Highlight
– Nationwide Finnish and Swedish registry analyses (n=505,474) found clozapine use linked to lower risk of psychiatric hospitalisation versus other oral antipsychotics across multiple disorders (schizophrenia-spectrum, bipolar disorder, severe depression), with no increased all-cause hospitalisation or mortality.
– The largest absolute relative benefits were in schizophrenia and schizoaffective disorder (maHR ≈0.70–0.71). Clozapine also showed benefit in delusional disorder, major depressive disorder with psychosis, psychotic depression and bipolar disorder.
– Clozapine prescribing outside schizophrenia remains rare despite potential benefit; registries and within-individual design strengthen causal inference but residual confounding and safety monitoring requirements limit broad extrapolation.
Background and clinical context
Clozapine is established as the most effective antipsychotic for treatment-resistant schizophrenia and is uniquely recommended in major guidelines for that indication because of superior efficacy on psychotic symptoms and suicidality. However, many clinical guidelines list clozapine as an optional or last-line agent for other severe psychiatric presentations—bipolar disorder with psychosis, psychotic depression, schizoaffective disorder and some refractory personality disorder presentations—largely due to sparse evidence, concerns about adverse events (notably agranulocytosis, myocarditis, seizures, and metabolic effects), and logistic barriers to safe initiation and monitoring.
The study by Luykx and colleagues (Lancet Psychiatry, 2025) addresses this evidence gap by using two large national registries to examine clozapine’s comparative effectiveness and safety across a broad set of psychiatric diagnoses using a within-individual design that reduces confounding by indication.
Study design and methods
Cohort and data sources
Investigators combined nationwide, register-based longitudinal data from Finland and Sweden including people aged ≥16 years with diagnoses of schizophrenia, schizoaffective disorder, delusional disorder, bipolar disorder, psychotic depression, major depressive disorder, and borderline personality disorder (BPD). The pooled study population comprised 505,474 individuals; clozapine was used by 19,910 people.
Exposure and comparators
Clozapine exposure was compared against other oral antipsychotics as a group. In bipolar disorder, clozapine was additionally compared with mood stabilisers. For the all-cause discontinuation outcome, clozapine was compared specifically with olanzapine to control for differences in tolerability and metabolic risk profiles.
Outcomes and analytical approach
The primary outcome was all-cause psychiatric hospitalisation. Secondary outcomes included a composite of all-cause hospitalisation or mortality, all-cause discontinuation, and disorder-specific hospitalisations (for example hospitalisation due to psychosis in schizophrenia-spectrum disorders or mood episodes in affective disorders). A within-individual (self-controlled) design was used so that each patient served as their own control, thereby minimizing time-invariant confounding. Analyses were conducted separately per country and combined via meta-analysis.
Key results
Overall cohort and clozapine utilisation
The pooled sample included 505,474 individuals (56.1% women) with mean age 41.6 years. Clozapine use proportions varied by diagnosis: approximately 12–19% in schizophrenia, 9–21% in schizoaffective disorder, and much lower rates in other conditions (0.3–0.6% in bipolar disorder and severe depression; 0.3% BPD [Sweden only]). Ethnicity data were not available.
Primary outcome: psychiatric hospitalisation
Clozapine was associated with a statistically significant reduction in risk of psychiatric hospitalisation versus other oral antipsychotics in all diagnostic groups except BPD. Key effect estimates (meta-analytic adjusted hazard ratios, maHR) included:
- Schizophrenia: maHR 0.70 (95% CI 0.67–0.72)
- Schizoaffective disorder: maHR 0.71 (0.67–0.74)
- Delusional disorder (Sweden only): aHR 0.73 (0.60–0.89)
- Major depressive disorder (with psychosis): maHR 0.74 (0.66–0.84)
- Psychotic depression: maHR 0.76 (0.61–0.96)
- Bipolar disorder: maHR 0.77 (0.69–0.87)
These hazard ratios indicate relative reductions in psychiatric hospitalisation risk of roughly 23–30% across responsive disorders, the largest being in schizophrenia-spectrum diagnoses.
Secondary outcomes: composite hospitalisation/mortality and discontinuation
No evidence was found that clozapine increased the combined risk of all-cause hospitalisation or death across the disorders studied. All-cause discontinuation rates were lower during clozapine treatment than during olanzapine in all diagnostic groups except BPD, suggesting better retention on clozapine in many severe illnesses despite its monitoring burden and adverse-effect profile.
Bipolar disorder comparisons
In bipolar disorder, clozapine outperformed mood stabilisers for the primary outcome of psychiatric hospitalisation and showed advantages over other antipsychotics for several disorder-specific outcomes. Although crude numbers of clozapine-treated bipolar patients were small (0.5–0.6%), effect estimates favour clozapine in severe, treatment-resistant bipolar presentations.
Safety signals
The study observed no increased risk of all-cause hospitalisation or mortality with clozapine. However, registry analyses cannot fully capture certain rare but serious laboratory-based adverse events (eg, agranulocytosis, myocarditis) that require active monitoring; they may be under-ascertained in administrative data. The known risks of clozapine—neutropenia/agranulocytosis, myocarditis and cardiomyopathy, seizures, severe constipation/ileus, sedation and metabolic syndrome—remain clinically important and require structured monitoring and management.
