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Bipolar Disorder Research and New Medicine Trials

Riluzole and Lithium to treat Depression in Bipolar Disorder

This study is currently recruiting patients.

Sponsored by: National Institute of Mental Health (NIMH)
Information provided by: Warren G Magnuson Clinical Center (CC)

Purpose

This study will examine the safety and effectiveness of riluzole (Rilutek trademark) in combination with the lithium, a mood stabilizer, for short-term treatment of depression symptoms, such as depressed mood, psychomotor retardation, and excessive sleeping in patients with bipolar disease. Riluzole is approved by the Food and Drug Administration (FDA) to treat amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease). Preliminary findings of a study using riluzole to treat acute depression in patients with unipolar depression indicate that it may have antidepressant properties in some patients.

Patients between 18 and 80 years of age with bipolar I or II disorder without psychosis may be eligible for this 8-week study. Candidates must be currently depressed, must have had at least one previous major depressive episode, and must have failed to improve with prior treatment with at least one antidepressant. They will be screened with a medical history, physical examination, electrocardiogram (EKG), blood and urine tests, and psychiatric evaluation. A blood or urine sample will be analyzed for illegal drugs. Women of childbearing potential will have a pregnancy test.

After screening, those enrolled in the study will be tapered off all psychiatric medications except lithium, and those who are not taking lithium will be started on the drug. Participants will then begin an 8-week course of treatment, starting with a placebo (a sugar pill formulated to look like the active drug) and, at some point, switching to riluzole. In addition to drug treatment, participants will undergo the following procedures:

- Physical examination and electrocardiogram (EKG) at the beginning and end of the study;

- Weekly check of vital signs (temperature, blood pressure and heart rate);

- Weekly 1-hour interviews consisting of psychiatric and psychomotor rating scales to assess treatment response;

- Weekly blood tests to measure blood levels of riluzole and evaluate drug side effects.

At the end of the study, participants' psychiatric status will be reassessed and appropriate long-term psychiatric treatment arranged.

Condition Phase
Bipolar Disorder
Phase II

MedlinePlus related topics:  Bipolar Disorder

Study Type: Interventional
Study Design: Treatment, Safety/Efficacy

Official Title: An Investigation of the Antidepressant Efficacy of an Antiglutamatergic Agent in Bipolar Depression

Further Study Details: 

Expected Total Enrollment:  25

Study start: February 5, 2003

The treatments for acute unipolar depression have been extensively researched. However, despite the availability of a wide range of antidepressant drugs, clinical trials indicate that 30% to 40% of depressed patients fail to respond to first-line antidepressant treatment, despite adequate dosage, duration, and compliance. Very few studies have examined the efficacy of somatic treatments for the acute phase of bipolar depression. Thus, there is a clear need to develop novel and improved therapeutics for bipolar depression. Recent preclinical studies suggest that antidepressants may exert delayed indirect effects on the glutamatergic system. It is noteworthy that lamotrigine reduces glutamatergic neurotransmission, has antidepressant effects in bipolar depression, and a pilot study has suggested that NMDA antagonists may have antidepressant effects. Together, this data suggests that the glutamatergic system may play a role in the pathophysiology and treatment of depression, and that agents, which more directly reduce glutamatergic neurotransmission, may represent a novel class of antidepressants.

Riluzole, an agent that is FDA-approved for Amyotrophic Lateral Sclerosis has significant antiglutamatergic properties, may prove to have antidepressant properties in depressed patients. In this study, we propose to investigate the potential antidepressant efficacy of riluzole in bipolar depression, an agent which reduces glutamatergic throughput via inhibition of its release.

This is an 8-week single-arm, single-blind add-on study that will examine the efficacy and safety of riluzole in combination with a mood stabilizer in acutely depressed bipolar patients.

The study has two Study Periods. Study Period I is the washout phase that will last 7 days. Study Period II is an add-on 8-week acute treatment phase in which the efficacy and tolerability of riluzole is compared to baseline.

Patients, ages 18 or older with a diagnosis of bipolar disorder I or II current episode depressed (without psychotic features), will in this pilot study (single arm, single-blind) receive riluzole (50-200 mg/day) for a period of 8 weeks. Acute efficacy will be determined by demonstrating a greater response rate using specified criteria.

Approximately 25 patients will enter the study to obtain 22 subjects who complete the 8 weeks of acute riluzole treatment. Therefore if 7/22 patients or greater have greater than 50% improvement on the primary efficacy measure, then based on statistically guidelines from the Optimal Two Stage Design for Clinical Trials, a controlled trial would be indicated to scientifically confirm the signal observed in the single arm trial.

