Emraclidine, a novel positive allosteric modulator of cholinergic M4 receptors, for the treatment of schizophrenia: a two-part, randomised, double-blind, placebo-controlled, phase 1b trial

Krystal, John H.; Kane, John M.; Correll, Christoph U.; Walling, David; Leoni, Matthew; Duvvuri, Sridhar; Patel, Shrinal; Chang, Ih; Iredale, Philip; Frohlich, Lillian; Versavel, Stacey; Perry, Pamela; Sanchez, Raymond; Renger, John J.

doi:10.1016/s0140-6736(22)01990-0

Cited by 67 publications

(34 citation statements)

References 32 publications

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“…These data complemented prior studies in which xanomeline was effective versus PANSS total scores and reduced psychosis-like behavioural disturbances in Alzheimer's disease patients [38,39]. Preclinical data suggest that it is primarily the M 4 receptor agonist activity (rather than the M 1 activity) that engenders the antipsychotic effect, which would be consistent with the recently reported antipsychotic activity of CVL-231, a subtype selective positive allosteric modulator of the M 4 receptor, in a phase 1b trial [40][41][42].…”

Section: The Past and The Present Of Schizophrenia Drug Developmentsupporting

confidence: 83%

Beyond antipsychotics: a twenty-first century update for preclinical development of schizophrenia therapeutics

et al. 2022

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Despite 50+ years of drug discovery, current antipsychotics have limited efficacy against negative and cognitive symptoms of schizophrenia, and are ineffective—with the exception of clozapine—against any symptom domain for patients who are treatment resistant. Novel therapeutics with diverse non-dopamine D2 receptor targets have been explored extensively in clinical trials, yet often fail due to a lack of efficacy despite showing promise in preclinical development. This lack of translation between preclinical and clinical efficacy suggests a systematic failure in current methods that determine efficacy in preclinical rodent models. In this review, we critically evaluate rodent models and behavioural tests used to determine preclinical efficacy, and look to clinical research to provide a roadmap for developing improved translational measures. We highlight the dependence of preclinical models and tests on dopamine-centric theories of dysfunction and how this has contributed towards a self-reinforcing loop away from clinically meaningful predictions of efficacy. We review recent clinical findings of distinct dopamine-mediated dysfunction of corticostriatal circuits in patients with treatment-resistant vs. non-treatment-resistant schizophrenia and suggest criteria for establishing rodent models to reflect such differences, with a focus on objective, translational measures. Finally, we review current schizophrenia drug discovery and propose a framework where preclinical models are validated against objective, clinically informed measures and preclinical tests of efficacy map onto those used clinically.

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Section: The Past and The Present Of Schizophrenia Drug Developmentsupporting

confidence: 83%

Beyond antipsychotics: a twenty-first century update for preclinical development of schizophrenia therapeutics

et al. 2022

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“…The medical questions were identified by selecting five research articles published at the end of 2022 in four high-impact factor medical journals (BMJ (13)(14)(15)(16)(17), CMAJ (18)(19)(20)(21)(22), the Lancet (23)(24)(25)(26)(27)(28)(29)(30)(31)(32) and NEJM). These 20 articles spanned different topics and fields.…”

Section: Methodsmentioning

confidence: 99%

Learning to fake it: limited responses and fabricated references provided by ChatGPT for medical questions

Gravel

D’Amours-Gravel

Osmanlliu

2023

Preprint

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Background: ChatGPT have gained public notoriety and recently supported manuscript preparation. Our objective was to evaluate the quality of the answers and the references provided by ChatGPT for medical questions. Methods: Three researchers asked ChatGPT a total of 20 medical questions and prompted it to provide the corresponding references. The responses were evaluated for quality of content by medical experts using a verbal numeric scale going from 0 to 100%. These experts were the corresponding author of the 20 articles from where the medical questions were derived. We planned to evaluate three references per response for their pertinence, but this was amended based on preliminary results showing that most references provided by ChatGPT were fabricated. Results: ChatGPT provided responses varying between 53 and 244 words long and reported two to seven references per answer. Seventeen of the 20 invited raters provided feedback. The raters reported limited quality of the responses with a median score of 60% (1st and 3rd quartile: 50% and 85%). Additionally, they identified major (n=5) and minor (n=7) factual errors among the 17 evaluated responses. Of the 59 references evaluated, 41 (69%) were fabricated, though they appeared real. Most fabricated citations used names of authors with previous relevant publications, a title that seemed pertinent and a credible journal format. Interpretation: When asked multiple medical questions, ChatGPT provided answers of limited quality for scientific publication. More importantly, ChatGPT provided deceptively real references. Users of ChatGPT should pay particular attention to the references provided before integration into medical manuscripts.

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“…Despite reducing striatal dopamine release, preliminary trials of emraclidine and xanomeline (M4 mAChR agonists, see Figure 2) have shown efficacy in the treatment of negative symptoms in schizophrenia (156,157). Cholinesterase inhibitors also reduce apathy in Alzheimer's disease, Parkinson's disease and Lewy Body dementia (156,158). However, to our knowledge, no study to date in humans has examined the effects of manipulating specific cholinergic receptors on reward processing.…”

Section: Acetylcholinementioning

confidence: 99%

Apathy and Motivation: Biological Basis and Drug Treatment

Costello¹,

Roiser²

2023

Preprint

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Apathy is a disabling syndrome associated with poor functional outcomes that is common across a broad range of neurological and psychiatric conditions. Currently there are no established therapies specifically for apathy, and safe and effective treatments are urgently needed. Advances in the understanding of motivation and goal-directed behaviour in humans and animals has shed light on the cognitive and neurobiological mechanisms contributing to apathy, providing an important foundation for the development of new treatments. Here, we review the cognitive components, neural circuitry, and pharmacology of apathy and motivation, highlighting converging evidence of shared transdiagnostic mechanisms. Though no pharmacological treatments have yet been licensed for apathy specifically, we summarise trials of existing and novel compounds to date, identifying several promising candidates for clinical use and avenues of future drug development.

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Emraclidine, a novel positive allosteric modulator of cholinergic M4 receptors, for the treatment of schizophrenia: a two-part, randomised, double-blind, placebo-controlled, phase 1b trial

Cited by 67 publications

References 32 publications

Beyond antipsychotics: a twenty-first century update for preclinical development of schizophrenia therapeutics

Beyond antipsychotics: a twenty-first century update for preclinical development of schizophrenia therapeutics

Learning to fake it: limited responses and fabricated references provided by ChatGPT for medical questions

Apathy and Motivation: Biological Basis and Drug Treatment

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