Nicotinic Receptors and Schizophrenia

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DESCRIPTION (provided by applicant): Although a number of antipsychotic drugs are available for Veterans with schizophrenia, three are used more frequently by VA prescribers-risperidone because of its overall favorable side effect profile, clozapine because of its superior efficacy, and olanzapine for many Veterans who do not respond completely to risperidone, but who also cannot take clozapine for various reasons. However, olanzapine, despite its persistent clinical use for patients resistant to safer drugs, produces significant morbidity and mortality from metabolic syndrome. Basic science and clinical studies suggest that one mechanism of the enhanced efficacy of clozapine and olanzapine is increased cholinergic neurotransmission, produced by the increased release of acetylcholine from presynaptic terminals. This effect possibly results from clozapine's and olanzapine's antagonism of serotonergic receptors like the 5-HT3 receptors on cholinergic terminals, which normally decrease acetylcholine release. We have preliminary data showing that the combination of risperidone, to achieve dopamine receptor blockade, and the investigational nicotinic agonist 3-(2,4-dimethoxy)benzylidene anabaseine (DMXB-A) has effects on neurocognition in schizophrenia of similar magnitude to olanzapine. DMXB-A does not significantly enhance the neurocognitive effect of olanzapine, consistent with the hypothesis that olanzapine is already activating cholinergic receptors. We therefore propose a randomized double-blind Phase 2 clinical trial in 60 veterans to test whether patients who currently are judged by their VA clinicians to require olanzapine can be safely and effectively treated with a risperidone DMXB-A combination. The primary outcome measure will be the NIMH MATRICS Consensus Cognitive Battery Total Scale Score, chosen because of its correlation with functional outcomes and its favorable psychometric properties. We hypothesize superiority of risperidone/DMXBA to risperidone/placebo and non-inferiority between risperidone/DMXB-A and olanzapine for neurocognition and clinical ratings, but improvement in metabolic parameters on the risperidone/DMXB-A combination. This phase 2 study will enable us to determine if a longer, more definitive trial, perhaps through the VA Cooperative Studies Program, is warranted.