Evaluate Pimavanserin, Risperidone or a combination of Pimavanserin and Risperidone in a treatment-resistant model of negative symptoms of schizophrenia

Negative symptoms represent one of the domains of psychopathology that is only partially addressed by current antipsychotic drugs (APDs). About 15% of patients have predominantly negative symptoms after treatment of their psychosis with antipsychotic drugs. The pathophysiology of negative symptoms is poorly understood. The pathway to an indication for negative symptoms that the FDA has spelled out is mainly for an augmentation treatment in patients with stable psychopathology. A useful animal model for negative symptoms is the abilty to restore social interaction (SI) in rodents with a social interaction deficit following withdrawal from subchronic phencyclidine (scPCP, see REF for details on the method). Using this model, we have found an effective dose (ED) of Pimavanserin alone (6mg/kg ip, with 3 mg/kg not effective), as well as an effective dose (ED) of the atypical antipsychotic Lurasidone (ED = 0.3 mg/kg, with 0.1 mg/kg not effective) and subeffective dose (SED) Pimavanserin (3 mg/kg) plus subeffective dose lurasidone (0.1 mg/kg), also being effective (Meltzer personal communication). This demonstrates that Pimavanserin is able to potentiate the actions of atypical APDs in resolving SI deficits in mice treated with scPCP. We wish to create a model of treatment-resistant schizophrenia by adding a component of stress to the negative symptoms scPCP model and determine if Pimavanserin can augment the efficacy of Risperidone in this model. If these studies are successful, we could then examine the effects of Pimavanserin on other atypical APDs in this model.