Download PDF
Pharmacopsychiatry
DOI: 10.1055/a-2437-4366
Original Paper

2001–2021 Comparative Persistence of Oral Antipsychotics in Patients Initiating Treatment: Superiority of Clozapine in Time-to-Treatment Discontinuation

Alberto Parabiaghi 
1   Unit for Quality of Care and Rights Promotion in Mental Health, Department of Health Policy, Istituto di Ricerche Farmacologiche “Mario Negri” – IRCCS, Milan, Italy
,
Alessia A. Galbussera
2   Laboratory of Geriatric Epidemiology, Department of Health Policy, Istituto di Ricerche Farmacologiche “Mario Negri” – IRCCS, Milan, Italy
,
Barbara D’Avanzo
3   Laboratory for Assessing Quality of Care and Services, Department of Health Policy, Istituto di Ricerche Farmacologiche “Mario Negri” – IRCCS, Milan, Italy
,
Mauro Tettamanti
2   Laboratory of Geriatric Epidemiology, Department of Health Policy, Istituto di Ricerche Farmacologiche “Mario Negri” – IRCCS, Milan, Italy
,
Ida Fortino
4   Directorate General for Health, Lombardy Region, Milan, Italy
,
Angelo Barbato
1   Unit for Quality of Care and Rights Promotion in Mental Health, Department of Health Policy, Istituto di Ricerche Farmacologiche “Mario Negri” – IRCCS, Milan, Italy
› Author Affiliations
› Further Information
Also available at
    Permissions and Reprints

Abstract

Background Continuous antipsychotic (AP) therapy is crucial for managing psychotic disorders, and its early interruption reflects the drugʼs failure. Real-world epidemiological research is essential for confirming experimental data and generating new research hypotheses.

Methods The persistence of oral APs in a large population sample from 2000 to 2021 was analyzed by comparing AP prescriptions over this period across four Italian provinces, using dispensing data linked via a record-linkage procedure among regional healthcare utilization databases. We calculated personalized daily dosages and assessed time-to-treatment discontinuation over a 3-month period for patients initiating AP treatment. Treatment persistence was evaluated using Kaplan-Meier curves and Cox regression, with adjustments for age and sex.

Results Second-generation antipsychotics (SGAs) were favored over first-generation antipsychotics (FGAs), with olanzapine as the most prescribed. Within the study time frame, 42,434 individuals were prescribed a new continuous AP regimen. The analysis revealed 24 significant differences within 28 comparisons. As a class, SGAs demonstrated better treatment persistence than FGAs (HR: 0.76; 95%CI: 0.73, 0.79). Clozapine stood out for its superior persistence, surpassing all other SGAs, notably olanzapine (HR: 0.85; 95%CI: 0.79–0.91) and risperidone (HR: 0.80; 95%CI: 0.74–0.87). Olanzapine and aripiprazole showed better results than both risperidone and quetiapine. Quetiapine showed inferior 3-month persistence in all pairwise comparisons.

Conclusion The study results provide insight into the performance dynamics among SGAs: clozapine, despite being one of the less frequently dispensed APs in our sample, emerged as a significant prescription choice. The significance of pharmacoepidemiological studies in complementing experimental findings is also underscored.

