This study is a six-week, open label trial of the novel antipsychotic agent, ziprasidone, added to a stable dose of clozapine or olanzapine in 40 diabetes mellitus patients, patients with an impaired fasting glucose or insulin resistance with schizophrenia or schizoaffective disorder. The first two weeks will be a fixed-dose of ziprasidone 40 mg twice a day. During weeks 2-6, the ziprasidone dose may be increased up to 80 mg twice a day.

Specific Aims:

This study is a six-week, open label trial of the novel antipsychotic agent, ziprasidone, added to a stable dose of clozapine or olanzapine in 40 diabetes mellitus patients, patients with an impaired fasting glucose or insulin resistance with schizophrenia or schizoaffective disorder.

STUDY PROCEDURES:

We have designed this trial to examine effects upon weight, lipids and glucose metabolism along with positive symptoms, negative symptoms, and depressive symptoms during a six-week open label study.

Location:

This study will be performed at the Freedom Trail Clinic by faculty of the Schizophrenia Program of the Massachusetts General Hospital and staff of the Freedom Trail Clinic.

Subjects:

Subjects will include 40 outpatients with schizophrenia or schizoaffective disorder treated with clozapine or olanzapine for at least one year. Twenty clozapine-treated subjects and twenty olanzapine-treated subjects with type 2 diabetes mellitus, impaired fasting glucose, or insulin resistance will be recruited. Patients will be excluded for significant medical illness, seizure disorder, substance abuse, or inability to provide informed consent.

Methods:

Medication Trial:

Patients will be treated with open label ziprasidone 40 mg 2x/day for the first 2 weeks. After 2 weeks the study drug may be increased up to ziprasidone 80 mg 2x/day. The clozapine or olanzapine dose will be unchanged during the trial. Patients will be given a two-week supply of medication at baseline and weeks 2 and 4 with additional capsules for study drug compliance and accountability. Following completion of the trial patients will have the option of continuing the ziprasidone. Subjects will return 4 weeks following study completion to examine whether any observed changes are persistent. Additionally, patients will be assessed at a 3 month follow-up post their 10 week assessment for metabolic changes.

Screening Visit The diagnosis of schizophrenia or schizoaffective disorder will be confirmed by a research psychiatrist using DSM IV criteria. A physical examination will be performed and medical history, vital signs, weight, waist/hip circumference, EKG and demographic information will be obtained. Demographic information will also include the date of onset or the duration of diabetes mellitus. Laboratory measures will include a CBC, fasting glucose, insulin, cholesterol (total, HDL and LDL), triglycerides, hemoglobin A1C and leptin. Plasma will also be obtained for assay of clozapine, norclozapine, or olanzapine concentrations at the screening visit.

Baseline Assessment:

The following scales will be completed at baseline and will comprise the treatment efficacy battery: Positive and Negative Syndrome Scale (PANSS), Scale for Assessment of Negative Symptoms (SANS), Clinical Global Impression Scale (CGI), Hamilton Depression Rating Scale (HAM-D), Global Assessment Scale (GAS), Fatigue Scale Inventory (FSI) and the Quality of Life Scale (QOL).

Safety Assessments:

Vital signs, weight, and waist/hip circumference will be performed at each visit (weeks 0, 2, 4, 6 and 10 and at the 3 month follow-up). Side effects will be monitored at baseline and weeks 2, 4, 6 and 10 using the SAFTEE (Levine and Schooler 1986). EPS will be evaluated at baseline and weeks 2, 4, 6 and 4 week follow-up using the Simpson-Angus Scale, Barnes Akathisia Scale, and the Abnormal Involuntary Movement Scale (AIMS). EKG will be performed at baseline, weeks 2, 4, 6, and 10. A patient will be discontinued from the study if their QTc interval is greater than 450. Changes in medication will be recorded throughout the study including changes to diabetes medication (weeks 0, 2, 4, 6 and 10 and at the 3-month follow-up).

Energy Expenditure and Dietary Assessment:

Patients will be asked to wear an accelerometer (Actigraph model 7164) to obtain an objective measure of physical activity. This is single channel accelerometer which measures and records vertical accelerations ranging from 0.05 to 2 G's with a frequency response of 0.25 to 2.50 hertz. These parameters detect normal body motion and filter out high frequency movement such as vibrations. The accelerometer is positioned at the waist and worn for four consecutive days except during sleep or while in water (i.e. swimming or taking a shower). The raw data is then read and processed by a custom data processing program to estimate energy expenditure. Patients will be instructed to complete a four-day food record to assess dietary intake. Food records will be reviewed for completeness and analyzed using Nutrition Data System (NDS). Energy expenditure and dietary intake will be assessed at baseline, weeks 4 and 6 and at the 3 month follow-up.

