CDP-choline and galantamine, a personalized α7 nicotinic acetylcholine receptor targeted treatment for the modulation of speech MMN indexed deviance detection in healthy volunteers: a pilot study

Choueiry, Joëlle; Blais, Crystal; Shah, Dhrasti; Smith, Dylan M.; Fisher, Derek J.; Illivitsky, Vadim; Knott, Verner

doi:10.1007/s00213-020-05646-1

Cited by 7 publications

(6 citation statements)

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“…Improved deviance detection in LG and worsening in HG SCZ individuals following CDP-choline/galantamine replicate our findings in healthy participants ( Choueiry et al, 2020 ), and extend previous reports of enhanced deviance detection in LG individuals with CDP-choline alone in healthy ( Knott et al, 2015a ) and SCZ ( Aidelbaum et al, 2021 ) and with nicotine ( Knott et al., 2014b ; Smith et al, 2015 ). Full group effects have been reported with nicotine in healthy ( Dulude et al, 2010 ; Inami et al, 2005 ), ketamine-induced SCZ model ( Mathalon et al, 2014 ), and psychiatric populations ( Baldeweg et al, 2006 ; Fisher et al, 2012a ; Martin et al, 2009 ).…”

Section: Discussionsupporting

confidence: 90%

“…At the basic sensory level, findings of interindividual differences in early auditory processing indexed by the tone-matching task (TMT) were reflected by a bi-modal distribution of early auditory processing deficits, with SCZ patients exhibiting markedly impaired performance showing poorer cognitive performance and functional capacity (Dondé et al, 2017(Dondé et al, , 2019a as well as greater cognitive benefits from auditory-training (Medalia et al, 2019) compared to patients with intact (TMT) performance. Interindividual differences in cognitive response to nAChR agonists are in part due to differences in baseline performance levels (Perkins, 1999) and parsing nicotinic effects on the basis of baseline levels of behavioral and electrophysiological markers has revealed subpopulations of responders and non-responders with regards to nicotine and CDP-choline effects on sensory gating (Knott et al, 2013(Knott et al, , 2014a, MMN (Knott et al, 2014b(Knott et al, , 2015a, P300 (Hyde et al, 2016), and cognition (Knott et al, 2015b) in healthy individuals and SCZ (Aidelbaum et al, 2021); antipsychotic treatment effects on sensory gating (Adler et al, 2004(Adler et al, , 2005; and combined CDP-choline/galantamine treatment effects on sensory gating in healthy and SCZ participants (Choueiry et al, 2019a(Choueiry et al, , 2019b and deviance detection in healthy low-baseline amplitude groups (Choueiry et al, 2020).…”

Section: Baseline-dependency Effectsmentioning

confidence: 99%

“…In parallel, positive allosteric modulators (PAMs) have been considered as an alternative approach increasing nAChR activity via orthosteric binding sites (Wallace and Bertrand, 2015). Hence, a synergistic strategy administering a selective α7 nAChR agonist, cytidine 5′-diphosphocholine (CDP-choline; a precursor and metabolite of acetylcholine), with a nAChR PAM, galantamine, was initially examined over 10 years ago (Deutsch et al, 2008a(Deutsch et al, , 2008b(Deutsch et al, , 2013 and recently with a novel electrophysiological biomarker-based baseline stratification approach which showed improved measures of auditory sensory gating, and auditory deviance detection deficits indexed in electroencephalography (EEG) derived P50 and mismatch negativity (MMN) event-related potentials (ERPs), respectively (Choueiry et al, 2019a(Choueiry et al, , 2019b(Choueiry et al, , 2020.…”

Section: Introductionmentioning

confidence: 99%

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An α7 nAChR approach for the baseline-dependent modulation of deviance detection in schizophrenia: A pilot study assessing the combined effect of CDP-choline and galantamine

et al. 2023

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Background: Cognitive operations including pre-attentive sensory processing are markedly impaired in patients with schizophrenia (SCZ) but evidence significant interindividual heterogeneity, which moderates treatment response with nicotinic acetylcholine receptor (nAChR) agonists. Previous studies in healthy volunteers have shown baseline-dependency effects of the α7 nAChR agonist cytidine 5′-diphosphocholine (CDP-choline) administered alone and in combination with a nicotinic allosteric modulator (galantamine) on auditory deviance detection measured with the mismatch negativity (MMN) event-related potential (ERP). Aim: The objective of this pilot study was to assess the acute effect of this combined α7 nAChR-targeted treatment (CDP-choline/galantamine) on speech MMN in patients with SCZ ( N = 24) stratified by baseline MMN responses into low, medium, and high baseline auditory deviance detection subgroups. Methods: Patients with a stable diagnosis of SCZ attended two randomized, double-blind, placebo-controlled and counter-balanced testing sessions where they received a placebo or a CDP-choline (500 mg) and galantamine (16 mg) treatment. MMN ERPs were recorded during the presentation of a fast multi-feature speech MMN paradigm including five speech deviants. Clinical measures were acquired before and after treatment administration. Results: While no main treatment effect was observed, CDP-choline/galantamine significantly increased MMN amplitudes to frequency, duration, and vowel speech deviants in low group individuals. Individuals with higher positive and negative symptom scale negative, general, and total scores expressed the greatest MMN amplitude improvement following CDP-choline/galantamine. Conclusions: These baseline-dependent nicotinic effects on early auditory information processing warrant different dosage and repeated administration assessments in patients with low baseline deviance detection levels.

