BACKGROUND: Lifestyle interventions, including exercise, can improve physical and mental health outcomes in first-episode psychosis (FEP), but availability of face-to-face programmes is limited. Teleconferencing software...BACKGROUND: Lifestyle interventions, including exercise, can improve physical and mental health outcomes in first-episode psychosis (FEP), but availability of face-to-face programmes is limited. Teleconferencing software (such as Zoom) presents new opportunities for lifestyle interventions, at scale. Thus, this study assessed the feasibility and preliminary impact of remotely delivered, supervised exercise sessions for FEP. METHODS: A single-arm, eight-week feasibility study was conducted in two NHS Early Intervention Services (EIS) for FEP. Participants aged 18-35 years were offered twice-weekly live Zoom sessions, streaming body-weight exercise videos followed by a brief lifestyle discussion facilitated by the research team. Feasibility metrics were recruitment, retention, attendance and adverse events, along with pre-post self-report measures of physical activity, weight, psychological distress, functioning, life satisfaction, and self-efficacy. RESULTS: Of 45 participants approached, 32 (71%) consented, 27/32 (84%) commenced the intervention, and 21/27 (78%) completed the follow-up assessment. Participants attended an average of 7.6 live online exercise sessions (±5.1) over their 8 week intervention period. Over 90% of 70 exercise sessions offered had participants in live attendance, with no adverse events. After 8 weeks, significant increases were seen in physical activity (p < 0.01) and psychosocial functioning (p = 0.05). Psychological distress decreased, particularly among those attending ≥50% of sessions (n = 12). No significant changes were observed in other measures. CONCLUSIONS: Twice-weekly online sessions, using pre-existing exercise videos, appears feasible, safe and engaging for young adults with FEP, and potentially beneficial for psychological wellbeing and functioning. Further research is required includes RCTs with an embedded process and economic evaluations, and implementation studies.
Saarikivi J, Hjellvik V, Tiihonen J
… +4 more, Lähteenvuo M, Taipale H, Odsbu I, Lieslehto J
Schizophr Res
· 2026 Jun · PMID 41904923
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BACKGROUND: Identifying patients with first-episode psychosis (FEP) at high mortality risk may facilitate personalized treatment regimen development and reduce the mortality gap between individuals with psychotic disorde...BACKGROUND: Identifying patients with first-episode psychosis (FEP) at high mortality risk may facilitate personalized treatment regimen development and reduce the mortality gap between individuals with psychotic disorders and the general population. Following validation studies in Sweden and Finland, we aimed to externally validate the recently developed mortality risk prediction machine learning model, MIRACLE-FEP, with a new Norwegian national cohort. METHODS: We analyzed a Norwegian national register-based cohort of patients with FEP (N = 4632), with follow-up extending to 8 years. The performance of MIRACLE-FEP was evaluated via the area under the receiver operating characteristic curve (AUROC) and calibration. In addition to all-cause mortality (primary outcome), we assessed the model's discrimination performance for specific causes of death. Finally, we examined whether the model demonstrates any bias toward gender, education level, or immigration status. RESULTS: MIRACLE-FEP demonstrated an AUROC of 0.71 (95% CI 0.63-0.79) for the prediction of 2-year all-cause mortality. Calibration was relatively good, with a calibration slope of 1.04 (95% CI 0.68-1.47) and a calibration-in-the-large value of 0.31 (-1.93-1.26). Among specific causes of death, the model showed the highest discrimination for deaths due to accidents (AUROC 0.86, 95% CI 0.79-0.93) and the lowest for suicide (AUROC 0.47, 95% CI 0.35-0.59). No evidence of bias was observed in discrimination accuracy by gender, education level, or immigration status. CONCLUSIONS: The performance metrics of this external validation study aligned with those reported in the development study. Efforts to enhance MIRACLE-FEP's performance in suicide prediction are needed.
BACKGROUND: The prognosis of psychosis with onset in childhood and adolescence is highly variable. This study explores long-term outcomes of early-onset psychosis (EOP) compared to controls (HC) and examines predictors o...BACKGROUND: The prognosis of psychosis with onset in childhood and adolescence is highly variable. This study explores long-term outcomes of early-onset psychosis (EOP) compared to controls (HC) and examines predictors of employment as well as psychiatric and somatic hospitalizations in EOP. METHODS: We combined data from four clinical studies, comprising a total of 205 individuals with first-episode EOP and 199 age- and sex-matched HCs. Long-term follow-up data (mean = 11 years) on demographic, functional, and clinical outcomes were retrieved from Danish national registers. Factors associated with employment, psychiatric hospitalizations, and somatic hospitalizations were analyzed in univariable and multivariable models. RESULTS: Compared to HCs, individuals with EOP had less favorable demographic, functional, and clinical outcomes. In EOP, higher household income and better neurocognitive functioning at baseline were associated with higher rates of competitive employment at follow-up in univariable albeit not multivariable analyses. Higher age, female sex, substance use, lower parental education and moderate household income at baseline were associated with more somatic inpatient days during follow-up in both uni- and multivariable analyses, while low social functioning was associated with somatic hospitalization in the univariable model only. We identified no baseline factors associated with frequency of psychiatric inpatient days during follow-up. CONCLUSION: Our study highlights the need for improving prognosis of EOP across functional, psychiatric, and somatic outcomes. The identified baseline factors associated with later unfavorable outcomes can serve as prognostic markers, potential treatment targets, and for identifying individuals in need of intensified support.
BACKGROUND: Sleep architecture is an essential lifestyle factor influencing health and well-being, and it may offer a trans-diagnostic window to understand the shared pathophysiology across schizophrenia (SCH), bipolar d...BACKGROUND: Sleep architecture is an essential lifestyle factor influencing health and well-being, and it may offer a trans-diagnostic window to understand the shared pathophysiology across schizophrenia (SCH), bipolar disorder (BD), and major depressive disorder (MDD). However, direct comparative evidence of sleep architecture features among these three major psychiatric disorders remains scarce, especially among patients in the first-episode phase. METHODS: Whole-night polysomnography (PSG) was performed in 109 SCH, 107 BD, and 258 MDD patients. All patients were first-episode and were drug-naive or had received minimal treatment prior to enrollment. LASSO regression-selected demographic, clinical, and PSG variables entered multinomial logistic models. Receiver Operating Characteristic (ROC), calibration, and decision-curve analyses were used to assess performance. RESULTS: LASSO retained BMI, course, sleep efficiency (SE), REM latency (REML), and N2%. Shorter disease course, higher BMI, lower SE and shorter REML differentiated SCH from MDD (all p < 0.05); higher BMI, longer course, shorter REML, and elevated N2% separated BD from MDD (all p < 0.05). The receiver operating characteristic curves (AUC) were 0.750 (MDD vs SCH) and 0.717 (MDD vs BD). The decision curves showed net clinical benefit across the wider threshold probabilities. CONCLUSIONS: A brief, five-variable panel-integrating three key PSG parameters with BMI and disease course-demonstrated modest but clinically significant discrimination among SCH, BD, and MDD, supporting sleep-based adjunctive tools that refine differential diagnosis and advance precision psychiatry.
Blunted affect is a prominent negative symptom of schizophrenia characterized by decreased facial, gesture, and vocal expressions. Blunted affect is prevalent in one-third of people with schizophrenia and is associated w...Blunted affect is a prominent negative symptom of schizophrenia characterized by decreased facial, gesture, and vocal expressions. Blunted affect is prevalent in one-third of people with schizophrenia and is associated with clinical and functional correlates, including social functioning, quality of life, and suicide. While treatments are sparse and generally noneffective, there is increasing research in the field seeking to elucidate underlying mechanisms in order to better understand pathways to blunted affect. This editorial defines blunted affect and discusses the prevalence, historical context, and assessment methods. Furthermore, we highlight possible mechanisms of blunted affect and discuss additional considerations that serve as future directions for this area of research.
