KCNQ Channel Potentiator Ezogabine Delivers Promising Results in Major Depressive Disorder

An open-label design study published in Molecular Psychiatry demonstrated that ezogabine, a first-in-class KCNQ channel potentiator, improved symptoms of depression and anhedonia in patients with major depressive disorder, with no serious adverse events. Furthermore, a significant increase in resilience occurred, which suggests that ezogabine may act to strengthen resilience to stress.

Aaron Tan, PhD candidate, of the mood and anxiety disorders program, department of psychiatry, and the department of neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, and colleagues enrolled 18 patients with major depressive disorder who were not currently taking medication. The individuals received ezogabine up to 900 mg/day orally over the course of 10 weeks. The investigators examined brain reward circuitry using resting state functional magnetic resonance imaging at baseline and posttreatment. They measured reward learning using a computerized probabilistic reward task and measured depressive symptoms using the Montgomery-Asberg Depression Rating Scale. Anhedonic symptoms were measured by the Snaith-Hamilton Pleasure Scale.

The investigators observed significant reductions in depression symptoms (−13.7; P <.001; d =2.08) and anhedonic symptoms (−6.1; P <.01; d =1.00). These reductions remained significant even after controlling for the severity of depression. The investigators found that improvement in depression was associated with decreased functional connectivity between the ventral caudate and clusters within the midcingulate cortex and posterior cingulate cortex. Of the 18 patients, 11 (61%) were either much improved or very much improved at the end of the 10-week trial. The most common adverse event was dizziness, which occurred in 44% of patients. Other, less frequent adverse events included confusion and headache. Results also indicated improved reward-learning.

As the study was open label, the results are limited by the lack of a placebo or control group. The small sample size is also a study limitation.

The investigators noted that the results of the study suggest that ezogabine may act by decoupling the ventral striatal reinforcement and the midcingulate cortex pain and negative affect systems. They contend that resilience-enhancing via the KCNQ channel represents a promising target for drug discovery for mood disorders.

Reference

Tan A, Costi S, Morris LS, et al. Effects of the KCNQ channel opener ezogabine on functional connectivity of the ventral striatum and clinical symptoms in patients with major depressive disorder [published online November 1, 2018]. Mol Psychiatry. doi: 10.1038/s41380-018-0283-2