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Clozapine for Cannabis Use in Schizophrenia (CLOCS)

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ClinicalTrials.gov Identifier: NCT01639872
Recruitment Status : Completed
First Posted : July 13, 2012
Results First Posted : December 26, 2019
Last Update Posted : May 5, 2020
Sponsor:
Collaborators:
University of South Carolina
Michigan State University
University of Miami
University of Massachusetts, Worcester
Information provided by (Responsible Party):
Dartmouth-Hitchcock Medical Center

Brief Summary:

Many individuals with schizophrenia also suffer from marijuana addiction that worsens their problems related to schizophrenia. Most of the medications prescribed for schizophrenia have no effect on reducing marijuana use. Preliminary data suggests that clozapine, an atypical antipsychotic, may limit marijuana use in people diagnosed with schizophrenia, but it is not commonly used due to its side effects and is reserved for people who do not respond to other antipsychotic medications.

In the proposed study, 132 individuals who are diagnosed with both schizophrenia and a cannabis use disorder will be randomized to a 12-week treatment course with either clozapine or risperidone (another commonly prescribed antipsychotic medication) to test the hypothesis that patient treated with clozapine will have decreased cannabis use as compared to patients treated with risperidone.

Should this study indicate that clozapine will lessen marijuana use in persons diagnosed with schizophrenia more than risperidone, it will provide evidence needed to begin to shift clinical practice toward its use in this population.


Condition or disease Intervention/treatment Phase
Schizophrenia Cannabis Abuse Cannabis Dependence Dual Diagnosis Drug: Clozapine Drug: Risperidone Phase 4

Detailed Description:

Cannabis use disorder (CUD), which is up to ten times more common in patients with schizophrenia (SCZ) than in the general population, worsens the course of this severe psychiatric disorder. Since SCZ occurs in 1% of the population, the co-occurrence of CUD in 13% to 42% of people with this disorder presents society with an important public health problem. Unfortunately, most antipsychotics available for treatment of patients with SCZ do not appear to limit their cannabis use. Moreover, the one antipsychotic that preliminary data suggest may well limit cannabis use in these patients, clozapine (CLOZ), is not used for this purpose; it is reserved for patients whose psychosis is treatment resistant.

The overarching idea behind this proposal, however, is that CLOZ's use is being unreasonably restricted and should be made more widely available for patients with SCZ who have a co-occurring CUD but whose psychosis is not necessarily treatment resistant. This notion is supported by our preliminary clinical and animal data on the effects of CLOZ, as well as our neurobiological model of the basis of cannabis use in patients with SCZ that provides a pharmacologic rationale for this effect of CLOZ.

Even given all the arguments favoring the potential benefits of CLOZ in patients with SCZ and CUD, however, its side effect profile will likely limit its use until a fully powered study demonstrates its ability to decrease cannabis use in patients with SCZ. This proposal aims to launch such a study. If, as we hypothesize, this study confirms and extends our previous preliminary data of the effects of CLOZ in patients with SCZ and CUD, it will provide a strong impetus to expand the use of CLOZ in this population.

In the proposed study, 132 patients who are comorbid for both SCZ and CUD will be randomized to a 12-week treatment course with either CLOZ or risperidone (RISP) to test the hypothesis that patients treated with CLOZ will have decreased cannabis use as compared to patients treated with RISP. In addition, the study will determine whether patients treated with CLOZ will have improvements in psychiatric symptoms, quality of life neuropsychological functions as compared to those taking RISP. We will also explore whether patients taking CLOZ show improved reward responsiveness as compared to those taking RISP. Finally, this study will explore whether those patients with the val/val genotype at the Catechol-O-methyltransferase (COMT) Val158Met locus are more likely to decrease cannabis use during CLOZ treatment than are those without the val/val COMT genotype.