Eligibility

Genders Eligible for Study:  Both

Criteria

INCLUSION CRITERIA:
Male or female subjects, 18-80 years of age.
Female subjects of childbearing potential must be using a medically accepted means of contraception.
Each subject must have a level of understanding sufficient to agree to all required tests and examinations.
Each subject must understand the nature of the study and must sign an informed consent document.
Subjects must fulfill the criteria bipolar I or II disorder, current episode depressed without psychotic features as defined in DSM-IV based on clinical assessment and confirmed by structured diagnostic interview SCID-P.
Subjects must have an initial score at Visit 1 and Visit 2 of at least 20 on the MADRS.
Subjects must not have a decrease in the total score of MADRS of greater than or equal to 20% during washout (between Visits 1 and 2).
Subjects must have experienced, in the opinion of the investigator, at least one previous major depressive episode as defined in DSM-IV (not including the current major depressive episode).
Subjects must be on the therapeutic dose of lithium for 4 weeks prior to Visit 2. If the subject is not taking lithium, the research physician may start them on lithium at the NIH.
EXCLUSION CRITERIA:
Presence of psychotic features.
Participation in a clinical trial of another investigational drug within 1 month (30 days) prior to study entry (visit 1).
Female subjects who are either pregnant or nursing.
Serious, unstable illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease), endocrinologic, neurologic, immunologic, or hematologic disease.
Subjects with uncorrected hypothyroidism or hyperthyroidism.
Abnormal levels of serum transaminases (ALT/SGPT); AST/SGOT), current or past blood dyscrasia.
Documented history of hypersensitivity or intolerance to riluzole.
DSM-IV substance abuse or dependence 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 MAOI, guanethidine, or guanadrel within 1 week or with fluoxetine within 6 weeks prior to Visit 2.
Treatment with any other concomitant medication with primarily CNS activity, other than specified in Appendix A.
Treatment with clozapine or ECT within 12 weeks prior to Visit 2.
Current diagnosis of schizophrenia or other psychotic disorder as defined in the DSM-IV.
Current Axis I Anxiety Disorder.
Judged clinically to be at serious suicidal risk.
Rapid cylers (greater than 6 DSM-IV mood episodes per year) in the past 12 months.

Location and Contact Information


Maryland
      National Institute of Mental Health (NIMH), 9000 Rockville Pike,  Bethesda,  Maryland,  20892,  United States; Recruiting
Patient Recruitment and Public Liaison Office  1-800-411-1222    prpl@mail.cc.nih.gov 
TTY  1-866-411-1010 

More Information

Detailed Web Page

Publications

Altamura CA, Mauri MC, Ferrara A, Moro AR, D'Andrea G, Zamberlan F. Plasma and platelet excitatory amino acids in psychiatric disorders. Am J Psychiatry. 1993 Nov;150(11):1731-3.

Auer DP, Putz B, Kraft E, Lipinski B, Schill J, Holsboer F. Reduced glutamate in the anterior cingulate cortex in depression: an in vivo proton magnetic resonance spectroscopy study. Biol Psychiatry. 2000 Feb 15;47(4):305-13.

Bae HJ, Lee YS, Kang DW, Koo JS, Yoon BW, Roh JK, Gu JS. Neuroprotective effect of low dose riluzole in gerbil model of transient global ischemia. Neurosci Lett. 2000 Nov 10;294(1):29-32.

Study ID Numbers:  030092; 03-M-0092
Record last reviewed:  November 5, 2003
Last Updated:  November 5, 2003
Record first received:  February 6, 2003
ClinicalTrials.gov Identifier:  NCT00054704
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2004-10-27

Bipolar Disorder Study

This study is currently recruiting patients.

Sponsored by: GlaxoSmithKline
Information provided by: GlaxoSmithKline

Purpose

The purpose of this study is to evaluate the safety of the investigational medication in patients with bipolar disorder.

