Patients with Alzheimer's dementia may experience co-occurring agitation and psychosis symptoms. This exploratory post hoc analysis aimed to analyze the efficacy and safety of brexpiprazole for agitation in patients with Alzheimer's dementia with and without co-occurring psychosis. Data were pooled from two Phase 3, 12-week, randomized, double-blind, placebo-controlled, fixed-dose trials of brexpiprazole versus placebo in participants with Alzheimer's dementia and agitation, conducted in Europe, Russia, and the US (ClinicalTrials.gov identifiers: NCT01862640, NCT03548584). Post hoc, participants were stratified into subgroups with or without co-occurring psychosis at baseline, defined as a score ≥4 on the Neuropsychiatric Inventory Delusions domain, Hallucinations domain, or both. Efficacy was assessed by the Cohen-Mansfield Agitation Inventory Total score. Safety was assessed by treatment-emergent adverse events (TEAEs). 142/607 participants (23.4%) had co-occurring psychosis at baseline. Brexpiprazole 2 or 3 mg/day was associated with greater improvement in agitation compared with placebo in participants with co-occurring psychosis (least squares mean difference at Week 12, -9.18 [95% confidence interval -15.2 to -3.12]; P=0.004; Cohen's d=0.52) and in participants without co-occurring psychosis (-4.22 [-6.91 to -1.54]; P=0.002; Cohen's d=0.29). In participants with co-occurring psychosis, for brexpiprazole and placebo respectively, 52.9% and 40.0% had TEAEs, and 3.4% and 9.1% discontinued due to TEAEs. No deaths occurred among participants with co-occurring psychosis. In participants without co-occurring psychosis, for brexpiprazole and placebo respectively, 49.3% and 38.2% had TEAEs, and 5.5% and 2.6% discontinued due to TEAEs. Two participants without co-occurring psychosis died; neither death was considered related to brexpiprazole treatment. In this post hoc analysis, brexpiprazole improved agitation and was generally well tolerated in patients with Alzheimer's dementia with and without co-occurring psychosis. These exploratory data suggest that brexpiprazole may be of value to patients with Alzheimer's dementia who present with agitation and psychosis in clinical practice. Alzheimer’s dementia is a brain disorder in which people’s thinking and memory decline slowly over time. Many people with Alzheimer’s dementia experience agitation, which can emerge as movement symptoms (restlessness, wandering) or as spoken or physical aggression (swearing, hitting). People with Alzheimer’s dementia may also experience psychosis, which refers to fixed, false beliefs that are not based in reality, or hearing and seeing things that are not there. Agitation and psychosis can both be treated with antipsychotic medications. However, some antipsychotic medications are thought to cause serious harm, even death, in people with Alzheimer’s dementia. The antipsychotic, brexpiprazole, is the only medicine approved by the United States FDA for the treatment of agitation in people with Alzheimer’s dementia. In this report, researchers used information from previous clinical trials to explore whether brexpiprazole can safely treat agitation in people with Alzheimer’s dementia with both agitation and psychosis. The results showed that brexpiprazole improved agitation more than placebo (a dummy drug), with no new safety concerns compared with previous studies. This suggests that brexpiprazole may be able to help people with agitation and Alzheimer’s dementia, even if they also have psychosis.
Some people with psychosis experience posttraumatic growth (PTG). PTG is defined as positive psychological changes which occurs after the experience of trauma or adversity, following an emotive struggle with the experience. There is some research into the process and domains of PTG in psychosis. However, limitations of the existing evidence base include a focus on experiences of first-episode psychosis, exclusive inclusion of participants who currently use clinical mental health services, and an emphasis on individual-level facilitators. Increasingly, psychosis is considered as a dimensional construct. The aim of this study was to address these gaps by using a dimensional understanding of psychosis to investigate the process of PTG in psychosis, and to validate the PROSPER framework. Semi-structured qualitative interviews about the experience of PTG were conducted with 25 individuals with diagnosed or self-reported experiences of psychosis who self-identify with having experiences of PTG. Inductive and deductive thematic analysis was used to identify PTG processes, mechanisms and outcomes. Participants described the experience of psychosis as a disruption to an individual's life course, which is moderated by personal and trauma factors. All participants could describe experiences of PTG, but some participants reported difficulty identifying current experiences of PTG, indicating that PTG is a dynamic process. The process from the experience of psychosis to PTG was influenced by two mechanisms: cognitive factors and social/societal factors. All seven domains of the PROSPER framework were validated. Experiencing PTG in psychosis is possible. Further research to quantify the effects of mechanisms utilising longitudinal designs would assist to strengthen the evidence base. Interventions to support PTG in psychosis are indicated, targeting both individual and population levels.
Patient-reported measures are increasingly central to early intervention in psychosis. Many persons with psychosis have lower educational attainment than the general population and cognitive difficulties, making the readability of measures salient for this population. However, the readability of patient-reported measures in psychosis has never been investigated. This study assessed the readability levels of patient-reported outcome measures (PROMs) and patient-reported experience measures (PREMs) in early intervention in psychosis. PROMs and PREMs were identified from a scoping review of measures used in early intervention services for psychosis (January 2000-January 2024). Of 111 measures identified, 104 (89 PROMs; 15 PREMs) were assessed using mean grade levels derived from 3 established readability formulas (Flesch-Kincaid Grade Level, Simple Measure of Gobbledygook index, FORCAST formula), applied to instructions, items, and total scales. Overall, 82.7% of patient-reported measures exceeded the recommended 6th-grade reading level. Instructions were harder to read than items (mean readability: 9.44 vs. 7.95; t(90) = 6.54, P < .001). PREMs demanded higher readability levels than PROMs. Readability scores were different across formulas, with Flesch-Kincaid consistently producing lower scores. Except for one, the strikingly few measures co-developed with patients (n = 14) also exceeded 6th-grade reading level. Most patient-reported measures in early psychosis exceed recommended readability levels, raising concerns about accessibility, validity, and whose experiences are represented in patient-reported data. This creates impetus for integrating readability assessments into measures development. More fundamentally, centering the participation of persons with lived experience can support readable, relevant, and patient-centered assessments reflecting the language, priorities, and realities of people with psychosis, and advance epistemic justice.
Among the various mechanisms implicated in abnormal aggression and violent behavior, impaired glutamatergic neurotransmission may represent one contributing factor. However, this hypothesis has been insufficiently explored in human studies. The purpose of the present study was to investigate associations between violent behavior in individuals with and without psychosis and electroencephalography (EEG)-based measures of long-term potentiation (LTP)-like plasticity of the visually evoked potential (VEP), which was previously linked to glutamatergic neurotransmission. Here, healthy controls (HC, n = 180), individuals with psychosis and history of aggression and violent behavior (violent-PSY, n = 16), individuals with psychosis without a history of violence (nonviolent-PSY, n = 25), and individuals with a history of violence without psychosis (violent non-PSY, n = 23) underwent EEG and clinical assessments. Plasticity of VEP component P2 was significantly reduced in violent-PSY compared to nonviolent-PSY (P = .004). Plasticity of P1 component was reduced in violent non-PSY compared to HCs (P = .031). There was no significant association between VEP plasticity and clinical measures of psychotic symptoms, global functioning, and psychopathic traits. Our findings suggest that synaptic plasticity-the adaptive strengthening or weakening of synaptic connections-may be reduced in patients with psychosis and in individuals with a history of violence. Further research is needed to clarify whether plasticity of the P2 component may serve as a marker of violent behavior in psychosis.
Restrictive interventions are used in the treatment of some people with severe mental disorders such as psychosis - including psychiatric intensive care unit (PICU) admission, seclusion and restraint. Early Intervention in Psychosis (EIP) service input may improve outcomes in psychosis, but it is unclear whether specific components of EIP care reduce the need for restrictive practice. To examine associations between EIP care components, demographic characteristics and restrictive interventions. We conducted a retrospective cohort study of 14 874 people who used EIP services in England, using linked data from the National Clinical Audit of Psychosis and the Mental Health Services Data Set. We examined associations between EIP components and time to PICU admission (primary outcome) alongside seclusion/physical restraint/injected chemical restraint/requests for police assistance (secondary outcomes), using multilevel Cox regression, adjusting for demographic factors and clustering by service. Higher hazards of restrictive interventions were observed among men, younger people and several minority ethnic groups. Individuals eligible for clozapine who were not offered it (hazard ratio 1.51, 95% CI 1.20-1.91) or refused it (hazard ratio 1.46, 95% CI 1.02-2.10) had higher hazards of PICU admission than those not eligible, whereas those who were eligible for clozapine and received it did not. There was weaker evidence of similar effects on hazards of physical restraint and seclusion. Receipt of CBT for psychosis was associated with reduced hazards of PICU admission (hazard ratio 0.80, 95% CI 0.67-0.95) and physical restraint (hazard ratio 0.68, 95% CI 0.47-0.98). Substance use was associated with increased hazards of PICU admission and requests for police assistance, although substance use interventions appeared to partially mitigate this. Marked demographic disparities exist in the use of restrictive practice. Specific EIP care components may be associated with reductions. Strengthening evidence-based EIP provision and addressing structural inequalities may support progress towards less coercive and more equitable care.
The early identification of psychosis risk is critical, particularly within the first 2 years of the at-risk phase, as timely intervention may reduce the likelihood of transitioning to psychosis. This study evaluates the reliability and validity of the Spanish version of the Comprehensive Assessment of At-Risk Mental States (CAARMS-S) interview. A prospective longitudinal study was conducted with 36 individuals at ultra-high risk (UHR), 43 with First-Episode Psychosis (FEP), and 14 matched controls, all of whom were part of the Early Intervention Program in Catalonia. Data collection involved clinical interviews and multiple validated scales, including the CAARMS-S, the Positive and Negative Syndrome Scale (PANSS), the Global Assessment of Functioning (GAF), the Structured Clinical Interview for DSM-IV Axis II Personality Disorders (SCID-II), and the Kiddie-Schedule for Affective Disorders and Schizophrenia (K-SADS-PL). Reliability testing showed excellent internal consistency (Cronbach's α = 0.93) and inter-observer reliability [intraclass correlation coefficient (ICC) = 0.92]. Construct validity was supported by significant differences in PANSS positive subscale scores among UHR, FEP, and control groups (p < 0.001). Strong correlations were observed between CAARMS-S and PANSS subscales (positive: r = 0.608; negative: r = 0.495; general: r = 0.577). After 6 months, only one UHR participant (3.3%) transitioned to psychosis. Both CAARMS-S and PANSS were sensitive to changes in positive symptoms, with CAARMS-S being more responsive to negative symptoms and PANSS to general psychopathology. These findings confirm that CAARMS-S is a reliable, valid, and sensitive tool for identifying and monitoring individuals at risk of psychosis in Spanish-speaking clinical settings, supporting its use in early intervention programs.
Understanding drivers of high healthcare utilisation costs among individuals experiencing first-episode psychosis (FEP) is essential for improving care in those with psychotic disorders. To characterise and compare patient-level factors and longitudinal healthcare utilisation costs across 3 years in FEP high-cost (HC) versus non-high-cost (NHC) patients. Commercial US insurance claims data from 2013 to 2019 were used to identify HC and NHC patients with FEP. HC were patients accounting for ≥50% of total direct healthcare expenditures within the FEP cohort. Binomial logistic regression was used to identify patient-level factors associated with the HC group. Total healthcare costs and service modalities, including inpatient, outpatient, emergency and prescription drugs, were compared between HC and NHC across time. Of 27 587 patients with FEP, 12% were HC with higher rates of multiple psychotic disorder diagnoses (p<0.001), chronic medical conditions (p<0.001) and exposure to adverse social determinants of health (p<0.01), particularly for economic category (p<0.001), with vitamin deficiency listed as the highest frequency. Cost analysis revealed a positive relationship between psychosis- and non-psychosis-related conditions, with HC having increased inpatient use for both. Factors associated with being HC in this nationally representative private-payer FEP population were behavioural diagnostic instability, comorbid mental and physical health conditions, and exposure to adverse social factors, including nutritional deficiency. Additionally, psychosis and non-psychosis-related costs stabilise within 2 years. These findings may be important in identifying individuals who may benefit from additional, more intensive services.
