A Placebo-Controlled, Cross-Over Trial of Aripiprazole

• Change From Baseline in Weight (Lbs) [ Time Frame: baseline, week 4 ] [ Designated as safety issue: No ]
  Evaluating change in weight (lbs) between Baseline and Week 4, comparing subjects treated with aripiprazole for 4 weeks to subjects treated with placebo for 4 weeks.
  
  
• Change From Baseline in Body Mass Index (BMI) [ Time Frame: baseline, week 4 ] [ Designated as safety issue: No ]
  Evaluating change in Body Mass Index (BMI) between Baseline and Week 4, comparing subjects treated with aripiprazole for 4 weeks to subjects treated with placebo for 4 weeks.
  
  
• Change From Baseline in Waist-hip Ratio (WHR) [ Time Frame: baseline, week 4 ] [ Designated as safety issue: No ]
  Evaluating change in waist-hip ratio (WHR) between Baseline and Week 4, comparing subjects treated with aripiprazole for 4 weeks to subjects treated with placebo for 4 weeks.
  
  
• Change From Baseline in Fasting Total Cholesterol [ Time Frame: baseline, week 4 ] [ Designated as safety issue: No ]
  Evaluating change in fasting total cholesterol between Baseline and Week 4, comparing subjects treated with aripiprazole for 4 weeks to subjects treated with placebo for 4 weeks.
  
  
• Change From Baseline in Low-density Lipoprotein (LDL) [ Time Frame: baseline, week 4 ] [ Designated as safety issue: No ]
  Evaluating change in low-density lipoprotein (LDL) between Baseline and Week 4, comparing subjects treated with aripiprazole for 4 weeks to subjects treated with placebo for 4 weeks.
  
  
• Change From Baseline in High-density Lipoprotein Cholesterol (HDL-C) [ Time Frame: baseline, week 4 ] [ Designated as safety issue: No ]
  Evaluating change in high-density lipoprotein cholesterol (HDL-C) between Baseline and Week 4, comparing subjects treated with aripiprazole for 4 weeks to subjects treated with placebo for 4 weeks.
  
  
• Change From Baseline in Triglycerides [ Time Frame: baseline, week 4 ] [ Designated as safety issue: No ]
  Evaluating change in triglyceride levels between Baseline and Week 4, comparing subjects treated with aripiprazole for 4 weeks to subjects treated with placebo for 4 weeks.
  
  

Specific Aims:

This study is a ten-week, placebo-controlled, double-blind, cross-over, randomized trial of the novel antipsychotic agent, aripiprazole, added to 20 obese stable olanzapine-treated patients with schizophrenia or schizoaffective disorder. The advantage of the crossover design is that each subject will act as their own control and fewer subjects will be required.

Study Procedures:

We have designed this trial to examine effects upon weight, lipids, glucose metabolism, positive symptoms, negative symptoms, and depressive symptoms. This project, examining the usefulness of combination therapy, may offer a possible intervention for patients who are obese and treated with olanzapine, but otherwise experiencing a good clinical response. Many patients, despite the medical problems that may occur, are reluctant to switch their antipsychotic agent.

Location:

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

Subjects:

Subjects will include 20 stable outpatients with schizophrenia or schizoaffective disorder treated with olanzapine for at least one year. Prior to enrollment, we will determine that the clinician has optimized the dose of the antipsychotic and maintained the medication at a stable dose for at least 1 month. Patients will be excluded for significant medical illness, substance abuse, or inability to provide informed consent.

Safety Assessments:

Medication Trial:

Patients will have a baseline assessment performed and then randomized to placebo or aripiprazole 15 mg/day for 4 weeks. After the initial 4 weeks of medication patients will be reassessed, have a 2-week washout period and then crossover to the other treatment for another 4 weeks. The olanzapine dose will be unchanged during the trial. Patients will be given a two-week supply of medication at baseline and week 2 and then again at weeks 6 and 8.

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, height, waist/hip circumference, skin-fold measurements, 12-lead EKG and demographic information will be obtained. Laboratory measures will include olanzapine blood levels, fasting glucose, insulin, basic chemistry profiles, liver enzymes, CBC, lipid profile, leptin, LDL- particle size, PAI-1, C-reactive protein, sICAM, vWF and a DNA sample will be drawn at screening for future analysis of the 5-HT-2C and H1 receptor genes.

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 Impressions scale (CGI), Hamilton Depression Rating Scale (HAM-D), Global Assessment Scale (GAS), Fatigue Scale Inventory (FSI) Trauma History Questionnaire (THQ) and the Quality of Life Scale (QOL). A single rater will perform all assessments. If it is necessary to use a second rater, inter-rater reliability will be established before the addition of the second rater and will be repeated every three months by use of videotaped interviews. The treatment efficacy battery will be repeated at week 4, 6 and 10 except for the THQ, which will only be administered at the beginning of the study.

Safety and Monitoring Assessments:

Blood pressure, heart rate, temperature, weight, waist/hip circumference will be performed at each visit (baseline, weeks 2, 4, 6, 8 and 10). Side effects will be monitored at baseline and weeks 2, 4, 6, 8, and 10 using the Systematic Assessment for Treatment Emergent Events (SAFTEE). Body fat composition will be measured by skin-fold calipers at baseline, week 4, 6 and 10. EPS will be evaluated at baseline and weeks 2, 4, 6, 8 and 10 using the Simpson-Angus Scale, Barnes Akathisia Scale, and the Abnormal Involuntary Movement Scale (AIMS).

Measure of Energy Expenditure and Dietary Assessment:

Patients will be asked to wear an accelerometer for four consecutive days to obtain an objective measure of physical activity. During the same four days the patients will maintain a four-day food record of all food and beverages consumed. This will provide a means of assessing energy intake verses energy output. Patients will also complete the Modifiable Activity Questionnaire (MAQ). Energy expenditure and dietary intake will be assessed at baseline, weeks 4, 6 and 10.

Randomization:

The double-blind, placebo-controlled, crossover study will consist of two random order 4-week treatment arms (aripiprazole 15 mg or placebo) separated by a 2-week adjuvant treatment washout. Following baseline, subjects will be randomized, double-blind, to either aripiprazole or placebo for 4 weeks. After the initial 4 weeks of medication patients will be reassessed, have a 2-week washout period and then crossover to the other treatment for another 4 weeks.

Subject Recruitment:

Potential subjects will be identified by their clinicians at the Freedom Trail Clinic. Patients will give their physician verbal permission to be contacted for research purposes. A member of the research team will meet with the subject 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 this time. 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. 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. The human rights officer of the North Suffolk Mental Health Association will be asked to participate in this meeting unless the patient declines. Family and residential staff will also be invited to participate if the patient agrees.

Potential Risks:

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

Benefits:

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

Data Management and Statistical Analysis:

Data management and statistical analysis will be provided by Dr. David Schoenfeld from the Massachusetts General Hospital, Biostatistics Center.

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 who is not a member of the research team 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.