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There is a paucity of research on treatment outcomes of patients with psychosis and cannabis use disorder CUD. We aimed to compare the effectiveness of antipsychotics in reducing the risk of hospitalization in patients with first-episode psychosis FEP and co-occurring CUD. We utilized a nationwide Swedish cohort of patients with longitudinal register data from the year to The main outcome was hospitalization due to psychotic relapse. Hospitalization due to any psychiatric disorder or substance use disorder SUD were examined as secondary outcomes. Within-individual Cox regression models were used to study these associations. Clozapine 0. The association between the LAI formulation of olanzapine and hospitalization due to psychosis was statistically non-significant 0. Of oral non-clozapine antipsychotics, aripiprazole was associated with the lowest risk of hospitalization due to psychotic relapse 0. These findings support the use of clozapine, LAI formulations of second-generation antipsychotics other than olanzapine, or oral aripiprazole to prevent hospitalization in FEP and co-occurring CUD. Cannabis use is ubiquitous among first-episode psychosis FEP patients with a significant proportion continuing use after recovery. Real-world treatment outcomes of patients with psychotic disorders and substance use disorder SUD have been examined in nationwide register-based studies. The few existing clinical trials examining the efficacy of antipsychotic drugs in dual disorders have merged groups of patients with psychosis and co-occurring cannabis use or CUD and groups of psychosis patients inflicted by other types of substance use comorbidities. A limited number of antipsychotic drugs were encompassed in this body of literature and only one of these studies focused on FEP specifically. The data utilized contains information on all antipsychotic agents used in clinical practice enhancing the generalizability of the results. To overcome selection bias, a within-individual design is utilized in the main analyses. The study population consisted of all persons aged 16—64 years residing in Sweden with a registered first treatment contact due to non-affective psychotic disorder used as a proxy for FEP ICD codes F2x. Data regarding sickness absences were derived from the MiDAS register, which is managed by the Swedish Social Insurance Agency and provides information on periods during which individuals have received sickness benefits due to health-related incapacity for work. For CUD to be classified as co-occurring, the time of registration of this diagnosis had to be at most two weeks prior or no more than 2 weeks later than the registration of the respective FEP diagnosis. Persons with previous diagnosis of non-affective psychotic disorder since were excluded from analyses. Monotherapies of different antipsychotic agents ATC codes N05A excluding lithium N05AN01 were analyzed by drug formulation, in addition to AP polytherapy concomitant use of two or more antipsychotics. The reference condition or group in each within-person or between-person analysis was the non-use of any antipsychotic. Medications with fewer than 20 outcomes were not reported. The main outcomes of this study were 1 hospitalization due to psychotic disorder ICD diagnoses F2x. ICD codes denoting these hospitalizations inpatient stay at least overnight were obtained from the National Patient Register, a database with nationwide coverage on all specialized inpatient care. The reference category was the non-use of any antipsychotic agents. A within-individual approach was taken to eliminate selection bias. The follow-up time is reset to zero after each outcome event. The stratified Cox models were adjusted for time-varying factors which were the use of other psychotropic medications, time since cohort entry, and temporal order of antipsychotic treatments. Traditional multivariable between-person Cox-regression analyses were also conducted to examine the association between the use of specific second-generation antipsychotics SGAs , ie, olanzapine, quetiapine, risperidone, and aripiprazole , antipsychotic polytherapy, any LAI and other antipsychotics excluding the aforementioned SGA:s with hospitalization due to psychotic relapse. Statistical analyses were performed using SAS version 9. Forest plot figures were created using R version 4. Demographic characteristics of the sample are presented in table 1. The sample totaled individuals At study entry, During the follow-up, The mean follow-up time in this analysis was 6. The number of users, number of events, and mean follow-up times are presented in Supplementary table 1. The results of the within-individual analysis models for SGAs and antipsychotic polytherapy regarding this outcome are presented in figure 1. Long-acting injectable LAI formulations of risperidone 0. Effect sizes for second-generation SGA LAI formulations were uniformly greater than for their respective oral formulations. In contrast to other LAI, the LAI formulation of olanzapine did not reach statistical significance for effectiveness in preventing hospitalization due to psychosis 0. Of oral non-clozapine antipsychotics, aripiprazole was found to be associated with the lowest risk of