Partial generalization of (-)DOM to fluvoxamine in the rat: Implications for SSRI-induced mania and psychosis

Recent reports have implicated selective serotonin-reuptake inhibitors in the induction of psychosis and mania when SSRIs are given in combination with neuroleptics. We hypothesize that the partial substitution of fluvoxamine for the hallucinogen, (-)DOM, in the rat provides evidence for a 5-HT₂-mediated effect of fluvoxamine which may in turn account for the adverse effects observed in humans. Male Fischer-344 rats were trained with (-)DOM (0.56 mg/kg) as a discriminative stimulus using standard operant procedures. Tests of generalization were then conducted with fluvoxamine either alone or in combination with the 5-HT_1A antagonist, WAY-100635, the 5-HT₂ antagonist, pirenperone, and the neuroleptics, fluphenazine, chlorpromazine, thioridazine, loxapine, risperidone, and clozapine. In rats trained with (-)DOM, fluvoxamine at a dose of 20 mg/kg yielded a maximum 58% (-)DOM-appropriate response. This partial generalization was potentiated by treatment with WAY-100635 and antagonized by pirenperone, loxapine, risperidone, and clozapine. The present data are compatible with a 5-HT₂-mediated effect of fluvoxamine which may play a role in SSRI-induced mania and psychosis. It is predicted by the results of this study that the probability of these adverse effects will be increased by the concurrent use or antagonists at 5-HT_1A receptors and decreased by neuroleptics with antagonistic activity at 5-HT₂ receptors.