Condition Treatment or Intervention Phase
Bipolar Disorder
 Drug: Investigational Bipolar Disorder Drug
Phase III

MedlinePlus related topics:  Bipolar Disorder

Study Type: Interventional
Study Design: Treatment, Randomized, Double-Blind, Placebo Control, Parallel Assignment, Safety/Efficacy Study

Official Title: A Placebo Controlled Study Evaluating Efficacy and Safety of Medication in Patients with Bipolar Disorder

Eligibility

Ages Eligible for Study:  18 Years and above,  Genders Eligible for Study:  Both

Criteria

Inclusion criteria:

  • Patients must provide written and informed consent
  • Diagnosis of Bipolar I Disorder and currently depressed for minimum of the previous 8 weeks
  • Patients must have been hospitalized for mood disorder or incarceration with or without formal charges as the result of mania related behavior
  • Patients must not be suicidal
  • Patients must not have a history or non-reponse to antidepressant treatment
  • Patients must not have a clinical history of substance dependence in the past year or abuse within the 4 weeks prior to study entry
  • Patients must not have had epilepsy or hypothyroidism

Location and Contact Information


California
      Study Site (4822), Los Angeles,  California,  90048,  United States; No longer recruiting

      Study Site (4820), Beverly Hills,  California,  90210,  United States; Recruiting
Study Coordinator  310-858-7448 

      Study Site (43067), San Diego,  California,  92018,  United States; Recruiting
Study Coordinator  619-688-6565 

      Study Site (26396), Santa Ana,  California,  92705,  United States; Recruiting
Study Coordinator  714-547-4100 

Georgia
      Study Site (67188), Marietta,  Georgia,  30060,  United States; Recruiting
Study Coordinator  770-422-2000 

Indiana
      Study Site (14379), Terre Haute,  Indiana,  47802,  United States; Recruiting
Study Coordinator  812-234-4899 

Kentucky
      Study Site (3889), Florence,  Kentucky,  41042,  United States; No longer recruiting

New Jersey
      Study Site (23059), Princeton,  New Jersey,  08540-2859,  United States; Recruiting
Study Coordinator  609-921-3555  Ext. 20 

New York
      Study Site (2539), New York,  New York,  10021,  United States; Recruiting
Study Coordinator  212-772-3570 

      Study Site (3941), Bronx,  New York,  10467,  United States; Recruiting
Study Coordinator  718-920-4664 

North Carolina
      Study Site (2783), Raleigh,  North Carolina,  27609,  United States; Recruiting
Study Coordinator  919-872-5620 

Ohio
      Study Site (44051), Cleveland,  Ohio,  44106,  United States; No longer recruiting

      Study Site (8907), Beachwood,  Ohio,  44122,  United States; Not yet recruiting
Study Coordinator  216-514-1803 

Oregon
      Study Site (18215), Portland,  Oregon,  92710,  United States; Recruiting
Study Coordinator  503-276-6224 

      Study Site (84054), Eugene,  Oregon,  97401,  United States; Recruiting
Study Coordinator  541-341-6565 

South Carolina
      Study Site (48191), Columbia,  South Carolina,  29201,  United States; Recruiting
Study Coordinator  803-988-0080 

Texas
      Study Site (51542), Houston,  Texas,  77090,  United States; Recruiting
Study Coordinator  281-893-4111 

Wisconsin
      Study Site (6301), Brown Deer,  Wisconsin,  53223,  United States; No longer recruiting

More Information

Study ID Numbers:  SCA30924
Record last reviewed:  September 2004
Record first received:  March 10, 2003
ClinicalTrials.gov Identifier:  NCT00056277
Health Authority: United States: Food and Drug Administration
ClinicalTrials.gov processed this record on 2004-10-27

Seroquel plus Mood Stabilizer Compared to Placebo plus Mood Stabilizer in the Maintenance of Bipolar I Disorder

This study is currently recruiting patients.

Sponsored by: AstraZeneca
Information provided by: AstraZeneca

Purpose

The purpose of this study is to determine whether quetiapine when used as adjunct to lithium or divalproex is safe and effective in the maintenance treatment of adult patients with Bipolar I Disorder. The study consists of enrollment and 2 phases, the Open-label treatment Phase and the Randomized treatment Phase.

Condition Treatment or Intervention Phase
Bipolar Disorder
 Drug: Seroquel®, quetiapine fumarate (atypical antipsychotic)
 Drug: lithium (mood stabilizer)
 Drug: divalproex (mood stabilizer)
Phase III

MedlinePlus related topics:  Bipolar Disorder

Study Type: Interventional
Study Design: Prevention

Official Title: and Safety of Seroquel plus mood stabilizer compared to placebo plus mood stabilizer in the maintenance of Bipolar I disorder

Eligibility

Ages Eligible for Study:  18 Years and above,  Genders Eligible for Study:  Both

Criteria

Inclusion Criteria - Open label Phase:

