European Journal of Clinical Pharmacology

, Volume 76, Issue 1, pp 41–49 | Cite as

Impact of age and CYP2D6 genetics on exposure of aripiprazole and dehydroaripiprazole in patients using long-acting injectable versus oral formulation: relevance of poor and intermediate metabolizer status

  • Marit TveitoEmail author
  • Espen Molden
  • Gudrun Høiseth
  • Christoph U. Correll
  • Robert Løvsletten Smith



Tailoring medication dosing for the individual patient is complex, and many factors can influence drug exposure. We investigated the effect of age and CYP2D6 genotype on aripiprazole and dehydroaripiprazole exposure in patients using long-acting injectable (LAI) or oral aripiprazole.


Matched data on serum concentration of aripiprazole and CYP2D6 genotype of patients using oral or LAI aripiprazole were included retrospectively from a therapeutic drug monitoring service. The patients were divided into the following CYP2D6 genotype-defined categories: poor metabolizers (PMs), intermediate metabolizers (IMs), normal metabolizers (NMs), and ultrarapid metabolizers (UMs). Linear mixed model analyses were used to evaluate the impact of CYP2D6 genotype on dose-adjusted serum concentrations of the active moiety of aripiprazole+dehydroaripiprazole in relation to age and formulation.


We identified 635 patients (mean age = 40.1 years, 9.4% ≥ 65 years, 53.7% females) using LAI (n = 166) or oral formulation (n = 469). The genotype-predicted CYP2D6 phenotype subgroups were 2.4% UMs, 82.0% NMs, 8.0% IMs, and 7.2% PMs. Age did not significantly affect exposure of the active moiety of aripiprazole+dehydroaripiprazole in the LAI (p = 0.071) or oral (p = 0.14) subgroups. Compared with CYP2D6 NMs, PMs and IMs had significantly increased exposure of the active moiety of aripiprazole+dehydroaripiprazole in the LAI (1.7-fold higher, p < 0.001, and 1.5-fold higher, p < 0.001) and oral (1.7-fold higher, p < 0.001, and 1.6-fold higher, p < 0.001) subgroups.


In conclusion, doses should be adjusted according to CYP2D6 genotype when initiating treatment with aripiprazole LAI or tablets, while advanced age do not affect the exposure of the active moiety of aripiprazole treatment regardless of formulation.


Aripiprazole Genotype CYP2D6 Age Therapeutic drug monitoring Long-acting injection 


Author contributions

Marit Tveito designed the research, analyzed the data, and wrote the manuscript.

Espen Molden designed the research and wrote the manuscript.

Gudrun Høiseth designed the research and wrote the manuscript.

Cristoph U. Correll wrote the manuscript.

Robert L. Smith analyzed data and wrote the manuscript.

Funding information

This work was funded by the South-Eastern Norway Regional Health Authority (grant numbers 2017085 and 2016097).

Compliance with ethical standards

Conflict of interest

Dr. Correll has been a consultant and/or advisor to or has received honoraria from Alkermes, Allergan, Angelini, Boehringer-Ingelheim, Gerson Lehrman Group, Indivior, Intra-Cellular Therapies, Janssen/J&J, LB Pharma, Lundbeck, MedAvante-ProPhase, Medscape, Merck, Neurocrine, Noven, Otsuka, Pfizer, Rovi, Servier, Sumitomo Dainippon, Sunovion, Supernus, Takeda, and Teva. He has provided expert testimony for Bristol-Myers Squibb, Janssen, and Otsuka. He served on a Data Safety Monitoring Board for Boehringer-Ingelheim, Lundbeck, Rovi, Supernus, and Teva. He received royalties from UpToDate and grant support from Janssen and Takeda. He is also a shareholder of LB Pharma. Prof. Molden has received speaker´s honoraria from Lundbeck and Lilly. The other authors have no conflicts of interest to declare.


