Modulation of antipsychotic-induced extrapyramidal side effects by medications for mood disorders.

Antipsychotic drugs are widely used not only for schizophrenia, but also for mood disorders such as bipolar disorder and depression. To evaluate the interactions between antipsychotics and drugs for mood disorders in modulating extrapyramidal side effects (EPS), we examined the effects of antidepressants and mood-stabilizing drugs on haloperidol (HAL)-induced bradykinesia and catalepsy in mice and rats. The selective serotonin reuptake inhibitors (SSRIs), fluoxetine and paroxetine, and the tricyclic antidepressant (TCA) clomipramine, which showed no EPS by themselves, significantly potentiated HAL-induced bradykinesia and catalepsy in a dose-dependent manner. In contrast, the noradrenergic and specific serotonergic antidepressant (NaSSA) mirtazapine failed to augment, but rather attenuated HAL-induced bradykinesia and catalepsy. Mianserin also tended to reduce the EPS induction. In addition, neither treatment with lithium, sodium valproate nor carbamazepine potentiated HAL-induced EPS. Furthermore, treatment of animals with ritanserin (5-HT2A/2C antagonist), ondansetron (5-HT3 antagonist), and SB-258585 (5-HT6 antagonist) significantly antagonized the EPS augmentation by fluoxetine. Intrastriatal injection of ritanserin or SB-258585, but not ondansetron, also attenuated the EPS induction. The present study suggests that NaSSAs are superior to SSRIs or TCAs in combined therapy for mood disorders with antipsychotics in terms of EPS induction. In addition, 5-HT2A/2C, 5-HT3 and 5-HT6 receptors seem to be responsible for the augmentation of antipsychotic-induced EPS by serotonin reuptake inhibitors.