KarXT (marketed as Cobenfy™), a fixed-dose combination of xanomeline and trospium chloride, represents the first new mechanism of action of an antipsychotic used for adult schizophrenia approved by the US Food and Drug Administration (FDA) in over 30 years. While mainstream drugs (e.g. haloperidol, chlorpromazine, risperidone, olanzapine, quetiapine, aripiprazole) mainly antagonize dopamine D2 or serotonin 5-HT2A receptors, KarXT acts through transient activation of muscarinic M1 and M4 receptors. M4 stimulation influences the functioning of mesolimbic dopaminergic pathways, providing an indirect means of regulating dopamine release that bypasses D2 blockade. Trospium, a peripherally acting muscarinic receptor antagonist, was used to reduce anticholinergic adverse effects (AEs). It does not cross the blood–brain barrier and therefore minimizes central adverse events. In a series of randomized placebo-controlled phase 2 and 3 studies, the KarXT significantly and clinically meaningfully reduced Positive and Negative Syndrome Scale (PANSS) total scores. The effect sizes were moderate to large with few extrapyramidal symptoms (EPS), minimal metabolic disturbances and no significant prolactin level increases. In this narrative review, we discuss in detail the pharmacological mechanism, basis of preclinical development, and clinical outcomes of KarXT. We also contextualize this drug within the development of a new wave of non-D2 antipsychotics, highlighting cholinergic dysfunction as one important mechanistic pathway within the broader multidimensional neurobiology of schizophrenia.
Methamphetamine-withdrawal catatonia resolved with mixed amphetamine salts: a case report
Catatonia is a well-recognized psychiatric emergency with an evolving understanding of its underlying pathophysiology. However, withdrawal-associated catatonia remains poorly characterized. Here we describe a 32-year-old man with symptoms consistent with methamphetamine-withdrawal catatonia, a previously undescribed etiology, which resolved only after treatment with mixed amphetamine salts. The patient remained catatonic (Bush-Francis Catatonia Rating Scale [BFCRS] >10) for four months despite 38 sessions of electroconvulsive therapy, lorazepam up to 24 mg daily, and multiple augmentation strategies. An extensive medical and neurologic workup excluded alternative causes. Following initiation of mixed amphetamine salts, his BFCRS decreased from 15 to 6 within 48 hours, with sustained resolution and no recurrence of psychosis despite discontinuation of antipsychotics. This case suggests that methamphetamine withdrawal may represent an underrecognized cause of catatonia and that dopaminergic augmentation may have a therapeutic role in refractory cases.
Ethical and Legal Considerations in the Collection and Analysis of Mental Health Lived Experience Narratives: Reflections on 4 Case Studies of Research Practice
Personal narratives describing lived experiences of the entire spectrum of mental health challenges are now widely available to the public, including through autobiographies from public figures, thematic collections of narratives assembled by mental health organizations, and individual narratives published on video sharing services. Mental health lived experience narratives have been used as an “active ingredient” in interventions intended to create change, such as in campaigns against mental health stigma. In the narrative inquiry research approach, they are used to explore mental health phenomenology. Researchers and organizations working with mental health lived experience narratives have to contend with a wide range of legal and ethical challenges, such as how to handle narratives disclosing sensitive personal information about third parties and the ethical trade-off between preserving narrator autonomy over their presentation of personal identity and protecting narrators from harm due to mental health stigma if a narrator is identifiable in their narrative. In 2022, we formed the Interdisciplinary Consortium on Narratives in Context (ICONIC) of people with knowledge of narrative practices across disciplines. Members are engaged in health research, liberal arts, modern languages, history, and philosophy. In this viewpoint, we present four case studies of narrative practices by ICONIC members: (1) a narrative inquiry into the experiences of Ethiopian citizens with schizophrenia, (2) work to curate and share 2 collections of mental health recovery narratives, (3) an exploration of the use of poetic transcription to condense narrative interviews with mental health content, and (4) the development of safe approaches to working with personal narratives shared through an online mental health peer support service. In presenting these case studies, we focused on documenting decision-making on ethical and legal challenges as the best knowledge on ethical and legal decision-making regarding mental health lived experience narratives may come from integrating knowledge across disciplines. Through reflecting on these case studies, we identified cross-cutting challenges regarding consent processes, narrative analysis, and the interpretation and dissemination of data and findings. These challenges have transdisciplinary and disciplinary-specific features and can be used as a preliminary checklist in research design processes. In presenting what we learned, our intent was to demonstrate that greater knowledge on narrative practices can emerge through interdisciplinary contact and inform future decision-making on narrative practices by researchers working across disciplines. We conclude by contemplating interdisciplinary explorations with the potential to expand knowledge, including examining the use of pathographic narratives in philosophical inquiry.
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Virtual Reality–Assisted Therapy Compared to Cognitive Behavioral Therapy for Patients With Treatment-Resistant Schizophrenia: Assessor-Blind Randomized Controlled Trial
Background: Auditory verbal hallucinations (AVH) are among the most disabling symptoms of schizophrenia and often persist despite treatment. Virtual reality–assisted therapies (VRTs) are a new generation of relational interventions for AVH, but comparative evidence against active interventions is currently lacking. Objective: This study aimed to assess whether VRT (9 sessions) is superior to a short course of cognitive behavioral therapy (CBT) targeting AVH (9 sessions) in reducing AVH in individuals with treatment-resistant schizophrenia. Methods: In this assessor-blind, parallel-group randomized controlled trial conducted from 2019 to 2026 at an academic center in Montreal (Canada), adults with schizophrenia or schizoaffective disorder and persistent AVH were either referred by their health care team or self-referred. A total of 136 participants were randomly assigned 1:1 to VRT or CBT, stratified by sex and clozapine use status. Both 9-session interventions targeted maladaptive beliefs and relationships with voices and were administered by trained psychotherapists. The predetermined primary outcome was the evolution of AVH severity over time, measured at baseline, post treatment, and 3 months post therapy using the auditory hallucination subscale of the Psychotic Symptoms Rating Scale. Secondary outcomes notably included the general psychotic symptomatology measured using the Positive and Negative Syndrome Scale. Linear mixed-effects models were used to assess time-by-treatment interactions. Psychotherapy sessions and assessments were conducted primarily in person, with CBT being occasionally delivered via videoconferencing during the COVID-19 pandemic. Results: Participants had a mean age of 40.3 (SD 12.8) years, 63.2% (86/136) were male, and 56.6% (77/136) received clozapine. Intention-to-treat analyses (VRT, n=67; CBT, n=69) showed a significant time-by-treatment interaction favoring VRT (=.013) with a moderate effect size at 3 months post therapy (Cohen =0.614). Both therapies showed significant within-group improvements in the primary outcome, with large effect sizes for VRT (Cohen =0.81 post therapy and Cohen =1.17 at 3 months) and moderate for CBT (Cohen =0.58 post therapy and Cohen =0.39 at 3 months). While there were no between-group differences for secondary outcomes, within-group improvements were observed in psychotic symptoms, emotional regulation, and voice acceptance for both therapies, and VRT also reduced maladaptive beliefs about voices and improved self-esteem. Conclusions: VRT outperformed a targeted short course of CBT in reducing persistent AVH for up to 3 months after the intervention in a North American population with treatment-resistant schizophrenia. Improvements were also seen in some secondary outcomes, such as general psychotic symptomatology, and those were similar for both interventions. Overall, these findings support the value of VRT as a personalized and clinically effective intervention. Trial Registration: ClinicalTrials.gov NCT04054778; https://clinicaltrials.gov/study/NCT04054778
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Neural encoding of auditory processing in schizophrenia
IntroductionAuditory processing abnormalities are a core feature of schizophrenia and are linked to deficits in speech perception, cognitive function, and everyday communication. It remains unclear which stages of auditory processing are most disrupted and how these disruptions relate to symptoms at the level of population-wide neural representations.MethodsWe used fMRI recordings acquired while individuals with schizophrenia and matched healthy controls completed a controlled block-design speech-perception task. Voxel-wise encoding models mapped self-supervised speech-model representations, together with complementary acoustic and linguistic features, to neural responses.ResultsAcross cross-validated evaluations, individuals with schizophrenia showed numerically higher encoding alignment than matched controls across all evaluated regions of interest, although no effect survived false discovery rate correction in this small sample. The largest numerical group differences occurred in frontal language regions, including the middle frontal gyrus and dorsomedial prefrontal cortex, and in early auditory cortex. Subgroup analyses suggested that patients without auditory verbal hallucinations drove much of this numerical separation.DiscussionThese descriptive, hypothesis-generating findings suggest that model-based encoding can reveal a frontal-auditory signature in schizophrenia, but they do not establish a clinically actionable biomarker or preserved or enhanced speech encoding. Larger, adequately powered studies with richer feature spaces are needed for confirmatory inference and to test whether encoding-based measures can serve as clinically meaningful biomarkers.
Neurophysiological Signatures of Negative Symptom Improvement After High-Definition Transcranial Direct Current Stimulation: A Transcranial Magnetic Stimulation-Electroencephalography Study
Schizophrenia remains a major health challenge, partly because conventional antipsychotics show limited efficacy for negative symptoms. High-definition transcranial direct current stimulation (HD-tDCS) may improve these symptoms, but its neurophysiological mechanisms remain unclear.
Dexamphetamine-induced striatal hyperdopaminergia attenuates reward-related neural activation: A11C-PHNO PET-fMRI study
Ventral striatum (VS) and ventromedial prefrontal cortex (vmPFC) encode the value of stimulus and outcome phases in a context-dependent manner to support motivated behaviour. In psychosis, disrupted motivational coding has been hypothesised to contribute to negative symptoms via reduced sensitivity to goal-relevant information, potentially linked to elevated striatal dopamine. Direct causal evidence for this mechanism in humans remains limited.
[Comment] Relapse or rebound: the case for personalisation in antipsychotic discontinuation
For people with schizophrenia and their psychiatrists, deciding whether to discontinue antipsychotic treatment is a crucial decision. On average, stopping medication roughly doubles relapse risk and increases rates of rehospitalisation and mortality.1,2 However, continued treatment carries its own burden of metabolic harm and sedation, leading many patients to consider stopping.3 The clinical challenge, then, is not a simple choice between continue and discontinue, but identifying who can safely discontinue, and when.
[Comment] Psychodynamic psychotherapy in schizophrenia: where do we stand?
The role of psychodynamic psychotherapy for schizophrenia spectrum disorders has been debated for decades. During the 1960s and 1970s, psychodynamic and psychoanalytical therapies were widely used and were often the main treatment for individuals with schizophrenia-spectrum disorders.1 However, as more rigorous randomised controlled studies and longitudinal naturalistic follow-up studies accumulated, psychodynamic approaches failed to show benefits beyond standard of care.2,3 Some studies even raised concerns about potential negative effects, including increased suicidality.
Mobile Application-Based Interventions for Cannabis Use in Young Adults With First Episode Psychosis
Conditions: First Episode Psychosis (FEP); Psychosis; Schizophreni-form Disorder; Dependence Addictive
Interventions: Other: CHAMPS; Other: I Can Change
Sponsors: Centre hospitalier de l’Université de Montréal (CHUM); Integrated University Health and Social Services Center of the Capitale-Nationale; Nova Scotia Health Authority; Centre Intégré de Santé et de Services Sociaux de la Montérégie-Centre; Centre Integre Universitaire de Sante et Services Sociaux du Nord de l’ile de Montreal; Ottawa Hospital Research Institute
Not yet recruiting
Interventions: Other: CHAMPS; Other: I Can Change
Sponsors: Centre hospitalier de l’Université de Montréal (CHUM); Integrated University Health and Social Services Center of the Capitale-Nationale; Nova Scotia Health Authority; Centre Intégré de Santé et de Services Sociaux de la Montérégie-Centre; Centre Integre Universitaire de Sante et Services Sociaux du Nord de l’ile de Montreal; Ottawa Hospital Research Institute
Not yet recruiting