Clozapine for Cannabis Use in Schizophrenia (CLOCS)

Clozapine for Cannabis Use Disorder in Schizophrenia

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.

Study Overview

• Status: Completed
• Conditions: Schizophrenia; Cannabis Dependence; Dual Diagnosis; Cannabis Abuse
• Intervention / Treatment: Drug: Clozapine; Drug: Risperidone

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.

• Study Type: Interventional
• Enrollment (Actual): 49
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • California
    • Garden Grove, California, United States, 92845
      • CNS Network Inc
    • Oakland, California, United States, 94607
      • Pacific Research Partners
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami
  • Massachusetts
    • Worcester, Massachusetts, United States, 01605
      • Unversity of Massachusetts Medical School
  • Michigan
    • Grand Rapids, Michigan, United States, 49503
      • Michigan State University / Cherry Street Health Services
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth Hitchcock Medical Center
  • North Carolina
    • Raleigh, North Carolina, United States, 27610
      • University of North Carolina/UNC Center for Excellence in Community Mental Health
  • South Carolina
    • Columbia, South Carolina, United States, 29203
      • University of South Carolina
  • Vermont
    • Rutland, Vermont, United States, 05701
      • Rutland Regional Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 53 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / 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 Names: 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 Names: Risperdal

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Average Over Time of Intensity of Cannabis Use (Used to Evaluate Treatment Efficacy)	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.	12 weeks
Average Over Time of Frequency of Cannabis Use	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.	12 weeks

Collaborators and Investigators

• Sponsor: Dartmouth-Hitchcock Medical Center
• Collaborators: University of Miami; University of South Carolina; University of Massachusetts, Worcester; Michigan State University
• Investigators: Study Chair: Alan I Green, MD, Dartmouth College

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2013
• Primary Completion (Actual): March 29, 2017
• Study Completion (Actual): March 29, 2017

Study Registration Dates

• First Submitted: July 11, 2012
• First Submitted That Met QC Criteria: July 12, 2012
• First Posted (Estimate): July 13, 2012

Study Record Updates

• Last Update Posted (Actual): May 5, 2020
• Last Update Submitted That Met QC Criteria: April 27, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: Schizophrenia; Clozapine; Risperidone; Dual Diagnosis; Cannabis Abuse; Cannabis Dependence
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Pathologic Processes; Substance-Related Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia; Disease; Marijuana Abuse; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Serotonin Agents; Dopamine Agents; Serotonin Antagonists; Dopamine Antagonists; GABA Agents; GABA Antagonists; Risperidone; Clozapine
• Other Study ID Numbers: 1R01DA032533-01A1 D13012; 1R01DA032533-01A1 (U.S. NIH Grant/Contract)