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Background and Hypothesis: This analysis examined the relationship between cannabis use, compliance with antipsychotics and risk for relapse in patients in remission following a first episode of schizophrenia, schizophreniform, or schizoaffective disorder., Study Design: Analyses were performed on data from a large European study on first episode of schizophrenia, schizophreniform, or schizoaffective disorder (OPTiMiSE). After 10 weeks of antipsychotic treatment, 282/446 patients (63%) met criteria for symptomatic remission; of whom 134/282 (47.5%) then completed a 1-year follow-up. Cross-lagged models and mediation models investigated the temporal relationships between cannabis use, compliance with antipsychotics, social functioning, and symptomatic worsening/relapse., Study Results: Compared to nonusers, cannabis use increased risk for relapse, adjusted hazard ratio (HR) = 3.03 (SE = 0.32), P < .001, even in patients who were compliant with antipsychotic medication, adjusted HR = 2.89, (SE = 0.32), P < .001. Cannabis use preceded symptomatic worsening and was followed by worsening of Positive and Negative Syndrome Scale total score at the 1-year end-point (standardized β = 0.62, SE = 0.19, P = .001) and by worsening of social functioning (coef = -0.66, P ≤ .001)., Conclusions: In patients in remission from their first episode of schizophrenia, schizophreniform, or schizoaffective disorder, cannabis use increases the rate of relapse in both compliant and noncompliant individuals. Importantly, the temporal relationship between cannabis and relapse was that cannabis use preceded later relapse, noncompliance, and decrease in social functioning, and not that patients began to relapse, then used cannabis. Further research with a precision psychiatry approach might identify those patients in particular danger of relapse when using cannabis., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Schizophrenia is a severe psychiatric disorder with periods of remission and relapse. As discontinuation of antipsychotic medication is the most important reason for relapse, long-term maintenance treatment is key. Whether intramuscular long-acting (depot) antipsychotics are more efficacious than oral medication in preventing medication discontinuation is still unresolved. We aimed to compare time to all-cause discontinuation in patients randomly allocated to long-acting injectable (LAI) versus oral medication., Methods: EULAST was a pragmatic, randomised, open-label trial conducted at 50 general hospitals and psychiatric specialty clinics in 15 European countries and Israel. Patients aged 18 years and older, with DSM-IV schizophrenia (as confirmed by the Mini International Neuropsychiatric Interview 5 plus) and having experienced their first psychotic episode from 6 months to 7 years before screening, were randomly allocated (1:1:1:1) using block randomisation to LAI paliperidone, LAI aripiprazole, or the respective oral formulations of these antipsychotics. Randomisation was stratified by country and duration of illness (6 months up to 3 years vs 4 to 7 years). Patients were followed up for up to 19 months. The primary endpoint was discontinuation, regardless of the reason, during 19 months of treatment. We used survival analysis to assess the time until all-cause discontinuation in the intention-to-treat (ITT) group, and per protocol analyses were also done. This trial is registered with ClinicalTrials.gov, NCT02146547, and is complete., Findings: Between Feb 24, 2015, and Dec 15, 2018, 533 individuals were recruited and assessed for eligibility. The ITT population included 511 participants, with 171 (33%) women and 340 (67%) men, and a mean age of 30·5 (SD 9·6) years. 410 (80%) of 511 participants were White, 35 (7%) were Black, 20 (4%) were Asian, and 46 (9%) were other ethnicity. In the combined oral antipsychotics treatment group of 247 patients, 72 (29%) patients completed the study and 175 (71%) met all-cause discontinuation criteria. In the combined LAI treatment arm of 264 patients, 95 (36%) completed the study and 169 (64%) met the all-cause discontinuation criteria. Cox regression analyses showed that treatment discontinuation for any cause did not differ between the two combined treatment groups (hazard ration [HR] 1·16, 95% CI 0·94-1·43, p=0·18). No significant difference was found in the time to all-cause discontinuation between the combined oral and combined LAI treatment groups (log rank test χ 2 =1·87 [df 1]; p=0·17). During the study, 121 psychiatric hospitalisations occurred in 103 patients, and one patient from each of the LAI groups died; the death of the patient assigned to paliperidone was assessed to be unrelated to the medication, but the cause of other patient's death was not shared with the study team. 86 (25%) of 350 participants with available data met akathisia criteria and 70 (20%) met parkinsonism criteria at some point during the study., Interpretation: We found no substantial advantage for LAI antipsychotic treatment over oral treatment regarding time to discontinuation in patients with early-phase schizophrenia, indicating that there