Clinical trial NCT02538081: Nicotinic Receptors and Schizophrenia
Official title: Nicotinic Receptors and Schizophrenia
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE1
PHASE2
Conditions: Schizophrenia
Keywords: schizophrenia
olanzapine
risperidone
alpha 7 nicotinic receptors
cognition
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
Collaborators: name: University of Colorado, Denver
First posted: 2015-09-02
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Change in Attention due to DMXB-A
timeFrame: measured at 6 weeks
measure: Change in Executive Function due to DMXB-A
timeFrame: measured at 6 weeks
Secondary outcomes:
measure: Change in LDL
timeFrame: measured at 6 weeks
measure: Change in HDL
timeFrame: measured at 6 weeks
measure: Change in glucose
timeFrame: measured at 6 weeks
measure: Change in Hemoglobin A1C
timeFrame: measured at 6 weeks
measure: Change in insulin levels
timeFrame: measured at 6 weeks
measure: Change in c-reactive protein
timeFrame: measured at 6 weeks
measure: Change in girth
timeFrame: measured at 6 weeks
measure: Change in BMI
timeFrame: measured at 6 weeks
measure: Change in Cholesterol
timeFrame: measured at 6 weeks
measure: Change in the total scale score of the brief psychiatric rating scale
timeFrame: 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.
measure: Change in the scale for the assessment of negative symptoms
timeFrame: measured at 2 weeks, 3 weeks, 4 weeks, 5 weeks and 6 weeks
measure: Change in Attention index with switch from olanzapine to risperidone plus DMXB-A
timeFrame: measured at baseline and 6 weeks
measure: Change in Executive function index with switch from olanzapine to risperidone plus DMXB-A
timeFrame: measured at baseline and 6 weeks
measure: Change in Total BPRS with switch from olanzapine to risperidone plus DMXB-A
timeFrame: measured at baseline and 6 weeks
measure: Change in SANS with switch from olanzapine to risperidone plus DMXB-A
timeFrame: measured at baseline and 6 weeks
measure: Change in BMI with switch from olanzapine to risperidone plus DMXB-A
timeFrame: measured at baseline and 6 weeks
measure: Change in c-reactive protein with switch from olanzapine to risperidone plus DMXB-A
timeFrame: measured at baseline and 6 weeks
measure: Change in LDL with switch from olanzapine to risperidone plus DMXB-A
timeFrame: measured at baseline and 6 weeks
measure: Change in HDL with switch from olanzapine to risperidone plus DMXB-A
timeFrame: measured at baseline and 6 weeks
measure: Change in glucose with switch from olanzapine to risperidone plus DMXB-A
timeFrame: measured at baseline and 6 weeks
measure: Change in cholesterol with switch from olanzapine to risperidone plus DMXB-A
timeFrame: measured at baseline and 6 weeks
measure: Change in cholesterol with switch from olanzapine to risperidone plus DMXB-A
timeFrame: measured at baseline and 6 weeks
measure: Change in girth with switch from olanzapine to risperidone plus DMXB-A
timeFrame: measured at baseline and 6 weeks
measure: Change in insulin levels with switch from olanzapine to risperidone plus DMXB-A
timeFrame: measured at baseline and 6 weeks
measure: Change in hemoglobin A1C with switch from olanzapine to risperidone plus DMXB-A
timeFrame: measured at baseline and 6 weeks
Other outcomes:
Locations:
city: Denver
country: United States
facility: VA Eastern Colorado Health Care System, Denver, CO
state: Colorado
Study officials:
affiliation: VA Eastern Colorado Health Care System, Denver, CO
name: Robert Freedman, MD
role: PRINCIPAL_INVESTIGATOR
References: