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.

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).

Inclusion Criteria:

• Male or female participants, 18-65 years of age;
• Current diagnosis of major depressive disorder according as determined by a psychiatrist and confirmed with The Mini-International Neuropsychiatric Interview (MINI);
• At least moderate depression severity as defined by a score of >= 21 on the Montgomery-Asberg Depression Rating Scale (MADRS);
• At least a moderate level of anhedonia based on a Snaith-Hamilton Pleasure Scale (SHAPS) score ≥ 20;
• If female of childbearing potential, must agree to use of a medically accepted form of contraception, or else agree to abstinent;
• Participants must have a level of understanding of the English language sufficient to agree to all tests and examinations required by the study and must be able to participate fully in the informed consent process.

Exclusion Criteria:

• Lifetime diagnosis of schizophrenia or any psychotic disorder, bipolar disorder, obsessive compulsive disorder or pervasive developmental disorders or mental retardation;
• Diagnosis of a substance use disorder within the past 6 months (excluding substance use disorder in sustained remission)
• Female participants who are pregnant, nursing, for may become pregnant;
• Any unstable medical illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease); endocrinologic, neurologic (including history of severe head injury), immunologic, or hematologic disease;
• Clinically significant abnormalities of laboratories, physical examination, or ECG;
• Prolonged QT Interval at screening, operationalized as a QTc of > 480 ms at baseline;
• Hypokalemia (potassium value less than 3.5mEq/L) or hypomagnesemia (magnesium value less than 1.6mEq/L) at baseline;
• A history of retinal abnormalities (ie, pigment changes, retinal dystrophy) or findings of retinal pathology on ophthalmological exam at baseline
• Antidepressant medication within 2 weeks of start of treatment (4 weeks for fluoxetine)*
• Other psychotropic medication, including antipsychotics and mood stabilizers within 2 weeks of start of treatment; subjects will be allowed to remain on a stable dose of zolpidem 10 mg nightly for sleep or a benzodiazepine as needed for sleep or anxiety (dosage equivalent to lorazepam 1 mg daily or less)
• No current or recent significantly elevated risk of self-harm or violence as determined by the PI.
• For subjects who may participate in the MRI portion of the study, claustrophobia, any trauma or surgery which may have left magnetic material in the body, magnetic implants or pacemakers, and inability to lie still for 1 hour or more.