# Developing Neuronal KCNQ Channel Modulators for Mood Disorders

> **NIH NIH R33** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $792,515

## Abstract

This 5-year R61/R33 phased-innovation award, “Developing KCNQ Channel Modulators for Mood Disorders,”
is designed to efficiently examine the neuronal KCNQ2/3 potassium (K+) channel subtype as a novel treatment
target for depression and related conditions. 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
giving rise to deficits in motivation, interest, and response to pleasure (e.g., anhedonia). The proposed
R61/R33 project capitalizes on a series of preclinical studies from our group that highlight the KCNQ subtype
of neuronal potassium (K+) channel as a novel target for the treatment of depressive disorders. In model
systems, up-regulation of KCNQ channels normalizes pathological functioning within the brain reward circuit,
reversing an anhedonic phenotype. Building on these data, the current project will assess reward circuit activity
following treatment with the KCNQ-selective channel opener ezogabine in depressed patients with anhedonia
[Aim 1], and will examine the relationship between change in reward circuit activity and clinically relevant
symptom and behavior outcomes [Aim 2]. Our project capitalizes on recent advances in conceptualizing and
measuring reward-processing alterations across species, and utilizes the Research Domain Criteria (RDoC)
domain of Positive Valence Systems (PVS) as a unifying framework. In particular, our animal and human work
indicate that enhancing KCNQ channel function within the reward circuit normalizes behavioral processes that
map to the PVS constructs of approach motivation (reward expectancy) and initial responsiveness to reward.
The project takes advantage of (1) availability of ezogabine (Potiga, GlaxoSmithKline) for human use as a
unique first-in-class KCNQ channel opener [FDA-approved for the treatment of seizure disorders], and (2)
availability of reliable methods for measuring reward processing at the level of neural, behavioral, and clinical
levels in humans. The proposed studies have significant potential to advance treatment discovery for
depression within an RDoC framework.

## Key facts

- **NIH application ID:** 9795114
- **Project number:** 4R33MH111932-03
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** James Warren Murrough
- **Activity code:** R33 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $792,515
- **Award type:** 4N
- **Project period:** 2017-01-20 → 2024-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9795114

## Citation

> US National Institutes of Health, RePORTER application 9795114, Developing Neuronal KCNQ Channel Modulators for Mood Disorders (4R33MH111932-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9795114. Licensed CC0.

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