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

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 helplessness 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 to 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 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 depressive disorder.

Study Population:

24 individuals with treatment-resistant major depressive disorder.

Design:

Male and female patients diagnosed with MDD, ages 18 to 65 years, currently experiencing a major depressive episode, will be recruited for this study. The study will comprise the double-blind crossover administration of either diazoxide (200-400 mg/day given orally) or placebo. The study will assess the efficacy of three 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 (as measured by decreases in Montgomery-Asberg Depression Rating Scale (MADRS) total scores) in response to diazoxide in patients with treatment-resistant MDD; and 2) examining other potential biomarkers of response.

Outcome Measures:

Primary: MADRS total score. Secondary outcome measures: proportion of subjects achieving remission (MADRS score less than or equal to 10) and response (more <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 (HAM-D), Visual Analog Scale (VAS), and the Columbia Suicide Severity Rating Scale (C-SSRS) total scores.

• Diazoxide (Drug): A nondiuretic vasodilator thiazide-related agent
• Placebo (Drug): Placebo

Primary outcomes

• MADRS Change at Day 7 [7 days]: 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.

Sex: All, ages: 18 Years to 65 Years

* 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 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).

EXCLUSION CRITERIA:

* 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.
* Treatment with clozapine or ECT within one 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 to respond to two adequate antidepressant trials (may be from the same chemical class). Adequacy of antidepressant trials will be determined via the clinician administered modified ATHF.

Participant flow

Outcome results

• MADRS Change at Day 7 (Primary), Median, percentage of change in units of scale: Diazoxide 0 (0 to 100); Placebo 10 (0 to 100)

Adverse events

Time frame: 12 weeks

Other adverse events by term

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.

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• Carlos A Zarate, M.D., Principal investigator, National Institute of Mental Health (NIMH)