BACKGROUND: Reducing the duration of untreated psychosis (DUP) is a key aim of early intervention in psychosis (EIP) services. While DUP accounts for a proportion of the time individuals experience psychotic symptoms, th...BACKGROUND: Reducing the duration of untreated psychosis (DUP) is a key aim of early intervention in psychosis (EIP) services. While DUP accounts for a proportion of the time individuals experience psychotic symptoms, the duration of active psychosis (DAP) concept provides a broader scope by including the duration of psychosis both before and after treatment initiation. This study aimed to describe DAP in a large naturalistic cohort of people with first-episode psychosis (FEP), and explore the relationship between DAP and early psychosis outcomes. METHODS: This study involved secondary analyses of an existing dataset of consecutive cases of FEP in young people aged 15 to 24 from an EIP service in Melbourne. The duration of active psychosis after treatment initiation (DAT), limited to the first year of care, was estimated using the short form Scale for the Assessment of Positive Symptoms measured repeatedly at regular intervals. This was combined with DUP to calculate DAP. DAP was divided into four groups according to quartiles and regression analysis was used to explore the relationship between DAP and outcomes at discharge. RESULTS: DAP was estimated for 749 individuals with FEP. The group with the longest DAP (>58 weeks) presented at a younger age (mean 18.6 vs mean 19.7) and had a higher proportion of females (49.7% vs 38.9%). Adjusted linear regression models demonstrated that longer DAP (>58 weeks) was a significant predictor of worse overall functioning (β = -7.07, p = .005) and negative symptom severity (β = 1.10, p = .006) at discharge from the EIP service. CONCLUSIONS: Time spent in active psychosis is an important consideration beyond the initial untreated period and further research is indicated to establish the relationship between DAP and outcomes in FEP.
Ricci V, Chiappini S, Martinotti G
… +1 more, Maina G
Schizophr Res
· 2026 Mar · PMID 41881716
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BACKGROUND: Substance-induced psychotic disorders (SIPDs) present significant clinical challenges with variable outcomes. While some patients achieve complete remission following substance cessation, others develop persi...BACKGROUND: Substance-induced psychotic disorders (SIPDs) present significant clinical challenges with variable outcomes. While some patients achieve complete remission following substance cessation, others develop persistent symptoms requiring extended intervention. Understanding treatment response predictors is critical for optimizing clinical management and prognostic accuracy. METHODS: Following PRISMA guidelines, we systematically searched PubMed, Scopus, Web of Science, PsycINFO, and Embase (inception to October 2024) for studies examining treatment response predictors in SIPDs. We assessed certainty of evidence using modified GRADE criteria for prognostic factor research. RESULTS: Twenty-seven studies representing approximately 33,500 SIPD patients with follow-up ranging from 1 month to 15.5 years met inclusion criteria. Moderate-certainty evidence indicates that acute symptom onset within 24-48 h of substance use predicts favorable treatment response, while prominent negative symptoms predict slower remission and higher transition to chronic psychotic disorders. Moderate-certainty evidence supports that poor premorbid functioning and bimodal response patterns (rapid remission within 30 days vs poor outcomes thereafter) distinguish treatment responders from non-responders. Low-certainty evidence suggests early age of substance use onset, family history of psychotic disorders, abstinence achievement, and premorbid cognitive capacity influence outcomes. Very low-certainty evidence from small neuroimaging studies suggests preserved brain structure and normal dopaminergic function may predict sustained remission. Cannabis-induced and methamphetamine-induced psychosis warrant particular caution given higher persistence rates and psychiatric comorbidity. CONCLUSIONS: Treatment response in SIPDs is determined by multiple interacting factors. Moderate-certainty predictors (temporal onset, negative symptoms, premorbid functioning) provide the strongest basis for clinical decision-making, while lower-certainty findings require validation before widespread implementation.
BACKGROUND: Clozapine is the most effective treatment for treatment-resistant schizophrenia, however early discontinuation remains common, preventing a substantial proportion of patients from achieving its full therapeut...BACKGROUND: Clozapine is the most effective treatment for treatment-resistant schizophrenia, however early discontinuation remains common, preventing a substantial proportion of patients from achieving its full therapeutic benefit. Evidence regarding predictors of early clozapine discontinuation under rapid titration in inpatient settings is limited. METHODS: We conducted a retrospective cohort study of 180 psychiatric inpatients who initiated clozapine, identified through screening of 3343 individuals hospitalised at a tertiary care hospital in Turkey between 2016 and 2025. Early discontinuation was defined as cessation within 90 days. Demographic and clinical variables, inpatient titration characteristics, and clozapine-related adverse effects were extracted from electronic medical records. Time to discontinuation was analyzed using Kaplan-Meier survival curves and Cox proportional hazards models. RESULTS: Within 90 days, 46 patients (25.5%) discontinued clozapine. Female sex (HR = 2.88, 95% CI 1.51-5.47, p = 0.001) and increasing age independently predicted a higher risk of discontinuation. Diagnosis, smoking, and valproate use were not associated with discontinuation. Clozapine-associated myocarditis occurred in 3.88% of the cohort, and when combined with transaminase elevations, inflammatory adverse events accounted for 7.2% of early discontinuations. These events clustered during early treatment phase under rapid inpatient titration, whereas most non-inflammatory adverse effects were manageable with monitoring and dose adjustment. CONCLUSIONS: Nearly one-quarter of patients discontinued clozapine within the first 90 days. Female sex and older age were key predictors of early cessation. The observed incidence of inflammatory adverse events during rapid inpatient titration underscores the importance of cautious, individualized titration strategies-particularly in patients at increased risk of early intolerance.
