Major depressive disorder (MDD) is a leading cause of disability in North America and in the world. For many patients with depression, full symptom remission remains elusive despite multiple trials of antidepressants. In the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, half of patients responded to an initial antidepressant trial, whereas a third of patients never achieved remission despite multiple adequate antidepressant trials.1 As every clinician knows, these outcomes are in-adequate.
For patients who do not respond to initial pharmacological treatment, several options exist. For the purposes of this article, we focus on psychopharmacological and related interventions. However, we recommend that all of these interventions occur in the context of a comprehensive treatment program that includes medications, psychotherapy, and other interventions.
Standard approaches to pharmacology include the optimization of the current treatment regimen and within-class or between-class switching. Before concluding that an antidepressant has failed, clinicians should ensure that adherence, dose, and duration are sufficient. An antidepressant trial should last at least 6 weeks and be at the minimum established clinically effective dose; some argue that a dose as high as two-thirds the maximum recommended dose is appropriate.
Antidepressant augmentation is another approach. Augmentation using an antidepressant with established efficacy may also be referred to as combination therapy. This may be more effective than other options, but it carries the risks of polypharmacy, such as drug-drug interactions and increased adverse-effect burden.
In this article, we briefly review the current options for pharmacological augmentation in MDD and their associated literature. Table 1 presents a summary of current augmentation strategies.
Traditional augmentation agents: STAR*D results
Lithium. Augmentation with lithium is one of the oldest strategies, and it is believed to work through the enhancement of serotonergic neurotransmission. Findings from 10 placebo-controlled trials of lithium augmentation (at dosages from 600 to 1200 mg/d, with serum levels of 0.5 to 1 mEq/L) indicate that lithium augmentation was more effective than placebo.2 One caveat with the lithium data is that the vast majority of these studies used a TCA as the principal antidepressant agent. Other limitations included variable lithium doses and outcome measures.
The evidence that exists for lithium augmentation of SSRIs is more sobering. Studies by Fava and colleagues3,4 showed no benefit of this augmentation compared with simply increasing the dose of the primary antidepressant. Additional factors to review when considering lithium augmentation are adverse effects, potential toxicity, and need for serum monitoring. Notably, in STAR*D, when lithium augmentation was compared with thyroid hormone augmentation, the two approaches were equally efficacious, but lithium had a higher adverse-effect burden.5
Thyroid hormone. Thyroid hormone augmentation, typically with triidothyronine (T3) but sometimes with thyroxine, is hypothesized to work by enhancing noradrenergic neurotransmission or correcting a brain bioenergetic deficiency. At a target dosage of 50 μg/d, treatment tends to be well tolerated with few adverse effects. As with lithium, much of the data on T3 augmentation involves TCAs rather than SSRIs.
Dr Warner is House Staff Officer in Psychiatry in the department of psychiatry and human behavior and Dr Philip is Assistant Professor of Psychiatry and Human Behavior, both at the Alpert Medical School of Brown University in Providence, RI. Dr Warner reports that she has no conflicts of interest concerning the subject matter of this article. Dr Philip reports that he has received research support from Neuronetics Inc and NeoSync Inc through contracts with Butler Hospital in Providence, RI.
1. Gaynes BN, Warden D, Trivedi MH, et al. What did STAR*D teach us? Results from a large-scale, practical, clinical trial for patients with depression. Psychiatr Serv. 2009;60:1439-1445.
2. 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.
3. 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;151:1372-1374.
4. 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.
5. Nierenberg AA, Fava M, Trivedi MH, et al. A comparison of lithium and T(3) augmentation following two failed medication treatments for depression: a STAR*D report. Am J Psychiatry. 2006;163:1519-1530; quiz 1665.
6. Cooper-Kazaz R, Apter JT, Cohen R, et al. Combined treatment with sertraline and liothyronine in major depression: a randomized, double-blind, placebo-controlled trial. Arch Gen Psychiatry. 2007;64:679-688.
7. Posternak M, Novak S, Stern R, et al. A pilot effectiveness study: placebo-controlled trial of adjunctive L-triiodothyronine (T3) used to accelerate and potentiate the antidepressant response. Int J Neuropsychopharmacol. 2008;11:15-25.
8. Appelhof BC, Brouwer JP, van Dyck R, et al. Triiodothyronine addition to paroxetine in the treatment of major depressive disorder. J Clin Endocrinol Metab. 2004;89:6271-6276.
9. Joffe RT, Sokolov ST, Levitt AJ. Lithium and triiodothyronine augmentation of antidepressants. Can J Psychiatry. 2006;51:791-793.
10. Iosifescu DV, Nierenberg AA, Mischoulon D, et al. An open study of triiodothyronine augmentation of selective serotonin reuptake inhibitors in treatment-resistant major depressive disorder. J Clin Psychiatry. 2005;66:1038-1042.