  1. 1.
    Bartels SJ, Clark RE, Peacock WJ, Dums AR, Pratt SI (2003) Medicare and medicaid costs for schizophrenia patients by age cohort compared with costs for depression, dementia, and medically ill patients. Am J Geriatr Psychiatry 11(6):648–657CrossRefGoogle Scholar
  2. 2.
    Cohen CI, Meesters PD, Zhao J (2015) New perspectives on schizophrenia in later life: implications for treatment, policy, and research. Lancet Psychiatry 2(4):340–350. CrossRefPubMedGoogle Scholar
  3. 3.
    Kovacs G, Almasi T, Millier A, Toumi M, Horvath M, Koczian K et al (2018) Direct healthcare cost of schizophrenia - European overview. Eur Psychiatry 48:79–92. CrossRefPubMedGoogle Scholar
  4. 4.
    Olfson M, Gerhard T, Huang C, Crystal S, Stroup TS (2015) Premature mortality among adults with schizophrenia in the United States. JAMA Psychiatry. 72(12):1172–1181. CrossRefPubMedGoogle Scholar
  5. 5.
    Talaslahti T, Alanen HM, Hakko H, Isohanni M, Hakkinen U, Leinonen E (2012) Mortality and causes of death in older patients with schizophrenia. Int J Geriatr Psychiatry 27(11):1131–1137. CrossRefPubMedGoogle Scholar
  6. 6.
    Correll CU, Solmi M, Veronese N, Bortolato B, Rosson S, Santonastaso P et al (2017) Prevalence, incidence and mortality from cardiovascular disease in patients with pooled and specific severe mental illness: a large-scale meta-analysis of 3,211,768 patients and 113,383,368 controls. World Psychiatry 16(2):163–180. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Hendrie HC, Tu W, Tabbey R, Purnell CE, Ambuehl RJ, Callahan CM (2014) Health outcomes and cost of care among older adults with schizophrenia: a 10-year study using medical records across the continuum of care. Am J Geriatr Psychiatry 22(5):427–436. CrossRefPubMedGoogle Scholar
  8. 8.
    Correll CU, Citrome L, Haddad PM, Lauriello J, Olfson M, Calloway SM et al (2016) The use of long-acting injectable antipsychotics in schizophrenia: evaluating the evidence. J Clin Psychiatry 77(suppl 3):1–24. CrossRefPubMedGoogle Scholar
  9. 9.
    Tiihonen J, Haukka J, Taylor M, Haddad PM, Patel MX, Korhonen P (2011) A nationwide cohort study of oral and depot antipsychotics after first hospitalization for schizophrenia. Am J Psychiatry 168(6):603–609. CrossRefPubMedGoogle Scholar
  10. 10.
    Subotnik KL, Casaus LR, Ventura J, Luo JS, Hellemann GS, Gretchen-Doorly D et al (2015) 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 72(8):822–829. CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Schreiner A, Aadamsoo K, Altamura AC, Franco M, Gorwood P, Neznanov NG et al (2015) Paliperidone palmitate versus oral antipsychotics in recently diagnosed schizophrenia. Schizophr Res 169(1-3):393–399. CrossRefPubMedGoogle Scholar
  12. 12.
    Kishimoto T, Nitta M, Borenstein M, Kane JM, Correll CU (2013) Long-acting injectable versus oral antipsychotics in schizophrenia: a systematic review and meta-analysis of mirror-image studies. J Clin Psychiatry. 74(10):957–965. CrossRefPubMedGoogle Scholar
  13. 13.
    Kishimoto T, Hagi K, Nitta M, Leucht S, Olfson M, Kane JM et al (2017) Effectiveness of long-acting injectable vs oral antipsychotics in patients with schizophrenia: a meta-analysis of prospective and retrospective cohort studies. Schizophr Bull. CrossRefGoogle Scholar
  14. 14.
    Taipale H, Mehtala J, Tanskanen A, Tiihonen J (2017) Comparative effectiveness of antipsychotic drugs for rehospitalization in schizophrenia-a nationwide study with 20-year follow-up. Schizophr Bull. CrossRefGoogle Scholar
  15. 15.
    Tiihonen J, Mittendorfer-Rutz E, Majak M, Mehtala J, Hoti F, Jedenius E et al (2017) Real-world effectiveness of antipsychotic treatments in a nationwide cohort of 29823 patients with schizophrenia. JAMA Psychiatry. 74(7):686–693. CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Taipale H, Mittendorfer-Rutz E, Alexanderson K, Majak M, Mehtala J, Hoti F et al (2017) Antipsychotics and mortality in a nationwide cohort of 29,823 patients with schizophrenia. Schizophr Res. CrossRefGoogle Scholar