relapse 0. The effect size of the oral formulation of olanzapine was moderate 0. Quetiapine was not found to be efficacious in preventing psychotic relapse 0. Association of second-generation antipsychotics with subsequent hospitalization due to psychotic relapse. The results of the between-person analyses are presented in Supplementary table 2. The HRs for first-generation antipsychotics with at least 20 events are presented in Supplementary table 3 for all outcomes. The number of users, number of events, and mean follow-up times are presented in Supplementary table 4. Results of the within-individual models for SGAs and AP polytherapy regarding this outcome are presented in figure 2. The lowest risk was found for LAI formulations of aripiprazole 0. The LAI formulation of olanzapine did not reach statistical significance for effectiveness in preventing hospitalization due to any psychiatric diagnosis 0. Of all non-clozapine antipsychotics, oral aripiprazole was associated with the lowest risk of hospitalization due to any psychiatric diagnosis 0. The aHR of the oral formulation of olanzapine was moderate 0. Oral formulations of quetiapine 0. Association of second-generation antipsychotics with subsequent hospitalization due to any psychiatric disorder. The number of users, number of events and mean follow-up times are presented in Supplementary table 5. The distribution of different SUD types for this outcome is provided in the Supplementary table 6. The results of the within-individual model for this outcome are presented in figure 3. Association of second-generation antipsychotics with subsequent hospitalization due to any substance use disorder. This is the first nationally representative register-linkage study focusing on treatment outcomes in first-episode psychosis FEP with co-occurring cannabis use disorder CUD. Most importantly, we found that LAI formulations of second-generation antipsychotics SGAs other than olanzapine were associated with the lowest risk of psychotic relapse and risk of any psychiatric hospitalization, in addition to oral clozapine. Clozapine seemed to be particularly effective in reducing the risk of subsequent SUD hospitalizations. Lastly, oral aripiprazole seemed to be the most effective oral non-clozapine SGA in reducing the risk of psychotic relapses and psychiatric hospitalizations. Only three previously published studies have focused exclusively on antipsychotic efficacy in psychotic disorders with co-occurring CUD. Only one previous study focused on FEP patients and found risperidone to be non-inferior to olanzapine in terms of effectiveness in this patient group. We found LAI formulations of SGAs excluding olanzapine to be equally efficacious as clozapine in reducing the risk of psychotic relapse and any psychiatric hospitalization in FEP patients. A Swedish nationwide register-linkage study focusing on treatment outcomes in persons with schizophrenia with lifetime SUD has been published previously. Also, clozapine was clearly associated with the lowest risk of subsequent psychiatric hospitalization in that study. However, that study cohort comprised of specifically schizophrenia patients, and many of them already had a long duration of illness. This is of significance, as treatment response in antipsychotic therapy is less likely after relapse to psychosis. We found clozapine to be associated with the lowest risk of hospitalization due to SUD. Findings from recent meta-analyses indicate clozapine to be superior to other antipsychotics in reducing substance use 19 and promoting abstinence 21 in patients with psychotic disorders and comorbid SUDs. Clozapine was also found to be superior to risperidone in reducing cue reactivity in a randomized fMRI study focusing on patients with schizophrenia and comorbid CUD. Our finding is also in line with the results of a previously published RCT focusing specifically on change in cannabis use. Switching to clozapine was found to be associated with a reduction of cannabis consumption. However, in another RCT focusing on this outcome, clozapine was not superior to ziprasidone in reducing cannabis use. Patients willing to initiate clozapine treatment may also be more ready to engage in the treatment of their comorbid SUD. Thus, it is possible that the results of clozapine represent a somewhat clinically selected patient group. In line with previous findings, 36 antipsychotic polytherapy was found to be associated with a reduced risk of all outcomes studied. This is of significance, as previous findings on the efficacy of antipsychotic polytherapy have been mixed 37 , 38 and this form of treatment has been discouraged in clinical guidelines. Lastly, aripiprazole was found to be the most effective oral non-clozapine antipsychotic. It has been proposed that patients with dual disorders might benefit from the modulation of dopaminergic pathways induced by partial agonists. Oral olanzapine was the most frequently prescribed antipsychotic in our study cohort. However, it was found to be associated with only a modest risk reduction with respect to any outcome studied. This was surprising, as meta-analytic evidence points to olanzapine and amisulpride to be more efficacious than other non-clozapine agents in FEP. Weight gain is particularly