Subject Recruitment:

The Freedom Trail Clinic has well established procedures for identifying, referring and recruiting subjects for research. Each week clinicians and research staff meet to discuss the research projects that are currently being conducted and open to enrollment. Using this information, clinicians approach their patients they deem to be appropriate for research and that meet inclusion criteria. If a patient expresses interest in participating in research, the clinician completes a Clinician Referral Form and refers the patient to the appropriate research assistant for additional information regarding the study. A member of the research team will meet with the subject and explain the study protocol, including a review of risks and potential benefits.

Patients who express interest after this first meeting will be evaluated for competency to provide informed consent by a physician who is not a member of the research team. Competence to provide consent is assessed by a research psychiatrist using the Assessment of Capacity to Participate in Clinical Research form. Patients who are judged to be competent will then be asked to meet with the principal investigator who will review the study protocol and consent form with the patient and obtain informed consent. A copy of the study consent form will be provided to the patient at this time.

In addition, the prospective subject must ultimately score a 100% correct score on a True/False quiz about informed consent and the study they are interested in participating in.

Potential Risks:

Ziprasidone did not produce any serious adverse effects in animal and human safety studies. No consistent abnormality of vital signs, laboratory, or EEG has emerged. Prolongation of the QTC on EKG has been observed with ziprasidone treatment. In clinical trials, no side effects occurred at rates greater than 2x placebo. Nausea, vomiting, anxiety, headache, dyspepsia, somnolence, orthostatic hypotension, tachycardia, insomnia, akathisia, and EPS may be potential side effects.

Benefits:

It is not known if ziprasidone added to clozapine or olanzapine will help a subject's mood, motivation, hallucinations, and unusual experiences. Other patients may benefit if this study finds that ziprasidone added to clozapine or olanzapine is useful for treating symptoms of schizophrenia.

Protection of Human Subjects:

Principal members of our research team have all completed certification for protection of human subjects in clinical trials. The clinical protocol will be submitted for approval by the institutional review boards of the Massachusetts Department of Mental Health. Potential subjects will be referred by their clinicians. Clinicians will be asked to sign a statement that verifies that the patient is interested in participating, understands that participation is voluntary, and understands that declining participation will not affect treatment at the facility. A member of the research team will meet with the patient and explain the study protocol, including a review of risks and potential benefits. A copy of the study consent form will be provided to the patient at that time to share with family members or residential staff. Patients who continue to express interest after this first meeting will be evaluated by a physician for capacity to provide informed consent. Patients who are judged to be competent will then be asked to meet with the principal investigator or co-investigator who will review the study protocol and consent form with the patient and obtain informed consent.

Each subject that enrolls in the study is asked to sign an authorization to release information to their clinician. Upon consent, a letter is sent to the clinician with notification of study enrollment, the duration of the study and the dose and duration of any study medications.

All laboratory work and physical assessments performed during the study are either conducted or reviewed by a research physician. Side effects and vital signs are monitored routinely by the research assistants. Should any abnormal lab values or adverse events occur during the course of the subject's participation, the research physician would be notified immediately of these values and consulted on how to proceed with patient care. Furthermore, the subject's clinician would also be informed of the results.

Inclusion Criteria:

• Diagnosis of Schizophrenia, any subtype or schizoaffective disorder
• Ages 18-65 years
• Capable of providing informed consent
• Antipsychotic Agents -associated diabetes mellitus, impaired fasting glucose or insulin resistance
• Stable dose of clozapine or olanzapine for at least 1 month
• Optimal dose of clozapine or olanzapine, or a maximal dose if limited by significant side effects

Exclusion Criteria:

• Serious medical or neurological illness (unstable cardiac disease including recent myocardial infarction or heart failure, seizure disorder, malignancy, liver or renal impairment, etc.)
• Current substance abuse
• Pregnancy, nursing, or unwilling to use appropriate birth control measures during participation if female and fertile
• History of serious blood dyscrasia requiring discontinuation of clozapine
• Serious suicidal or homicidal risk within the past six months
• History of diabetes mellitus prior to treatment with clozapine or olanzapine
• H/o prolongation of QTc interval (>450) on EKG or clinically significant EKG abnormalities.
• Treatment with medications that significantly prolong QTc interval such as dofetilde, sotalol, quinidine, class Ia and III antiarrhythmics, mesoridazine, thioridazine, chlorpromazine, droperidol, pimozide, sparfloxacin, gatifloxacin, moxifloxacine, halofantrine, mefloquine, pentamidine, arsenic trioxide, levomethadyul acetate, dolasetron myselate, probucol, or tacrolimus.

The sample size in this study may not have been adequate to demonstrate the effectiveness of ziprasidone as an adjuvant therapy. The receptor-binding profile of ziprasidone may not significantly counteract the mechanisms of metabolic disturbances.