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Background The role of duration of untreated psychosis (DUP) as an early detection and intervention target to improve outcomes for individuals with first-episode psychosis is unknown. Study Design PRISMA/MOOSE-compliant systematic review to identify studies until February 1, 2023, with an intervention and a control group, reporting DUP in both groups. Random effects meta-analysis to evaluate (1) differences in DUP in early detection/intervention services vs the control group, (2) the efficacy of early detection strategies regarding eight real-world outcomes at baseline (service entry), and (3) the efficacy of early intervention strategies on ten real-world outcomes at follow-up. We conducted quality assessment, heterogeneity, publication bias, and meta-regression analyses (PROSPERO: CRD42020163640). Study Results From 6229 citations, 33 intervention studies were retrieved. The intervention group achieved a small DUP reduction (Hedges' g  = 0.168, 95% CI = 0.055–0.283) vs the control group. The early detection group had better functioning levels (g  = 0.281, 95% CI = 0.073–0.488) at baseline. Both groups did not differ regarding total psychopathology, admission rates, quality of life, positive/negative/depressive symptoms, and employment rates (P  > .05). Early interventions improved quality of life (g  = 0.600, 95% CI = 0.408–0.791), employment rates (g  = 0.427, 95% CI = 0.135–0.718), negative symptoms (g  = 0.417, 95% CI = 0.153–0.682), relapse rates (g  = 0.364, 95% CI = 0.117–0.612), admissions rates (g  = 0.335, 95% CI = 0.198–0.468), total psychopathology (g  = 0.298, 95% CI = 0.014–0.582), depressive symptoms (g  = 0.268, 95% CI = 0.008–0.528), and functioning (g  = 0.180, 95% CI = 0.065–0.295) at follow-up but not positive symptoms or remission (P  > .05). Conclusions Comparing interventions targeting DUP and control groups, the impact of early detection strategies on DUP and other correlates is limited. However, the impact of early intervention was significant regarding relevant outcomes, underscoring the importance of supporting early intervention services worldwide. [ABSTRACT FROM AUTHOR]

Duration of untreated psychosis (DUP) has been associated with poor mental health outcomes. We aimed to meta-analytically estimate the mean and median DUP worldwide, evaluating also the influence of several moderating factors. This PRISMA/MOOSE-compliant meta-analysis searched for non-overlapping individual studies from inception until 9/12/2022, reporting mean ± s.d. or median DUP in patients with first episode psychosis (FEP), without language restrictions. We conducted random-effect meta-analyses, stratified analyses, heterogeneity analyses, meta-regression analyses, and quality assessment (PROSPERO:CRD42020163640). From 12 461 citations, 369 studies were included. The mean DUP was 42.6 weeks (95% confidence interval (CI) 40.6–44.6, k = 283, n = 41 320), varying significantly across continents (p < 0.001). DUP was (in descending order) 70.0 weeks (95% CI 51.6–88.4, k = 11, n = 1508) in Africa; 48.8 weeks (95% CI 43.8–53.9, k = 73, n = 12 223) in Asia; 48.7 weeks (95% CI 43.0–54.4, k = 36, n = 5838) in North America; 38.6 weeks (95% CI 36.0–41.3, k = 145, n = 19 389) in Europe; 34.9 weeks (95% CI 23.0–46.9, k = 11, n = 1159) in South America and 28.0 weeks (95% CI 20.9–35.0, k = 6, n = 1203) in Australasia. There were differences depending on the income of countries: DUP was 48.4 weeks (95% CI 43.0–48.4, k = 58, n = 5635) in middle-low income countries and 41.2 weeks (95% CI 39.0–43.4, k = 222, n = 35 685) in high income countries. Longer DUP was significantly associated with older age (β = 0.836, p < 0.001), older publication year (β = 0.404, p = 0.038) and higher proportion of non-White FEP patients (β = 0.232, p < 0.001). Median DUP was 14 weeks (Interquartile range = 8.8–28.0, k = 206, n = 37 215). In conclusion, DUP is high throughout the world, with marked variation. Efforts to identify and intervene sooner in patients with FEP, and to promote global mental health and access to early intervention services (EIS) are critical, especially in developing countries. [ABSTRACT FROM AUTHOR]

Identification of robust biomarkers that predict individualized response to antipsychotic treatment at the early stage of psychotic disorders remains a challenge in precision psychiatry. The aim of this study was to investigate whether any functional connectome-based neural traits could serve as such a biomarker. In a discovery sample, 49 patients with first-episode psychosis received multi-paradigm fMRI scans at baseline and were clinically followed up for 12 weeks under antipsychotic monotherapies. Treatment response was evaluated at the individual level based on the psychosis score of the Brief Psychiatric Rating Scale. Cross-paradigm connectivity and connectome-based predictive modeling were employed to train a predictive model that uses baseline connectomic measures to predict individualized change rates of psychosis scores, with model performance evaluated as the Pearson correlations between the predicted change rates and the observed change rates, based on cross-validation. The model generalizability was further examined in an independent validation sample of 24 patients in a similar design. The results revealed a paradigm-independent connectomic trait that significantly predicted individualized treatment outcome in both the discovery sample (predicted-versus-observed r=0.41) and the validation sample (predicted-versus-observed r=0.47, mean squared error=0.019). Features that positively predicted psychosis change rates primarily involved connections related to the cerebellar-cortical circuitry, and features that negatively predicted psychosis change rates were chiefly connections within the cortical cognitive systems. This study discovers and validates a connectome-based functional signature as a promising early predictor for individualized response to antipsychotic treatment in first-episode psychosis, thus highlighting the potential clinical value of this biomarker in precision psychiatry. [ABSTRACT FROM AUTHOR]

Malaria diagnosis continues to be one of the most important steps in the cycle of control specially in endemic countries with low parasitic load infections. Loop-mediated isothermal amplification (LAMP) and ultrasensitive PCR (Us-PCR) are two promising candidates for malaria diagnosis. A cross sectional study performed at King Faisal Hospital, Taif KSA involved patients suffering from signs and symptoms suggesting Of malaria, 35 blood samples diagnosed by Nested Multiplex PCR as a reference method (13 P. falciparum, 17 P. vivax, 3 mixed P. falciparum and P. vivax) plus two negative controls were selected to be included in this study to analyse the performance of two LAMP methods (LAMP OptiGene® and LAMP WarmStart®) and two ultrasensitive PCRs (Us-PCR TARE-2 and Us-PCR Var-ATS). LAMP OptiGene® and LAMP WarmStart® performances were identical and better than the performance of Us PCR TARE 2 and Us-PCR var-ATS for P. falciparum, achieving 93.75% sensitivity, 100% specificity and 97.17% accuracy versus 87.5% sensitivity, 100% specificity and 94.29% accuracy for the Us PCR TARE 2 and 81.25% sensitivity, 94.74% specificity and 88.57% accuracy for the Us PCR var-ATS respectively. InF. vzvax diagnosis LAMP OptiGene® performed excellently with 100% sensitivity, specificity, and accuracy while LAMP WarmStart® and Us-PCR Coxl achieved 100% sensitivity, specificity 93.33% and 97.14% accuracy. The study results highlighted the benefits of using LAM P techniques for field diagnosis of malaria in different settings where the need for a more sensitive and reliable molecular tool is mandatory but at the same time removing the high cost, long turnaround time and the need of highly specialized trained technicians to perform more sophisticated molecular techniques. [ABSTRACT FROM AUTHOR]

Background: Digital technology has the potential to transform psychiatry, but its adoption has been limited. The proliferation of telepsychiatry during the COVID-19 pandemic has increased the urgency of optimizing technology for clinical practice. Understanding clinician attitudes and preferences is crucial to effective implementation and patient benefit. Objective: Our objective was to elicit clinician perspectives on emerging digital technology. Methods: Clinicians in a large psychiatry department (inpatient and outpatient) were invited to complete a web-based survey about their attitudes toward digital technology in practice, focusing on implementation, clinical benefits, and expectations about patients' attitudes. The survey consisted of 23 questions that could be answered on either a 3-point or 5-point Likert scale. We report the frequencies and percentages of responses. Results: In total, 139 clinicians completed the survey--they represent a variety of years of experience, credentials, and diagnostic subspecialties (response rate 69.5%). Overall, 83.4% (n=116) of them stated that digital data could improve their practice, and 23.0% (n=32) of responders reported that they had viewed patients' profiles on social media. Among anticipated benefits, clinicians rated symptom self-tracking (n=101, 72.7%) as well as clinical intervention support (n=90, 64.7%) as most promising. Among anticipated challenges, clinicians mostly expressed concerns over greater time demand (n=123, 88.5%) and whether digital data would be actionable (n=107, 77%). Furthermore, 95.0% (n=132) of clinicians expected their patients to share digital data. Conclusions: Overall, clinicians reported a positive attitude toward the use of digital data to not only improve patient outcomes but also highlight significant barriers that implementation would need to overcome. Although clinicians' self-reported attitudes about digital technology may not necessarily translate into behavior, our results suggest that technologies that reduce clinician burden and are easily interpretable have the greatest likelihood of uptake. [ABSTRACT FROM AUTHOR]

Antipsychotic drugs are the cornerstone in the management of psychotic disorders, but most patients fail to have a 'good' response in short-term trials. Therefore, alternative strategies including dose escalation, switching [...]

