Treatment of Schizophrenia and Comorbid Cannabis Use Disorder: Comparing Clozapine to Treatment-as-Usual

• Sponsor: Dartmouth-Hitchcock Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00498550
• Collaborator: National Institute on Drug Abuse (NIDA) (NIH), University of Missouri, Kansas City (Other), VA Medical Center-West Los Angeles (U.S. Fed), University of South Carolina (Other)
• Enrollment: 31
• Locations: 4
• Arms: 2
• Duration (Months): 101
• Patients Per Site: 7.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Many individuals with schizophrenia also suffer from marijuana addiction. Clozapine, an atypical antipsychotic medication, may prove useful at preventing drug relapse in schizophrenic individuals who are seeking treatment for marijuana addiction. The purpose of this study is to compare the effectiveness of clozapine, vs. treatment-as-usual with other oral antipsychotics at reducing marijuana use in schizophrenic individuals.

Condition or Disease	Intervention/Treatment	Phase
Schizophrenia; Dual Diagnosis; Schizoaffective Disorder; Psychotic Disorder; Cannabis Abuse	Drug: Clozapine; Drug: Treatment as usual	Phase 4

Detailed Description

Individuals with schizophrenia have a high risk of becoming addicted to drugs; between 13 to 42% of schizophrenics are addicted to marijuana. These individuals often have difficulties adhering to a substance abuse treatment program, and have an increased chance of marijuana relapse. Marijuana use by schizophrenics has also been associated with clinical exacerbations, noncompliance with antipsychotic medications, poor global functioning, and increased rehospitalization rates. While antipsychotic medications are often effective in controlling symptoms of schizophrenia, they are not always effective in preventing substance abuse. Clozapine, an atypical antipsychotic drug, is currently used to treat schizophrenia. Preliminary research has shown that clozapine is more successful at reducing drug relapse rates in individuals with schizophrenia, as compared to other antipsychotic medications, including olanzapine and risperidone. The purpose of this study is to compare the effectiveness of clozapine as compared to other oral antipsychotic treatment, including combinations of up to two antipsychotics, in reducing marijuana use in schizophrenic individuals.

This study will enroll individuals with schizophrenia who are currently taking any oral antipsychotic other than clozapine, including those taking up to two oral antipsychotic, and who are also addicted to marijuana. The study will begin with a 1-week assessment phase, during which all participants will continue taking olanzapine or risperidone. Participants will undergo a physical examination and have blood drawn for laboratory tests. Information pertaining to their medical, psychiatric, and substance use history will also be collected. Urine tests and breathalyzers will be used to screen for the presence of alcohol and drugs. Following the assessment phase, participants will be randomly assigned to switch to clozapine or remain on their prestudy antipsychotic for 12 weeks. Participants remaining on their prestudy antipsychotic treatment will continue to receive the same dose for the entire study. Participants taking clozapine will initially receive a daily dose of 12.5 mg, which will be increased to a maximum of 400 mg per day, as tolerated. Study visits will take place once a week. At each visit, medication side effects, physical and psychological symptoms, substance use, treatment services received, and living situation will be assessed. Blood will be drawn for laboratory tests. Drug and alcohol levels will be monitored three times a week through urine and breathalyzer tests. Quality of life questionnaires will be administered once a month.

Study Design

• Study Type: Interventional
• Actual Enrollment: 31 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Cannabis and Schizophrenia: Effects of Clozapine
• Study Start Date: Oct 1, 2000
• Actual Primary Completion Date: Mar 1, 2009
• Actual Study Completion Date: Mar 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Clozapine Clozapine, Clozaril	Drug: Clozapine; Clozapine up to 550mg per day; Other Names: Clozaril
Active Comparator: Treatment as usual Treatment as usual with any antipsychotic other than Clozapine.	Drug: Treatment as usual; Remain on pre-study antipsychotic treatment

