Real-world effectiveness of antipsychotic medication in relapse prevention after cannabis-induced psychosis
Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden
Department of Psychiatry, Seinäjoki Central Hospital, Seinäjoki, Finland
Department of Forensic Psychiatry, Niuvanniemi Hospital, University of Eastern Finland, Kuopio, Finland
School of Pharmacy, University of Eastern Finland, Kuopio, Finland
Department of Psychiatry, Faculty of Medicine, University of Turku, Turku, Finland
Addiction Psychiatry Unit, Department of Psychiatry, Turku University Hospital, Wellbeing County of South-West Finland, Turku, Finland
Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
South London and Maudsley NHS Mental Health Foundation Trust, London, UK
National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London, London, UK
Neuroscience Center, University of Helsinki, Helsinki, Finland
Center for Psychiatry Research, Stockholm Region, Stockholm, Sweden
Abstract
Background
Cannabis use is linked to treatment non-adherence and relapses in psychotic disorders. Antipsychotic medication is effective for relapse prevention in primary psychoses, but its effectiveness after cannabis-induced psychosis (CIP) remains unclear.
Aims
To examine the effectiveness of antipsychotic medication for relapse prevention following the first clinically diagnosed CIP.
Method
A cohort of 1772 patients (84.1% men) with incident CIP was identified from the Swedish National Patient and Micro Data for Analyses of Social Insurance registers. The primary outcome was hospitalisation due to any psychotic episode. Drug use data were collected from the Prescribed Drug Register and modelled into drug use periods using the PRE2DUP method. A within-individual Cox regression model was used to study the risk of outcomes during the use of different oral or long-acting injectable (LAI) antipsychotics compared with non-use.
Results
The mean age at first diagnosis was 26.6 years (s.d. = 8.3). Of the cohort, 1343 (75.8%) used antipsychotics and 914 (51.3%) experienced psychosis hospitalisation during the follow-up. Any antipsychotic use was associated with a decreased risk of psychosis hospitalisation (adjusted hazard ratio (aHR) 0.75; 95% CI 0.67–0.84). Specific antipsychotics associated with decreased risk included aripiprazole LAI (aHR 0.27; 95% CI 0.14–0.51), olanzapine LAI (aHR 0.28; 95% CI 0.15–0.53), clozapine (aHR 0.55; 95% CI 0.34–0.90), oral aripiprazole (aHR 0.64; 95% CI 0.45–0.91), antipsychotic polytherapy (aHR 0.74; 95% CI 0.63–0.87) and oral olanzapine (aHR 0.81; 95% CI 0.69–0.94).
Conclusions
In particular, LAIs, clozapine and oral aripiprazole were associated with a decreased risk of psychosis relapse following CIP. Prescribers should consider using more LAIs for better treatment outcomes after CIP.
Untitled section
Keywords: Cannabis, cannabis-induced psychosis, relapse, antipsychotics, psychotic disorders
Article notes
Untitled section
Received 2024 Oct 28; Revised 2025 Feb 1; Accepted 2025 Feb 17; Issue date 2026 Apr.
The association of cannabis use and primary psychoses such as schizophrenia is well established, with studies suggesting early onset and heavy cannabis use associating with risk of psychotic outcomes.1 In people with established psychotic disorder, cannabis use disorder (CUD) is common, ranging from 21% in schizophrenia to 36% in first-episode psychosis (FEP) samples,2 and most patients with psychotic disorders continue use after remission of a psychotic episode.3 Cannabis use worsens prognosis of psychotic disorders and associates with increased non-adherence to antipsychotic medications,4,5 risk of relapse, more intense and frequent in-patient treatment6–9 and treatment resistance.10
Compared to primary psychotic disorders, prognosis of substance-induced psychoses (SIPs) is much more unclear. According to a recent meta-analysis by Murrie et al,11 among SIPs, cannabis-induced psychosis (CIP) associates with worst prognosis in terms of schizophrenia conversion with one out of three later converting into schizophrenia. This manifests especially among young males and those with familial predisposition to psychosis.12,13 This matter is topical as recent studies report rising rates of CIP during the past ten years,14,15 which may be a proxy for increased burden of disease from psychotic disorders associated with cannabis use. This might be preventable with treatment optimisation.
Treatment of psychotic disorders impacted by cannabis use
Psychosis relapses associate with poor prognosis, and antipsychotic medication is effective in preventing relapses in primary psychoses.16 Although effectiveness of antipsychotic medication in patients with psychotic disorder and CUD have been studied in clinical trials17–19 and community samples,20–22 only one study has focused on long-term outcomes.20 Recently, using nationwide Swedish register data, we reported that use of any antipsychotic medication was associated with 33% risk reduction of psychotic relapse in people with first clinically diagnosed psychosis and comorbid CUD. In our study, use of clozapine and long-acting injectable (LAI) formulations of antipsychotic medications were associated with lowest risk of psychotic relapse.20
However, data on effectiveness of antipsychotic medication after CIP is scarce, and data is based on a few small clinical trials23,24 and case reports.25 Most importantly, there are no reports where effectiveness of antipsychotic medications is studied in CIP populations on any long-term outcome. Further, our current diagnostic guidelines consider SIP as a brief psychotic syndrome that occurs during or following psychoactive substance use and no guidelines on how antipsychotic medications should be prescribed exist. Thus, it remains unclear how pharmacotherapy should be optimised after CIP.
Using data from linkage of nationwide registers in Sweden, our aim was to examine whether antipsychotic medication is effective in preventing admissions to hospital caused by psychosis relapse after first onset of clinically diagnosed CIP (n = 1772). Secondary outcomes included hospital admission caused by substance use disorder (SUD) and any somatic disorder.
Method
Study population
Data are based on several Swedish nationwide registers that include all individuals with Swedish residency. All Swedish residents are assigned a unique personal identification number, which enables linkage between various registers after de-identification. These registers include the National Patient Register (NPR), Micro Data for Analyses of Social Insurance (MiDAS) register, Cause of Death Register (CDR), Prescribed Drug Register (PDR) and Longitudinal Integration Database for Health Insurance (LISA) register.
The NPR includes data on in-patient and specialised out-patient care periods, while the MiDAS register includes data on sickness absence and disability pension, namely data on periods during which individuals have received sickness benefits because of health-related incapacity for work. From the NPR and MiDAS register we sampled all individuals aged 16–64 years that were registered for the first time with clinically diagnosed CIP (ICD-1026 code F12.5) between January 2006 and December 2021. They were identified based on not having a previous (from 1997 to 2005) episode of SIP (F1x.5) or schizophrenia-spectrum disorder (F20–F29) or bipolar disorder (F30 and F31) to account for solely incident psychosis cases. Sociodemographic data (age, gender, educational level, country of birth, occupational data) were derived from the LISA register.
We used data from the REWHARD consortium that was supported by the Swedish Research Council (grant number 2021-00154). The research project was approved by the Regional Ethics Board of Stockholm, Karolinska Institutet, Stockholm, Sweden (decision 2007/762-31 and Dnr 2021-06441-02). According to current Swedish law, the use of registry data for research purposes does not require informed consent from individuals held in these registries.
Exposure variables
Medication data were gathered from the PDR from July 2005 to December 2023 and were categorised into antipsychotics based on Anatomical Therapeutic Chemical (ATC) classification27 code N05A, excluding N05AN01 (lithium). Antipsychotics were categorised into oral and LAI formulations. Most common antipsychotics were second-generation oral and LAI antipsychotics, namely risperidone and paliperidone LAI, oral and LAI aripiprazole, oral and LAI olanzapine, clozapine and quetiapine. Use of other antipsychotic medications, ‘other oral antipsychotic monotherapy’, use of two or more concurrent antipsychotics, ‘antipsychotic polytherapy’, and all LAI formulations of first-generation antipsychotics, ‘first-generation LAI’ (FG-LAI), were pooled to provide adequate power for analysis. Antipsychotic medication use was compared with non-use of antipsychotics. Medication data were modelled into medication use periods (i.e. when medication use started and ended) with the PRE2DUP (from prescription drug purchases to drug use periods) method.28 Exposure to antipsychotics was modelled in a time-dependent manner and updated in the models when any change to antipsychotics in use happened (i.e. switch, add-on, discontinuation). Medication data with less than five events are not reported.
Outcomes
The primary outcome was hospital admission caused by any psychotic episode, that is, primary psychotic disorder (ICD-10 codes F20–F29) or any SIP (ICD-10 codes F1x.5 as a main diagnosis). Secondary outcomes were (a) hospital admission caused by SUD (ICD-10 codes F10–F19 as a main diagnosis) and (b) hospital admission caused by any somatic disorder (ICD-10 codes A00–N99, excluding F00–F99 as a main diagnosis). Hospital admission caused by any somatic disorder was included as a marker of serious somatic problems leading to hospital admission, as antipsychotics can have adverse effects.
Covariates
Temporal order of antipsychotic medication treatments, time since cohort entry and time-varying use of other psychotropic medication were adjusted in analyses. These medications were categorised based on their ATC classification as medications for SUDs (N07BB, N07BC), medications for attention-deficit hyperactivity disorder (N06BA), mood stabilisers (N03AF01, N03AG01, N03AX09, N05AN01), antidepressants (N06A), benzodiazepines and related drugs (N05BA, N05CD, N05CF).
