Demonstrate the Effects of Pramlintide on Weight Reduction in Schizophrenia

This study is a sixteen week placebo-controlled, double-blind investigation of the effect of
pramlintide on body weight in clozapine- and olanzapine-induced weight gain. We will recruit
approximately 72 volunteers with the plan of having a final N = 25 in each of the 2 treatment
groups. (This number is to allow for normal attrition in this patient population. If needed,
we will recruit more than 72 volunteers in order to achieve the appropriate number of
completed subjects.) Patients will be recruited from the local Dallas public and VA mental
health systems as volunteers for this study. This study is anticipated to last 20 weeks (2
weeks lead-in [approximately 2-3 visits], 1 week training [4 visits], 16 weeks active
drug/placebo [one visit per week for the first 4 weeks, then one visit every 2 weeks for the
remainder], and one week follow-up [one visit]. Please see attached chart for more details
about each visit.) Volunteers will have to have a history of significant weight gain
accompanying olanzapine or clozapine treatment and have a BMI=>27 and =<40. Each volunteer
will be maintained on their optimal dose of clozapine or olanzapine and be randomized blindly
to pramlintide or placebo. Pramlintide will be administered by the patients in a
self-injectable form and dosing will begin at 180 mcg bid for 2 weeks and then increase to
360 mcg bid for the remainder of the study. The randomization to pramlintide/placebo will be
preceded by a week-long self-administration training program using placebo for pramlintide
(with additional information regarding nutrition, exercise, general self-care, and risk
factors for diabetes being provided to the patients during this training program).

Inclusion Criteria:

- Volunteers will be males or females 18-65 yrs of age with a diagnosis of schizophrenia
or schizoaffective disorder who have a history of significant weight gain with
olanzapine or clozapine administration.

- Volunteers will have a current BMI=>27 but equal to or less than 40.

- Volunteers will have been taking a stable dose (less than 10% dose change) of
clozapine or olanzapine or at least two months prior to study start.

- Volunteers will be willing and able to participate in the subcutaneous administration
training week prior to study start.

- Able and willing to give informed consent.

Exclusion Criteria:

- Clinically significant abnormal pre-admission vital signs, positive HIV, or clinical
laboratory evaluations, in which the principal investigator deems the
subject-volunteer ineligible for the study

- Positive results for infectious diseases and sexually-transmitted diseases will
be reported according to the Texas Department of State Health and Texas
Administrative Code rules and guidelines

- Any patient with current diabetes mellitus, even if caused by antipsychotic use .

- Patients with active liver disease requiring current treatment. Positive hepatitis C
volunteers will only be excluded if they have active liver disease or they have enzyme
values are two times the upper limit of normal.

- Any patients with medical disorders that are not properly controlled by medications.

- Pregnant women or women who are breast feeding.

- Patients concomitantly treated with another conventional or second generation
antipsychotic medication or with any other anti-obesity drug.

- Mental capacity is limited to the extent that the patient cannot understand the nature
of the study along with its risks and benefits.

- Subjects with a high risk of suicide since there is a potential that the study
medication will lower the subject's glucose levels.

- Any patient judged by the principal investigator to be inappropriate for the study.

- Known hypersensitivity to study medication or its components

- Non-English speaking

- The clinical assessments that will be used are not available in valid and
reliable forms for non-English speaking populations.