WAY-163909, a 5-HT_2C agonist, enhances the preclinical potency of current antipsychotics

Introduction: 5-HT_2C agonists, by decreasing mesolimbic dopamine without affecting nigrostriatal dopamine, are predicted to have antipsychotic efficacy with low extrapyramidal side effects (EPS). Combining 5-HT_2C agonists with low doses of existing antipsychotics could increase treatment efficacy while reducing treatment liabilities such as EPS (typical antipsychotics), and the propensity for weight gain (atypical antipsychotics). Objectives: The objectives of these studies were to combine WAY-163909, a selective 5-HT_2C agonist, with either the typical antipsychotic haloperidol, or the atypical antipsychotic clozapine, at doses that were ineffective on their own, with the expectation that a shift in potency in several rodent behavior models predictive of antipsychotic activity would occur. Results and discussion: In mice, co-administration of either haloperidol, or clozapine, produced a significant leftward shift in the ability of WAY-163909 to block apomorphine-induced climbing behavior, without any affect on apomorphine-induced stereotypy or an increased propensity for catalepsy. In the rat-conditioned avoidance model, WAY-163909 was combined with either haloperidol or clozapine at doses that individually produced reductions in avoidance response on the order of 10%, while the combination of WAY-163909 and either of the antipsychotics resulted in a greater than 70% reduction in avoidance, with no evidence of response failures, or pharmacokinetic interaction. Conclusion: Doses of either haloperidol or clozapine, that failed to antagonize an MK-801 induced deficit in prepulse inhibition, significantly attenuated the sensory gating deficit when combined with WAY-163909. Data support the notion that 5-HT_2C receptor agonists, co-administered with other marketed antipsychotics, allow for dose sparing with a more favorable side-effect profile.