Search tips
Search criteria 


Logo of jpnSubmit a ManuscriptEmail AlertsAbout JPNJournal of Psychiatry and Neuroscience
J Psychiatry Neurosci. 1997 November; 22(5): 327–331.
PMCID: PMC1188880

Refractory depression: treatment strategies, with particular reference to the thyroid axis.


In the last few years, it has become evident that major depressive disorder often runs a chronic and recurrent course. Early effective intervention may increase the liklihood of a good long-term prognosis. The main treatment options for patients who fail to respond to antidepressant therapy and the relative advantages of each are critically reviewed. These include substitution, replacing one antidepressant with another, and augmentation/combination, in which a second antidepressant is added to the first. Particular emphasis is placed on the role of triiodothyronine (T3) in augmentation therapy. The theoretic rationale for using augmentation/combination therapy and its relative advantages and disadvantages over substitution therapy are critically reviewed.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.1M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Mueller TI, Keller MB, Leon AC, Solomon DA, Shea MT, Coryell W, Endicott J. Recovery after 5 years of unremitting major depressive disorder. Arch Gen Psychiatry. 1996 Sep;53(9):794–799. [PubMed]
  • Keller MB, Lavori PW, Mueller TI, Endicott J, Coryell W, Hirschfeld RM, Shea T. Time to recovery, chronicity, and levels of psychopathology in major depression. A 5-year prospective follow-up of 431 subjects. Arch Gen Psychiatry. 1992 Oct;49(10):809–816. [PubMed]
  • Keller MB, Lavori PW, Rice J, Coryell W, Hirschfeld RM. The persistent risk of chronicity in recurrent episodes of nonbipolar major depressive disorder: a prospective follow-up. Am J Psychiatry. 1986 Jan;143(1):24–28. [PubMed]
  • Joffe RT, Levitt AJ. Antidepressant failure: augmentation or substitution? J Psychiatry Neurosci. 1995 Jan;20(1):7–9. [PMC free article] [PubMed]
  • Fava M, Davidson KG. Definition and epidemiology of treatment-resistant depression. Psychiatr Clin North Am. 1996 Jun;19(2):179–200. [PubMed]
  • Phillips KA, Nierenberg AA. The assessment and treatment of refractory depression. J Clin Psychiatry. 1994 Feb;55 (Suppl):20–26. [PubMed]
  • Price LH. What is the duration for augmentation with T3 or lithium in resistant depression? J Clin Psychopharmacol. 1989 Feb;9(1):73–73. [PubMed]
  • Joffe RT, Singer W, Levitt AJ, MacDonald C. A placebo-controlled comparison of lithium and triiodothyronine augmentation of tricyclic antidepressants in unipolar refractory depression. Arch Gen Psychiatry. 1993 May;50(5):387–393. [PubMed]
  • Joffe RT, Singer W. A comparison of triiodothyronine and thyroxine in the potentiation of tricyclic antidepressants. Psychiatry Res. 1990 Jun;32(3):241–251. [PubMed]
  • de Montigny C, Cournoyer G, Morissette R, Langlois R, Caillé G. Lithium carbonate addition in tricyclic antidepressant-resistant unipolar depression. Correlations with the neurobiologic actions of tricyclic antidepressant drugs and lithium ion on the serotonin system. Arch Gen Psychiatry. 1983 Dec;40(12):1327–1334. [PubMed]
  • Dinan TG, Barry S. A comparison of electroconvulsive therapy with a combined lithium and tricyclic combination among depressed tricyclic nonresponders. Acta Psychiatr Scand. 1989 Jul;80(1):97–100. [PubMed]
