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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 (?-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 ?4?2 and ?7nACh 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.

SUBMITTER: Koola MM

PROVIDER: S-EPMC6323397 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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

Koola Maju Mathew MM

Molecular neuropsychiatry 20181119 3

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 <i>N</i>-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 positiv ...[more]

PMID: 30643787

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Project description:BackgroundThe donepezil-memantine combination is a US Food and Drug Administration (FDA)-approved medication to treat Alzheimer's disease (AD). Galantamine is superior to donepezil because it is a positive allosteric modulator of the alpha-7 nicotinic acetylcholine receptor (α7nAChR). Although galantamine and memantine are both FDA approved for the treatment of AD, the combination is still underutilized in clinical practice.AimThe objective of this review was to critically examine the mechanisms by which the galantamine-memantine combination may be superior to the donepezil-memantine combination in AD by targeting the cholinergic-nicotinic and glutamatergic systems concurrently.MethodPubMed and Google Scholar were searched using the keywords Alzheimer's disease, cholinergic, glutamatergic, α7nAChR, N-methyl-D-aspartate (NMDA) receptors, donepezil, galantamine, memantine, clinical trials, and biomarkers.ResultsAD is associated with several biomarkers such as kynurenine pathway (KP) metabolites, mismatch negativity (MMN), brain-derived neurotrophic factor (BDNF), and oxidative stress. In several preclinical studies, cognitive impairments significantly improved with the galantamine-memantine combination compared to either medication alone. Synergistic benefits were also seen with the combination. In a randomized controlled trial (RCT) in prodrome AD, cognition significantly improved with the galantamine-memantine combination compared to galantamine alone; cognition declined after galantamine was discontinued. However, in an RCT in AD, cognition did not significantly improve with the galantamine-memantine combination compared to galantamine alone. In a retrospective study in AD, the galantamine-memantine combination significantly improved cognition compared to the donepezil-memantine combination. Galantamine and memantine via the α7nACh and NMDA receptors can counteract the effects of kynurenic acid and enhance MMN and BDNF.ConclusionFuture studies with the galantamine-memantine combination with KP metabolites, MMN, and BDNF as biomarkers are warranted. Positive RCTs in AD may lead to FDA approval of the combination, resulting in greater utilization in clinical practice. In the meantime, clinicians may continue to use the galantamine-memantine combination to treat patients with AD.

Project description:Autism spectrum disorder (ASD) and schizophrenia (SZ) are heterogenous neurodevelopmental disorders that overlap in symptom presentation. The purpose of this study was to specify overlapping symptom domains and to identify symptoms that can reliably differentiate adults with ASD (n = 53), SZ (n = 39), and typical development (TD; n = 40). All participants regardless of diagnosis were administered gold-standard diagnostic assessments of ASD and SZ characteristics including the Autism Diagnostic Observation Schedule (ADOS-2) and the Positive and Negative Syndrome Scale (PANSS). Sensitivity and specificity of the ADOS were assessed using diagnostic cut-off scores. The degree of symptom overlap on these measures between participant groups was analyzed using Analyses of Variance (ANOVAs), Receiver Operating Characteristic (ROC) Curves, and Analyses of Covariance (ANCOVAs) to control for group differences in IQ and sex distributions. The ADOS reliably discriminated ASD and TD adults, but there was a high rate of "false positives" in SZ patients who did not meet the DSM-5 criteria for ASD. To identify the reasons for low specificity in the SZ sample, we categorized ASD and SZ symptoms into 'positive' (presence of atypical behaviors) and 'negative' (absence of typical behaviors) symptoms. ASD and SZ groups overlapped on negative symptoms largely related to the absence of typical social and communicative behaviors, whereas disorder-specific positive symptoms differentiated ASD and SZ. For example, those with ASD scored higher on restricted and repetitive behaviors and stereotyped language, whereas those with SZ scored higher on psychotic symptoms such as delusions and hallucinations. These results suggest that, when making a differential diagnosis between ASD and SZ, clinicians may benefit from focusing on the presence or absence of positive ASD and SZ symptoms. Standardized measures to classify ASD symptoms into positive and negative symptoms have not yet been developed but represent a potentially viable clinical tool.

Dataset Information

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

Publications

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

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