Approximately 32 to 35 million adults in the United States have an episode of major depression sometime during their lifetime, and many of them do not respond to initial treatment.1 The results of an analysis undertaken by Fava and Davidson2 suggest that between 29% and 46% of depressed patients fail to respond fully to antidepressant treatment of adequate dose and duration; about 15% of patients fail to respond to multiple treatment trials.3 Fagiolini and Kupfer4 have suggested that patients with treatment-resistant depression (TRD) may represent a biologically unique subtype of depressed patients. Unfortunately, the chances for full recovery diminish the longer a patient remains depressed—a fact that lends a sense of urgency for appropriate therapy.5
Before discussing the effectiveness of individual agents in TRD, it is important to review recent evidence regarding the principles of using these agents to maximize the chance of a response.6-9 Some of the most salient findings from the STAR*D trial on this topic are summarized in Table 1.
The standard strategy for managing patients who are depressed includes an adequate clinical trial; when the response is unsatisfactory, the clinician’s options are:
• Switch to another antidepressant
• Combine a second antidepressant with the first
• Add a second drug that is not approved as an antidepressant
• Start psychotherapy
Antidepressants can be grouped into 6 major categories: tricyclic antidepressants (TCAs), SSRIs, serotonin norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), serotonin neurotransmitter (5-HT2)-receptor antagonists (eg, nefazodone, trazodone), and novel agents (eg, mirtazapine, bupropion). If a patient fails to respond to one antidepressant class, it makes sense (at least conceptually) to switch to another, although most guidelines acknowledge that 2 failed trials of SSRIs may be justifiable before switching classes.7,8 When examining switching studies, be certain that the reason for switching was a failure to respond to an adequate antidepressant trial rather than a lack of tolerability, as these are fundamentally different issues.
The concept of switching classes of antidepressants is only as valid as the theoretical basis by which the antidepressants are grouped. As noted, some treatment guidelines allow 2 SSRI trials before switching classes. For example, in a study by Thase and colleagues,10 58 patients failed
a trial of fluoxetine; however, there was a 76% response rate to citalopram among completers. Although this study was not blinded, it is interesting that citalopram (which is believed to be the most selective of the SSRIs) was effective when another SSRI was not. It is hoped that as our knowledge of the mechanism of action of antidepressants grows more sophisticated, methods of classifying these agents will evolve to better guide clinicians in switching and combination strategies.
The clinical trial data on switching are surprisingly sparse—a recent meta-analysis identified only 4 randomized controlled trials.11 These trials include data from level 2 of the STAR*D study in which patients who were switched from citalopram to sertraline, venlafaxine XR, or bupropion SR showed remission rates of 27%, 25%, and 26% (respectively) based on the Quick Inventory of Depressive Symptomatology, Self-Report (QIDS-SR-16).12 The meta-analysis found a modest but statistically significant advantage in switching from SSRIs to non-SSRIs. Of the 5 comparisons, 3 used venlafaxine, which is predominately a serotonergic agent (the serotonin-norepinephrine Ki ratio is 30), although it is classified as an SNRI. This may account for the relative lack of separation. One wonders if duloxetine, with a Ki ratio of 9 and relatively greater noradrenergic potency, might show greater separation.13 However, only one open-label switching study with duloxetine has been published to date.14
In switching antidepressants, 2 pharmacokinetic issues are important:
• Drugs with potent cytochrome P-450 (CYP450) effects—particularly fluoxetine (because of its long half-life)—may produce toxic levels of medications taken concurrently, such as TCAs that are also metabolized by these systems. (This effect is even more of an issue with combinations.)
• Antidepressants that are associated with discontinuation symptoms (eg, paroxetine, venlafaxine, duloxetine) may produce discontinuation syndromes when stopped that can be erroneously attributed to adverse effects of the new drug, particularly if the new drug does not possess a significant degree of serotonin reuptake inhibition.
Drugs Mentioned in This Article
Agomelatine (Valdoxan, Melitor)
Bupropion (Wellbutrin, Zyban)
Bupropion SR (Wellbutrin SR)
Carbamazepine (Carbatrol, Tegretol, others)
Desipramine (Norpramin; Pertofrane)
Dexamethasone (Decadron, others)
Fluoxetine (Prozac, Sarafem)
Folic acid (Folacin, Folate, Pteroylglutamic acid, Vitamin B9)
Lithium (Eskalith, Lithane, Lithobid)
Omega-3-acid ethyl esters (Lovaza)
Selegiline (Emsam, Atrapryl, Carbex, others)
Valproate/valproic acid (Depakote, others)
1. Kessler RC, Berglund P, Demler O, et al. The epidemiology of major depressive disorder. results from the National Comorbidity Survey replication (NCS-R). JAMA. 2003:289:3095-3105.
2. Fava M, Davidson KG. Definition and epidemiology of treatment-resistant depression. Psychiatr Clin North Am. 1996;19:179-200.
3. Berlim MT, Turecki G. Definition, assessment and staging of treatment-resistant refractory major depression: a review of current concepts and methods. Can J Psychiatry. 2007;52:46-54.
4. Fagiolini A, Kupfer DJ. Is treatment-resistant depression a unique subtype of depression? Biol Psychiatry. 2003;53:640-648.
5. Keller MB, Shapiro RW, Lavori PW, Wolfe N. Recovery in major depression disorder: analysis with the life table and regression models. Arch Gen Psychiatry. 1982;39:905-910.
6. Bauer M, Bschor T, Pfennig A, et al. World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Unipolar Depressive Disorders in Primary Care. World J Biol Psychiatry. 2007;8:67-104.
7. Crismon ML, Trivedi M, Pigott TA, et al. The Texas Medication Algorithm Project: report of the Texas Consensus Conference Panel on Medication Treatment of Major Depressive Disorder. J Clin Psychiatry. 1999;60:142-156.
8. Kennedy SH, Lam RW, Cohen NL, et al. Clinical guidelines for the treatment of depressive disorders IV. Medications and other biological treatments. Can J Psychiatry. 2001;46(suppl 1):38S-58S.
9. American Psychiatric Association. Practice guidelines for the treatment of patients with major depressive disorder (revision). Am J Psychiatry. 2000;157(4 suppl):1-45.
10. Thase ME, Feighner JP, Lydiard RB. Citalopram treatment of fluoxetine nonresponders. J Clin Psychiatry. 2001;62:683-687.
11. Papakostas GI, Fava M, Thase ME. Treatment of SSRI-resistant depression: A meta-analysis comparing within- versus across-class switches. Biol Psychiatry. 2008;63:699-704.
12. Rush AJ, Trivedi MH, Wisniewski SR, et al. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med. 2006;354:1231-1242.
13. Koch S, Hemrick-Luecke SK, Thompson LK, et al. Comparison of effects of dual transporter inhibitors on monoamine transporters and extracellular levels in rats. Neuropharmacology. 2003;45:935-944.
14. Karp JF, Whyte EM, Lenze EJ, et al. Rescue pharmacotherapy with duloxetine for selective serotonin reuptake inhibitor nonresponders in late-life depression: outcome and tolerability. J Clin Psychiatry. 2008;69:457-463.
15. Norman TR, Burrows GD. Emerging treatments for major depression. Expert Rev Neurotherapeutics. 2007;7:203-213.
16. Overstreet DH, Stemmelin J, Griebel G. Confirmation of antidepressant potential of the selective b3 adrenoreceptor agonist amibegron in an animal model of depression. Pharmacol Biochem Behav. 2008; 89:623-626.
17. Tsai SJ. Sipatrigine could have therapeutic potential for major depression and bipolar depression through antagonism of the two-pore-domain K+ channel TREK-1. Med Hypotheses. 2008;70:548-550.
18. Krishnan V, Nestler EJ. The molecular neurobiology of depression. Nature. 2008;455:894-902.
19. Maeng S, Zarate CA Jr, Du J, et al. Cellular mechanisms underlying the antidepressant effects of ke-tamine: role of a-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptors. Biol Psychiatry. 2008;63:349-352.
20. Skolnick P. AMPA receptors: a target for novel antidepressants? Biol Psychiatry. 2008:63:347-348.
21. Zarate CA, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-d-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63:856-864.
22. Ferguson JM, Shingleton RN. An open-label, flexible-dose study of memantine in major depressive disorder. Clin Neuropharmacolgy. 2007;30:136-144.
23. Muhonen LH, Lönngvist J, Juva K, Alho H. Double-blind, randomized comparison of memantine and escitalopram for the treatment of major depressive disorder comorbid with alcohol dependence. J Clin Psychiatry. 2008;69:392-399.
24. Zarate CA, Singh JB, Quiroz JA, et al. A double-blind placebo-controlled study of memantine in the treatment of major depression. Am J Psychiatry. 2006;163:153-155.
25. Berlim MT, Fleck MP, Turecki G. Current trends in the assessment and somatic treatment of resis-tant/refractory major depression: an overview. Ann Med. 2008:40:149-159.
26. Papkostas GI, Worthington JJ, Iosifescu DV, et al. The combination of duloxetine and bupropion for treatment-resistant major depressive disorder. Depress Anxiety. 2006;23:178-181.