  • Heninger GR, Charney DS, Sternberg DE. Lithium carbonate augmentation of antidepressant treatment. An effective prescription for treatment-refractory depression. Arch Gen Psychiatry. 1983 Dec;40(12):1335–1342. [PubMed]
  • Ontiveros A, Fontaine R, Elie R. Refractory depression: the addition of lithium to fluoxetine or desipramine. Acta Psychiatr Scand. 1991 Mar;83(3):188–192. [PubMed]
  • Price LH, Charney DS, Heninger GR. Variability of response to lithium augmentation in refractory depression. Am J Psychiatry. 1986 Nov;143(11):1387–1392. [PubMed]
  • Schöpf J, Baumann P, Lemarchand T, Rey M. Treatment of endogenous depressions resistant to tricyclic antidepressants or related drugs by lithium addition. Results of a placebo-controlled double-blind study. Pharmacopsychiatry. 1989 Sep;22(5):183–187. [PubMed]
  • Thase ME, Kupfer DJ, Jarrett DB. Treatment of imipramine-resistant recurrent depression: I. An open clinical trial of adjunctive L-triiodothyronine. J Clin Psychiatry. 1989 Oct;50(10):385–388. [PubMed]
  • Austin MP, Souza FG, Goodwin GM. Lithium augmentation in antidepressant-resistant patients. A quantitative analysis. Br J Psychiatry. 1991 Oct;159:510–514. [PubMed]
  • Jacobsen FM. Possible augmentation of antidepressant response by buspirone. J Clin Psychiatry. 1991 May;52(5):217–220. [PubMed]
  • Joffe RT, Schuller DR. An open study of buspirone augmentation of serotonin reuptake inhibitors in refractory depression. J Clin Psychiatry. 1993 Jul;54(7):269–271. [PubMed]
  • Blier P, Bergeron R. Effectiveness of pindolol with selected antidepressant drugs in the treatment of major depression. J Clin Psychopharmacol. 1995 Jun;15(3):217–222. [PubMed]
  • FLACH FF, CELIAN CI, RAWSON RW. Treatment of psychiatric disorders with triiodothyronine. Am J Psychiatry. 1958 Mar;114(9):841–842. [PubMed]
  • FELDMESSER-REISS EE. The application of triiodothyronine in the treatment of mental disorders. J Nerv Ment Dis. 1958 Dec;127(6):540–545. [PubMed]
  • Prange AJ, Jr, Wilson IC, Rabon AM, Lipton MA. Enhancement of imipramine antidepressant activity by thyroid hormone. Am J Psychiatry. 1969 Oct;126(4):457–469. [PubMed]
  • Wheatley D. Potentiation of amitriptyline by thyroid hormone. Arch Gen Psychiatry. 1972 Mar;26(3):229–233. [PubMed]
  • Bánki C. Trijódthyronin alkalmazása a depressio kezelésében. Orv Hetil. 1975 Oct 26;116(43):2543–2546. [PubMed]
  • Earle BV. Thyroid hormone and tricyclic antidepressants in resistant depressions. Am J Psychiatry. 1970 May;126(11):1667–1669. [PubMed]
  • Goodwin FK, Prange AJ, Jr, Post RM, Muscettola G, Lipton MA. Potentiation of antidepressant effects by L-triiodothyronine in tricyclic nonresponders. Am J Psychiatry. 1982 Jan;139(1):34–38. [PubMed]
  • Gitlin MJ, Weiner H, Fairbanks L, Hershman JM, Friedfeld N. Failure of T3 to potentiate tricyclic antidepressant response. J Affect Disord. 1987 Nov-Dec;13(3):267–272. [PubMed]
  • Schwarcz G, Halaris A, Baxter L, Escobar J, Thompson M, Young M. Normal thyroid function in desipramine nonresponders converted to responders by the addition of L-triiodothyronine. Am J Psychiatry. 1984 Dec;141(12):1614–1616. [PubMed]
  • Tsutsui S, Yamazaki Y, Namba T, Tsushima M. Combined therapy of T3, and antidepressants in depression. J Int Med Res. 1979;7(2):138–146. [PubMed]
  • Aronson R, Offman HJ, Joffe RT, Naylor CD. Triiodothyronine augmentation in the treatment of refractory depression. A meta-analysis. Arch Gen Psychiatry. 1996 Sep;53(9):842–848. [PubMed]

Articles from Journal of Psychiatry & Neuroscience : JPN are provided here courtesy of Canadian Medical Association