Risperidone as a Janus in Mood Disorder

To examine the double-edged thymoleptic (antidepressant and antimanic) effects of risperidone in mood disorders, we reviewed published reports both on the therapeutic effects of risperidone and on risperidone-induced mania (RIM) in mood disorders. We also reviewed the risk factors of RIM, the possible neurochemical mechanisms of its thymoleptic effects, and the pathophysiological and clinical significance of these effects. Furthermore, we attempted to provide a therapeutic guideline for the use of risperidone in the treatment of mood disorders. The risk factors of RIM were identified as follows: refractory mood disorder, especially in the case of bipolar I disorder; refractory schizoaffective disorder, especially that of the bipolar type; refractory chronic schizophrenia; psychotic features; higher initial dosage of risperidone; rapid titration of dosage; combined therapy with antidepressants for refractory depression; and risperidone monotherapy in mania/hypomania. At low doses, risperidone preferentially blocks 5-HT2 receptors and, with increasing dosage, the effects of a D2 blockade gradually emerge. Therefore, the dose-related balance of the antidepressant and antimanic effects of risperidone, depending on the dosage and treatment duration, might explain a continuum of effects produced by risperidone, i.e. antidepressant effect, antimanic effect, behavioral stimulation, and induction/exacerbation of mania or hypomania. In conclusion, risperidone might be administered as an alternative or adjuvant medication to patients with mood disorders, even in those cases without psychotic features or which are refractory to typical antipsychotics. Conservative dosage (titrated gradually from an initial dose of 1-3 mg/day) of risperidone with concomitant mood stabilizers is recommended for patients with mood disorder who are associated with the risk factors of RIM. Key points：1) Risperidone has a double-faced effect of both improving and exacerbating the symptoms of mood disorders. 2) Risperidone has both antimanic and antidepressant effects, but no mood-stabilizing effect. 3) Risperidone exhibits dual actions of blocking both D2 and 5-HT2 receptors, of which the relative occupancy ratio depends on the dosage and duration of the risperidone therapy, which might explain the wide spectrum of effects produced by risperidone, i.e. its antidepressant effect, antimanic effect, behavioral stimulation, and induction/exacerbation of mania or hypomania. 4) Risperidone-induced mania was observed in some patients with mood disorder, schizoaffective disorder, or schizophrenia, which indicates that these disorders might share certain common biological factors. 5) For mood disorders, risperidone therapy is started initially at a much lower dose than for schizophrenia and gradually titrated until the optimal minimum dose is reached.