The objective of this work is to analyze which features are most important in the recognition of facial expressions. To achieve this, we built a facial expression recognition system that learns from a controlled capture data set. The system uses different representations and combines them from a learned model. We studied the most important features by applying different feature extraction methods for facial expression representation, transforming each obtained representation into a sparse representation (SR) domain, and trained combination models to classify signals, using the extended Cohn–Kanade (CK+), BU-3DFE, and JAFFE data sets for validation. We compared 14 combination methods for 247 possible combinations of eight different feature spaces and obtained the most explanatory features for each facial expression. The results indicate that the LPQ (83%), HOG (82%), and RAW (82%) features are those features most able to improve the classification of expressions and that some features apply specifically to one expression (e.g., RAW for neutral, LPQ for angry and happy, LBP for disgust, and HOG for surprise). [ABSTRACT FROM AUTHOR]

Objective To quantify the risk and predictors of relapse among individuals with schizophrenia randomly withdrawn from antipsychotic maintenance treatment. Methods We re-analyzed time-to-event and baseline predictors from placebo arms in five placebo-controlled randomized trials of antipsychotics (n = 688 individuals; 173 stabilized on oral antipsychotic [OAP] and 515 on long-acting injectables [LAI]) for relapse-prevention available in the Yale Open Data Access repository. Using a survival and Cox-proportional hazards regression analyses, we estimated survival rates of "relapse-free" individuals by the end of follow-up (median = 118 days, IQR = 52.0–208.0), the rate of study-confirmed relapse, and adjusted hazard ratios (aHR, 95% confidence intervals [CI]) associated with baseline predictors. We also estimated these parameters for individuals followed for >5 half-lives of the stabilizing antipsychotic, and studied predictors of "rebound psychosis" in OAP-stabilized participants, defined as occurring within 30 days of antipsychotic withdrawal. Results 29.9% (95%CI = 23.2–38.5) remained relapse-free by the end of follow-up, 11.1% (95%CI = 5.65–21.9) among those OAP-stabilized, 36.4% (95%CI = 28.4–46.7) among those LAI-stabilized. The study-confirmed relapse rate was 45.2%, 62.4% among those OAP-stabilized and 39.4% among those LAI-stabilized. Predictors of relapse included smoking (aHR = 1.54, 95%CI = 1.19–2.00), female sex (aHR = 1.37, 95%CI = 1.08–1.79), and having been stabilized on OAPs vs LAIs (aHR = 3.56, 95%CI = 2.68–4.72). Greater risk of relapse on OAP persisted even after sufficient time had elapsed to clear antipsychotic plasma level among LAI-stabilized (aHR = 5.0, 95%CI = 3.5–7.1). "Rebound psychosis" did not show predictors. Conclusions and relevance Our results corroborate the high relapse risk following antipsychotic withdrawal after symptom stabilization with limited patient-related predictors of safe treatment discontinuation. Stabilization with LAIs reduces the short-/medium-term relapse risk. [ABSTRACT FROM AUTHOR]

There is an ongoing debate about the potential risks and benefits of long-term antipsychotic treatment in schizophrenia. The data for and against the chronic use of these medicines is mostly indirect, either from observational studies potentially exposed to reverse causation bias or randomized controlled studies that do not cover beyond 2–3 years. We propose that perseverating on the question of what positive or negative outcomes are causally associated with chronic antipsychotic treatment may not lead to better answers than the limited ones that we have, given the limited feasibility of more conclusive studies. Rather, we argue that addressing the research question of the risks and benefits of antipsychotic discontinuation from a perspective of personalized medicine, can be more productive and meaningful to people living with schizophrenia. To this end, research that can quantify the risk of relapse after treatment continuation for a given individual should be prioritized. We make the case that clinically feasible neuroimaging biomarkers have demonstrated promise in related paradigms, and that could be offering a way past this long debate on the risks and benefits of chronic antipsychotic use. [ABSTRACT FROM AUTHOR]

