Improving Metabolic Parameters of Antipsychotic Child Treatment With Ziprasidone, Aripiprazole, and Clozapine
Improving Metabolic Parameters of Antipsychotic Child Treatment With Ziprasidone, Aripiprazole, and Clozapine
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.
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.
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.