Statistical methods
We used a within-individual design with a stratified Cox regression model in which each individual formed his or her own stratum. This reduces selection bias29 as it controls for time-invariant factors such as genetics and baseline comorbidities. Among the incident CIP sample, we calculated adjusted hazard ratios (aHRs) and 95% confidence intervals comparing the risk of outcomes during time periods of use of specific antipsychotics with time periods of non-use of antipsychotics. The follow-up time was reset to zero after the outcome event, meaning that main outcomes were treated as recurrent events. Patients were followed up from CIP – diagnosis until emigration (LISA register), death (CDR) or end of the data linkage (December 2023), whichever occurred first. As a sensitivity analysis, between-individual Cox regression analyses were conducted for the main outcome (see the Supplementary Material online available at https://doi.org/10.1192/bjp.2025.72). Statistical significance was considered at >0.05. Statistical analyses were performed using SAS version 9.4 for Windows (SAS Institute Inc., Cary, NC, USA; https://www.sas.com/fi_fi/software/iml-sas9.html). Forest plot figures were created using R version 4.1.1 for Windows (R Foundation for Statistical Computing, Vienna, Austria; https://www.R-project.org/127).
Results
The sample totalled 1772 individuals with CIP, of which 1490 (84.1%) were men and the mean (s.d.) age was 26.6 (8.3) years at first diagnosis. Most had low or medium educational level (Table 1). A total of 995 patients (56.2%) had work income at baseline, 96 (5.4%) had more than 90 days of sickness absence during the calendar year before study entry and 123 (6.9%) were receiving a disability pension at study entry.
| Variable | Frequency | Percent |
|---|---|---|
| Age (years) | ||
| 16–19 | 232 | 13.09% |
| 20–24 | 681 | 38.43% |
| 25–29 | 399 | 22.52% |
| ≥30 | 460 | 25.96% |
| Gender | ||
| Female | 282 | 15.91% |
| Male | 1490 | 84.09% |
| Born in Sweden | ||
| No | 501 | 28.27% |
| Yes | 1271 | 71.73% |
| Educationa | ||
| Elementary | 830 | 46.83% |
| High school | 752 | 42.44% |
| University/college | 190 | 10.72% |
| Income from work | ||
| No | 777 | 43.85% |
| Yes | 995 | 56.15% |
| Sickness absence previous year | ||
| No | 1495 | 84.37% |
| 1–90 days | 181 | 10.21% |
| ≥90 days | 96 | 5.42% |
| Disability pension at cohort entry | ||
| No | 1649 | 93.06% |
| Yes | 123 | 6.94% |
The individuals were followed up at 8.26 years (s.d. 4.35) on average. Of the sample, 1343 (75.8%) used antipsychotics during the follow-up. Most commonly used antipsychotics were oral olanzapine (1013; 57.2% of the sample), antipsychotic polytherapy (675; 38.1%), quetiapine (385; 21.7%), oral aripiprazole (331; 18.7%) and oral risperidone (261; 14.7%). For the primary outcome, medication-specific results by the number of individuals prescribed medications, number of events, person years and aHR are shown in Table S1 in the Supplementary Material.
During the follow-up, 69.7% (n = 1235) were re-diagnosed with any cannabis use-related diagnosis (F12.x), and 52.0% (n = 921) specifically with CIP (F12.5), 27.9% (n = 495) with F12.1 Harmful use of cannabis and 27.5% (n = 488) with F12.2 Cannabis dependence.
Risk of hospital admission caused by any psychotic episode
During the follow-up, 914 (51.3%) individuals experienced hospital admission caused by psychosis. In total, there were 3920 hospital admissions, of which 57.2% were caused by primary psychotic disorder and the rest caused by substance-induced psychotic disorder. The most common specific categories within this outcome were F29 (unspecified non-organic psychosis; 23.5% of all hospital admissions), F12.5 (CIP; 23.0% of all hospital admissions) and F20 (schizophrenia; 17.9% of all hospital admissions). Any antipsychotic use (versus no-use) was associated with decreased risk of hospital admission caused by any psychotic episode (aHR 0.75; 95% CI 0.67–0.84). Of the specific antipsychotics, aripiprazole LAI (aHR 0.27; 95% CI 0.14–0.51), olanzapine LAI (aHR 0.28; 95% CI 0.15–0.53), clozapine (aHR 0.55; 95% CI 0.34–0.90), oral aripiprazole (aHR 0.64; 95% CI 0.45–0.91), antipsychotic polytherapy (aHR 0.74; 95% CI 0.63–0.87) and oral olanzapine (aHR 0.81; 95% CI 0.69–0.94) were associated with decreased risk, whereas risperidone LAI (aHR 0.52; 95% CI 0.26–1.03), paliperidone LAI (aHR 0.68; 95% CI 0.45–1.04), FG-LAIs (aHR 0.78; 95% CI 0.55–1.10), other oral antipsychotic monotherapy (aHR 0.88; 95% CI 0.68–1.15), oral risperidone (aHR 0.91; 95% CI 0.66–1.25) and quetiapine (aHR 0.94; 95% CI 0.70–1.26) did not reach statistical significance (Fig. 1).