  17. 17.
    Kane JM, Kishimoto T, Correll CU (2013) Non-adherence to medication in patients with psychotic disorders: epidemiology, contributing factors and management strategies. World Psychiatry 12(3):216–226. CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Correll CU, Rubio JM, Kane JM (2018) What is the risk-benefit ratio of long-term antipsychotic treatment in people with schizophrenia? World Psychiatry 17(2):149–160. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Leucht S, Cipriani A, Spineli L, Mavridis D, Orey D, Richter F et al (2013) Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet. 382(9896):951–962. CrossRefPubMedGoogle Scholar
  20. 20.
    Potkin SG, Preda A (2016) Aripiprazole once-monthly long-acting injectable for the treatment of schizophrenia. Expert Opin Pharmacother 17(3):395–407. CrossRefPubMedGoogle Scholar
  21. 21.
    Naber D, Baker RA, Eramo A, Forray C, Hansen K, Sapin C et al (2018) Long-term effectiveness of aripiprazole once-monthly for schizophrenia is maintained in the QUALIFY extension study. Schizophr Res 192:205–210. CrossRefPubMedGoogle Scholar
  22. 22.
    Leucht S, Leucht C, Huhn M, Chaimani A, Mavridis D, Helfer B et al (2017) Sixty years of placebo-controlled antipsychotic drug trials in acute schizophrenia: systematic review, bayesian meta-analysis, and meta-regression of efficacy predictors. Am J Psychiatry 174(10):927–942. CrossRefPubMedGoogle Scholar
  23. 23.
    Samara MT, Nikolakopoulou A, Salanti G, Leucht S (2018) How many patients with schizophrenia do not respond to antipsychotic drugs in the short term? An analysis based on individual patient data from randomized controlled trials. Schizophr Bull. CrossRefGoogle Scholar
  24. 24.
    Keks NA, Hope J, Culhane C (2016) Aripiprazole long-acting injection: promising but more evidence needed. Australas Psychiatry 24(4):368–370. CrossRefPubMedGoogle Scholar
  25. 25.
    Dong AN, Tan BH, Pan Y, Ong CE (2018) Cytochrome P450 genotype-guided drug therapies: an update on current states. Clin Exp Pharmacol Physiol 45(10):991–1001. CrossRefPubMedGoogle Scholar
  26. 26.
    Paine MF, Hart HL, Ludington SS, Haining RL, Rettie AE, Zeldin DC (2006) The human intestinal cytochrome P450 "pie". Drug Metab Dispos 34(5):880–886. CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Balestrieri M, Marcon G, Samani F, Marini M, Sessa E, Gelatti U et al (2005) Mental disorders associated with benzodiazepine use among older primary care attenders--a regional survey. Soc Psychiatry Psychiatr Epidemiol 40(4):308–315. CrossRefPubMedGoogle Scholar
  28. 28.
    Hiemke C, Bergemann N, Clement HW, Conca A, Deckert J, Domschke K et al (2017) Consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology: update 2017. Pharmacopsychiatry. PubMedGoogle Scholar
  29. 29.
    Hendset M, Molden E, Knape M, Hermann M (2014) Serum concentrations of risperidone and aripiprazole in subgroups encoding CYP2D6 intermediate metabolizer phenotype. Ther Drug Monit 36(1):80–85. CrossRefPubMedGoogle Scholar
  30. 30.
    Jukic MM, Smith RL, Haslemo T, Molden E, Ingelman-Sundberg M (2019) Effect of CYP2D6 genotype on exposure and efficacy of risperidone and aripiprazole: a retrospective, cohort study. Lancet Psychiatry 6(5):418–426. CrossRefPubMedGoogle Scholar
  31. 31.
    Castberg I, Westin AA, Skogvoll E, Spigset O (2017) Effects of age and gender on the serum levels of clozapine, olanzapine, risperidone, and quetiapine. Acta Psychiatr Scand 136(5):455–464. CrossRefPubMedGoogle Scholar
  32. 32.
    Gaedigk A, Simon S, Pearce R, Bradford L, Kennedy M, Leeder J (2008) The CYP2D6 activity score: translating genotype information into a qualitative measure of phenotype. Clinical Pharmacology & Therapeutics 83(2):234–242. CrossRefGoogle Scholar
  33. 33.
    Valenstein M, Taylor KK, Austin K, Kales HC, McCarthy JF, Blow FC (2004) Benzodiazepine use among depressed patients treated in mental health settings. Am J Psychiatry 161(4):654–661CrossRefGoogle Scholar
