Antiobsessional Effect of Risperidone Add-On Treatment in Serotonin Reuptake Inhibitor-Refractory Obsessive-Compulsive Disorder May Be Dose-Dependent

In reply

We thank Ramasubbu for the interest in our article. They raise an important question related to the mechanism of action of risperidone when used in combination with serotonin reuptake inhibitors (SRIs) in refractory obsessive-compulsive disorder (OCD). As they point out, risperidone has greater affinity for serotonin 5-HT₂ receptors at lower doses, with an increasing occupancy of dopamine D₂ receptors with dosage escalation. As discussed in our article,¹ risperidone's affinity in vitro is 20 times higher for 5-HT_2A receptors than D₂ receptors; in vivo, it occupies 5-HT_2A receptors at a dose 10 times lower than it does D₂ receptors.² We previously demonstrated, in our controlled study of haloperidol addition in refractory patients, that D₂ antagonism contributes to an antiobsessional effect in combination with serotonin reuptake.³ In their letter, Ramasubbu suggests that upward titration of risperidone may be required to alleviate OCD symptoms, thus emphasizing the importance of D₂ blockade. The letter refers to the study by Saxena et al,⁴ in which SRI-treated patients with OCD who received an average daily dose of 2.75 mg of risperidone had a higher response rate than those who received an average daily dose of 1.25 mg. However, the Saxena et al study was open-label rather than double-blinded and placebo-controlled. Moreover, a daily dose of 2.75 mg of risperidone remains relatively low. To our knowledge, there have been no published open-label or controlled studies of monotherapy, with any typical or atypical antipsychotic drug, that have shown efficacy in treating OCD as it is currently defined. In our open-label investigation of clozapine,⁵ we observed no change in OCD symptoms in refractory patients. Thus, while D₂ antagonism may be important in the treatment of OCD, the available data suggest this to be so only in combination with an SRI.