Improvement of Negative and Positive Symptoms in Treatment-Refractory Schizophrenia

Lucena, David Freitas de; Fernandes, Brisa S.; Berk, Michael; Dodd, Seetal; Medeiros, Dalton Wiggers; Pedrini, Mariana; Kunz, Maurício; Gomes, Fabiano A.; Giglio, Larriany F.; Lobato, Maria Inês Rodrigues; Belmonte-de-Abreu, Paulo; Gama, Clarissa Severino

doi:10.4088/jcp.08m04935gry

Cited by 106 publications

(39 citation statements)

References 47 publications

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“…In a 12-week RCT, memantine did not improve cognition in 26 participants with chronic schizophrenia (Lee et al, 2012). In another 12-week RCT (N=21), memantine as an augmentation treatment significantly (p<0.01) improved cognition in participants with schizophrenia on clozapine (de Lucena et al, 2009). The last two studies used Mini-Mental State Examination to assess cognition.…”

Section: Memantine For Cognitive Impairments In Schizophreniamentioning

confidence: 96%

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

Koola

Boyer

Pillai

et al. 2014

Schizophrenia Research

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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.

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Section: Memantine For Cognitive Impairments In Schizophreniamentioning

confidence: 96%

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

Koola

Boyer

Pillai

et al. 2014

Schizophrenia Research

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“…Four studies enrolled only participants with schizophrenia [68, 85-87]. Two studies excluded those with schizoaffective disorder, bipolar type [59-60], and one study excluded those with schizoaffective disorder [88].…”

Section: Lack Of Adherence To the Fda-nimh-matrics Guidelinesmentioning

confidence: 99%

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

Koola¹

2018

Complex Psychiatry

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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.

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“…However, among the small number of placebo-controlled studies of MEM’s pro-cognitive effects in patients with SZ (Lee et al 2012; de Lucena et al 2009; Lieberman et al 2009; Krivoy et al 2007; Zdanys and Tampi 2008), results are inconsistent. Importantly, these studies did not focus specifically on potential neurocognitive benefits of MEM or on the engagement of neural targets linked with neurocognitive processes.…”

Section: Introductionmentioning

confidence: 99%

Effects of acute memantine administration on MATRICS Consensus Cognitive Battery performance in psychosis: Testing an experimental medicine strategy

et al. 2016

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Rationale Pro-cognitive agents for chronic psychotic disorders (CPDs) might be detected via experimental medicine models, in which neural targets engaged by the drug predict sensitivity to the drug’s pro-cognitive effects. Objective This study aims to use an experimental medicine model to test the hypothesis that “target engagement” predicts pro-cognitive effects of the NMDA antagonist, memantine (MEM), in CPDs. Methods MATRICS Consensus Cognitive Battery (MCCB) performance was assessed in CPD (n = 41) and healthy subjects (HS; n = 41) in a double-blind, randomized cross-over design of acute (single dose) MEM (placebo vs. 10 or 20 mg p.o.). Measures of prepulse inhibition (PPI) and mismatch negativity previously reported from this cohort substantiated target engagement. Biomarkers predicting MEM neurocognitive sensitivity were assessed. Results Testing confirmed MCCB deficits associated with CPD diagnosis, age, and anticholinergic exposure. MEM (20 mg p.o.) reduced MCCB performance in HS. To control for significant test order effects, an “order-corrected MEM effect” (OCME) was calculated. In CPD subjects, greater age, positive MEM effects on PPI, and SNP rs1337697 (within the ionotropic NMDA receptor gene, GRIN3A) predicted greater positive OCME with 20 mg MEM. Conclusions An experimental medicine model to assess acute pro-cognitive drug effects in CPD subjects is feasible but not without challenges. A single MEM 20 mg dose had a negative impact on neurocognition among HS. In CPD patients, age, MEM effects on PPI, and rs1337697 predicted sensitivity to the neurocognitive effects of MEM. Any potential clinical utility of these predictive markers for pro-cognitive effects of MEM in subgroups of CPD patients cannot be inferred without a validating clinical trial.

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Improvement of Negative and Positive Symptoms in Treatment-Refractory Schizophrenia

Abstract: clinicaltrials.gov Identifier: NCT00757978.

Cited by 106 publications

References 47 publications

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

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

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

Effects of acute memantine administration on MATRICS Consensus Cognitive Battery performance in psychosis: Testing an experimental medicine strategy

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