Lynch ST, Renard KB, Chaia AI
… +2 more, Cohen LJ, Kymissis CM
Schizophr Res
· 2026 Jul · PMID 41875616
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OBJECTIVE: Schizophrenia and schizoaffective disorder are primarily treated with antipsychotic medications, including long-acting injectables (LAIs) which help reduce relapse/readmission. New LAIs have longer duration of...OBJECTIVE: Schizophrenia and schizoaffective disorder are primarily treated with antipsychotic medications, including long-acting injectables (LAIs) which help reduce relapse/readmission. New LAIs have longer duration of action, including aripiprazole which now is available in bimonthly and monthly formulations. This study aimed to examine if bimonthly aripiprazole LAI (ARI-2) led to reduced readmissions and longer time to readmission compared to monthly aripiprazole LAI (ARI-1). METHODS: This retrospective cohort study examined all patients psychiatrically hospitalized in a metropolitan health system who had the diagnosis of schizophrenia or schizoaffective disorder, and who received aripiprazole LAI between January 1, 2020 and October 13, 2022 (N = 160). Baseline sociodemographic and clinical data were collected, as well as information on readmission. Differences between ARI-1 and ARI-2 groups were examined across a 1-year period. RESULTS: ARI-1 and ARI-2 groups were largely similar in terms of baseline characteristics, with ARI-2 having more undomiciled patients and ARI-1 a greater number of prior hospitalizations. Readmission rates between the groups were similar. ARI-2 had significantly longer time to rehospitalization compared to ARI-1, by over 60 days on average. When controlling for confounding variables, such as prior hospitalizations, being undomiciled, and length of stay, only receiving ARI-2 was found to independently predict longer time to rehospitalization among those rehospitalized within 1 year. CONCLUSION: This real-world study found that receiving bimonthly aripiprazole LAI may be associated with improved outcomes over the course of one year compared to monthly, specifically in delaying time to rehospitalization. Our results are consistent with prior literature. Further research is needed to directly compare ARI-1 and ARI-2 over longer periods of time.
Zhao C, Lin B, Naderi E
… +11 more, Moazzen S, Habtewold TD, Bruggeman R, van Amelsvoort T, Cahn W, de Haan L, van der Pluijm M, Simons CJP, van Os J, Veling W, Alizadeh BZ
Schizophr Res
· 2026 Jun · PMID 41861696
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Patients with schizophrenia spectrum disorders (SSDs) have a higher risk for post-diagnostic cardiometabolic comorbidities. While antipsychotic use partly explains this, the contribution of genetic susceptibility remains...Patients with schizophrenia spectrum disorders (SSDs) have a higher risk for post-diagnostic cardiometabolic comorbidities. While antipsychotic use partly explains this, the contribution of genetic susceptibility remains unclear. We investigated the relationships between cardiometabolic-related polygenic risk scores (PRSes) with cardiometabolic outcomes using data from 671 patients with SSDs in the Dutch Genetic Risk and Outcome of Psychosis study. Seven PRSes were calculated for body mass index (BMI), high- and low-density lipoprotein cholesterol (HDL, LDL), triglycerides, glucose, systolic (SBP) and diastolic blood pressure (DBP) using summary statistics from most recent genome-wide association studies. Four linear regression models assessed the cross-sectional associations between PRSes and cardiometabolic outcomes including BMI, HDL, LDL, triglycerides, glycated hemoglobin, SBP, DBP, and a composite metabolic score. Model #1 included baseline factors (age, sex, and population substructure); #2 included model 1 with a single-trait PRS; #3 included model 1 with all PRSes of designated traits; and #4 included model 1 and a composite PRS score. All seven cardiometabolic PRSes were significantly associated with their corresponding outcomes. Significant cross-trait associations were observed including PRS with lower HDL (explained variance (R) = 2.33%), higher DBP (R = 3.35%), and higher SBP (R = 2.29%); PRS with higher HDL(R = 2.05%) and LDL levels(R = 2.31%); PRS with higher SBP(R = 1.75%), and PRS with higher DBP(R = 2.94%). The current study suggests that genetic susceptibility contributes modestly but significantly to poor cardiometabolic outcomes. Shared genetic susceptibility may underpin the frequent co-occurrence of cardiometabolic morbidities in SSDs, supporting the potential utility of PRSes in identifying high-risk patients for early intervention in practice.
