Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Tricyclic and tetracyclic drugs: Pharmacology, administration, and side effects

Michael Hirsch, MD
Robert J Birnbaum, MD, PhD
Section Editor
Peter P Roy-Byrne, MD
Deputy Editor
David Solomon, MD


The use of tricyclic and tetracyclic antidepressants to treat depression began with reports in 1958 that imipramine was particularly effective for melancholic depression, marked by symptoms such as psychomotor retardation, anergia, dysphoria, hopelessness, and diurnal variation [1,2]. Many other cyclic antidepressants were subsequently developed, including the tricyclics amitriptyline, amoxapine, clomipramine, desipramine, doxepin, nortriptyline, protriptyline, and trimipramine, as well as the tetracyclic antidepressant maprotiline. These cyclic compounds became first-line treatment for depression for the next 30 years, until the selective serotonin reuptake inhibitors were introduced.

Clinicians use tricyclic antidepressants to treat many other psychiatric disorders besides depression, including panic attacks, generalized anxiety disorder, post-traumatic stress disorder, bulimia nervosa, and smoking cessation. Tricyclics are used to treat a variety of chronic pain states such as chronic daily headache and neuropathy. See appropriate topic reviews.

This topic reviews the pharmacology, administration, and side effects of tricyclic and tetracyclic antidepressants. Switching and discontinuing antidepressants, the pharmacology, administration, and side effects of other antidepressant classes, choosing an antidepressant for the initial treatment of depression and treatment of resistant depression, and management of tricyclic overdose are discussed separately.

(See "Switching antidepressant medications in adults".)

(See "Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects".)


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Sep 2016. | This topic last updated: Feb 11, 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
  1. KUHN R. The treatment of depressive states with G 22355 (imipramine hydrochloride). Am J Psychiatry 1958; 115:459.
  2. LEHMANN HE, CAHN CH, DE VERTEUIL RL. The treatment of depressive conditions with imipramine (G 22355). Can Psychiatr Assoc J 1958; 3:155.
  3. Nelson, JC. Tricyclic and tetracyclic drugs. In: The American Psychiatric Publishing Textbook of Psychopharmacology, 4th ed, Schatzberg, AF, Nemeroff, CB (Eds), American Psychiatric Publishing, Washington, DC 2009. p.263.
  4. Thummel, KE, et, al. Design and optimization of dosage regimens: pharmacokinetic data (appendix II). In: Goodman & Gilman's Pharmacological Basis of Therapeutics, 11th ed, Brunton, LL, Lazo, JS, Parker, KL (Eds), McGraw-Hill, New York 2006.
  5. DeBattista, C. Antidepressant agents. In: Basic and Clinical Pharmacology, 11th ed, Katzung, BG, Masters, SB, Trevor, AJ (Eds), McGraw-Hill Lange, New York 2009.
  6. MedicinesComplete [Internet database]. Pharmaceutical Press, London, 2010 http://www.medicinescomplete.com (Accessed on September 28, 2010).
  7. DRUGDEX® System [Internet database]. Greenwood Village, CO, Thomson Reuters (Healthcare) Inc, 2002-2010. (Accessed September 28, 2010).
  8. Labbate, LA, Fava, M, Rosenbaum, JF, et al. Drugs for the treatment of depression. In: Handbook of Psychiatric Drug Therapy, 6th ed, Lippincott Williams & Wilkins, Philadelphia 2010. p.54.
  9. Furukawa TA, McGuire H, Barbui C. Meta-analysis of effects and side effects of low dosage tricyclic antidepressants in depression: systematic review. BMJ 2002; 325:991.
  10. Adli M, Baethge C, Heinz A, et al. Is dose escalation of antidepressants a rational strategy after a medium-dose treatment has failed? A systematic review. Eur Arch Psychiatry Clin Neurosci 2005; 255:387.
  11. Hiemke C, Baumann P, Bergemann N, et al. AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Psychiatry: Update 2011. Pharmacopsychiatry 2011; 44:195.
  12. AHFS Drug Information. © Copyright, 1959-2010, Selected Revisions January 2010, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.
  13. Anderson IM, Ferrier IN, Baldwin RC, et al. Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 2000 British Association for Psychopharmacology guidelines. J Psychopharmacol 2008; 22:343.
  14. Arana, GW, Rosenbaum, JF. Antidepressant drugs. In: Handbook of Psychiatric Drug Therapy, 4th ed, Lippincott Williams & Wilkins, Philadelphia 2000. p.53.
  15. Ray WA, Meredith S, Thapa PB, et al. Cyclic antidepressants and the risk of sudden cardiac death. Clin Pharmacol Ther 2004; 75:234.
  16. Cohen HW, Gibson G, Alderman MH. Excess risk of myocardial infarction in patients treated with antidepressant medications: association with use of tricyclic agents. Am J Med 2000; 108:2.
  17. Hamer M, Batty GD, Seldenrijk A, Kivimaki M. Antidepressant medication use and future risk of cardiovascular disease: the Scottish Health Survey. Eur Heart J 2011; 32:437.
  18. Leonard CE, Bilker WB, Newcomb C, et al. Antidepressants and the risk of sudden cardiac death and ventricular arrhythmia. Pharmacoepidemiol Drug Saf 2011; 20:903.
  19. Fanoe S, Kristensen D, Fink-Jensen A, et al. Risk of arrhythmia induced by psychotropic medications: a proposal for clinical management. Eur Heart J 2014; 35:1306.
  20. Norpramin (desipramine hydrochloride) - Dear Healthcare Professional Letter www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm192655.htm. (Accessed on December 10, 2009).
  21. Hippisley-Cox J, Pringle M, Hammersley V, et al. Antidepressants as risk factor for ischaemic heart disease: case-control study in primary care. BMJ 2001; 323:666.
  22. Evidence report/technology assessment: Number 7. Treatment of depression - Newer pharmacotherapies. Agency for Health Care Policy and Research, Rockville, MD, 1999 www.ahcpr.gov/clinic/epcsums/deprsumm.htm (Accessed on March 07, 2005).