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

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.

Figure 1.. Change in Clinical Outcomes in Patients with Major Depressive Disorder Treated with the KCNQ Channel Opener Ezogabine.

(a) Mean MADRS and QIDS-SR score (± SEM) over time during course of ezogabine treatment. MADRS score decreased significantly from pre-treatment (week 0) to post-treatment (week 10) (mean change: −13.7±9.6, t₁₇=−6.01, p<0.001, Cohen’s d=2.08) and throughout the study as a function of time (RM-ANOVA: F_3,52=21.96, p<0.001, partial-η²=0.56). Likewise, QIDS-SR score was significantly reduced at study end compared to pre-treatment (mean change: −5.72±4.4, t₁₇ =−5.53, p<0.001, Cohen’s d=1.64). (b) CGI-I category at study post-treatment. Eleven out of 18 (61%) of patients were classified as ‘much improved’ or ‘very much improved’ according to the CGI-I. CGI-I, Clinical Global Impression—Improvement; MADRS, Montgomery-Asberg Depression Rating Scale; QIDS-SR, Quick Inventory of Depression-Self Report.

Figure 2.. Functional Connectivity of the Ventral Caudate in Patients with Major Depressive Disorder Treated with the KCNQ Channel Opener Ezogabine.

(a) Clusters where reduction of RSFC with the vCa significantly correlated with reduction in MADRS score. (b) Clusters where reduction in RSFC with the vCa significantly correlated with reduction in SHAPS score. (c) Cluster where increased pre-treatment RSFC with the vCa significantly correlated with reduction in MADRS scores. (d) vCa, NAc, and VTA seeds, 3D view. Yellow: vCa, Blue: NAc, Red: VTA. MADRS, Montgomery-Asberg Depression Rating Scale; NAc, nucleus accumbens; PCC, posterior cingulate cortex; RSFC, resting state functional connectivity; SHAPS, Snaith-Hamilton Pleasure Scale; vCa, ventral caudate; VTA, ventral tegmental area.

Figure 3.. Change in Reward Learning and Association with Anhedonia in Patients with Major Depressive Disorder Treated with the KCNQ Channel Opener Ezogabine.

(a) Mean (± SEM) response bias across the three blocks of the PRT at pre-treatment and post-treatment. The main effect of block was significant due to a significant increase in response bias across blocks, indicating that the asymmetrical reinforcement ratio was successful at inducing a behavioral response bias (F_2,16=5.38, p=0.02, η²=0.40). Furthermore, the main effect of time was significant due to a significant increase in overall response bias from pre-treatment to post-treatment, indicating that treatment improved the ability to modulate behavior based on prior reinforcement (F_1,8=6.34, p=0.04, η²=0.44). (b) Higher pre-treatment response bias averaged across blocks 2 and 3 was associated with greater improvements in anhedonic symptom severity on the SHAPS following treatment (r=0.64, p=0.04). SHAPS, Snaith-Hamilon Pleasure Scale.