  34. 34.
    Ravyn D, Ravyn V, Lowney R, Nasrallah HA (2013) CYP450 pharmacogenetic treatment strategies for antipsychotics: a review of the evidence. Schizophr Res 149(1-3):1–14. CrossRefPubMedGoogle Scholar
  35. 35.
    Spina E, de Leon J (2015) Clinical applications of CYP genotyping in psychiatry. J Neural Transm (Vienna) 122(1):5–28. CrossRefGoogle Scholar
  36. 36.
    Swen JJ, Nijenhuis M, de Boer A, Grandia L (2011) Maitland-van der Zee AH, Mulder H et al. Pharmacogenetics: from bench to byte--an update of guidelines. Clin Pharmacol Ther 89(5):662–673. CrossRefPubMedGoogle Scholar
  37. 37.
    Burton DG, Allen MC, Bird JL, Faragher RG (2005) Bridging the gap: ageing, pharmacokinetics and pharmacodynamics. J Pharm Pharmacol 57(6):671–679. CrossRefPubMedGoogle Scholar
  38. 38.
    Masand PS (2000) Side effects of antipsychotics in the elderly. J Clin Psychiatry. 61(Suppl 8):43–49 discussion 50-1PubMedGoogle Scholar
  39. 39.
    Tveito M, Smith RL, Molden E, Haslemo T, Refsum H, Hartberg C et al (2018) Age impacts olanzapine exposure differently during use of oral versus long-acting injectable formulations: an observational study including 8,288 patients. J Clin Psychopharmacol.
  40. 40.
    Mallikaarjun S, Salazar DE, Bramer SL (2004) Pharmacokinetics, tolerability, and safety of aripiprazole following multiple oral dosing in normal healthy volunteers. J Clin Pharmacol 44(2):179–187. CrossRefPubMedGoogle Scholar
  41. 41.
    Mallikaarjun S, Kane JM, Bricmont P, McQuade R, Carson W, Sanchez R et al (2013) Pharmacokinetics, tolerability and safety of aripiprazole once-monthly in adult schizophrenia: an open-label, parallel-arm, multiple-dose study. Schizophr Res 150(1):281–288. CrossRefPubMedGoogle Scholar
  42. 42.
    de Bartolomeis A, Tomasetti C, Iasevoli F (2015) Update on the mechanism of action of aripiprazole: translational insights into antipsychotic strategies beyond dopamine receptor antagonism. CNS Drugs 29(9):773–799. CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Kim JR, Seo HB, Cho JY, Kang DH, Kim YK, Bahk WM et al (2008) Population pharmacokinetic modelling of aripiprazole and its active metabolite, dehydroaripiprazole, in psychiatric patients. Br J Clin Pharmacol 66(6):802–810. CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    van Assema DM, Lubberink M, Boellaard R, Schuit RC, Windhorst AD, Scheltens P et al (2012) P-glycoprotein function at the blood-brain barrier: effects of age and gender. Mol Imaging Biol 14(6):771–776. CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Genomes Project C, Auton A, Brooks LD, Durbin RM, Garrison EP, Kang HM et al (2015) A global reference for human genetic variation. Nature. 526(7571):68–74. CrossRefGoogle Scholar
  46. 46.
    Hicks J, Swen J, Gaedigk A (2014) Challenges in CYP2D6 Phenotype assignment from genotype data: a critical assessment and call for standardization. Curr Drug Metab 15(2):218–232. CrossRefPubMedGoogle Scholar
  47. 47.
    Haslemo T, Eliasson E, Jukic MM, Ingelman-Sundberg M, Molden E (2019) Significantly lower CYP2D6 metabolism measured as the O/N-desmethylvenlafaxine metabolic ratio in carriers of CYP2D6*41 versus CYP2D6*9 or CYP2D6*10: a study on therapeutic drug monitoring data from 1003 genotyped Scandinavian patients. Br J Clin Pharmacol 85(1):194–201. CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Center for PsychopharmacologyDiakonhjemmet HospitalOsloNorway
  2. 2.Department of Pharmaceutical Biosciences, School of PharmacyUniversity of OsloOsloNorway
  3. 3.Department of Forensic SciencesOslo University HospitalOsloNorway
  4. 4.Department of Psychiatry, Northwell HealthThe Zucker Hillside HospitalGlen OaksUSA
  5. 5.Department of Psychiatry and Molecular MedicineHofstra Northwell School of MedicineHempsteadUSA
  6. 6.Department of Child and Adolescent PsychiatryCharité UniversitätsmedizinBerlinGermany

Personalised recommendations