Study to Determine if Enhancing Glutamate Transporter Function Produces Antidepressant Effects in People With Major Depressive Disorder

This study is currently recruiting participants. (see Contacts and Locations)
Verified November 2013 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Mental Health (NIMH) )
ClinicalTrials.gov Identifier:
NCT02049385
First received: January 28, 2014
Last updated: July 31, 2014
Last verified: November 2013

January 28, 2014
July 31, 2014
January 2014
September 2016   (final data collection date for primary outcome measure)
MADRS total score [ Time Frame: 3 weeks ] [ Designated as safety issue: No ]
Same as current
Complete list of historical versions of study NCT02049385 on ClinicalTrials.gov Archive Site
  • Proportion of subjects achieving remission (MADRS less than/equal to 10) & amp; response (MADRS more than/equal to 50%) change from baseline in Beck Depression Inventory, Hamilton Anxiety Rating Scale, & amp; Hamilton Depression Rating... [ Time Frame: 3 weeks ] [ Designated as safety issue: No ]
  • Imaging and electrophysiological (MRS, MEG, EEG), pharmacokinetic and pharmacodynamic measures, BDNF and other neurochemicals [ Time Frame: 3 weeks ] [ Designated as safety issue: No ]
Proportion of subjects achieving remission (MADRS less than/equal to 10) & response (MADRS more than/equal to 50%) change from baseline in Beck Depression Inventory, Hamilton Anxiety Rating Scale, & Hamilton Depression Rating Scale. [ Time Frame: 3 weeks ] [ Designated as safety issue: No ]
Not Provided
Not Provided
 
Study to Determine if Enhancing Glutamate Transporter Function Produces Antidepressant Effects in People With Major Depressive Disorder
A Pathophysiological Study to Determine if Enhancing Glutamate Transporter Function Produces Antidepressant Effects in Patients With Major Depressive Disorder

Background:

- Depressed people appear to have problems regulating levels of a brain chemical called glutamate than people who are not depressed. The drug diazoxide may help regulate glutamate levels in people with depression. Researchers want to know if it can rapidly improve depression symptoms. This would help many people with depression, because most medications take a long time to work.

Objectives:

- To see if diazoxide can quickly improve depressive symptoms in people with treatment-resistant major depressive disorder (MDD).

Eligibility:

- Adults 18 to 65 years old with MDD, who are currently depressed without psychotic features.

Design:

  • Participants will be hospitalized for the entire study, 11 13 weeks. They may be allowed short leaves. Participants will be interviewed many times during the study. They will also fill out questionnaires.
  • Phase I will last about 4 weeks.

< TAB> - Participants will be screened with lab tests, and psychiatric and medical history and exams.

< TAB> - Participants will slowly go off current medications. They will be drug-free for 2 weeks.

  • Phase II will last about 8 to 9 weeks.
  • Participants will be monitored, answer questions, and give blood samples. They will drink a glucose drink, give saliva samples, and have scans of their brains taken.
  • Participants will take the study drug daily by mouth for one 3-week session.
  • They will take a placebo daily by mouth for the other 3-week session.
  • There will be a drug-free period of 14 to 21 days between sessions.

Objective:

To date, available pharmacological treatments for major depressive disorder (MDD) have proven to be only modestly effective during the acute phase. We have been systematically testing different glutamatergic modulators in patients with mood disorders in order to develop improved therapeutics. A recent report found that the (beta)-lactam antibiotic ceftriaxone increased glutamate uptake by increasing GLT1(EAAT2) function, and had antidepressant-like effects in animal models. Using the learned helpless model of depression we developed outbred lines, defined a new anatomy of helplessness, and determined that synaptic loss due to excess extracellular glutamate appears to be involved in the pathophysiology of helplessness; these animals show a 40% decrease in EAAT2 astrocytic transporter expression. Together, these data suggest that astrocytic glutamate reuptake systems may be central in the pathophysiology and treatment of depression, and that agents that directly increase astrocytic glutamate uptake may represent a novel class of antidepressants.

With this protocol, we propose to test a specific, new mechanism that uses diazoxide to chronically increase the expression of the glutamate transporter EAAT2, resulting in removal of glutamate from the synaptic cleft. Diazoxide enhances glutamate uptake in glia by activating ATP-sensitive potassium (KATP) channels. We expect that this effect will reduce excessive glutamate transmission and be associated with acute antidepressant effects. The model presented here is a clinically testable one. If successful, it may lead to the development of a group of novel pharmacological treatments for major depression.

Study Population:

24 individuals with treatment-resistant major depressive disorder.

Design:

Male and female patients, ages 18 to 65 years, with a diagnosis of MDD, currently in an episode of major depression, will be recruited for this study. This study will consist of the double-blind crossover administration of either diazoxide (200-400 mg/day given orally) or placebo. The study will assess the efficacy of 3 weeks of a glutamate transporter enhancer (diazoxide, 200-400 mg/day given orally) compared with placebo in improving overall depressive symptomatology in patients with treatment-resistant MDD. Other aims of the study include: 1) determining whether changes in brain neurochemicals (glutamate) correlate with antidepressant response (decrease in Montgomery Asberg Depression Rating Scale (MADRS) total scores) to diazoxide in patients with treatment-resistant MDD, and 2) examine other biomarkers of response.

