Examination of Tamoxifen in Acute Mania in Patients With Bipolar I Disorder
Condition: Bipolar Disorder
MeSH terms: Bipolar Disorder
Study type: Interventional
Phase: Phase 2

Summary: 
      The purpose of this study is to examine how the drug tamoxifen affects the brain in patients
      with bipolar I disorder.

      Bipolar Disorder (BD) is a severe, chronic, and often life-threatening illness for which safe
      and effective treatments are necessary. The mood stabilizing effects of lithium and valproate
      have revolutionized the treatment of patients with BD. However, a significant percentage of
      patients do not respond fully to these drugs, and the biochemical basis for the antimanic and
      mood-stabilizing actions of lithium and valproate is unclear. Both drugs inhibit protein
      kinase C (PKC). There is a need to investigate the efficacy of a direct PKC inhibitor in the
      treatment of acute mania. Tamoxifen is currently the only relatively selective PKC inhibitor
      available for human use.

      Participants in this study will be screened with a physical, psychiatric, and eye examination
      and blood and urine tests. Eligible participants will be hospitalized at the Clinical Center
      for at least 4 weeks. They will be tapered off all psychiatric medication and kept drug free
      for 2 to 7 days. They will also be put on a low-monoamine, low-caffeine diet. Participants
      will be randomly assigned to receive either tamoxifen or placebo (an inactive pill) for 3
      weeks. During this time, participants will have daily pulse and blood pressure measurements,
      several electrocardiograms (EKGs), and blood draws. Weight measurements will be taken at
      least twice during the study, and caffeine or dextromethorphan will be given at the beginning
      and end of the study to test how tamoxifen affects the way the body eliminates other
      medications. Participants will have a physical examination at the end of the study.

      At the end of this 4-week study, some participants may continue the study and will receive
      tamoxifen for an additional 3 weeks. At the conclusion of the study, participants'
      psychiatric status will be reassessed and long-term psychiatric treatment for their mood
      disorders will be arranged.
    

Detailed description: 
      Bipolar Disorder (BD) is a common, severe, chronic and often life-threatening illness.
      Suicide is the cause of death in 10-20% of individuals with BD. The discovery of lithium's
      efficacy as a mood-stabilizing agent has since revolutionized the treatment of patients with
      BD. However, approximately 50% of patients do not respond fully to lithium, and the
      biochemical basis for lithium's antimanic and mood-stabilizing actions remains to be fully
      elucidated. Elucidation of the mechanism(s) by which lithium stabilizes an underlying
      dysregulation of limbic and limbic-associated function also offers the potential to delineate
      the underlying pathophysiology of BD; however, a major problem inherent in neuropharmacologic
      research is the difficulty in attributing therapeutic relevance to any observed biochemical
      finding. One powerful approach is to identify common biochemical targets, which are modified
      by drugs belonging to the same therapeutic class (e.g. mood-stabilizing agents) but
      possessing distinct chemical structures when administered in a therapeutically relevant
      paradigm (i.e., effects which are observed upon chronic drug administration, and yet persist
      beyond abrupt drug discontinuation). In this context, it is noteworthy that both valproic
      acid (VPA) and lithium, with different chemical structures, belong to the same therapeutic
      class and cause considerable inhibition of protein kinase C (PKC). The PKC signaling pathway
      is clearly a target for the actions of two structurally highly dissimilar antimanic agents --
      lithium and VPA. Do these effects of lithium and VPA on PKC signaling have any clinical
      relevance? There is thus a clear need to investigate the potential efficacy of a direct PKC
      inhibitor in the treatment of acute mania. There is currently only one relatively selective
      PKC inhibitor available for human use- Tamoxifen. Tamoxifen (TAM), a synthetic nonsteroidal
      antiestrogen, has been widely used in the treatment of breast cancer. TAM's potent inhibitory
      effects on PKC are striking. Recently, our group conducted the first open-label study with
      TAM in acute mania. In this study, TAM resulted in a significant decrease in manic symptoms
      within a short period of time (3-7 days).

      The overarching goal of this proposal is to test the hypothesis that PKC inhibition is part
      of the mechanism of the therapeutic effect of mood stabilizing drugs. The proposal derives
      from and builds on our published open-label study of TAM in acute mania (Bebchuk et al.,
      2000). However, the efficacy of TAM monotherapy in acute mania has only been reported in an
      open-label study and has not yet been evaluated in a randomized, double blind,
      placebo-controlled study.

      Male or female patients, ages 18 to 65, with a diagnosis of bipolar I disorder manic or mixed
      (with or without psychotic features), will be randomized to double-blind treatment to receive
      either TAM (20-140 mg/day) or placebo, for a period of 3 weeks. Following this acute period,
      the patients will receive either open-label TAM or treatment as clinically indicated.
      Approximately 50 patients with acute mania will be enrolled in the study. Biochemical
      measures will be obtained during the study.
    

Intervention name(s): Tamoxifen
Intervention type(s): Drug
Intervention MeSH terms: Tamoxifen
Primary purpose: Treatment
Keywords: Bipolar Disorder; Antimanic; Placebo Controlled; Randomized; Cytochrome P450; Mania; PKC Inhibitor; Tamoxifen; Bipolar; Manic; BPD