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Antipsychotic treatment and risk of discontinuation and hospitalization in first-episode schizophrenia: a nationwide population-based study

Published online by Cambridge University Press:  15 April 2021

Sung Woo Joo
Department of Psychiatry, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
Harin Kim
Department of Psychiatry, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
Young Tak Jo
Department of Psychiatry, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
Young Jae Choi
Department of Psychiatry, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
Soojin Ahn
Department of Psychiatry, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
Jungsun Lee*
Department of Psychiatry, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
Author for correspondence: Jungsun Lee, E-mail:



Current evidence on antipsychotic treatment and risk of psychiatric hospitalization in first-episode schizophrenia (FES) is largely based on the findings from randomized clinical trials (RCTs). However, the generalization of the findings to real-world patients is limited due to inherent caveats of the RCT. We aimed to investigate the treatment discontinuation and risk of psychiatric hospitalization using a nationwide population database.


The Health Insurance Review Agency database in South Korea was obtained, and the observation period started from 1 January 2009 to 31 December 2016. We defined the maintenance period as the period from 6-month after the diagnosis of schizophrenia, which is utilized for the main results. For a total of 44 396 patients with FES, a within-individual Cox regression model was used to compare the risk of the treatment discontinuation and psychiatric hospitalization.


In group comparison, a long-acting injectable (LAI) antipsychotic group was associated with the lowest risk of the treatment discontinuation (0.64, 0.55–0.75) and psychiatric hospitalization (0.29, 0.22–0.38) in comparison with a typical antipsychotic group and no use, respectively. Among individual antipsychotics, the lowest risk of the treatment discontinuation was observed in LAI paliperidone (0.46, 0.37–0.66) compared to olanzapine. Clozapine was found to be the most effective antipsychotic in lowering the risk of psychiatric hospitalization as monotherapy compared to no use (0.23, 0.18–0.31).


In real-world patients with FES, LAI paliperidone and clozapine were associated with low treatment discontinuation and better effectiveness in lowering the risk of psychiatric hospitalization.

Original Article
Copyright © The Author(s), 2021. Published by Cambridge University Press

