No CrossRef data available.
Article contents
Antipsychotic therapy and suicide risk in patients with treatment-resistant depression: target trial emulation framework study
Published online by Cambridge University Press: 08 April 2025
Abstract
Background
Previous studies investigating the effectiveness of augmentation therapy have been limited.
Aims
To evaluate the effectiveness of antipsychotic augmentation therapies among patients with treatment-resistant depression.
Method
We included patients diagnosed with depression receiving two antidepressant courses within 1 year between 2009 and 2020 and used the clone-censor-weight approach to address time-lag bias. Participants were assigned to either an antipsychotic or a third-line antidepressant. Primary outcomes were suicide attempt and suicide death. Cardiovascular death and all-cause mortality were considered as safety outcomes. Weighted pooled logistic regression and non-parametric bootstrapping were used to estimate approximate hazard ratios and 95% confidence intervals.
Results
The cohort included 39 949 patients receiving antipsychotics and the same number of matched antidepressant patients. The mean age was 51.2 (standard deviation 16.0) years, and 37.3% of participants were male. Compared with patients who received third-line antidepressants, those receiving antipsychotics had reduced risk of suicide attempt (sub-distribution hazard ratio 0.77; 95% CI 0.72–0.83) but not suicide death (adjusted hazard ratio 1.08; 95% CI 0.93–1.27). After applying the clone-censor-weight approach, there was no association between antipsychotic augmentation and reduced risk of suicide attempt (hazard ratio 1.06; 95% CI 0.89–1.29) or suicide death (hazard ratio 1.22; 95% CI 0.91–1.71). However, antipsychotic users had increased risk of all-cause mortality (hazard ratio 1.21; 95% CI 1.07–1.33).
Conclusions
Antipsychotic augmentation was not associated with reduced risk of suicide-related outcomes when time-lag bias was addressed; however, it was associated with increased all-cause mortality. These findings do not support the use of antipsychotic augmentation in patients with treatment-resistant depression.
Keywords
- Type
- Original Article
- Information
- Copyright
- © The Author(s), 2025. Published by Cambridge University Press on behalf of Royal College of Psychiatrists
References
Lundberg, J, Cars, T, Lööv, S-Å, Söderling, J, Sundström, J, Tiihonen, J, et al. Association of treatment-resistant depression with patient outcomes and health care resource utilization in a population-wide study. JAMA Psychiatry 2022; 80: 167–75.CrossRefGoogle Scholar
Gaynes, BN, Lux, L, Gartlehner, G, Asher, G, Forman-Hoffman, V, Green, J, et al. Defining treatment-resistant depression. Depress Anxiety 2020; 37: 134–45.Google ScholarPubMed
Rybak, YE, Lai, KSP, Ramasubbu, R, Vila-Rodriguez, F, Blumberger, DM, Chan, P, et al. Treatment-resistant major depressive disorder: Canadian expert consensus on definition and assessment. Depress Anxiety 2021; 38: 456–67.Google ScholarPubMed
Sforzini, L, Worrell, C, Kose, M, Anderson, IM, Aouizerate, B, Arolt, V, et al. A Delphi-method-based consensus guideline for definition of treatment-resistant depression for clinical trials. Mol Psychiatry 2022; 27: 1286–99.Google ScholarPubMed
Voineskos, D, Daskalakis, ZJ, Blumberger, DM. Management of treatment-resistant depression: challenges and strategies. Neuropsychiatr Dis Treat 2020; 16: 221–34.CrossRefGoogle ScholarPubMed
Goodwin, GM, Aaronson, ST, Alvarez, O, Arden, PC, Baker, A, Bennett, JC, et al. Single-dose psilocybin for a treatment-resistant episode of major depression. N Engl J Med 2022; 387: 1637–48.Google ScholarPubMed
Nunez, NA, Joseph, B, Pahwa, M, Kumar, R, Resendez, MG, Prokop, LJ, et al. Augmentation strategies for treatment resistant major depression: a systematic review and network meta-analysis. J Affect Disord 2022; 302: 385–400.Google ScholarPubMed
Dai, J, Ports, KD, Corrada, MM, Odegaard, AO, O’Connell, J, Jiang, L. Metformin and dementia risk: a systematic review with respect to time related biases. J Alzheimers Dis Rep 2022; 6: 443–59.Google Scholar
Hsieh, CY, Su, CC, Shao, SC, Sung, SF, Lin, SJ, Kao Yang, YH, et al. Taiwan’s National Health Insurance Research Database: past and future. Clin Epidemiol 2019; 11: 349–58.Google ScholarPubMed
