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,^{Reference Arango, Fagiolini, Gorwood, Kane, Diaz-Mendoza and Sahota30} 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.^{Reference Schoeler, Petros, Di Forti, Klamerus, Foglia and Murray9}

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 SUD^{Reference Tiihonen, Mittendorfer-Rutz, Majak, Mehtälä, Hoti and Jedenius16,Reference Lähteenvuo, Luykx, Taipale, Mittendorfer-Rutz, Tanskanen and Batalla31} or FEP and CUD.^{Reference Denissoff, Taipale, Tiihonen, Di Forti, Mittendorfer-Rutz and Tanskanen20} The findings are plausible in the context of a similar relapse rate in SIP versus FEP^{Reference O’Connell, Sunwoo, McGorry and O’Donoghue32,Reference Thompson, Marwaha, Winsper, Everard, Jones and Fowler33} and similar rates of individuals converting into schizophrenia after CIP versus FEP.^{Reference Murrie, Lappin, Large and Sara11} 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.^{Reference Levi, Bar-Haim, Winter-Van Rossum, Davidson, Leucht and Fleischhacker34} Further, there are studies where treatment with clozapine^{Reference Machielsen, Veltman, van den Brink and de Haan35,Reference MacHielsen, Beduin, Dekker, Kahn, Linszen and Van Os36} and olanzapine^{Reference MacHielsen, Beduin, Dekker, Kahn, Linszen and Van Os36} 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.^{Reference Temmingh, Williams, Siegfried and Stein37} 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.^{Reference Rafizadeh, Danilewitz, Bousman, Mathew, White and Bahji38} Cannabis use also associates with treatment resistance in schizophrenia^{Reference Arsalan, Iqbal, Tariq, Ayonrinde, Vincent and Ayub10} 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.^{Reference Denissoff, Taipale, Tiihonen, Di Forti, Mittendorfer-Rutz and Tanskanen20}

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.^{Reference Correll, Detraux, De Lepeleire and De Hert39}

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 functionality^{Reference Chiappini, Cavallotto, Mosca, Di Carlo, Piro and Giovannetti40} and also to reduce craving.^{Reference Chiappini, Cavallotto, Mosca, Di Carlo, Piro and Giovannetti40,Reference Lombardozzi, Trovini, Amici, Kotzalidis, Perrini and Giovanetti41} 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 studies^{Reference Tiihonen, Mittendorfer-Rutz, Majak, Mehtälä, Hoti and Jedenius16,Reference Denissoff, Taipale, Tiihonen, Di Forti, Mittendorfer-Rutz and Tanskanen20,Reference Lähteenvuo, Luykx, Taipale, Mittendorfer-Rutz, Tanskanen and Batalla31} 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,^{Reference Tiihonen, Taipale, Mehtälä, Vattulainen, Correll and Tanskanen42} 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.^{Reference Correll, Detraux, De Lepeleire and De Hert39}

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.^{Reference Schoeler, Monk, Sami, Klamerus, Foglia and Brown43} 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.