Risk of hospital admission caused by SUD
During the follow-up, 1021 (57.6%) experienced hospital admission caused by SUD. Any antipsychotic use (versus no-use) was associated with decreased risk of hospital admission caused by SUD (aHR 0.78; 95% CI 0.71–0.87). Of the specific antipsychotics, clozapine (aHR 0.27; 95% CI 0.09–0.79), olanzapine LAI (aHR 0.39; 95% CI 0.20–0.76), aripiprazole LAI (aHR 0.42; 95% CI 0.21–0.82), paliperidone LAI (aHR 0.46; 95% CI 0.24–0.89), oral risperidone (aHR 0.67; 95% CI 0.47–0.96), antipsychotic polytherapy (aHR 0.70; 95% CI 0.60–0.82), other oral antipsychotic monotherapy (aHR 0.73; 95% CI 0.56–0.94) and oral olanzapine (aHR 0.84; 95% CI 0.73–0.97) were associated with decreased risk, whereas risperidone LAI (aHR 0.54; 95% CI 0.26–1.12), oral aripiprazole (aHR 0.86; 95% CI 0.59–1.24), quetiapine (aHR 0.96; 95% CI 0.78–1.19) and FG-LAIs (aHR 1.25; 95% CI 0.86–1.80) did not reach statistical significance (Fig. 2).
Risk of hospital admission caused by somatic disorder
During the follow-up, 306 (17.2%) experienced hospital admission caused by somatic disorder. By ICD-10 main categories, the most common reasons for somatic hospital admissions were diseases of the digestive system (K) at 20.6%, diseases of the musculoskeletal system and connective tissue (M) at 18.4%, diseases of the nervous system (G) at 12.6%, diseases of the respiratory system (J) at 10.4% and diseases of the circulatory system (I) at 9.9%. Any antipsychotic use (versus no-use) was associated with decreased risk of hospital admission caused by somatic disorder (aHR 0.58; 95% CI 0.38–0.89). Most specific antipsychotics lacked statistical power for drug-level analysis, and none were associated with either an increased or decreased risk (Fig. 3). There were too few events (less than five) to run medication modelling for aripiprazole LAI, paliperidone LAI, risperidone LAI, FG-LAIs and clozapine.
Discussion
Using nationwide Swedish register data, we report that antipsychotic medications, especially LAIs, were effective in preventing hospital admission caused by psychosis relapse and SUD after first diagnosis of CIP. While a recent expert consensus statement recommends the use of LAIs in FEP,30 our findings suggest this to be beneficial even in CIP. This is especially important as cannabis use is associated with non-adherence to medication in psychotic disorders.9
LAI formulations of aripiprazole and olanzapine were associated with the lowest risk of psychosis relapses after CIP, followed by clozapine, risperidone LAI, oral aripiprazole, antipsychotic polytherapy and oral olanzapine. Paliperidone LAI, risperidone (neither oral nor LAI), FG-LAI, other oral antipsychotic monotherapy or quetiapine did not reach statistical significance for effectiveness. Compared to non-use, the use of aripiprazole and olanzapine LAIs was associated with a 72–73% reduction in the risk of psychosis relapse. In contrast, their oral counterparts were associated with a 19–36% risk reduction. Although neither the oral nor LAI formulation of risperidone reached statistical significance for effectiveness in preventing psychosis relapses, these medications followed a similar pattern (LAI 48% v. oral 9%). This pattern was also observed in our sensitivity analyses using a between-individual design. These results suggest that LAIs are more effective than oral antipsychotics (excluding clozapine) in preventing psychosis relapse after CIP, thereby encouraging the use of LAIs for better treatment outcomes.
