Bipolar DisorderPhase 2NCT00512616
A Glutamate Transporter GLT1, in the Treatment of Bipolar Disorder
A Phase 2 study testing Ceftriaxone in people with Bipolar Disorder, run by National Institute of Mental Health (NIMH) at 1 site in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Bipolar Disorder
- What is being tested?
- Ceftriaxone
- How many people
- 0 participants
- Where
- 1 siteUnited States
- Study dates
- 1 Aug 2007to 15 Sep 2009
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Show all 9Show fewer
- 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.
Who cannot join
- 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.
Show all 18Show fewer
- 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).
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
Official title: An Investigation of the Efficacy of the Glutamate Transporter GLT 1 in the Treatment of Bipolar Depression
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.
Read more
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.
Read the 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.
- Conditions
- Bipolar Disorder
- Being tested
- Ceftriaxone
- Keywords
- Ceftriaxone, Acute Antidepressant Effects, Glutamatergic System, Double-Blind, Mood Disorders, Bipolar Disorder, Depression
- Medical subject headings
- Bipolar Disorder, Mood Disorders, Depression
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
CeftriaxoneDrug
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 6-weeks
Secondary outcomes (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.
Measured: 6-weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Aug 2007 (estimated)
- Study start1 Aug 2007
- Primary completion15 Sep 2009
- Study completion15 Sep 2009 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Bipolar DisorderStudies of the same condition, open and under way.
- More trials run by National Institute of Mental Health (NIMH)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Institute of Mental Health (NIMH)
- Sponsor type
- US National Institutes of Health
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00512616
- Sponsor's protocol ID
- 070201
- Other IDs
- 07-M-0201
- Status last verified
- 15 Sep 2009
- First submitted
- 4 Aug 2007
- Last updated
- 2 Jul 2017
- Results posted
- No
Publications
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. doi: 10.1038/378182a0.
PubMed 7477320Benoit E, Escande D. Riluzole specifically blocks inactivated Na channels in myelinated nerve fibre. Pflugers Arch. 1991 Dec;419(6):603-9. doi: 10.1007/BF00370302.
PubMed 1664937Bittner 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. doi: 10.1128/AAC.23.2.261.
PubMed 6301365
Study at a glance
From the registry record, last updated by the sponsor on 2 Jul 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- An Investigation of the Efficacy of the Glutamate Transporter GLT 1 in the Treatment of Bipolar Depression
- ClinicalTrials.gov ID
- NCT00512616
- Acronym / sponsor ID
- 070201
- Conditions
- Bipolar Disorder
- Keywords
- Ceftriaxone, Acute Antidepressant Effects, Glutamatergic System, Double-Blind, Mood Disorders, Bipolar Disorder, Depression
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Withdrawn
- Enrolment
- 0 participants (actual)
- Lead sponsor
- National Institute of Mental Health (NIMH)US National Institutes of Health
- Study start
- 1 Aug 2007
- Primary completion
- 15 Sep 2009 (actual)
- Study completion
- 15 Sep 2009 (estimated)
- First posted
- 7 Aug 2007 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (9 listed)
- 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.
Key exclusion criteria (18 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Ceftriaxone | Drug | – |
Primary outcome
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
1 secondary outcome
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
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Jul 2017.
- Background: PubMed 7477320Bannerman 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. doi: 10.1038/378182a0.
- Background: PubMed 1664937Benoit E, Escande D. Riluzole specifically blocks inactivated Na channels in myelinated nerve fibre. Pflugers Arch. 1991 Dec;419(6):603-9. doi: 10.1007/BF00370302.
- Background: PubMed 6301365Bittner 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. doi: 10.1128/AAC.23.2.261.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Ceftriaxone in people with Bipolar Disorder, run by National Institute of Mental Health (NIMH) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 18 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 2 Jul 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00512616, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Jul 2017.