Outcome Measures

Primary Outcome Measures

1. Average Over Time of Intensity of Cannabis Use (Used to Evaluate Treatment Efficacy) [Week 1 to week 12]

   Intensity of cannabis use is obtained for each week retrospectively as the number of joints smoked during the prior week (assessed by the Timeline Followback Scale). 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Meets Diagnostic and Statical Manual of Mental Disorders IV (DSM-IV) diagnostic criteria for schizophrenia or schizoaffective disorder

• Meets diagnostic criteria for marijuana use disorder, as determined by a rating of 3 or higher on the Drug Use Scale (Abuse or Dependence)

• Used marijuana on 5 or more days during the 3 weeks prior to study entry

• Taking any oral antipsychotic other than clozapine in the month prior to study entry. (Patients may take a second oral antipsychotic medication, if approved by the Medication Adjustment Group)

• If female, willing to use effective contraception throughout the study

Exclusion Criteria:

• Unable to take clozapine for medical reasons, including previous clozapine-induced granulocytopenia, myeloproliferative disorder, white blood cell count less than 3500/mm3, or history of seizures

• Currently taking clozapine

• Currently taking other psychotropic medications for the treatment of substance use (e.g., disulfiram, naltrexone, acamprosate, inderol, tegretol, topiramate, and pramipexole)

• Participated in a clinical trial of an investigational drug within 30 days of study entry

• Currently participating in a psychosocial intervention clinical trial

• Has medical or legal problems that may entail a jail or hospital stay during the study

• Has a developmental disability that would make study participation difficult

• Currently enrolled in a live-in treatment program for substance use disorders

• Pregnant or plans to become pregnant during the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	West LA VAHCS	Los Angeles	California	United States	90073
2	University Missouri	Kansas City	Missouri	United States	64108
3	Mental Health Center of Greater Manchester	Manchester	New Hampshire	United States	03101
4	University South Carolina	Columbia	South Carolina	United States	29203

Sponsors and Collaborators

• Dartmouth-Hitchcock Medical Center
• National Institute on Drug Abuse (NIDA)
• University of Missouri, Kansas City
• VA Medical Center-West Los Angeles
• University of South Carolina

Investigators

• Principal Investigator: Alan Green, MD, Dartmouth-Hitchcock Medical Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Alan Green, Principal Investigator, Dartmouth-Hitchcock Medical Center
• ClinicalTrials.gov Identifier: NCT00498550
• Other Study ID Numbers: NCT00149955; R01DA013196; DPMCDA; NCT00149955
• First Posted: Jul 10, 2007
• Last Update Posted: Mar 13, 2019
• Last Verified: Feb 1, 2019

• Keywords provided by Alan Green, Principal Investigator, Dartmouth-Hitchcock Medical Center: Clozapine; Schizophrenia; Dual Diagnosis; Substance Abuse; Cannabis Abuse
• Additional relevant MeSH terms: Disease; Marijuana Abuse; Schizophrenia; Mental Disorders; Psychotic Disorders; Clozapine

Study Results

Participant Flow

Arm/Group Title	Clozapine	Treatment as Usual
Arm/Group Description	Clozapine, Clozaril	Treatment as usual with any antipsychotic other than Clozapine.
Period Title: Overall Study
STARTED	15	16
COMPLETED	15	15
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	Clozapine	Treatment as Usual	Total
Arm/Group Description	Clozapine, Clozaril	Treatment as usual with any antipsychotic other than Clozapine.	Total of all reporting groups
Overall Participants	15	16	31
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	15 100%	16 100%	31 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	33.3 (10.0)	39.0 (10.2)	36 (10.3)
Sex: Female, Male (Count of Participants)
Female	3 20%	4 25%	7 22.6%
Male	12 80%	12 75%	24 77.4%
Region of Enrollment (Count of Participants)
United States	15 100%	16 100%	31 100%

Outcome Measures

1. Primary Outcome

Title	Average Over Time of Intensity of Cannabis Use (Used to Evaluate Treatment Efficacy)
Description	Intensity of cannabis use is obtained for each week retrospectively as the number of joints smoked during the prior week (assessed by the Timeline Followback Scale). 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.
Time Frame	Week 1 to week 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Clozapine	Treatment as Usual
Arm/Group Description	Clozapine, Clozaril	Treatment as usual with any antipsychotic other than Clozapine.
Measure Participants	15	16
Number (95% Confidence Interval) [Joints per week]	0.02	4.56

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clozapine, Treatment as Usual
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.088
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	difference in treatment means
	Estimated Value	-4.54
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.57
	Estimation Comments	We report the estimated coefficient for difference in treatment means in a mixed model and its standard error.

