Hostname: page-component-cd9895bd7-q99xh Total loading time: 0 Render date: 2024-12-18T06:34:21.209Z Has data issue: false hasContentIssue false
  • English
  • Français

Converting oral to long-acting injectable antipsychotics: a guide for the perplexed

Published online by Cambridge University Press:  19 January 2018

Jonathan M. Meyer
Jonathan M. Meyer*
Affiliation:
Psychopharmacology Resource Network, California Dept. of State Hospitals, Patton, California, USA Dept. of Psychiatry, University of California, San Diego, La Jolla, California, USA
*
*Address for correspondence: Jonathan M. Meyer, MD, UCSD Dept. of Psychiatry, 4225 Executive Square #1130, La Jolla, CA 92037. (Email: [email protected])
Get access Rights & Permissions [Opens in a new window]

Abstract

There has been increasing recognition that antipsychotic nonadherence is common across all stages of schizophrenia, starting from the first episode. Moreover, numerous meta-analyses of the existing literature indicate superiority of long-acting injectable (LAI) over oral antipsychotics when one adjusts for the greater illness severity and duration among patients in LAI antipsychotic trials. The increasing availability of LAI antipsychotic options has raised interest in converting patients from oral medication; however, the successful transition from oral to the comparable LAI antipsychotic requires an understanding of the current extent of antipsychotic exposure, the kinetics of the LAI preparation, and the expected plasma levels achieved by the LAI formulation. The purpose of this article is to provide, in a concise format, the essential information for converting patients to the LAI forms of haloperidol, fluphenazine, risperidone, paliperidone, olanzapine, and aripiprazole from the comparable oral medication, and how the use of plasma antipsychotic levels can be invaluable for this process.

Keywords

Antipsychoticdepotkineticslong-acting injectable
Type
CME Review Article
Information
CNS Spectrums , Volume 22 , Supplement S1: CME SUPPLEMENT , December 2017 , pp. 14 - 28
Copyright
© Cambridge University Press 2018 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Footnotes

This activity is supported by an unrestricted educational grant from Alkermes.

