Background Impulsive aggression is a prevalent problem and yet little is known about its neurobiology. Preclinical and human studies suggest that the orbital frontal cortex and anterior cingulate cortex play an inhibitory role in the regulation of aggression. Methods Using positron emission tomography, regional metabolic activity in response to a serotonergic stimulus, meta-chlorophenylpiperazine (m-CPP), was examined in 13 subjects with impulsive aggression and 13 normal controls. The anterior cingulate and medial orbitofrontal regions were hypothesized to respond differentially to m-CPP in patients and controls. In the frontal cortex, regional metabolic glucose response to m-CPP was entered into a group (impulsive aggressive, control) × slice (dorsal, middle, orbital) × position (medial, lateral) × location (anterior, posterior) × hemisphere (right, left) mixed-factorial analysis of variance design. A separate group (impulsive aggressive, controls) × anteroposterior location (Brodmann areas 25, 24, 31, 29) × hemisphere (right, left) analysis of variance was used to examine regional glucose metabolism in the cingulate gyrus. Results Unlike normal subjects, patients with impulsive aggression did not show activation specifically in the left anteromedial orbital cortex in response to m-CPP. The anterior cingulate, normally activated by m-CPP, was deactivated in patients; in contrast, the posterior cingulate gyrus was activated in patients and deactivated in controls. Conclusions The decreased activation of inhibitory regions in patients with impulsive aggression in response to a serotonergic stimulus may contribute to their difficulty in modulating aggressive impulses.

Serotonin (5-HT) dysregulation has been associated with major depressive disorder (MDD); a blunted prolactin (PRL) response to D,L-fenfluramine (FEN) has been associated with MDD. Pharmacologic manipulation of the serotonin system with a selective serotonin reuptake inhibitor (SSRI) is effective in the treatment of depression. However, the relationship between pre-treatment 5-HT activity and response to SSRIs is not well understood. This study investigated the relationship between 5-HT dysregulation and response to fluoxetine (FLU). Twenty patients with MDD entered a double-blind placebo-controlled trial of fluoxetine preceded by D,L-fenfluramine stimulation. Patients were assigned randomly to either FLU, 20 mg QD, or placebo (PLA) for an 11-week trial. No relationship was found between the PRL response to FEN and response to FLU. Among the seven responding to FLU, there was a significant negative correlation between PRL response and the time until sustained response to FLU (r = -0.93, P < 0.001, n = 7). Although preliminary, this study suggests that low baseline serotonin activity may be associated with a slower response to FLU in depression.

Decreased serum cholesterol has been associated with impulsive aggressive behaviors. This study was designed to explore the relationship between serum cholesterol levels and measures of impulsive aggression in personality disordered patients. Forty-two personality disordered patients (14 borderline personality disorder, 28 other personality disorders) were included. Fasting serum cholesterol was measured by standard enzymatic assay. An ANOVA was performed with factors of gender and diagnosis, looking at two-way interactions between the factors and serum cholesterol. Patients with borderline personality disorder were found to have significantly lower serum cholesterol than non-borderline personality disorders. A significant interaction effect was also seen between gender and diagnosis with the male patients having lower cholesterol levels. This study suggests there may be a relationship between borderline personality disorder and low serum cholesterol.

Dysregulation of the central serotonergic (5-HT) system has been associated with personality disorders and with suicidality, impulsive aggression, and irritability utilizing CSF 5-HIM and fenfluramine challenge test, which is not selective for any serotonin receptor subtype as a serotonergic measure. A dose response study of ipsapirone (1PS), a 5-HT-1A agonist, has shown that it is a useful probe of 5-HT1A function in normal subjects when temperature and cortisol are used as response variables. To preliminarily investigate the potential usefulness of IPS as a possible 5-HT-subtype specific probe in personality disorder patients, we did a pilot study evaluating the response to IPS in patients and normal controls (NC). Twenty mg of IPS was administered orally in a placebo-controlled double-blind design to l0 NC and 9 patients with DSM-III-R personality disorder. Temperature, CORT, and prolactin (PRL) levels were measured prior to IPS/placebo administration and at half-hour intervals over the next 3 hours. IPS significantly reduced temperature in all subjects (F[ 1,21 ] ~ 13.3, p < 0.01 ) and increased CORT levels (F[ 1,22] 9.27, p < 0.01). There was no diagnosis by drug interaction in either of the two measures. The temperature response to IPS correlated inversely with PRL response to fenfluramine (r 0.82, p < 0.01 ) and positively with the Barratt Impulsiveness Scale (Risk Taking subscale; r 0.86, p < 0.01). Although this sample size was too small to draw any definitive conclusions, temperature and possibly CORT response to IPS and their clinical correlates may be useful measures in future studies of impulsivity in personality disordered patients.