Effectiveness of Long-Acting Injectable Antipsychotics in Schizophrenia: A Literature Review and Bayesian Meta-Analysis Informing Economic Considerations

  • Orietta Zaniolo AdRes – Health Economics & Outcome Research, Turin
  • Gianni Ghetti AdRes – Health Economics & Outcome Research, Turin
  • Massimiliano Povero AdRes – Health Economics & Outcome Research, Turin
  • Lorenzo Pradelli AdRes – Health Economics & Outcome Research, Turin


BACKGROUND: Although the use of long-acting injectable antipsychotics (LAIs) is considered an important option in the management of schizophrenia two recent meta-analysis, which aimed to compare LAIs vs oral antipsychotics (OAPs) in terms of relapse rate, showed discordant results.

AIM: To investigate factors affecting the efficacy of antipsychotics in terms of relapse prevention in the real-world and to estimate the management cost of an episode of relapse.

METHODS: We conducted a literature search using MEDLINE/PubMed with the aim to extract efficacy, effectiveness and adherence data of LAIs and OAPs. The primary outcome was the relative risk (RR) of relapse between two strategies. The extracted RR were included in a series of Bayesian statistical models based on the starting hypotheses. The RR rates obtained from the meta-analysis have been used as input for an economic evaluation of the total costs associated with the management of the patient with schizophrenia from the Italian NHS perspective.

RESULTS: The literature search identified 34 studies which met the inclusion criteria and were analyzed. According to the model that best explains the data, in the real-world setting the effectiveness with LAIs is greater than with OAPs, with a more pronounced effect for SGAs than for FGAs. Taking into account generation, route and frequency of administration, the RR decreased with lower administration frequency, with SGA LAI administered once every 90 days which is associated with the greatest reduction in the risk of relapse (-85%). When the results of the meta-analysis are used to feed an economic evaluation the results show that the SGA administered every 90 days is the strategy with the least expected cumulative cost both at 1 (€ 3,509) and 5 years (€ 19,690).

CONCLUSION: SGA LAIs administered every 90 days seems to be the best option for the treatment of patient with schizophrenia from both the clinical and economic perspectives.


An erratum to this article is available online at: https://doi.org/10.7175/fe.v20i1.1406


Olivares JM, Sermon J, Hemels M, et al. Definitions and drivers of relapse in patients with schizophrenia: a systematic literature review. Ann Gen Psychiatry 2013; 12: 32; https://doi.org/10.1186/1744-859X-12-32

Fagiolini A. Il ruolo dei LAI nel percorso del paziente. Journal of Psychopathology 2015; 21(Suppl): 13-5

Spina E, Canonico PL, de Bartolomeis A. Antipsicotici iniettabili a lunga durata d’azione nel trattamento della schizofrenia. Società Italiana di Farmacologia. Position Paper, 2015

Kane JM. Treatment strategies to prevent relapse and encourage remission. J Clin Psychiatry 2007; 68 Suppl 14: 27-30

Kane JM. Improving patient outcomes in schizophrenia: achieving remission, preventing relapse, and measuring success. J Clin Psychiatry 2013; 74: e18; https://doi.org/10.4088/JCP.12117tx1c

Miyamoto S, Wolfgang Fleischhacker W. The Use of Long-Acting Injectable Antipsychotics in Schizophrenia. Curr Treat Options Psychiatry 2017; 4: 117-26; https://doi.org/10.1007/s40501-017-0115-z

Correll CU, Citrome L, Haddad PM, et al. The Use of Long-Acting Injectable Antipsychotics in Schizophrenia: Evaluating the Evidence. J Clin Psychiatry 2016; 77: 1-24; https://doi.org/10.4088/JCP.15032su1

Kane JM, Garcia-Ribera C. Clinical guideline recommendations for antipsychotic long-acting injections. Br J Psychiatry Suppl 2009; 52: S63-7; https://doi.org/10.1192/bjp.195.52.s63