References

1. Emsley, R. On discontinuing treatment in schizophrenia: a clinical conundrum. NPJ Schizophr. 2017; 3(1): 4.Google Scholar
2. Karson, C, Duffy, RA, Eramo, A, Nylander, AG, Offord, SJ. Long-term outcomes of antipsychotic treatment in patients with first-episode schizophrenia: a systematic review. Neuropsychiatr Dis Treat. 2016; 12: 57–67.CrossRefGoogle ScholarPubMed
3. Robinson, D, Woerner, MG, Alvir, JM, et al. Predictors of relapse following response from a first episode of schizophrenia or schizoaffective disorder. Arch Gen Psychiatry. 1999; 56(3): 241–247.CrossRefGoogle ScholarPubMed
4. Agid, O, Foussias, G, Remington, G. Long-acting injectable antipsychotics in the treatment of schizophrenia: their role in relapse prevention. Exp Opin Pharmacother. 2010; 11(14): 2301–2317.CrossRefGoogle ScholarPubMed
5. Leucht, C, Heres, S, Kane, JM, Kissling, W, Davis, JM, Leucht, S. Oral versus depot antipsychotic drugs for schizophrenia--a critical systematic review and meta-analysis of randomised long-term trials. Schizophr Res. 2011; 127(1–3): 83–92.Google Scholar
6. Tiihonen, J, Haukka, J, Taylor, M, Haddad, PM, Patel, MX, Korhonen, P. A nationwide cohort study of oral and depot antipsychotics after first hospitalization for schizophrenia. Am J Psychiatry. 2011; 168(6): 603–609.Google Scholar
7. Kishimoto, T, Hagi, K, Nitta, M, et al. Effectiveness of long-acting injectable vs oral antipsychotics in patients with schizophrenia: a meta-analysis of prospective and retrospective cohort studies. Schizophr Bull. In press. doi: 10.1093/schbul/sbx090.Google Scholar
8. Patel, MX, David, AS. Why aren’t depot antipsychotics prescribed more often and what can be done about it? Advances in Psychiatric Treatment. 2005; 11(3): 203–211.Google Scholar
9. Byerly, MJ, Thompson, A, Carmody, T, et al. Validity of electronically monitored medication adherence and conventional adherence measures in schizophrenia. Psychiatr Serv. 2007; 58(6): 844–847.CrossRefGoogle ScholarPubMed
10. Weiden, PJ, Schooler, NR, Weedon, JC, Elmouchtari, A, Sunakawa-McMillan, A. Maintenance treatment with long-acting injectable risperidone in first-episode schizophrenia: a randomized effectiveness study. J Clin Psychiatry. 2012; 73(9): 1224–1233.Google Scholar
11. Subotnik, KL, Casaus, LR, Ventura, J, et al. Long-acting injectable risperidone for relapse prevention and control of breakthrough symptoms after a recent first episode of schizophrenia: a randomized clinical trial. JAMA Psychiatry. 2015; 72(8): 822–829.Google Scholar
12. Gray, R, Spilling, R, Burgess, D, Newey, T. Antipsychotic long-acting injections in clinical practice: medication management and patient choice. Br J Psychiatry Suppl. 2009; 52: S51–S56.Google Scholar
13. Remington, G, Teo, C, Mann, S, Hahn, M, Foussias, G, Agid, O. Examining levels of antipsychotic adherence to better understand nonadherence. J Clin Psychopharmacol. 2013; 33(2): 261–263.Google Scholar
14. McCutcheon, R, Beck, K, D’Ambrosio, E, et al. Antipsychotic plasma levels in the assessment of poor treatment response in schizophrenia. Acta Psychiatr Scand. In press. doi: 10.1111/acps.12825.Google Scholar
15. Meyer, JM. A rational approach to employing high plasma levels of antipsychotics for violence associated with schizophrenia: case vignettes. CNS Spectr. 2014; 19(5): 432–438.Google Scholar
16. Zanger, UM, Schwab, M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther. 2013; 138(1): 103–141.Google Scholar
17. Ingelman-Sundberg, M. Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity. Pharmacogenomics J. 2005; 5(1): 6–13.Google Scholar
18. Velligan, DI, Wang, M, Diamond, P, et al. Relationships among subjective and objective measures of adherence to oral antipsychotic medications. Psychiatr Serv. 2007; 58(9): 1187–1192.CrossRefGoogle ScholarPubMed
19. Ereshefsky, L, Mascarenas, CA. Comparison of the effects of different routes of antipsychotic administration on pharmacokinetics and pharmacodynamics. Journal of Clinical Psychiatry. 2003; 64(Suppl 16): 18–23.Google Scholar
20. Spanarello, S, La Ferla, T. The pharmacokinetics of long-acting antipsychotic medications. Curr Clin Pharmacol. 2014; 9(3): 310–317.Google Scholar
21. Jann, MW, Ereshefsky, L, Saklad, SR. Clinical pharmacokinetics of the depot antipsychotics. Clin Pharmacokinet. 1985; 10(4): 315–333.CrossRefGoogle ScholarPubMed
22. Ereshefsky, L, Toney, G, Saklad, SR, Anderson, C, Seidel, D. A loading-dose strategy for converting from oral to depot haloperidol. Hosp Community Psychiatry. 1993; 44(12): 1155–1161.Google Scholar
23. Meyer, JM. Understanding depot antipsychotics: an illustrated guide to kinetics. CNS Spectr. 2013; 18(Suppl 1): 55–68.Google Scholar
24. Ereshefsky, L, Jann, MW, Saklad, SR, Davis, CM, Richards, AL, Burch, NR. Effects of smoking on fluphenazine clearance in psychiatric inpatients. Biol Psychiatry. 1985; 20(3): 329–332.Google Scholar
25. Marder, SR, Midha, KK, Van Putten, T, et al. Plasma levels of fluphenazine in patients receiving fluphenazine decanoate. Relationship to clinical response. Br J Psychiatry. 1991; 158(5): 658–665.Google Scholar
26. Selmin, F, Blasi, P, DeLuca, PP. Accelerated polymer biodegradation of risperidone poly(D, L-lactide-co-glycolide) microspheres. AAPS PharmSciTech. 2012; 13(4): 1465–1472.CrossRefGoogle ScholarPubMed
27. Harrison, TS, Goa, KL. Long-acting risperidone: a review of its use in schizophrenia. CNS Drugs. 2004; 18(2): 113–132.Google Scholar
28. Janssen Pharmaceuticals Inc. Risperdal Consta Package Insert. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2017.Google Scholar
29. de Leon, J, Sandson, NB, Cozza, KL. A preliminary attempt to personalize risperidone dosing using drug–drug interactions and genetics, Part II. Psychosomatics. 2008; 48(4): 347–361.CrossRefGoogle Scholar
30. Samtani, MN, Vermeulen, A, Stuyckens, K. Population pharmacokinetics of intramuscular paliperidone palmitate in patients with schizophrenia: a novel once-monthly, long-acting formulation of an atypical antipsychotic. Clin Pharmacokinet. 2009; 48(9): 585–600.Google Scholar
31. Meyer, JM. Drug-drug interactions with antipsychotics. CNS Spectr. 2007; 12(12 Suppl 21): 6–9.Google Scholar
32. Panagiotidis, G, Arthur, HW, Lindh, JD, Dahl, ML, Sjöqvist, F. Depot haloperidol treatment in outpatients with schizophrenia on monotherapy: impact of CYP2D6 polymorphism on pharmacokinetics and treatment outcome. Ther Drug Monit. 2007; 29(4): 417–422.Google Scholar
33. Zhou, SF. Polymorphism of human cytochrome P450 2D6 and its clinical significance: part II. Clin Pharmacokinet. 2009; 48(12): 761–804.CrossRefGoogle ScholarPubMed
34. Hendset, M, Molden, E, Refsum, H, Hermann, M. Impact of CYP2D6 genotype on steady-state serum concentrations of risperidone and 9-hydroxyrisperidone in patients using long-acting injectable risperidone. J Clin Psychopharmacol. 2009; 29(6): 537–541.CrossRefGoogle ScholarPubMed
35. Hough, D, Gopal, S, Vijapurkar, U, Lim, P, Morozova, M, Eerdekens, M. Paliperidone palmitate maintenance treatment in delaying the time-to-relapse in patients with schizophrenia: a randomized, double-blind, placebo-controlled study. Schizophr Res. 2010; 116(2–3): 107–117.Google Scholar
36. Pandina, GJ, Lindenmayer, J-P, Lull, J, et al. A randomized, placebo-controlled study to assess the efficacy and safety of 3 doses of paliperidone palmitate in adults with acutely exacerbated schizophrenia. J Clin Psychopharmacol. 2010; 30(3): 235–244.Google Scholar
37. Nazirizadeh, Y, Vogel, F, Bader, W, et al. Serum concentrations of paliperidone versus risperidone and clinical effects. Eur J Clin Pharmacol. 2010; 66(8): 797–803.Google Scholar
38. Mamo, D, Kapur, S, Keshavan, M, et al. D2 receptor occupancy of olanzapine pamoate depot using positron emission tomography: an open-label study in patients with schizophrenia. Neuropsychopharmacology. 2008; 33(2): 298–304.CrossRefGoogle ScholarPubMed
39. Frampton, JE. Olanzapine long-acting injection: a review of its use in the treatment of schizophrenia. Drugs. 2010; 70(17): 2289–2313.Google Scholar
40. Detke, HC, Zhao, F, Garhyan, P, Carlson, J, McDonnell, D. Dose correspondence between olanzapine long-acting injection and oral olanzapine: recommendations for switching. Int Clin Psychopharmacol. 2011; 26(1): 35–42.CrossRefGoogle ScholarPubMed
41. Detke, HC, McDonnell, DP, Brunner, E, et al. Post-injection delirium/sedation syndrome in patients with schizophrenia treated with olanzapine long-acting injection, I: analysis of cases. BMC Psychiatry. 2010; 10: 43.Google Scholar
42. McDonnell, DP, Detke, HC, Bergstrom, RF, et al. Post-injection delirium/sedation syndrome in patients with schizophrenia treated with olanzapine long-acting injection, II: investigations of mechanism. BMC Psychiatry. 2010; 10: 45.CrossRefGoogle ScholarPubMed
43. Eli Lilly and Company. Relprevv Package Insert. Indianapolis, IN: Lilly USA, LLC; 2017.Google Scholar
44. Bishara, D, Olofinjana, O, Sparshatt, A, Kapur, S, Taylor, D, Patel, MX. Olanzapine: a systematic review and meta-regression of the relationships between dose, plasma concentration, receptor occupancy, and response. J Clin Psychopharmacol. 2013; 33(3): 329–335.Google Scholar