Antipsychotics other than strong dopamine antagonists performed similarly in relapse prevention after CIP than after first onset of schizophrenia with or without SUD16,31 or FEP and CUD.20 The findings are plausible in the context of a similar relapse rate in SIP versus FEP32,33 and similar rates of individuals converting into schizophrenia after CIP versus FEP.11 In contrast to these previous studies, none of the oral or LAI strong dopamine antagonists associated with a statically significant decreased risk of psychosis relapse. Possible reasons for some of these results are the low number of users and non-adherence to the oral formulations of these antipsychotics. However, cannabis use has been shown to increase the rate of relapse in patients with remitted FEP who both do and do not adhere to treatment. In the light of these and our findings, not only medication adherence, but also the type of antipsychotic medication might also affect relapse risk of psychotic disorders.34 Further, there are studies where treatment with clozapine35,36 and olanzapine36 have led to weaker craving for cannabis versus risperidone in people with schizophrenia, but the extant evidence base is too scarce to provide clinical recommendations.37 If replicated, our findings have clinical relevance to promote the use of drugs other than strong dopamine blockers for prevention of psychosis relapses after CIP.
Of the oral antipsychotic medications, clozapine was the most effective for preventing either psychosis or SUD relapses. Recent systematic review and meta-analysis suggests clozapine is superior to the other antipsychotic medications in people with schizophrenia and SUD and associated with significantly higher odds of remaining abstinent from substance use and decreased likelihood of psychiatric hospital admission.38 Cannabis use also associates with treatment resistance in schizophrenia10 where use of clozapine is indicated. The findings also align with our recent study, where clozapine was the most effective oral antipsychotic in relapse prevention for psychosis and SUD in FEP and a comorbid CUD sample.20
Almost three-quarters of the sample had used antipsychotics after their first episode of CIP. This is interesting, as there are no guidelines to how antipsychotic treatment should be prescribed after CIP. Olanzapine was the most frequently used antipsychotic medication and was effective in preventing relapses caused by both psychosis and SUD. Although it is considered as effective treatment for acute presentations of psychosis, it might not be feasible medication for long-term relapse prevention because of known metabolic and cardiovascular side-effects.39
Further, oral aripiprazole was the most effective non-clozapine antipsychotic in preventing psychosis relapses, but it did not reach statistical significance in relapse prevention for SUD. However, aripiprazole LAI was effective and the effect sizes were similar to other LAIs. This finding is likely related to non-adherence to oral medications and encourages the use of LAI formulations. Preliminary evidence and case reports suggest that partial agonists might be beneficial for the treatment of dual disorders where psychotic symptoms are present. This has been theorised to be partly related to their ability to bolster weakened prefrontal dopaminergic transmission that could improve cognitive dysfunctions and symptoms linked to lower dopaminergic functionality40 and also to reduce craving.40,41 However, further studies are required to prove whether aripiprazole and other partial agonists have a special role in treatment of dual disorders or SIP.
Similar to previous register studies16,20,31 antipsychotic polytherapy was effective in preventing psychosis or SUD relapses, suggesting that prescribers should consider it as a viable option for relapse prevention also after CIP. The combination of clozapine and aripiprazole is considered best in terms of relapse prevention,42 both of which are also associated with favourable substance use outcomes. In this relatively small sample, we did not study specific polytherapy combinations but that is an important topic for future studies.
Concerning somatic outcome, any antipsychotic use was a protective factor for subsequent hospital treatment caused by somatic disorder. However, none of the antipsychotics reached statistical significance for effectiveness, and hospital admission caused by somatic disorder was too rare to run medication modelling for most antipsychotics. Nonetheless, the use of these antipsychotics did not lead to increased severe physical morbidity leading to hospital admission. This is of importance, as antipsychotic use has been linked to adverse somatic outcomes.39
Our study has notable strengths, but also significant limitations. This study is the first to examine the long-term outcomes of different antipsychotic medications after CIP. Our novel findings contribute to the development of future clinical recommendations. The nationwide register-based data-set with information on all Swedish residents provides exceptional generalisability and the use of within-person analyses eliminates the effect of familial and genetic confounders.
This study identified individuals based on their first-time psychosis diagnosis, including those initially diagnosed with F12.5, and followed them over time. Not having information on the continuation of cannabis use should be seen as a limitation, as continued cannabis use associates with worse prognosis in psychosis than discontinued use.43 However, 69.7% of the sample were re-diagnosed with CUD (F12.x) by the end of the follow-up, suggesting persistence of these diagnoses after CIP. Because of power issues, we were not able to study whether there are specific antipsychotic medications that should be used as polytherapy and to run comprehensive medication modelling for somatic outcomes over even longer-term follow-up.
In particular, LAIs, clozapine and oral aripiprazole were associated with decreased risk of psychosis relapse after the first clinically diagnosed episode of CIP. This carries an important message that prescribers should consider more LAIs for better treatment outcomes after the first episode of CIP.