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Section: Discussionsupporting

confidence: 90%

Section: Baseline-dependency Effectsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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An α7 nAChR approach for the baseline-dependent modulation of deviance detection in schizophrenia: A pilot study assessing the combined effect of CDP-choline and galantamine

et al. 2023

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“…Galantamine is an isoquinoline alkaloid found in the flowers and bulbs of Galanthus caucasicus , Galanthus sworonowii , and Leucojum aestivum , all of which are members of the Amaryllidaceae family [ 67 ]. Galantamine functions as an allosteric modulator of nicotinic acetylcholine receptors (nAChRs) [ 68 , 69 ]. Several galantamine derivatives were synthesized by connecting them to memantine with linkers of various lengths and compositions.…”

Section: Natural Productsmentioning

confidence: 99%

Bioactive Compounds and Their Derivatives: An Insight into Prospective Phytotherapeutic Approach against Alzheimer’s Disease

Islam

Khadija

Harun-Or-Rashid

et al. 2022

Oxidative Medicine and Cellular Longevity

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Alzheimer’s disease (AD) is a common neurodegenerative brain disorder that causes cellular response alterations, such as impaired cholinergic mechanism, amyloid-beta (Aβ) AD aggregation, neuroinflammation, and several other pathways. AD is still the most prevalent form of dementia and affects many individuals across the globe. The exact cause of the disorder is obscure. There are yet no effective medications for halting, preventing, or curing AD’s progress. Plenty of natural products are isolated from several sources and analyzed in preclinical and clinical settings for neuroprotective effects in preventing and treating AD. In addition, natural products and their derivatives have been promising in treating and preventing AD. Natural bioactive compounds play an active modulatory role in the pathological molecular mechanisms of AD development. This review focuses on natural products from plant sources and their derivatives that have demonstrated neuroprotective activities and maybe promising to treat and prevent AD. In addition, this article summarizes the literature pertaining to natural products as agents in the treatment of AD. Rapid metabolism, nonspecific targeting, low solubility, lack of BBB permeability, and limited bioavailability are shortcomings of most bioactive molecules in treating AD. We can use nanotechnology and nanocarriers based on different types of approaches.

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“…In general, even in "optimal" paradigms such as the one applied here, MMN analyses are usually performed on each deviant type individually, both by ourselves [66,67] and others [94][95][96]. Our secondary analysis suggests that a multivariate approach across deviant types may increase sensitivity to treatment effects and thus increase statistical power.…”

Section: Discussionmentioning

confidence: 98%

Mismatch negativity as an index of target engagement for excitation/inhibition-based treatment development: a double-blind, placebo-controlled, randomized, single-dose cross-over study of the serotonin type-3 receptor antagonist CVN058

Sehatpour

Javitt

Baun

et al. 2021

Neuropsychopharmacol.

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Serotonin type-3 receptor (5-HT 3 R) antagonists show potential as a treatment for cognitive deficits in schizophrenia. CVN058, a brain-penetrant, potent and selective 5-HT 3 R antagonist, shows efficacy in rodent models of cognition and was well-tolerated in Phase-1 studies. We evaluated the target engagement of CVN058 using mismatch negativity (MMN) in a randomized, double-blind, placebo-controlled, cross-over study. Subjects were stable outpatients with schizophrenia or schizoaffective disorder treated with antipsychotics. Subjects were not permitted to use other 5-HT 3 R modulators or serotonin reuptake inhibitors. Each subject received a high (150 mg) and low (15 mg or 75 mg) oral dose of CVN058 and placebo in a randomized order across 3 single-day treatment visits separated by at least 1 week. The primary pre-registered outcome was amplitude of duration MMN. Amplitude of other MMN deviants (frequency, intensity, frequency modulation, and location), P50, P300 and auditory steady-state response (ASSR) were exploratory endpoints. 19 of 22 randomized subjects (86.4%) completed the study. Baseline PANSS scores indicated moderate impairment. CVN058 150 mg led to significant improvement vs. placebo on the primary outcome of duration MMN (p = 0.02, Cohen's d = 0.48). A significant treatment effect was also seen in a combined analysis across all MMN deviants (p < 0.001, d = 0.57). Effects on location MMN were independently significant (p < 0.007, d = 0.46). No other significant effects were seen for other deviants, doses or EEG measures. There were no clinically significant treatment related adverse effects. These results show MMN to be a sensitive target engagement biomarker for 5-HT 3 R, and support the potential utility of CVN058 in correcting the excitatory/ inhibitory imbalance in schizophrenia.

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CDP-choline and galantamine, a personalized α7 nicotinic acetylcholine receptor targeted treatment for the modulation of speech MMN indexed deviance detection in healthy volunteers: a pilot study

Cited by 7 publications

References 149 publications

An α7 nAChR approach for the baseline-dependent modulation of deviance detection in schizophrenia: A pilot study assessing the combined effect of CDP-choline and galantamine

An α7 nAChR approach for the baseline-dependent modulation of deviance detection in schizophrenia: A pilot study assessing the combined effect of CDP-choline and galantamine

Bioactive Compounds and Their Derivatives: An Insight into Prospective Phytotherapeutic Approach against Alzheimer’s Disease

Mismatch negativity as an index of target engagement for excitation/inhibition-based treatment development: a double-blind, placebo-controlled, randomized, single-dose cross-over study of the serotonin type-3 receptor antagonist CVN058

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