Open trial of flutamide for treatment of obsessive-compulsive disorder.

BACKGROUND: Several lines of evidence suggest that gonadal steroid hormones play a role in the onset and exacerbation of obsessive-compulsive disorder (OCD). In this study, we examined the effects of treatment with flutamide, a synthetic, nonsteroidal, competitive antagonist of the androgen receptor, on OCD symptoms. METHOD: Eight outpatients meeting DSM-III-R criteria for OCD participated in an 8-week open trial of flutamide. The dose was increased from 250 mg/day to 750 mg/day over the first 4 weeks and maintained at 750 mg/day for the final 4 weeks. The primary outcome measures for OCD symptoms were the Yale-Brown Obsessive Compulsive Scale and the Maudsley Inventory and for anxiety symptoms, the Beck Anxiety Inventory and the Hamilton Rating Scale for Anxiety. Subjects also provided self-ratings of aggression and sexual interest and activity. RESULTS: There were no reductions in measures of obsession and compulsions or measures of anxiety over the 8-week trial. However, self-ratings of feelings of aggression did fall significantly over the 8-week trial (p < .001). CONCLUSION: The lack of response to treatment with flutamide, an androgen receptor antagonist, suggests that any effects of gonadal steroids to exacerbate OCD symptoms are more likely to be mediated through estrogen receptors or through mechanisms that do not involve classical intracellular androgen receptors. Future treatment trials should examine agents that antagonize estrogen receptors or otherwise inhibit estrogen activity.

Delayed obsessive-compulsive disorder symptom exacerbation after a single dose of a serotonin antagonist in fluoxetine-treated but not untreated patients.

Enhanced serotonergic transmission may underlie therapeutic effects of serotonin reuptake inhibitors in obsessive-compulsive disorder. However, such treatment may decrease serotonin receptor responsivity. We investigated whether the serotonin antagonist metergoline would exacerbate or further improve systems in fluoxetine-responsive patients. Pilot results suggested open metergoline produced delayed symptom worsening in fluoxetine-treated patients. Fourteen patients continuing fluoxetine received metergoline and placebo (double-blind, randomized). Symptom ratings continued for 1 week afterwards. Ten unmedicated patients underwent the same procedures. Symptoms improved 4 h after both metergoline and placebo. The day after metergoline but not placebo, fluoxetine-treated patients had significantly increased anxiety, obsessions and compulsions, abating over several days. Depression was unchanged. Metergoline had no similar delayed effects in unmedicated patients. Metergoline levels were higher in fluoxetine-treated patients. These results, consistent with less conclusive earlier findings, suggest that prolonged changes in brain serotonin function underlie symptom re-emergence following administration of metergoline to fluoxetine-treated patients with obsessive-compulsive disorder.

Differentiation between MK-801- and apomorphine-induced stereotyped behaviors in mice.

The ability of phencyclidine (PCP) to model schizophreniform psychosis is believed to be related to its ability to produce both hypoglutamatergia and hyperdopaminergia. As such, identification of PCP-stimulated behaviors may be important for the development of animal models of schizophrenia. In this study, MK-801 [(+)-5-methyl-10,11-dihydro-5H- dibenzo[a,d]cycloheptane-5,10-imine maleate], a high-affinity PCP analogue, was administered to mice in order to stimulate "PCP behaviors." These PCP behaviors were compared with behaviors stimulated by apomorphine, a dopamine agonist. Stereotyped behavior was assessed by both visual observations and automated measurements. Visual observations showed highly intense gnawing and sniffing in apomorphine-treated mice and the absence of gnawing in MK-801-treated mice. Automated stereotypic measures showed that, compared with vehicle-treated controls, there were frequent dissociations between MK-801 and apomorphine. Conceivably, a compound that attenuates PCP-stimulated behaviors while sparing apomorphine-stimulated behaviors would possess both antipsychotic efficacy and be devoid of undesirable side effects associated with dopamine blockade.