Schizophrenia is still all too frequently associated with a chronic relapsing course, poor functional outcome, and decreased life expectancy. The chronicity and refractoriness of this illness is particularly pronounced in early onset schizophrenia (EOS=onset <18 years). Although the limited data suggest that clozapine is the most efficacious option for youth with refractory EOS (Kumra et al. 1996;Shaw et al. 2006;Kumra et al. 2008a,b) it is still underutilized, in part due to a profound negative impact on weight and metabolic parameters. To improve the benefit/risk ratio of clozapine in refractory youth, the development of concurrent interventions to limit cardiometabolic effects and enhance effectiveness is sorely needed. For this reason, other medications, often a second antipsychotic, are commonly combined with clozapine in clinical practice. However, a sound evidence base for this clinical strategy is absent, particularly in youth. To fill this critical gap in knowledge, we propose a 12-week, placebo-controlled trial of clozapine supplementation with aripiprazole in 50 youths (age 10-18 years) with refractory schizophrenia. This study aims to: Specific Primary Aim 1: To test whether the concurrent initiation of clozapine with aripiprazole will result in the reduction of key metabolic adverse events compared to cotreatment with placebo. Primary Hypothesis 1: Compared to placebo, augmentation of clozapine with aripiprazole will lead to significantly less increase in weight and BMI z-score, insulin resistance, and lipid levels. Secondary Hypothesis 1: Compared to placebo, augmentation of clozapine with aripiprazole will lead to significantly less increase in risk markers of coronary heart disease (i.e., C-reactive protein, plasminogen activator inhibitor-1, soluble intercellular adhesion molecule-1, and adiponectin). Specific Secondary Aim 1: To test whether the concurrent initiation of clozapine with aripiprazole will result in greater efficacy compared to cotreatment with placebo. Secondary Hypothesis 1: Compared to placebo, augmentation of clozapine with aripiprazole will lead to significantly greater improvement in BPRS total, positive and negative symptom scores. Secondary Hypothesis 2: Compared to placebo, augmentation of clozapine with aripiprazole will lead to a significantly greater number of patients meeting the criteria for a positive treatment response (i.e., at least a 30% reduction in the BPRS total score AND a score of no more than "mildly ill" on the CGI). Exploratory Aim 1: To identify mediators and moderators of changes in primary and secondary outcomes, such as patient characteristics, antipsychotic blood levels, and markers of metabolic and cardiovascular health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Center Core Grants (P30)
Project #
5P30MH090590-04
Application #
8463880
Study Section
Special Emphasis Panel (ZMH1-ERB-N)
Project Start
Project End
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
4
Fiscal Year
2013
Total Cost
$50,894
Indirect Cost
$20,235
Name
Feinstein Institute for Medical Research
Department
Type
DUNS #
110565913
City
Manhasset
State
NY
Country
United States
Zip Code
11030
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