A Glutamate Transporter GLT1, in the Treatment of Bipolar Disorder

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00512616
Recruitment Status : Withdrawn
First Posted : August 7, 2007
Last Update Posted : July 2, 2017
Information provided by:
National Institutes of Health Clinical Center (CC)

Brief 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.

Condition or disease Intervention/treatment Phase
Bipolar Disorder Drug: Ceftriaxone Phase 2

Detailed Description:

Bipolar affective disorder (BPD, manic-depressive illness) is a common, severe, chronic and often life-threatening illness. Increasingly, it is being recognized that it is the depressive phase of the illness, which contributes much of the morbidity and mortality. To date, only a few of the available somatic treatments have been proven to be effective 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. Clinical data suggests that glutamatergic modulators may have antidepressant effects in humans. We first tested the glutamatergic modulator riluzole, an inhibitor of glutamate release and enhancer of glutamate reuptake in astrocytes and found it to have antidepressant properties in patients with treatment-resistant major depression and bipolar depression. In a recent study, we found that a single intravenous dose of the non-competitive NMDA antagonist ketamine produced a rapid and relatively sustained antidepressant effect in patients with treatment-resistant major depression. A recent report found that the Beta-lactam antibiotic ceftriaxone increased uptake of glutamate via increased GLT1 function (Rothstein et al 2005) and had antidepressant-like effects in animal models (Mineur et al 2006). Together, these data suggest 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.

We propose to expand our previous findings on the efficacy of glutamatergic modulators in patients with unipolar and bipolar depression by testing a specific, new mechanism where by we use ceftriaxone to chronically increase the expression of the glutamate transporter GLT1 in order to facilitate the removal of glutamate from the synaptic cleft in an effort to reduce excessive glutamate transmission and as a result produce acute antidepressant effects. The model presented here is a clinical testable one, and one that, if successful, holds the potential to develop a group of novel pharmacological treatments for major depression.

Patients, ages 18 to 65, with a diagnosis of bipolar depression (without psychotic features), will be randomized to double-blind treatment to receive either ceftriaxone (1-4 g/day) or placebo intravenously for a period of 6 weeks. Acute efficacy will be determined by demonstrating a greater response rate using specified criteria. Approximately 86 patients with bipolar depression will be enrolled in the study.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: An Investigation of the Efficacy of the Glutamate Transporter GLT 1 in the Treatment of Bipolar Depression
Study Start Date : August 1, 2007
Actual Primary Completion Date : September 15, 2009
Estimated Study Completion Date : September 15, 2009

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Bipolar Disorder
U.S. FDA Resources

Primary Outcome Measures :
  1. Assess the efficacy of acute ceftriaxone therapy compared with placebo in pts with bipolar disorder current episode depressed w/o psychotic features, in improving overall depressive symptomatology. [ Time Frame: 6-weeks ]

Secondary Outcome Measures :
  1. Assess the efficacy of acute ceftriaxone therapy compared with placebo in pts with bipolar disorder current episode depressed w/o psychotic features, in improving overall depressive symptomatology. [ Time Frame: 6-weeks ]

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.


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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00512616

United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
National Institute of Mental Health (NIMH)

Responsible Party: Carlos A. Zarate, M.D./National Institute of Mental Health, National Institutes of Health Identifier: NCT00512616     History of Changes
Other Study ID Numbers: 070201
First Posted: August 7, 2007    Key Record Dates
Last Update Posted: July 2, 2017
Last Verified: September 15, 2009

Keywords provided by National Institutes of Health Clinical Center (CC):
Acute Antidepressant Effects
Glutamatergic System
Mood Disorders
Bipolar Disorder

Additional relevant MeSH terms:
Bipolar Disorder
Pathologic Processes
Bipolar and Related Disorders
Mental Disorders
Anti-Bacterial Agents
Anti-Infective Agents