CNS Drugs

, Volume 4, Issue 5, pp 341–350

Practical Guidelines for Combination Drug Therapy of Treatment-Resistant Depression

  • Stephen T. H. Sokolov
  • Russell T. Joffe
Practical Therapeutics

Summary

Although antidepressants are effective in many individuals with major depression, there remains a significant proportion of patients who do not respond to initial treatment. Recent evidence suggests that the persistence of major depressive symptoms increases the risk of developing a chronic depressive illness, and emphasises the importance of pursuing effective therapies for patients who fail to respond to initial treatment.

Classically, approaches to antidepressant failure have included: (i) optimisation of current therapy; (ii) substitution with a second antidepressant; (iii) combination of antidepressant agents; and (iv) augmentation (combination) with a second medication that alone does not possess inherent antidepressant properties. These strategies are discussed in the present article. Emphasis is placed on the discussion of the latter 2 strategies, which may offer advantages including reasonable efficacy, tolerability and ease of introduction.

Of the strategies presented, augmentation with lithium or liothyronine are the best evaluated. However, these drugs have only been assessed systematically in patients who have failed to respond to tricyclic antidepressants. Their value in patients who have not responded to other classes of antidepressants is supported by anecdotal case reports only. Furthermore, although it is known that these agents produce a response within several weeks, the required duration of treatment once a response is achieved is not known.