Keywords

antipsychotics - prescribing - schizophrenia - pharmacoepidemiology

Supplementary Material



Publication History

Received: 04 July 2024
Received: 17 September 2024

Accepted: 30 September 2024

Article published online:
11 November 2024

© 2024. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Dunayevich E, Ascher-Svanum H, Zhao F. et al. Longer time to antipsychotic treatment discontinuation for any cause is associated with better functional outcomes for patients with schizophrenia, schizophreniform disorder, or schizoaffective disorder. J Clin Psychiatry 2007; 68: 1163-1171
    CrossrefPubMedSearch in Google Scholar
  • 2 Gitlin M, Nuechterlein KH, Subotnik KL. et al. Clinical outcome following neuroleptic discontinuation in patients with remitted recent-onset schizophrenia. Am J Psychiatry 2001; 158: 1835-1842
    CrossrefPubMedSearch in Google Scholar
  • 3 Ascher-Svanum H, Faries DE, Zhu B. et al. Medication adherence and long-term functional outcomes in the treatment of schizophrenia in usual care. J Clin Psychiatry 2006; 67: 453-460
    CrossrefPubMedSearch in Google Scholar
  • 4 Verdoux H, Tournier M, Begaud B. Antipsychotic prescribing trends: A review of pharmaco-epidemiological studies. Acta Psychiatr Scand 2010; 121: 4-10
    CrossrefPubMedSearch in Google Scholar
  • 5 Turner T. Chlorpromazine: Unlocking psychosis. BMJ 2007; 334: s7
    CrossrefPubMedSearch in Google Scholar
  • 6 Miyamoto S, Duncan GE, Marx CE. et al. Treatments for schizophrenia: A critical review of pharmacology and mechanisms of action of antipsychotic drugs. Mol Psychiatry 2005; 10: 79-104
    CrossrefPubMedSearch in Google Scholar
  • 7 Newcomer JW. Antipsychotic medications: Metabolic and cardiovascular risk. J Clin Psychiatry 2007; 68: 8-13
    PubMedSearch in Google Scholar
  • 8 Leucht S, Corves C, Arbter D. et al. Second-generation versus first-generation antipsychotic drugs for schizophrenia: A meta-analysis. Lancet 2009; 373: 31-41
    CrossrefPubMedSearch in Google Scholar
  • 9 Leucht S, Cipriani A, Spineli L. et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: A multiple-treatments meta-analysis. Lancet 2013; 382: 951-962
    CrossrefPubMedSearch in Google Scholar
  • 10 Huhn M, Nikolakopoulou A, Schneider-Thoma J. et al. 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. Lancet 2019; 394: 939-951
    CrossrefPubMedSearch in Google Scholar
  • 11 Kishimoto T, Agarwal V, Kishi T. et al. Relapse prevention in schizophrenia: A systematic review and meta-analysis of second-generation antipsychotics versus first-generation antipsychotics. Mol Psychiatry 2013; 18: 53-66
    CrossrefPubMedSearch in Google Scholar
  • 12 Kishimoto T, Hagi K, Nitta M. et al. Long-term effectiveness of oral second-generation antipsychotics in patients with schizophrenia and related disorders: A systematic review and meta-analysis of direct head-to-head comparisons. World Psychiatry 2019; 18: 208-224
    CrossrefPubMedSearch in Google Scholar
  • 13 Lieberman JA, Stroup TS, McEvoy JP. et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005; 353: 1209-1223
    CrossrefPubMedSearch in Google Scholar
  • 14 McEvoy JP, Lieberman JA, Stroup TS. et al. Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry 2006; 163: 600-610
    CrossrefPubMedSearch in Google Scholar
  • 15 Jones PB, Barnes TR, Davies L. et al. Randomized controlled trial of the effect on quality of life of second- vs first-generation antipsychotic drugs in schizophrenia: Cost utility of the latest antipsychotic drugs in schizophrenia study (CUtLASS 1). Arch Gen Psychiatry 2006; 63: 1079-1087
    CrossrefPubMedSearch in Google Scholar
  • 16 Lewis SW, Barnes TR, Davies L. et al. Randomized controlled trial of effect of prescription of clozapine versus other second-generation antipsychotic drugs in resistant schizophrenia. Schizophr Bull 2006; 32: 715-723