Nagendra A, Mesholam-Gately R, Shafrin J
… +1 more, Keshavan MS
Schizophr Res
· 2026 Jun · PMID 41856023
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BACKGROUND: Schizophrenia is traditionally classified as a serious mental illness (SMI), emphasizing chronicity and disability. However, growing evidence supports that it also shows features of a neurodevelopmental syndr...BACKGROUND: Schizophrenia is traditionally classified as a serious mental illness (SMI), emphasizing chronicity and disability. However, growing evidence supports that it also shows features of a neurodevelopmental syndrome, highlighting disruptions in early brain development and a diverse spectrum of trajectories. OBJECTIVE: This paper proposes expanding the conceptualization of schizophrenia as both an SMI and a neurodevelopmental syndrome. METHODS: We review biological, clinical, and epidemiological evidence supporting a neurodevelopmental model of schizophrenia. We then propose a three-pronged strategy to operationalize this reframing: (i) reclassification in the ICD-11 and DSM-5 as a neurodevelopmental syndrome; (ii) renaming to reflect established and evolving scientific evidence; and (iii) reshaping societal narratives so schizophrenia is understood as a developmental condition that remains modifiable. RESULTS: A neurodevelopmental framing may advance access, quality, and equity in schizophrenia care. CONCLUSION: Reframing schizophrenia as a neurodevelopmental syndrome reflects modern science and, based on precedent from other countries, could catalyze systemic changes to improve care, access, and equity.
Tang JY, Wong GH, Zhou H
… +6 more, Zhou J, Lau GKK, Lee EH, Lum TY, Wong IC, Luo H
Schizophr Res
· 2026 Jun · PMID 41856022
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BACKGROUND: Existing atherosclerotic cardiovascular disease (ASCVD) prediction models developed for the general population may inaccurately estimate risk in Chinese patients with schizophrenia-spectrum disorders. This un...BACKGROUND: Existing atherosclerotic cardiovascular disease (ASCVD) prediction models developed for the general population may inaccurately estimate risk in Chinese patients with schizophrenia-spectrum disorders. This underscores the need to validate an existing risk score or to develop a population-specific risk score. OBJECTIVE: To develop a Hong Kong-Chinese (HK-Chinese) model for 10-year ASCVD risk estimation, incorporating both psychiatric and non-psychiatric risk factors, and to compare it against an existing comparison model. METHODS: The sample consisted of 39,250 Chinese adults with schizophrenia-spectrum disorders between 2005 and 2015. The index date was set one year following the date of the diagnosis (range 2006-2016). The HK-Chinese model examined psychiatric comorbidities, psychiatric prescriptions and other non-psychiatric factors. The comparison model was developed by the Prediction and Management of Cardiovascular Risk in People with Severe Mental Illnesses (PRIMROSE) study, with a reduced set of predictors. The primary outcome was incident ASCVD over 10 years. Model performance was evaluated. RESULTS: Over 10 years, 4.4% of patients developed an ASCVD. Significant predictors included duration of FGA, sex, age, hypertension, diabetes mellitus, and calendar year at index date. The HK-Chinese model showed satisfactory performance, comparable to the reduced PRIMROSE model but with greater parsimony. Both models tend to overestimate risk among patients in the highest predicted risk category (>90th percentile). CONCLUSIONS: The HK-Chinese model performs reasonably well in estimating ASCVD risk among Chinese patients with schizophrenia-spectrum disorders. With further external validation, it could support cardiovascular monitoring and promote integrated care for ASCVD in this population.
