Antipsychotic Use and Psychiatric Hospitalization in First-Episode Psychosis and Cannabis Use Disorder


Gone in a puff of smoke? Researchers investigated the effectiveness of antipsychotics in reducing the risk of hospitalization in patients with first-episode psychosis and co-occurring CUD.




“Mr Adam” is a 43-year-old Black male with a history of chronic schizophrenia, and cannabis use disorder (CUD). He started smoking cannabis almost daily in his teens. At age 23 years, he was in a motor vehicle accident while under the influence of substances and suffered a traumatic brain injury. Several months later, he was hospitalized for a first episode of psychosis (FEP) and started on antipsychotic medication.

For the past 20 years, Mr Adam has been maintained on a long-acting injectable (LAI) antipsychotic and is adherent with appointments. He tends to get paranoid during periods of significant stress, but he has not had any subsequent psychiatric hospitalizations. However, he has continued to smoke cannabis daily for more than 20 years.

Although he worked prior to the onset of his psychotic disorder, he has since been chronically unemployed. He lives at home with his parents, has never married, and does not have any children. He remains precontemplative regarding the need for treatment for CUD.

Prevalence estimates for comorbid CUD in patients with FEP range from 10% to 50%.1-3 CUD is associated with antipsychotic non-adherence as well as an increased frequency and duration of relapses of psychosis.4 Data on antipsychotic efficacy in patients with FEP and comorbid CUD, however, is scarce.5

The Current Study

Denisoff and colleagues6 studied real-world treatment outcomes of patients with FEP and comorbid CUD using Swedish register-linkage data. The cohort consisted of all individuals aged 16 to 64 years living in Sweden with a registered first treatment contact for non-affective psychosis (ICD-10 F2x.1-9) and comorbid CUD (ICD-10 F12.0-12.9), identified between July 2006 and December 2021. Comorbidity was defined as a registration of a CUD diagnosis within 2 weeks (before or after) of the registration of the respective FEP diagnosis.

Data on dispensed antipsychotics and other psychotropics were acquired from the Prescribed Drug Register. Antipsychotic use periods were estimated utilized the PRE2DUP approach.7 The primary study outcomes were: (1) hospitalization due to a psychotic disorder, (2) hospitalization due to any psychiatric disorder, and (3) hospitalization due to any substance use disorder (SUD), based on data from the National Patient Register.

Data were analyzed using Cox regression analysis with hazard ratios (HR) and 95% confidence intervals (CIs). The reference category was non-use of any antipsychotic agents. A within-individual approach was used to eliminate selection bias.

Cox models were adjusted for time-varying factors (use of other psychotropics, time since cohort entry, and temporal order of antipsychotic treatments). Traditional multivariable between-person Cox regression analyses were used to investigate the association between specific antipsychotics and hospitalization due to psychotic relapse.

The study cohort consisted of 1820 individuals (85% male) with a mean age of 27 years. During follow-up, 64% of individuals were rediagnosed with any cannabis use-related diagnosis, and 47% with either harmful cannabis use (F12.1) or cannabis dependence (F12.2). Over a mean 6.1 years of follow-up, 61% of individuals were hospitalized due to psychotic relapse. Oral olanzapine was the most frequently prescribed antipsychotic (n=1038).

Use of any antipsychotic was associated with a 33% risk reduction of psychotic relapse compared with non-use (aHR=0.67, 95% CI 0.60-0.75). The lowest risk of relapse was for individuals taking risperidone LAI (aHR=0.40), aripiprazole LAI (aHR=0.42), paliperidone LAI (aHR=0.46), and clozapine (aHR=0.43). Of oral non-clozapine antipsychotics, the lowest risk of relapse was for aripiprazole (aHR=0.61) and olanzapine (aHR=0.80). Antipsychotic polytherapy was associated with a 40% risk reduction of psychotic relapse (aHR=0.60).