    CrossrefPubMedSearch in Google Scholar
  • 17 Rosenheck RA, Leslie DL, Sindelar J. et al. Cost-effectiveness of second-generation antipsychotics and perphenazine in a randomized trial of treatment for chronic schizophrenia. Am J Psychiatry 2006; 163: 2080-2089
    CrossrefPubMedSearch in Google Scholar
  • 18 Davies LM, Lewis S, Jones PB. et al. Cost-effectiveness of first- v. second-generation antipsychotic drugs: Results from a randomised controlled trial in schizophrenia responding poorly to previous therapy. Br J Psychiatry 2007; 191: 14-22
    CrossrefPubMedSearch in Google Scholar
  • 19 Kahn RS, Fleischhacker WW, Boter H. et al. Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: An open randomised clinical trial. Lancet 2008; 371: 1085-1097
    CrossrefPubMedSearch in Google Scholar
  • 20 Essock SM, Schooler NR, Stroup TS. et al. Effectiveness of switching from antipsychotic polypharmacy to monotherapy. Am J Psychiatry 2011; 168: 702-708
    CrossrefPubMedSearch in Google Scholar
  • 21 Parabiaghi A, Tettamanti M, DʼAvanzo B. et al. Metabolic syndrome and drug discontinuation in schizophrenia: A randomized trial comparing aripiprazole, olanzapine, and haloperidol. Acta Psychiatr Scand 2016; 133: 63-75
    CrossrefPubMedSearch in Google Scholar
  • 22 Gómez-Revuelta M, Pelayo-Terán JM, Juncal-Ruiz M. et al. Antipsychotic treatment effectiveness in first episode of psychosis: PAFIP 3-year follow-up randomized clinical trials comparing haloperidol, olanzapine, risperidone, aripiprazole, quetiapine, and ziprasidone. Int J Neuropsychopharmacol 2020; 23: 217-229
    CrossrefPubMedSearch in Google Scholar
  • 23 Adams CE, Jayaram M. Do findings from new trials for schizophrenia fit with existing evidence: Not duped...just beguiled?. Epidemiol Psichiatr Soc 2007; 16: 199-202
    CrossrefPubMedSearch in Google Scholar
  • 24 Fries JF, Krishnan E. Equipoise, design bias, and randomized controlled trials: The elusive ethics of new drug development. Arthritis Res Ther 2004; 6: 250-255
    CrossrefPubMedSearch in Google Scholar
  • 25 Lundh A, Lexchin J, Mintzes B. et al. Industry sponsorship and research outcome. Cochrane Database Syst Rev 2017; 2
    CrossrefPubMedSearch in Google Scholar
  • 26 Hansen C, Lundh A, Rasmussen K. et al. Financial conflicts of interest in systematic reviews: Associations with results, conclusions, and methodological quality. Cochrane Database Syst Rev 2019; 5: 8
    CrossrefPubMedSearch in Google Scholar
  • 27 Cameron C, Fireman B, Hutton B. et al. Network meta-analysis incorporating randomized controlled trials and non-randomized comparative cohort studies for assessing the safety and effectiveness of medical treatments: Challenges and opportunities. Syst Rev 2015; 4: 147
    CrossrefPubMedSearch in Google Scholar
  • 28 Rosenman ETR, Basse G, Owen AB. et al. Combining observational and experimental datasets using shrinkage estimators. Biometrics 2023; 79: 2961-2973
    CrossrefPubMedSearch in Google Scholar
  • 29 Parabiaghi A, Franchi C, Tettamanti M. et al. The declining use of reboxetine in years 2000 to 2006: A pharmacoepidemiological comparative study. J Clin Psychopharmacol 2012; 32: 303-305
    CrossrefPubMedSearch in Google Scholar
  • 30 Eyding D, Lelgemann M, Grouven U. et al. Reboxetine for acute treatment of major depression: Systematic review and meta-analysis of published and unpublished placebo and selective serotonin reuptake inhibitor controlled trials. BMJ 2010; 341
    CrossrefPubMedSearch in Google Scholar
  • 31 WHO Collaborating Centre for Drug Statistics. Guidelines for ATC Classification and DDD Assignment 2023. Vol. 4. 2023; https://www.whocc.no/filearchive/publications/2023_guidelines_web.pdf
    PubMed
  • 32 Johnson RE, McFarland BH. Lithium use and discontinuation in a health maintenance organization. Am J Psychiatry 1996; 153: 993-1000