Supporting information
Supplementary material
The supplementary material can be found at https://doi.org/10.1192/bjp.2025.72
Data availability
The data used in this study cannot be made publicly available because of privacy regulations. According to the General Data Protection Regulation, the Swedish law SFS 2018:218, the Swedish Data Protection Act, the Swedish Ethical Review Act and the Public Access to Information and Secrecy Act, these types of sensitive data can only be made available for specific purposes, including research, that meet the criteria for access to this sort of sensitive and confidential data, as determined by a legal review. Readers may contact Professor Kristina Alexanderson (kristina.alexanderson@ki.se) regarding the data.
Funding
This work utilised data from the REWHARD consortium supported by the Swedish Research Council (grant number: 2021-00154). The funders of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report.
Declaration of interest
A.M. has received funding from Juho Vainio Foundation, The Wellbeing Services County of South Ostrobothnia and The Finnish Foundation for Alcohol Studies. A.D. has received funding from Juho Vainio Foundation and Yrjö Jahnsson Foundation and personal fees from Finnish State Research Funding (ERVA). H.T. is funded by Sigrid Juselius Foundation. J.T., E.M.-R., H.T. and A.T. have participated in research projects funded by grants from Janssen-Cilag to their employing institution. S.N. reports personal fees from dne Pharma, Otsuka, Lundbeck, Recordati and Shire-Takeda. H.T. reports personal fees from Gedeon Richter, Janssen-Cilag, Lundbeck and Otsuka. J.T. has served as a consultant for Healthcare Global Village, HLS Therapeutics, Janssen, Orion, Teva and WebMD Global and has received honoraria from Janssen-Cilag, Lundbeck and Otsuka. M.D.F. has received honoraria for educational seminars from Recordati and Janssen. V.E. reports no conflicts of interest.
Transparency declaration
A.M. affirms that the manuscript is an honest, accurate and transparent account of the study being reported. No important aspects of the study have been omitted and any discrepancies from the study as planned have been explained.
References
Untitled section
References
- 1. D’Souza DC, DiForti M, Ganesh S, George TP, Hall W, Hjorthøj C, et al. Consensus paper of the WFSBP task force on cannabis, cannabinoids and psychosis. World J Biol Psychiatry 2022; 23: 719–42.
- 2. Hunt GE, Large MM, Cleary M, Lai HMX, Saunders JB. Prevalence of comorbid substance use in schizophrenia spectrum disorders in community and clinical settings, 1990–2017: systematic review and meta-analysis. Drug Alcohol Depend 2018; 191: 234–58.
- 3. Myles H, Myles N, Large M. Cannabis use in first episode psychosis: meta-analysis of prevalence, and the time course of initiation and continued use. Aust N Z J Psychiatry 2016; 50: 208–19.
- 4. Foglia E, Schoeler T, Klamerus E, Morgan K, Bhattacharyya S. Cannabis use and adherence to antipsychotic medication: a systematic review and meta-analysis. Psychol Med 2017; 47: 1691–705.
- 5. El Abdellati K, De Picker L, Morrens M. Antipsychotic treatment failure: a systematic review on risk factors and interventions for treatment adherence in psychosis. Front Neurosci 2020; 14: 531763.
- 6. Patel R, Wilson R, Jackson R, Ball M, Shetty H, Broadbent M, et al. Association of cannabis use with hospital admission and antipsychotic treatment failure in first episode psychosis: an observational study. BMJ Open 2016; 6: e009888.
- 7. Colizzi M, Burnett N, Costa R, De Agostini M, Griffin J, Bhattacharyya S. Longitudinal assessment of the effect of cannabis use on hospital readmission rates in early psychosis: a 6-year follow-up in an inpatient cohort. Psychiatry Res 2018; 268: 381–7.
- 8. Schoeler T, Petros N, Di Forti M, Klamerus E, Foglia E, Ajnakina O, et al. Effects of continuation, frequency, and type of cannabis use on relapse in the first 2 years after onset of psychosis: an observational study. Lancet Psychiatry 2016; 3: 947–53.
- 9. Schoeler T, Petros N, Di Forti M, Klamerus E, Foglia E, Murray R, et al. Poor medication adherence and risk of relapse associated with continued cannabis use in patients with first-episode psychosis: a prospective analysis. Lancet Psychiatry 2017; 4: 627–33.
- 10. Arsalan A, Iqbal Z, Tariq M, Ayonrinde O, Vincent JB, Ayub M. Association of smoked cannabis with treatment resistance in schizophrenia. Psychiatry Res 2019; 278: 242–7.