Despite these limitations, augmentation approaches have substantial inherent value because of their efficacy and rapid onset of effect. This latter feature is particularly important given recent evidence suggesting that chronicity of illness may be preventable by obtaining an early response.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Smith AL, Weissman MM. The epidemiology of depressive disorders: national and international perspectives. In: Feighner JP, Boyer WF, editors. Diagnosis of depression. Chichester, England: John Wiley & Sons, 1991: 17–30Google Scholar
  2. 2.
    Kessler RC, McGonagle KA, Zhao S, et al. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States: results from the national comorbidity survey. Arch Gen Psychiatry 1994; 51(1): 8–19PubMedCrossRefGoogle Scholar
  3. 3.
    Elkin I, Shea T, Watkins JT, et al. National Institute of Mental Health treatment of depression collaborative research program: general effectiveness of treatments. Arch Gen Psychiatry 1989; 46: 971–82PubMedCrossRefGoogle Scholar
  4. 4.
    Frank E, Kupfer DJ, Perel JM, et al. Three-year outcomes for maintenance therapies in recurrent depression. Arch Gen Psychiatry 1990; 47: 1093–9PubMedCrossRefGoogle Scholar
  5. 5.
    Klein DE, Gittelman R, Quitkin F. Diagnosis and drug treatment of psychiatric disorders. 2nd ed. Baltimore: Williams and Wilkins Co., 1980Google Scholar
  6. 6.
    Kupfer DJ, Frank E, Perel JM. The advantage of early treatment intervention in recurrent depression. Arch Gen Psychiatry 1989; 46: 771–5PubMedCrossRefGoogle Scholar
  7. 7.
    Keller MB, Lavori PW, Mueller TI, et al. Time to recovery, chronicity, and levels of psychopathology in major depression. A 5-year prospective follow-up of 431 subjects. Arch Gen Psychiatry 1992; 49: 809–16PubMedCrossRefGoogle Scholar
  8. 8.
    Price LH. Pharmacological strategies in refractory depression. In: Post R, editor. Treatment of refractory mood disorders, APA Review of Psychiatry, vol 9. Washington (DC): American Psychiatric Association Press, 1990: 116–31Google Scholar
  9. 9.
    Quitkin FM, Rabkin JG, Stewart JW, et al. Study duration in antidepressant research: advantages of a 12-week trial. J Psy-chiatr Res 1986; 20(3): 211–6CrossRefGoogle Scholar
  10. 10.
    Quitkin FM, Rabkin JG, Ross D, et al. Duration of antidepressant drug treatment. What is an adequate trial?. Arch Gen Psychiatry 1984; 41(3): 238–45PubMedCrossRefGoogle Scholar
  11. 11.
    Roose SP, Glassman AH, Walsh BT, et al. Tricyclic nonresponders: phenomenology and treatment. Am J Psychiatry 1986; 143(3): 345–8PubMedGoogle Scholar
  12. 12.
    Liebowitz MR, Quitkin FM, Stewart JW, et al. Antidepressant specificity in atypical depression. Arch Gen Psychiatry 1988; 45(2): 129–37PubMedCrossRefGoogle Scholar
  13. 13.
    Quitkin FM, McGrath PJ, Stewart JW, et al. Atypical depression, panic attacks, and response to imipramine and phenelzine: a replication. Arch Gen Psychiatry 1990; 47: 935–41PubMedCrossRefGoogle Scholar
  14. 14.
    Quitkin FM, Stewart JW, McGrath PJ, et al. Phenelzine versus imipramine in the treatment of probable atypical depression: defining syndrome boundaries of selective MAOI responders. Am J Psychiatry 1988; 145(3): 306–11PubMedGoogle Scholar
  15. 15.
    Thase ME, Frank E, Mallinger A, et al. Treatment of imipramine-resistant recurrent depression: III. Efficacy of monoamine oxidase inhibitors. J Clin Psychiatry 1992; 53(1): 5–11PubMedGoogle Scholar
  16. 16.
    Reimherr FW, Wood DR, Byerley B, et al. Characteristics of responders to fluoxetine. Psychopharmacol Bull 1984; 20(1): 70–2PubMedGoogle Scholar
  17. 17.
    Kaskey GB, Nasr S, Meitzer HY. Drug treatment in delusional depression. Psychiatry Res 1980; 2(3): 267–77PubMedCrossRefGoogle Scholar
  18. 18.
    Minter RE, Mandel MR. A prospective study of the treatment of psychotic depression. Am J Psychiatry 1979; 136(11): 1470–2PubMedGoogle Scholar
  19. 19.
    Minter RE, Mandel M. The treatment of psychotic major depressive disorder with drugs and electroconvulsive therapy. J Nerv Ment Dis 1979; 167(12): 726–33PubMedCrossRefGoogle Scholar
  20. 20.
    Moradi SR, Muniz CE, Belar CD. Male delusional depressed patients: response to treatment. Br J Psychiatry 1979; 135: 136–8PubMedCrossRefGoogle Scholar
  21. 21.
    Nelson JC, Bowers Jr MB. Delusional unipolar depression: description and drug response. Arch Gen Psychiatry 1978; 35: 1321–8PubMedCrossRefGoogle Scholar
  22. 22.
