Clinical trial NCT02149836
Conditions: Major Depressive Disorder Depression
Keywords: major depressive disorder depression treatment resistent depression
Sponsor: Icahn School of Medicine at Mount Sinai
Start date: 2014-08-01; Completion date: 2016-12-01
Enrollment: 18 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to test the antidepressant effects of Ezogabine in major depressive disorder (MDD). The investigators also aim to determine the safety and tolerability Ezogabine in patients with MDD. The investigators hypothesize that depressive symptoms will be significantly decreased following an 8-week treatment period of the medication compared to baseline.

Detailed description:
Study Introduction:

Major depressive disorder (MDD) is a global health disease associated with significant morbidity and costs. Many anti-depressants exist within the monoaminergic system yet novel therapeutics are still needed outside of this system. Ezogabine, currently approved by the FDA for adjunctive treatment of partial-onset seizures, may serve as a potential key agent for those with MDD. Ezogabine is known to bind to and activate KCNQ transmembrane K+ ion channels, specifically targeting KCNQ2 in the VTA. Such membrane activity has been show to play a role in previous studies involving a social defeat model of depression. Specifically, data has shown that KCNQ channels were upregulated only in resilient mice and moreover, ezogabine was able to potentiate KCNQ channel activity to result in a fast reversal of the depressed phenotype.

General Investigational Plan:

Objectives:

A. Primary Efficacy Objective: To test the antidepressant effects of Ezogabine in MDD.

B. Primary Safety Objective: To characterize the safety and tolerability of Ezogabine in patients with MDD.

C. Secondary Objectives: To measure the effects of Ezogabine on ventral tegmental area (VTA)-striatal reward circuitry in MDD using reward task-based functional MRI. Rationale: Ezogabine is hypothesized to modulate the firing rate of VTA dopamine (DA) neurons and thereby influence the functioning of the mesolimbic reward system.

Hypotheses

A. Efficacy Hypothesis:

Hypothesis 1a: Depressive symptoms will be significantly decreased following an 8-week treatment period compared to baseline, as measured by change in Montgomery-Åsberg Depression Rating Scale (MADRS).

Hypothesis 1b: The antidepressant response rate at study end (defined as 50% in depressive symptoms compared to baseline) will exceed 50%, consistent with known response rates of current antidepressant agents.

B. Safety Hypothesis: Ezogabine will be safe and adverse event rates will be similar to rates observed in other adult populations. Specific safety items to be monitored include frequency and intensity of adverse events as measured by the Patient Rated Inventory of Side Effects (PRISE) and treatment-emergent suicidal ideation or behavior as measured by the Columbia-Suicide Severity Rating Scale (C-SSRS).

Arms: arm 1: Ezogabine dosage plan to 900mg and then tapered down
Interventions: intervention 1: ezogabine
Intervention descriptions: intervention 1: Treatment Week 1: 100mg of Ezogabine by mouth three times per day (total daily dose = 300mg) Treatment Week 2: dose will be increased to 150 mg Ezogabine by mouth three times per day (total daily dose = 450mg).

Treatment Week 3: dose will be increased to 200mg of Ezogabine by mouth three times per day (total daily dose = 600mg).

Treatment Week 4: dose will be increased to 250mg of Ezogabine by mouth three times per day (total daily dose = 750mg).

Treatment Week 5: dose will be increased to 300mg of Ezogabine by mouth three times per (total daily dose = 900mg).

Participants will continue to take 900mg of Ezogabine per day and return weekly to the clinic for the remainder of the study.

Following this primary outcome visit, participants will be instructed to taper the study medication over the following 3 weeks based on FDA recommended guidelines as follows:

250 mg po TID daily x 1 week, then 200 mg po daily x 1 week, then 100 mg po daily x 1 week, then discontinue

Protocol documents: