Long-acting second-generation antipsychotics : challenges and benefits of available treatments
Abstract
Long-acting injectable antipsychotics were developed in the second half of the twentieth century as an important element in the deinstitutionalization process of psychiatric patients. Today, their role is significant in improving compliance, achieving stable drug concentrations in plasma, preventing relapses, and enhancing cognitive functioning in chronic patients. Although several long-acting second- and third-generation antipsychotic preparations have been registered over the past two decades, only four preparations are currently registered in our region: long-acting risperidone microspheres and in situ microparticle-based (ISM) formulations; paliperidone palmitate formulations for one and three months. This review aims to present their pharmacokinetics and pharmacodynamics, clinical efficacy, side effects, and challenges in titration and interchangeability of these preparations.
Keywords: long-acting antipsychotics; risperidone microspheres; risperidone ISM; paliperidone palmitate.
References
Crocq MA. Histoire des traitements antipsychotiques à action prolongée dans la schizophrénie [A history of antipsychotic long-acting injections in the treatment of schizophrenia]. Encephale. 2015; 41(1):84-92. French. Doi: 10.1016/j.encep.2014.12.002.
Wing, JK, Brown, GW. Social treatment of chronic schizophrenia: a comparative study of three mental hospitals. J Ment Sci 1961; 107:847–61.
Ley P, Spelman MS. Communicating with the Patient. Staples Press.1667; 37–78.
Hogarty GE, Schooler NR, Ulrich R, Mussare F, Ferro P, Herron E. 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. Doi:10.1001/archpsyc.1979.01780120013001.
Hogarty GE, Ulrich R, Goldberg SC. Sociotherapy and the prevention of relapse among schizophrenic patients. In Evaluation of Psychological Therapies (eds Spitzer, RL, Klein, DF): Johns Hopkins University Press; 1976; 285–93. PMID: 177968.
Pietzcker A, Gaebel W, Kopcke W, Linden M, Muller P. A German multicenter study on the neuroleptic long-term therapy of schizophrenic patients. Pharmacopsychiatry 1986; 19:161–6 Doi: 10.1016/0022-3956(93)90059-B.
Kissling W (ed). Neuroleptic relapse prevention. In Guidelines for Neuroleptic Relapse Prevention in Schizophrenia Springer; 1991; 50–2. Doi: 10.1007/978-3-642-86922-8_12.
Maric NP, Jovicic MJ, Mihaljevic M, Miljevic C. Improving Current Treatments for Schizophrenia. Drug Dev Res. 2016 Nov; 77(7):357-367. Doi: 10.1002/ddr.21337.
Leucht S, Cipriani A, Spineli L et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia. A multiple-treatments meta-analysis. The Lancet. 2013; 382:951–962. Doi: 10.1016/S0140-6736(13)60733-3.
Nikolić-Kokić A, Tatalović N, Miljević Č et al. Antipsychotic Drug-Mediated Adverse Effects on Rat Testicles May Be Caused by Altered Redox and Hormonal Homeostasis. Int J Mol Sci. 2022 Nov 8; 23(22):13698. Doi: 10.3390/ijms232213698.
Ostuzzi G, Mazzi MA, Terlizzi S et al. STAR Network Investigators. Factors associated with first- versus second-generation long-acting antipsychotics prescribed under ordinary clinical practice in Italy. PLoS One. 2018 Aug 2; 13(8):e0201371. Doi: 10.1371/journal.pone.0201371.
Miljević ČD, Vuković PG, Munjiza-Jovanović A. Clinical challenges in the dosing and titration of cariprazine. Front Psychiatry. 2024; 15:1427482. Doi: 10.3389/fpsyt.2024.1427482.
Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis JM. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet. 2009; 373(9657):31–41 Doi: 10.1016/S0140-6736(08)61764-X.
Miljević C, Nikolić-Kokić A, Saicić ZS et al. Correlation analysis confirms differences in antioxidant defence in the blood of types I and II schizophrenic male patients treated with anti-psychotic medication. Psychiatry Res. 2010; 178(1):68-72. Doi: 10.1016/j.psychres.2008.10.038.
Miljević ČD, Nikolić-Kokić A, Blagojević D et al. Association between neurological soft signs and antioxidant enzyme activity in schizophrenic patients. Psychiatry Res. 2018; 269:746-752. Doi: 10.1016/j.psychres.2018.09.009.
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(10):957–965. Doi: 10.4088/JCP.13r08440.
Patel RS, Tankersley WE. Real-world Effectiveness of Long-Acting Injectable (LAI) Antipsychotics to Reduce 90-day and Annual Readmission in Psychotic Disorders: Insights from a State Psychiatric Hospital. CNS Spectrums. 2021; 1–19. Doi10.1017/s109285292100050x.
Keepers GA, Fochtmann LJ, Anzia JM et al. The American Psychiatric Association practice guideline for the treatment of patients with schizophrenia. Am J Psychiatry. 2020; 177(9):868–872. Doi10.1176/appi. ajp.2020.177901.
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(Suppl 3):1–24. Doi: 10.4088/JCP.15032su1.
Citrome L, Belcher E, Stacy S, Suett M, Mychaskiw M, Salinas GD. Management of schizophrenia with long-acting injectable antipsychotic medications: an assessment of the educational needs of clinicians. Neuropsychiatr Dis Treat. 2022; 18:111–23 Doi: 10.2147/NDT.S326299.
Álamo C. Risperidone ISM as a New Option in the Clinical Management of Schizophrenia: A Narrative Review. Adv Ther. 2022; 39(11):4875-4891. Doi: 10.1007/s12325-022-02299-8. Epub 2022 Sep 1.
Jašović-Gašić M, Ivković M, Damjanović A, Paunović V. Nove mogućnosti u dugotrajnoj terapiji shozofrenih pacijenata: dugodelujući risperidone (rispolept consta). Engrami 2004; 26(12): 107-110.
Knox ED, Stimmel GL. Clinical review of a long-acting, injectable formulation of risperidone. Clinical Therapeutics. 2004; 26(12):1994–2002. Doi: 10.1016/j.clinthera.2004.12.009.
Gefvert O, Eriksson B, Persson P et al.Pharmacokinetics and D2 receptor occupancy of long-acting injectable risperidone (Risperdal Consta) in patients with schizophrenia. Int J Neuropsychopharmacol. 2005; 8(1):27-36. Doi: 10.1017/S1461145704004924.
Lasser RA, Bossie CA, Gharabawi GM, Baldessarini RJ. Clinical improvement in 336 stable chronically psychotic patients changed from oral to long-acting risperidone: a 12-month open trial. Int J Neuropsychopharmacol. 2005; 8(3):427-38. Doi: 10.1017/S1461145705005225.
Malempati RN, Bond DJ, Yatham LN. Depot risperidone in the outpatient management of bipolar disorder: a 2-year study of 10 patients. Int Clin Psychopharmacol. 2008; 23(2):88-94. Doi: 10.1097/YIC.0b013e3282f2b4c5.
Keith S. Use of long-acting risperidone in psychiatric disorders: focus on efficacy, safety and cost-effectiveness. Expert Rev Neurother. 2009; 9(1):9-31. Doi: 10.1586/14737175.9.1.9.
Correll CU, Litman RE, Filts Y et al. Efficacy and safety of once-monthly Risperidone ISM in schizophrenic patients with an acute exacerbation. NPJ Schizophr. 2020; 6(1):37 Doi: 10.1038/s41537-020-00127-y.
Clark I, Taylor D. Newer formulations of risperidone: role in the management of psychotic disorders. CNS Drugs. 2020; 34(8):841–52 Doi: 10.1007/s40263-020-00735-3.
Anta L, Llaudo´ J, Ayani I, Martı´nez J, Litman RE, Gutierro I. A phase II study to evaluate the pharmacokinetics, safety, and tolerability of Risperidone ISM multiple intramuscular injections once every 4 weeks in patients with schizophrenia. Int Clin Psychopharmacol. 2018; 33(2):79–87 Doi: 10.1097/YIC.0000000000000203.
Llaudó J, Anta L, Ayani I, Martínez J et al. Phase I, open-label, randomized, parallel study to evaluate the pharmacokinetics, safety, and tolerability of one intramuscular injection of risperidone ISM at different dose strengths in patients with schizophrenia or schizoaffective disorder (PRISMA-1). Int Clin Psychopharmacol. 2016; 31(6):323-31. Doi: 10.1097/YIC.0000000000000139.
Bioque M, Bernardo M. The current data on the 3-month paliperidone palmitate formulation for the treatment of schizophrenia. Expert Opin Pharmacother. 2018; 19(14):1623-1629. Doi: 10.1080/14656566.2018.1515915.
Parellada E, Bioque M, Serrano M et al. An open-treatment sixweek study of the clinical effectiveness of paliperidone palmitate in schizophrenia: data from acute units in Spain (SHADOW study). Int J Psychiatry Clin Pract. 2018; 22(3):191–199 Doi: 10.1080/13651501.2017.1404112.
Janssen-Cilag International NV. Sažetak karakteristika leka – Xeplion® (paliperidonpalmitat) [Internet]. Beograd: Janssen; 2024 [cited 2025 May 13]. Available from: https://static.janssen-emea.com/sites/default/files/Serbia/SMPC/RS-PL-0047.pdf
Chue P, & Chue J. . A review of paliperidone palmitate. Expert Review of Neurotherapeutics,.2012;12(12):1383–1397. Doi: 10.1586/ern.12.137.
European Medicines Agency. European public assessment report [Internet]. 2018 [cited 2025 May 13]. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/004066/human_med_001829.jsp&mid=WC0b01ac058001d124.
Ravenstijn P, Remmerie B, Savitz A et al. Pharmacokinetics, safety, and tolerability of paliperidone palmitate 3-month formulation in patients with schizophrenia: a phase-1, single-dose, randomized, open-label study. J Clin Pharmacol. 2016; 56(3):330–339 Doi: 10.1002/jcph.597.
Gonzalez-Rodriguez A, Catalan R, Penades R et al. Profile of paliperidone palmitate once-monthly long-acting injectable in the management of schizophrenia: long-term safety, efficacy, and patient acceptability - a review. Patient Prefer Adherence. 2015; 9:695–706 Doi: 10.1136/bcr-2015-212149.
Schreiner A, Bergmans P, Cherubin P et al. A prospective flexibledose study of paliperidone palmitate in nonacute but symptomatic patients with schizophrenia previously unsuccessfully treated with oral antipsychotic agents. Clin Ther. 2014; 36(10):1372–1388 Doi: 10.1016/j.clinthera.2014.08.014.
Emsley R, Parellada E, Bioque M, Herrera B, Hernando T, García-Dorado M. Real-world data on paliperidone palmitate for the treatment of schizophrenia and other psychotic disorders: a systematic review of randomized and nonrandomized studies. Int Clin Psychopharmacol. 2018; 33(1):15-33. Doi: 10.1097/YIC.0000000000000195.
Savitz AJ, Xu H, Gopal S et al. Paliperidone palmitate 3-month treatment results in symptomatic remission in patients with schizophrenia: a randomized, multicenter, double-blind, and noninferiority study. Int Clin Psychopharmacol. 2017; 32(6):329–336 Doi: 10.1097/YIC.0000000000000190.
Citrome L. Paliperidone palmitate - review of the efficacy, safety and cost of a new second-generation depot antipsychotic medication. Int J Clin Pract. 2010; 64(2):216-39. Doi: 10.1111/j.1742-1241.2009.02240.x.
Berwaerts J, Liu Y, Gopal S, et al. Efficacy and Safety of the 3-month formulation of paliperidone palmitate vs placebo for relapse prevention of schizophrenia: a randomized clinical trial. JAMA Psychiatry. 2015; 72(8):830–839 Doi: 10.1001/jamapsychiatry.2015.0241.
Laux G, Heeg B, van Hout BA, Mehnert A. Costs and effects of long-acting risperidone compared with oral atypical and conventional depot formulations in Germany. Pharmacoeconomics. 2005; 23 Suppl 1:49-61. Doi: 10.2165/00019053-200523001-00005.
Koshikawa Y, Takekita Y, Kato M, et al.The Comparative Effects of Risperidone Long-Acting Injection and Paliperidone Palmitate on Social Functioning in Schizophrenia: A 6-Month, Open-Label, Randomized Controlled Pilot Trial. Neuropsychobiology. 2016; 73(1):35-42. Doi: 10.1159/000442209.
Drug Information for Paliperidone Palmitate: Interview Form of Xeplion ® – Aqueous Suspension for IM Injection, ed 5. http://www. info.pmda.go.jp/go/pack/1179409G1025_ 1_07/. 2014.
Tost M, González-Rodríguez A, Aguayo R et al. Switching from risperidone to paliperidone palmitate in schizophrenia: Changes in social functioning and cognitive performance. Prog Neuropsychopharmacol Biol Psychiatry. 2023; 120:110619. Doi: 10.1016/j.pnpbp.2022.110619.
Janssen-Cilag International NV. Sažetak karakteristika leka – Trevicta® (paliperidonpalmitat) [Internet]. Beograd: Janssen; 2024 [cited 2025 May 13]. Available from: https://static.janssen-emea.com/sites/default/files/Serbia/SMPC/RS-PL-0041.pdf
Correll CU, Kim E, Sliwa JK, et al.Pharmacokinetic Characteristics of Long-Acting Injectable Antipsychotics for Schizophrenia: An Overview. CNS Drugs. 2021; 35(1):39-59. Doi: 10.1007/s40263-020-00779-5.
Maini K, Gould H, Hicks J et al. Aripiprazole Lauroxil, a Novel Injectable Long-Acting Antipsychotic Treatment for Adults with Schizophrenia: A Comprehensive Review. Neurol Int. 2021;13(3):279-296. Doi: 10.3390/neurolint13030029.
Peters L, Dyer M, Schroeder E, D'Souza MS. Invega Hafyera (Paliperidone Palmitate): Extended-Release Injectable Suspension for Patients With Schizophrenia. J Pharm Technol. 2023; 39(2):88-94. Doi: 10.1177/87551225231153541.
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