This review evaluates structural neuroimaging research on substance-related psychosis to determine if these conditions share common neurobiological pathways with primary psychotic disorders, such as schizophrenia, or exhibit unique signatures. Research indicates that methamphetamine, cannabis, and cocaine induce significant structural changes, including cortical thinning and grey matter loss. Methamphetamine-induced psychosis is associated with frontal lobe reductions and smaller hippocampal and amygdalar volumes. Cannabis use is linked to alterations in the cingulate cortex and cerebellar networks, particularly when use begins early in life. While many neuroimaging patterns overlap with schizophrenia substance-specific variations exist. For instance, methamphetamine users show more pronounced amygdalar reduction than those with primary psychosis. Generally, structural deficits are more severe and widespread in schizophrenia than in purely substance-induced cases. Substance-induced psychoses exhibit neuroanatomical signatures largely similar to primary psychoses, though distinct regional variations suggest partially divergent mechanisms. Future longitudinal and multimodal research is essential to identify definitive biomarkers for clinical differentiation.
Childhood trauma and other early adverse experiences are consistently associated with increased risk for psychopathology and greater positive symptom severity for individuals on the psychosis spectrum. Mounting evidence suggests that childhood trauma may lead to impairments in reward and motivational processes, contributing to negative symptoms of psychosis such as anhedonia and avolition. However, the mechanisms underlying this relationship are not well characterized. This review proposes a model in which hippocampal alterations following childhood trauma contribute to later reward-related deficits, which in turn influences risk for psychopathology. Drawing on both human and animal literature, we discuss the critical role of the hippocampus in modulating dopaminergic circuits crucial to reward learning and motivation. Although much of the literature on reward processes emphasizes striatal function, we focus on hippocampal circuitry to highlight its influence on sustained motivational states and goal-directed behaviors. Additionally, we address the broader impact of stress on hippocampal structure and function. By integrating findings across clinical and non-clinical populations, we aim to advance understanding of the hippocampus as a potential mediator between early life adversity and negative symptoms, offering insights into potential therapeutic targets to mitigate the long-term effects of childhood trauma on mental health outcomes.
Family psychoeducation is a key psychosocial strategy in early psychosis care, but its specific effects for relatives of people with first-episode psychosis (FEP) remain uncertain. We conducted a systematic review and meta-analysis, registered in PROSPERO (CRD42024585814) and following PRISMA, to evaluate clinical and caregiver outcomes. Randomized and nonrandomized trials comparing structured programs with treatment as usual or other interventions were searched in PubMed, Embase, Scopus, and the Cochrane Library to April 2024. Fifteen studies (n=2,271) met criteria. Pooled results showed benefits for patients: lower risk of psychiatric hospitalization (risk ratio 0.64; 95% CI 0.45-0.90) and shorter inpatient stays (standardized mean difference [SMD] -0.29; 95% CI -0.50 to -0.09). Symptoms also improved, with reductions in general psychopathology (SMD -0.45; 95% CI -0.80 to -0.09), positive symptoms (SMD -0.36; 95% CI -0.63 to -0.09), and negative symptoms (SMD -0.32; 95% CI -0.49 to -0.15). Effects on negative symptoms persisted at two-year follow-up. No significant effects emerged for functioning or caregiver burden. Overall, family psychoeducation is a low-cost, feasible intervention that improves clinical outcomes and reduces service utilization in FEP, supporting incorporation into early-intervention programs.
Adults with schizophrenia exhibit substantial and widespread cognitive impairment, with subtle cognitive deficits already apparent in childhood and adolescence - many years prior to the onset of psychosis. Here, we focus on evidence from population-based research highlighting findings specific to cognitive impairment (as indexed by IQ) that precedes the onset of schizophrenia. We illustrate that (i) cognitive impairment worsens from early childhood onwards through to the onset of psychosis; (ii) this early and progressive cognitive impairment is rarely present in other psychotic disorders. At the same time, (iii) early cognitive impairment is not universal in schizophrenia; and (iv) a substantial role for genes affecting both schizophrenia and early life cognitive impairment has not been unequivocally proven. We suggest that a subgroup of patients with schizophrenia is characterized by progressive premorbid cognitive impairment. This group is developmentally distinguishable from the rest of patients with psychoses. Future studies should focus on understanding the (possibly unique) etiology in this neurodevelopmental subgroup of schizophrenia patients.