    Spiker DG, Weiss JC, Dealy RS, et al. The pharmacological treatment of delusional depression. Am J Psychiatry 1985; 142(4): 430–6PubMedGoogle Scholar
  23. 23.
    Avery D, Lubrano A. Depression treated with imipramine and ECT: the DeCarolis study reconsidered. Am J Psychiatry 1979; 136: 559–62PubMedGoogle Scholar
  24. 24.
    Avery D, Winokur G. The efficacy of electroconvulsive therapy and antidepressants in depression. Biol Psychiatry 1977; 12(4): 507–23PubMedGoogle Scholar
  25. 25.
    Brown RP, Frances A, Kocsis JH, et al. Psychotic vs non-psychotic depression: comparison of treatment response. J Nerv Ment Dis 1982; 170(10): 635–7PubMedCrossRefGoogle Scholar
  26. 26.
    Charney DS, Nelson JC. Delusional and nondelusional unipolar depression: further evidence for distinct subtypes. Am J Psychiatry 1981; 138: 328–33PubMedGoogle Scholar
  27. 27.
    Davidson JR, McLeod MN, Kurland AA, et al. Antidepressant drug therapy in psychotic depression. Br J Psychiatry 1977; 131: 493–6PubMedCrossRefGoogle Scholar
  28. 28.
    DeCarolis V, Gilberti F, Roccatagliata G, et al. Imipramine and electroshock in the treatment of depression: a clinical statistical analysis of 437 cases. Dis Nerv Syst 1964; 25: 29–42Google Scholar
  29. 29.
    Frances A, Brown RP, Kocsis JH, et al. Psychotic depression: a separate entity?. Am J Psychiatry 1981; 138: 831–3PubMedGoogle Scholar
  30. 30.
    Glassman AH, Kantor SJ, Shostak M. Depression, delusions, and drug response. Am J Psychiatry 1975; 132(7): 716–9PubMedGoogle Scholar
  31. 31.
    Lykouras E, Malliaras D, Christodoulou GN, et al. Delusional depression: phenomenology and response to treatment. Psychopathology 1986; 19(4): 157–64PubMedCrossRefGoogle Scholar
  32. 32.
    Lykouras E, Malliaras D, Christodoulou GN, et al. Delusional depression: phenomenology and response to treatment: a prospective study. Acta Psychiatr Scand 1986; 73(3): 324–9PubMedCrossRefGoogle Scholar
  33. 33.
    Nies A, Robinson DS, Lambom KR, et al. The efficacy of the monoamine oxidase inhibitor, phenelzine: dose effects and prediction of response. In: Boissier JR, Hippius H, Pichot P, editors. Neuropsychopharmacology. Amsterdam: Excerpta Medica, 1975: 765–70Google Scholar
  34. 34.
    Robinson DS, Kayser A, Corcella J, et al. Panic attacks in out-patients with depression: response to antidepressant treatment. Psychopharmacol Bull 1985; 21: 562–7PubMedGoogle Scholar
  35. 35.
    Joffe RT, Levitt AJ, Sokolov STH, et al. Response to a second SSRI in major depression. J Clin Psychiatry. In pressGoogle Scholar
  36. 36.
    McGrath PJ, Stewart JM, Harrison W, et al. Treatment of tricyclic refractory depression with a monoamine oxidase inhibitor antidepressant. Psychopharmacol Bull 1987; 23: 169–72PubMedGoogle Scholar
  37. 37.
    Beasley CM, Sayler ME, Cunningham GE, et al. Fluoxetine in tricyclic refractory major depressive disorder. J Aff Disord 1990; 20: 193–200CrossRefGoogle Scholar
  38. 38.
    Peaslow ED, Filippi AM, Goodnick P, et al. The short- and long-term efficacy of paroxetine HCL: B. data from a double-blind crossover study and from a year-long trial vs. imipramine and placebo. Psychopharmacol Bull 1989; 25: 272–6Google Scholar
  39. 39.
    Leyjoyeux M, Adès J, Rouillon F. Serotonin syndrome: incidence, symptoms and treatment. CNS Drugs 1994; 2(2): 132–43CrossRefGoogle Scholar
  40. 40.
    White K, Simpson G. The combined use of MAOIs and tricyclics. J Clin Psychiatry 1984; 45(7, Sec. 2): 67–9PubMedGoogle Scholar
  41. 41.
    Thase ME, Rush AJ. Treatment-resistant depression. In: Bloom FE, Kufper DJ, editors. Psychopharmacology: the fourth generation of progress. New York: Raven Press, 1995: 1081–97Google Scholar
  42. 42.
    Davidson J, McLeod M, Law-Yone B, et al. A comparison of electroconvulsive therapy and combined phenelzine-amitrip-tyline in refractory depression. Arch Gen Psychiatry 1978; 35: 639–42PubMedCrossRefGoogle Scholar
  43. 43.
    De Montigny C, Grunberg F, Mayer A, et al. Lithium induces rapid relief of depression in tricyclic antidepressant drug non-responders. Br J Psychiatry 1981; 138: 252–6PubMedCrossRefGoogle Scholar
  44. 44.
    De Montigny C, Cournoyer G, Morissett R, et al. Lithium carbonate addition in tricyclic antidepressant-resistant unipolar depression. Arch Gen Psychiatry 1983; 40: 1327–34PubMedCrossRefGoogle Scholar
  45. 45.
    Price LH, Conwell Y, Nelson JC. Lithium augmentation of combined neuroleptic-tricyclic treatment in delusional depression. Am J Psychiatry 1983; 140: 318–22PubMedGoogle Scholar
