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

Abstract

Schizophrenia is, in part, a cognitive illness. There are no approved medications for cognitive impairments associated with schizophrenia (CIAS) and primary negative symptoms. Cholinergic and glutamatergic systems, alpha-7 nicotinic acetylcholine (α-7nACh) and N-methyl-D-aspartate (NMDA) receptors, kynurenic acid (KYNA), and mismatch negativity have been implicated in the pathophysiology of CIAS and negative symptoms. Galantamine is an acetylcholinesterase inhibitor that is also a positive allosteric modulator at the α4β2 and α7nACh receptors. Memantine is a noncompetitive NMDA receptor antagonist. Galantamine and memantine alone and in combination were effective for cognition in animals and people with Alzheimer’s disease. The objective of this article is to critically dissect the published randomized controlled trials with galantamine and memantine for CIAS to highlight the efficacy signal. These studies may have failed to detect a clinically meaningful efficacy signal due to limitations, methodological issues, and possible medication nonadherence. There is evidence from a small open-label study that the galantamine-memantine combination may be effective for CIAS with kynurenine pathway metabolites as biomarkers to detect the severity of cognitive impairments. Given that there are no available treatments for cognitive impairments and primary negative symptoms in schizophrenia, testing of this “five-pronged strategy” (quintuple hypotheses: dopamine, nicotinic-cholinergic, glutamatergic/NMDA, GABA, and KYNA) is a “low-risk high-gain” approach that could be a major breakthrough in the field. The galantamine-memantine combination has the potential to treat positive, cognitive, and negative symptoms, and targeting the quintuple hypotheses concurrently may lead to a major scientific advancement – from antipsychotic treatment to antischizophrenia treatment.

Does kynurenic acid act on nicotinic receptors? An assessment of the evidence

“…Clearly, these agonist actions of galantamine on NMDARs would explain its ability to reverse the behavioural effects of NMDA receptor inhibitors such as dizocilpine (MK-801) as well as the effects of kynurenic acid without involving nicotinic receptors at all. Recent reports that a combination of galantamine and memantine show improved cognition-enhancing activity compared to either alone (Koola 2018) are compatible with these data since galantamine could increase the beneficial effects of memantine on the neuronal signal-tonoise ratio by potentiating NMDA receptor activation without the need to invoke nicotinic receptor involvement.…”

Activation of alpha7 nicotinic and NMDA receptors is necessary for performance in a working memory task

“…Using informative pharmacological tools, our experiments provide new conceptual insights through proof-of-principle studies. From a therapeutic perspective, the results provide further justification for accelerated development of cognition-enhancing agents based on the positive modulation of both α7nACh and NMDA receptors (Koola 2018). Effects of acute kynurenine (KYN) administration, with and without galantamine (GAL), on working memory performance in the delay non-match to position (DNMTP) task.…”

Pharmacogenomics of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia

“…Rivastigmine is a dual inhibitor of acetylcholinesterase (AChE; EC 3.1.1.7) and butyrylcholinesterase (BuChE; EC 3.1.1.8) in AD [152,153]. APOE, APP, CHAT, ACHE, BCHE, CHRNA4, CHRNB2, and MAPT variants may affect rivastigmine pharmacokinetics and pharmacodynamics.…”