Risperidone Augmentation in Patients With Schizophrenia
Condition: Schizophrenia
MeSH terms: Schizophrenia
Study type: Interventional
Phase: Phase 4

Summary: 
      We propose a double-blind, placebo-controlled trial to study the effectiveness and
      tolerability of adding risperidone to stable yet only partially remitted patients with
      schizophrenia maintained on clozapine.
    

Detailed description: 
      Specific Aims - We propose a double-blind, placebo-controlled trial to study the
      effectiveness and tolerability of adding risperidone to stable yet only partially remitted
      patients with schizophrenia maintained on clozapine. We anticipate enrolling a total of 40
      subjects over a period of two years at the Freedom Trail Clinic and affiliated sites in
      Boston, Massachusetts. Our primary outcome measure will be change in total score on the
      Positive and Negative Syndrome Scale (PANSS). Secondary hypotheses are (1) that the
      clozapine-risperidone combination is well tolerated, (2) that clozapine levels will not be
      influenced by risperidone, and (3) that prolactin elevation is suitable as a surrogate marker
      of sufficient D2 blockade to predict response.

      Background - Despite a new generation of antipsychotics, many patients with schizophrenia
      achieve only partial syndromal remission. In an effort to improve symptomatic and functional
      outcomes, it has become common practice to combine antipsychotic medications. Since this
      strategy is largely unproven and expensive, empirical trials are urgently needed. Our group
      has found in an open trial that adding risperidone to clozapine was well tolerated and led to
      improvement in psychopathology. Additional support for increasing D2 blockade in clozapine
      partial responders comes form two small studies using sulpiride and pimozide. We hypothesize
      that there is a subgroup of patients who might benefit from additional D2 blockade beyond
      what clozapine alone accomplishes.

      Methods - The proposed trial will be placebo-controlled, randomized, and double-blind, and it
      will last 8 weeks. We expect to enroll 40 subjects overall. Subjects will be eligible if they
      are diagnosed with schizophrenia and treated with clozapine. In addition, they must have
      residual symptoms of schizophrenia as we are interested in improvement of residual
      psychopathology. Subjects with dementia or mental retardation as well as pregnant women will
      be excluded. After a 2-week placebo lead-in period to assure stable psychopathology and
      minimize placebo-response, subjects will be randomly allocated to receive 6 weeks of either
      risperidone (20 subjects), or matching placebo (20 subjects) added onto their customary
      antipsychotic medication, clozapine. Overall, there are 5 study visits every 2 weeks plus the
      initial screening visit. On each visit, subjects will be evaluated with standard psychiatric
      rating scales of psychopathology and side effects. In addition, we will measure serum levels
      of the medications used, clozapine and risperidone.

      Fasting glucose will be measured at screening, week 4, and week 8 visits. This is done to
      monitor subjects for worsening glucose control. This is a possible concern due to the
      association between atypical antipsychotics, including risperidone, and hyperglycemia.
      Subjects who are discovered to either have diabetes or develop diabetes during the study, or
      who have worsening glucose control if diabetic, will be discontinued and referred to their
      PCP for further work-up and treatment. This additional blood test will not lead to additional
      blood draws but will simply be added to the subject's routine and mandated biweekly WBC
      monitoring.

      The study endpoint will be a 20% improvement on our primary rating scale of psychopathology,
      the Positive and Negative Syndrome Scale (PANSS). No worsening of psychopathology is expected
      in this trial as subjects are maintained on primary antipsychotic, clozapine.

      Benefits - There are no definite benefits to participating in this trial. Subjects will
      receive a thorough psychiatric evaluation, a review of their pharmacologic treatment, and a
      physical exam with some baseline laboratory studies. The results of the initial evaluation
      will be communicated to the treating psychiatrist. Subjects will receive a nominal fee of $20
      per study visit (5 study visits are scheduled overall).

      The proposed study has direct clinical applications, and it is of theoretical interest. Few
      data are available from controlled trials to guide clinicians when patients remain
      symptomatic on clozapine. From a conceptual standpoint, the study will clarify the value of
      additional D2 blockade for treatment response.

      Risks and Discomforts - Risperidone is approved by the FDA for the treatment of
      schizophrenia. The dose of 4 mg is on the lower end of the dosing recommendations and is
      usually well tolerated. Possible side effects are sedation, extrapyramidal symptoms,
      akathisia, hyperprolactinemia, or orthostatic hypotension. Tardive dyskinesia is a long-term
      side effect and would not be expected in a 6-week trial. However, existing tardive dyskinesia
      could worsen.

      Blood drawing entails transient discomfort, and it might lead to a hematoma at the site.
      Being interviewed for clinical symptoms with the help of rating scales can be tiring and
      upsetting if sensitive psychological experiences are discussed. There is also an association
      between atypical antipsychotics, including risperidone, and hyperglycemia, requiring some
      monitoring of blood sugars during treatment. No inpatient hospital time is required.

      Minimization of Risks - To minimized discomfort from blood draws, the study blood work will
      be added onto the mandatory blood draws that subjects undergo because they receive clozapine.
      Vital signs will be monitored at baseline and every two weeks. Side effects will be monitored
      at baseline and every two weeks. The Systematic Assessment for Treatment Emergent Events
      (SAFTEE) will be the primary instrument used to detect side effects. The SAFTEE will be used
      to tabulate side effects for the yearly IRB summary. Serious adverse events, as well as
      adverse events, will be reviewed by the PI and reported to the IRB according to institutional
      policy. The PIs in our group meet weekly to review study protocols and study events.

      Fasting glucose will be measured at screening, week 4, and week 8 visits. This is done to
      monitor subjects for worsening glucose control. This is a possible concern due to the
      association between atypical antipsychotics, including risperidone, and hyperglycemia.
      Subjects who are discovered to either have diabetes or develop diabetes during the study or
      who have worsening glucose control (poor glucose control as judged by new-onset diabetes or
      new-onset glucose intolerance.) will be discontinued and referred to their primary care
      physician (PCP) for further work-up and treatment. In patients with established diabetes, the
      six weeks of active treatment will not be long enough to meaningfully judge if diabetes
      control is more difficult than usual (typical parameters of glucose control such as
      hemoglobin A1C are a reflection of long-term glucose control, i.e. several months). We will
      follow those patients clinically in cooperation with the PCP to decide if patients can stay
      in the trial. This additional blood test will not lead to additional blood draws but will
      simply be added to the subject's routine and mandated biweekly white blood cell count
      monitoring.

      Patients will be withdrawn from the study if they become suicidal or deteriorate
      psychiatrically. This will be assessed every 2 weeks using the PANSS and Calgary Depression
      Scale for Schizophrenia (CDSS): clinical deterioration will be defined as a 20% increase in
      total PANSS scores, and suicidality will be defined as a rating of "mild" (frequent thoughts
      of being better off dead, or occasional thought of suicide) on the CDSS. Subjects who have
      worsening symptoms of tardive dyskinesia (TD) will be discontinued and referred to their
      psychiatrist for further work-up and treatment (Worsening TD as judged by 20% increase in
      Abnormal Involuntary Movement Scale (AIMS)).
    

Intervention name(s): Risperidone; placebo
Intervention type(s): Drug; Drug
Intervention MeSH terms: Risperidone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double
Primary purpose: Treatment
Keywords: Schizophrenia; risperidone; prolactin; clozapine