- 11. Murrie B, Lappin J, Large M, Sara G. Transition of substance-induced, brief, and atypical psychoses to schizophrenia: a systematic review and meta-analysis. Schizophr Bull 2020; 46: 505–16.
- 12. Kendler KS, Ohlsson H, Sundquist J, Sundquist K. Prediction of onset of substance-induced psychotic disorder and its progression to schizophrenia in a Swedish national sample. Am J Psychiatry 2019; 176: 711–9.
- 13. Myran DT, Harrison LD, Pugliese M, Solmi M, Anderson KK, Fiedorowicz JG, et al. Transition to schizophrenia spectrum disorder following emergency department visits due to substance use with and without psychosis. JAMA Psychiatry 2023; 80: 1169–74.
- 14. Hjorthøj C, Larsen MO, Starzer MSK, Nordentoft M. Annual incidence of cannabis-induced psychosis, other substance-induced psychoses and dually diagnosed schizophrenia and cannabis use disorder in Denmark from 1994 to 2016. Psychol Med 2019; 51: 617–22.
- 15. Rognli EB, Taipale H, Hjorthøj C, Mittendorfer-Rutz E, Bramness JG, Heiberg IH, et al. Annual incidence of substance-induced psychoses in Scandinavia from 2000 to 2016. Psychol Med 2023; 53: 5246–55.
- 16. Tiihonen J, Mittendorfer-Rutz E, Majak M, Mehtälä J, Hoti F, Jedenius E, et al. Real-world effectiveness of antipsychotic treatments in a nationwide cohort of 29 823 patients with schizophrenia. JAMA Psychiatry 2017; 74: 686–93.
- 17. Brunette MF, Dawson R, O’Keefe CD, Narasimhan M, Noordsy DL, Wojcik J, et al. A randomized trial of clozapine versus other antipsychotics for cannabis use disorder in patients with schizophrenia. J Dual Diagn 2011; 7: 50–63.
- 18. Sevy S, Robinson DG, Sunday S, Napolitano B, Miller R, McCormack J, 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 outcomes. Psychiatry Res 2011; 188: 310–4.
- 19. Schnell T, Koethe D, Krasnianski A, Gairing S, Schnell K, Daumann J, et al. Ziprasidone versus clozapine in the treatment of dually diagnosed (DD) patients with schizophrenia and cannabis use disorders: a randomized study. Am J Addict 2014; 23: 308–12.
- 20. Denissoff A, Taipale H, Tiihonen J, Di Forti M, Mittendorfer-Rutz E, Tanskanen A, et al. Antipsychotic use and psychiatric hospitalization in first-episode non-affective psychosis and cannabis use disorder: a Swedish nationwide cohort study. Schizophr Bull 2024; 50: 1287–94.
- 21. Green AI, Burgess ES, Dawson R, Zimmet SV, Strous RD. Alcohol and cannabis use in schizophrenia: effects of clozapine vs. risperidone. Schizophr Res 2003; 60: 81–5.
- 22. Potvin S, Stip E, Lipp O, Élie R, Mancini-Marië A, Demers MF, et al. Quetiapine in patients with comorbid schizophrenia-spectrum and substance use disorders: an open-label trial. Curr Med Res Opin 2006; 22: 1277–85.
- 23. Berk, S Brook, F Nur M. Risperidone compared to haloperidol in cannabis-induced psychotic disorder: a double blind randomized controlled trial. Int J Psychiatry Clin Pract 2000; 4: 139–42.
- 24. Berk M, Brook S, Trandafir A. A comparison of olanzapine with haloperidol in cannabis-induced psychotic disorder: a double-blind randomized controlled trial. Int Clin Psychopharmacol 1999; 14: 177–80.
- 25. Ricci V, De Berardis D, Maina G. Third-generation antipsychotics and Lurasidone in the treatment of substance-induced psychoses: a narrative review. Healthcare (Switzerland) 2024; 12: 339.
- 26. World Health Organization. ICD-10: International Statistical Classification of Diseases and Related Health Problems: Tenth Revision (2nd edn). WHO, 2004.
- 27. Norwegian Institute of Public Health. ATCDDD – Structure and Principles. Norwegian Institute of Public Health, 2022. (https://atcddd.fhi.no/atc/structure_and_principles/ [cited 6 Sep 2024]).
- 28. Tanskanen A, Taipale H, Koponen M, Tolppanen AM, Hartikainen S, Ahonen R, et al. From prescription drug purchases to drug use periods: a second generation method (PRE2DUP). BMC Med Inform Decis Mak 2015; 15: 21.
