Improving Metabolic Parameters of Antipsychotic Child Treatment With Ziprasidone, Aripiprazole, and Clozapine (ZAC)

The purpose of this study is to evaluate the relative risks and benefits of two approaches to the control of weight gain and other negative side effects in children and adolescents on 2nd generation antipsychotics (SGA):

• Healthy lifestyle instruction (nutritional and physical activity surveillance and advice) + continuation of current SGA;
• Add the diabetes drug, metformin + continuation of current SGA.

Study Overview

• Status: Terminated
• Conditions: Weight Gain
• Intervention / Treatment: Drug: metformin; Behavioral: healthy lifestyle intervention

Detailed Description

The proposed pilot study is being conducted to obtain pilot data to support a grant application for a multi-site randomized controlled trial. The primary objective is to evaluate the relative risks and benefits of two approaches to the control of weight gain and other negative side effects in children and adolescents on 2nd generation antipsychotics (SGA). The critical question being addressed is: What can be done for the many youth who have gained substantial weight or developed high levels of lipids or glucose in their blood on an SGA; but due to their illness require continued treatment with an antipsychotic?

At least 40 youths (and no more than 60) age 10-17 that have gained substantial weight while taking a frequently used SGA: ziprasidone, aripiprazole or clozapine will be randomized to one of two treatments for 6 months:

• Healthy lifestyle instruction (nutritional and physical activity surveillance and advice) + continuation of current SGA;
• Add the diabetes drug, metformin + continuation of current SGA.
• Subjects may also elect to be in an observational arm that involves no intervention but the same major assessments.

Height, weight, body fat, and various blood tests indicative of general health will be collected during the 6 month trial to monitor the health benefits and safety of the interventions.

SGAs are associated with concerning degrees of weight gain and metabolic consequences. Children and adolescents, in whom SGAs are used increasingly for a wide variety of conditions, are particularly vulnerable to these side effects, which adversely affect health and longevity. It is imperative that researchers evaluate the efficacy and safety of interventions designed to prevent and treat the weight gain and metabolic problems caused by antipsychotic treatment of children. Lifestyle interventions and adjunctive medications all hold some promise of efficacy. However, it is essential that these strategies be rigorously evaluated as soon as possible in order to prevent the ongoing health consequences of SGA treatment in another generation of children with serious psychiatric illnesses.

• Study Type: Interventional
• Enrollment (Actual): 1
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Chapel HIll, North Carolina, United States, 27599
      • University of North Carolina, Department of Psychiatry

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 years to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Ages 10 to 17 years (inclusive).
• Receiving treatment with ziprasidone, aripiprazole or clozapine for the past 56 days or longer.
• Clinically stable on current treatment regimen (see Rationales below).
• Stable dose of current psychotropic co-medications for at least 30 days.
• BMI increase of > 7% within 3 months OR a > 0.5 BMI z-score increase within the past 24 months while taking olanzapine, quetiapine or risperidone, with maintenance of the threshold level of weight gain.
• Lifetime diagnosis of a schizophrenia spectrum disorder (schizophrenia, schizoaffective disorder, psychotic disorder NOS), a bipolar spectrum disorder (bipolar disorder, bipolar disorder NOS), certain mood disorders (mood disorder NOS, major depressive disorder with psychotic features), or certain disruptive/aggressive disorders (conduct disorder, intermittent explosive disorder, autism spectrum disorder with history of clinically significant levels of disruptive behaviors as defined below) using DSM-IV criteria determined by clinical interview and K-SADS-PL.
• Sexually active girls must agree to use an effective form of birth control or be abstinent.
• Principle caretaker is able to participate in study appointments as is clinically indicated.
• guardian and the child must agree (legally consent and assent) to participation.

Exclusion Criteria:

• Any medication that would significantly alter glucose, insulin or lipid levels. Prohibited medications will include, but are not limited to: insulin, steroids, topiramate, sibutramine, orlistat, metformin, amantadine, vitamin E (other than in standard multivitamins), antidiabetic drugs, HIV drugs.
• Major neurological disorder or medical illness that affects weight gain (e.g., unstable thyroid disease), requires a prohibited systemic medication or procedure (e.g., diabetes mellitus [insulin], chronic renal failure [steroids]) or that would prevent participation in physical activity in the healthy lifestyle program.
• Current active thyroid (TSH >18 microIU/ml), hepatic (2 LFTs >4x upper limits of normal), renal (serum Creatinine >1.4 mg/dL in females and serum Creatinine >1.5 mg/dL in males), cardiac, gastrointestinal, or adrenal disease.
• Fasting glucose > 125 mg/dL on two occasions indicating need for prompt treatment for diabetes.
• Child meets DSM-IV criteria for substance abuse or dependence disorder within the past month, not including tobacco abuse or dependence • Current treatment with more than one antipsychotic medication.
• Current treatment with more than 5 total psychotropic medications (i.e., 4 psychotropics plus SGA).
• Known hypersensitivity to metformin.
• Pregnant or breast feeding.
• Current or lifetime diagnosis of anorexia nervosa or bulimia nervosa.
• Significant risk for dangerousness to self or to others that makes participating inadvisable.
• Language issues that prevent child and/or parent from completing assessments or treatment.
• Ongoing or previously undisclosed child abuse requiring new department of social service intervention.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1; metformin, 250mg-2000 mg/day, in BID to TID doses for 26 weeks. Open, flexibly adjusted.	Drug: metformin; open dosed, randomly assigned flexible dose treatment with 250-2000mg/day divided BID or TID; Other Names: Glucophage
Experimental: 2; Healthy lifestyle intervention. Additional meeting at each psychiatric visit to review weight changes, level of physical activity and healthy eating behaviors	Behavioral: healthy lifestyle intervention; additional component to regular psychiatric visits that includes monitoring of lifestyle and eating behaviors.
No Intervention: 3; Self-selected patients will be followed at major timepoints to assess weight and related measures.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Percent Change in BMI	24 weeks
Absolute Change in Weight	24 weeks
Percent Change in Fat Mass	24 weeks
Percent Change in Weight	24 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
Percent Change in Insulin Levels	24 weeks
Percent Change in Total Cholesterol	24 weeks
Percent Change in Triglycerides	24 weeks
Incidence of Metabolic Syndrome	24 weeks
Percent Change in Glucose Levels	24 weeks
Percent Change in HDL	24 weeks
Percent Change in LDL	24 weeks

Collaborators and Investigators

• Sponsor: University of North Carolina, Chapel Hill
• Collaborators: Foundation of Hope, North Carolina
• Investigators: Principal Investigator: Linmarie Sikich, MD, University of North Carolina, Department of Psychiatry

Study record dates

Study Major Dates

• Study Start: March 1, 2007
• Primary Completion (Actual): June 1, 2010
• Study Completion (Actual): September 1, 2010

Study Registration Dates

• First Submitted: February 5, 2008
• First Submitted That Met QC Criteria: February 14, 2008
• First Posted (Estimate): February 15, 2008

Study Record Updates

• Last Update Posted (Estimate): December 31, 2012
• Last Update Submitted That Met QC Criteria: November 28, 2012
• Last Verified: November 1, 2012

More Information

Terms related to this study

• Keywords: children; adolescents; metformin; antipsychotic
• Additional Relevant MeSH Terms: Body Weight; Body Weight Changes; Weight Gain; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: 05-3110 GCRC-2529