Nicotinic Receptors and Schizophrenia

Basic investigations in both animals and humans point to an increase in cholinergic neurotransmission as one possible mechanism of clozapine and olanzapine's enhanced therapeutic effects. However, there has not been a specific clinical trial to determine if stimulation of a nicotinic cholinergic receptor would capture this enhancement and be safer for patients. In the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) those assigned to risperidone from olanzapine had significantly higher discontinuation rates, with the primary reason being lack of efficacy. Olanzapine assignment for all patients was associated with continuing weight gain, which was not seen in patients assigned to risperidone. Many patients assigned to olanzapine from risperidone discontinued because of intolerability of the olanzapine, with metabolic problems being the chief reason. Thus, risperidone is a safer drug and, while equally effective for some patients, for others olanzapine continues to be more effective and tolerated despite its metabolic effect. The baseline rates on entry into the study are typical of most surveys of chronically ill patient populations; about twice as many were receiving olanzapine as were receiving risperidone, which suggests that clinicians choose to treat many patients on olanzapine, despite its side effects, because they do not do well on most other antipsychotic drugs.

This study proposes to conduct a clinical trial comparison of olanzapine and the combination of a nicotinic cholinergic agonist, 3-[2,4-Dimethoxybenzylidene]anabaseine (DMXB-A) with a dopamine D2 receptor antagonist, the mechanism common to all antipsychotic drugs, to test the hypothesis that 7-nicotinic receptor agonism may be an additional necessary factor that enhances the efficacy of olanzapine that allows its slight superiority to risperidone. In pilot data, the investigators studied 11 patients who received DMXB-A 300 mg plus olanzapine 20 mg (n=5) or risperidone 4 mg (n=6). The investigators found that DMXB-A improved performance on the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) mean battery score of the risperidone-treated patients to the level of the olanzapine-treated patient.

This trial would enroll patients taking olanzapine and record baseline measurements of clinical symptoms, cognition, metabolic parameters, and extrapyramidal side effects. The subjects would then be randomized to receive either risperidone or risperidone plus DMXB-A for 6 weeks and then would again have measurements of clinical symptoms, cognition, metabolic parameters and extrapyramidal side effects.