Adverse Events

Time Frame	12 Weeks
Arm/Group Title	Clozapine		Treatment as Usual
Arm/Group Description	Clozapine, Clozaril		Treatment as usual with any antipsychotic other than Clozapine.
All Cause Mortality
	Clozapine		Treatment as Usual
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Clozapine		Treatment as Usual
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/15 (26.7%)		4/16 (25%)
Gastrointestinal disorders
Vomiting	1/15 (6.7%)	1	0/16 (0%)	0
Pancreatitis	0/15 (0%)	0	1/16 (6.3%)	2
General disorders
Non-Cardiac Chest Pain	0/15 (0%)	0	1/16 (6.3%)	1
Psychiatric disorders
Psychiatric Disorder - Other: Accidental Overdose	0/15 (0%)	0	1/16 (6.3%)	1
Suicide Attempt	1/15 (6.7%)	1	1/16 (6.3%)	2
Depression	1/15 (6.7%)	1	0/16 (0%)	0
Psychosis	1/15 (6.7%)	1	0/16 (0%)	0
Other (Not Including Serious) Adverse Events
	Clozapine		Treatment as Usual
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/15 (100%)		15/16 (93.8%)
Cardiac disorders
Hypertension	2/15 (13.3%)	2	2/16 (12.5%)	2
Gastrointestinal disorders
Constipation	4/15 (26.7%)	4	0/16 (0%)	0
Dry Mouth	2/15 (13.3%)	3	2/16 (12.5%)	2
Gastrointestinal Disorder - Other: Hypersalivation	10/15 (66.7%)	11	0/16 (0%)	0
Nausea	2/15 (13.3%)	5	1/16 (6.3%)	1
Vomiting	2/15 (13.3%)	2	3/16 (18.8%)	3
General disorders
Fatigue	3/15 (20%)	3	0/16 (0%)	0
Flu Like Symptoms	0/15 (0%)	0	2/16 (12.5%)	2
Irritability	1/15 (6.7%)	1	1/16 (6.3%)	1
Non-Cardiac Chest Pain	1/15 (6.7%)	1	1/16 (6.3%)	1
Investigations
Weight Gain	6/15 (40%)	7	2/16 (12.5%)	3
Musculoskeletal and connective tissue disorders
Musculoskeletal And Connective Tissue Disorder - Other: Muscle Spasms	2/15 (13.3%)	2	0/16 (0%)	0
Nervous system disorders
Akathisia	1/15 (6.7%)	1	1/16 (6.3%)	1
Dizziness	5/15 (33.3%)	8	1/16 (6.3%)	1
Headache	2/15 (13.3%)	3	1/16 (6.3%)	1
Nervous Sytem Disorder - Other: Unusual Dream Activity	0/15 (0%)	0	2/16 (12.5%)	2
Somnolence	9/15 (60%)	12	2/16 (12.5%)	2
Psychiatric disorders
Agitation	1/15 (6.7%)	1	1/16 (6.3%)	1
Depression	1/15 (6.7%)	1	1/16 (6.3%)	1
Insomnia	2/15 (13.3%)	2	1/16 (6.3%)	1
Renal and urinary disorders
Urinary Incontinence	2/15 (13.3%)	2	0/16 (0%)	0
Reproductive system and breast disorders
Libido Decreased	1/15 (6.7%)	1	1/16 (6.3%)	1
Respiratory, thoracic and mediastinal disorders
Nasal Congestion	0/15 (0%)	0	2/16 (12.5%)	3

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.