Glutamatergic deficit and schizophrenia-like negative symptoms: new evidence from ketamine-induced mismatch negativity alterations in healthy male humans

Thiebes, Stephanie; Leicht, Gregor; Ćurić, Stjepan; Steinmann, Saskia; Polomac, Nenad; Andreou, Christina; Eichler, Iris-Carola; Eichler, Lars; Zöllner, Christian; Gallinat, Jürgen; Hanganu‐Opatz, Ileana L.; Mulert, Christoph

doi:10.1503/jpn.160187

Cited by 37 publications

(45 citation statements)

References 66 publications

(78 reference statements)

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“…This reduction of the MMN was due to reduced activity in a priori defined sources: the bilateral superior temporal lobes for the early MMN time frame and the right inferior temporal gyrus as well as the anterior cingulate gyrus for the late MMN time frame [ 55 ]. In another randomized, placebo-controlled, single-blind EEG-study, Thiebes et al [ 56 ] demonstrated comparable results. Ketamine decreased the auditory MMN amplitude for duration as well as frequency deviants.…”

Section: Resultsmentioning

confidence: 89%

Glutamatergic Deficits in Schizophrenia – Biomarkers and Pharmacological Interventions within the Ketamine Model

Haaf

Leicht

Ćurić

et al. 2018

CPB

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Background: The observation that N-methyl-D-aspartate glutamate receptor (NMDAR) antagonists such as ketamine transiently induce schizophrenia-like positive, negative and cognitive symptoms has led to a paradigm shift from dopaminergic to glutamatergic dysfunction in pharmacological models of schizophrenia. NMDAR hypofunction can explain many schizophrenia symptoms directly due to excitatory-to-inhibitory (E/I) imbalance, but also dopaminergic dysfunction itself. However, so far no new drug targeting the NMDAR has been successfully approved. In the search for possible biomarkers it is interesting that ketamine-induced psychopathological changes in healthy participants were accompanied by altered electro-(EEG), magnetoencephalographic (MEG) and functional magnetic resonance imaging (fMRI) signals.Methods: We systematically searched PubMed/Medline and Web of Knowledge databases (January 2006 to July 2017) to identify EEG/MEG and fMRI studies of the ketamine model of schizophrenia with human subjects. The search strategy identified 209 citations of which 46 articles met specified eligibility criteria.Results: In EEG/MEG studies, ketamine induced changes of event-related potentials, such as the P300 potential and the mismatch negativity, similar to alterations observed in schizophrenia patients. In fMRI studies, alterations of activation were observed in different brain regions, most prominently within the anterior cingulate cortex and limbic structures as well as task-relevant brain regions. These alterations were accompanied by changes in functional connectivity, indicating a balance shift of the underlying brain networks. Pharmacological treatments did alter ketamine-induced changes in EEG/MEG and fMRI studies to different extents.Conclusion: This review highlights the potential applicability of the ketamine model for schizophrenia drug development by offering the possibility to assess the effect of pharmacological agents on schizophrenia-like symptoms and to find relevant neurophysiological and neuroimaging biomarkers.

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Section: Resultsmentioning

confidence: 89%

Glutamatergic Deficits in Schizophrenia – Biomarkers and Pharmacological Interventions within the Ketamine Model

Haaf

Leicht

Ćurić

et al. 2018

CPB

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“…Interactive effects of the α7nACh and NMDA receptors on MMN are well documented [144-146]. MMN is not only a cognitive biomarker but also a biomarker for negative symptoms in schizophrenia [147]. The pharmacology of cognition as a panacea for neuropsychiatric diseases was recently published [148].…”

Section: Mismatch Negativitymentioning

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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“…For the following data analysis 19 subjects with a mean age of 25 years (SD = 2.32, range = 20-29) were included. The sample of the study is part of a larger project, of which some results have been published already [30].…”

Section: Participantsmentioning

confidence: 99%

“…With respect to AVH in schizophrenia, we derived a more specific AUA subscore that included only AUA related to auditory verbal distortions (AVD) and AVH (AUA-AVD/AVH) in contrast to non-verbal auditory distortions and hallucinations. The AUA score includes 16 items of the 5D-ASC (items: 4,5,11,13,19,25,30,48,49,55,65,66,74,76, 92, and 93), the AUA-AVD/AVH scores includes 6 items (4, 13, 19, 25, 30, and 65). Fig.…”

Section: Psychometric Assessmentmentioning

confidence: 99%

Alterations in interhemispheric gamma-band connectivity are related to the emergence of auditory verbal hallucinations in healthy subjects during NMDA-receptor blockade

Thiebes

Steinmann

Ćurić

et al. 2018

Neuropsychopharmacol

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Auditory verbal hallucinations (AVH) are a common positive symptom of schizophrenia. Excitatory-to-inhibitory (E/I) imbalance related to disturbed N-methyl-D-aspartate receptor (NMDAR) functioning has been suggested as a possible mechanism underlying altered connectivity and AVH in schizophrenia. The current study examined the effects of ketamine, a NMDAR antagonist, on glutamate-related mechanisms underlying interhemispheric gamma-band connectivity, conscious auditory perception during dichotic listening (DL), and the emergence of auditory verbal distortions and hallucinations (AVD/AVH) in healthy volunteers. In a single-blind, pseudo-randomized, placebo-controlled crossover design, nineteen male, right-handed volunteers were measured using 64 channel electroencephalography (EEG). Psychopathology was assessed with the PANSS interview and the 5D-ASC questionnaire, including a subscale to detect auditory alterations with regard to AVD/AVH (AUA-AVD/AVH). Interhemispheric connectivity analysis was performed using eLORETA source estimation and lagged phase synchronization (LPS) in the gamma-band range (30-100 Hz). Ketamine induced positive symptoms such as hallucinations in a subgroup of healthy subjects. In addition, interhemispheric gamma-band connectivity was found to be altered under ketamine compared to placebo, and subjects with AUA-AVD/AVH under ketamine showed significantly higher interhemispheric gamma-band connectivity than subjects without AUA-AVD/AVH. These findings demonstrate a relationship between NMDAR functioning, interhemispheric connectivity in the gamma-band frequency range between bilateral auditory cortices and the emergence of AVD/AVH in healthy subjects. The result is in accordance with the interhemispheric miscommunication hypothesis of AVH and argues for a possible role of glutamate in AVH in schizophrenia.

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Glutamatergic deficit and schizophrenia-like negative symptoms: new evidence from ketamine-induced mismatch negativity alterations in healthy male humans

Cited by 37 publications

References 66 publications

Glutamatergic Deficits in Schizophrenia – Biomarkers and Pharmacological Interventions within the Ketamine Model

Glutamatergic Deficits in Schizophrenia – Biomarkers and Pharmacological Interventions within the Ketamine Model

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

Alterations in interhemispheric gamma-band connectivity are related to the emergence of auditory verbal hallucinations in healthy subjects during NMDA-receptor blockade

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