Galantamine-Memantine Combination for Cognitive Impairments Due to Electroconvulsive Therapy, Traumatic Brain Injury, and Neurologic and Psychiatric Disorders: Kynurenic Acid and Mismatch Negativity Target Engagement

Cognitive impairments due to electroconvulsive therapy (ECT), traumatic brain injury (TBI), and neurologic and psychiatric disorders are prevalent. Cholinergic and glutamatergic pathways, α-7 nicotinic acetylcholine (α-7nACh) receptor, and N-methyl-d-aspartate (NMDA) receptor are potential pathophysiologic mechanisms in all of these conditions. Galantamine not only is an acetylcholinesterase inhibitor but has a dual mode of action as a α-7nACh receptor modulator as well. Memantine is a noncompetitive NMDA receptor antagonist. Galantamine and memantine are approved by the US Food and Drug Administration (FDA) for the treatment of Alzheimer's disease (AD). Galantamine and memantine have shown efficacy for the treatment of ECT- and TBI-induced cognitive impairments. The kynurenine pathway (KP) metabolites are associated with ECT- and TBI-induced cognitive impairments and several neurologic and psychiatric disorders. Kynurenic acid (KYNA) is an antagonist to the α-7nACh and NMDA receptors. The galantamine-memantine combination has been shown to modulate several KP metabolites in schizophrenia, thereby improving several cognitive domains. There are no FDA-approved treatments for ECT-induced cognitive impairments or for cognitive impairments in neurologic and psychiatric disorders except AD. This article is timely because the pharmacology of cognition as a panacea for neuropsychiatric diseases was recently published. Hence, randomized controlled trials are warranted with this combination in these diseases, with KYNA and mismatch negativity as novel target engagement. Future positive studies may lead to standard of care, which is likely to significantly improve socio-occupational functioning.