First Episode Schizophrenia and Cannabis-Related Disorder Study
Condition: Cannabis-Related Disorder; Substance-Related Disorders; Schizophrenia; Psychotic Disorders
MeSH terms: Marijuana Abuse; Substance-Related Disorders; Schizophrenia; Psychotic Disorders
Study type: Interventional

Summary: 
      Many individuals with schizophrenia abuse cannabis at the onset of their illness, portending
      a poorer course of illness and poorer treatment response. Preliminary evidence suggests that
      clozapine may uniquely reduce substance use in patients with schizophrenia. The purpose of
      this study is to establish an effective methodology for studying early treatment with
      clozapine in patients with co-occurring schizophrenia and cannabis use disorder, while
      generating pilot data comparing clozapine vs. risperidone on substance use, psychiatric
      symptoms, side effects, and treatment discontinuation.
    

Detailed description: 
      Schizophrenia is a relapsing disorder that produces profound effects on those afflicted once
      it becomes chronic, often leading to a severe and long-term disability. However, during the
      initial years of illness many patients are more treatment responsive and may achieve
      substantial periods of remission. Comorbid substance use disorder, a common concomitant of
      schizophrenia, is associated with increases in morbidity and mortality. Within the early
      phases of schizophrenia, comorbid cannabis use disorder (CUD), the most common comorbid
      disorder (approximately 50%), appears to be linked to a poor outcome in these patients, and
      may be a factor in their long-term deterioration. While data indicate that first episode
      patients presenting with comorbid CUD have an earlier onset of illness and a poorer outcome
      than those without CUD, continued cannabis use after antipsychotic treatment, which occurs in
      approximately 50% of these patients in the initial months after hospitalization, is
      associated with an even worse outcome. The apparent "toxicity" of cannabis use in first
      episode patients is paralleled by data from chronic patients, in whom CUD is associated with
      clinical exacerbations, non-compliance with treatment, poor global functioning, and increased
      relapse. A growing body of data suggests that a critical period exists in patients with
      schizophrenia during the early phases of psychosis in which symptoms and functioning continue
      to worsen, and that treatment with antipsychotic medications during this period may improve
      the natural course of the disorder. While the availability of novel antipsychotic medications
      has sparked further research in the early phases of schizophrenia, there have been few
      studies including clozapine (CLOZ). We hypothesize that CLOZ may be more effective than other
      novel agents in controlling cannabis use in patients with first episode schizophrenia who are
      comorbid for CUD. We postulate that standard antipsychotic medications do not decrease
      substance use in this population largely because they do not restore normal functioning of
      the dysfunctional dopamine (DA) pathways. CLOZ, by contrast, through its varied actions on
      dopaminergic, serotonergic and, particularly, noradrenergic neurons, coupled with its weak D2
      and potent noradrenergic alpha2 blocking ability, may tend to have a "normalizing" effect on
      the signal detection capability of these dysfunctional DA systems. CLOZ is rarely used in
      first episode patients even though it is generally considered a highly effective medication,
      and more likely to prevent relapses than typical antipsychotics in both treatment refractory
      and non-refractory populations. While side effects of CLOZ are a clinical concern and need to
      be taken seriously, experience over the past 2 decades has increased the comfort level for
      its use. For example, agranulocytosis has actually occurred in 0.37% with implementation of
      the required white count monitoring system, and granulocyte stimulating therapy has provided
      an effective treatment for those few patients who do develop agranulocytosis. Gradual dose
      titration schedules appear to reduce risk for seizure and myocarditis, and experience in
      first episode patients suggesting that the clinically effective dose of CLOZ is lower than in
      chronic patients indicates that these risk should be even lower. If our hypothesis is
      correct, CLOZ, despite its side effect profile, may have a key therapeutic role in these
      patients, a role with important public health implications. Yet without a clear demonstration
      of the benefit/risk and benefit/burden profiles of its use, the naturalistic experiment of
      assessing the overall effectiveness of CLOZ in first episode patients who are comorbid for
      CUD is unlikely to be undertaken.

      This study is enrolling individuals who are in their first episode of schizophrenia or
      schizoaffective disorder and who are currently using cannabis. Study participants undergo a
      screening visit including the Structured Clinical Interview for Diagnostic and Statistical
      Manual of Mental Disorders (DSM-IV) for diagnostic evaluation, and a physical examination,
      blood tests, and review of medical, psychiatric, and substance use history. Following the
      screening visit, eligible participants are randomly assigned to single-blind treatment with
      clozapine or risperidone for 24 weeks. Participants assigned to clozapine initially receive a
      daily dose of 12.5 mg, which is carefully titrated to the lowest dose necessary to manage
      psychotic symptoms and well tolerated. Participants assigned to risperidone initially receive
      0.5 mg daily and are carefully titrated in the same fashion. Cross titration off of the
      previous antipsychotic (if any) and onto study medication is completed within 2-4 weeks.
      Participants on clozapine have weekly blood tests. Concomitant medications are minimized and
      kept stable throughout the protocol except as needed to manage side effects or urgent
      clinical symptoms. Study medication, psychiatric visits, assessments and labwork are all
      provided without charge to participants. Study visits take place once a week. At study
      visits, medication side effects, physical and psychiatric symptoms, substance use, and
      treatment services received are assessed. A Lifestyle Intervention is also provided to help
      prevent metabolic side-effects in this vulnerable population, and assist with recovery. The
      investigators meet weekly to review clinical care and manage any variations in study
      protocol.
    

Intervention name(s): clozapine; risperidone
Intervention type(s): Drug; Drug
Intervention description(s): clozapine--tabs, 450mg. max, daily, 24 weeks; risperidone--tabs, 6mg max, daily, 24 weeks
Other intervention name(s): Clozaril; Risperdal
Intervention MeSH terms: Risperidone; Clozapine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Treatment
Keywords: Clozapine, risperidone, first episode,