114. Ondansetron Improves P50 Auditory Sensory Gating in Medicated Schizophrenic Patients

P50 auditory sensory gating is impaired in schizophrenic patients. A schizophrenic patient does not show a decrease in the amplitude of the P50 waveform of the auditory evoked potential to the second of two closely paired click stimuli. In contrast, a normal control has a greatly decreased amplitude of the P50 waveform to the second stimulus. Expressed as a percentage (amplitude to the 2 stimulus/amplitude to the first stimulus 3 100), the P50 ratio is significantly higher in schizophrenic patients. This genetic deficit in inhibitory neuronal processing is mediated by the alpha-7 nicotinic receptor, which is rapidly desensitizing to nicotine. Nicotine briefly ameliorates this deficit in schizophrenic patients, but the effect is usually lost after one hour. Clozapine treatment, but not conventional antipsychotic medication, improves P50 auditory gating. We hypothesized that blockade of the 5HT3 receptor by clozapine may result in release of acetylcholine which then acts directly at the alpha-7 nicotinic receptor to enhance gating. To test this hypothesis, we gave 16 mg of oral ondansetron, a selective 5HT3 receptor antagonist, to 7 stable medicated schizophrenic outpatients in a double-blind placebo design. On two different days, the same subject had baseline auditory evoked responses recorded followed by either oral ondansetron or placebo. ERPs were recorded hourly for the next three hours. Ondansetron, but not placebo, resulted in a significant decrease in P50 ratio in these patients (Repeated measures ANOVA: F 5 21.44, d.f. 5 1, 12, p 5 0.001) that lasted significantly longer than nicotine treatment. These results support a possible role of 5HT3 antagonism in enhancing P50 gating by atypical antipsychotics.