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Acosta, F. J., Hernandez, J. L., Pereira, J., Herrera, J., & Rodriguez, C. J. (2012). Medication adherence in schizophrenia. World Journal of Psychiatry, 2(5), 7482. doi:10.5498/wjp.v2.i5.74.CrossRefGoogle ScholarPubMed
Ascher-Svanum, H., Zhu, B., Faries, D. E., Lacro, J. P., Dolder, C. R., & Peng, X. (2008). Adherence and persistence to typical and atypical antipsychotics in the naturalistic treatment of patients with schizophrenia. Patient Preference and Adherence, 2, 6777. doi:10.2147/ppa.s2940.CrossRefGoogle ScholarPubMed
Blonde, L., Khunti, K., Harris, S. B., Meizinger, C., & Skolnik, N. S. (2018). Interpretation and impact of real-world clinical data for the practicing clinician. Advances in Therapy, 35(11), 17631774. doi:10.1007/s12325-018-0805-y.CrossRefGoogle ScholarPubMed
Crossley, N. A., Constante, M., McGuire, P., & Power, P. (2010). Efficacy of atypical v. typical antipsychotics in the treatment of early psychosis: Meta-analysis. British Journal of Psychiatry, 196(6), 434439. doi:10.1192/bjp.bp.109.066217.CrossRefGoogle ScholarPubMed
Decuypere, F., Sermon, J., Geerts, P., Denee, T. R., De Vos, C., Malfait, B., … Mulder, C. L. (2017). Treatment continuation of four long-acting antipsychotic medications in the Netherlands and Belgium: A retrospective database study. PLoS ONE, 12(6), e0179049. doi:10.1371/journal.pone.0179049.CrossRefGoogle ScholarPubMed
Dolder, C. R., Lacro, J. P., Dunn, L. B., & Jeste, D. V. (2002). Antipsychotic medication adherence: Is there a difference between typical and atypical agents? American Journal of Psychiatry, 159(1), 103108. doi:10.1176/appi.ajp.159.1.103.CrossRefGoogle Scholar
Emsley, R., Chiliza, B., Asmal, L., & Harvey, B. H. (2013). The nature of relapse in schizophrenia. BMC Psychiatry, 13, 50. doi:10.1186/1471-244X-13-50.CrossRefGoogle ScholarPubMed
Emsley, R., Oosthuizen, P. P., Koen, L., Niehaus, D. J., & Martinez, G. (2012). Symptom recurrence following intermittent treatment in first-episode schizophrenia successfully treated for 2 years: A 3-year open-label clinical study. Journal of Clinical Psychiatry, 73(4), e541e547. doi:10.4088/JCP.11m07138.CrossRefGoogle Scholar
Fleischhacker, W. W., & Uchida, H. (2014). Critical review of antipsychotic polypharmacy in the treatment of schizophrenia. International Journal of Neuropsychopharmacology, 17(7), 10831093. doi:10.1017/S1461145712000399.CrossRefGoogle ScholarPubMed
Gaebel, W., Riesbeck, M., Wolwer, W., Klimke, A., Eickhoff, M., von Wilmsdorff, M., … German Study Group on First-Episode, S. (2011). Relapse prevention in first-episode schizophrenia – maintenance vs intermittent drug treatment with prodrome-based early intervention: Results of a randomized controlled trial within the German research network on schizophrenia. Journal of Clinical Psychiatry, 72(2), 205218. doi:10.4088/JCP.09m05459yel.CrossRefGoogle Scholar
Galletly, C., Castle, D., Dark, F., Humberstone, V., Jablensky, A., Killackey, E., … Tran, N. (2016). Royal Australian and New Zealand college of psychiatrists clinical practice guidelines for the management of schizophrenia and related disorders. Australian and New Zealand Journal of Psychiatry, 50(5), 410472. doi:10.1177/0004867416641195.CrossRefGoogle ScholarPubMed
Gardner, D. M., Murphy, A. L., O'Donnell, H., Centorrino, F., & Baldessarini, R. J. (2010). International consensus study of antipsychotic dosing. American Journal of Psychiatry, 167(6), 686693. doi:10.1176/appi.ajp.2009.09060802.CrossRefGoogle ScholarPubMed
Huhn, M., Nikolakopoulou, A., Schneider-Thoma, J., Krause, M., Samara, M., Peter, N., … Leucht, S. (2019). Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: A systematic review and network meta-analysis. The Lancet, 394(10202), 939951. doi:10.1016/s0140-6736(19)31135-3.CrossRefGoogle ScholarPubMed
