A Double-Blind Randomized Placebo Controlled Study of Quetiapine for the Treatment of Depression in Adolescents With Bipolar Disorder
Condition: Bipolar I Disorder
MeSH terms: Bipolar Disorder
Study type: Interventional
Phase: Phase 3

Summary: 
      In this study, quetiapine is being tested for the possible treatment of bipolar I disorder
      with an acute depressive episode in children and adolescents.

      We hypothesize that quetiapine will be more efficacious than placebo for the treatment of
      episodes of major depression associated with adolescent BP. Moreover, we hypothesize that
      quetiapine will be safe and well-tolerated compared with placebo for the treatment of
      depression associated with adolescent BP. Based on data from the BOLDER study and other
      studies of atypical antipsychotics in patients with bipolar depression (Calabrese et al.,
      2004, Macfadden et al., 2004, Tohen et al., 2004), which in general reveal effect sizes of
      approximately 0.5, a conservative sample size calculation, assuming power of .8, estimates we
      would need approximately 15 patients in each group to identify a statistically significant
      group difference in our main outcome measure, change form baseline to endpoint in the
      Children's Depression Rating Scale (Poznanski, 1979).
    

Detailed description: 
      This is a double-blind, randomized 56-day treatment trial of quetiapine vs. placebo for the
      treatment of bipolar adolescents with acute depression. Randomization will be stratified by
      sex, the presence of psychotic features, and a site specific randomization schedule will be
      determined. Stratification of randomization by sex is necessary to control for the higher
      rate of co-occurring ADHD in males than in females with bipolar disorder. Bipolar disorder
      with ADHD may be more treatment refractory than bipolar disorder without ADHD. Stratification
      by the presence of psychosis is necessary to avoid all patients with psychosis being assigned
      to one treatment group. A randomization schedule will be developed by the Children's Hospital
      Medical Center Investigational Pharmacy.

      Procedures Thirty adolescents who are hospitalized for an episode of major depression
      associated with BP, type I, (ages 12-18) will be recruited for the study over two years.

      After providing informed consent (the parent or legal guardian), informed assent (the child),
      and signing the document (both the parent and the child), subjects will be evaluated using
      the Washington University at St. Louis Kiddie-Schedule for Affective Disorders and
      Schizophrenia (K-SADS, Geller et al., 1998) by raters with extensive training in the
      instrument and established inter-rater reliability (ICC>0.9) (DelBello et al., 2004). The
      WASH-U K-SADS is a semi-structured clinical interview with established validity and
      reliability to assess the presence of DSM-IV Axis I psychiatric disorders in children and
      adolescents (Geller et al., 1998). The K-SADS involves an interview with the child and
      another interview with the parent.

      If the diagnosis of bipolar disorder, type I, current episode depressed is confirmed by the
      K-SADS, the following scales will also be performed:

        1. The Children's Depression Rating Scale (CDRS) to assess the severity of depressive
           symptoms (Poznanski et al., 1979);

        2. The Young Mania Scale (YMRS) to assess the severity of manic symptoms (Fristad et al.,
           1992; Young et al., 1978);

        3. The Hamilton Anxiety Rating Scale (HAM-A) to assess the severity of anxiety symptoms
           (Hamilton, 1959)

        4. The Clinical Global Impression Scale BP Version (CGI-BP) to quantify the child's overall
           baseline functioning (National Institute of Mental health, 1985); The CGI-BP is used by
           the clinician to record the severity of illness at the time of assessment. The score
           ranges from 1 (normal, not at all ill) to 7 (among the most extremely ill patients). At
           all visits following baseline, we will also perform the CGI-BP Improvement Scale to
           quantify the change from baseline in overall functioning. The score ranges from 1 (very
           much improved) to 7 (very much worse).

        5. The Simpson-Angus Scale (Simpson and Angus, 1970), Barnes Akathisia Scale (Barnes 1989)
           and Abnormal Involuntary Movement Scale (AIMS, US Department of Health, 1976) to assess
           for extrapyramidal symptoms.