Repetitive negative thinking may contribute to negative symptoms in psychosis. We report clinical outcomes from a pilot randomized clinical trial evaluating the feasibility and efficacy of group rumination-focused cognitive behavioural therapy (RFCBT) added to early outpatient care (OPUS) versus OPUS alone, i.e., treatment-as-usual (TAU). Young adults with schizophrenia spectrum disorders receiving OPUS care were randomized 1:1 to 13 weeks of group RFCBT plus OPUS or to TAU. Assessments were conducted at baseline and post-treatment. Feasibility was defined as ≥80% of participants completing ≥six sessions. The primary outcome was Brief Negative Symptom Scale (BNSS). Secondary outcomes were Perseverative Thinking Questionnaire (PTQ), Ruminative Responses Scale (RRS), Scale for the Assessment of Positive Symptoms (SAPS), Calgary Depression Scale for Schizophrenia (CDSS), Behavior Rating Inventory of Executive Function (BRIEF), and Social Functioning Scale (SFS). Between-group differences in change scores were tested with Welch t-tests. Fifty-nine participants were included, but one withdrew consent, meaning fifty-eight participants were analyzed intention-to-treat (RFCBT n=28, TAU n=30). The treatment was feasible with 82.14 % of participants in the RFCBT group completing ≥six sessions. Compared with TAU, RFCBT produced greater improvement in BNSS (between-group Δ -5.90; p=0.05; d=0.72). Repetitive negative thinking and rumination improved significantly: PTQ (Δ -8.35; p=0.016; d=0.89) and RRS (Δ -9.62; d=1.15; p=0.001). No significant between-group differences were observed for SAPS, CDSS, BRIEF, or SFS. Adding group RFCBT to OPUS was feasible and yielded large reductions in negative symptoms and repetitive negative thinking relative to TAU, supporting progression to a fully powered trial.
This paper applies principles and perspectives emerging from free energy neuroscience to the psychoanalytic concept of the death drive. The aim is to offer a contemporary reappraisal of this controversial aspect of psychoanalytic theory and its link to psychosis. The paper begins with a review of the death drive as proposed by Sigmund Freud, before proceeding to briefly outline Karl Friston's free energy principle. Building on proposals from Gustaw Sikora and Bernard Penot, it then explores how the combined and coordinating processes of minimising [binding] free energy and dismantling [unbinding] inexpedient generative models of reality may be understood as essential to life, growth, and adaptation. The question is thus raised: if a periodic unbinding-even destruction and demise-of generative models is vital to adaptive living, how might the death drive be conceptualised? The paper then proceeds to develop the notion that what Freud identified as the (defused) death drive may reflect a critical breakdown in the reciprocal ebb and flow of binding free energy/unbinding generative models of reality. Two illustrations-both of which concern psychotic phenomena-are given in an attempt to depict how the death drive in defused form may be recognised as manifesting both as arrested unbinding and/or interminable binding. The discussion explores how such a breakdown in the vital rhythms of life and self-organisation can sabotage the ability to think, compromise the mind's capacity to function as a container, and produce a boundless infinitisation of experience therein.
[This corrects the article DOI: 10.3389/fpsyt.2026.1774487.].
