Abstract

Background: Pharmacotherapy with clozapine is listed as an optional treatment for several psychiatric disorders in guidelines across the globe. Nonetheless, its transdiagnostic effectiveness across most psychiatric disorders remains uncertain due to scant evidence. We therefore aimed to assess the effectiveness and safety of clozapine across multiple psychiatric disorders.

Methods: This cohort study used nationwide register-based data from Finland and Sweden in individuals aged 16 years or older diagnosed with schizophrenia, schizoaffective disorder, delusional disorder, bipolar disorder, psychotic depression, major depressive disorder, and borderline personality disorder (BPD). The effectiveness of clozapine was compared with other oral antipsychotics as a group, and for bipolar disorder additionally against mood stabilisers. The primary outcome was all-cause psychiatric hospitalisation. Secondary outcomes were all-cause hospitalisation or mortality as a composite outcome, all-cause discontinuation (for which clozapine use was compared with olanzapine use), and disorder-specific hospitalisations (eg, hospitalisation due to psychosis for schizophrenia-spectrum disorders and hospitalisation due to mood episodes for affective disorders). A within-individual design was used, where each patient served as their own control, minimising selection bias. Data were analysed separately in each country and combined using meta-analytical methods. People with lived experience were not involved in the research and writing process.

Findings: The study population included 505 474 individuals, of whom 283 809 (56·1%) were women and 221 665 (43·9%) were men, with a mean age of 41·6 years (SD 4·4). Data on ethnicity were unavailable. Altogether, clozapine was used by 19 910 individuals. Parsed by disorder, clozapine was used by 12·2-18·7% (n=5258 in Sweden, 10 115 in Finland) of people with schizophrenia, 8·8-20·7% (n=1131, n=1591) with schizoaffective disorder, 1·8% (n=341; data only available in Sweden) with delusional disorder, 0·5% (n=118, n=331) with major depressive disorder, 0·5-0·6% (n=490, n=371) with bipolar disorder, 0·3-0·6% (n=39, n=111) with psychotic depression, and 0·3% (n=36; data only available in Sweden) with BPD. Clozapine use was associated with reduced psychiatric hospitalisation risks versus other oral antipsychotics in all disorders, except for BPD. The greatest reductions were observed in schizophrenia (meta-analysis of adjusted hazard ratios [maHR] 0·70 [95% CI 0·67-0·72]) and schizoaffective disorder (maHR 0·71 [0·67-0·74]), followed by delusional disorder (adjusted hazard ratio 0·73 [0·60-0·89]), major depressive disorder (maHR 0·74 [0·66-0·84]), psychotic depression (maHR 0·76 [0·61-0·96]), and bipolar disorder (maHR 0·77 [0·69-0·87]). Moreover, we found no evidence of increased all-cause hospitalisation or mortality risks associated with clozapine use for all disorders examined. Furthermore, for all disorders studied except for BPD, all-cause discontinuation rates were lower during clozapine than olanzapine use. For bipolar disorder, clozapine outperformed mood stabilisers on all-cause psychiatric hospitalisation and other antipsychotics for several disorder-specific outcomes.

Interpretation: These findings support the transdiagnostic effectiveness and safety of clozapine, particularly in schizophrenia-spectrum disorders, bipolar disorder, and severe depression. Given the overall consistent findings across two large national cohorts, these results could inform several treatment guidelines and clinical decision-making for individuals with such severe psychiatric disorders.

Funding: Sigrid Jusélius Foundation.