TY - JOUR
T1 - Effects of the KCNQ channel opener ezogabine on functional connectivity of the ventral striatum and clinical symptoms in patients with major depressive disorder
AU - Tan, Aaron
AU - Costi, Sara
AU - Morris, Laurel S.
AU - Van Dam, Nicholas T.
AU - Kautz, Marin
AU - Whitton, Alexis E.
AU - Friedman, Allyson K.
AU - Collins, Katherine A.
AU - Ahle, Gabriella
AU - Chadha, Nisha
AU - Do, Brian
AU - Pizzagalli, Diego A.
AU - Iosifescu, Dan V.
AU - Nestler, Eric J.
AU - Han, Ming Hu
AU - Murrough, James W.
N1 - Publisher Copyright:
© 2018, Springer Nature Limited.
PY - 2020/6/1
Y1 - 2020/6/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85055984549&partnerID=8YFLogxK
U2 - 10.1038/s41380-018-0283-2
DO - 10.1038/s41380-018-0283-2
M3 - Article
C2 - 30385872
AN - SCOPUS:85055984549
SN - 1359-4184
VL - 25
SP - 1323
EP - 1333
JO - Molecular Psychiatry
JF - Molecular Psychiatry
IS - 6
ER -