Protocol Number: 07-M-0201

Title:

An Investigation of the Efficacy of the Glutamate Transporter GLT 1 in the Treatment of Bipolar Depression

Number:

07-M-0201

Summary:

This study examines if Ceftriaxone, an antibiotic, will improve symptoms of depression in Bipolar Disorder.

Purpose: This study will examine whether the drug ceftriaxone can help patients with bipolar depression during short-term treatment of symptoms such as depressed mood, psychomotor retardation (slowed down thinking and movements), and problems with sleep. Recent studies suggest that abnormalities in the brain levels of the chemical glutamate may be involved in causing depression. Ceftriaxone increases a protein in the brain called GLT1, which is responsible for regulating brain levels of glutamate.

People between 18 and 65 years of age with bipolar disorder who are currently in a depressive episode of at least 4 weeks but no longer than 12 months duration may be eligible for this study.

Participants are admitted to the NIH Clinical Center for about 10 weeks. During the first 1 to 2 weeks, they are evaluated and tapered off any antidepressant or mood stabilizers they have been taking. They remain free of all medication for 2 weeks and are then randomly assigned to take either ceftriaxone or placebo for 6 weeks. The study drugs are given intravenously (through a vein) every day. To minimize discomfort, patients are given a PICC line - a tube that is inserted in a vein in the arm and remains there for the duration of drug treatment. This prevents the need for repeated intravenous injections.

Patients have a physical examination at the beginning and at the end of the study and two electrocardiograms (ECG) during the study. They are evaluated periodically with a series of psychiatric rating scales to determine the effects of the study drug on mood and thinking and they have periodic blood tests to assess their health status.

In addition, patients are asked to undergo a lumbar puncture (spinal tap) twice during the study to collect a sample of cerebrospinal fluid (CSF, the fluid that bathes the brain and spinal cord). The CSF is examined to try to understand how brain chemicals are related to depression and to the effects of ceftriaxone. A local anesthetic is given and a needle is inserted in the space between the bones in the lower back where the CSF circulates below the spinal cord. A small amount of fluid is collected through the needle. This test is optional.

At the end of the study patients are offered free treatment for up to 3 months with standard medications for bipolar depression and a referral to a community physician for long-term treatment will be made.

Sponsoring Institute:

National Institute of Mental Health (NIMH)

Recruitment Detail

Type: Participants currently recruited/enrolled

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): Children

Eligibility Criteria:

INCLUSION CRITERIA

Male or female subjects, 18 to 65 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 for 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 have an initial score at Visit 1 and Visit 2 of less than or equal to 12 on the YMRS.

Current duration of depressive episode should be at least 4 weeks (full criteria) but no longer than 12 months in duration.

For Bipolar II, subjects must have experienced, in the opinion of the investigator, at least two previous hypomanic and two major depressive episodes as defined in DSM-IV.

EXCLUSION CRITERIA

Presence of psychotic features.

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.

Current or past colitis.

Subjects with uncorrected hypothyroidism or hyperthyroidism.

Clinically significant abnormal laboratory tests.

Current or past blood dyscrasia.

Documented history of hypersensitivity or intolerance to penicillins, cephalosporins or ceftriaxone.

Subjects who are immunocompromised.

DSM-IV substance abuse or dependence within the past 90 days.

Current or past seizure disorder.

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 5 weeks prior to Visit 2.

Treatment with any other concomitant medication with primarily CNS activity, other than specified in Appendix A of the protocol.

Treatment with clozapine or ECT within 4 weeks prior to Visit 2.

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

Diagnosed with an axis I disorder other than bipolar disorder that was the primary focus of treatment within 6 months before the screening.

MADRS score of greater than 4 on item 10 (active suicidal plan).

Special Instructions:

Currently Not Provided

Keywords:

Ceftriaxone

Acute Antidepressant Effects

Glutamatergic System

Double-Blind

Mood Disorders

Recruitment Keyword(s):

Bipolar Disorder

Depression

Mood Disorders

Condition(s):

Bipolar Disorder

Investigational Drug(s):

Ceftriaxone

Investigational Device(s):

None

Intervention(s):

Drug: Ceftriaxone

Supporting Site:

National Institute of Mental Health

Contact(s):

Libby Jolkovsky
National Institutes of Health
Building 10
Room 7-5563
10 Center Drive
Bethesda, Maryland 20892
Phone: (877) 646-3644
Fax: (301) 402-9360
Electronic Address: libby_jolkovsky@nih.gov

Citation(s):

Bannerman DM, Good MA, Butcher SP, Ramsay M, Morris RG. Distinct components of spatial learning revealed by prior training and NMDA receptor blockade. Nature. 1995 Nov 9;378(6553):182-6.

Benoit E, Escande D. Riluzole specifically blocks inactivated Na channels in myelinated nerve fibre. Pflugers Arch. 1991 Dec;419(6):603-9.

Bittner MJ, Dworzack DL, Preheim LC, Tofte RW, Crossley KB. Ceftriaxone therapy of serious bacterial infections in adults. Antimicrob Agents Chemother. 1983 Feb;23(2):261-6.

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