Back to top Open menu arrow
Download Reprints
The Journal of Clinical Psychiatry The Journal of Clinical Psychiatry

The Journal of
Clinical Psychiatry
Access icon

Clinical and Practical Psychopharmacology August 1, 2022

Psychotropic Drugs With Long Half-Lives: Implications for Drug Discontinuation, Occasional Missed Doses, Dosing Interval, and Pregnancy Planning

Chittaranjan Andrade, MD

J Clin Psychiatry 2022;83(4):22f14593

ABSTRACT

The half-life of a drug is the time taken for the blood level of the drug to fall by half, provided that no more doses of the drug are administered in the intervening period. Many psychotropic drugs and their active metabolites, if any, have very long half-lives that extend for 2 days or longer. Examples are chlordiazepoxide, diazepam, fluoxetine, vortioxetine, aripiprazole, brexpiprazole, cariprazine, penfluridol, donepezil, and memantine. Other drugs with long half-lives that psychiatrists may prescribe include levothyroxine and zonisamide. Psychotropic drugs with long half-lives take long to reach steady state; this is seldom a problem. They also take long to wash out; this is an advantage because the risk of drug withdrawal or discontinuation syndromes is small, and a disadvantage if rapid washout is desired for any reason, including the experience of drug adverse effects or toxicity, or the discovery of an unplanned pregnancy. Other clinical issues related to drugs with long half-lives include the relevance of occasional missed doses, the possibility of once-weekly dosing, and the need for pregnancy planning.

Continue Reading...

Did you know members enjoy unlimited free PDF downloads as part of their subscription? Subscribe today for instant access to this article and our entire library in your preferred format. Alternatively, you can purchase the PDF of this article individually.

