Off-label antipsychotics prescription to adolescents with acute psychotic episodes does not cause adverse drug reactions

Antipsychotics are often used to treat children and adolescents. Because of their age, there are a lot of off-label prescribed antipsychotics in that population. However, the off-label use of medications is considered to be potentially unsafe.

Objective: to evaluate whether the off-label prescription of antipsychotics outside of the approved age group increased the risk of adverse drug reactions in adolescents experiencing an acute psychotic episode.

Patients and methods. We analyzed 450 charts of adolescents hospitalized due to an acute psychotic episode (only completed cases). In addition, we evaluated adverse drug reactions adjusted by off-label antipsychotics prescription outside the approved age group using the Global Trigger Tool (GTT). We also registered prescriptions with duplicates drug classes and potentially dangerous drug interactions.

Results and discussion. Off-label antipsychotics prescription outside the approved age group was less frequently associated with adverse drug reactions (3.2% vs. 10.5%; p=0.013). The logistic regression analysis did not show any significant associations between the off-label antipsychotic use and increased risk of adverse drug reactions (Odds ratio=0.994 (95% confidence interval 0.572-1.726), p=0.982). Although, patients with off-label use of antipsychotics were more likely to have potentially dangerous drug interactions (35.2% vs. 16.15%; p=0.0001) and prescriptions with duplicates drug classes (39.6% vs. 15.43%; p=0.0001).

Conclusion. Off-label antipsychotic prescription outside the approved age group in adolescents with acute psychotic episode does not increase the risk of adverse drug reactions. However, an increase in potentially dangerous drug interactions and prescriptions with duplicates drug classes frequency could be considered red flags. Therefore, we have concluded that the concerns about off-label antipsychotics prescription outside of approved age groups in adolescents with acute psychotic episodes were overrated.

1. Haddad PM, Correll CU. The acute efficacy of antipsychotics in schizophrenia: a review of recent meta-analyses. Ther Adv Psychopharmacol. 2018 Oct 8;8(11):303-18. doi: 10.1177/2045125318781475. eCollection 2018 Nov.

2. Cacabelos R, Hashimoto R, Takeda M. Pharmacogenomics of antipsychotics efficacy for schizophrenia. Psychiatry Clin Neurosci. 2011 Feb;65(1):3-19. doi: 10.1111/j.1440-1819.2010.02168.x

3. Gründer G, Heinze M, Cordes J, et al. Effects of first-generation antipsychotics versus second-generation antipsychotics on quality of life in schizophrenia: a double-blind, randomised study. Lancet Psychiatry. 2016 Aug;3(8):717-29. doi: 10.1016/S2215-0366(16)00085-7. Epub 2016 Jun 2.

4. Maayan L, Correll CU. Weight gain and metabolic risks associated with antipsychotic medications in children and adolescents. J Child Adolesc Psychopharmacol. 2011 Dec;21(6):517- 35. doi: 10.1089/cap.2011.0015. Epub 2011 Dec 13.

5. Dinnissen M, Dietrich A, van der Molen JH, et al. Prescribing antipsychotics in child and adolescent psychiatry: guideline adherence. Eur Child Adolesc Psychiatry. 2020 Dec;29(12):1717-27. doi: 10.1007/s00787-020-01488-6. Epub 2020 Feb 12.

6. Baeza I, De La Serna E, Calvo-Escalona R, et al. Antipsychotic use in children and adolescents: A 1-year follow-up study. J Clin Psychopharmacol. 2014 Oct;34(5):613-9. doi: 10.1097/JCP.0000000000000190

7. Stafford MR, Mayo-Wilson E, Loucas CE, et al. Efficacy and safety of pharmacological and psychological interventions for the treatment of psychosis and schizophrenia in children, adolescents and young adults: A systematic review and meta-analysis. PLoS One. 2015 Feb 11;10(2):e0117166. doi: 10.1371/journal.pone.0117166. eCollection 2015.

8. Sohn M, Moga DC, Blumenschein K, et al. National trends in off-label use of atypical antipsychotics in children and adolescents in the United States. Medicine (Baltimore). 2016 Jun;95(23):e3784. doi: 10.1097/MD.0000000000003784

9. Kaguelidou F, Holstiege J, Schink T, et al. Use of antipsychotics in children and adolescents: a picture from the ARITMO populationbased European cohort study. Epidemiol Psychiatr Sci. 2020 Apr 20;29:e117. doi: 10.1017/S2045796020000293

10. Varimo E, Saastamoinen LK, Rättö H, et al. New Users of Antipsychotics Among Children and Adolescents in 2008–2017: A Nationwide Register Study. Front Psychiatry. 2020 Apr 24;11:316. doi: 10.3389/fpsyt.2020.00316. eCollection 2020.

11. Patten SB, Waheed W, Bresee L. A review of pharmacoepidemiologic studies of antipsychotic use in children and adolescents. Can J Psychiatry. 2012 Dec;57(12):717- 21. doi: 10.1177/070674371205701202

12. Kostev K, Osina G, Konrad M. Treatment patterns of patients with schizophrenia based on the data from 44,836 outpatients in Russia. Hear Mind. 2019;3(4):161.

13. Korn∅ K, Aagaard L. Off-label prescribing of antipsychotics in a Danish child and adolescent mental health center: A register-based study. J Res Pharm Pract. Oct-Dec 2018;7(4):205-9. doi: 10.4103/jrpp.JRPP_18_42

14. Schröder C, Dörks M, Kollhorst B, et al. Outpatient antipsychotic drug use in children and adolescents in Germany between 2004 and 2011. Eur Child Adolesc Psychiatry. 2017 Apr;26(4):413-20. doi: 10.1007/s00787-016-0905-7. Epub 2016 Sep 13.

15. Schröder C, Dörks M, Kollhorst B, et al. Extent and Risks of Antipsychotic Off-Label Use in Children and Adolescents in Germany between 2004 and 2011. J Child Adolesc Psychopharmacol. 2017 Nov;27(9):806-13. doi: 10.1089/cap.2016.0202. Epub 2017 Jun 15.

16. Russian Government Registry of Drugs. Available from: https://grls.rosminzdrav.ru/ Default.aspx (accessed 01.09.2020).

17. Lee J-H, Byon H-J, Choi S, et al. Safety and Efficacy of Off-label and Unlicensed Medicines in Children. J Korean Med Sci. 2018 Jul 19;33(37):e227. doi: 10.3346/jkms.2018.33.e227. eCollection 2018 Sep 10.

18. Schröder C, Dörks M, Kollhorst B, et al. Extent and risks of antidepressant off-label use in children and adolescents in Germany between 2004 and 2011. Pharmacoepidemiol Drug Saf. 2017 Nov;26(11):1395-402. doi: 10.1002/pds.4289. Epub 2017 Aug 24.

19. Gardner DM, Murphy AL, O’Donnell H, et al. International Consensus Study of Antipsychotic Dosing. Am J Psychiatry. 2010 Jun;167(6):686-93. doi: 10.1176/appi.ajp.2009.09060802. Epub 2010 Apr 1.

20. Drugs interaction checker. Available from: https://drugs.com/

21. Landrigan CP, Stockwell D, Toomey SL, et al. Performance of the Global Assessment of Pediatric Patient Safety (GAPPS) Tool. Pediatrics. 2016 Jun;137(6):e20154076. doi: 10.1542/peds.2015-4076

22. Classen DC, Resar R, Griffin F, et al. «Global trigger tool» shows that adverse events in hospitals may be ten times greater than previously measured. Health Aff (Millwood). 2011 Apr;30(4):581-9. doi: 10.1377/hlthaff.2011.0190