Antipsychotic Polypharmacy and Epigenetic Age Acceleration in Schizophrenia

Abstract

Introduction

Schizophrenia spectrum disorders (SSD) are debilitating psychiatric illnesses that require extensive pharmacologic, cognitive, and functional management. SSD patients are often prescribed different medications, most commonly antipsychotics, which bear numerous side effects. Recently, accumulating evidence has shown epigenetic aging changes in SSD. However, the effects of antipsychotic medications on this phenomenon remain unexplored.

Methods

We investigated whether antipsychotic medications are associated with epigenetic age acceleration (EAA) in 153 SSD patients. EAA was estimated using six different epigenetic clocks, based on the methylation patterns of peripheral blood cells.

Results

The analysis revealed some evidence of aging deceleration based on the Hannum DNAm Age in individuals on antipsychotic polypharmacy, relative to their monopharmacy counterparts (mean difference=–0.59 years, p=0.0109), which was only nearing significance after adjusting for multiple comparisons (p_adjusted=0.0654). In sex-specific analysis, only females displayed significantly decelerated epigenetic aging in the polypharmacy group in three of the six clocks. Furthermore, we observed no dose-dependent effects of antipsychotics on EAA in all clocks using three dose standardization methods (daily defined dose, chlorpromazine equivalents, and percent of maximum allowed dose).

Discussion

The findings suggest that antipsychotic treatment may modulate biological aging in SSD; however, this effect is not dose-dependent. Moreover, there appears to be an interplay between sex, polypharmacy, and epigenetic aging. These findings contribute to our understanding of the biological effects of antipsychotic treatment, and future research in this area is key for weighing the benefits and the risks of pharmacological management of SSD.

Keywords

schizophrenia - aging - antipsychotic drugs - epigenetics - DNA methylation

Publication History

Received: 04 October 2024

Accepted after revision: 24 March 2025

Article published online:
03 November 2025

• References

• 1 Ringeisen H, Edlund M, Guyer H. et al. Mental and substance use disorders prevalence study (MDPS): Findings report. RTI International. 2023
• 2 Laursen TM, Nordentoft M, Mortensen PB. Excess early mortality in schizophrenia. Annu Rev Clin Psychol 2014; 10: 425-448
• 3 Peritogiannis V, Ninou A, Samakouri M. Mortality in schizophrenia-spectrum disorders: Recent advances in understanding and management. Healthcare 2022; 10: 2366
• 4 Caspi A, Shireby G, Mill J. et al. Accelerated pace of aging in schizophrenia: Five case-control studies. Biol Psychiatry 2024; 95: 1038-1047
• 5 Teeuw J, Ori APS, Brouwer RM. et al. Accelerated aging in the brain, epigenetic aging in blood, and polygenic risk for schizophrenia. Schizophr Res 2021; 231: 189-197
• 6 Higgins-Chen AT, Boks MP, Vinkers CH. et al. Schizophrenia and epigenetic aging biomarkers: Increased mortality, reduced cancer risk, and unique clozapine effects. Biol Psychiatry 2020; 88: 224-235
• 7 Jylhävä J, Pedersen NL, Hägg S. Biological age predictors. EBioMedicine 2017; 21: 29-36
• 8 Horvath S, Raj K. DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nat Rev Genet 2018; 19: 371-384
• 9 Lu AT, Seeboth A, Tsai PC. et al. DNA methylation-based estimator of telomere length. Aging 2019; 11: 5895-5923
• 10 Hannum G, Guinney J, Zhao L. et al. Genome-wide methylation profiles reveal quantitative views of human aging rates. Mol Cell 2013; 49: 359-367
• 11 Lu AT, Quach A, Wilson JG. et al. DNA methylation GrimAge strongly predicts lifespan and healthspan. Aging 2019; 11: 303-327
• 12 Fisher MD, Reilly K, Isenberg K. et al. Antipsychotic patterns of use in patients with schizophrenia: Polypharmacy versus monotherapy. BMC Psychiatry 2014; 14: 341
• 13 Okazaki S, Otsuka I, Horai T. et al. Accelerated extrinsic epigenetic aging and increased natural killer cells in blood of suicide completers. Prog Neuropsychopharmacol Biol Psychiatry 2020; 98: 109805
• 14 Sheehan DV, Lecrubier Y, Sheehan KH. et al. The Mini-International Neuropsychiatric Interview (M.I.N.I.): The development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 1998; 59: 22-57
• 15 Qian J, Fischer C, Burhan A. et al. GWAS of biological aging to find longevity genes in schizophrenia. Eur Arch Psychiatry Clin Neurosci 2024; 274: 1025-1036
• 16 Aryee MJ, Jaffe AE, Corrada-Bravo H. et al. Minfi: A flexible and comprehensive bioconductor package for the analysis of infinium DNA methylation microarrays. Bioinformatics 2014; 30: 1363-1369
• 17 ATCDDD – ATC/DDD Index. Cited 2025 Mar 20. Available from https://atcddd.fhi.no/atc_ddd_index/
• 18 Brown E, Shah P, Kim J. et al. ChlorpromazineR. CRAN. 2021 (chlorpromazineR: Convert antipsychotic doses to chlorpromazine equivalents). Available from https://cran.r-project.org/web/packages/chlorpromazineR/index.html
• 19 R Foundation for Statistical Computing. R: A Language and Environment for Statistical Computing. Vienna, Austria: R Core Team; 2024. . Available from https://www.R-project.org/
• 20 Ori APS, Olde Loohuis LM, Guintivano J. et al. Meta-analysis of epigenetic aging in schizophrenia reveals multifaceted relationships with age, sex, illness duration, and polygenic risk. Clin Epigenetics 2024; 16: 53
• 21 Pérez-Aldana BE, Martínez-Magaña JJ, Mayén-Lobo YG. et al. Clozapine long-term treatment might reduce epigenetic age through hypomethylation of longevity regulatory pathways genes. Front Psychiatry. 2022 13. Available from https://www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2022.870656/full
• 22 Dada O, Adanty C, Dai N. et al. Biological aging in schizophrenia and psychosis severity: DNA methylation analysis. Psychiatry Res 2021; 296: 113646
• 23 Wolkowitz OM, Jeste DV, Martin AS. et al. Leukocyte telomere length: Effects of schizophrenia, age, and gender. 2017 Available from https://escholarship.org/uc/item/0kh1v39q
• 24 Du J, Nakachi Y, Fujii A. et al. Antipsychotics function as epigenetic age regulators in human neuroblastoma cells. Schizophrenia 2022; 8: 69