      Patients who received prior treatment with lithium or valproate must have serum
      concentrations of <0.4 mEq/L and 50 mg/L respectively before receiving quetiapine or placebo.
      Patients treated with antipsychotics (po or IM, non-depot), stimulants, or other mood
      stabilizers must have a 48 hr. interval without receiving these agents prior to
      randomization, except for patients recently (within one dosing interval) treated with depot
      antipsychotics, who will be excluded from this trial. Patients treated with prior
      antidepressants must have a 7 day washout period (patients treated with fluoxetine will be
      excluded from this trial because of its long half-life).

      Medication in this study will be administered in a double-blind manner. Patients randomized
      to quetiapine will be administered beginning at day 0, a dose of 100mg/day which will be
      titrated to 300mg/day by day 3, with flexible titration to 600mg/day (in 100mg/day
      increments) until day 28.

      Patients will be evaluated by a blinded (to treatment status and adverse events) rater at
      baseline (day 0) (MPD), prior to being randomized to placebo or quetiapine. Ratings 1-4 will
      be done at baseline (day 0) and on days 7, 14, 21, 28, 35, 42, 49, and 56 (or termination
      from the study).

      Extrapyramidal rating scales and adverse events will be assessed on days of efficacy ratings
      by a different rater from the rater who is performing rating scales. Adverse events will be
      evaluated by open-ended questions about side effects and by vital sign measures. Adverse
      events will be monitored, documented and tabulated by occurrence, frequency and severity. Any
      extrapyramidal symptoms that develop in patients will be appropriately treated via dose
      reduction and/or administration of anticholinergic agents (e.g. benztropine), and this will
      be recorded. Patients will receive no other psychotropic agents during the study except for
      lorazepam, as needed for anxiety or agitation, up to 4 mg/d for days 0-6, 2 mg/d on days 7 to
      14, and 1mg/day on days 14-21. The doses of lorazepam administered to patients will be
      recorded. Patients requiring other psychotropic medications will be terminated at the point
      at which such interventions are required. Please see Table 1 for schedule of assessments and
      laboratory tests.

      Investigators will be responsible for monitoring the safety of patients who have entered this
      protocol and for alerting AstraZeneca to any event that seems unusual, even if this event may
      be considered an unanticipated benefit to the patient. Additionally, baseline medical
      history, physical examination, laboratory tests, and vital signs (blood pressure, pulse,
      weight, height and temperature) will be performed. Blood pressure and pulse will be taken
      after a patient has been lying down for 5 minutes (supine) and after standing for
      approximately 2 minutes (standing). Laboratory tests will include a urine pregnancy test and
      serum complete blood count (CBC), liver function tests (LFTs), thyroid stimulating hormone
      (TSH), renal profile, prolactin level, fasting glucose, fasting lipid profile, and an EKG.
      Vital signs, including Body Mass Index (BMI) and waist circumference will be repeated on days
      7, 14, 21, 28, 35, 42, 49, and 56 (or endpoint). All other labs will be performed at baseline
      (day 0) and day 56 (or termination from the study), with the exception of fasting plasma
      glucose, fasting plasma lipid profile, and complete blood count, which will also be repeated
      at day 28 (and days 0 and 56). A funduscopic and physical exam will be performed prior to and
      at termination of trial.

      If at any point during the study if a patient has a CDRS suicide item score > one point
      higher than their baseline for any one week, or a score of > 3 they will be withdrawn from
      the study. Additionally, patients will be withdrawn from the study (and treated as clinically
      indicated) if they have a worsening of symptoms at day 14 or later, as indicated by a CGI-I
      score of > 6 or more at any time during the study or a minimal worsening of symptoms at day
      21 or later as indicated by a CGI-I score of > 5 at 2 consecutive visits, starting at day 14.

      Additionally, if at any point during the study patients has a CBC with differential that
      shows an Absolute Neutrophil Count (ANC) < 1.0 x 10-9/L, we will repeat the test within 24
      hours, if it remains < 1.0 x 10-9/L, the patient will be discontinued from the study.

      Patients will be discharged form the hospital when they are felt to be clinically stable as
      determined by their inpatient attending and treatment team in collaboration with Dr.
      DelBello.
    

Intervention name(s): Quetiapine
Intervention type(s): Drug
Intervention MeSH terms: Quetiapine Fumarate
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: Double
Primary purpose: Treatment
Keywords: bipolar; with acute depressive episode