Attenuation of the prolactin-stimulating and hyperthermic effects of nefazodone after subacute treatment.

The acute administration of the antidepressant drug nefazodone (100 mg orally) to healthy male volunteers increased prolactin concentrations in plasma and elevated oral temperature. After repeated treatment with 100 mg of nefazodone twice daily for 7 days, these effects were attenuated. We propose that the ability of nefazodone given acutely to increase prolactin concentrations and oral temperature is mediated via metabolism to the 5-hydroxytryptamine1C (5-HT1C) receptor agonist meta-chlorophenylpiperazine. The attenuation of these effects after subacute treatment could be due to an adaptive down-regulation of 5-HT1C receptors or to direct blockade of 5-HT1C receptors by nefazodone and its metabolite hydroxynefazodone (OH-nefazodone), the concentrations in plasma of which increase substantially during the 7-day treatment period.