Man, KKC, Shao, SC, Chaiyakunapruk, N, Dilokthornsakul, P, Kubota, K, Li, J, et al. Metabolic events associated with the use of antipsychotics in children, adolescents and young adults: a multinational sequence symmetry study. Eur Child Adolesc Psychiatry 2022; 31: 99–120.CrossRefGoogle Scholar
Tsai, DHT, Chang, WH, Lin, HW, Lin, SJ, Shao, SC, Lai, ECC. Post-discharge use of antipsychotics in patients with hospital-acquired delirium and associated risk of mortality – a population-based nested case-control study. Asian J Psychiatr 2023; 83: 103533.CrossRefGoogle ScholarPubMed
Huang, WC, Yang, ASH, Tsai, DHT, Shao, SC, Lin, SJ, Lai, ECC. Association between recently raised anticholinergic burden and risk of acute cardiovascular events: nationwide case-case-time-control study. BMJ 2023; 382: e076045.Google ScholarPubMed
Abrahami, D, Pradhan, R, Yin, H, Honig, P, Baumfeld Andre, E, Azoulay, L. Use of real-world data to emulate a clinical trial and support regulatory decision making: assessing the impact of temporality, comparator choice, and method of adjustment. Clin Pharmacol Ther 2021; 109: 452–61.CrossRefGoogle ScholarPubMed
Matthews, AA, Danaei, G, Islam, N, Kurth, T. Target trial emulation: applying principles of randomised trials to observational studies. BMJ 2022; 378: e071108.Google ScholarPubMed
Cepeda, MS, Reps, J, Fife, D, Blacketer, C, Stang, P, Ryan, P. Finding treatment-resistant depression in real-world data: how a data-driven approach compares with expert-based heuristics. Depress Anxiety 2018; 35: 220–8.Google ScholarPubMed
Huang, YT, Chen, YJ, Chang, SH, Kuo, CF, Chen, MH. Discharge status validation of the Chang Gung Research database in Taiwan. Biomed J 2022; 45: 907–13.Google Scholar
Kutcher, SA, Brophy, JM, Banack, HR, Kaufman, JS, Samuel, M. Emulating a randomised controlled trial with observational data: an introduction to the target trial framework. Can J Cardiol 2021; 37: 1365–77.Google Scholar
Austin, PC. An introduction to propensity score methods for reducing the effects of confounding in observational studies. Multivariate Behav Res 2011; 46: 399–424.CrossRefGoogle ScholarPubMed
Austin, P, Lee, D, Fine, J. Introduction to the analysis of survival data in the presence of competing risks. Circulation 2016; 133: 601–9.CrossRefGoogle Scholar
Ruberto, VL, Jha, MK, Murrough, JW. Pharmacological treatments for patients with treatment-resistant depression. Pharmaceuticals 2020; 13: 116.Google ScholarPubMed
Tundo, A, de Filippis, R, Proietti, L. Pharmacologic approaches to treatment resistant depression: evidences and personal experience. World J Psychiatry 2015; 5: 330–41.Google ScholarPubMed
Kennedy, SH, Lam, RW, McIntyre, RS, Tourjman, SV, Bhat, V, Blier, P, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 3. Pharmacological treatments. Can J Psychiatry 2016; 61: 540–60.CrossRefGoogle Scholar
Lenze, EJ, Mulsant, BH, Roose, SP, Lavretsky, H, Reynolds, CF, Blumberger, DM, et al. Antidepressant augmentation versus switch in treatment-resistant geriatric depression. N Engl J Med 2023; 388: 1067–79.Google ScholarPubMed
Maringe, C, Benitez Majano, S, Exarchakou, A, Smith, M, Rachet, B, Belot, A, et al. Reflection on modern methods: trial emulation in the presence of immortal-time bias. Assessing the benefit of major surgery for elderly lung cancer patients using observational data. Int J Epidemiol 2020; 49: 1719–29.Google ScholarPubMed
Chen, A, Ju, C, Mackenzie, IS, MacDonald, TM, Struthers, AD, Wei, L, et al. Impact of beta-blockers on mortality and cardiovascular disease outcomes in patients with obstructive sleep apnoea: a population-based cohort study in target trial emulation framework. Lancet Reg Health Eur 2023; 33: 100715.Google ScholarPubMed
Reif, A, Bitter, I, Buyze, J, Cebulla, K, Frey, R, Fu, D-J, et al. Esketamine nasal spray versus quetiapine for treatment-resistant depression. N Engl J Med 2023; 389: 1298–309.CrossRefGoogle ScholarPubMed
Tsai, DHT, Bell, JS, Abtahi, S, Baak, BN, Bazelier, MT, Brauer, R, et al. Cross-regional data initiative for the assessment and development of treatment for neurological and mental disorders. Clin Epidemiol 2023; 15: 1241–52.CrossRefGoogle Scholar
Tsai et al. supplementary material
Tsai et al. supplementary material
File
10.7 MB
eLetters
No eLetters have been published for this article.