45. Haslemo, T, Eikeseth, PH, Tanum, L, Molden, E, Refsum, H. The effect of variable cigarette consumption on the interaction with clozapine and olanzapine. Eur J Clin Pharmacol. 2006; 62(12): 1049–1053.CrossRefGoogle ScholarPubMed
46. Kane, JM, Sanchez, R, Perry, PP, et al. Aripiprazole intramuscular depot as maintenance treatment in patients with schizophrenia: a 52-week, multicenter, randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2012; 73(5): 617–624.Google Scholar
47. Fleischhacker, WW, Sanchez, R, Johnson, B, et al. Long-term safety and tolerability of aripiprazole once-monthly in maintenance treatment of patients with schizophrenia. Int Clin Psychopharmacol. 2013; 28(4): 171–176.Google Scholar
48. Mallikaarjun, S, Kane, JM, Bricmont, P, et al. Pharmacokinetics, tolerability and safety of aripiprazole once-monthly in adult schizophrenia: an open-label, parallel-arm, multiple-dose study. Schizophr Res. 2013; 150(1): 281–288.CrossRefGoogle ScholarPubMed
49. Otsuka Pharmaceutical Co. Ltd. Maintena Package Insert. Tokyo: Otsuka Pharmaceutical Co.; 2017.Google Scholar
50. Alkermes Inc. Aristada Package Insert. Waltham, MA: Alkermes Inc.; 2017.Google Scholar
51. Hard, ML, Mills, RJ, Sadler, BM, Turncliff, RZ, Citrome, L. Aripiprazole lauroxil: pharmacokinetic profile of this long-acting injectable antipsychotic in persons with schizophrenia. J Clin Psychopharmacol. 2017; 37(3): 289–295.CrossRefGoogle ScholarPubMed
52. Hard, ML, Mills, RJ, Sadler, BM, Wehr, AY, Weiden, PJ, von Moltke, L. Pharmacokinetic profile of a 2-month dose regimen of aripiprazole lauroxil: a phase I study and a population pharmacokinetic model. CNS Drugs. 2017; 31(7): 617–624.Google Scholar
53. Sparshatt, A, Taylor, D, Patel, MX, Kapur, S. A systematic review of aripiprazole—dose, plasma concentration, receptor occupancy, and response: implications for therapeutic drug monitoring. J Clin Psychiatry. 2010; 71(11): 1447–1456.Google Scholar
54. Kapur, S, Zipursky, R, Roy, P, et al. The relationship between D2 receptor occupancy and plasma levels on low dose oral haloperidol: a PET study. Psychopharmacology. 1997; 131(2): 148–152.Google Scholar
55. Wei, FC, Jann, MW, Lin, HN, Piao-Chien, C, Chang, WH. A practical loading dose method for converting schizophrenic patients from oral to depot haloperidol therapy. J Clin Psychiatry. 1996; 57(7): 298–302.Google Scholar
56. De Leon, J, Wynn, G, Sandson, NB. The pharmacokinetics of paliperidone versus risperidone. Psychosomatics. 2010; 51(1): 80–88.Google Scholar
57. de Leon, J, Sandson, NB, Cozza, KL. A preliminary attempt to personalize risperidone dosing using drug–drug interactions and genetics: part II. Psychosomatics. 2008; 49(4): 347–361.CrossRefGoogle ScholarPubMed
58. Chang, WH, Juang, DJ, Lin, SK, et al. Disposition of haloperidol and reduced haloperidol plasma levels after single dose haloperidol decanoate administration. Hum Psychopharmacol. 1995; 10(1): 47–51.Google Scholar
59. Jann, MW, Wei, FC, Lin, HN, Piao-Chien, C, Chang, WH. Haloperidol and reduced haloperidol plasma concentrations after a loading dose regimen with haloperidol decanoate. Prog Neuropsychopharmacol Biol Psychiatry. 1996; 20(1): 73–86.CrossRefGoogle ScholarPubMed
60. Kane, JM, Eerdekens, M, Lindenmayer, JP, Keith, SJ, Lesem, M, Karcher, K. Long-acting injectable risperidone: efficacy and safety of the first long-acting atypical antipsychotic. Am J Psychiatry. 2003; 160(6): 1125–1132.Google Scholar
61. Fleischhacker, WW, Eerdekens, M, Karcher, K, et al. Treatment of schizophrenia with long-acting injectable risperidone: a 12-month open-label trial of the first long-acting second-generation antipsychotic. J Clin Psychiatry. 2003; 64(10): 1250–1257.Google Scholar
62. Meltzer, HY, Lindenmayer, JP, Kwentus, J, Share, DB, Johnson, R, Jayathilake, K. A six month randomized controlled trial of long-acting injectable risperidone 50 and 100mg in treatment-resistant schizophrenia. Schizophr Res. 2014; 154(1–3): 14–22.Google Scholar
63. Janssen Pharmaceuticals Inc. Invega Sustenna Package Insert. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2017.Google Scholar
64. Pandina, GJ, Lindenmayer, JP, Lull, J, et al. A randomized, placebo-controlled study to assess the efficacy and safety of 3 doses of paliperidone palmitate in adults with acutely exacerbated schizophrenia. J Clin Psychopharmacol. 2010; 30(3): 235–244.Google Scholar