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Impact of age andCYP2D6 genotype on exposure of zuclopenthixol in patients using long-acting injectable versus oral formulation—an observational study including 2044 patients

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Zuclopenthixol is an antipsychotic available as oral and long-acting injectable (LAI) formulations. The aim of this study was to investigate the effect of age on zuclopenthixol exposure during oral and LAI administrations without and with adjustment forCYP2D6 genotype.

Methods

Data on serum concentrations of zuclopenthixol andCYP2D6 genotype (available for 28.2% of the population) from patients using oral or LAI zuclopenthixol were included retrospectively from a therapeutic drug monitoring service during the period 2005–2019. As a measure of exposure, dose-adjusted serum concentration (C/D ratio) was used. Based on age, patients were grouped to older (≥ 65 years) or younger (18–64 years). Linear mixed model analyses without and with adjustment forCYP2D6 genotype were used.

Results

Serum concentrations of zuclopenthixol from 1145 (14.1% older) and 899 patients (24.6% older) in the LAI and oral groups were included, respectively. Compared with younger patients, older patients had a higher C/D ratio of zuclopenthixol for LAI (+ 25–33%,p < 0.001) and oral formulation (+ 25–29%,p ≤ 0.003) without and with adjustment forCYP2D6 genotype. The doses were lower in older versus younger patients (oral: − 30%; LAI: − 20%;p < 0.001). Compared with the younger LAI users without reduced CYP2D6 function, a higher C/D ratio was observed in the older LAI users with reduced CYP2D6 function (+ 104%,p < 0.001).

Conclusion

The present study showed that zuclopenthixol exposure increases in older patients and that the older LAI users with reduced CYP2D6 function are exposed to high serum concentrations. Also, the present study showed that similar dose reductions are required for oral and LAI users.

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Data availability

The data that supports the findings of this study are available upon reasonable request from the corresponding author. The data are not publicly available due to privacy and ethical restrictions.

References

  1. Jablensky A, Sartorius N, Ernberg G, Anker M, Korten A, Cooper JE, Day R, Bertelsen A (1992) Schizophrenia: manifestations, incidence and course in different cultures. A World Health Organization ten-country study. Psychol Med Monogr Suppl 20:1–97.https://doi.org/10.1017/s0264180100000904

    Article CAS PubMed  Google Scholar 

  2. Laursen TM (2011) Life expectancy among persons with schizophrenia or bipolar affective disorder. Schizophr Res 131:101–104.https://doi.org/10.1016/j.schres.2011.06.008

    Article PubMed  Google Scholar 

  3. Walker ER, McGee RE, Druss BG (2015) Mortality in mental disorders and global disease burden implications: a systematic review and meta-analysis. JAMA Psychiatry 72:334–341.https://doi.org/10.1001/jamapsychiatry.2014.2502

    Article PubMed PubMed Central  Google Scholar 

  4. Cohen CI, Meesters PD, Zhao J (2015) New perspectives on schizophrenia in later life: implications for treatment, policy, and research. Lancet Psych 2:340–350.https://doi.org/10.1016/S2215-0366(15)00003-6

    Article  Google Scholar 

  5. Cohen CI, Vahia I, Reyes P, Diwan S, Bankole AO, Palekar N, Kehn M, Ramirez P (2008) Focus on geriatric psychiatry: schizophrenia in later life: clinical symptoms and social well-being. Psychiatr Serv 59:232–234.https://doi.org/10.1176/ps.2008.59.3.232

    Article PubMed  Google Scholar 

  6. Bryan EJ, Purcell MA, Kumar A (2017) Zuclopenthixol dihydrochloride for schizophrenia. Cochrane Database Syst Rev 11:CD005474.https://doi.org/10.1002/14651858.CD005474.pub2

    Article PubMed  Google Scholar 

  7. Tiihonen J, Mittendorfer-Rutz E, Majak M, Mehtala J, Hoti F, Jedenius E, Enkusson D, Leval A, Sermon J, Tanskanen A, Taipale H (2017) Real-world effectiveness of antipsychotic treatments in a nationwide cohort of 29823 patients with schizophrenia. JAMA Psychiatry 74:686–693.https://doi.org/10.1001/jamapsychiatry.2017.1322

    Article PubMed PubMed Central  Google Scholar 

  8. 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.https://doi.org/10.1093/schbul/sbx176

  9. Davies SJ, Westin AA, Castberg I, Lewis G, Lennard MS, Taylor S, Spigset O (2010) Characterisation of zuclopenthixol metabolism by in vitro and therapeutic drug monitoring studies. Acta Psychiatr Scand 122:444–453.https://doi.org/10.1111/j.1600-0447.2010.01619.x

    Article CAS PubMed  Google Scholar 

  10. Lisbeth P, Vincent H, Kristof M, Bernard S, Manuel M, Hugo N (2016) Genotype and co-medication dependent CYP2D6 metabolic activity: effects on serum concentrations of aripiprazole, haloperidol, risperidone, paliperidone and zuclopenthixol. Eur J Clin Pharmacol 72:175–184.https://doi.org/10.1007/s00228-015-1965-1

