Effectiveness of Aripiprazole for Improving Side Effects of Clozapine in the Treatment of People With Schizophrenia

• Change in Total Cholesterol [ Time Frame: Measured at Baseline and Week 8 ] [ Designated as safety issue: Yes ]
  A comparison of aripiprazole group and placebo group in change in total cholesterol measured at Baseline and Week 8.
• Change in Weight [ Time Frame: Measured at Baseline and Week 8 ] [ Designated as safety issue: Yes ]
  A comparison between aripiprazole group and placebo group in change in weight measured at Baseline and Week 8.
• Change in Body Mass Index (BMI) [ Time Frame: Measured at Baseline and Week 8 ] [ Designated as safety issue: Yes ]
  A comparison between aripiprazole group and placebo group of change in Body Mass Index (BMI) measured at Baseline and Week 8.
• Change in Glucose Metabolism [ Time Frame: Measured at Baseline and Week 8 ] [ Designated as safety issue: Yes ]
  A comparison between the aripiprazole group and placebo group in change in glucose metabolism measured at Baseline and Week 8.
• Change in Triglycerides [ Time Frame: Measured at Baseline and Week 8 ] [ Designated as safety issue: Yes ]
• Change in Insulin Resistance [ Time Frame: Measured at Baseline and Week 8 ] [ Designated as safety issue: Yes ]
  A comparison between aripiprazole group and placebo group of change in insulin resistance measured at Baseline and Week 8.

• Measured at Week 12: Fasting lipids, including triglycerides and total cholesterol
• Body Mass Index (BMI)
• Weight
• Insulin resistance and glucose metabolism
• Predictions for improvement in these outcomes

• Measured at Week 12: Food intake
• Energy expenditure
• Systematic Assessment for Treatment Emergent Effects (SAFTEE)
• Vital signs
• Plasminogen activator molecule-1 (PAI-1)
• LDL particle size
• C-reactive protein
• Soluble intercellular adhesion molecule-1
• Lipid abnormalities

This study will evaluate the effects of combination treatment with aripiprazole and clozapine on insulin resistance, blood fat levels, and weight gain in people with schizophrenia.

Schizophrenia is a severely disabling brain disorder. People with schizophrenia often experience hallucinations and delusions, as well as overall difficulty with everyday functioning. Although the medications available to treat the disorder are generally effective, many cause undesirable side effects. Clozapine, for example, is a strong tranquilizer that functions like an antipsychotic medication. It has been shown to be effective in reducing the symptoms of schizophrenia, but can bring about serious side effects, including heart failure, weight gain, and diabetes. Aripiprazole, an atypical antipsychotic medication, has been shown to have fewer side effects than older antipsychotic drugs. The addition of aripiprazole to a clozapine treatment regimen may reduce the negative side effects of clozapine. This study will evaluate the effects of combination treatment with aripiprazole and clozapine on insulin resistance, blood fat levels, and weight gain in people with schizophrenia.

Individuals interested in participating in this 8-week, double-blind study will first attend a screening session at the study site. Medical and psychiatric evaluations will be completed, blood samples will be taken, and an EKG will be performed. Eligible participants will undergo baseline assessments and then be randomly assigned to receive either aripiprazole or placebo in addition to their prescribed dose of clozapine. Participants will take one 15-mg capsule of their assigned medication once a day for 8 weeks. Study visits will occur biweekly for the first 8 weeks, followed by one final follow-up visit at Week 12. At each study visit, medication will be distributed, and the following criteria will be assessed: vital signs; weight; complete blood count; medication side effects; and extrapyramidal symptoms (EPS), which are potential neurological side effects of antipsychotic medications and may include involuntary movements, tremors, and rigidity. The Week 8 visit will include an EKG, and assessments of the following criteria: vital signs; medication side effects; treatment efficacy; blood counts; weight and height; and waist and hip circumference. At baseline and Week 8, participants will also undergo a frequently sampled intravenous glucose tolerance test (FSIVGTT). This involves intravenous infusion of glucose followed by frequent blood sampling to measure insulin and glucose concentrations. During the 4 days prior to each FSIVGTT, participants will record their food intake and wear an activity monitor.

• Schizophrenia
• Insulin Resistance

• Drug: Aripiprazole
  15-mg dose once a day for 8 weeks
• Drug: Placebo
  1 tablet placebo dose once a day for 8 weeks

• Experimental: 1
  Participants will take aripiprazole 15mg/day for 8 weeks.
  Intervention: Drug: Aripiprazole
• Placebo Comparator: 2
  Participants will take placebo for 8 weeks.
  Intervention: Drug: Placebo

• Casey DE, Carson WH, Saha AR, Liebeskind A, Ali MW, Jody D, Ingenito GG; Aripiprazole Study Group. Switching patients to aripiprazole from other antipsychotic agents: a multicenter randomized study. Psychopharmacology (Berl). 2003 Apr;166(4):391-9. Epub 2003 Feb 28.
• Goldstein LE, Sporn J, Brown S, Kim H, Finkelstein J, Gaffey GK, Sachs G, Stern TA. New-onset diabetes mellitus and diabetic ketoacidosis associated with olanzapine treatment. Psychosomatics. 1999 Sep-Oct;40(5):438-43. No abstract available.
• Hadigan C, Miller K, Corcoran C, Anderson E, Basgoz N, Grinspoon S. Fasting hyperinsulinemia and changes in regional body composition in human immunodeficiency virus-infected women. J Clin Endocrinol Metab. 1999 Jun;84(6):1932-7.
• Henderson DC, Cagliero E, Gray C, Nasrallah RA, Hayden DL, Schoenfeld DA, Goff DC. Clozapine, diabetes mellitus, weight gain, and lipid abnormalities: A five-year naturalistic study. Am J Psychiatry. 2000 Jun;157(6):975-81.
• Marder SR, McQuade RD, Stock E, Kaplita S, Marcus R, Safferman AZ, Saha A, Ali M, Iwamoto T. Aripiprazole in the treatment of schizophrenia: safety and tolerability in short-term, placebo-controlled trials. Schizophr Res. 2003 Jun 1;61(2-3):123-36.
• Visser M, Fuerst T, Lang T, Salamone L, Harris TB. Validity of fan-beam dual-energy X-ray absorptiometry for measuring fat-free mass and leg muscle mass. Health, Aging, and Body Composition Study--Dual-Energy X-ray Absorptiometry and Body Composition Working Group. J Appl Physiol. 1999 Oct;87(4):1513-20.
• Wirshing DA, Boyd JA, Meng LR, Ballon JS, Marder SR, Wirshing WC. The effects of novel antipsychotics on glucose and lipid levels. J Clin Psychiatry. 2002 Oct;63(10):856-65.

Inclusion Criteria:

• Diagnosis of schizophrenia (any subtype) or schizoaffective disorder (any subtype)
• Treatment with clozapine for at least 1 year
• Stable dose of clozapine for at least 1 month
• Well established compliance with outpatient medications
• Female participants of non-childbearing potential or of childbearing potential and willing to practice appropriate birth control methods (complete abstinence from sexual intercourse, female sterilization, sterilization of male partner, implants of levonorgestrel, injectable progestogen, oral contraceptives, intrauterine devices, or double barrier methods of contraception using spermicide with either a condom or diaphragm) during the study

Exclusion Criteria:

• Current substance abuse
• Psychiatrically unstable
• Significant medical illness, including severe cardiovascular, hepatic, or renal disease
• History of immunosuppression
• Current or recent radiation or chemotherapy treatment for cancer
• Chronic use of steroids
• Pregnant or breastfeeding