Study to Treat Major Depressive Disorder With a New Medication

This project is designed to examine the neuronal KCNQ2/3 potassium (K+) channel subtype as a novel treatment target for mood disorders through the administration of the KCNQ-selective channel opener ezogabine (Potiga, GlaxoSmithKline; FDA-approved for the treatment of seizure disorders).

Depressive disorders are among the most disabling medical conditions worldwide and currently available treatments fall short of addressing this large public health burden. Dysfunction within the brain reward system is emerging as a core feature of depressive disorders, in particular related to deficits in motivation, interest, and response to pleasure (e.g., anhedonia: markedly diminished response to pleasure). Evidences from a series of preclinical studies from our group highlighted the KCNQ subtype of neuronal potassium (K+) channel as a novel target for the treatment of depressive disorders and our human pilot study showed a reduction in anhedonia and related symptoms, and an increased brain response to reward (as measured by functional magnetic resonance imaging \[fMRI\]) following treatment with ezogabine. Building on this data, the current project will assess reward circuit activity following treatment with ezogabine in depressed patients with a current depressive disorder (Major depressive disorder \[MDD\], persistent depressive disorder, other specified depressive disorder) and anhedonia (defined by a score ≥ 20 on the Snaith-Hamilton Pleasure Scale \[SHAPS\]), using fMRI to investigate the cortico-striatal circuit to reward.

This study represents the first part of the R61/R33 National Institutes of Health (NIH) founded project. A clear increase in reward circuit activation in at least one ezogabine treatment group compared to placebo, given acceptable tolerability, will constitute a "go" and the project will move to the next phase (R33), where we aim to examine the relationship between treatment, reward circuit activity, and behavioral and clinical outcomes in a larger, confirmatory efficacy trial of ezogabine for depression with anhedonia.

Eligibility Criteria:
Inclusion Criteria:

* Written informed consent obtained from subject and ability for subject to comply with the requirements of the study;
* Men and women, age 18-65;
* Participants must meet DSM-V criteria for current depressive disorder (major depressive disorder \[MDD\], persistent depressive disorder, other specified depressive disorder) as determined by a study psychiatrist and confirmed using the Structured Clinical Interview for DSM-V (SCID);
* Clinically significant anhedonia as determined by a SHAPS score ≥ 20 at screening;
* Current illness severity is at least moderate, defined as a score of ≥4 on the Clinical Global Impression-Severity (CGI-S) Scale;
* If female of childbearing potential, must agree to use of a medically accepted form of contraception, or else agree to abstinence.

Exclusion Criteria:

* A primary psychiatric diagnosis other than a depressive disorder as defined by DSM-V \[co-morbid anxiety disorders (including agoraphobia, generalized anxiety disorder, social anxiety disorder and panic disorder) and Posttraumatic Stress Disorder (PTSD) are allowed\] or major cognitive disorder;
* Meets criteria for a substance or alcohol use disorder in the past 6 months;
* Female participants who are pregnant, breastfeeding, or may become pregnant, or unwilling to practice birth control during participation in the study;
* Positive urine toxicology screen for drugs of abuse at the time of screening;
* Any unstable medical illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease), endocrinologic, neurologic, immunologic, or hematologic disease;
* Clinically significant abnormalities of laboratory tests, physical examination, or ECG;
* Prolonged QT Interval at screening, operationalized as a QTc of \> 480 ms;
* A history of retinal abnormalities (i.e., pigment changes, retinal dystrophy) or findings of retinal pathology on ophthalmological exam at baseline;
* Presence of a condition or abnormality that in the opinion of the Investigator would compromise the safety of the patient or the quality of the data;
* Use of any dis-allowed medication according to the study protocol;
* Serious and imminent risk of self harm or violence as determined by the PI;
* Extreme illness severity as defined by a GCI-S score \>6;
* Any contraindication to MRI including 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;
* History of non-response to electroconvulsive therapy in the current depressive episode

  * Exceptions:

    1. Subjects with a positive urine drug screen for cannabinoids, barbiturates, opiates, amphetamines, or benzodiazepines may be allowed in the study provided that the drug was used for a documented, legitimate medical purpose and/or the use of such products may be discontinued (documented by a negative repeat test) prior to randomization;
    2. Medically appropriate episodic use (up to 3 days) of narcotic analgesics for acute medical indications is allowed (Discussion with PI required)

       * Potential participants will not be discontinued from medication for the purposes of this study. If a patient is taking a protocol dis-allowed medication at the time of screening, the patient may discontinue the medication under the supervision of the treating physician in the case that the patient is not benefiting from the medication or otherwise wishes to discontinue the medication. In no case will a dis-allowed medication be discontinued for the purpose of study participation if the patient is receiving clinical benefit from the medication.