Schizophrenia often requires long-term treatment with antipsychotic medication. This study aims to measure the continuity of antipsychotic treatment over the course of illness in schizophrenia, as well as factors involved in the interruption of treatment. For this, we followed up a national cohort of first-episode psychosis patients in Finland for up to 18 years. Stratified Cox proportional hazards regressions were conducted for "within-participant" risk of discontinuation of subsequent treatments compared to the first, and by specific antipsychotic compared to oral olanzapine, the most prescribed antipsychotic in this cohort. Adjusted hazard ratios (aHRs) and 95% confidence intervals (95% CIs) were calculated. Among 3343 participants followed up for a mean of 8 years (SD = 4.93), the median number of continuous treatment episodes was 6 (interquartile range [IQR] = 3–11) with a median duration of 11.4 months (IQR = 5.3–25.6). In the first year after diagnosis, the incidence rate of treatment discontinuation was 30.12 (95% CI = 29.89–30.35) events per 100 participant-years, decreasing to 8.90 (95% CI = 8.75–9.05) in the 10th year. The risk of discontinuation progressively decreased over successive treatment episodes (aHR = 0.30; 95% CI = 0.20–0.46 for episodes after the 15th compared to the first). Individuals were 67% less likely to interrupt treatment with long-acting injectable than oral antipsychotics (aHR = 0.33; 95% CI = 0.27–0.41). Treatment for schizophrenia over the long term is often characterized by recurrent cycles of interruptions and reintroductions of antipsychotic medication, which is typically not recommended by management guidelines. Greater utilization of long-acting injectable formulations earlier in the course of illness may facilitate the continuity of antipsychotic treatment in schizophrenia. [ABSTRACT FROM AUTHOR]

Introduction Long-acting injectable antipsychotics (LAIs) are associated with multiple positive outcomes in psychosis, but it is unclear whether LAIs are associated with worse outcomes if neuroleptic malignant syndrome (NMS), a potentially lethal adverse effect, occurs. Methods We used nationwide and nationally representative databases of healthcare encounters in Finland to study the incidence and outcome predictors of NMS in patients diagnosed with schizophrenia/schizoaffective disorder between January 01, 1972 and December 31, 2017. Using a nested case-control design, we also explored differences by antipsychotic formulation (LAI vs oral antipsychotic [OAP]) and class (first-generation antipsychotic [FGA] vs second-generation antipsychotic [SGA]). Results One hundred seventy-two NMS cases and 1441 sex-, age-, and diagnosis-matched controls were included (age = 58.8 ± 13.1 years, males = 59.9%). Incidence of NMS was 1.99 (1.98–2.00) per 10 000 person-years. The likelihood of developing NMS did not differ by antipsychotic formulation (adjusted odds ratio [aOR]: 0.89, 95% confidence intervals [95% CI]: 0.59–1.33, for LAIs vs OAPs) or class (FGA-OAP vs SGA-OAP [aOR: 1.08, 95% CI: 0.66–1.76], FGA-LAI [aOR: 0.89, 95% CI: 0.52–1.53], SGA-LAI [aOR: 1.35, 95% CI: 0.58–3.12]). NMS risk factors included antipsychotic treatment change: increased number (odds ratios [OR]: 5.00, 95% CI: 2.56–9.73); decreased number/switch (OR: 2.43, 95% CI: 1.19–4.96); higher antipsychotic dose (>2DDDs–OR: 3.15, 95% CI: 1.61–6.18); co-treatment with anticholinergics (OR: 2.26, 95% CI: 1.57–3.24), lithium (OR: 2.16, 95% CI: 1.30–3.58), benzodiazepines (OR: 2.02, 95% CI: 1.44–3.58); and comorbid cardiovascular disease (OR: 1.73, 95% CI: 1.22–2.45). Within 30 days, 4.7% of cases with NMS died (15.1% within 1 year) without differences by antipsychotic formulation. NMS reoccurred in 5 of 119 subjects (4.2%), after a median = 795 (range = 77–839) days after rechallenge with antipsychotics. Conclusion NMS remains a potentially life-threatening risk, yet these results should further contribute to mitigate concerns about LAI safety regarding NMS onset or outcomes, including mortality. [ABSTRACT FROM AUTHOR]

Salt also affects the production of exopolysaccharide (EPS) in the halotolerant strain Rhizobium meliloti EFB1. The difference in the production of EPS II in the presence and absence of salt is regulated at the transcriptional level. These were the findings in a study of EPS production in Rhizobium meliloti EFB1. The transposon-induced mutant was isolated, that, when grown in the absence of salt, had a colony morphology similar to that of the wild type grown in the presence of salt. Results indicated that galactoglucan is produced by strain EFB1 and that this production declines when the organism is grown in the presence of salt.