27. Lam RW, Hossie H, Solomons K, Yatham LN. Citalopram and bupropion SR: combining versus switching in patients with treatment-resistant depression. J Clin Psychiatry. 2004;65:337-340.
28. Barowsky J, Schwartz TL. Part 1: An evidence-based approach to augmentation and combination strategies for treatment-resistant depression. Psychiatry 2008. 2006;3:42-61.
29. Carvalho AF, Cavalcante JL, Castelo MS, Lima MC. Augmentation strategies for treatment-resistant depression: a literature review. J Clin Pharm Ther. 2007;32:415-428.
30. DeBattista C, Lembke A. Update on augmentation of antidepressant response in resistant depression. Curr Psychiatry Rep. 2005;7:435-440.
31. Nierenberg AA, Katz J, Fava M. A critical overview of the pharmacologic management of treatment-resistant depression. Psychiatr Clin North Am. 2007;30:13-29.
32. Thase ME. Pharmacologic strategies for treatment-resistant depression. Psychiatr Ann. 2005;35: 970-978.
33. Fava M, Alpert J, Nierenberg A, et al. Double-blind study of high-dose fluoxetine versus lithium or desipramine augmentation of fluoxetine in partial responders and nonresponders to fluoxetine. J Clin Psychopharmacol. 2002;22:379-387.
34. Crossley NA, Bauer M. Acceleration and augmentation of antidepressants with lithium for depressive disorders: two meta-analyses of randomized, placebo-controlled trials. J Clin Psychiatry. 2007;68:935-940.
35. Gaynes BN, Rush AJ, Trivedi MH, et al. The STAR*D study: treating depression in the real world. Cleve Clin J Med. 2008;75:57-66.
36. Joffe RT, Sokolov ST. Thyroid hormone treatment of primary unipolar depression: a review. Int J Neuro-psychopharmacol. 2000;3:143-147.
37. Aronson R, Offman HJ, Joffe RT, Naylor CD. Triiodothyronine augmentation in the treatment of refractory depression. A meta-analysis. Arch Gen Psychiatry. 1996;53:842-848.
38. Papakostas GI, Shelton RC, Smith J, Fava M. Augmentation of antidepressants with atypical antipsychotics for treatment-resistant major depressive disorder: a meta-analysis. J Clin Psychiatry. 2007;68: 826-831.
39. Sokolski KN. Adjunctive aripiprazole for bupropion-resistant major depression. Ann Pharmacother. 2008;42:1124-1129.
40. Goforth HW, Carroll BT. Aripiprazole augmentation of tranylcypromine in treatment-resistant major depression. J Clin Psychopharmacol. 2007;27:216-217.
41. Schüle C, Baghai TC, Eser D, et al. Mirtazapine monontherapy versus combination therapy with mirtazapine and aripiprazole in depressed patients without psychotic features: a 4-week open-label parallel-group study. World J Biol Psychiatry. 2007;8:112-122.
42. Physicians’ Desk Reference. 61st ed. Montvale, NJ: Thompson PDR; 2007:1527-1529.
43. Schmidt AW, Lebel LA, Johnson CG, et al. The novel antipsychotic ziprasidone has a unique human receptor binding profile compared to other agents. Soc Neurosci Abstr. 1998;24:2177.
44. Stoll AL, Haura G. Tranylcypromine plus risperidone for treatment-refractory major depression. J Clin Psychopharmacol. 2000;20:495-496.
45. Azzaro AJ, Ziemniak J, Kemper E, et al. Selegiline transdermal system: an examination of the potential for CYP450-dependent pharmacokinetic interactions with 3 psychotropic medications. J Clin Pharmacol. 2007;47:146-158.
46. Barbee JG, Conrad EJ, Jamhour NJ. The effectiveness of olanzapine, risperidone, quetiapine, and ziprasidone as augmentation agents in treatment-resistant major depressive disorder. J Clin Psychiatry. 2004;65:975-981.
47. Barbee JG, Conrad EJ, Jamhour NJ. Aripiprazole augmentation in treatment-resistant depression. Ann Clin Psychiatry. 2004;16:189-194.
48. Schneider LS, Small GW, Clary CM. Estrogen replacement therapy and antidepressant response to sertraline in older depressed women. Am J Geriatr Psychiatry. 2001;9:393-399.
49. Pope HG Jr, Cohane GH, Kanayama G, et al. Testosterone gel supplementation for men with refractory depression. A randomized, placebo-controlled trial. Am J Psychiatry. 2003;160:105-111.
