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Markers of muscarinic deficit for individualized treatment in schizophrenia.

ABSTRACT: Recent clinical studies have shown that agonists at muscarinic acetylcholine receptors effectively reduce schizophrenia symptoms. It is thus conceivable that, for the first time, a second substance class of procholinergic antipsychotics could become established alongside the usual antidopaminergic antipsychotics. In addition, various basic science studies suggest that there may be a subgroup of schizophrenia in which hypofunction of muscarinic acetylcholine receptors is of etiological importance. This could represent a major opportunity for individualized treatment of schizophrenia if markers can be identified that predict response to procholinergic vs. antidopaminergic interventions. In this perspective, non-response to antidopaminergic antipsychotics, specific symptom patterns like visual hallucinations and strong disorganization, the presence of antimuscarinic antibodies, ERP markers such as mismatch negativity, and radiotracers are presented as possible in vivo markers of muscarinic deficit and thus potentially of response to procholinergic therapeutics. Finally, open questions and further research steps are outlined.

SUBMITTER: Stuke H

PROVIDER: S-EPMC9868756 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Markers of muscarinic deficit for individualized treatment in schizophrenia.

Stuke Heiner H

Frontiers in psychiatry 20230109

Recent clinical studies have shown that agonists at muscarinic acetylcholine receptors effectively reduce schizophrenia symptoms. It is thus conceivable that, for the first time, a second substance class of procholinergic antipsychotics could become established alongside the usual antidopaminergic antipsychotics. In addition, various basic science studies suggest that there may be a subgroup of schizophrenia in which hypofunction of muscarinic acetylcholine receptors is of etiological importance ...[more]

PMID: 36699495

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Project description:ImportanceLittle guidance exists to date on how to select antipsychotic medications for patients with first-episode schizophrenia.ObjectiveTo develop a preliminary individualized treatment rule (ITR) for patients with first-episode schizophrenia.Design, setting, and participantsThis prognostic study obtained data from Taiwan's National Health Insurance Research Database on patients with prescribed antipsychotic medications, ambulatory claims, or discharge diagnoses of a schizophrenic disorder between January 1, 2005, and December 31, 2011. An ITR was developed by applying a targeted minimum loss-based ensemble machine learning method to predict treatment success from baseline clinical and demographic data in a 70% training sample. The model was validated in the remaining 30% of the sample. The probability of treatment success was estimated for each medication for each patient under the model. The analysis was conducted between July 16, 2018, and July 15, 2019.ExposuresFifteen different antipsychotic medications.Main outcomes and measuresTreatment success was defined as not switching medication and not being hospitalized for 12 months.ResultsAmong the 32 277 patients in the analysis, the mean (SD) age was 36.7 (14.3) years, and 15 752 (48.8%) were male. In the validation sample, the treatment success rate (SE) was 51.7% (1.0%) under the ITR and was 44.5% (0.5%) in the observed population (Z = 7.1; P < .001). The estimated treatment success if all patients were given a prescription for 1 medication was significantly lower for each of the 13 medications than under the ITR (Z = 4.2-16.8; all P < .001). Aripiprazole (3088 [31.9%]) and amisulpride (2920 [30.2%]) were the medications most often recommended by the ITR. Only 1054 patients (10.9%) received ITR-recommended medications. Observed treatment success, although lower than the success under the ITR, was nonetheless significantly higher than if medications had been randomized (44.5% [SE, 0.55%] vs 41.3% [SE, 0.4%]; Z = 6.9; P < .001), although only marginally higher than if medications had been randomized in their observed population proportions (44.5% [SE, 0.5%] vs 43.5% [SE, 0.4%]; Z = 2.2; P = .03]).Conclusions and relevanceThese results suggest that an ITR may be associatded with an increase in the treatment success rate among patients with first-episode schizophrenia, but experimental evaluation is needed to confirm this possibility. If confirmed, model refinement that investigates biomarkers, clinical observations, and patient reports as additional predictors in iterative pragmatic trials would be needed before clinical implementation.

Project description:BackgroundThe muscarinic receptor agonist xanomeline has antipsychotic properties and is devoid of dopamine receptor-blocking activity but causes cholinergic adverse events. Trospium is a peripherally restricted muscarinic receptor antagonist that reduces peripheral cholinergic effects of xanomeline. The efficacy and safety of combined xanomeline and trospium in patients with schizophrenia are unknown.MethodsIn this double-blind, phase 2 trial, we randomly assigned patients with schizophrenia in a 1:1 ratio to receive twice-daily xanomeline-trospium (increased to a maximum of 125 mg of xanomeline and 30 mg of trospium per dose) or placebo for 5 weeks. The primary end point was the change from baseline to week 5 in the total score on the Positive and Negative Syndrome Scale (PANSS; range, 30 to 210, with higher scores indicating more severe symptoms of schizophrenia). Secondary end points were the change in the PANSS positive symptom subscore, the score on the Clinical Global Impression-Severity (CGI-S) scale (range, 1 to 7, with higher scores indicating greater severity of illness), the change in the PANSS negative symptom subscore, the change in the PANSS Marder negative symptom subscore, and the percentage of patients with a response according to a CGI-S score of 1 or 2.ResultsA total of 182 patients were enrolled, with 90 assigned to receive xanomeline-trospium and 92 to receive placebo. The PANSS total score at baseline was 97.7 in the xanomeline-trospium group and 96.6 in the placebo group. The change from baseline to week 5 was -17.4 points with xanomeline-trospium and -5.9 points with placebo (least-squares mean difference, -11.6 points; 95% confidence interval, -16.1 to -7.1; P<0.001). The results for the secondary end points were significantly better in the xanomeline-trospium group than in the placebo group, with the exception of the percentage of patients with a CGI-S response. The most common adverse events in the xanomeline-trospium group were constipation, nausea, dry mouth, dyspepsia, and vomiting. The incidences of somnolence, weight gain, restlessness, and extrapyramidal symptoms were similar in the two groups.ConclusionsIn a 5-week trial, xanomeline-trospium resulted in a greater decrease in the PANSS total score than placebo but was associated with cholinergic and anticholinergic adverse events. Larger and longer trials are required to determine the efficacy and safety of xanomeline-trospium in patients with schizophrenia. (Funded by Karuna Therapeutics and the Wellcome Trust; ClinicalTrials.gov number, NCT03697252.).

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Markers of muscarinic deficit for individualized treatment in schizophrenia.

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Markers of muscarinic deficit for individualized treatment in schizophrenia.

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