Objective: Neuroleptic malignant syndrome (NMS) is a potentially fatal, idiosyncratic reaction to antipsychotics. Due to low incidence of NMS, research on risk factors of mortality associated with NMS is limited. Methods: Two authors independently searched Medline/Embase/Cochrane/CINAHL/PsychINFO databases for case reports with author‐defined NMS published in English until 05/30/2020. Demographic, clinical, treatment, and outcome data were independently extracted following PRISMA guidelines. NMS severity was rated using the Francis‐Yacoub scale. Mortality risk factors were identified using a multivariable regression analysis including all characteristics that were significantly different between NMS cases resulting vs. not resulting in death. Results: 683 cases with NMS were analyzed (median age = 36 years, males = 62.1%). In a multivariable model, independent predictors of NMS mortality were lack of antipsychotic discontinuation (odds ratio (OR) = 4.39 95% confidence interval (CI) = 2.14–8.99; p < 0.0001), respiratory problems (OR = 3.54 95%CI = 1.71–7.32; p = 0.0004), severity of hyperthermia (Unit‐OR = 1.30, 95%CI = 1.16–1.46; p < 0.0001), and older age (Unit‐OR = 1.05, 95%CI = 1.02–1.07; p = 0.0014). Even in univariate, patient‐level analyses, antipsychotic formulation was not related to death (oral antipsychotic (OAP): n = 39/554 (7.0%) vs. long‐acting injectable (LAI): n = 13/129 (10.1%); p = 0.2413). Similarly, death with NMS was not related to antipsychotic class (first‐generation antipsychotic: n = 38/433 (8.8%) vs. second‐generation antipsychotic: n = 8/180 (4.4%); p = 0.0638). Non‐antipsychotic co‐treatments were not associated with NMS mortality. Conclusion: Despite reliance on case reports, these findings indicate that presence of respiratory alterations, severity of hyperthermia, and older age should alert clinicians to a higher NMS mortality risk, and that antipsychotics should be stopped to reduce mortality, yet when NMS arises on LAIs, mortality is not increased vs. OAPs. [ABSTRACT FROM AUTHOR]

Background: The drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a drug-induced hypersensitivity reaction. Aims: Aim was to review reports of clozapine-related reactions fulfilling the registry of severe cutaneous adverse reaction (RegiSCAR) criteria for DRESS syndrome reported as such or otherwise, to provide a descriptive overview of demographic patterns, clinical manifestations, and DRESS course and investigate associations between demographic, DRESS parameters, and clinical outcomes. Methods: This review was conducted following preferred reporting items for systematic reviews and meta-analyses guidelines and registered with PROSPERO (registration number CRD42020156385). We searched PubMed/Embase/PsychInfo/Cochrane for reports of clozapine-related reactions meeting RegiSCAR criteria. Associations between RegiSCAR scores and time-to-recovery with demographic/clinical variables were assessed. Demographic/clinical characteristics of patients with versus without reported DRESS were compared using non-parametrical tests. Results: We identified 26 reports of 27 patients meeting RegiSCAR criteria. Males (n = 19, 70.4%) and patients with schizophrenia (n = 18, 66.7%) were mainly affected. Twelve patients (44.4%) received clozapine-monotherapy. DRESS symptoms manifested within a month after clozapine initiation (n = 24, 88.9%). Lungs and liver were the most common organs involved (n = 12, 44.4%; n = 11, 40.7%), with a mean time to recovery of 33.75 days. Clozapine rechallenge led to DRESS recurrence in four patients. Death rate was 7.4%. No associations were detected between RegiSCAR criteria or days to recovery with any demographic/clinical variables. No differences between patients with versus without reported DRESS were detected. Conclusions: Clozapine-related DRESS may be rare, but also underreported. Clinicians need to be aware of it even in patients under clozapine-monotherapy or without skin rash. [ABSTRACT FROM AUTHOR]

