Nicotinic Receptors and Schizophrenia

May 25, 2017 updated by: VA Office of Research and Development
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.

Study Overview

Status

Withdrawn

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Colorado
      • Denver, Colorado, United States, 80220
        • VA Eastern Colorado Health Care System, Denver, CO

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 70 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Risperidone plus placebo
Risperidone titrated to a dose equivalency of the patients' prior dose of olanzapine plus placebo
Drug: Risperidone plus Placebo
Standard of care including Risperidone plus Placebo
Other Names:
  • Risperdal
Active Comparator: Risperidone plus DMXB-A
Risperidone titrated to a dose equivalency of the patients' prior dose of olanzapine plus DMXB-A
Drug: Risperidone plus DMXB-A
Standard of care including Risperidone plus DMXB-A
Other Names:
  • Risperdal

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in Attention due to DMXB-A
Time Frame: measured at 6 weeks
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
Time Frame: measured at 6 weeks
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
Time Frame: measured at 6 weeks
the difference in LDL at 6 weeks on risperidone plus placebo or risperidone plus DMXB-A
measured at 6 weeks
Change in HDL
Time Frame: measured at 6 weeks
the difference in HDL measured at 6 weeks between risperidone plus placebo and risperidone plus DMXB-A
measured at 6 weeks
Change in glucose
Time Frame: measured at 6 weeks
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
Time Frame: measured at 6 weeks
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
Time Frame: measured at 6 weeks
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
Time Frame: measured at 6 weeks
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
Time Frame: measured at 6 weeks
The difference in girth measured at 6 weeks between risperidone plus placebo and risperidone plus DMXB-A
measured at 6 weeks
Change in BMI
Time Frame: measured at 6 weeks
The difference in BMI measured at 6 weeks between risperidone plus placebo and risperidone plus DMXB-A
measured at 6 weeks
Change in Cholesterol
Time Frame: measured at 6 weeks
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
Time Frame: 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.
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
Time Frame: measured at 2 weeks, 3 weeks, 4 weeks, 5 weeks and 6 weeks
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
Time Frame: measured at baseline and 6 weeks
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
Time Frame: measured at baseline and 6 weeks
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
Time Frame: measured at baseline and 6 weeks
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
Time Frame: measured at baseline and 6 weeks
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
Time Frame: measured at baseline and 6 weeks
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
Time Frame: measured at baseline and 6 weeks
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
Time Frame: measured at baseline and 6 weeks
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
Time Frame: measured at baseline and 6 weeks
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
Time Frame: measured at baseline and 6 weeks
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
Time Frame: measured at baseline and 6 weeks
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
Time Frame: measured at baseline and 6 weeks
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
Time Frame: measured at baseline and 6 weeks
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
Time Frame: measured at baseline and 6 weeks
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
Time Frame: measured at baseline and 6 weeks
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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

VA Office of Research and Development

Collaborators

University of Colorado, Denver

Investigators

  • Principal Investigator: Robert Freedman, MD, VA Eastern Colorado Health Care System, Denver, CO

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 1, 2015

Primary Completion (Actual)

August 1, 2016

Study Completion (Actual)

August 1, 2016

Study Registration Dates

First Submitted

August 10, 2015

First Submitted That Met QC Criteria

August 28, 2015

First Posted (Estimate)

September 2, 2015

Study Record Updates

Last Update Posted (Actual)

May 30, 2017

Last Update Submitted That Met QC Criteria

May 25, 2017

Last Verified

May 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CLNA-008-14S
  • 14-1443 (Other Identifier: University of Colorado, Denver)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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