Treatment Strategy for Refractory Schizophrenia: Drug Interaction Between Clozapine and Fluvoxamine
Condition: Schizophrenia
MeSH terms: Schizophrenia; Schizophrenia, Treatment-Resistant
Study type: Interventional
Phase: Phase 4

Summary: 
      Clozapine has been virtually the only psychopharmacological choice in patients with
      schizophrenia who either did not response to typical neuroleptics or experienced severe
      extrapyramidal side effects and consequently did not tolerate this medication. There are
      patients who do not respond to clozapine, and the need to treat these severely ill patients
      frequently compels clinicians to adopt therapeutic innovations that lack a sound empirical
      basis. One strategy is the combination of various other somatic treatments with clozapine.

      Recently, the investigators conduct a preliminary open trial to evaluate the safety and
      efficacy of fluvoxamine coadministration with clozapine in refractory schizophrenic patients.
      The combined treatment is well tolerated, and clinical improvement is observed in our
      patients. And the concomitant fluvoxamine could attenuate the clozapine-induced weight gain
      and metabolic disturbance. However, the effects of fluvoxamine on the safety and therapeutic
      efficacy of clozapine need to be further clarified in double-blind study.
    

Detailed description: 
      Background Schizophrenia is one of the most severe mental illnesses. The prevalence of
      schizophrenia has been variously reported as ranging from 1 to 1.5 percent. More than 50% of
      patients can be described as having a poor outcome, with repeated hospitalizations,
      exacerbations of symptoms, episodes of major mood disorders, and suicide attempts.
      Schizophrenia is costly in medical care, treatment and rehabilitation, and reduced or lost
      productivity. Therefore, the development of effective treatment for schizophrenic patients is
      an important issue.

      The classical antipsychotic drugs are the dopamine receptor antagonists, which are effective
      in the treatment of schizophrenia, particularly of the positive symptoms. Even with treatment
      of typical antipsychotics, about 50% of schizophrenic patients lead severely debilitated
      lives. Second, the classical antipsychotic drugs are associated with annoying and serious
      adverse effects. Clozapine has been virtually the only psychopharmacological choice in
      patients with schizophrenia who either did not response to typical neuroleptics or
      experienced severe extrapyramidal side effects and consequently did not tolerate this
      medication. There are patients who do not respond to clozapine, and the need to treat these
      severely ill patients frequently compels clinicians to adopt therapeutic innovations that
      lack a sound empirical basis. One strategy is the combination of various other somatic
      treatments with clozapine.

      Recently, the investigators conduct a preliminary open trial to evaluate the safety and
      efficacy of fluvoxamine coadministration with clozapine in refractory schizophrenic patients.
      The mean plasma clozapine levels obtained by clozapine 100 mg/day plus fluvoxamine 50 mg/day
      is close to that produced by 300-mg/day clozapine monotherapy in one of our previous studies.
      The combined treatment is well tolerated, and clinical improvement is observed in our
      patients. And the concomitant fluvoxamine could attenuate the clozapine-induced weight gain
      and metabolic disturbance. However, the effects of fluvoxamine on the safety and therapeutic
      efficacy of clozapine need to be further clarified in double-blind study.

      Methods This study is a three-year proposal. Sixty treatment-resistant schizophrenic
      inpatients will participate in this project. The subjects will be randomized to one of two
      parallel groups: clozapine monotherapy and clozapine plus fluvoxamine treatment. The
      double-blind active treatment will consist of two periods.

      The measures of clinical efficacy will be the Positive And Negative Syndrome Scale, Clinical
      Global Impression, and Nurses'Observation Scale for Inpatient Evaluation. The measures of
      side effects will be the Extrapyramidal Symptom Rating Scale and the UKU Side Effect Rating
      Scale. Fasting serum samples are collected to determine the lipid profile (total cholesterol,
      triglycerides, HDL, and LDL), glucose level, and insulin level. Plasma levels of clozapine,
      norclozapine, and clozapine N-oxide will be determined by high performance liquid
      chromatography with ultraviolet detection.

      The following results are expected:

        1. In treatment-resistant schizophrenic patients, global antipsychotic effect of clozapine
           plus fluvoxamine treatment is superior to clozapine monotherapy.

        2. Clozapine plus fluvoxamine treatment has less adverse effects than clozapine
           monotherapy.

        3. The effect of clozapine plus fluvoxamine treatment on body weight and metabolic
           disturbances is superior to clozapine monotherapy.

        4. Steady-state plasma levels of clozapine and its metabolites account for a proportion of
           variance of clinical effects.
    

Intervention name(s): clozapine plus fluvoxamine; clozapine plus placebo
Intervention type(s): Drug; Drug
Intervention description(s): clozapine 100 mg/day plus fluvoxamine 50 mg/day; clozapine 300 mg/day plus placebo
Intervention MeSH terms: Clozapine; Fluvoxamine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: schizophrenia; clozapine; fluvoxamine; metabolic syndrome