Subscribe Now

Already a member? Login

  1. Andrade C. The practical importance of half-life in psychopharmacology. J Clin Psychiatry. 2022;83(4):22f14584.
  2. Svensson EM, Acharya C, Clauson B, et al. Pharmacokinetic interactions for drugs with a long half-life—evidence for the need of model-based analysis. AAPS J. 2016;18(1):171–179. PubMed CrossRef
  3. Schwartz MA, Postma E, Gaut Z. Biological half-life of chlordiazepoxide and its metabolite, demoxepam, in man. J Pharm Sci. 1971;60(10):1500–1503. PubMed CrossRef
  4. Roberts RK, Wilkinson GR, Branch RA, et al. Effect of age and parenchymal liver disease on the disposition and elimination of chlordiazepoxide (Librium). Gastroenterology. 1978;75(3):479–485. PubMed CrossRef
  5. Barton K, Auld PW, Scott MG, et al. Chlordiazepoxide metabolite accumulation in liver disease. Med Toxicol. 1989;4(1):73–76. PubMed CrossRef
  6. Abernethy DR, Greenblatt DJ, Divoll M, et al. Prolonged accumulation of diazepam in obesity. J Clin Pharmacol. 1983;23(8-9):369–376. PubMed CrossRef
  7. Greenblatt DJ, Harmatz JS, Zhang Q, et al. Slow accumulation and elimination of diazepam and its active metabolite with extended treatment in the elderly. J Clin Pharmacol. 2021;61(2):193–203. PubMed CrossRef
  8. Andrade C. Lorazepam for alcohol withdrawal. Indian J Psychiatry. 2003;45(1):67. PubMed
  9. Kumar CN, Andrade C, Murthy P. A randomized, double-blind comparison of lorazepam and chlordiazepoxide in patients with uncomplicated alcohol withdrawal. J Stud Alcohol Drugs. 2009;70(3):467–474. PubMed CrossRef
  10. Brett J, Murnion B. Management of benzodiazepine misuse and dependence. Aust Prescr. 2015;38(5):152–155. PubMed CrossRef
  11. Lemberger L, Bergstrom RF, Wolen RL, et al. Fluoxetine: clinical pharmacology and physiologic disposition. J Clin Psychiatry. 1985;46(3 Pt 2):14–19. PubMed
  12. DeVane CL. Pharmacokinetics of the selective serotonin reuptake inhibitors. J Clin Psychiatry. 1992;53(suppl):13–20. PubMed
  13. Preskorn SH. Clinically relevant pharmacology of selective serotonin reuptake inhibitors. An overview with emphasis on pharmacokinetics and effects on oxidative drug metabolism. Clin Pharmacokinet. 1997;32(suppl 1):1–21. PubMed CrossRef
  14. Prozac. FDA website. https://www.google.com/url?esrc=s&q=&rct=j&sa=U&url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/018936s076lbl.pdf&ved=2ahUKEwj4obOy7ub4AhXLRmwGHVUjDCYQFnoECAoQAg&usg=AOvVaw3eKUJDJ4a8_XERkYPGhvvi. Accessed July 7, 2022.
  15. Hamelin BA, Turgeon J, Vallée F, et al. The disposition of fluoxetine but not sertraline is altered in poor metabolizers of debrisoquin. Clin Pharmacol Ther. 1996;60(5):512–521. PubMed CrossRef
  16. Sanchez C, Asin KE, Artigas F. Vortioxetine, a novel antidepressant with multimodal activity: review of preclinical and clinical data. Pharmacol Ther. 2015;145(1):43–57. PubMed CrossRef
  17. Chen G, Højer A-M, Areberg J, et al. Vortioxetine: clinical pharmacokinetics and drug interactions. Clin Pharmacokinet. 2018;57(6):673–686. PubMed CrossRef
  18. Schatzberg AF, Blier P, Delgado PL, et al. Antidepressant discontinuation syndrome: consensus panel recommendations for clinical management and additional research. J Clin Psychiatry. 2006;67(suppl 4):27–30. PubMed
  19. Calil HM. Fluoxetine: a suitable long-term treatment. J Clin Psychiatry. 2001;62(suppl 22):24–29. PubMed
  20. Fava GA, Gatti A, Belaise C, et al. Withdrawal symptoms after selective serotonin reuptake inhibitor discontinuation: a systematic review. Psychother Psychosom. 2015;84(2):72–81. PubMed CrossRef
  21. Baldwin DS, Chrones L, Florea I, et al. The safety and tolerability of vortioxetine: Analysis of data from randomized placebo-controlled trials and open-label extension studies. J Psychopharmacol. 2016;30(3):242–252. PubMed CrossRef
  22. Keks N, Hope J, Keogh S. Switching and stopping antidepressants. Aust Prescr. 2016;39(3):76–83. PubMed
  23. Benazzi F. Fluoxetine for the treatment of SSRI discontinuation syndrome. Int J Neuropsychopharmacol. 2008;11(5):725–726. PubMed CrossRef
  24. Wilson E, Lader M. A review of the management of antidepressant discontinuation symptoms. Ther Adv Psychopharmacol. 2015;5(6):357–368. PubMed CrossRef
  25. Fava GA, Cosci F. Understanding and managing withdrawal syndromes after discontinuation of antidepressant drugs. J Clin Psychiatry. 2019;80(6):19com12794. PubMed CrossRef
  26. Winans E. Aripiprazole. Am J Health Syst Pharm. 2003;60(23):2437–2445. PubMed CrossRef
  27. Dean L. Aripiprazole Therapy and CYP2D6 Genotype. 2016 Sep 22. In: Pratt VM, Scott SA, Pirmohamed M, et al, eds. Medical Genetics Summaries. Bethesda, MD: National Center for Biotechnology Information (US); 2012. [Internet], Available at https://www.ncbi.nlm.nih.gov/books/NBK385288/bin/20160922aripiprazole.pdf. Accessed July 10, 2022.
  28. Abilify Prescribing Information. FDA website. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021436s038,021713s030,021729s022,021866s023lbl.pdf. Accessed on July 10, 2022.
  29. Rexulti Prescribing Information. Otsuka website. https://www.otsuka-us.com/sites/g/files/qhldwo4671/files/media/static/Rexulti-PI.pdf. Accessed on July 10, 2022.
