This is a competing renewal of studies of P50 auditory sensory gating in schizophrenia. Schizophrenic patients have a deficit in processing auditory sensory information. This can be demonstrated using a P50 auditory evoked potential paradigm. In this paradigm, a schizophrenic patient fails to decrease the amplitude of the second of two closely paired auditory click stimuli. In contrast, normal controls decrease the amplitude of the response to the second sound, compared to the first. Thus, schizophrenic patients, in comparison to normal controls have a deficit in the functioning of inhibitory neuronal pathways, i.e., they fail to gate incoming stimuli. Treatment with multiple conventional neuroleptics failed to normalize this P50 auditory gating deficit in schizophrenic patients. Treatment with clozapine, a prototypical atypical antipsychotic agent, has normalized P50 auditory gating in 10 neuroleptic-resistant schizophrenic patients. This normalization of P50 auditory gating in some treatment-resistant patients has lasted up to two years. In contrast, treatment of a similar number of patients with risperidone, did not normalize P50 auditory gating in a similar group of patients. The investigator hypothesized that although both atypical antipsychotics had high 5-HT2/D2 blocking ratios, only clozapine blocks the 5-HT3 receptor. Preliminary data indicates that olanzapine, which also blocks the 5-HT3 receptor, enhances P50 auditory gating in nongating relatives of schizophrenic patients, as does ondansetron, a pure 5-HT3 receptor antagonist. The investigator's specific aims are to assess whether atypical antipsychotics that block the 5-HT3 receptor also enhance P50 auditory sensory gating. The investigator will study 4 groups of patients: 25 patients treated with clozapine, 25 patients treated with risperidone, 25 patients treated with olanzapine, and 25 schizophrenic patients treated with haloperidol and ondansetron in combination and follow them for two years of treatment. If it is the combination of dopaminergic blockade with blockade of the 5-HT3 receptor that is responsible for the therapeutic effect, then all three treatments, except risperidone should normalize P50 gating in these patients. The investigator will also study other atypical antipsychotics as they become available. In previous research, he has documented that the alpha-7 nicotinic receptor mediates P50 auditory sensory gating. Blockade of the 5-HT3 receptor in animals releases acetylcholine at these sites in the hippocampus. These are rapidly desensitizing. Nicotine briefly enhances P50 gating in schizophrenics, but the effect is rapidly lost. If clozapine's effect on P50 gating is primarily through the alpha-7 nicotinic receptor, then treatment with oral nicotine should not show an enhancement of P50 gating in clozapine-treated patients. If oral nicotine enhances P50 gating in clozapine-treated patients, this suggests that the clozapine effect is not mediated solely by the alpha-7 nicotinic receptor. The investigator will study 25 subjects in a double-blind placebo crossover design. These studies would add new insight to the question of how clozapine and related neuroleptics produce enhanced therapeutic effects.
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