Outcome Measures:

Primary: MADRS total score. Secondary outcome measures: Proportion of subjects achieving remission (MADRS less than or equal to 10) and response (less than or equal to 50% reduction from baseline in MADRS total score); change from baseline in Beck Depression Inventory (BDI), Hamilton Anxiety Rating Scale (HAM-A), Hamilton Depression Rating Scale (HDRS), Visual Analog Scale (VAS), and the Columbia Suicide Severity Rating Scale (C-SSRS) total scores.

Interventional
Phase 1
Phase 2
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Depression
  • Drug: Diazoxide
    A nondiuretic vasodilator thiazide related agent
  • Drug: Placebo
    N/A
  • Experimental: Diazoxide
    Three weeks of 200-400 mg/day of diazoxide, a KATP channel activator. Patients.
    Intervention: Drug: Diazoxide
  • Experimental: Placebo
    Three weeks of 200-400 mg/day of placebo administered orally by mouth
    Intervention: Drug: Placebo
  • Experimental: Placebo 2
    Three weeks of 200-400 mg/day of placebo administered orally by mouth
    Intervention: Drug: Placebo
  • Experimental: Placebo 3
    Three weeks of 200-400 mg/day of placebo
    Intervention: Drug: Placebo
  • Experimental: Diazoxide 2
    Three weeks of 200-400 mg/day of diazoxid administered orally
    Intervention: Drug: Diazoxide
  • Experimental: Placebo 4
    Three weeks of 200-400 mg/day of diazoxide
    Intervention: Drug: Placebo
  • Placebo Comparator: Placebo 5
    Three weeks of 200-400 mg/day of diazoxide
    Intervention: Drug: Placebo

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
24
September 2016
September 2016   (final data collection date for primary outcome measure)
  • INCLUSION CRITERIA:

    • 18 to 65 years of age.
    • Women of child bearing potential must have a negative serum pregnancy test and confirmed (by the investigator) use of 2 effective methods of contraception (see below).
    • Each subject must be capable of understanding all required tests and examinations and sign an informed consent document.
    • Subjects must fulfill DSM-IV criteria for MDD, single episode or recurrent without psychotic features, based on clinical assessment and confirmed by a structured diagnostic interview (SCID-P). Subjects must be experiencing a current major depressive episode of at least 4 weeks duration.
    • Subjects must have an initial score of at least 20 on the MADRS at screening and at baseline of study phase I.
    • Subjects must have a current or past history of lack of response to two adequate antidepressant trials (may be from the same chemical class) operationally defined using the modified-Antidepressant Treatment History Form (ATHF).

EXCLUSION CRITERIA:

  • Current psychotic features or a diagnosis of schizophrenia or any other psychotic disorder as defined in the DSM-IV.
  • Subjects with a history of DSM-IV drug or alcohol dependency or abuse (except for caffeine or nicotine dependence) within the preceding 3 months.
  • Head injury that results in loss of consciousness exceeding 5 minutes (for the imaging component of the study).
  • Subjects with a DSM IV Axis II diagnosis of borderline or antisocial personality disorder.
  • Pregnant or nursing women or women of child bearing potential not using 2 medically accepted means of contraception (to include oral, injectible, or implant birth control, condom, diaphragm with spermicide, intrauterine devices (IUD), tubal ligation, abstinence or partner with vasectomy).
  • Serious, unstable illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease), endocrinologic, neurologic, immunologic, or hematologic disease.
  • Subjects with hyperthyroidism or clinical hypothyroidism.
  • Subjects with one or more seizures without a clear and resolved etiology.
  • Clinically significant abnormal laboratory tests (including blood glucose).
  • Diabetes
  • Fasting plasma glucose concentration > 120 mg/dl
  • Upright blood pressure < 60mmHg on three occasions 30 minutes apart (based on scheduled research measurements).
  • Treatment with a reversible MAOI within 4 weeks of study phase II.
  • Treatment with fluoxetine within 5 weeks of study phase II.
  • Treatment with any other disallowed concomitant medication 14 days before randomization.
  • Treatment with clozapine or ECT within 1 month of randomization.
  • Lifetime history of deep brain stimulation.
  • Subjects who, in the investigator s judgment, pose a current serious suicidal or homicidal risk.
  • Positive HIV test
  • Contraindications to MRI (metal in body, claustrophobia, etc)

No structured psychotherapy will be permitted during the study.

Definition of treatment-resistance

All subjects are required to have previously failed two adequate antidepressant trials (may be from the same chemical class). Adequacy of antidepressant trials will be determined with the modified ATHF.

Both
18 Years to 65 Years
No
Contact: Yamila Carmona (301) 402-9348 carmonay@mail.nih.gov
Contact: Carlos A Zarate, M.D. (301) 451-0861 zaratec@mail.nih.gov
United States
 
NCT02049385
140041, 14-M-0041
Not Provided
National Institutes of Health Clinical Center (CC) ( National Institute of Mental Health (NIMH) )
National Institute of Mental Health (NIMH)
Not Provided
Principal Investigator: Carlos A Zarate, M.D. National Institute of Mental Health (NIMH)
National Institutes of Health Clinical Center (CC)
November 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP