Reducing Weight Gain and Improving Metabolic Function in Children Being Treated With Antipsychotics

Disorders that involve severe dysregulation of mood or thoughts in children -- such as early
onset bipolar spectrum (BPS) and schizophrenia spectrum (SS) disorders -- are commonly
treated with antipsychotic medications. However, many of the newest and most commonly
prescribed antipsychotic medications can cause weight gain and metabolic dysfunctions. Use
of these newer antipsychotics, called second generation antipsychotics (SGAs), is increasing
rapidly in children, and the risk of weight gain from SGAs is higher among children than
adults. Excessive weight gain can lead to obesity, which, in turn, can lead to increased
health care costs, increased risk of sickness, and lower life expectancy. These factors are
enhanced in children and adolescents who grow up obese.

Two different strategies to reduce weight gain and metabolic side effects from SGAs will be
tested in this study. The first strategy involves switching from the current SGA to a lower
risk agent (aripiprazole or perphenazine) hypothesized to result in weight loss and improved
metabolic functioning. The second strategy involves taking the medication metformin in
addition to the current SGA. Metformin is approved by the Food and Drug Administration (FDA)
to promote weight loss in youth with diabetes and has been effective in reducing weight in
youth taking SGAs.

Participation in this study will last between 26 and 27 weeks and will be divided into two
parts. The first part will last 2 to 3 weeks and include three study visits. During this
part, participants will undergo a physical exam, an electrocardiogram (EKG), a dual energy
X-ray absorptiometry (DXA) test, and blood tests. The DXA measures body fat.

The second part will last 24 weeks and include nine study visits. During this part,
participants will be randomly assigned to one of three conditions: gradual switch of current
SGA medication to either aripiprazole or perphenazine, addition of metformin to current SGA
medication, or no change to treatment with current SGA medication. Visits will take place on
Weeks 1, 2, 4, 6, 8, 12, 16, 20, and 24. At each visit, participants will meet with a study
doctor who will assess symptoms and side effects, and participants and their guardians will
receive information and recommendations about childhood obesity and weight loss. There will
also be monthly urine pregnancy tests, and two blood tests.

Inclusion Criteria:

- DSM diagnoses that have an FDA indication for atypical antipsychotic use for at least
one agent in the respective pediatric or adult age group. Specifically, primary
DSM-IV diagnosis of Early Onset Schizophrenia Spectrum (EOSS; schizophrenia,
schizoaffective disorder, schizophreniform disorder, psychotic disorder NOS); Bipolar
Spectrum (bipolar I, II and NOS); Major depressive disorder with psychosis; Mood
disorder NOS corresponding to Leibenluft and colleagues severely mood dysregulated
(SMD) broad spectrum bipolar disorder; Mood disorder NOS corresponding to
irritability associated with autism spectrum disorders; or - for adult teen
participants aged 18-19 years - Major depressive disorder. Diagnoses will be
determined by clinical interview, Leibenluft's modification of the K-SADS-PL, and the
"Aberrant Behavior Checklist" (cutoff score of 18, as used by FDA for approval of
risperidone and aripiprazole in minors).

- Clinically stable on current treatment regimen for at least 30 days, as assessed in a
three-step process

- Current SGA treatment with olanzapine, quetiapine, risperidone, ziprasidone
aripiprazole, asenapine, iloperidone, lurasidone, paliperidone, or
olanzapine/fluoxetine for ≥ 8 weeks

- Stable dose of current SGA and psychotropic co-medications for at least 30 days

- Body mass index (BMI) at least in the 85th percentile for age and gender

- Substantial weight gain over the previous 3 years while taking a SGA, as reflected by
family and referring physician's judgment. The weight gain did not have to occur on
the child's current SGA. Weight needs to have remained stable or increased over past
year.

- Agrees to use two effective forms of birth control or to remain abstinent

- Has a primary caretaker who has known the child well for at least 6 months before
study entry

- Primary caretaker is able to participate in study appointments as clinically
indicated

Exclusion Criteria:

- Treatment with any medication (other than the currently prescribed psychotropic
medications) that would significantly alter glucose, insulin, or lipid levels.
Exception: orlistat and amantadine are permitted if the individual has taken the drug
for at least one year without weight loss.

- Major neurological or medical illness that affects weight gain or that would prevent
participation in physical activities

- Fasting glucose levels indicating need for prompt treatment

- Pediatrician or pediatric gastroenterologist recommendation to address abnormal
fasting labs by pursuing more active treatment than those in the 2007 American
Medical Association guidelines

- Diagnosis of anorexia nervosa or bulimia nervosa, as based on current or lifetime
DSM-IV criteria

- Diagnosis of substance dependence disorder (other than tobacco dependence) within the
past month, as based on DSM-IV criteria

- Positive urine toxicology indicating ongoing use of illicit substance

- Current treatment with more than one antipsychotic medication

- Current treatment with more than 3 total psychotropic medications (i.e., 2
psychotropics plus SGA), with the exception of subjects taking 2 medications for ADHD
in which a total of 4 psychotropic medications are allowed.

- Known hypersensitivity to metformin

- Prior treatment with aripiprazole and perphenazine for more than 2 weeks that was
stopped for inefficacy or intolerability

- Pregnant, breastfeeding, or unwilling to comply with contraceptive requirements of
study

- IQ score less than 55

- Significant risk of dangerousness to self or to others that would make study
participation 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