  46. 46.
    Cournoyer G, De Montigny C, Ouellette J, et al. Lithium addition in tri-cyclic resistant unipolar depression [abstract]. Collegium Internationale Neuropsychopharmacoligicum: 1984 June 19–23: Florence, 179Google Scholar
  47. 47.
    Louie AK, Meitzer HY. Lithium potentiation of antidepressant treatment. J Clin Psychopharmacol 1984; 4: 316–21PubMedCrossRefGoogle Scholar
  48. 48.
    Nelson JC, Mazure CM. Lithium augmentation in psychotic depression refractory to combined drug treatment. Am J Psychiatry 1986; 143: 363–6PubMedGoogle Scholar
  49. 49.
    Price LH, Charney DS, Heninger GR. Variability of response to lithium augmentation in refractory depression. Am J Psychiatry 1986; 143: 1387–92PubMedGoogle Scholar
  50. 50.
    Dinan TG, Barry S. A comparison of electroconvulsive therapy with a combined lithium and tricyclic combination among depressed tricyclic nonresponders. Acta Psychiatr Scand 1989; 80: 97–100PubMedCrossRefGoogle Scholar
  51. 51.
    Thase ME, Kupfer DJ, Frank E, et al. Treatment of imipramine-resistant recurrent depression: II. An open trial of lithium augmentation. J Clin Psychiatry 1989; 50: 413–7PubMedGoogle Scholar
  52. 52.
    Schopf J. Treatment of depressions resistant to tricyclic antidepressants, related drugs or MAO-inhibitors by lithium addition: review of the literature. Pharmacopsychiatry 1989; 22: 174–82PubMedCrossRefGoogle Scholar
  53. 53.
    Ontiveros A, Fontaine R, Elie R. Refractory depression: the addition of lithium to fluoxetine or desipramine. Acta Psychiatry Scand 1991; 83: 188–92CrossRefGoogle Scholar
  54. 54.
    Joffe RT, Singer W, Levitt AJ, et al. A placebo-controlled comparison of lithium and triiodothyronine augmentation of tricyclic antidepressants in unipolar refractory depression. Arch Gen Psychiatry, 1993; 50: 387–93PubMedCrossRefGoogle Scholar
  55. 55.
    Heninger GR, Charney DS, Sternberg DE. Lithium carbonate augmentation of antidepressant treatment. Arch Gen Psychiatry 1983; 40: 1335–42PubMedCrossRefGoogle Scholar
  56. 56.
    Kantor D, McNevin S, Leichner P, et al. The benefit of lithium carbonate adjunct in refractory depression — fact or fiction?. Can J Psychiatry 1986; 31: 416–8PubMedGoogle Scholar
  57. 57.
    Stein G, Bernadt MD. Double blind trial of lithium carbonate in tricyclic resistant depression. In: Birch NJ, editor. Lithium: inorganic pharmacology and psychiatric use. Oxford: IRL Press, 1988: 35–6Google Scholar
  58. 58.
    Zusky PM, Biederman J, Rosenbaum JF, et al. Adjunct low dose lithium carbonate in treatment-resistant depression: a placebo-controlled study. J Clin Psychopharmacol 1988; 8: 120–4PubMedCrossRefGoogle Scholar
  59. 59.
    Schopf J, Bauman P, Lemarchand T, et al. Treatment of endogenous depressions resistant to tricyclic antidepressants or related drugs by lithium addition. Results of a placebo-controlled double-blind study. Pharmacopsychiatry 1989; 22: 183–7PubMedCrossRefGoogle Scholar
  60. 60.
    Stein G, Bernadt M. Lithium augmentation therapy in tricyclic-resistant depression. A controlled trial using lithium in low and normal doses. Br J Psychiatry 1993; 162: 634–40PubMedCrossRefGoogle Scholar
  61. 61.
    Schou M. Lithium and treatment-resistant depressions: a review. Lithium 1990; 1: 3–8Google Scholar
  62. 62.
    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; 50: 385–8PubMedGoogle Scholar
  63. 63.
    Joffe RT, Levitt AJ. The thyroid and depression. In: Joffe RT, Levitt AJ, editors. The thyroid axis and psychiatric illness. Washington (DC): American Psychiatric Press, Inc., 1993: 195–254Google Scholar
  64. 64.
    Prange Jr AJ, Wilson IC, Rabon SM, et al. Enhancement of the imipramine antidepressant activity by thyroid hormone. Am J Psychiatry 1969; 126: 457–69PubMedGoogle Scholar
  65. 65.
    Wilson IC, Prange Jr AJ, McClane TK, et al. Thyroid hormone enhancement of imipramine in nonretarded depression. N Engl J Med 1970; 282: 1063–7PubMedCrossRefGoogle Scholar
  66. 66.
    Wheathley D. Potentiation of amitriptyline by thyroid hormone. Arch Gen Psychiatry 1972; 26: 229–33CrossRefGoogle Scholar
  67. 67.
    Coppen A, Whybrow PC, Noguera R, et al. The comparative antidepressant value of L-tryptophan and imipramine with and without attempted potentiation by liothyronine. Arch Gen Psychiatry 1972; 26: 234–41PubMedCrossRefGoogle Scholar
  68. 68.
    Earle BV. Thyroid hormone and tricyclic antidepressants in resistant depression. Am J Psychiatry 1970; 126: 1667–9PubMedGoogle Scholar