  30. Vraylar Prescribing Information. FDA website. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/204370lbl.pdf. Accessed on July 10, 2022.
  31. Claghorn JL, Mathew RJ, Mirabi M. Penfluridol: a long acting oral antipsychotic drug. J Clin Psychiatry. 1979;40(2):107–109. PubMed
  32. Migdaloft BH, Grindel JM, Heykants JJ, et al. Penfluridol: a neuroleptic drug designed for long duration of action. Drug Metab Rev. 1979;9(2):281–299. PubMed CrossRef
  33. Grindel JM, Migdalof BH, Cressman WA. The comparative metabolism and disposition of penfluridol-3H in the rat, rabbit, dog, and man. Drug Metab Dispos. 1979;7(5):325–329. PubMed
  34. Lu J, Wang X, Wan L, et al. Gene polymorphisms affecting the pharmacokinetics and pharmacodynamics of donepezil efficacy. Front Pharmacol. 2020;11:934. PubMed CrossRef
  35. Noetzli M, Eap CB. Pharmacodynamic, pharmacokinetic and pharmacogenetic aspects of drugs used in the treatment of Alzheimer’s disease. Clin Pharmacokinet. 2013;52(4):225–241. PubMed CrossRef
  36. Bode H, Ivens B, Bschor T, et al. Association of hypothyroidism and clinical depression: a systematic review and meta-analysis. JAMA Psychiatry. 2021;78(12):1375–1383. PubMed CrossRef
  37. Hirtz R, Föcker M, Libuda L, et al. Increased prevalence of subclinical hypothyroidism and thyroid autoimmunity in depressed adolescents: results from a clinical cross-sectional study in comparison to the general pediatric population. J Clin Psychiatry. 2021;82(2):20m13511. PubMed
  38. Howland RH. Thyroid dysfunction in refractory depression: implications for pathophysiology and treatment. J Clin Psychiatry. 1993;54(2):47–54. PubMed
  39. Kleiner J, Altshuler L, Hendrick V, et al. Lithium-induced subclinical hypothyroidism: review of the literature and guidelines for treatment. J Clin Psychiatry. 1999;60(4):249–255. PubMed CrossRef
  40. Colucci P, Yue CS, Ducharme M, et al. A review of the pharmacokinetics of levothyroxine for the treatment of hypothyroidism. Eur Endocrinol. 2013;9(1):40–47. PubMed CrossRef
  41. Buoli M, Grassi S, Ciappolino V, et al. The use of zonisamide for the treatment of psychiatric disorders: a systematic review. Clin Neuropharmacol. 2017;40(2):85–92. PubMed CrossRef
  42. Lim J, Ko YH, Joe SH, et al. Zonisamide produces weight loss in psychotropic drug-treated psychiatric outpatients. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35(8):1918–1921. PubMed CrossRef
  43. Brodie MJ, Ben-Menachem E, Chouette I, et al. Zonisamide: its pharmacology, efficacy and safety in clinical trials. Acta Neurol Scand suppl. 2012;126(194):19–28. PubMed CrossRef
  44. Okpako DT, Thomas M, Oriowo MA. Principles of Pharmacology: A Tropical Approach. 2nd ed. Cambridge University Press; 2002:141.
  45. Johansson B. A review of the pharmacokinetics and pharmacodynamics of disulfiram and its metabolites. Acta Psychiatr Scand suppl. 1992;86(S369):15–26. PubMed CrossRef
  46. Weiden PJ, Kim E, Bermak J, et al. Does half-life matter after antipsychotic discontinuation? a relapse comparison in schizophrenia with 3 different formulations of paliperidone. J Clin Psychiatry. 2017;78(7):e813–e820. PubMed CrossRef
  47. Schmidt ME, Fava M, Robinson JM, et al. The efficacy and safety of a new enteric-coated formulation of fluoxetine given once weekly during the continuation treatment of major depressive disorder. J Clin Psychiatry. 2000;61(11):851–857. PubMed CrossRef
  48. Genaro-Mattos TC, Anderson A, Allen LB, et al. Maternal cariprazine exposure inhibits embryonic and postnatal brain cholesterol biosynthesis. Mol Psychiatry. 2020;25(11):2685–2694. PubMed CrossRef
  49. Tallman KA, Allen LB, Klingelsmith KB, et al. Prescription medications alter neuronal and glial cholesterol synthesis. ACS Chem Neurosci. 2021;12(4):735–745. PubMed CrossRef
  50. Korade Z, Heffer M, Mirnics K. Medication effects on developmental sterol biosynthesis. Mol Psychiatry. 2022;27(1):490–501. PubMed CrossRef
  51. Jonklaas J, Bianco AC, Bauer AJ, et al; American Thyroid Association Task Force on Thyroid Hormone Replacement. Guidelines for the treatment of hypothyroidism: prepared by the American Thyroid Association Task Force on thyroid hormone replacement. Thyroid. 2014;24(12):1670–1751. PubMed CrossRef
Download Free PDF

Save Save

Share Share

Cite Cite

Vol 85 • 2024 • Number 3

Read the Current Issue

Editorial

Focus on Women’s Mental Health: Twenty Years and Counting

Original Research

Esmethadone in Patients With Major Depressive Disorder and Inadequate Response to Standard Antidepressants

Commentary

Can Our Collective Experiences As Clinicians Improve Mental Health Care?

Original Research

Prescription Opioid Use Disorder in US Adults Reporting Prescription Opioid Use

Original Research

Symptomatic Disorders Comorbid with Borderline Personality Disorder Over Time

Original Research

Aripiprazole Lauroxil Initiation Regimens
View current Issue

Celebrating
85 Years

Read the Journal of Clinical Psychiatry

Subscribe to read
more articles

Subscribe