There are conflicting data on the effect of the acute administration of mCPP, a mixed 5-HT2A/2C agonist, to patients with schizophrenia, with one study reporting a decrease in psychotic symptoms (Kahn et al. 1992); three others, a mild exacerbation of positive symptoms (Iqbal et al. 1991; Krystal et al. 1993); and two, no significant effect (Maes and Meltzer 1996; Koreen et al. 1997). The reasons for these discrepancies are unclear. It is not related to route of administration, severity of symptoms, or gender. Maes and Meltzer (1996) also reported no differences in the mCPP-induced prolactin, cortisol, or temperature responses in patients with schizophrenia who were neuroleptic free at the time of study. Clozapine has been reported to antagonize the cortisol response to mCPP in patients with schizophrenia, consistent with its 5-HT2C antagonist properties (Kahn et al. 1994; Owen et al. 1993). Two studies reported no difference in the cortisol or adrenocorticotropic hormone (ACTH) response between patients with schizophrenia and controls but both found that the greater the cortisol or ACTH response to mCPP prior to subsequent treatment with clozapine, the better the response to clozapine (Owen et al. 1993; Kahn et al. 1993). A possible explanation of the relationship between the cortisol or ACTH response to mCPP and the subsequent response to clozapine is that subjects with relatively enhanced 5-HT2C receptor activation throughout the brain, compared with other patients with schizophrenia, might benefit from inhibition of such activity by clozapine. However, there is no evidence as yet to suggest that patients with schizophrenia as a group have enhanced 5-HT2C receptor activity relative to controls. The opposite may be the case, as suggested by the mRNA expression studies previous mentioned (Castensson et al. 2003, 2005). It should also be noted that the cortisol response to mCPP in rats was blocked by the selective 5-HT2A inverse agonist MDL 100907 but not by the selective 5-HT2C inverse agonist SB 242084 (Hemrick-Luecke and Evans 2002). It will be of interest to determine the endocrine, temperature, and behavioral responses to WAY 100639 in patients with schizophrenia and normal controls and to follow this up with a clinical trial with WAY 163909 or other antipsychotic drugs to determine if the cortisol or ACTH response in the unmedicated state is predictive of response. It would also be of interest to couple these to data from genotyping of the three common SNPs of the 5-HT2C receptor previously discussed.
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