Comparative mortality risk of antipsychotics

Title: Comparative mortality risk of antipsychotics in 41,695 patients with schizophrenia: an 11‑year population‑based cohort study in Hong Kong. 

Journal: European Neuropsychopharmacology, Volume 96, July 2025, pages 58–66 (Epub May 23, 2025)

Authors: Fang CZ, Chan JKN, Solmi M, Wong CSM, Lui SSY, Correll CU, Chang WC

🔬 Study Overview

• Population: 41,695 adults with diagnosed schizophrenia treated in Hong Kong public healthcare (2006–2016), with an incident subcohort of 13,283 

• Design: Cox regression using time-varying antipsychotic exposure, comparing monotherapy (perphenazine as reference) and regimen-level (first-gen oral antipsychotics as reference) risk for:

  • All‑cause mortality

  • Natural‑cause mortality

  • Unnatural‑cause mortality 

🏆 Key Findings

1. Clozapine monotherapy had the lowest mortality risk:

   • All-cause: aHR = 0.41

   • Natural causes: aHR = 0.52

   • Unnatural causes: aHR = 0.16 

2. Among long-acting injectables (LAIs), paliperidone LAI showed significantly reduced:

   • All-cause: aHR = 0.51

   • Natural-cause mortality: aHR = 0.55 

3. Several second-generation oral antipsychotics—olanzapine, quetiapine, risperidone, aripiprazole, amisulpride—also had lower overall mortality compared to perphenazine 

4. Polypharmacy benefits depended on composition:

   • Regimens including clozapine or LAI were associated with lower mortality than oral first-gen alone.

   • In contrast, first-gen LAI monotherapy, generic polypharmacy, or oral polypharmacy without clozapine were linked to elevated mortality risk 

5. Results were consistent in the incident (newly treated) cohort 

🧠 Clinical Implications

• Clozapine emerges as the top protective antipsychotic against mortality, reinforcing its critical role in treatment-resistant schizophrenia despite monitoring burdens.

• LAI formulations, especially paliperidone LAI, are associated with improved longevity—likely due to better adherence.

• Thoughtful regimen choice is essential: polypharmacy should ideally include clozapine or LAI; blind polypharmacy may be harmful.

• The study underscores the importance of early and equitable access to clozapine and LAIs within public mental health services.

https://pubmed.ncbi.nlm.nih.gov/40412293/