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Housing insecurity and substance use disorder (SUD) are critical public health issues in the USA, with significant implications for health outcomes. This study evaluated the intersection of housing insecurity, SUD, and psychosis among Medicaid enrollees in an urban center in Oregon. Using data from Health Share of Oregon, we identified three distinct cohorts-individuals with housing insecurity, those with SUD/psychosis, and those with both conditions. Key outcomes included inpatient admission rates, average lengths of stay, and 30-day readmissions. The findings indicate that housing-insecure individuals with SUD/psychosis show greater acute care utilization than the other two cohorts. Inpatient admissions for housing-insecure individuals with SUD/psychosis were over twice as high as those without housing insecurity (29.7% vs. 12.4%), nearly three times as high as those without SUD/psychosis (29.7% vs. 9.5%), and almost ten times higher than those without either (29.7% vs. 3.0%). There were likewise corresponding increases in ambulatory-sensitive hospitalizations, 30-day readmissions, and longer hospital stays. Effective interventions should address both housing and healthcare needs, including comprehensive case management and improved access to physical, behavioral, and mental health services integrated with housing programs and services. These strategies could mitigate acute care utilization and improve overall health outcomes for these vulnerable populations.
Psychotic symptoms in children and adolescents may represent either normative developmental phenomena or severe psychiatric and medical conditions, requiring careful differential diagnosis. This retrospective study aimed to evaluate the medical workup of children and adolescents admitted for a first presentation of psychotic symptoms at a tertiary pediatric center over a 10-year period. The sample included 68 patients (mean age 13.7 ± 3.7 years) who underwent clinician-directed evaluations including physical exams, laboratory tests, toxicology screens, neuroimaging, and lumbar puncture when indicated. Sixteen patients (23.5%) were diagnosed with substance-/medication-induced or medically-associated psychosis. In this cohort, younger age, very early onset psychosis (<13 years), and catatonia at first presentation were more frequently observed among patients with secondary etiologies, whereas documented prior subthreshold symptoms were more frequently documented among those diagnosed with primary psychiatric disorders. Most investigations did not identify a secondary cause, reflecting clinician-directed evaluation in routine practice; however, selected cases (e.g., autoimmune encephalitis, multiple sclerosis) illustrate the clinical importance of careful assessment when specific suspicion is present. These findings suggest that targeted medical evaluation may be useful in pediatric psychosis, particularly when clinical features raise suspicion for secondary etiologies, and may help inform clinical decision-making in tertiary pediatric settings.
Copy number variants (CNVs) at 22q11.2 confer substantial risk for neurodevelopmental and psychiatric disorders. Both the 22q11.2 deletion (22qDel) and 22q11.2 duplication (22qDup) are associated with increased risk for autism spectrum disorder and intellectual disability. In contrast, while 22qDel markedly increases risk for schizophrenia, 22qDup may be protective. Prior neuroimaging work has focused primarily on the cerebrum, leaving cerebellar contributions understudied, despite growing evidence for their relevance to cognition and psychopathology. Here, we characterized regional cerebellar structure and examined multivariate cerebellar-behavior associations in individuals with reciprocal 22q11.2 CNVs. We analyzed 514 structural magnetic resonance imaging scans from 315 participants (mean age = 16.4 ± 8.8 years; 52% female), comprising 22qDel carriers (n = 111), 22qDup carriers (n = 37), and typically developing (TD) control participants (n = 167). The cerebellum was parcellated into 28 subregions using ACAPULCO. Group differences in total and regional cerebellar volumes were examined using linear mixed-effects models with false discovery rate correction. Multivariate brain-behavior associations were assessed using partial least squares correlation (PLSC). Relative to TD control participants, 22qDel carriers showed widespread cerebellar volume reductions, whereas alterations in 22qDup were milder and regionally selective. Vermis VII was reduced in both 22q11.2 CNVs, indicating a shared site of anatomical vulnerability. PLSC identified domain-specific cerebellar patterns, with posterior regions-most prominently bilateral lobule VIIIA-associated with cognitive and social functioning and bilateral crus II and medial regions associated with psychosis-risk symptoms. Reciprocal 22q11.2 CNVs showed shared and divergent cerebellar alterations, with distinct subregions contributing to different behavioral domains, underscoring the cerebellum's multifaceted role in neurodevelopment and psychiatric disease risk. People with small DNA changes on chromosome 22q11.2 have greater risk for autism and intellectual disability, but only the deletion increases psychosis risk. Here, we studied brain scans from people with these conditions to see how the cerebellum is affected. Deletions were linked to widespread cerebellar reductions, while duplications showed milder changes. One region, vermis VII, was smaller in both groups. Different cerebellar reduction patterns were associated with poorer cognition and social functioning and increased psychosis symptoms.
Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis involving multiple systems, with central nervous system (CNS) involvement present in a significant subset. Neuropsychiatric symptoms such as cognitive decline, mood disturbances, and psychosis have been documented. However, sensitivity to psychotropic medications in CNS-involved ECD remains underreported. This case highlights a multi-mechanistically compromised CNS posing diagnostic and therapeutic challenges by such sensitivity. A 50-year-old woman with biopsy-confirmed ECD and CNS involvement presented with persistent neuropsychiatric symptom confusion, psychosis, cognitive decline, mood lability, and agitation despite radiologic remission following cladribine and radiotherapy. She exhibited marked sensitivity to multiple psychotropics: haloperidol induced QTc prolongation; risperidone and aripiprazole triggered akathisia and insomnia; olanzapine caused hypotension; chlorpromazine and quetiapine led to oversedation; and benzodiazepines paradoxically worsened agitation. Only valproic acid was tolerated. Factors such as previous chemotherapy, brain radiotherapy, hypernatremia, endocrine dysfunction, and a family history of psychiatric illness were suspected to have a role in predisposition. Imaging showed lesions of the hypothalamus, pituitary stalk, and mesial temporal lobes. Persistent symptoms shared features with Lewy Body Dementia and raised the diagnostic ambiguity. To our knowledge, this is one of the first detailed reports to describe heightened neuropsychiatric instability and psychotropic intolerance in a patient with a compromised CNS through several suspected mechanisms. The case underscores the need for multidisciplinary care and cautious psychiatric management in patients with a compromised CNS. Clinicians should suspect psychotropic sensitivity in cases with paradoxical responses and consider systemic causes such as ECD as a possible contributor.
Treatment-resistant schizophrenia (TRS) is defined as nonresponse to at least two adequate antipsychotic trials at therapeutic doses for six or more weeks. Currently, clozapine is the only antipsychotic approved for TRS by the FDA and a plethora of evidence indicates that it is the most efficacious antipsychotic for treatment of chronic and refractory cases of schizophrenia. However, its utilization is often limited by metabolic, hematologic, and anticholinergic side effects. Notably, clozapine-induced obsessive-compulsive symptoms (OCS) or obsessive-compulsive disorder (OCD) have been increasingly recognized, attributed to its potent serotonergic antagonism. In 2024, the FDA approved xanomeline-trospium, a dual agent combining a central muscarinic M1/M4 agonist with a peripheral antimuscarinic, which offers a novel approach to treating psychosis. Early evidence suggests comparable efficacy to other antipsychotics, with fewer metabolic and extrapyramidal side effects. We present a case of a woman with longstanding schizophrenia and clozapine-induced OCD successfully transitioned to xanomeline-trospium, resulting in remission of both psychotic and obsessive-compulsive symptoms. A 57-year-old woman with a chronic history of schizophrenia, requiring multiple hospitalizations and maintenance electroconvulsive therapy (ECT), stabilized on clozapine 300 mg nightly after failing several antipsychotics. Despite adherence, she exhibited persistent hallucinations, negative symptoms, and later developed clozapine-induced OCD characterized by intrusive counting and numerical obsessions refractory to high-dose sertraline. Due to distressing OCD and passive suicidal ideation, she was admitted for a discontinuation of clozapine and initiation of xanomeline-trospium. Clozapine was tapered and discontinued before initiating xanomeline-trospium, titrated to 100 mg/20 mg twice daily. Within one week after starting xanomeline-trospium, her counting obsessions resolved, psychosis improved, and suicidality resolved. At discharge, three weeks post-admission, she remained stable on xanomeline-trospium, ziprasidone, and sertraline, with complete remission of hallucinations and obsessions. This case highlights a successful switch from clozapine to xanomeline-trospium for management of chronic schizophrenia and clozapine induced OCD. The patient's improvement raises important considerations regarding clozapine-induced OCD, cautious discontinuation, and the benefit of muscarinic receptor agonists. Xanomeline-trospium may represent a viable alternative for patients intolerant of clozapine. Not applicable.