Does Enhanced Glutamate Transporter Function Produce Antidepressant Effects in People With Major Depression?

NCT02049385 | Terminated Phase 1 Results DMC FDA Drug

• 2 other identifiers: 14004114-M-0041
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief Summary

Background: \- At least one third of individuals with major depressive disorder (MDD) remain treatment-refractory after receiving currently available antidepressants underscoring the urgent need for new antidepressant therapies. Of the novel pharmacotherapeutic strategies seeking to rapidly alleviate depressive symptoms, glutamatergic modulators have emerged as promising potential targets. The present study sought to examine the potassium (KATP) channel activator diazoxide as a possible treatment for MDD. Diazoxide increases glutamate uptake from the synaptic cleft by activating the KATP channel to chronically increase expression of the excitatory amino acid transporter (EAAT)-2 system in glial cells. Diazoxide is FDA-approved for the treatment of sulfonylurea-induced hypoglycemia, hypoglycemia due to hyperinsulinemia, and hypertension. Objectives: \- To assess the ability of diazoxide, potassium channel activator, to improve overall depressive symptomatology in patients with treatment-resistant MDD currently experiencing a major depressive episode. The efficacy of a three-week course of diazoxide will be compared to three weeks of placebo. The MADRS will serve as the main outcome measure Eligibility: \- Adults 18 to 65 years old with MDD who are currently depressed without psychotic features. Design:

• Study Phase I (Day -28 to 0): \-- Screen and taper off medications (Days -28 to -14): Prior to consenting to this study, subjects will have undergone a screening consisting of laboratory tests, psychiatric and medical history, and psychiatric and physical examinations under protocol 01-M-0254, "The Evaluation of Patients with Mood and Anxiety Disorders and Healthy Volunteers". After consenting to this study, patients will be tapered off medications. Medications allowed and not allowed are listed in Appendix 1. Patients will be reminded to report all drugs, OTC products, and other agents to the investigators so that they can screen to avoid interactions that might make participation unsafe or might confound the research results. Patients are expected to meet all inclusion and exclusion criteria before medications are tapered (which is usually 1-2 weeks long). Subjects who are not taking medications will enter the drug-free period directly. All participants must have a score of ≥20 on the MADRS at screening and baseline of Study Phase I. Subjects who do not have a score of ≥20 on the MADRS by the end of Study Phase I will be excluded and will receive standard treatment.
• Drug-free period (Day -14 to day 0): \-- Subjects will begin a 2-week drug-free period prior to the administration of diazoxide or placebo.
• Study Phase II (Day 0 to 56):
• In this study phase, subjects will be blindly randomized to receive either diazoxide 200-400 mg/day (given BID) or a placebo administered daily by mouth for three weeks. All patients except those who have a 50% or greater decrease in MADRS from baseline at the end of the first cross over point will cross over. To avoid carry-over effects between the different test sessions, there will be an interval of 14-21 days, pending response to test session 1. Subjects will then be blindly crossed over to the second experimental condition (either diazoxide or placebo) for another three weeks. All subjects who discontinue the study or who complete study phase II will then receive either clinical treatment or the opportunity to participate in another research protocol. Patients maintaining response to treatment condition 1 after two weeks will receive an additional one week washout before being crossed over to condition 2.The total duration of the study is approximately 11-13 weeks. The duration of Study Phase I including the 14-day drug-free period is approximately 4 weeks. Study phase II is 8-9 weeks long. Thus, the total duration of the study is approximately 11-13 weeks, except for those patients who were unmedicated at time of entry into the study and therefore do not need to undergo the initial tapering off medications. Subjects will be required to be hospitalized during the entire study. Passes will be permitted if the subject is clinically stable and the pass does not interfere with the study or unit procedures.

Conditions

Depression

Keywords

Glutamate; Pathophysiology; Depression; Treatment

Outcome Measures

Primary Outcomes (1)

• MADRS Change at Day 7

  Change in Montgomery Asberg Depression Rating Scale (MADRS) from baseline to 7 days post-treatment. The range of values is from 0 - 60, with a higher score indicating increased depressive symptoms. A score of 7-19 indicates mild depression; 20-34 indicates moderate depression; \>34 indicates severe depression.

  7 days

Study Arms (2)

Diazoxide

EXPERIMENTAL

Subjects received 200-400 mg daily of diazoxide orally for three weeks; the dose was, adjusted depending on side effects and response.

Drug: Diazoxide

Placebo

EXPERIMENTAL

Subjects received a matched placebo for three weeks

Drug: Placebo

Interventions

Diazoxide DRUG

A nondiuretic vasodilator thiazide-related agent

Diazoxide

Placebo DRUG

Placebo

Placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• to 65 years of age.
• Women of child bearing potential must have a negative serum pregnancy test and confirmed (by the investigator) use of two effective methods of contraception (see below).
• Each subject must be capable of understanding all required tests and examinations and must 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 four 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).

You may not qualify if:

• Current psychotic features or a current or past 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 three months.
• Head injury that results in loss of consciousness exceeding five 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 two medically accepted means of contraception (including oral, injectable, or implant birth control, condoms, a diaphragm with spermicide; intrauterine devices (IUD); tubal ligation; abstinence; or partner with vasectomy).
• Serious, unstable medical 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 diastolic blood pressure \<60mmHg on three occasions 30 minutes apart (based on scheduled research measurements).
• Treatment with a reversible MAOI within four weeks of study Phase II.
• Treatment with fluoxetine within five weeks of study Phase II.
• Treatment with any other disallowed concomitant medication 14 days before randomization.

Sponsors & Collaborators

• National Institute of Mental Health (NIMH): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• Aitken RC. Measurement of feelings using visual analogue scales. Proc R Soc Med. 1969 Oct;62(10):989-93. doi: 10.1177/003591576906201005. No abstract available.

  PMID: 4899510 BACKGROUND

• Akhondzadeh S, Mojtahedzadeh V, Mirsepassi GR, Moin M, Amini-Nooshabadi H, Kamalipour A. Diazoxide in the treatment of schizophrenia: novel application of potassium channel openers in the treatment of schizophrenia. J Clin Pharm Ther. 2002 Dec;27(6):453-9. doi: 10.1046/j.1365-2710.2002.00445.x.

  PMID: 12472985 BACKGROUND

• 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. doi: 10.1176/ajp.150.11.1731.

  PMID: 8214185 BACKGROUND

MeSH Terms

Conditions

Depression

Interventions

Diazoxide

Condition Hierarchy (Ancestors)

Behavioral Symptoms; Behavior

Intervention Hierarchy (Ancestors)

Benzothiadiazines; Sulfonamides; Sulfones; Sulfur Compounds; Organic Chemicals; Thiazides; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Limitations and Caveats

As only 1 participant completed both treatment arms, no formal statistical analysis of the primary outcome (MADRS) possible. Study halted due to severe side effects \& lack of target (KATP channel) engagement measured by insulin sensitivity index.

Results Point of Contact

• Title: Zarate, Carlos
• Organization: National Institute of Mental Health

zaratec@mail.nih.gov

+1 301 451 0861

Study Officials

• Carlos A Zarate, M.D.

  National Institute of Mental Health (NIMH)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 28, 2014
• First Posted: January 30, 2014
• Study Start: January 3, 2014
• Primary Completion: July 21, 2016
• Study Completion: July 21, 2016
• Last Updated: October 13, 2017
• Results First Posted: October 13, 2017

Record last verified: 2017-07

Locations

US (1)