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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-HT2A receptors than D2 receptors;
in vivo, it occupies 5-HT2A 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.
McDougle CJ, Price LH. Antiobsessional Effect of Risperidone Add-On Treatment in Serotonin Reuptake Inhibitor-Refractory Obsessive-Compulsive Disorder May Be Dose-Dependent. Arch Gen Psychiatry. 2002;59(5):472–473. doi:
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