Potential role of the combination of galantamine and memantine to improve cognition in schizophrenia

Abstract

The Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) and Treatment Units for Research on Neurocognition and Schizophrenia projects were designed to facilitate the development of new drugs for the treatment of cognitive impairments in people with schizophrenia. The MATRICS project identified three drug mechanisms of particular interest: dopaminergic, cholinergic, and glutamatergic. As a group, while people with schizophrenia have moderate cognitive impairment, it is the best predictor of long-term outcome. Unfortunately, there are no approved medications for cognitive impairment in this population. Hence, the development of new pharmacological approaches is critical for reducing illness-related disability. The combination of an acetylcholinesterase inhibitor (AChEI) and memantine is more effective than either medication alone to improve cognition in Alzheimer's dementia. Galantamine is not only an AChEI, but also a positive allosteric modulator of the α4β2 and α7 nicotinic receptors. Hypofunction of N-methyl-d-aspartate (NMDA) receptors has been implicated in the pathophysiology of cognitive symptoms in schizophrenia and hence memantine may positively impact cognition. Memantine decreases the tonic NMDA current and galantamine enhances the action potential mediated by a postsynaptic NMDA current. This results in an increased signal transmission; therefore, a greater signal-to-noise ratio occurs with the combination than memantine alone. Galantamine improves the α-amino-3-hydroxy-5-methyl-4-isoxazol-propionate (AMPA)-mediated signaling which could be neuroprotective and may improve memory coding. The combination of galantamine and memantine may be particularly effective in schizophrenia in order to increase the selective cognition enhancement produced by either medication alone. In the future, multitarget-directed ligands may play a role in the treatment of complex diseases like schizophrenia.

Keywords: Cognitive impairments; Galantamine; Memantine; Schizophrenia.

Conflict of interest statement

Conflict of Interest

Dr. Buchanan has served as a DSMB member for Otsuka and Pfizer; has consulted with Abbott; Amgen; Bristol-Meyers Squibb; EnVivo; Omeros; Pfizer and have served on the following Advisory Boards: Amgen; EnVivo; Janssen Pharmaceutical, Inc; NuPathe, Inc.; Pfizer; Roche and Takeda. Other authors declare no conflict of interest.

Copyright © 2014 Elsevier B.V. All rights reserved.

Figures

Figure 1

Galantamine may augment the noise suppression of memantine’s glutamatergic action. Galantamine potentiates glutamatergic neurotransmission mediated by α-amino-3-hydroxy-5-methyl-4-isoxazol-propionate (AMPA) and N-methyl-D-aspartate (NMDA) receptors. Reproduced with permission.

Figure 2

Excess Kynurenic acid (KYNA) is associated with cognitive impairments in schizophrenia. Galantamine and Memantine combination may target α7nACh-R and NMDA-R respectively to decrease KYNA thereby improving cognitive impairments.