Kishimoto T, Nitta M, Borenstein M, et al. Long-acting injectable versus oral antipsychotics in schizophrenia: a systematic review and meta-analysis of mirror-image studies. J Clin Psychiatry 2013; 74: 957-65; https://doi.org/10.4088/JCP.13r08440

Kishimoto T, Robenzadeh A, Leucht C, et al. Long-acting injectable vs oral antipsychotics for relapse prevention in schizophrenia: a meta-analysis of randomized trials. Schizophr Bull 2014; 40: 192-213; https://doi.org/10.1093/schbul/sbs150

Moher D, Liberati A, Tetzlaff J, et al.; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol 2009; 62: 1006-12; https://doi.org/10.1016/j.jclinepi.2009.06.005

IQVIA S.p.A – data on file

Informatore Farmaceutico on-line. Available at: http://www.codifa.it/ (last accessed June 2018)

Pilon D, Joshi K, Tandon N, et al. Treatment patterns in Medicaid patients with schizophrenia initiated on a first- or second-generation long-acting injectable versus oral antipsychotic. Patient Preference and Adherence 2017; 11: 619-29

Ascher-Svanum H, Zhu B, Faries DE, et al. The cost of relapse and the predictors of relapse in the treatment of schizophrenia. BMC Psychiatry 2010; 10: 2; https://doi.org/10.1186/1471-244X-10-2

Rahmati M, Rahgozar M, Fadaei F, et al. Identifying Some Risk Factors of Time to Relapses in Schizophrenic Patients using Bayesian Approach with Event-Dependent Frailty Model. Iran J Psychiatry 2015; 10: 123-7

Baser O, Xie L, Pesa J, et al. Healthcare utilization and costs of Veterans Health Administration patients with schizophrenia treated with paliperidone palmitate long-acting injection or oral atypical antipsychotics. J Med Econ 2015; 18: 357-65; https://doi.org/10.3111/13696998.2014.1001514

Bitter I, Katona L, Zámbori J, et al. Comparative effectiveness of depot and oral second generation antipsychotic drugs in schizophrenia: a nationwide study in Hungary. Eur Neuropsychopharmacol 2013; 23: 1383-90; https://doi.org/10.1016/j.euroneuro.2013.02.003

Grimaldi-Bensouda L, Rouillon F, Astruc B, et al.; CGS Study Group. Does long-acting injectable risperidone make a difference to the real-life treatment of schizophrenia? Results of the Cohort for the General study of Schizophrenia (CGS). Schizophr Res 2012; 134: 187-94; https://doi.org/10.1016/j.schres.2011.10.022

Guo X, Fang M, Zhai J, et al. Effectiveness of maintenance treatments with atypical and typical antipsychotics in stable schizophrenia with early stage: 1-year naturalistic study. Psychopharmacology (Berl) 2011; 216: 475-84; https://doi.org/10.1007/s00213-011-2242-3

Joshi K, Pan X, Wang R, et al. Healthcare resource utilization of second-generation long-acting injectable antipsychotics in schizophrenia: risperidone versus paliperidone palmitate. Curr Med Res Opin 2016; 32: 1873-81

Lafeuille MH, Grittner AM, Fortier J, et al. Comparison of rehospitalization rates and associated costs among patients with schizophrenia receiving paliperidone palmitate or oral antipsychotics. Am J Health Syst Pharm 2015; 72: 378-89; https://doi.org/10.2146/ajhp140219

Marcus SC, Zummo J, Pettit AR, et al. Antipsychotic Adherence and Rehospitalization in Schizophrenia Patients Receiving Oral Versus Long-Acting Injectable Antipsychotics Following Hospital Discharge. J Manag Care Spec Pharm 2015; 21: 754-68

Morrato EH, Parks J, Campagna EJ, et al. Comparative effectiveness of injectable paliperidone palmitate versus oral atypical antipsychotics: early postmarketing evidence. J Comp Eff Res 2015; 4: 89-99; https://doi.org/10.2217/cer.14.50

