Study to Determine if Enhancing Glutamate Transporter Function Produces Antidepressant Effects in People With Major Depressive Disorder
- 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.
- To see if diazoxide can quickly improve depressive symptoms in people with treatment-resistant major depressive disorder (MDD).
- Adults 18 to 65 years old with MDD, who are currently depressed without psychotic features.
- 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.
|Study Design:||Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Crossover Assignment
Primary Purpose: Treatment
|Official Title:||A Pathophysiological Study to Determine if Enhancing Glutamate Transporter Function Produces Antidepressant Effects in Patients With Major Depressive Disorder|
- MADRS total score [ Time Frame: 3 weeks ] [ Designated as safety issue: No ]
- 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 ]
|Study Start Date:||January 2014|
|Estimated Study Completion Date:||September 2014|
|Estimated Primary Completion Date:||September 2014 (Final data collection date for primary outcome measure)|
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.
24 individuals with treatment-resistant major depressive disorder.
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.
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT02049385
|Contact: Yamila Carmona||(301) firstname.lastname@example.org|
|Contact: Carlos A Zarate, M.D.||(301) email@example.com|
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Recruiting|
|Bethesda, Maryland, United States, 20892|
|Contact: For more information at the NIH Clinical Center contact Patient Recruitment and Public Liaison Office (PRPL) 800-411-1222 ext TTY8664111010 firstname.lastname@example.org|
|Principal Investigator:||Carlos A Zarate, M.D.||National Institute of Mental Health (NIMH)|