11. Abraham G, Milev R, Stuart Lawson J. T3 augmentation of SSRI resistant depression. J Affect Disord. 2006;91:211-215.
12. Kelly TF, Lieberman DZ. Long term augmentation with T3 in refractory major depression. J Affect Disord. 2009;115:230-233.
13. 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.
14. Trivedi MH, Fava M, Wisniewski SR, et al; STAR*D Study Team. Medication augmentation after the failure of SSRIs for depression. N Engl J Med. 2006;354:1243-1252.
15. Carpenter LL, Jocic Z, Hall JM, et al. Mirtazapine augmentation in the treatment of refractory depression. J Clin Psychiatry. 1999;60:45-49.
16. Carpenter LL, Yasmin S, Price LH. A double-blind, placebo-controlled study of antidepressant augmentation with mirtazapine. Biol Psychiatry. 2002;51:183-188.
17. Fava M, Rush AJ, Wisniewski SR, et al. A comparison of mirtazapine and nortriptyline following two consecutive failed medication treatments for depressed outpatients: a STAR*D report. Am J Psychiatry. 2006;163:1161-1172.
18. Mowla A, Kardeh E. Topiramate augmentation in patients with resistant major depressive disorder: a double-blind placebo-controlled clinical trial. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35:970-973.
19. Santos MA, Rocha FL, Hara C. Efficacy and safety of antidepressant augmentation with lamotrigine in patients with treatment-resistant depression: a randomized, placebo-controlled, double-blind study. Prim Care Companion J Clin Psychiatry. 2008;10:187-190.
20. Barbosa L, Berk M, Vorster M. A double-blind, randomized, placebo-controlled trial of augmentation with lamotrigine or placebo in patients concomitantly treated with fluoxetine for resistant major depressive episodes. J Clin Psychiatry. 2003;64:403-407.
21. Barbee JG, Thompson TR, Jamhour NJ, et al. A double-blind placebo-controlled trial of lamotrigine as an antidepressant augmentation agent in treatment-refractory unipolar depression. J Clin Psychiatry. 2011;72:1405-1412.
22. Patkar AA, Masand PS, Pae CU, et al. A randomized, double-blind, placebo-controlled trial of augmentation with an extended release formulation of methylphenidate in outpatients with treatment-resistant depression. J Clin Psychopharmacol. 2006;26:653-656.
23. Ravindran AV, Kennedy SH, O’Donovan MC, et al. Osmotic-release oral system methylphenidate augmentation of antidepressant monotherapy in major depressive disorder: results of a double-blind, randomized, placebo-controlled trial. J Clin Psychiatry. 2008;69:87-94.
24. Dunlop BW, Crits-Christoph P, Evans DL, et al. Coadministration of modafinil and a selective serotonin reuptake inhibitor from the initiation of treatment of major depressive disorder with fatigue and sleepiness: a double-blind, placebo-controlled study. J Clin Psychopharmacol. 2007;27:614-619.
25. Fava M, Thase ME, DeBattista C. A multicenter, placebo-controlled study of modafinil augmentation in partial responders to selective serotonin reuptake inhibitors with persistent fatigue and sleepiness. J Clin Psychiatry. 2005;66:85-93.
26. Michelson D, Adler LA, Amsterdam JD, et al. Addition of atomoxetine for depression incompletely responsive to sertraline: a randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2007;68:582-587.
27. Pérez V, Gilaberte I, Faries D, et al. Randomised, double-blind, placebo-controlled trial of pindolol in combination with fluoxetine antidepressant treatment. Lancet. 1997;349:1594-1597.
28. Sokolski KN, Conney JC, Brown BJ, DeMet EM. Once-daily high-dose pindolol for SSRI-refractory depression. Psychiatry Res. 2004;125:81-86.
29. Pérez V, Soler J, Puigdemont D, et al. A double-blind, randomized, placebo-controlled trial of pindolol augmentation in depressive patients resistant to serotonin reuptake inhibitors. Grup de Recerca en Trastorns Afectius. Arch Gen Psychiatry. 1999;56:375-379.
30. Perry EB, Berman RM, Sanacora G, et al. Pindolol augmentation in depressed patients resistant to selective serotonin reuptake inhibitors: a double-blind, randomized, controlled trial. J Clin Psychiatry. 2004;65:238-243.
31. Geretsegger C, Bitterlich W, Stelzig R, et al. Paroxetine with pindolol augmentation: a double-blind, randomized, placebo-controlled study in depressed in-patients. Eur Neuropsychopharmacol. 2008;18:141-146.
32. 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.
33. Orengo CA, Fullerton L, Kunik ME. Safety and efficacy of testosterone gel 1% augmentation in depressed men with partial response to antidepressant therapy. J Geriatr Psychiatry Neurol. 2005;18:20-24.
34. Seidman SN, Rabkin JG. Testosterone replacement therapy for hypogonadal men with SSRI-refractory depression. J Affect Disord. 1998;48:157-161.
35. Rasgon NL, Altshuler LL, Fairbanks LA, et al. Estrogen replacement therapy in the treatment of major depressive disorder in perimenopausal women. J Clin Psychiatry. 2002;63(suppl 7):45-48.