Cano JF, Galindo-Pita S, Méndez D
… +8 more, Vallejo-Silva A, Córdoba R, Mejía-Salgado G, Nessim J, Torres-Morales E, Valencia MC, Gómez-Marín JE, de-la-Torre A
Schizophr Res
· 2026 Jun · PMID 41833571
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Whether Toxoplasma gondii contributes to schizophrenia remains debated. We evaluated this association using a matched case-control design with two comparison groups and examined serotype distribution and clinical/cogniti...Whether Toxoplasma gondii contributes to schizophrenia remains debated. We evaluated this association using a matched case-control design with two comparison groups and examined serotype distribution and clinical/cognitive correlates. We included 100 schizophrenia cases, 97 genetic controls (biological relatives up to third degree), and 100 environmental controls (age- and neighborhood-matched). Anti-T. gondii IgG/IgM were measured using an enzyme-linked fluorescence assay; among IgG-positive participants, serotyping was performed with GRA6-based ELISA. Associations were estimated using unadjusted odds ratios, Mantel-Haenszel common odds ratios, and conditional logistic regression by matched sets. Symptoms, functioning, and MATRICS cognitive performance were compared by serostatus among cases. Serology was available for 292 participants. IgG seropositivity was lower in cases than in genetic and environmental controls (20.2% vs 45.7% and 31.3% respectively). The unadjusted odds ratio for schizophrenia was 0.41 (95% CI 0.23-0.72), and the Mantel-Haenszel estimate was 0.32 (95% CI 0.17-0.62). In conditional models, the inverse association persisted for the case-environmental contrast after adjustment (aOR 0.32, 95% CI 0.07-1.51), whereas the case-genetic contrast was non-estimable due to quasi-complete separation. Serotyping showed predominance of GRA6-III without group differences. Among cases, symptoms, functioning, and MATRICS performance did not differ by serostatus, and leave-one-stratum-out analyses supported stable directionality. In this Colombian sample, findings do not support a positive association between T. gondii exposure and schizophrenia. Regional factors such as strain diversity, exposure timing, and host/environmental characteristics may modify risk. Prospective studies incorporating molecular genotyping and temporal measures of exposure are warranted.
Sabé M, Grof P, Sackett NB
… +24 more, Tai S, Kryskow P, Bershad A, Turkington D, Buonarroti M, De Pieri M, Baniotopoulos P, Eskinazi M, Böge K, Leucht S, Seragnoli F, Furtado L, Brakha TA, Curtis L, Kirschner M, Kaiser S, Penzenstadler L, Zullino D, Højlund M, Gallo J, Solmi M, Sapienza J, Bosia M, La Torre J
Schizophr Res
· 2026 Jun · PMID 41830808
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Serotonergic psychedelics are re-emerging as therapeutic candidates across psychiatry, particularly for treatment-resistant depression. Their rapid and sustained antidepressant effects, alongside evidence for neuroplasti...Serotonergic psychedelics are re-emerging as therapeutic candidates across psychiatry, particularly for treatment-resistant depression. Their rapid and sustained antidepressant effects, alongside evidence for neuroplastic, dopaminergic, and glutamatergic modulation, have prompted interest in whether they could address depressive and negative symptoms in schizophrenia spectrum disorders (SSDs). This narrative review summarizes mechanistic, preclinical, and early clinical findings relevant to psychedelic use in SSDs. Schizophrenia and major depressive disorder share disturbances in dopamine, glutamate, and neuroplasticity, and both involve large-scale network abnormalities. Schizophrenia is associated with widespread dysconnectivity, mesocortical hypodopaminergia, and striatal hyperdopaminergia linked to NMDA receptor hypofunction. Depression is characterized by fronto-limbic and default mode network hyperconnectivity, mesolimbic hypodopaminergia, and reduced cortical glutamatergic tone. Depressive symptoms within SSDs may reflect an intermediate phenotype combining depressive-like hyperconnectivity with schizophrenia-related global dysconnectivity, suggesting that psychedelics' capacity to transiently increase network flexibility and recalibrate maladaptive connectivity may be clinically relevant. Preclinical studies show increased dendritic spine density, enhanced BDNF expression, restored reward sensitivity, and modulation of network dynamics after psychedelic administration. Clinically, uncontrolled exposure appears associated with increased psychosis-related presentations, whereas limited case reports suggest controlled administration may be tolerated in carefully selected, clinically stable individuals with SSDs. To date, only one early-phase trial (MDMA in schizophrenia) is ongoing, and no randomized trials have evaluated psilocybin or LSD in SSDs. Overall, psychedelics are biologically and mechanistically plausible but remain unproven for depressive and negative symptoms in SSDs, which partially overlap. Carefully designed, safety-focused early-phase studies in clinically stable patients are therefore a prerequisite for broader clinical application.