  • A diagnosis of Bipolar I Disorder, Most Recent Episode Manic (296.4x), or Bipolar I Disorder, Most Recent Episode Depressed (296.5x), or Bipolar I Disorder, Most recent Episode Mixed (296.6x), with or without psychotic features, as defined by Diagnostic and Statistical Manual of Mental Disorders- Fourth Edition (DSM-IV)
  • At least 1 manic, depressed or mixed episode in the 2 years prior to the index episode
  • One of the following: a. A current manic, depressed or mixed episode by DSM-IV criteria. b. A past manic, depressed or mixed episode within 26 weeks as documented by medical records, that was treated with quetiapine and mood stabilizer (lithium or divalproex). Since this episode, treatment with this combination must not have been interrupted for more than 2 weeks continuously.

Inclusion Criteria - Randomized Treatment Phase:

  • Has been prescribed a dose of quetiapine within the range 400 to 800 mg/day and mood stabilizer (lithium or divalproex) for at least 12 weeks.
  • YMRS ≤12 and MADRS ≤ 12 assessed at a minimum of 4 consecutive visits spanning at least 12 weeks, with the allowance of a single excursion. An excursion is defined as a visit in which the YMRS or MADRS (or both) score equals 13 or 14. The excursion may not occur at the last of the consecutive visits.

Exclusion Criteria - Open-label Phase:

  • Diagnosis of an anxiety disorder as defined by DSM-IV, which was treated with medication within the past year
  • Known intolerance or lack of response to quetiapine fumarate or to the assigned mood stabilizer, as judged by the investigator
  • Pregnancy or lactation. Female patients of childbearing potential must have a negative serum human chorionic gonadotropin (HCG) test at enrollment
  • Substance or alcohol dependence at enrollment (except dependence in full remission, and except for caffeine or nicotine dependence), as defined by DSM-IV criteria

Exclusion Criteria - Randomized Treatment Phase:

  • Hospitalization due to a mood event (manic, depressed or mixed) during the Open-label treatment Phase
  • Electroconvulsive therapy (ECT) during the Open-label treatment Phase
  • Attempt to commit suicide or homicide during the Open-label treatment Phase
  • Substance or alcohol dependence (except dependence in full remission, and except for caffeine or nicotine dependence), as defined by DSM-IV criteria

Location and Contact Information

AstraZeneca Information Center (US - 8a-7p EST)      800-236-9933 

Alabama
      Research Site, Birmingham,  Alabama,  United States; Recruiting

Arizona
      Research Site, Scottsdale,  Arizona,  United States; Recruiting

Arkansas
      Research Site, Little Rock,  Arkansas,  United States; Recruiting

California
      Research Site, Anaheim,  California,  United States; Recruiting

      Research Site, Cerritos,  California,  United States; Recruiting

      Research Site, Chula Vista,  California,  United States; Recruiting

      Research Site, Garden Grove,  California,  United States; Recruiting

      Research Site, La Mesa,  California,  United States; Recruiting

      Research Site, Culver City,  California,  United States; Recruiting

      Research Site, Oceanside,  California,  United States; Recruiting

      Research Site, Orange,  California,  United States; Recruiting

      Research Site, Pico Rivera,  California,  United States; Recruiting

      Research Site, Rosemead,  California,  United States; Recruiting

      Research Site, Riverside,  California,  United States; Recruiting

      Research Site, San Diego,  California,  United States; Recruiting

      Research Site, San Francisco,  California,  United States; Recruiting

      Research Site, Santa Ana,  California,  United States; Recruiting

Connecticut
      Research Site, Farmington,  Connecticut,  United States; Recruiting

      Research Site, New Britain,  Connecticut,  United States; Recruiting

Florida
      Research Site, Jacksonville,  Florida,  United States; Recruiting

      Research Site, Miami,  Florida,  United States; Recruiting

      Research Site, Orlando,  Florida,  United States; Recruiting

      Research Site, West Palm Beach,  Florida,  United States; Recruiting

      Research Site, Winter Park,  Florida,  United States; Recruiting

Georgia
      Research Site, Atlanta,  Georgia,  United States; Recruiting

      Research Site, Marietta,  Georgia,  United States; Recruiting

      Research Site, Smyrna,  Georgia,  United States; Recruiting

      Research Site, Decatur,  Georgia,  United States; Recruiting

Hawaii
      Research Site, Honolulu,  Hawaii,  United States; Recruiting

Illinois
      Research Site, Chicago,  Illinois,  United States; Recruiting

      Research Site, Hoffman Estates,  Illinois,  United States; Recruiting

      Research Site, Joliet,  Illinois,  United States; Recruiting

Indiana
      Research Site, Evansville,  Indiana,  United States; Recruiting

      Research Site, Greenwood,  Indiana,  United States; Recruiting

      Research Site, Indianapolis,  Indiana,  United States; Recruiting

Kansas
      Research Site, Wichita,  Kansas,  United States; Recruiting

Kentucky
      Research Site, Florence,  Kentucky,  United States; Recruiting

Louisiana
      Research Site, New Orleans,  Louisiana,  United States; Recruiting

