Exenatide for the Treatment of Weight Gain Associated With Olanzapine in Obese Adults

Double-blind studies suggest that olanzapine is highly effective for the treatment of
individuals with bipolar disorder. However, weight gain and impaired glucose tolerance remain
significant concerns associated with olanzapine. Exenatide is an anti-diabetic medication
that is associated with weight loss and improved glucose regulation. Therefore, the overall
goal of the proposed study is to conduct a 16-week double-blind placebo-controlled study of
exenatide for the treatment of weight gain associated with olanzapine in 60 obese adults with
bipolar disorder treated with olanzapine. We propose to conduct the study over the course of
24 months, with an expected enrollment of approximately 3 patients per month. The primary
outcome measure will be change from baseline to endpoint in weight. The secondary outcome
measures will include changes from baseline to endpoint, in body mass index (BMI), abdominal
circumference, metabolic parameters, clinical global improvement of psychiatric symptoms, and
change in manic, depressive and psychotic symptoms. Rates of adverse events also will be
assessed.

Inclusion Criteria:

1. Subjects must be between the ages of 18 and 55 years old.

2. Subjects must have bipolar I disorder, schizophrenia, schizoaffective disorder or MDD
as defined by DSM-IV-TR criteria and diagnosed using the Structured Clinical Interview
for DSM-IV (SCID).

3. Subjects must have a Young Mania Rating Scale (YMRS) score < 16 and a
Montgomery-Asberg Depression Rating Scale (MADRS) score < 24 at screening and baseline
visits.

4. Subjects must have the Scale for the Assessment of Positive Symptoms (SAPS) scores <2
on all subscales.

5. Subjects must have gained > 7% of their body weight following treatment with
olanzapine as either documented in their medical records or by patient report.

6. Subjects must be obese, as defined by a current Body Mass Index (BMI) > 30 kg/m2.

7. Subjects must sign the Informed Consent Document after the nature of the trial has
been fully explained.

8. If female, subjects must be: postmenopausal, surgically incapable of childbearing, or
practicing medically acceptable method(s) of contraception (e.g., hormonal methods,
intrauterine device, abstinence) for at least one month prior to study entry and
throughout the study.

9. Subjects must be on a stable dose of olanzapine for at least 14 days and must have
been on 5-30mg/day for at least 1 month.

Major Exclusion Criteria

1. Subjects with clinically significant suicidal or homicidal ideation.

2. Subjects who have a DSM-IV lifetime diagnosis of a substance dependence disorder
within the past 6 months or within the past month have been diagnosed with a substance
abuse disorder, (except for nicotine abuse or dependence), as determined by
psychiatric history or SCID interview.

3. Subjects with a clinically significant or unstable medical disease, including hepatic,
renal, gastroenterologic, respiratory, cardiovascular, endocrinologic, immunologic,
hematologic or other systemic medical conditions, that could interfere with diagnosis,
assessment, or treatment of bipolar disorder or obesity, as well as subjects with a
history of pancreatitis.

4. Patients with clinically significant laboratory abnormalities (> 3 times upper limit
of normal), on any of the following tests: CBC with differential, electrolytes, BUN,
creatinine, hepatic transaminases, lipid profile, fasting glucose, urinalysis, or
thyroid indices or clinically abnormal ECG.

5. Female patients who are either pregnant or lactating.

6. Any female patient whose sexual activity is unknown or in questions.

7. Any history of current or past diabetes that has been treated with pharmacological
intervention. Subjects who have a diagnosis of diabetes, are currently receiving
exenatide, insulin, or an oral anti-hyperglycemic medication, or who have a nonfasting
blood glucose ≥ 200 mg/dl or a fasting blood glucose ≥126 mg/dl on 2 separate tests.
Subjects with pre-diabetes will not be excluded.

8. Neurological disorders including epilepsy, stroke, or severe head trauma. Mental
retardation (IQ <70).

10. Treatment with an injectable depot neuroleptic within less than one dosing interval
between depot neuroleptic injections and day 0.

11. Treatment with concurrent mood stabilizers (except lithium), anticonvulsants, or
antipsychotics.

12. Other psychotic disorders (including delusional disorder, brief psychotic disorder,
psychotic disorder due to a general medical condition, substance-induced psychotic
disorder, psychotic disorder not otherwise specified) as defined in the DSM-IV.

13. Dysthymic disorder or depressive disorder not otherwise specified, bipolar disorder not
otherwise specified.

14. Subjects previously enrolled in this study or have previously been treated with
exenatide.

15. Subjects who have received an experimental drug within 30 days. 16. Subjects who are
displaying current clinically significant depressive or manic symptoms, defined as a MADRS
score >24 or a YMRS score > 16 or who currently meet DSM-IV-TR criteria for a manic, mixed,
hypomanic, or depressive episode.

17. Subjects who are displaying current clinically significant psychotic symptoms, defined
as any SAPS subscale score > 2 18. Subjects with a history of pancreatitis in themselves or
any risk factors for developing pancreatitis (risk factors include but are not limited to:
alcohol use, history of gallbladder disease or gallstones, diabetes or a family history of
pancreatitis) 19. Subjects with elevated amylase or lipase levels as measured at the
screening visit