pronounced in young patients using olanzapine, 45 and this adverse effect has been associated with non-adherence to antipsychotic treatment. This study presents with several strengths: Focusing exclusively on co-occurring CUD among persons with FEP is to be regarded as a strength, as cannabis use, in particular, has been associated with more deleterious outcomes than the use of other substances within this population 10 Nationwide register-based data with information on all patients presenting with this type of dual diagnosis and all antipsychotics used provides with exceptional generalizability of these results. The use of within-person analyses reduces the possibility of selection bias. Attrition was small as very few patients emigrated or died during follow-up. However, there are limitations: Not having information on cannabis use trajectories during follow-up is to be regarded as a limitation, as continued cannabis use has been associated with poorer outcomes than discontinued use in FEP. Thus, it is reasonable to believe that a considerable proportion of patients continued their cannabis use after their first diagnosis of psychotic disorder. As underdiagnosis of SUD is common, 47 it is possible that some patients with CUD may have not been included in the study cohort for this reason. As we focused on FEP patients with a diagnosis of co-occurring CUD made in clinical practice, our findings are not necessarily representative of patients with less severe cannabis use. Finally, CUD was defined to encompass all F However, a diagnosis of CIP evidently implies the fulfillment of the criteria of F In FEP patients with co-occurring CUD, LAI formulations of SGAs other than olanzapine were associated with a similarly decreased risk as clozapine in terms of hospitalization due to psychotic relapse or other psychiatric disorders. While clozapine was found to be associated with a substantial risk reduction of subsequent hospitalization due to SUDs, this finding might not be void of selection bias. MDF has received honoraria for educational seminars from Recordati and Janssen. The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. HT and AT performed data analysis. All authors approved the final version of the manuscript. Cannabis use in first episode psychosis: meta-analysis of prevalence, and the time course of initiation and continued use. Aust N Z J Psychiatry. Google Scholar. 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Stopping cannabis use benefits outcome in psychosis: findings from year follow-up study in the PAFIP-cohort. Acta Psychiatr Scand. Poor medication adherence and risk of relapse associated with continued cannabis use in patients with first-episode psychosis: a prospective analysis. Lancet Psychiatry. Association between continued cannabis use and risk of relapse in first-episode psychosis: a quasi-experimental investigation within an observational study. JAMA Psychiatry. Cannabis and first-episode psychosis: different long-term outcomes depending on continued or discontinued use. Clinical and treatment predictors of relapse during a three-year follow-up of a cohort of first episodes of schizophrenia. Does a history of cannabis use influence onset and course of schizophrenia? Association of cannabis use with hospital admission and antipsychotic treatment failure in first episode psychosis: an observational study. BMJ Open. 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Late reduction of cocaine cravings in a randomized, double-blind trial of aripiprazole vs perphenazine in schizophrenia and comorbid cocaine dependence. J Clin Psychopharmacol. Head-to-head comparison of 1-year aripiprazole long-acting injectable LAI versus paliperidone LAI in comorbid psychosis and substance use disorder: impact on clinical status, substance craving, and quality of life. Neuropsychiatr Dis Treat. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet London, England. Efficacy and safety of individual second-generation vs. Int J Neuropsychopharmacol. Antipsychotic-induced weight gain in chronic and first-episode psychotic disorders: a systematic critical reappraisal. CNS Drugs. Obesity as a risk factor for antipsychotic noncompliance. Comparison of data sources on alcohol problems: an exploratory exercise using surveys vs. Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide. Sign In or Create an Account. Sign in through your institution. Schizophrenia Bulletin Journals. Advanced Search. Search Menu. Article Navigation. Close mobile search navigation Article Navigation. Article Contents Abstract. Conflict of interest. Author contributions. Journal Article. Alexander Denissoff , Alexander Denissoff. Oxford Academic. Heidi Taipale. Department of Clinical Neuroscience, Karolinska Institutet. Jari Tiihonen. Marta Di Forti. Ellenor Mittendorfer-Rutz. Antti Tanskanen. Antti Mustonen. Select Format Select format. Permissions Icon Permissions. Abstract Background and Hypothesis. Table 1. Open in new tab. Demographic Characteristics of Cohort. Open in new tab Download slide. Google Scholar Crossref. Search ADS. Does a history of cannabis use influence onset and course of schizophrenia. Google Scholar PubMed. Issue Section:. Download all slides. 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