In the cohort, 76% were hospitalized due to any psychiatric reason at least once during follow-up. Use of any antipsychotic was associated with a 24% risk reduction compared with non-use (aHR=0.76, 95% CI 0.70-0.83). The lowest risk was for individuals taking aripiprazole LAI (aHR=0.45), paliperidone LAI (aHR=0.43), and clozapine (aHR=0.44). Of oral non-clozapine antipsychotics, the lowest risk was for aripiprazole (aHR=0.73) and olanzapine (aHR=0.83). Antipsychotic polytherapy was associated with a 31% risk reduction of hospitalization due to any psychiatric disorder (aHR=0.69).

In the cohort, 63% were hospitalized due to SUD at least once during follow-up. Use of any antipsychotic was associated with a 24% risk reduction of psychotic relapse compared with non-use (aHR=0.76, 95% CI 0.69-0.85). The lowest risk of relapse was for subjects taking clozapine (aHR=0.14), paliperidone LAI (aHR=0.37), and risperidone LAI (aHR=0.33). Antipsychotic polytherapy was associated with a 33% risk reduction of hospitalization due to any SUD (aHR=0.67).

Study Conclusions

The investigators performed the first nationally representative register-linkage study of treatment outcomes in FEP with comorbid CUD. Use of any antipsychotic (versus non-use) was associated with a 33% decreased risk of psychotic relapse. Oral clozapine and LAI aripiprazole, paliperidone, and risperidone were associated with the lowest risk of psychotic relapse and risk of psychiatric hospitalization. Clozapine was especially effective in reducing risk of hospitalizations for SUD.

Study strengths included the large cumulative sample size, the exclusive focus on comorbid FEP and CUD, and the use of nationwide register-based data and within-person analyses. Study limitations included the absence of data on cannabis use trajectories during follow-up, the potential for undiagnosed CUD, and the fact that the findings may not be representative of those with less severe cannabis use.

The Bottom Line

In patients with FEP and comorbid CUD, clozapine and non-olanzapine LAI formulations of second-generation antipsychotics (SGAs) were associated with decreased risk of hospitalization. Early use of SGA LAIs and clozapine is an important secondary prevention strategy to reduce hospitalizations in this patient population.

Dr Miller is a professor in the Department of Psychiatry and Health Behavior at Augusta University in Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for Psychiatric Times®. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, and the Stanley Medical Research Institute.


1. Brunette MF, Mueser KT, Babbin S, et al. Demographic and clinical correlates of substance use disorders in first episode psychosisSchizophr Res. 2018;194:4-12.

2. Schimmelmann BG, Conus P, Cotton S, et al. Prevalence and impact of cannabis use disorders in adolescents with early onset first episode psychosisEur Psychiatry. 2012;27(6):463-469.

3. Strålin P, Hetta J. Substance use disorders before, at and after first episode psychosis hospitalizations in a young national Swedish cohortDrug Alcohol Depend. 2020;209:107919.

4. Schoeler T, Petros N, Di Forti M, et al. Poor medication adherence and risk of relapse associated with continued cannabis use in patients with first-episode psychosis: a prospective analysisLancet Psychiatry. 2017;4(8):627-633.

5. Sevy S, Robinson DG, Sunday S, et al. Olanzapine vs. risperidone in patients with first-episode schizophrenia and a lifetime history of cannabis use disorders: 16-week clinical and substance use outcomesPsychiatry Res. 2011;188(3):310-314.

6. Denissoff A, Taipale H, Tiihonen J, et al. Antipsychotic use and psychiatric hospitalization in first-episode non-affective psychosis and cannabis use disorder: a Swedish nationwide cohort studySchizophr Bull. Published online March 26, 2024.

7. Tanskanen A, Taipale H, Koponen M, et al. From prescription drug purchases to drug use periods – a second generation method (PRE2DUP)BMC Med Inform Decis Mak. 2015;15:21.

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