36. Morgan ML, Cook IA, Rapkin AJ, Leuchter AF. Estrogen augmentation of antidepressants in perimenopausal depression: a pilot study. J Clin Psychiatry. 2005;66:774-780.
37. Dias RS, Kerr-Corrêa F, Moreno RA, et al. Efficacy of hormone therapy with and without methyltestosterone augmentation of venlafaxine in the treatment of postmenopausal depression: a double-blind controlled pilot study. Menopause. 2006;13:202-211.
38. Nelson JC, Papakostas GI. Atypical antipsychotic augmentation in major depressive disorder: a meta-analysis of placebo-controlled randomized trials. Am J Psychiatry. 2009;166:980-991.
39. Gao K, Kemp DE, Fein E, et al. Number needed to treat to harm for discontinuation due to adverse events in the treatment of bipolar depression, major depressive disorder, and generalized anxiety disorder with atypical antipsychotics. J Clin Psychiatry. 2011;72:1063-1071.
40. El-Khalili N, Joyce M, Atkinson S, et al. Extended-release quetiapine fumarate (quetiapine XR) as adjunctive therapy in major depressive disorder (MDD) in patients with an inadequate response to ongoing antidepressant treatment: a multicentre, randomized, double-blind, placebo-controlled study. Int J Neuropsychopharmacol. 2010;13:917-932.
41. Bauer M, Pretorius HW, Constant EL, et al. Extended-release quetiapine as adjunct to an antidepressant in patients with major depressive disorder: results of a randomized, placebo-controlled, double-blind study. J Clin Psychiatry. 2009;70:540-549.
42. Bauer M, El-Khalili N, Datto C, et al. A pooled analysis of two randomised, placebo-controlled studies of extended release quetiapine fumarate adjunctive to antidepressant therapy in patients with major depressive disorder. J Affect Disord. 2010;127:19-30.
43. Philip NS, Carpenter LL, Tyrka AR, Price LH. Augmentation of antidepressants with atypical antipsychotics: a review of the current literature. J Psychiatr Pract. 2008;14:34-44.
44. Lin PY, Su KP. A meta-analytic review of double-blind, placebo-controlled trials of antidepressant efficacy of omega-3 fatty acids. J Clin Psychiatry. 2007;68:1056-1061.
45. Gertsik L, Poland RE, Bresee C, Rapaport MH. Omega-3 fatty acid augmentation of citalopram treatment for patients with major depressive disorder. J Clin Psychopharmacol. 2012;32:61-64.
46. Lyoo IK, Yoon S, Kim TS, et al. A randomized, double-blind placebo-controlled trial of oral creatine monohydrate augmentation for enhanced response to a selective serotonin reuptake inhibitor in women with major depressive disorder. Am J Psychiatry. 2012;169:937-945.
47. Papakostas GI, Mischoulon D, Shyu I, et al. S-adenosyl methionine (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant nonresponders with major depressive disorder: a double-blind, randomized clinical trial. Am J Psychiatry. 2010;167:942-948.
48. Papakostas GI, Shelton RC, Zajecka JM, et al. L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials. Am J Psychiatry. 2012;169:1267-1274.
49. Lattanzi L, Dell’Osso L, Cassano P, et al. Pramipexole in treatment-resistant depression: a 16-week naturalistic study. Bipolar Disord. 2002;4:307-314.
50. Inoue T, Kitaichi Y, Masui T, et al. Pramipexole for stage 2 treatment-resistant major depression: an open study. Prog Neuropsychopharmacol Biol Psychiatry. 2010;34:1446-1449.
51. Hori H, Kunugi H. The efficacy of pramipexole, a dopamine receptor agonist, as an adjunctive treatment in treatment-resistant depression: an open-label trial. Scientific World Journal. 2012;2012:372474.
52. Franco-Chaves JA, Mateus CF, Luckenbaugh DA, et al. Combining a dopamine agonist and selective serotonin reuptake inhibitor for the treatment of depression: a double-blind, randomized pilot study. J Affect Disord. 2013;149:319-325.
53. Zarate CA Jr, 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.
54. Zarate CA Jr, 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.
55. Sanacora G, Kendell SF, Levin Y, et al. Prelim-inary evidence of riluzole efficacy in antidepressant-treated patients with residual depressive symptoms. Biol Psychiatry. 2007;61:822-825.
56. Berlim MT, Van den Eynde F, Daskalakis ZJ. High-frequency repetitive transcranial magnetic stimulation accelerates and enhances the clinical response to antidepressants in major depression: a meta-analy-sis of randomized, double-blind and sham-controlled trials. J Clin Psychiatry. 2013;74:e122-e129.
57. Brunoni AR, Valiengo L, Baccaro A, et al. The sertraline vs. electrical current therapy for treating depression clinical study: results from a factorial, randomized, controlled trial. JAMA Psychiatry. 2013;70:383-391.