Kishimoto, T., Hagi, K., Nitta, M., Leucht, S., Olfson, M., Kane, J. M., & Correll, C. U. (2018). Effectiveness of long-acting injectable vs oral antipsychotics in patients with schizophrenia: A meta-analysis of prospective and retrospective cohort studies. Schizophrenia Bulletin, 44(3), 603619. doi:10.1093/schbul/sbx090.CrossRefGoogle ScholarPubMed
Kroken, R. A., Kjelby, E., Wentzel-Larsen, T., Mellesdal, L. S., Jorgensen, H. A., & Johnsen, E. (2014). Time to discontinuation of antipsychotic drugs in a schizophrenia cohort: Influence of current treatment strategies. Therapeutic Advances in Psychopharmacology, 4(6), 228239. doi:10.1177/2045125314545614.CrossRefGoogle Scholar
Kuhl, J. O. G., Laursen, T. M., Thorup, A., & Nordentoft, M. (2016). The incidence of schizophrenia and schizophrenia spectrum disorders in Denmark in the period 2000–2012. A register-based study. Schizophrenia Research, 176(2-3), 533539. doi:10.1016/j.schres.2016.06.023.CrossRefGoogle ScholarPubMed
Lacro, J. P., Dunn, L. B., Dolder, C. R., Leckband, S. G., & Jeste, D. V. (2002). Prevalence of and risk factors for medication nonadherence in patients with schizophrenia: A comprehensive review of recent literature. Journal of Clinical Psychiatry, 63(10), 892909. doi:10.4088/jcp.v63n1007.CrossRefGoogle ScholarPubMed
Lehman, A. F., Lieberman, J. A., Dixon, L. B., McGlashan, T. H., Miller, A. L., Perkins, D. O., & Steering Committee on Practice, G. (2004). Practice guideline for the treatment of patients with schizophrenia, second edition. American Journal of Psychiatry, 161(Suppl 2), 156.Google ScholarPubMed
Lichtenstein, P., Halldner, L., Zetterqvist, J., Sjolander, A., Serlachius, E., Fazel, S., … Larsson, H. (2012). Medication for attention deficit-hyperactivity disorder and criminality. New England Journal of Medicine, 367(21), 20062014. doi:10.1056/NEJMoa1203241.CrossRefGoogle ScholarPubMed
Lieberman, J. A., Alvir, J. M., Koreen, A., Geisler, S., Chakos, M., Sheitman, B., & Woerner, M. (1996). Psychobiologic correlates of treatment response in schizophrenia. Neuropsychopharmacology 14(Suppl 3), 13S21S. doi:10.1016/0893-133X(95)00200-W.CrossRefGoogle ScholarPubMed
Lieberman, J. A., Tollefson, G., Tohen, M., Green, A. I., Gur, R. E., Kahn, R., … Group, H. S. (2003). Comparative efficacy and safety of atypical and conventional antipsychotic drugs in first-episode psychosis: A randomized, double-blind trial of olanzapine versus haloperidol. American Journal of Psychiatry, 160(8), 13961404. doi:10.1176/appi.ajp.160.8.1396.CrossRefGoogle ScholarPubMed
Masuda, T., Misawa, F., Takase, M., Kane, J. M., & Correll, C. U. (2019). Association with hospitalization and all-cause discontinuation among patients with schizophrenia on clozapine vs other oral second-generation antipsychotics: A systematic review and meta-analysis of cohort studies. JAMA Psychiatry, 76(10), 10521062. doi:10.1001/jamapsychiatry.2019.1702.CrossRefGoogle ScholarPubMed
Meier, J., Becker, T., Patel, A., Robson, D., Schene, A., Kikkert, M., … Puschner, B. (2010). Effect of medication-related factors on adherence in people with schizophrenia: A European multi-centre study. Epidemiologia e Psichiatria Sociale, 19(3), 251259. doi:10.1017/s1121189x00001184.CrossRefGoogle ScholarPubMed
Novick, D., Haro, J. M., Bertsch, J., Anand, H., Jemiai, N., & Haddad, P. M. (2012). Comparison of treatment discontinuation and hospitalization among nonadherent patients initiating depot or oral typical antipsychotic medications. International Clinical Psychopharmacology, 27(5), 275282. doi:10.1097/YIC.0b013e328354db12.CrossRefGoogle ScholarPubMed
Oh, S., Lee, T. Y., Kim, M., Kim, S. H., Lee, S., Cho, S., … Kwon, J. S. (2020). Effectiveness of antipsychotic drugs in schizophrenia: A 10-year retrospective study in a Korean tertiary hospital. Npj Schizophrenia, 6(1), 32. doi:10.1038/s41537-020-00122-3.CrossRefGoogle Scholar
R Core Team. (2017). R: A language and environment for statistical computing. Retrieved from Scholar
Roberts, T., Miguel Esponda, G., Krupchanka, D., Shidhaye, R., Patel, V., & Rathod, S. (2018). Factors associated with health service utilisation for common mental disorders: A systematic review. BMC Psychiatry, 18(1), 262. doi:10.1186/s12888-018-1837-1.CrossRefGoogle ScholarPubMed
