The Potential of KCNQ Potassium Channel Openers as Novel Antidepressants

Major depressive disorder (MDD) is a leading cause of disability worldwide and less than one-third of patients with MDD achieve stable remission of symptoms, despite currently available treatments. Although MDD represents a serious health problem, a complete understanding of the neurobiological mechanisms underlying this condition continues to be elusive. Accumulating evidence from preclinical and animal studies provides support for the antidepressant potential of modulators of KCNQ voltage-gated potassium (K⁺) channels. KCNQ K⁺ channels, through regulation of neuronal excitability and activity, contribute to neurophysiological mechanisms underlying stress resilience, and represent potential targets of drug discovery for depression. The present article focuses on the pharmacology and efficacy of KCNQ2/3 K⁺ channel openers as novel therapeutic agents for depressive disorders from initial studies conducted on animal models showing depressive-like behaviors to recent work in humans that examines the potential for KCNQ2/3 channel modulators as novel antidepressants. Data from preclinical work suggest that KCNQ-type K⁺ channels are an active mediator of stress resilience and KCNQ2/3 K⁺ channel openers show antidepressant efficacy. Similarly, evidence from clinical trials conducted in patients with MDD using the KCNQ2/3 channel opener ezogabine (retigabine) showed significant improvements in depressive symptoms and anhedonia. Overall, KCNQ channel openers appear a promising target for the development of novel therapeutics for the treatment of psychiatric disorders and specifically for MDD.