50. Levitan RD, Shen JH, Jindal R, et al. Preliminary randomized double-blind placebo-controlled trial of tryptophan combined with fluoxetine to treat major depressive disorder: antidepressant and hypnotic effects. J Psychiatry Neurosci. 2000;25:337-346.
51. Nemets B, Stahl Z, Belmaker RH. Addition of omega-3 fatty acid to maintenance medication treatment for recurrent unipolar depressive disorder. Am J Psychiatry. 2002;159:477-479.
52. Appelberg BG, Syvälahti EK, Koskinen TE, et al. Patients with severe depression may benefit from buspirone augmentation of selective serotonin reuptake inhibitors: results from a placebo-controlled, randomized, double-blind, placebo wash-in study. J Clin Psychiatry. 2001;62:448-452.
53. Landén M, Björling G, Agren H, Fahlén T. A randomized, double-blind placebo-controlled trial of buspirone in combination with an SSRI in patients with treatment-refractory depression. J Clin Psychiatry. 1998;59:664-668.
54. Trivedi MH, Fava M, Wisniewski SR, et al. Medication augmentation after the failure of SSRIs for depression. N Eng J Med. 2006;354:1243-1252.
55. Barbee JG, Jamhour NJ, Stewart JS, et al. La-motrigine as an antidepressant augmentation agent in treatment refractory unipolar depression. Presented at: Annual Meeting of the American Psychiatric Association; May 19-24, 2007; San Diego.
56. DeBattista C, Doghramji K, Menza MA, et al. Adjunct modafinil for the short-term treatment of fatigue and sleepiness in patients with major depressive disorder: a preliminary double-blind, placebo-controlled study. J Clin Psychiatry. 2003;64:1057-1064.
57. Fava M, Thase ME, DeBattista C. A multicenter, placebo-controlled study of modafanil augmentation in partial responders to selective serotonin reuptake inhibitors with persistent fatigue and sleepiness. J Clin Psychiatry. 2005;66:85-93.
58. Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluations of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry. 2006;163:28-40.
59. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163:1905-1917.
60. Fava M, Rush AJ, Alpert JE, et al. Difference in treatment outcomes in outpatients with anxious versus nonanxious depression: a STAR*D report. Am J Psychiatry. 2008;165:342-351.
61. Zarate CA Jr, Payne JL, Quiroz J, et al. An open-label trial of riluzole in patients with treatment-resis-tant major depression. Am J Psychiatry. 2004;161: 171-174.
62. Binneman B, Feltner D, Kolluri S, et al. A 6-week randomized placebo-controlled trial of CP-316, 311 (a selective CRH1 antagonist) in the treatment of major depression. Am J Psychiatry. 2008;165:617-620.
63. Berman RM, Marcus RN, Swanink R, et al. The efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder: a multicenter, randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2007;68:843-853.
64. Marcus RN, McQuade RD, Carson WH, et al. The efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder. A second multicenter, randomized, double-blind placebo-controlled study. J Clin Psychopharmacol. 2008;28:156-165.
65. Mahmoud RA, Pandina GJ, Turkoz I, et al. Risperidone for treatment-refractory major depressive disorder. A randomized trial. Ann Intern Med. 2007;147: 593-602.
66. Dunner DL, Amsterdam JD, Shelton RC, et al. Efficacy and tolerability of adjunctive ziprasidone in treatment-resistant depression: a randomized, open-label, pilot study. J Clin Psychiatry. 2007;68:1071-1077.
67. Pilhatsch MK, Burghardt R, Wandinger KP, et al. Augmentation with atomoxetine in treatment-resis-tant depression with psychotic features. A case report. Pharmacopsychiatry. 2006;39:79-80.
68. Carpenter LL, Milosavljevic N, Schechter JM, et al. Augmentation with open-label atomoxetine for partial or nonresponse to antidepressants. J Clin Psychiatry. 2005;66:1234-1238.
69. Sanacora G, Kendell SF, Levin Y, et al. Preliminary evidence of riluzole efficacy in antidepressant-treated patients with residual depressive symptoms. Biol Psychiatry. 2007;61:822-825.
70. Müller N, Schwarz MJ, Dehning S, et al. The cyclooxygenase—2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine. Mol Psychiatry. 2006;11:680-684.
71. Roitman S, Green T, Osher Y, et al. Creatine monohydrate in resistant depression: a preliminary study. Bipolar Disord. 2007;9:754-758.
Barowsky J, Schwartz TL. Part 1: An evidence-based approach to augmentation and combination strategies for treatment-resistant depression. Psychiatry 2008. 2006;3:42-61.
Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163:1905-1917.