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.

Inclusion Criteria:

- BMI > 25

- Diagnosis of schizophrenia or schizoaffective disorder

- 18-75 years of age

- Taking olanzapine at least 10 mg

- If female, willing to use acceptable birth control during the study

- fluent in english

Exclusion Criteria:

- No emergent serious medical issues:

- cardiovascular disease

- neurological illnesses including -

- severe head injury

- HIV infection

- liver disease

- blood diseases

- kidney disease

- No drugs of abuse

- Not pregnant

- Not able to fast

- History of severe head injury