Should this study indicate that CLOZ will lessen cannabis use in patients with SCZ more than RISP, it will provide evidence needed to begin to shift clinical practice toward its use in these patients.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 49 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Clozapine for Cannabis Use Disorder in Schizophrenia
Actual Study Start Date : May 1, 2013
Actual Primary Completion Date : March 29, 2017
Actual Study Completion Date : March 29, 2017

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Clozapine
The blinded CLOZ will be titrated on a recommended standard schedule, supervised by a study physician (or other prescriber) who can make the necessary adjustments to account for symptom control and tolerability. The titration is recommended to begin at 12.5 mg and then increase while the open-label base antipsychotic is tapered with a recommended goal of decreasing the base antipsychotic by 25% each week. If clinically tolerated, the target dose of CLOZ is 400 mg/day.
Drug: Clozapine
Clozapine: target dose of 400mg per day with a maximum dose of 550mg per day
Other Name: Clozaril

Active Comparator: Risperidone
The blinded RISP will also be titrated in the first weeks, using a titration schedule, with a target dose of 4 mg/day, while the open label base antipsychotic is tapered in a similar fashion.
Drug: Risperidone
Clozapine: target dose of 4mg per day with a maximum dose of 6mg per day
Other Name: Risperdal




Primary Outcome Measures :
  1. Average Over Time of Intensity of Cannabis Use (Used to Evaluate Treatment Efficacy) [ Time Frame: 12 weeks ]
    Intensity of cannabis use is obtained each week retrospectively as the number of joints smoked during the prior week (assessed using the Timeline Followback). Mixed models are used to obtain estimates of efficacy from the partial data provided by each subject while adherent to assigned treatment (under the 'missing at random' assumption). The 'explanatory' estimands (target of the mixed model estimation) are defined in terms of population quantities that would have occurred had all subjects remained on assigned treatment throughout the study. The point estimate for each arm is reported under Number.

  2. Average Over Time of Frequency of Cannabis Use [ Time Frame: 12 weeks ]
    Frequency of cannabis use is obtained each week retrospectively as the number of days of cannabis use during the prior week (assessed using the Timeline Followback). Mixed models are used to obtain estimates of efficacy from the partial data provided by each subject while adherent to assigned treatment (under the 'missing at random' assumption). The 'explanatory' estimands (target of the mixed model estimation) are defined in terms of population quantities that would have occurred had all subjects remained on assigned treatment throughout the study. The point estimate for each arm is reported under Number.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Clinical diagnosis of schizophrenia
  • Clinical diagnosis of a cannabis use disorder (abuse or dependence)

Exclusion Criteria:

  • Pregnant,trying to become pregnant or nursing
  • History of a seizure disorder
  • Current treatment with clozapine or risperidone
  • Contraindication to treatment with clozapine or risperidone

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): NCT01639872


Locations
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United States, California
CNS Network Inc
Garden Grove, California, United States, 92845
Pacific Research Partners
Oakland, California, United States, 94607
United States, Florida
University of Miami
Miami, Florida, United States, 33136
United States, Massachusetts
Unversity of Massachusetts Medical School
Worcester, Massachusetts, United States, 01605
United States, Michigan
Michigan State University / Cherry Street Health Services
Grand Rapids, Michigan, United States, 49503
United States, New Hampshire
Dartmouth Hitchcock Medical Center
Lebanon, New Hampshire, United States, 03756
United States, North Carolina
University of North Carolina/UNC Center for Excellence in Community Mental Health
Raleigh, North Carolina, United States, 27610
United States, South Carolina
University of South Carolina
Columbia, South Carolina, United States, 29203
United States, Vermont
Rutland Regional Medical Center
Rutland, Vermont, United States, 05701
Sponsors and Collaborators
Dartmouth-Hitchcock Medical Center
University of South Carolina
Michigan State University
University of Miami
University of Massachusetts, Worcester
Investigators
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Study Chair: Alan I Green, MD Dartmouth College
  Study Documents (Full-Text)

Documents provided by Dartmouth-Hitchcock Medical Center:
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Responsible Party: Dartmouth-Hitchcock Medical Center
ClinicalTrials.gov Identifier: NCT01639872    
Other Study ID Numbers: 1R01DA032533-01A1 D13012
1R01DA032533-01A1 ( U.S. NIH Grant/Contract )
First Posted: July 13, 2012    Key Record Dates
Results First Posted: December 26, 2019
Last Update Posted: May 5, 2020
Last Verified: April 2020
Keywords provided by Dartmouth-Hitchcock Medical Center:
Schizophrenia
Cannabis Abuse
Cannabis Dependence
Dual Diagnosis
Clozapine
Risperidone
Additional relevant MeSH terms:
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Marijuana Abuse
Schizophrenia
Schizophrenia Spectrum and Other Psychotic Disorders
Mental Disorders
Substance-Related Disorders
Chemically-Induced Disorders
Risperidone
Clozapine
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
GABA Antagonists
GABA Agents