Ren XS, Crivera C, Sikirica M, et al. Evaluation of health services use following the initiation of risperidone long-acting therapy among schizophrenia patients in the veterans health administration. J Clin Pharm Ther 2011; 36: 383-9; https://doi.org/10.1111/j.1365-2710.2010.01211.x

Schreiner A, Svensson A, Wapenaar R, et al. Long-acting injectable risperidone and oral antipsychotics in patients with schizophrenia: results from a prospective, 1-year, non-interventional study (InORS). World J Biol Psychiatry 2014; 15: 534-45; https://doi.org/10.3109/15622975.2014.902990

Tiihonen J, Haukka J, Taylor M, et al. A nationwide cohort study of oral and depot antipsychotics after first hospitalization for schizophrenia. Am J Psychiatry 2011; 168: 603-9; https://doi.org/10.1176/appi.ajp.2011.10081224

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: 686-93; https://doi.org/10.1001/jamapsychiatry.2017.1322

Tiihonen J, Wahlbeck K, Lönnqvist J, et al. Effectiveness of antipsychotic treatments in a nationwide cohort of patients in community care after first hospitalisation due to schizophrenia and schizoaffective disorder: observational follow-up study. BMJ 2006; 333: 224

Voss EA, Ryan PB, Stang PE, et al. Switching from risperidone long-acting injectable to paliperidone long-acting injectable or oral antipsychotics: analysis of a Medicaid claims database. Int Clin Psychopharmacol 2015; 30: 151-7; https://doi.org/10.1097/YIC.0000000000000068

Alphs L, Benson C, Cheshire-Kinney K, et al. Real-world outcomes of paliperidone palmitate compared to daily oral antipsychotic therapy in schizophrenia: a randomized, open-label, review board-blinded 15-month study. J Clin Psychiatry 2015; 76: 554-61; https://doi.org/10.4088/JCP.14m09584

Buckley PF, Schooler NR, Goff DC, et al.; PROACTIVE Study. Comparison of SGA oral medications and a long-acting injectable SGA: the PROACTIVE study. Schizophr Bull 2015; 41: 449-59; https://doi.org/10.1093/schbul/sbu067

Carpenter WT Jr, Buchanan RW, Kirkpatrick B, et al. Comparative effectiveness of fluphenazine decanoate injections every 2 weeks versus every 6 weeks. Am J Psychiatry 1999; 156: 412-8

Csernansky JG, Mahmoud R, Brenner R; Risperidone-USA-79 Study Group. A comparison of risperidone and haloperidol for the prevention of relapse in patients with schizophrenia. N Engl J Med 2002; 346: 16-22; https://doi.org/10.1056/NEJMoa002028

Detke HC, Weiden PJ, Llorca PM, et al. Comparison of olanzapine long-acting injection and oral olanzapine: a 2-year, randomized, open-label study in outpatients with schizophrenia. J Clin Psychopharmacol 2014; 34: 426-34; https://doi.org/10.1097/JCP.0000000000000140

Fleischhacker WW, Sanchez R, Perry PP, et al. Aripiprazole once-monthly for treatment of schizophrenia: double-blind, randomised, non-inferiority study. Br J Psychiatry 2014; 205: 135-44; https://doi.org/10.1192/bjp.bp.113.134213

Glick ID, Berg PH. Time to study discontinuation, relapse, and compliance with atypical or conventional antipsychotics in schizophrenia and related disorders. Int Clin Psychopharmacol 2002; 17: 65-8; https://doi.org/10.1097/00004850-200203000-00004

Hogarty GE, Schooler NR, Ulrich R, et al. Fluphenazine and social therapy in the aftercare of schizophrenic patients. Relapse analyses of a two-year controlled study of fluphenazine decanoate and fluphenazine hydrochloride. Arch Gen Psychiatry 1979; 36: 1283-94; https://doi.org/10.1001/archpsyc.1979.01780120013001

Ishigooka J, Nakamura J, Fujii Y, et al.; ALPHA Study Group. Efficacy and safety of aripiprazole once-monthly in Asian patients with schizophrenia: a multicenter, randomized, double-blind, non-inferiority study versus oral aripiprazole. Schizophr Res 2015; 161: 421-8; https://doi.org/10.1016/j.schres.2014.12.013

Kane JM, Detke HC, Naber D, et al. Olanzapine long-acting injection: a 24-week, randomized, double-blind trial of maintenance treatment in patients with schizophrenia. Am J Psychiatry 2010; 167: 181-9; https://doi.org/10.1176/appi.ajp.2009.07081221

Kane JM, Osuntokun O, Kryzhanovskaya LA, et al. A 28-week, randomized, double-blind study of olanzapine versus aripiprazole in the treatment of schizophrenia. J Clin Psychiatry 2009; 70: 572-81; https://doi.org/10.4088/JCP.08m04421

Keks NA, Ingham M, Khan A, et al. Long-acting injectable risperidone v. olanzapine tablets for schizophrenia or schizoaffective disorder. Randomised, controlled, open-label study. Br J Psychiatry 2007; 191: 131-9; https://doi.org/10.1192/bjp.bp.105.017020

Kim B, Lee SH, Choi TK, et al. Effectiveness of risperidone long-acting injection in first-episode schizophrenia: in naturalistic setting. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32: 1231-5; https://doi.org/10.1016/j.pnpbp.2008.03.012

Lieberman JA, Stroup TS, McEvoy JP, et al.; Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005; 353: 1209-23; https://doi.org/10.1056/NEJMoa051688

Malla A, Chue P, Jordan G, et al. An Exploratory, Open-Label, Randomized Trial Comparing Risperidone Long-Acting Injectable with Oral Antipsychotic Medication in the Treatment of Early Psychosis. Clin Schizophr Relat Psychoses 2016; 9: 198-208; https://doi.org/10.3371/CSRP.MACH.061213

McEvoy JP, Byerly M, Hamer RM, et al. Effectiveness of paliperidone palmitate vs haloperidol decanoate for maintenance treatment of schizophrenia: a randomized clinical trial. JAMA 2014; 311: 1978-87; https://doi.org/10.1001/jama.2014.4310

Rosenheck RA, Krystal JH, Lew R,et al.; CSP555 Research Group. Long-acting risperidone and oral antipsychotics in unstable schizophrenia. N Engl J Med 2011; 364: 842-51; https://doi.org/10.1056/NEJMoa1005987

Savitz AJ, Xu H, Gopal S, et al. Efficacy and Safety of Paliperidone Palmitate 3-Month Formulation for Patients with Schizophrenia: A Randomized, Multicenter, Double-Blind, Noninferiority Study. Int J Neuropsychopharmacol 2016; 19; https://doi.org/10.1093/ijnp/pyw018

Schooler N, Rabinowitz J, Davidson M, et al.; Early Psychosis Global Working Group. Risperidone and haloperidol in first-episode psychosis: a long-term randomized trial. Am J Psychiatry 2005; 162: 947-53; https://doi.org/10.1176/appi.ajp.162.5.947

Schooler NR, Levine J, Severe JB, et al. Prevention of relapse in schizophrenia. An evaluation of fluphenazine decanoate. Arch Gen Psychiatry 1980; 37: 16-24; https://doi.org/10.1001/archpsyc.1980.01780140018002

Kovács G, Almási T, Millier A, et al. Direct healthcare cost of schizophrenia - European overview. Eur Psychiatry 2018; 48: 79-92; https://doi.org/10.1016/j.eurpsy.2017.10.008

How to Cite
Zaniolo, O., Ghetti, G., Povero, M., & Pradelli, L. (2019). Effectiveness of Long-Acting Injectable Antipsychotics in Schizophrenia: A Literature Review and Bayesian Meta-Analysis Informing Economic Considerations. Farmeconomia. Health Economics and Therapeutic Pathways, 20(1). https://doi.org/10.7175/fe.v20i1.1393
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