Tamoxifen in Treatment of Acute Mania
Condition: Bipolar Disorder
MeSH terms: Bipolar Disorder
Study type: Interventional
Phase: Phase 3

Summary: 
      Objective: Evidence indicates that the protein kinase C-PKC signaling cascade may be one of
      the direct targets in treatment of mania. The aim of this study is to investigate whether the
      PKC inhibitor-tamoxifen has anti-manic properties. Method: Bipolar subjects with manic/mixed
      episode were randomly assigned to receive either tamoxifen (80mg/day) or identical placebo
      tablets in 1:1 ratio for three weeks.
    

Detailed description: 
      Patients aged 18-65 years, diagnosed with Bipolar Disorder (BD), most recent episode manic or
      mixed, with or without psychotic features were admitted to the inpatient unit at the Dokuz
      Eylul University, Department of Psychiatry, Izmir, Turkey. Subjects were recruited from the
      local community, an urban area in the western part of Turkey, surrounding suburbs, and towns
      as well as all over the country (expert-seeking patients who reached the principle
      investigator-PI, via the internet and news media) between April, 2003 and June, 2006. All
      diagnoses were based on the Structured Clinical Interview for the DSM-IV, administered by a
      trained investigator (AYY). After the protocol explained to the patient and at least one
      first degree relative, both gave written informed consent for participation of the patient in
      the trial. The study was approved by the Turkish Ministry of Health, General Directorate of
      Drugs and Pharmaceutics, Central Review Board, and Local Ethical Committee of Drug
      Investigations at the Dokuz Eylul University. Subject screening included medical and
      psychiatric history, physical examination, and laboratory screen including LFTs, TSH, HCG,
      BUN, Cr, and serum toxicology. All psychotropic medication (except benzodiazepines) was
      discontinued at least 1 day before randomization. Subjects entering the study were randomly
      assigned to receive the PKC inhibitor, tamoxifen or identical placebo tablets in a 1:1 ratio
      and double-blind fashion for 3 weeks. Computer-generated codes were used to create
      randomization kits (prepared by the ARGEFAR, Izmir, Turkey, a contract research
      organization). The starting dose of tamoxifen was 20 mg bid. After the first treatment day,
      daily dose was adjusted upward by 10 mg per day up to 80 mg/d in divided doses. Similar
      tablet adjustments were applied for the patients in placebo group. Concomitant use of oral
      lorazepam (2.5mg dissolving tables) was allowed during double-blind therapy as clinically
      indicated. In cases where lorazepam is thought to be ineffective and the symptoms are such
      that an antipsychotic is required, risperidone liquid formulations (2-6 mg/day) were used
      under emergency circumstances. Those subjects who were given risperidone were assumed as drop
      out at the time of first exposure to risperidone; and new subjects for replacement of those
      cases have been recruited. Subjects were seen twice daily and investigators (AYY, SG) were on
      call 24 hours a day.

      Assessment tools; Young Mania Rating Scale (YMRS), Hamilton Depression Rating Scale-17 item
      (HAMD-17), Montgomery-Asberg Depression Rating Scale (MADRS), Clinical Global
      Impressions-Bipolar Version of Severity of Illness (CGI), and Positive and Negative Syndrome
      Scale (PANSS) and side effect questionnaire were administered by semi-structured interviews
      at each week. Vital signs and weight were monitored. The PI, who is trained in the rating
      instruments and blind to the treatment condition (training and certification at the
      Massachusetts Hospital, Bipolar Program), performed all the study assessments on a weekly
      basis by using all the available clinical information, provided by the prospective daily
      interviews by the investigators, staff reports including the security team' observations, and
      first degree relative reports.

      Power calculations were performed to determine the sample size required to achieve 80% power
      to detect a difference of 0.40 in the response rate, assuming a 0.15 response rate in placebo
      using a chi-square test at the .05 level. Assuming 30% drop out and non compliance rate,
      randomization kits were prepared for 70 subjects. Following eligibility considerations and
      drop out the final sample size used in the analysis was 50. The primary efficacy variable is
      defined as the reduction from baseline of the YMRS score after 3 weeks of therapy. Positive
      treatment response was defined as >=50% decrease in YMRS from baseline to 3 weeks.
    

Intervention name(s): Tamoxifen Citrate; Placebo
Intervention type(s): Drug; Drug
Intervention MeSH terms: Tamoxifen
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Protein kinase C, tamoxifen, acute mania, clinical trial