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.

Potential Role of Antipsychotic-Galantamine-Memantine Combination in the Treatment of Positive, Cognitive, and Negative Symptoms of Schizophrenia

“…The KYNA hypothesis in schizophrenia is well documented [98, 99]. The galantamine-memantine combination may be effective for CIAS with KYNA as a biomarker to detect the severity of cognitive impairments and monitor progress (target engagement) with treatment [100, 101]. There is also evidence from a small open-label study that this combination may be effective for CIAS with concurrent improvement in KP metabolite concentrations [102].…”

“…Given that there are no available treatments for CIAS and negative symptoms, testing of quintuple hypotheses (dopamine, nicotinic-cholinergic, glutamatergic/NMDA, GABA, and KYNA) is a “low-risk high-gain” approach that could significantly advance our field. Multitarget drug discovery may play a role in the treatment of complex diseases [161] including, but not limited to, schizophrenia [100, 162]. …”

Memantine in the prevention or alleviation of electroconvulsive therapy induces cognitive disorders: A placebo controlled trial

“…For example Atri et al have shown that combination treatment with memantine added to donepezil in patients with moderate to severe Alzheimer's disease is associated with significant benefits in reducing 24 weeks decline in cognition, function and global status (Atri et al, 2013). In another study, the combination of galantamine and memantine was effective in schizophrenia in order to increase the selective cognition enhancement produced by either medication alone (Koola et al, 2014).…”

Attenuated Mismatch Negativity in Attenuated Psychosis Syndrome Predicts Psychosis: Can Galantamine-Memantine Combination Prevent Psychosis?

“…The galantamine-memantine combination may be effective for cognitive impairments in schizophrenia [37, 41, 43-46]. Excess kynurenic acid (KYNA) may be associated with cognitive impairments in schizophrenia [47].…”

“…KYNA is an antagonist of the α-7nACh and NMDA receptors. The galantamine-memantine combination through the α-7nACh and NMDA receptors may counteract the effects of KYNA, thereby improving cognition [37, 41, 43-46]. Although the KYNA hypothesis is well established in schizophrenia [48, 49], there is no evidence of abnormal kynurenine pathway (KP) metabolites in CHR due to a lack of studies.…”