Cardio Risk of Acute Schizophrenia Olanzapine Duke — CRASOD  

Schizophrenia Clinical Trial

Official title: Combined Treatment of Cardiovascular Risk Factors In Newly Admitted Patients With Schizophrenia or Schizoaffective Disorder Who Are Receiving Olanzapine And Matched Controls

Status Withdrawn

Clinical Trial Summary

Primary Objective: To compare added metformin and/or added simvastatin versus no intervention in reducing or eliminating increased cardiovascular risk (as estimated by elevation in non-HDL cholesterol levels) during the treatment of schizophrenia with olanzapine.

Secondary Objective(s): To compare added metformin and/or added simvastatin versus no intervention in reducing or eliminating increased cardiovascular risk (as estimated by elevation in triglyceride levels) during the treatment of schizophrenia with olanzapine. To compare added metformin and/or added simvastatin versus no intervention in reducing or eliminating increased cardiovascular risk (as estimated by C-reactive protein levels) during the treatment of schizophrenia with olanzapine

Clinical Trial Description

Olanzapine offers greater therapeutic antipsychotic benefit than the other non-clozapine antipsychotic medications available in the U.S., making it a desirable choice for the long-term maintenance treatment of patients with schizophrenia (Lieberman et al, 2005). Long-term compliance with an efficacious antipsychotic medication is fundamental to optimal therapeutic outcomes. Toward this goal, a long-acting injectable preparation of olanzapine will soon be available.

However, the long-term use of olanzapine has been limited by its substantial, un-wanted effects on metabolism that result in weight gain, increases in insulin resistance, increases in non-HDL-cholesterol, and increases in C-reactive protein (Lieberman et al, 2005; McEvoy et al, 2005;Meyer et al, 2008; McEvoy et al, in submission). Over the long term, insulin resistance contributes to the accelerated incidence of diabetes mellitus that has been observed among patients with schizophrenia since the availability of the atypical antipsychotic medication (Basu A, 2006). Over the long term, elevated non-HDL-cholesterol and increased inflammation contribute independently to the accelerated cardiovascular mortality that has been observed among patients with schizophrenia since the availability of the atypical antipsychotic medications (Saha et al, 2007, Capasso et al, 2007). Inflammation, as measured by C-reactive protein, provides added, independent predictive value of cardiovascular risk beyond that of measures of insulin resistance and elevated non-HDL-cholesterol.

Established strategies exist that may attenuate these unwanted effects of olanzapine on metabolism and inflammation. Metformin has been shown to reduce weight gain and insulin resistance in pre-diabetic, obese individuals without mental problems (Salpeper et al, 2008) and in patients treated with atypical antipsychotic medications (Wu et al, 2008). Statins have been shown to reduce non-HDL-cholesterol and cardiovascular morbidity and mortality (Lee et al, 2007). Both metformin and statins have been shown to reduce C-reactive protein (Bulcau et al, 2007).

We propose to implement a pilot study to estimate the effects sizes (for change in triglycerides, change in non-HDL-cholesterol, and change in CRP) of added metformin, added simvastatin, or added metformin and simvastatin, versus added no intervention in 120 newly-admitted, acutely psychotic, recently un-medicated patients with schizophrenia over 4 weeks of prospective treatment with olanzapine. We will also compare these patients (baseline values, in the not recently medicated state) to 40 age, race, and gender matched control subjects on fasting triglycerides, non-HDL-cholesterol, and CRP levels.

We will recruit newly admitted patients experiencing an acute psychotic relapse of schizophrenia (related to failure to take their prescribed antipsychotic medication). After baseline assessments and samplings have been completed, all patient will be treated with olanzapine zydis 15 mg QHS for 28 days. All patients will be randomized 1:1:1:1 to added metformin, added simvastatin, added metformin and simvastatin, or no intervention. All treatments will be open label. Repeated assessments of weight, non-HDL-cholesterol, triglycerides and C-reactive protein will be obtained. Subjects will remain as inpatients at JUH for the duration of the study. ;

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Factorial Assignment, Masking: Open Label, Primary Purpose: Prevention

Related Conditions & MeSH terms

• Psychotic Disorders
• Schizoaffective Disorder
• Schizophrenia

• NCT number: NCT00672464
• Study type: Interventional
• Source: Duke University
• Status: Withdrawn
• Phase: Phase 4
• Start date: April 2008
• Completion date: February 2010