Nicotinic Receptors and Schizophrenia

Study Overview
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Brief Summary
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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. 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.

Detailed Description
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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.

Official Title
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Nicotinic Receptors and Schizophrenia

Conditions
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Schizophrenia

Intervention / Treatment
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* Drug: Risperidone plus Placebo
* Drug: Risperidone plus DMXB-A


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Risperidone plus placebo<br>Risperidone titrated to a dose equivalency of the patients' prior dose of olanzapine plus placebo | Drug: Risperidone plus Placebo<br>* Standard of care including Risperidone plus Placebo<br>* Other names: Risperdal;|
| Active Comparator: Risperidone plus DMXB-A<br>Risperidone titrated to a dose equivalency of the patients' prior dose of olanzapine plus DMXB-A | Drug: Risperidone plus DMXB-A<br>* Standard of care including Risperidone plus DMXB-A<br>* Other names: Risperdal;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Attention due to DMXB-A | the difference in the attention index from the RBANS measured at 6 weeks between risperidone plus DMXB-A and risperidone plus placebo | measured at 6 weeks | 
| Change in Executive Function due to DMXB-A | the difference in the executive function index from the RBANS measured at 6 weeks between risperidone plus DMXB-A and risperidone plus placebo | measured at 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in LDL | the difference in LDL at 6 weeks on risperidone plus placebo or risperidone plus DMXB-A | measured at 6 weeks | 
| Change in HDL | the difference in HDL measured at 6 weeks between risperidone plus placebo and risperidone plus DMXB-A | measured at 6 weeks | 
| Change in glucose | the difference in glucose measured at 6 weeks on either risperidone plus placebo and risperidone plus DMXB-A | measured at 6 weeks | 
| Change in Hemoglobin A1C | The difference in hemoglobin A1C measured at 6 weeks on either risperidone plus placebo and risperidone plus DMXB-A | measured at 6 weeks | 
| Change in insulin levels | The difference in insulin levels measured at 6 weeks between on either risperidone plus placebo and risperidone plus DMXB-A | measured at 6 weeks | 
| Change in c-reactive protein | The difference in C-reactive protein measured at 6 weeks between risperidone plus placebo and risperidone plus DMXB-A | measured at 6 weeks | 
| Change in girth | The difference in girth measured at 6 weeks between risperidone plus placebo and risperidone plus DMXB-A | measured at 6 weeks | 
| Change in BMI | The difference in BMI measured at 6 weeks between risperidone plus placebo and risperidone plus DMXB-A | measured at 6 weeks | 
| Change in Cholesterol | The difference in Cholesterol measured at 6 weeks between risperidone plus placebo and risperidone plus DMXB-A | measured at 6 weeks | 
| Change in the total scale score of the brief psychiatric rating scale | The difference in the Total scale score of the Brief Psychiatric Rating Scale BPRS measured at 6 weeks or at study conclusion on either risperidone plus placebo and risperidone plus DMXB-A | measured at 2 weeks, 3 weeks, 4 weeks, 5 weeks and 6 weeks of drug administration, or, if the subject exits the study prematurely, on the day of study exit. | 
| Change in the scale for the assessment of negative symptoms | The difference in the clinical Scale for the Measurement of Negative Symptoms (SANS) measured at 6 weeks on either risperidone plus placebo and risperidone plus DMXB-A | measured at 2 weeks, 3 weeks, 4 weeks, 5 weeks and 6 weeks | 
| Change in Attention index with switch from olanzapine to risperidone plus DMXB-A | The difference in the attention index from the RBANS measured on olanzapine at baseline and at 6 weeks on risperidone plus DMXB-A | measured at baseline and 6 weeks | 
| Change in Executive function index with switch from olanzapine to risperidone plus DMXB-A | The difference in the executive function index from the RBANS measured on olanzapine at baseline and at 6 weeks on risperidone plus DMXB-A | measured at baseline and 6 weeks | 
| Change in Total BPRS with switch from olanzapine to risperidone plus DMXB-A | The difference in the Total BPRS measured on olanzapine at baseline and at 6 weeks on risperidone plus DMXB-A | measured at baseline and 6 weeks | 
| Change in SANS with switch from olanzapine to risperidone plus DMXB-A | The difference in the SANS measured on olanzapine at baseline and at 6 weeks on risperidone plus DMXB-A | measured at baseline and 6 weeks | 
| Change in BMI with switch from olanzapine to risperidone plus DMXB-A | The difference in the BMI measured on olanzapine at baseline and at 6 weeks on risperidone plus DMXB-A | measured at baseline and 6 weeks | 
| Change in c-reactive protein with switch from olanzapine to risperidone plus DMXB-A | The difference in the c-reactive protein measured on olanzapine at baseline and at 6 weeks on risperidone plus DMXB-A | measured at baseline and 6 weeks | 
| Change in LDL with switch from olanzapine to risperidone plus DMXB-A | The difference in the LDL measured on olanzapine at baseline and at 6 weeks on risperidone plus DMXB-A | measured at baseline and 6 weeks | 
| Change in HDL with switch from olanzapine to risperidone plus DMXB-A | The difference in the HDL measured on olanzapine at baseline and at 6 weeks on risperidone plus DMXB-A | measured at baseline and 6 weeks | 
| Change in glucose with switch from olanzapine to risperidone plus DMXB-A | The difference in the glucose measured on olanzapine at baseline and at 6 weeks on risperidone plus DMXB-A | measured at baseline and 6 weeks | 
| Change in cholesterol with switch from olanzapine to risperidone plus DMXB-A | The difference in the cholesterol measured on olanzapine at baseline and at 6 weeks on risperidone plus DMXB-A | measured at baseline and 6 weeks | 
| Change in cholesterol with switch from olanzapine to risperidone plus DMXB-A | The difference cholesterol measured on olanzapine at baseline and at 6 weeks on risperidone plus DMXB-A | measured at baseline and 6 weeks | 
| Change in girth with switch from olanzapine to risperidone plus DMXB-A | The difference girth measured on olanzapine at baseline and at 6 weeks on risperidone plus DMXB-A | measured at baseline and 6 weeks | 
| Change in insulin levels with switch from olanzapine to risperidone plus DMXB-A | The difference insulin levels measured on olanzapine at baseline and at 6 weeks on risperidone plus DMXB-A | measured at baseline and 6 weeks | 
| Change in hemoglobin A1C with switch from olanzapine to risperidone plus DMXB-A | The difference in Hemoglobin A1C measured on olanzapine at baseline and at 6 weeks on risperidone plus DMXB-A | measured at baseline and 6 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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schizophrenia, olanzapine, risperidone, alpha 7 nicotinic receptors, cognition