      Research Site, Shreveport,  Louisiana,  United States; Recruiting

      Research Site, Lake Charles,  Louisiana,  United States; Recruiting

Maryland
      Research Site, Baltimore,  Maryland,  United States; Recruiting

      Research Site, Rockville,  Maryland,  United States; Recruiting

Massachusetts
      Research Site, Pittsfield,  Massachusetts,  United States; Recruiting

Michigan
      Research Site, New Baltimore,  Michigan,  United States; Recruiting

Missouri
      Research Site, St. Louis,  Missouri,  United States; Recruiting

New Jersey
      Research Site, Clementon,  New Jersey,  United States; Recruiting

      Research Site, Moorestown,  New Jersey,  United States; Recruiting

      Research Site, West Caldwell,  New Jersey,  United States; Recruiting

New Mexico
      Research Site, Albuquerque,  New Mexico,  United States; Recruiting

New York
      Research Site, Bronx,  New York,  United States; Recruiting

      Research Site, Brooklyn,  New York,  United States; Recruiting

      Research Site, New York,  New York,  United States; Recruiting

North Carolina
      Research Site, Butner,  North Carolina,  United States; Recruiting

      Research Site, Raleigh,  North Carolina,  United States; Recruiting

Ohio
      Research Site, Beachwood,  Ohio,  United States; Recruiting

      Research Site, Cincinnati,  Ohio,  United States; Recruiting

      Research Site, Dayton,  Ohio,  United States; Recruiting

      Research Site, Medina,  Ohio,  United States; Recruiting

Oklahoma
      Research Site, Oklahoma City,  Oklahoma,  United States; Recruiting

      Research Site, Tulsa,  Oklahoma,  United States; Recruiting

Oregon
      Research Site, Eugene,  Oregon,  United States; Recruiting

      Research Site, Portland,  Oregon,  United States; Recruiting

Pennsylvania
      Research Site, Emmaus,  Pennsylvania,  United States; Recruiting

      Research Site, Moon Township,  Pennsylvania,  United States; Recruiting

      Research Site, Philadelphia,  Pennsylvania,  United States; Recruiting

South Carolina
      Research Site, Charleston,  South Carolina,  United States; Recruiting

Tennessee
      Research Site, Memphis,  Tennessee,  United States; Recruiting

Texas
      Research Site, Austin,  Texas,  United States; Recruiting

      Research Site, Dallas,  Texas,  United States; Recruiting

      Research Site, Desoto,  Texas,  United States; Recruiting

      Research Site, Houston,  Texas,  United States; Recruiting

      Research Site, Irving,  Texas,  United States; Recruiting

      Research Site, San Antonio,  Texas,  United States; Recruiting

      Research Site, Wichita Falls,  Texas,  United States; Recruiting

Virginia
      Research Site, Charlottesville,  Virginia,  United States; Recruiting

      Research Site, Falls Church,  Virginia,  United States; Recruiting

      Research Site, Virginia Beach,  Virginia,  United States; Recruiting

      Research Site, Richmond,  Virginia,  United States; Recruiting

Washington
      Research Site, Bellevue,  Washington,  United States; Recruiting

      Research Site, Kirkland,  Washington,  United States; Recruiting

West Virginia
      Research Site, Morgantown,  West Virginia,  United States; Recruiting

Canada
      Research Site, Quebec,  Canada; Recruiting

Canada, Alberta
      Research Site, Edmonton,  Alberta,  Canada; Recruiting

Canada, British Columbia
      Research Site, Vancouver,  British Columbia,  Canada; Recruiting

      Research Site, Victoria,  British Columbia,  Canada; Recruiting

Canada, Manitoba
      Research Site, Winnipeg,  Manitoba,  Canada; Recruiting

Canada, Nova Scotia
      Research Site, Halifax,  Nova Scotia,  Canada; Recruiting