Expert commentary and interpretation
This study provides compelling, large-scale, real-world evidence supporting clozapine’s transdiagnostic effectiveness for severe psychiatric disorders beyond its established role in treatment-resistant schizophrenia. The use of two national registries and within-individual comparisons strengthens causal inference: by comparing outcomes during periods on clozapine with outcomes in the same person while not on clozapine, the authors minimized confounding by time-invariant factors (e.g., baseline illness severity, personality traits, genetic vulnerability).
Mechanistically, clozapine’s unique receptor profile (weak D2 antagonism, high affinity for 5-HT2A, 5-HT2C, muscarinic, and glutamatergic modulatory effects) and anti-suicidal properties may underlie benefits across psychotic and affective disorders, particularly in severe, treatment-resistant phenotypes where conventional drugs fail.
Strengths
- Very large, population-based cohorts with long follow-up.
- Within-individual design reducing selection bias and confounding by indication.
- Consistent findings across two national contexts increasing external validity in high-income settings with structured healthcare systems.
Limitations
- Observational design cannot fully exclude time-varying confounding (eg, changes in concurrent psychosocial care, access to crisis services, or illness phase).
- Registries lack granular clinical detail (symptom scales, exact reasons for hospitalisation, lab-confirmed adverse events), and ethnicity data were not available, limiting assessment of disparities.
- Clozapine exposure was relatively rare outside schizophrenia, producing small samples in some diagnostic subgroups and wider uncertainty about safety in those groups.
- Monitoring and selection biases: patients selected for clozapine may receive closer follow-up, which could contribute to improved outcomes (detection bias for adverse events but also active management lowering hospitalisation risk).
Clinical implications and practice considerations
These findings argue for reconsidering clozapine’s role in selected non-schizophrenia severe mental illnesses—especially schizoaffective disorder, refractory bipolar disorder with psychosis, and severe depressive illness with psychotic features—when patients have not responded to standard treatments. Key practical points:
- Clozapine initiation demands infrastructure: baseline cardiac and hematologic assessment, mandatory regular blood monitoring for neutropenia, protocols for myocarditis surveillance, and systems to manage metabolic risk.
- Before expanding clozapine use, services must ensure capacity for safe initiation and follow-up and training to manage side effects and drug interactions.
- Shared decision-making is essential: discuss likely benefits (reduced hospitalisation, improved symptom control) alongside risks and monitoring burden.
- Low current prescribing rates in non‑schizophrenia diagnoses suggest a gap between potential effectiveness and clinical uptake, often driven by safety concerns, regulatory caution, and logistic barriers.
Research and policy gaps
The registry evidence supports broader study but does not replace well-designed pragmatic randomized trials in non-schizophrenia indications to quantify efficacy and harms under controlled conditions. Future research priorities include:
- Randomized or pragmatic trials of clozapine for treatment-resistant bipolar disorder and psychotic depression.
- Detailed pharmacoepidemiology integrating laboratory and imaging data to better characterize rare but serious adverse events in diverse populations.
- Implementation research on models of care that enable safe, equitable clozapine provision (e.g., community monitoring, point-of-care neutrophil testing).
- Equity analyses to evaluate whether certain groups are under‑represented among clozapine recipients and to identify barriers to access.
Conclusion
Luykx et al.’s transnational registry analysis offers robust real-world evidence that clozapine reduces the risk of psychiatric hospitalisation across multiple severe psychiatric disorders, with no observed increase in overall hospitalisation or mortality. The strongest and most consistent benefits are in schizophrenia-spectrum disorders, but notable benefits were also seen in bipolar disorder and severe depressive disorders with psychosis. These results should prompt guideline committees, clinicians, and health systems to re-evaluate clozapine’s role beyond schizophrenia while ensuring adequate infrastructure for safe use and ongoing surveillance for serious adverse effects.
Funding and trial registration
Funding: Sigrid Jusélius Foundation. The study was registry-based and not registered on clinicaltrials.gov as an interventional trial.
References
1. Luykx JJ, Colgan M, Vieta E, Hamina A, Schulte PFJ, Correll CU, Mittendorfer-Rutz E, Siskind D, Lieslehto J, Tanskanen A, Tiihonen J, Taipale H. Transdiagnostic effectiveness and safety of clozapine in individuals with psychotic, affective, and personality disorders: nationwide and meta-analytic comparisons with other antipsychotics. Lancet Psychiatry. 2025 Dec;12(12):921-931. doi: 10.1016/S2215-0366(25)00297-4. PMID: 41192460.
2. National Institute for Health and Care Excellence (NICE). Psychosis and schizophrenia in adults: prevention and management (Clinical guideline [CG178]). 2014 (updated sections since). Available at: https://www.nice.org.uk/guidance/cg178
3. American Psychiatric Association. Practice Guideline for the Treatment of Patients With Schizophrenia. 2020. American Psychiatric Association Publishing.
AI image prompt for article thumbnail
A clinical vignette-style illustration: a diverse group of adults (different ages, sexes and ethnicities) in a modern outpatient psychiatric clinic; one clinician reviews a chart labeled ‘Clozapine’ while another team member speaks with a patient; soft, warm lighting; hospital corridor subtly visible in the background; an overlaid translucent line graph showing a downward trend to signal improved outcomes; realistic photographic style, high resolution.
