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Home > "E" Clinical Trials Conditions > Examination of Tamoxifen in Acute Mania in Patients with Bipolar I Disorder  Examination of Tamoxifen in Acute Mania in Patients with Bipolar I Disorder
Examination of Tamoxifen in Acute Mania in Patients with Bipolar I Disorder
For Condition: Bipolar Disorder
Status: Recruiting
Sponsor(s): National Institute of Mental Health (NIMH) ,
Synopsis: 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.
Details: Bipolar Disorder (BD) is a severe, chronic and often life-threatening illness. 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 mood 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. 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, a synthetic nonsteroidal antiestrogen, has been widely used in the treatment of breast cancer. Tamoxifen's potent inhibitory effects on PKC are striking. Recently, our group conducted the first open-label study with tamoxifen in acute mania. In this study, tamoxifen 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 efficacy of tamoxifen monotherapy in acute mania has not yet been evaluated in a randomized, double blind, placebo-controlled study. Male patients, ages 18 to 60, with a diagnosis of bipolar I disorder manic or mixed, will be randomized to double-blind treatment to receive either tamoxifen (20-140 mg/day) or placebo, for a period of 3-weeks. Approximately 50 patients with acute mania will be enrolled in the study. Biochemical measures and brain imaging will be obtained during the study.
Eligibility:
Study Type: Interventional, Treatment, Safety/Efficacy
Minimum Age/Maximum Age: /
Genders: Male
Protocol Entry 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.
Total Enrollment: 50
Location and Contact Information:
National Institute of Mental Health (NIMH) *Recruiting*
Bethesda, Maryland, 20892
United States
Recruiting Patient and Public Liaison Office 1-800-411-1222
Additional Information:
Study ID Numbers: 020037; 02-M-0037
Study Start Date: November 9, 2001
Record last reviewed: November 5, 2003
Additional information available at: clinicaltrials.gov
Clinicaltrials.gov Reference link: NCT00026585
Other Bipolar Disorder Studies:
1. Effects of Sex Hormones on Circadian Rhythm in Men and Women
2. Clinical Trial of Mifepristone for Bipolar Depression
3. Safety and Efficacy Trial of the Use of Quetiapine Fumarate (SEROQUEL®) in the Treatment of Patients with Bipolar Depression
4. Brain Tissue Collection for Neuropathological Studies
5. Depakote Monotherapy, Olanzapine Monotherapy, and Combination Therapy of Depakote Plus Olanzapine in Stable Subjects during the Maintenance Phase of Bipolar Illness
Related Studies:
Other Bipolar Disorder Clinical Trials
Other Maryland Clinical Trials
Other Bethesda Clinical Trials
Examination of Tamoxifen in Acute Mania in Patients with Bipolar I Disorder
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