  69. 69.
    Banki CM. Triiodothyronine in the treatment of depression. Orv Hetil 1975; 116: 2543–7PubMedGoogle Scholar
  70. 70.
    Ogura C, Okuma T, Uchida Y, et al. Combined thyroid (triio-dothyronine)-tricyclic antidepressant treatment in depressed states. Folia Psychiatr Neurol Jpn 1974; 28: 179–86PubMedGoogle Scholar
  71. 71.
    Banki C. Cerebrospinal fluid amine metabolites after combined amitriptyline-triiodothyronine treatment of depressed women. Eur J Clin Pharmacol 1977; 11: 311–5PubMedCrossRefGoogle Scholar
  72. 72.
    Tsutsui S, Yamazaki Y, Nanba T, et al. Combined therapy of T3 and antidepressants in depression. J Int Med Res 1979; 7: 138–46PubMedGoogle Scholar
  73. 73.
    Goodwin FK, Prange Jr AJ, Post RM, et al. Potentiation of antidepressant effects by L-triiodothyronine in tricyclic non-responders. Am J Psychiatry 1982; 139: 34–8PubMedGoogle Scholar
  74. 74.
    Schwarcz G, Halaris A, Baxter L, et al. Normal thyroid function in desipramine nonresponders compared to responders by the addition of L-triiodothyronine. Am J Psychiatry 1984; 141: 1614–6PubMedGoogle Scholar
  75. 75.
    Gitlin MJ, Weiner H, Fairbanks L, et al. Failure of T3 to potentiate tricyclic antidepressant response. J Affect Disord 1987; 13: 267–72PubMedCrossRefGoogle Scholar
  76. 76.
    Joffe RT, Singer W. A comparison of triiodothyronine and thyroxine in the potentiation of tricyclic antidepressants. Psychiatr Res 1990; 32: 241–52CrossRefGoogle Scholar
  77. 77.
    Nelson JC, Mazure CM, Bowers MB, et al. A preliminary open study of the combination of fluoxetine and desipramine for rapid treatment of major depression. Arch Gen Psychiatry 1991; 48: 303–7PubMedCrossRefGoogle Scholar
  78. 78.
    Fava M, Rosenbaum JF, McGrath PJ, et al. Lithium and tricyclic augmentation of fluoxetine treatment for resistant major depression: a double-blind, controlled study. Am J Psychiatry 1994; 151: 1372–4PubMedGoogle Scholar
  79. 79.
    Coppen A, Shaw DM, Farrell JP. Potentiation of antidepressant effect of a monoamine oxidase inhibitor by tryptophan. Lancet 1963; 1: 79–80PubMedCrossRefGoogle Scholar
  80. 80.
    Glassman AH, Platman SR. Potentiation of a monoamine oxidase inhibitor by tryptophan. J Psychiatry Res 1969; 7: 83–8CrossRefGoogle Scholar
  81. 81.
    Walinder J, Skott A, Carlsson A, et al. Potentiation of the antidepressant action of clomipramine by tryptophan. Arch Gen Psychiatry 1976; 33: 1384–9PubMedCrossRefGoogle Scholar
  82. 82.
    Baldessarini RJ. Chemotherapy in psychiatry: principles and practice. Cambridge (MA): Harvard University Press, 1985: 224Google Scholar
  83. 83.
    Joffe RT, Schuller DR. An open study of buspirone augmentation of serotonin reuptake inhibitors in refractory depression. J Clin Psychiatry 1993; 54: 269–71PubMedGoogle Scholar
  84. 84.
    Feighner JP, Herbstein J, Damlouji N. Combined MAOI, TCA, and direct stimulant therapy of treatment-resistant depression. J Clin Psychiatry 1985; 46: 206–9PubMedGoogle Scholar
  85. 85.
    Fawcett J, Kravitz HM, Zajecka JM, et al. CNS stimulant potential of monoamine oxidase inhibitors in treatment-refractory depression. J Clin Psychopharmacol 1991; 11: 127–32PubMedCrossRefGoogle Scholar
  86. 86.
    Wharton RN, Perel JM, Dayton PG, et al. A potential clinical use for methylphenidate (Ritalin) with tricyclic antidepressants. Am J Psychiatry 1971; 127: 1619–25PubMedGoogle Scholar
  87. 87.
    Drimmer EJ, Gitlin MH, Gwirtsman HE. Desipramine and methylphenidate combination treatment for depression: case report. Am J Psychiatry 1983; 142(2): 241–3Google Scholar
  88. 88.
    Gwirtsman HE, Szuba MP, Toren L, et al. The antidepressant response to tricyclics in major depressives is accelerated with adjunctive use of methylphenidate. Psychopharmacol Bull 1994; 30(2): 157–64PubMedGoogle Scholar
  89. 89.
    Linet LS. Treatment of refractory depression with a combination of fluoxetine and d-amphetamine. Am J Psychiatry 1989; 146(6): 803–4PubMedGoogle Scholar
  90. 90.
    Nelson JC. The use of antipsychotic drugs in the treatment of depression. In: Zohar J, Belmaker RH, editors. Treating resistant depression. New York: PMA Publishing, 1987: 131–46Google Scholar

Copyright information

© Adis International Limited 1995

Authors and Affiliations

  • Stephen T. H. Sokolov
    • 1
  • Russell T. Joffe
    • 1
  1. 1.Department of PsychiatryMcMaster UniversityHamiltonCanada
  2. 2.Mood Disorders ClinicHamilton Psychiatric HospitalHamiltonCanada

Personalised recommendations