- 29. D’Allison P. Fixed Effects Regression Models. Fixed Effects Regression Models. SAGE Publications, 2009.
- 30. Arango C, Fagiolini A, Gorwood P, Kane JM, Diaz-Mendoza S, Sahota N, et al. Delphi panel to obtain clinical consensus about using long-acting injectable antipsychotics to treat first-episode and early-phase schizophrenia: treatment goals and approaches to functional recovery. BMC Psychiatry 2023; 23: 1–11.
- 31. Lähteenvuo M, Luykx JJ, Taipale H, Mittendorfer-Rutz E, Tanskanen A, Batalla A, et al. Associations between antipsychotic use, substance use and relapse risk in patients with schizophrenia: real-world evidence from two national cohorts. Br J Psychiatry 2022; 221: 758–65.
- 32. O’Connell J, Sunwoo M, McGorry P, O’Donoghue B. Characteristics and outcomes of young people with substance induced psychotic disorder. Schizophr Res 2019; 206: 257–62.
- 33. Thompson A, Marwaha S, Winsper C, Everard L, Jones PB, Fowler D, et al. Short-term outcome of substance-induced psychotic disorder in a large UK first episode psychosis cohort. Acta Psychiatr Scand 2016; 134: 321–8.
- 34. Levi L, Bar-Haim M, Winter-Van Rossum I, Davidson M, Leucht S, Fleischhacker WW, et al. Cannabis use and symptomatic relapse in first episode schizophrenia: trigger or consequence? Data from the OPTIMISE study. Schizophr Bull 2023; 49: 903–13.
- 35. Machielsen MWJ, Veltman DJ, van den Brink W, de Haan L. Comparing the effect of clozapine and risperidone on cue reactivity in male patients with schizophrenia and a cannabis use disorder: a randomized fMRI study. Schizophr Res 2018; 194: 32–8.
- 36. MacHielsen M, Beduin AS, Dekker N, Kahn RS, Linszen DH, Van Os J, et al. Differences in craving for cannabis between schizophrenia patients using risperidone, olanzapine or clozapine. J Psychopharmacol 2012; 26: 189–95.
- 37. Temmingh HS, Williams T, Siegfried N, Stein DJ. Risperidone versus other antipsychotics for people with severe mental illness and co-occurring substance misuse. Cochrane Database Syst Rev 2018; 1: CD011057.
- 38. Rafizadeh R, Danilewitz M, Bousman CA, Mathew N, White RF, Bahji A, et al. Effects of clozapine treatment on the improvement of substance use disorders other than nicotine in individuals with schizophrenia spectrum disorders: a systematic review and meta-analysis. J Psychopharmacol 2023; 37: 135–43.
- 39. Correll CU, Detraux J, De Lepeleire J, De Hert M. Effects of antipsychotics, antidepressants and mood stabilizers on risk for physical diseases in people with schizophrenia, depression and bipolar disorder. World Psychiatry 2015; 14:119–36.
- 40. Chiappini S, Cavallotto C, Mosca A, Di Carlo F, Piro T, Giovannetti G, et al. Investigating the effectiveness of brexpiprazole in subjects with schizophrenia spectrum illness and co-occurring substance use disorder: a prospective, multicentric, real-world study. Pharmaceuticals (Basel) 2024; 17: 535.
- 41. Lombardozzi G, Trovini G, Amici E, Kotzalidis GD, Perrini F, Giovanetti V, et al. Brexpiprazole in patients with schizophrenia with or without substance use disorder: an observational study. Front Psychiatry 2023; 14: 1321233.
- 42. Tiihonen J, Taipale H, Mehtälä J, Vattulainen P, Correll CU, Tanskanen A. Association of antipsychotic polypharmacy vs monotherapy with psychiatric rehospitalization among adults with schizophrenia. JAMA Psychiatry 2019; 76: 499–507.
- 43. Schoeler T, Monk A, Sami MB, Klamerus E, Foglia E, Brown R, et al. Continued versus discontinued cannabis use in patients with psychosis: a systematic review and meta-analysis. Lancet Psychiatry 2016; 3: 215–25.
Associated Data
Supplementary Materials
Data Availability Statement
The data used in this study cannot be made publicly available because of privacy regulations. According to the General Data Protection Regulation, the Swedish law SFS 2018:218, the Swedish Data Protection Act, the Swedish Ethical Review Act and the Public Access to Information and Secrecy Act, these types of sensitive data can only be made available for specific purposes, including research, that meet the criteria for access to this sort of sensitive and confidential data, as determined by a legal review. Readers may contact Professor Kristina Alexanderson (kristina.alexanderson@ki.se) regarding the data.