is no reason to prescribe LAIs instead of oral antipsychotics if the goal is to prevent discontinuation of antipsychotic medication in daily clinical practice., Funding: Lundbeck and Otsuka., Competing Interests: Declaration of interests SG reports consulting fees from Angelini, Janssen Pharmaceuticals, Gedeon-Richter, Recordati, and Innova Pharma; and honoraria and expenses from Angelini, Gedeon-Richter, Recordati, Janssen Pharmaceuticals, Janssen-Cilag, Lundbeck, Lundbeck Italia, and Sunovion. SL reports payments to the institution from European Group for Research In Schizophrenia for the conduct of the trial; consulting fees from Alkermes, Angelini, Lundbeck, Lundbeck Foundation, Otsuka, Recordati, Rovi, and Teva; and honoraria for lectures from Angelini, Eisai, Gedeon, Lundbeck, Medichem, Merck, Mitsubishi, Otsuka, Recordati, and Sanofi-Aventis. IB reports grants from the EU to the Semmelweise University; royalties from Oxford University for a published book (editor); consulting fees from Gedeon Richter, Janssen, Janssen Cilag; speaker fees from Hikma Janssen, Janssen Cilag, Gedeon Richter, Medichem Pharmaceuticals by Unilab, and Mitsubishi Tanabe Pharma Signapure; and leadership or fiduciary roles with European College of Neuropsychopharmacology, the European Psychiatry Association, and Clincal Pharmacological Ethics Committee and Medical Research Council (Hungary). BG has been the leader of a Lundbeck Foundation Centre of Excellence for Clinical Intervention and Neuropsychiatric Schizophrenia Research (January, 2009–December, 2021), which was partially financed by an independent grant from the Lundbeck Foundation based on international review and partially financed by the Mental Health Services in the Capital Region of Denmark, the University of Copenhagen, and other foundations; all grants are the property of the Mental Health Services in the Capital Region of Denmark and administrated by them. AH reports speaker fees from Lundbeck, Otsuka, Janssen, Recordati, and Rovi; was member of advisory boards for Lundbeck, Otsuka, Janssen, Recordati, and Rovi; and is an Editor of the German Association of Scientific Medical Societies in Germany and World Federation of Societies of Biological Psychiatry schizophrenia guidelines. GP reports honoraria from Lundbeck, Janssen, Schwabe Austria; support for attending meetings from Schwabe Austria; being president at the Austrian Society for Social Psychiatry and Gerontopsychiatry; and stock with Janssen. PR reports an advisory board role for Angelini. NS reports honoraria for lectures from Recordati Hellas, BGP Pharmaceuticals, Lundbeck Hellas, and Vianex. MD is an employee of Minerva Neurosciences with stock options. RSK reports consulting fees from Alkermes, Sunovion, Gedeon-Richter, and Otsuka. WWF reports consultant fees from Angelini, Richter, Recordati, Lundbeck, Otsuka, Teva, Boehringer-Ingelheim, Pierre Fabre, Janssen, Sunovion, Dainippon-Sumitomo, Takeda, and Pfizer; speaker fees from Janssen, Lundbeck, Otsuka, Richter, and Recordati; and grants from Janssen, Lundbeck, and Otsuka. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Some, but not all, studies have found longer duration of untreated psychosis (DUP) to be associated with poor response to treatment and more severe negative symptoms in schizophrenia. The aim of the current analysis was to investigate these parameters in a large cohort of patients in their first psychotic episode. The OPTiMiSE cohort included 446 patients with DUP up to two years, who were administered amisulpride for 4 weeks (Phase I). Patients who did not meet Andreasen remission criteria were randomized to double-blind continuation of amisulpride or olanzapine for 6 additional weeks in a blinded study (Phase II). Analyses showed that shorter DUP was associated with lower baseline CGI scores (p<0.001, r = 0.184), PANSS total (p = 0.025, r = 0.106) and PANSS negative subscale scores (p = 0.023, r = 0.107). Remitters had a significantly shorter mean DUP compared to non-remitters both in Phase I (24.5 weeks ±24.3 vs. 35 weeks ± 32.2, p = 0.01, t=-2.521) and in Phase II (24.3 weeks ± 26.4 vs. 38.3 weeks ± 31.3, p = 0.031, t=-2.194). Logistic regression analyses showed a significant effect of DUP on treatment response both in phase I (p = 0.008) and phase II (p = 0.041). Linear regression analyses found that DUP significantly affects PANSS Total change at the end of phase I (p = 0.028) but not at the end of phase II (p = 0.236). Based on these findings, it is possible to conclude that shorter DUP is associated with better response to treatment, particularly during the first weeks after treatment initiation. These findings highlight the need for early identification of the first psychotic episode., Competing Interests: Conflict of interest Michael Davidson MD is an employee of Minerva Neurosciences Inc. a biotech company developing drugs for CNS indications. Renè Kahn is a consultant for Alkermes, Otsuka, Janssen-Cilag, Luye Pharma and Sunovion since September 2019. All other authors do not have any conflicts of interest to declare, according to the Journal's requirements., (Copyright © 2020 Elsevier B.V. and ECNP. All rights reserved.)