    Article CAS PubMed  Google Scholar 

  11. Molden E, Waade RB, Hoff M, Haslemo T (2016) Impact of ageing on serum concentrations of risperidone and its active metabolite in patients with known CYP2D6 genotype. Basic Clin Pharmacol Toxicol 119:470–475.https://doi.org/10.1111/bcpt.12614

    Article CAS PubMed  Google Scholar 

  12. Waade RB, Molden E, Refsum H, Hermann M (2012) Serum concentrations of antidepressants in the elderly. Ther Drug Monit 34:25–30.https://doi.org/10.1097/FTD.0b013e318241dce0

    Article CAS PubMed  Google Scholar 

  13. Tveito M, Smith RL, Molden E, Haslemo T, Refsum H, Hartberg C, Correll CU, Hoiseth G (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. 38:570–576.https://doi.org/10.1097/JCP.0000000000000961

    Article CAS PubMed  Google Scholar 

  14. Tveito M, Molden E, Hoiseth G, Correll CU, Smith RL (2019) 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. Eur J Clin Pharmacol.https://doi.org/10.1007/s00228-019-02768-0

  15. Nolan L, O’Malley K (1992) Adverse effects of antidepressants in the elderly. Drugs Aging 2:450–458.https://doi.org/10.2165/00002512-199202050-00008

    Article CAS PubMed  Google Scholar 

  16. Kratz T, Diefenbacher A (2019) Psychopharmacological treatment in older people. Dtsch Arztebl Int 116:508–518.https://doi.org/10.3238/arztebl.2019.0508

    Article PubMed PubMed Central  Google Scholar 

  17. database U (2020) Drug prescribing for older adults.https://www.uptodate.com/contents/drug-prescribing-for-older-adults. Accessed 11 June 2020

  18. Trifiro G, Spina E (2011) Age-related changes in pharmacodynamics: focus on drugs acting on central nervous and cardiovascular systems. Curr Drug Metab 12:611–620

    Article CAS  Google Scholar 

  19. Leinonen E (1991) Serum mianserin concentrations in psychiatric inpatients of different ages. Acta Psychiatr Scand 83:278–282.https://doi.org/10.1111/j.1600-0447.1991.tb05540.x

    Article CAS PubMed  Google Scholar 

  20. 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 136:455–464.https://doi.org/10.1111/acps.12794

    Article CAS PubMed  Google Scholar 

  21. Castberg I, Westin AA, Spigset O (2009) Does level of care, sex, age, or choice of drug influence adherence to treatment with antipsychotics? J Clin Psychopharmacol 29:415–420.https://doi.org/10.1097/JCP.0b013e3181b2fced

    Article PubMed  Google Scholar 

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Funding

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

Author information

Authors and Affiliations

  1. Center for Psychopharmacology, Diakonhjemmet Hospital, PO Box 85, Vinderen, 0319, Oslo, Norway

    Marit Tveito, Robert Løvsletten Smith, Espen Molden & Gudrun Høiseth

  2. Norwegian National Advisory Unit on Aging and Health, Vestfold Hospital Trust, Tønsberg, Norway

    Marit Tveito

  3. Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway

    Espen Molden

  4. Department of Forensic Sciences, Oslo University Hospital, Oslo, Norway

    Gudrun Høiseth

  5. Institute of Clinical Medicine, University of Oslo, Oslo, Norway

    Gudrun Høiseth

Authors
  1. Marit Tveito

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  2. Robert Løvsletten Smith

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  3. Espen Molden

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  4. Gudrun Høiseth

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Contributions

All authors were involved in the ideation, conceptualisation, and design of the study. RLS and MT collected and prepared the data material. RLS analysed the data. RLS, MT, and GH interpreted the data. MT, RLS, and GH drafted the manuscript. All other authors critically reviewed the manuscript and approved the submitted version.

Corresponding author

Correspondence toMarit Tveito.

Ethics declarations

Conflict of interest

Prof. Molden has received speaker’s honoraria from Lundbeck and Lilly. The other authors have no conflicts of interest to declare.

Ethics approval

The study was approved by the Regional Committee for Medical and Health Research Ethics (2017/9121) and Health Research Ethics and the Hospital Investigational Review Board.

Consent to participate

The use of historical patient data for the purpose of this study was approved by the Regional Committee for Medical and Health Research Ethics and the Hospital Investigational Review Board without consent from the patients, as the study was based on retrospective data only.

Consent for publication

All authors have approved the submission.

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Not applicable.

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Marit Tveito and Robert Løvsletten Smith shared first authorship.

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Tveito, M., Smith, R.L., Molden, E.et al. Impact of age andCYP2D6 genotype on exposure of zuclopenthixol in patients using long-acting injectable versus oral formulation—an observational study including 2044 patients.Eur J Clin Pharmacol77, 215–221 (2021). https://doi.org/10.1007/s00228-020-03002-y

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