Effect of clozapine and olanzapine on the use of drugs and alcohol by patients with schizophrenia and related disorders

The lifetime prevalence of alcohol- and substance use disorders of patients with schizophrenia varies
from 40% to 70%.Substances commonly abused by patients with schizophrenia include nicotine, alcohol and drugs, such as cannabis, cocaine and amphetamines. Studies of patients with schizophrenia have clearly indicated that co-morbid substance abuse is associated with overall poorer outcome of schizophrenia. Recent correlational studies suggest that clozapine has a favourable effect on substance abuse and dependence in schizophrenia. This possible benefit should be weighted against the risk of adverse effects. However, evidence to include clozapine in treatment recommendations in patients with schizophrenia or related disorders and substance use disorders is missing. Therefore we propose to conduct a double blind randomized clinical trial comparing the effects of clozapine with olanzapine on the severity of substance use based on urine analysis and self report. Secondary outcome measures will include hospitalization, improvement of psychosis and negative symptoms, relapse of florid psychosis, side effects, non-compliance, drop-out rate, psychosocial functioning and quality of life. Direct and indirect medical and non-medical costs of treatment with clozapine compared with olanzapine will be evaluated. The direct treatment costs of clozapine are estimated to be higher than those of treatment with other atypical antipsychotic medications. However, we expect that clozapine treatment will also decrease substance abuse and dependence outcomes and reduce associated resource utilization (direct medical and non-medical costs) more than olanzapine. Participants of the study will be in- and outpatients age 18 to 50, meeting DSM-IV criteria for schizophrenia, schizoaffective or schizophreniform disorder and substance use disorders. Eligible patients will be recruited from in-and outpatient settings of the Academic Medical Centre (Amsterdam) and several mental health services. In a double blind randomized controlled trial patients will be randomized to receive clozapine or olanzapine.
The total sample size of the study will be 120 patients. With an estimated attrition rate of 15% this will lead to a total study sample of 140 patients.

Primary research question: Is there a difference in effectiveness and costs of clozapine treatment compared to olanzapine treatment in the reduction of substance use disorders of patients with schizophrenia and related psychotic disorders?

Secondary research question: Are there differences in effectiveness and costs of clozapine treatment compared to olanzapine treatment in: psychopathology, adverse effects, compliance, drop out rate, psychosocial functioning and quality of life?

baseline, month 1, month 2, month 6 and at drop out

RCT: olanzapine or clozapine. In the first period the study
drug dose is titrated over 4 weeks according to a fixed dose schedule (see attached scheme).
All patients in both treatment arms will receive additional standard treatment and care.
Treatment failure or medication switch during will be a secondary endpoint.
At baseline, week 4, week 8 and month 6 or at drop out from study we will assess: