Cannabis Abuse, Cannabis Dependence, Dual Diagnosis, Schizophrenia
Conditions
Keywords
Schizophrenia, Cannabis Abuse, Cannabis Dependence, Dual Diagnosis, Clozapine, Risperidone
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.
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.
Interventions
DRUGClozapine
Clozapine: target dose of 400mg per day with a maximum dose of 550mg per day
DRUGRisperidone
Clozapine: target dose of 4mg per day with a maximum dose of 6mg per day
Sponsors
University of South Carolina
Michigan State University
University of Miami
University of Massachusetts, Worcester
Dartmouth-Hitchcock Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Average Over Time of Intensity of Cannabis Use (Used to Evaluate Treatment Efficacy) | 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. |
| Average Over Time of Frequency of Cannabis Use | 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. |
Countries
United States
Participant flow
Pre-assignment details
During the course of the study a pharmacy issue precipitated the need to conduct the study as open label for a period of time. 7 participants (5 CLOZ and 2 RISP) were randomized under open label. Once a replacement pharmacy was in place the study returned to double blind status.
Participants by arm
| Arm | Count |
|---|---|
| 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.
Clozapine: Clozapine: target dose of 400mg per day with a maximum dose of 550mg per day | 23 |
| 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.
Risperidone: Clozapine: target dose of 4mg per day with a maximum dose of 6mg per day | 24 |
| Total | 47 |
Baseline characteristics
| Characteristic | Total | Clozapine | Risperidone |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 47 Participants | 23 Participants | 24 Participants |
| Age, Continuous | 39.26 years STANDARD_DEVIATION 8.99 | 36.87 years STANDARD_DEVIATION 7.83 | 41.54 years STANDARD_DEVIATION 9.58 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants | 6 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 38 Participants | 17 Participants | 21 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 19 Participants | 7 Participants | 12 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 27 Participants | 15 Participants | 12 Participants |
| Region of Enrollment United States | 47 Participants | 23 Participants | 24 Participants |
| Sex: Female, Male Female | 5 Participants | 1 Participants | 4 Participants |
| Sex: Female, Male Male | 42 Participants | 22 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 23 | 0 / 24 |
| other Total, other adverse events | 23 / 23 | 21 / 24 |
| serious Total, serious adverse events | 3 / 23 | 3 / 24 |
Outcome results
Primary
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.
Time frame: 12 weeks
Population: Average number of days of cannabis use over time was calculated using the midpoint 6.5 weeks. NOTE: Outlying data for a CLOZ and RISP subject were removed from the analyses. Additionally, two subjects and their data were excluded from the study due to unreliability (1 CLOZ, 1 RISP).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clozapine | Average Over Time of Frequency of Cannabis Use | 4.26 days of cannabis use during prior week |
| Risperidone | Average Over Time of Frequency of Cannabis Use | 4.58 days of cannabis use during prior week |
p-value: 0.25Mixed Models Analysis
Primary
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.
Time frame: 12 weeks
Population: Average number of joints Over Time was calculated using the midpoint of 6.5 weeks. NOTE: Outlying data for a CLOZ and RISP subject were removed from the analyses . Additionally, two subjects were excluded from the study due to unreliability (1 CLOZ, 1 RISP).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clozapine | Average Over Time of Intensity of Cannabis Use (Used to Evaluate Treatment Efficacy) | 10.21 joints smoked during the prior week |
| Risperidone | Average Over Time of Intensity of Cannabis Use (Used to Evaluate Treatment Efficacy) | 10.2 joints smoked during the prior week |
p-value: 0.99Mixed Models Analysis