Study of Amantadine for Weight Stabilization During Olanzapine Treatment
Condition: Psychotic Disorder; Schizophreniform Disorder; Schizophrenia; Schizoaffective Disorder; Mood Disorders With Psychotic Features
MeSH terms: Schizophrenia; Mental Disorders; Psychotic Disorders; Mood Disorders
Study type: Interventional
Phase: Phase 1

Summary: 
      Weight gain associated with antipsychotic medication use is a major side effect that limits
      the tolerability of these drugs. This often significant weight gain adversely affects health,
      increasing risks for developing cardiovascular disease, diabetes, sleep apnea, cancers of the
      colon, kidneys, uterus, endometrium and esophagus and osteoarthritis. Beasley and colleagues
      (1997) reported that 40.5% of olanzapine-treated patients gained more than 7% of baseline
      weight. Much of the olanzapine induced weight gain occurs early in treatment, and
      antipsychotic-naïve and young patients (Woods et al., 2002) are particularly vulnerable to
      this side effect. One of the most promising medications to aid weight loss in patients taking
      olanzapine is amantadine.

      Attempts at preventing weight gain are expected to be more successful than attempts to
      reverse it once it occurs. It is now common clinical practice to educate all patients
      beginning treatment with olanzapine, and other antipsychotics, about healthy eating and the
      need for exercise. However, despite this effort, weight gain in this population continues.
      Beginning a weight-stabilizing medication after a low threshold of weight gain has occurred
      may have significant impact on patients' health and their willingness to continue to take
      antipsychotics.

      We propose to investigate the efficacy of amantadine as a weight-stabilizing agent in a
      population of first-episode psychotic subjects just beginning treatment with antipsychotic
      agents. This population is generally young and medically healthy, without contraindications
      to amantadine. They are often of normal body mass index and without obesity-related medical
      problems. They have much to gain in preventing the weight gain which so often progresses
      steadily over the course of treatment, is difficult to reverse and results in significant
      morbidity and mortality. Additionally, the first episode psychotic population tends to take
      fewer concomitant psychiatric medications. This is important since these medications may
      cause weight gain (long term use of mirtazapine, lithium, depakote) or weight loss (short
      term use of SSRI's) which could confound the effectiveness of amantadine to combat weight
      gain.
    

Detailed description: 
      Screening: Screening will include demographics, medical and psychiatric histories and a
      clinical interview to determine psychiatric diagnosis. Screening will also include a physical
      examination and laboratory assessments (CBC, electrolytes, kidney function, liver function,
      TSH) to rule out concurrent medical illness that could be a contraindication to amantadine
      treatment. Blood will also be drawn for fasting lipid profile, glucose, insulin, C reactive
      protein, adiponectin, and leptin. Subjects will also have the option of allowing us to draw 2
      additional tubes for as yet to be determined studies, not to include HIV or genetic testing.
      Subjects will also have the option of allowing us to draw 1 additional tube for
      platelet-specific protein assay, termed SEPT5. The rationale for measuring SEPT5 levels is to
      test a hypothesis that individuals with clinically-defined mental disorders have altered
      levels of this protein in their circulating blood platelets. A urine drug screen will be
      performed.

      Phase 1: Subjects may enter Phase 1 within the first 12 weeks of treatment with olanzapine.
      At entry into Phase 1, anthropometric measurements will be taken (height, weight, waist and
      hip circumference) and BMI calculated. Baseline assessments will include questionnaires about
      hunger (to be done in the fasting state) (Subjective Satiety Scale), and activity (Baeckea
      Activity Questionnaire), respiratory quotient (RQ) and resting energy expenditure (REE)
      assessed using the Medgraphics metabolic cart, and body composition determined by dual x-ray
      absorptiometry (DXA, Hologic Delphia). Prior to every DXA scan Body Composition Lab personnel
      will administer a safety questionnaire and women of reproductive age will have a blood
      pregnancy test. Visits will be scheduled weekly to monitor weight and to provide healthy
      lifestyle counseling based on the Solutions for Wellness program developed by Lilly. During
      the first 3 weeks, subjects will be called by research personnel once per week to complete a
      24 hour diet recall by phone. During the first 4 weeks of the study, RQ and capillary glucose
      will be repeated weekly since it is anticipated that changes to these parameters may occur
      early on. At monthly intervals clinical interviews will monitor for changes in psychosis and
      blood pressure will be assessed. When subjects gain 1 BMI unit, fasting bloodwork and
      baseline assessments are repeated and they are enrolled in Phase 2. Subjects who do not gain
      1 BMI unit within 12 weeks of olanzapine treatment will end study participation at the end of
      Phase 1.

      Phase 2: Subjects may enter Phase 2 following Phase 1 or enter directly if there is
      documentation of more than 1 but less than 3 BMI units of weight gain and they have started
      olanzapine within the previous 12 weeks. Phase 2 is a double blind placebo controlled
      addition of amantadine to ongoing olanzapine therapy. All subjects entering Phase 2 will have
      anthropometric measurements, and BMI will be calculated. Fasting lipid profile, glucose,
      insulin, C reactive protein, adiponectin, and leptin will be obtained, as will liver function
      tests and a urine drug screen. Body composition by DXA as well as RQ and REE will be
      determined. Prior to every DXA scan the Body Composition Lab will administer a safety
      questionnaire and women of reproductive age will have a pregnancy test. A Food Propensity
      questionnaire will be administered to document recent trends in food choices, and the
      exercise and hunger questionnaires will also been done. Following completion of baseline
      assessments, randomization to amantadine or placebo will occur. Subjects will begin taking 1
      capsule daily for 2 days, 2 capsules daily for 5 days, and then 3 capsules daily. Amantadine
      capsules will each contain 100 mg of amantadine. Clinical state and emergence of side
      effects, including orthostatic hypotension, will be monitored at all visits by research
      clinicians. If subjects experience mild side effects with increase in number of capsules, the
      titration will be slowed. During Phase 2, subjects will be called by research personnel on 3
      nonconsecutive days to complete a 24 hour diet recall by phone. Biweekly, all subjects will
      meet with a study physician or nurse for standardized healthy lifestyle counseling based on
      the Solutions for Wellness program available from Lilly. BMI will be calculated biweekly and
      baseline measures will be repeated at the final study visit. Urine pregnancy test will be
      performed monthly on all women. When subjects gain an additional 3 BMI units (approximately
      15 lbs), or when they complete 16 weeks of double blind medication they will repeat all Visit
      13 measures and end study participation.
    

Intervention name(s): Olanzapine, Amantadine; Olanzapine and placebo
Intervention type(s): Drug; Drug
Intervention description(s): Olanzapine continuing as clinically indicated, Amantadine 100 mg tid; Olanzapine continuing as clinically indicated
Intervention MeSH terms: Amantadine; Olanzapine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: First episode psychosis