Cardio Risk of Acute Schizophrenia Olanzapine Duke

NCT ID: NCT00672464

Last Updated: 2014-07-31

Basic Information

• Recruitment Status: WITHDRAWN
• Clinical Phase: PHASE4
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-04-30
• Study Completion Date: 2010-02-28

Brief 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

Detailed 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.

Conditions

Schizophrenia; Schizoaffective Disorder

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: FACTORIAL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: NONE

Study Groups

Olanzapine only

Newly Admitted Patients with Schizophrenia or Schizoaffective Disorder Who Are Receiving Olanzapine

Group Type: ACTIVE_COMPARATOR

Olanzapine

Intervention Type: DRUG

Olanzapine zydis 15 mg QHS for 28 days

Added Metformin

Newly Admitted Patients with Schizophrenia or Schizoaffective Disorder Who Are Receiving Olanzapine with Added Metformin

Group Type: EXPERIMENTAL

Olanzapine

Intervention Type: DRUG

Olanzapine zydis 15 mg QHS for 28 days

Metformin

Intervention Type: DRUG

Metformin capsules will be started at 500 mg twice a day (before breakfast and before dinner) for days 1-3, then 500 mg before breakfast and 1000 mg before dinner for days 4-7, and then 1000 mg twice a day thereafter.

Added Simvastatin

Newly Admitted Patients with Schizophrenia or Schizoaffective Disorder Who Are Receiving Olanzapine with Added Simvastatin

Group Type: EXPERIMENTAL

Olanzapine

Intervention Type: DRUG

Olanzapine zydis 15 mg QHS for 28 days

Simvastatin

Intervention Type: DRUG

Simvastatin will be started at 10 mg at bed time for the first week and 20 mg at bedtime thereafter.

Added Metf. + Simv.

Newly Admitted Patients with Schizophrenia or Schizoaffective Disorder Who Are Receiving Olanzapine with Added Metformin and Simvastatin

Group Type: EXPERIMENTAL

Olanzapine

Intervention Type: DRUG

Olanzapine zydis 15 mg QHS for 28 days

Metformin

Intervention Type: DRUG

Metformin capsules will be started at 500 mg twice a day (before breakfast and before dinner) for days 1-3, then 500 mg before breakfast and 1000 mg before dinner for days 4-7, and then 1000 mg twice a day thereafter.

Simvastatin

Intervention Type: DRUG

Simvastatin will be started at 10 mg at bed time for the first week and 20 mg at bedtime thereafter.

Matched Controls

Matched Control Subjects by age, race, and gender

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

Olanzapine

Olanzapine zydis 15 mg QHS for 28 days

Intervention Type: DRUG

Metformin

Metformin capsules will be started at 500 mg twice a day (before breakfast and before dinner) for days 1-3, then 500 mg before breakfast and 1000 mg before dinner for days 4-7, and then 1000 mg twice a day thereafter.

Intervention Type: DRUG

Simvastatin

Simvastatin will be started at 10 mg at bed time for the first week and 20 mg at bedtime thereafter.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• We will include patients who come to us free of antipsychotic medication, i.e., patients with chronic schizophrenia (with at least one prior psychiatric hospitalization) who have been off antipsychotic medication for at least 3 weeks and who are newly hospitalized for treatment of an acute psychotic relapse; these patients will be male or female, 18-60 years of age, meet DSM-IV criteria for schizophrenia, and have scores >=4 on at least two of the PANSS Positive subscale items.

Exclusion Criteria

• We will exclude patients whose psychoses are predominantly affective in nature or explainable on the basis of substance abuse or a co-morbid medical condition, patients with diabetes mellitus, epilepsy, mental retardation, or organic mental syndromes, and patients currently taking metformin or a statin.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Duke University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Joseph P McEvoy, MD

Role: PRINCIPAL_INVESTIGATOR

Duke University Medical Center, Dep't. Psychiatry

Locations

John Umstead Hospital

Butner, North Carolina, United States

Duke University Medical Center

Durham, North Carolina, United States

Countries

United States

Other Identifiers

None (investigator sponsored)

Identifier Type: -

Identifier Source: secondary_id

Pro00006916

Identifier Type: -

Identifier Source: org_study_id