Objective: Coordinated specialty care (CSC) has become the standard of care for first-episode psychosis (FEP). The gap between CSC best practices and the actual care delivered is unknown. This longitudinal study aimed to measure that gap by using a large Medicaid claims database and 10 quality indicators (QIs) reflecting aspects of CSC and to study the relationship between these QIs and future health care utilization.Methods: Individuals with FEP were identified in a Missouri Medicaid claims database. Participants were required to have been eligible for Medicaid benefits for at least 10 months in the year prior to and the year after their first episode of psychosis and to have had no evidence of a prior psychosis diagnosis. Descriptive statistics were generated for each of the QIs, and a stratified Cox regression was used to identify predictors of subsequent health care utilization.Results: Data were obtained for 6,246 participants, and follow-up lasted a mean of 4.24 years. Significant practice gaps were found in the use and monitoring of antipsychotic medications. Of those prescribed antipsychotic medication, 5% received prescriptions above recommended daily doses, 16% received two or more antipsychotics, and 20% were treated with olanzapine or clozapine. Among the QIs, lack of monitoring for smoking (hazard ratio [HR]=2.71, 95% confidence interval [CI]=2.47-2.97) and lack of integrated care delivery in treatment (HR=2.00, 95% CI=1.92-2.08) were most associated with psychiatric hospitalization.Conclusions: In most cases, treatment was far from meeting CSC recommendations, suggesting that implementation of CSC requires substantial modifications to delivery of care for individuals with FEP. [ABSTRACT FROM AUTHOR]

The Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome is a severe, multiorganic, and potentially life-threatening drug-induced hypersensitivity reaction, linked to several common drugs, including antiepileptics, antibiotics, and several psychotropic drugs, including clozapine. Due to the importance of clozapine in the management of treatment-resistant schizophrenia, a systematic review and characterization of clozapine-related DRESS syndrome is long overdue. This systematic review was conducted following PRISMA guidelines. PubMed, Embase, PsychINFO, and the Cochrane Library databases were independently reviewed up to 1 November 2019 for articles reporting clozapine-related DRESS syndrome cases. The RegiSCAR score system was applied to systematically characterize the clinical presentations of selected studies. Clozapine-related DRESS syndrome was reported in six patients from four articles. Five patients received polypharmacy. Skin rash and liver involvement with elevated liver enzymes were very common. No fatal cases were found. Treatment mainly included clozapine discontinuation and immunosuppression. The mismatch between incidences of DRESS with other responsible drugs, the common misdiagnosis of this syndrome, and the fact that an extensive literature search only identified six cases suggests that clozapine-related DRESS may be overlooked. It is, therefore, necessary to optimize diagnostic strategies to identify immune-related side effects of clozapine. [ABSTRACT FROM AUTHOR]

Background: There is uncertainty about the incidence of breakthrough psychosis in treatment adherent patients, and the role that factors, such as cumulative antipsychotic exposure, play in this phenomenon. Methods: In a nationwide cohort of individuals treated for schizophrenia-spectrum disorders in Finland between 1 January 1996 and 31 December 2015, 'Breakthrough Psychosis on Antipsychotic Maintenance Medication' (BAMM) was defined as hospitalization for psychosis despite ongoing continuous treatment with long-acting injectable antipsychotics (LAIs) or oral antipsychotics (OAPs) for ⩾8 weeks. Incidence rates, survival curves, and risk factors were presented. Results: In a cohort of 16 031 continuous LAI treatment episodes with virtually assured adherence [median duration = 441 days, interquartile range (IQR) = 155–1277], BAMM incidence was 31.5%. For 42 867 OAPs treatment episodes (median duration = 483 days, IQR = 167–1491), for whom adherence was modeled by the PRE2DUP method, BAMM incidence was 31.1%. Factors related to illness instability at treatment onset were associated with BAMM, although median time to BAMM was 291 days (IQR = 121–876) for LAIs and 344 days (IQR = 142–989) for OAPs, and 27.4% (N = 1386) of the BAMM events in the LAI, and 32.9% (N = 4378) in the OAP group occurred despite >1 year since last hospitalization at treatment onset. Cumulative antipsychotic exposure was not a consistent risk factor. Conclusion: BAMM was relatively common even when adherence was confirmed with LAIs. Illness instability at treatment onset accounted for most cases, but relapse after years of continuous treatment was still prevalent. There was insufficient evidence to support causality between cumulative antipsychotic exposure and BAMM. Future research needs to address the role of symptom severity and neurobiology in BAMM. [ABSTRACT FROM AUTHOR]