Canada, Ontario
      Research Site, Hamilton,  Ontario,  Canada; Recruiting

      Research Site, Kingston,  Ontario,  Canada; Recruiting

      Research Site, Markham,  Ontario,  Canada; Recruiting

      Research Site, Mississauga,  Ontario,  Canada; Recruiting

      Research Site, Oshawa,  Ontario,  Canada; Recruiting

      Research Site, Toronto,  Ontario,  Canada; Recruiting

Canada, Quebec
      Research Site, Montreal,  Quebec,  Canada; Recruiting

      Research Site, Verdun,  Quebec,  Canada; Recruiting

More Information

Study ID Numbers:  D1447C00127
Record last reviewed:  April 2004
Record first received:  April 9, 2004
ClinicalTrials.gov Identifier:  NCT00081380
Health Authority: United States: Food and Drug Administration
ClinicalTrials.gov processed this record on 2004-10-27

Study of Aripiprazole in Patients with Bipolar I Disorder with a Major Depression Episode

This study is currently recruiting patients.

Sponsored by: Bristol-Myers Squibb
Information provided by: Bristol-Myers Squibb

Purpose

The purpose of this study is to evaluate flexible doses (5-30mg) of aripiprazole versus placebo in patients with bipolar depression.

Condition Treatment or Intervention Phase
Bipolar Disorder
 Drug: Aripiprazole
Phase III

MedlinePlus related topics:  Bipolar Disorder

Study Type: Interventional
Study Design: Treatment, Placebo Control

Official Title: A Placebo-Controlled Study of Aripiprazole in Patients with Bipolar I Disorder with a Major Depression Episode

Eligibility

Ages Eligible for Study:  18 Years   -   65 Years,  Genders Eligible for Study:  Both

Criteria

  • ages 18-65
  • Men and women, who have experienced a prior manic episode that required hospitalization, and now meet criteria for a major depressive episode.

Location and Contact Information

Bristol Myers Squibb Call Center      1-866-892-1BMS  Ext. Locator 121 

Connecticut
      Bristol-Myers Squibb, Wallingford,  Connecticut,  United States; Recruiting
Call Center  1-866-892-1BMS  Ext. Locator 121 

More Information

Study ID Numbers:  CN138-096
Record last reviewed:  October 2004
Record first received:  March 26, 2004
ClinicalTrials.gov Identifier:  NCT00080314
Health Authority: United States: Food and Drug Administration
ClinicalTrials.gov processed this record on 2004-10-27

Examination of Tamoxifen in Acute Mania in Patients with Bipolar I Disorder

This study is currently recruiting patients.

Sponsored by: National Institute of Mental Health (NIMH)
Information provided by: Warren G Magnuson Clinical Center (CC)

Purpose

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.

Condition Phase
Bipolar Disorder
Phase II

MedlinePlus related topics:  Bipolar Disorder

Study Type: Interventional
Study Design: Treatment, Safety/Efficacy

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

Further Study Details: 

Expected Total Enrollment:  50

Study start: November 9, 2001

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

Genders Eligible for Study:  Male

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.

Location and Contact Information


Maryland
      National Institute of Mental Health (NIMH), 9000 Rockville Pike,  Bethesda,  Maryland,  20892,  United States; Recruiting
Patient Recruitment and Public Liaison Office  1-800-411-1222    prpl@mail.cc.nih.gov 
TTY  1-866-411-1010 

More Information

Detailed Web Page

Publications

Apparsundaram S, Schroeter S, Giovanetti E, Blakely RD. Acute regulation of norepinephrine transport: II. PKC-modulated surface expression of human norepinephrine transporter proteins. J Pharmacol Exp Ther. 1998 Nov;287(2):744-51.

Anelli TF, Anelli A, Tran KN, Lebwohl DE, Borgen PI. Tamoxifen administration is associated with a high rate of treatment-limiting symptoms in male breast cancer patients. Cancer. 1994 Jul 1;74(1):74-7.

Alfaro CL, Lam YW, Simpson J, Ereshefsky L. CYP2D6 status of extensive metabolizers after multiple-dose fluoxetine, fluvoxamine, paroxetine, or sertraline. J Clin Psychopharmacol. 1999 Apr;19(2):155-63.

Study ID Numbers:  020037; 02-M-0037
Record last reviewed:  November 5, 2003
Last Updated:  November 5, 2003
Record first received:  November 10, 2001
ClinicalTrials.gov Identifier:  NCT00026585
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2004-10-27

 

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