Augmenting Zyprexa With Naltrexone to Ameliorate Metabolic Side-Effects

Zyprexa is one of the most commonly prescribed second generation antipsychotic drugs (SGAs),
but its (and other SGA's) side effects contribute to the development of obesity and to the
"Metabolic Syndrome." Both conditions, which are more prevalent even in unmedicated
schizophrenic patients, are associated with increased cardiovascular morbidity and
mortality. The mechanisms of these side effects are likely to be multifactorial and to
involve peripheral and central factors alike. The present proposal asks a fundamental
question: How the endogenous opioidergic systems are involved in Zyprexa-induced obesity and
in related metabolic disturbances. We further hypothesize that if the excess of central
opioid activity creates metabolic problems for patients, it is reasonable to expect
amelioration of the symptoms through blockade of opioid receptors. The proposed project is
designed to test this hypothesis by complimenting clinical psychopharmacology with pain
medicine research and functional magnetic resonance imaging (fMRI) to empirically measure
clinical outcomes of Zyprexa pharmacotherapy augmentation with the opioid receptor
antagonist, naltrexone. Our objectives and hypotheses are as follows: to determine the
effects of naltrexone on weight gain, metabolic (e.g., cholesterol, lipids, insulin, leptin
and glucose levels), anthropometric and nutritional characteristics in Zyprexa treated
schizophrenic patients, to examine the effects of naltrexone on subjective pain ratings, and
to investigate the safety and tolerability of naltrexone in Zyprexa-treated schizophrenic
patients.

Inclusion Criteria:

- Meeting DSM-IV-TR criteria for schizophrenia/schizoaffective disorder, confirmed by
clinical interview with PI and SCID-I.

- On a stable dose of Zyprexa (i.e., greater than or equal to 10mg/day and less than or
equal to 30mg/day) for at least 2 months; patients on typical antipsychotics or in a
medications-free state will be also included and used for baseline comparison.

- Sufficient clinical stability (i.e., BPRS psychotic symptoms score of less than 19;
BPRS anxiety/depression symptoms score of less than 15).

- Participation approved by the treating psychiatrist.

- BMI greater than or equal to 30kg/m^2 or BMI greater than or equal to 27kg/m^2 plus
one symptom of the "Metabolic Syndrome" (i.e., fasting blood sugar greater than
125mg/dL, hypertension or dyslipidemia).

- Sufficient social stability following study admission, such as having safe, reliable
living quarters, telephone access and at least one living relative or significant
other willing to assist the subject following discharge from the study and to assist
the staff if necessary to locate the subject subsequently.

- English speaking and reading ability sufficient to comprehend consent without
assistance.

- Good physical health, no history of significant medical, surgical, or neurological
illness, including any history of head trauma.

- Right-handedness

- Able to cooperate and comply with study procedures.

Exclusion Criteria:

- DSM-IV-TR diagnosis of current drug/alcohol dependence.

- Any lifetime history of dementia, bipolar disorder, major depression, other psychotic
disorder, past or current drug/alcohol dependence, past or current eating disorder.

- Potentially confounding neurological condition (e.g., seizure disorder, head trauma
accompanied by loss of consciousness greater than ten minutes or amnesia, brain
surgery, multiple sclerosis, Parkinson's disease), or potentially confounding medical
condition (e.g., diabetes mellitus or other endocrinopathy, chronic obstructive
pulmonary disease, congestive heart failure, hepatitis, hepatic failure or cirrhosis,
AIDS, pacemaker, kidney problems, hypokalemia, edema, and allergy to glucose).

- Allergy or hypersensitivity to naltrexone

- Abnormal laboratory, ECG or EEG results, elevated serum aminotransferases.

- Use within the previous month of any potentially confounding medications such as
opioid agonists (e.g., morphine or codeine) or drugs with prominent
orexigenic/anorexigenic effects (e.g., anticholinergics), insulin, oral
hypoglycemics, amphetamines, opioid analgesics, anti-depressants including
tricyclics, MAO inhibitors or mirtazapine, as determined by history and/or urine
toxicology screen.

- Patient is pregnant or planning on becoming pregnant.

- Any cognitive impairment that precludes informed consent.

- Any chronic pain condition and/or any condition that may require opioid treatment in
the course of the study.

- Dangerousness: any suicidal, assaultive or homicidal risks