Shivakumar G, Szymaniak K, Bell E
… +1 more, Malhi GS
Schizophr Res
· 2026 Jun · PMID 41825118
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The continued use of schizoaffective disorder (SAD) as a diagnostic category remains puzzling, given its well-documented lack of validity, reliability, and clinical utility. In practice, the reflexive application of this...The continued use of schizoaffective disorder (SAD) as a diagnostic category remains puzzling, given its well-documented lack of validity, reliability, and clinical utility. In practice, the reflexive application of this diagnosis to patients presenting with features of both schizophrenia and a mood disorder (MD) undermines the potential for personalised care and often leads to unnecessary prescription of psychotropic medications, without adequate reassessment of diagnosis or treatment. While criticisms of SAD have typically centred upon its nosological weaknesses, far less attention has been paid to its broader implications for clinical care and psychiatric research. In this paper, we critically examine the reasons SAD fails to meet the criteria of a legitimate medical diagnosis and explore the downstream consequences of its continued use-particularly in terms of clinical outcomes and the integrity of population and treatment response data. Notably, studies claiming to investigate schizophrenia frequently include patients diagnosed with SAD, thereby introducing heterogeneity that compromises the clarity and reliability of findings. We refer to this as diagnostic conglomeration and argue that the flawed conceptual foundation of SAD has far-reaching ramifications for illness detection, research quality, and therapeutic decision-making. Acknowledging the absence of compelling evidence for the validity of SAD as a discrete entity, we contend that this issue of diagnostic ambiguity that stems from the illogical amalgamation of disorders demands reconsideration-both in study design and clinical practice- if we are to enhance care for the many patients burdened by this problematic diagnosis.
Targum SD, Watson C, Claxton A
… +8 more, Nicolas P, Novak KD, Kaul I, Marder SR, Lin WC, Horan WP, Marcus R, Brannan SK
Schizophr Res
· 2026 Jun · PMID 41825117
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BACKGROUND: Extrapyramidal symptoms (EPS) have long been associated with the use of antipsychotic medications. The etiology of EPS has often been attributed to dopamine D receptor antagonism. Most currently available ant...BACKGROUND: Extrapyramidal symptoms (EPS) have long been associated with the use of antipsychotic medications. The etiology of EPS has often been attributed to dopamine D receptor antagonism. Most currently available antipsychotics bind to the D receptor, albeit with different affinities, and consequently yield different EPS risk. Some novel medications for schizophrenia do not directly affect dopaminergic systems at all. For instance, xanomeline, a preferential M and M muscarinic receptor agonist combined with trospium chloride (KarXT) is approved for the treatment of schizophrenia and has shown a lower EPS liability. METHODS: We conducted a comprehensive review of the cumulative data regarding the occurrence of EPS in several studies of KarXT in schizophrenia that included 3 double-blind, placebo-controlled hospital-based studies and 2 open-label outpatient studies. We also tracked the progression of EPS in a small subgroup of study participants who presented with EPS prior to randomization. RESULTS: A small proportion of individuals receiving KarXT reported EPS-related treatment-emergent adverse events (3.8% in the 3 combined double-blind studies and 2.6% in 2 open-label studies), and most instances were not considered study drug-related. Akathisia occurred in 2.4% of participants receiving KarXT in the double-blind studies, but only 0.6% of cases were attributed to KarXT, and most resolved within 1 day without concomitant medication. Further, preexisting EPS identified by EPS scales before initiating KarXT treatment, particularly akathisia, attenuated during the studies. CONCLUSIONS: Non-dopamine-focused medications like KarXT offer an effective, alternative treatment for schizophrenia with minimal EPS liability that may benefit individuals who require these medications.