Rosenheck, R., Chang, S., Choe, Y., Cramer, J., Xu, W., Thomas, J., … Charney, D. (2000). Medication continuation and compliance: A comparison of patients treated with clozapine and haloperidol. Journal of Clinical Psychiatry, 61(5), 382–36.CrossRefGoogle ScholarPubMed
Song, Y. J. (2009). The South Korean health care system. Japan Medical Association Journal, 52(3), 206209.Google Scholar
Taipale, H., Mehtala, J., Tanskanen, A., & Tiihonen, J. (2018). Comparative effectiveness of antipsychotic drugs for rehospitalization in schizophrenia-A nationwide study with 20-year follow-up. Schizophrenia Bulletin, 44(6), 13811387. doi:10.1093/schbul/sbx176.CrossRefGoogle ScholarPubMed
Takacs, P., Czobor, P., Feher, L., Gimesi-Orszagh, J., Fadgyas-Freyler, P., Bacskai, M., … Bitter, I. (2019). Comparative effectiveness of second generation long-acting injectable antipsychotics based on nationwide database research in Hungary. PLoS ONE, 14(6), e0218071. doi:10.1371/journal.pone.0218071.CrossRefGoogle ScholarPubMed
Therneau, T. (2015). A Package for Survival Analysis in S_. version 2.38. Retrieved from Scholar
Tiihonen, J., Mittendorfer-Rutz, E., Majak, M., Mehtala, J., Hoti, F., Jedenius, E., … Taipale, H. (2017). Real-world effectiveness of antipsychotic treatments in a nationwide cohort of 29823 patients with schizophrenia. JAMA Psychiatry, 74(7), 686693. doi:10.1001/jamapsychiatry.2017.1322.CrossRefGoogle Scholar
Tiihonen, J., Taipale, H., Mehtala, J., Vattulainen, P., Correll, C. U., & Tanskanen, A. (2019). Association of antipsychotic polypharmacy vs monotherapy with psychiatric rehospitalization among adults with schizophrenia. JAMA Psychiatry, 76(5), 499507. doi:10.1001/jamapsychiatry.2018.4320.CrossRefGoogle ScholarPubMed
Tiihonen, J., Tanskanen, A., & Taipale, H. (2018). 20-Year nationwide follow-up study on discontinuation of antipsychotic treatment in first-episode schizophrenia. American Journal of Psychiatry, 175(8), 765773. doi:10.1176/appi.ajp.2018.17091001.CrossRefGoogle ScholarPubMed
Uchida, H., Suzuki, T., Takeuchi, H., Arenovich, T., & Mamo, D. C. (2011). Low dose vs standard dose of antipsychotics for relapse prevention in schizophrenia: Meta-analysis. Schizophrenia Bulletin, 37(4), 788799. doi:10.1093/schbul/sbp149.CrossRefGoogle ScholarPubMed
Velligan, D. I., Weiden, P. J., Sajatovic, M., Scott, J., Carpenter, D., Ross, R., & Persistent Mental, I. (2009). The expert consensus guideline series: Adherence problems in patients with serious and persistent mental illness. Journal of Clinical Psychiatry, 70 (Suppl 4), 146; quiz 47-8.Google ScholarPubMed
Wang, P. S., Aguilar-Gaxiola, S., Alonso, J., Angermeyer, M. C., Borges, G., Bromet, E. J., … Wells, J. E. (2007). Use of mental health services for anxiety, mood, and substance disorders in 17 countries in the WHO world mental health surveys. Lancet, 370(9590), 841850. doi:10.1016/S0140-6736(07)61414-7.CrossRefGoogle ScholarPubMed
Weiden, P. J., Schooler, N. R., Weedon, J. C., Elmouchtari, A., Sunakawa, A., & Goldfinger, S. M. (2009). A randomized controlled trial of long-acting injectable risperidone vs continuation on oral atypical antipsychotics for first-episode schizophrenia patients: Initial adherence outcome. Journal of Clinical Psychiatry, 70(10), 13971406. doi:10.4088/JCP.09m05284yel.CrossRefGoogle ScholarPubMed
Wyatt, R. J. (1997). Research in schizophrenia and the discontinuation of antipsychotic medications. Schizophrenia Bulletin, 23(1), 39. doi:10.1093/schbul/23.1.3.CrossRefGoogle ScholarPubMed
Yun, J.-Y., Lee, J. S., Kang, S. H., Nam, B., Lee, S. J., Lee, S.-H., … Chung, Y.-C. (2019). Korean treatment guideline on pharmacotherapy of co-existing symptoms and antipsychotics-related side effects in patients with schizophrenia. Korean Journal of Schizophrenia Research, 22(2), 2133.CrossRefGoogle Scholar
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