Protocol Number: 02-M-0037

Title:

A Double-Blind Study Examining the Efficacy of the Protein Kinase C Inhibitor Tamoxifen in the Treatment of Acute Mania

Number:

02-M-0037

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.

Sponsoring Institute:

National Institute of Mental Health (NIMH)

Recruitment Detail

Type: Active Accrual Of New Subjects

Gender: Male

Referral Letter Required: No

Population Exclusion(s): Female

Children

Eligibility Criteria:

INCLUSION CRITERIA:

Male patients, 18 to 60 years of age.

Each patient must have a level of understanding sufficient to agree to all tests and examinations required by the protocol.

Each patients must understand the nature of the study and must sign an informed consent document. We will not permit patients with a Durable Power of Attorney (DPA) to participate in this study.

Patients must have a diagnosis of bipolar I disorder and currently display an acute manic or mixed episode (with or without psychotic features) according to the DSM-IV based on clinical assessment and confirmed by structured diagnostic interview SCID-P. This includes the following diagnoses: Bipolar I Disorder, Most Recent Episode Manic; Bipolar I Disorder, Most Recent Episode Mixed.

Patients must have a YMRS total score of greater than or equal to 14 at both Visits 1 and 2.

No decrease in total score of YMRS of greater than or equal to 20% during washout (between Visits 1 and 2).

Patients must have experienced at least two manic or mixed episodes within five years prior to study entry and one manic or mixed episode in the last 24 months (not including the current episode).

DSM-IV rapid cyclers will be permitted to participate in this study. There will be no exclusion on the number of Bipolar Disorder episodes that meet DSM-IV criteria in the 12-month period prior to enrollment.

Duration of current manic episode of not more than 4 weeks.

Patients must meet criteria for either a or b:

a) Have previously failed to respond to an adequate trial of either lithium or valproate (but not both) and be intolerant to the other one or

b) Intolerant (but not have previously failed to respond) to both lithium and valproate.

EXCLUSION CRITERIA:

QTc greater than 450 msec.

Participation in a clinical trial of another investigational drug within 1 month (30 days) prior to study entry (Visit 1).

Has received an antidepressant within 4 weeks prior to Visit 1 [8 weeks for fluoxetinel].

Serious, unstable illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease), endocrinologic, neurologic, immunologic, or hematologic disease.

Presence of a coagulation disorder, history of deep venous thrombosis or pulmonary embolism.

Uncorrected hypothyroidism or hyperthyroidism.

Presence of corneal opacities or retinal pathology.

One or more seizures without a clear and resolved etiology.

Current leukopenia or thrombocytopenia.

Current jaundice, positive hepatitis B surface antigen (HbsAg) or positive IgM fraction of the hepatitis B core antibody (anti-Bc[IgM]).

HIV positive.

Documented history of hypersensitivity or intolerance to TAM.

DSM-IV substance abuse or dependence (except nicotine and caffeine) within the past 90 days.

Treatment with an injectable depot neuroleptic within less than one dosing interval between depot neuroleptic injections prior to Visit 2.

Treatment with a reversible monoamine oxidase inhibitor, guanethidine, or guanadrel within 1 week prior to Visit 2.

Treatment with a nonreversible monoamine oxidase inhibitor within 2 weeks prior to Visit 2.

Treatment with psychotropic medication (except lorazepam) within 1 day of Visit 2.

Treatment with any other concomitant medication with primarily CNS activity 1 day prior to Visit 2.

Treatment with clozapine within 4 weeks prior to Visit 2.

Current diagnosis of schizophrenia or other psychotic disorder as defined in the DSM-IV.

Judged clinically to be at serious suicidal risk.

Concomitant treatment with a coumarin-type anticoagulant, Phenobarbital, Cyclophosphamide, or Bromocriptine.

First manic episode.

Special Instructions: Currently Not Provided

Keywords:

Bipolar Disorder

Antimanic

Placebo Controlled

Randomized

Cytochrome P450

Mania

PKC Inhibitor

Tamoxifen

Recruitment Keywords:

Bipolar

Mania

Manic

BPD

Conditions:

Bipolar Disorder

Investigational Drug(s):

None

Investigational Device(s):

None

Contacts:

Patient Recruitment and Public Liaison Office
Building 61
10 Cloister Court
Bethesda, Maryland 20892-4754
Toll Free: 1-800-411-1222
TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
Fax: 301-480-9793

Electronic Mail:prpl@mail.cc.nih.gov

Citations:

Acute regulation of norepinephrine transport: II PKC-modulated surface expression of human norepinephrine transporter proteins

Tamoxifen administration is associated with a high rate of treatment-limiting symptoms in male breast cancer patients

CYP2D6 status of extensive metabolizers after multiple-dose fluoxetine, fluvoxamine, paroxetine, or sertraline

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Bethesda, Maryland 20892. Last update: 10/15/2004