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Nicotinic Receptors and Schizophrenia

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ClinicalTrials.gov Identifier: NCT02538081
Recruitment Status : Withdrawn (Withdrawn)
First Posted : September 2, 2015
Last Update Posted : May 30, 2017
Sponsor:
Collaborator:
University of Colorado, Denver
Information provided by (Responsible Party):
VA Office of Research and Development

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.

Condition or disease Intervention/treatment Phase
Schizophrenia Drug: Risperidone plus Placebo Drug: Risperidone plus DMXB-A Phase 1 Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double
Primary Purpose: Treatment
Official Title: Nicotinic Receptors and Schizophrenia
Actual Study Start Date : August 2015
Actual Primary Completion Date : August 2016
Actual Study Completion Date : August 2016

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Schizophrenia
Drug Information available for: Risperidone

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 Name: 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 Name: Risperdal




Primary Outcome Measures :
  1. 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

  2. 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


Secondary Outcome Measures :
  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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

  17. 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

  18. 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

  19. 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

  20. 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

  21. 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

  22. 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

  23. 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

  24. 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

  25. 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



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02538081


Locations
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United States, Colorado
VA Eastern Colorado Health Care System, Denver, CO
Denver, Colorado, United States, 80220
Sponsors and Collaborators
VA Office of Research and Development
University of Colorado, Denver
Investigators
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Principal Investigator: Robert Freedman, MD VA Eastern Colorado Health Care System, Denver, CO

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Responsible Party: VA Office of Research and Development
ClinicalTrials.gov Identifier: NCT02538081     History of Changes
Other Study ID Numbers: CLNA-008-14S
14-1443 ( Other Identifier: University of Colorado, Denver )
First Posted: September 2, 2015    Key Record Dates
Last Update Posted: May 30, 2017
Last Verified: May 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by VA Office of Research and Development:
schizophrenia
olanzapine
risperidone
alpha 7 nicotinic receptors
cognition
Additional relevant MeSH terms:
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Schizophrenia
Schizophrenia Spectrum and Other Psychotic Disorders
Mental Disorders
Olanzapine
Risperidone
3-(2,4-dimethoxybenzylidene)anabaseine
Serotonin Antagonists
Serotonin Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Antipsychotic Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs
Dopamine Antagonists
Dopamine Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Gastrointestinal Agents
Serotonin Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Nicotinic Agonists
Cholinergic Agonists
Cholinergic Agents