Question. I need some information about risperidone. Can you tell me about its pharmacologic properties, its intended use and its impact on patients?
Answer. Chemically, risperidone (RSP) belongs to the benzisoxazole group of antipsychotics. Its precise mechanism of action in psychosis is not known, but is probably related to its antagonism of dopamine-2 (D2) and serotonin-2 (5HT-2) receptors in the brain. Risperidone (Risperdal) also has effects at alpha adrenergic and histaminic receptors. Risperidone is known to antagonize the effects of LSD, probably via action at the 5HT2 receptor. Risperidone (Risperdal) was developed by P. Janssen and colleagues after previous experience with D2 and 5HT2 antagonists led them to believe that an agent combining these properties would be especially effective in treating the positive and negative features of schizophrenia. For details, see the paper by Janssen et al. in the Journal of Pharmacology & Experimental Therapeutics, vol. 244, 1988.
Risperidone (Risperdal) is FDA-labeled for the management of psychotic disorders. Its efficacy was established in several six to eight week controlled trials against both placebo and haloperidol. Risperidone has some atypical properties, in that it seems to improve both positive and negative features of schizophrenia, while producing few extrapyramidal side effects (EPS) at low doses (2-6 mg/day); however, at doses greater than 8 mg to 10 mg/day, Risperidone begins to lose its atypical properties, in that EPS become more common. Risperidone is typically prescribed on a BID (twice daily) schedule, beginning with 1 mg bid. However, this is often excessive in elderly or medically ill patients, who may not tolerate more than 0.5 mg per day at first. The dose is usually increased to as tolerated to 3 mg bid, over a week or so. The optimal dosage for most patients is roughly 4 mg to 8 mg/day. Risperidone is well-absorbed after oral administration and this is not affected by food.
PET studies have shown that at doses of 4 mg to 10 mg daily, Risperidone produces 5HT2 and D2 occupancy in the living human brain. Risperidone (Risperdal) has an elimination half-life of about three hours, but its active metabolite, 9-OH-RSP has a half-life of about 21 hours. Some preliminary data suggest that plasma levels of the 9-OH-RSP metabolite are related to efficacy, but no clear-cut therapeutic blood levels have yet been documented via rigorous controlled studies. Risperidone is metabolized mainly via the cytochrome 2D6 system in the liver. To my knowledge, no clear demonstration of tolerance has emerged, though anecdotal data are common, concerning patients whose initial good response to Risperidone petered out over several months. It is not clear that this is more common with Risperidone (Risperdal) than with other antipsychotics, though my own impression is that clozapine often produces more enduring benefits in some patients. For more details, you may want to ask Janssen Pharmaceutica to send you some literature.