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Mol Psychiatry. 2018 Nov 1. doi: 10.1038/s41380-018-0283-2. [Epub ahead of print]

Effects of the KCNQ channel opener ezogabine on functional connectivity of the ventral striatum and clinical symptoms in patients with major depressive disorder.

Author information

1
Mood and Anxiety Disorders Program, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
2
Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
3
Melbourne School of Psychological Sciences, University of Melbourne, Melbourne, VIC, Australia.
4
Department of Psychiatry, Harvard Medical School, Belmont, MA, USA.
5
Department of Biological Sciences, Hunter College, The City University of New York, New York, NY, USA.
6
Department of Psychology, Thomas Jefferson University, Philadelphia, PA, USA.
7
Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
8
Roski Eye Institute, Keck School of Medicine at the University of Southern California, Los Angeles, CA, USA.
9
Department of Psychiatry, New York University School of Medicine, New York, NY, USA.
10
Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA.
11
Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
12
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
13
Mood and Anxiety Disorders Program, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA. james.murrough@mssm.edu.
14
Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA. james.murrough@mssm.edu.
15
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. james.murrough@mssm.edu.

Abstract

Major depressive disorder (MDD) is a leading cause of disability worldwide, yet current treatment strategies remain limited in their mechanistic diversity. Recent evidence has highlighted a promising novel pharmaceutical target-the KCNQ-type potassium channel-for the treatment of depressive disorders, which may exert a therapeutic effect via functional changes within the brain reward system, including the ventral striatum. The current study assessed the effects of the KCNQ channel opener ezogabine (also known as retigabine) on reward circuitry and clinical symptoms in patients with MDD. Eighteen medication-free individuals with MDD currently in a major depressive episode were enrolled in an open-label study and received ezogabine up to 900 mg/day orally over the course of 10 weeks. Resting-state functional magnetic resonance imaging data were collected at baseline and posttreatment to examine brain reward circuitry. Reward learning was measured using a computerized probabilistic reward task. After treatment with ezogabine, subjects exhibited a significant reduction of depressive symptoms (Montgomery-Asberg Depression Rating Scale score change: -13.7 ± 9.7, p < 0.001, d = 2.08) and anhedonic symptoms (Snaith-Hamilton Pleasure Scale score change: -6.1 ± 5.3, p < 0.001, d = 1.00), which remained significant even after controlling for overall depression severity. Improvement in depression was associated with decreased functional connectivity between the ventral caudate and clusters within the mid-cingulate cortex and posterior cingulate cortex (n = 14, voxel-wise p < 0.005). In addition, a subgroup of patients tested with a probabilistic reward task (n = 9) showed increased reward learning following treatment. These findings highlight the KCNQ-type potassium channel as a promising target for future drug discovery efforts in mood disorders.

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