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.
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
General Investigational Plan:
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.
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).
- 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
- 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.
- Lifetime diagnosis of schizophrenia or any psychotic disorder, bipolar disorder,
obsessive compulsive disorder or pervasive developmental disorders or mental
- 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
- 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
- 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.