    CrossrefPubMedSearch in Google Scholar
  • 33 Baldessarini RJ, Leahy L, Arcona S. et al. Patterns of psychotropic drug prescription for U.S. patients with diagnoses of bipolar disorders. Psychiatr Serv 2007; 58: 85-91
    CrossrefPubMedSearch in Google Scholar
  • 34 World Health Organization. Introduction to Drug Utilization Research: Drug utilization metrics and their applications: Prescribed daily dose and consumed daily dose. Available from: chrome-extension://efaidnbmnnnibpcajpcglclefindmkaj/https://iris.who.int/bitstream/handle/10665/42627/924156234X.pdf?sequence=1
  • 35 Franchi C, Tettamanti M, Pasina L. et al. Changes in drug prescribing to Italian community-dwelling elderly people: The EPIFARM–Elderly Project 2000–2010. Eur J Clin Pharmacol 2014; 70: 433-439
    CrossrefPubMedSearch in Google Scholar
  • 36 National Institute for Health and Care Excellence (NICE). Real-world evidence framework. 2022; https://www.nice.org.uk/corporate/ecd9/chapter/overview
    PubMed
  • 37 Langan SM, Schmidt SA, Wing K. et al. The reporting of studies conducted using observational routinely collected health data statement for pharmacoepidemiology (RECORD-PE). BMJ 2018; 363
    CrossrefPubMedSearch in Google Scholar
  • 38 Dyer O. Lilly investigated in US over the marketing of olanzapine. BMJ 2007; 334: 171
    CrossrefPubMedSearch in Google Scholar
  • 39 Leucht S, Komossa K, Rummel-Kluge C. et al. A meta-analysis of head-to-head comparisons of second-generation antipsychotics in the treatment of schizophrenia. Am J Psychiatry 2009; 166: 152-163
    CrossrefPubMedSearch in Google Scholar
  • 40 Soares-Weiser K, Béchard-Evans L, Lawson AH. et al. Time to all-cause treatment discontinuation of olanzapine compared to other antipsychotics in the treatment of schizophrenia: A systematic review and meta-analysis. Eur Neuropsychopharmacol 2013; 23: 118-125
    CrossrefPubMedSearch in Google Scholar
  • 41 Masuda T, Misawa F, Takase M. et al. 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 2019; 76: 1052-1062
    CrossrefPubMedSearch in Google Scholar
  • 42 Weiser M, Davis JM, Brown CH. et al. Differences in antipsychotic treatment discontinuation among veterans with schizophrenia in the U.S. Department of Veterans Affairs. Am J Psychiatry 2021; 178: 932-940
    CrossrefPubMedSearch in Google Scholar
  • 43 Moisan J, Grégoire JP. Patterns of discontinuation of atypical antipsychotics in the province of Québec: A retrospective prescription claims database analysis. Clin Ther 2010; 32: Suppl 1-S31
    CrossrefPubMedSearch in Google Scholar
  • 44 Brodeur S, Vanasse A, Courteau J. et al. Comparative effectiveness and safety of antipsychotic drugs in patients with schizophrenia initiating or reinitiating treatment: A real-world observational study. Acta Psychiatr Scand 2022; 145: 456-468
    CrossrefPubMedSearch in Google Scholar
  • 45 Haidary HA, Padhy RK. Clozapine. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023. https://www.ncbi.nlm.nih.gov/pubmed/30571020
    Search in Google Scholar
  • 46 Parabiaghi A, Monzio Compagnoni M, DʼAvanzo B. et al. Association of antipsychotic polypharmacy and two-year all-cause mortality: A population-based cohort study of 33,221 Italian continuous users. J Clin Med 2024; 13: 2073
    CrossrefPubMedSearch in Google Scholar
  • 47 Tiihonen J, Mittendorfer-Rutz E, Majak M. et al. Real-world effectiveness of antipsychotic treatments in a nationwide cohort of 29,823 patients with schizophrenia. JAMA Psychiatry 2017; 74: 686-693
    CrossrefPubMedSearch in Google Scholar
  • 48 Efthimiou O, Taipale H, Radua J. et al. Efficacy and effectiveness of antipsychotics in schizophrenia: Network meta-analyses combining evidence from randomised controlled trials and real-world data. Lancet Psychiatry 2024; 11: 102-111
    CrossrefPubMedSearch in Google Scholar