Despite the progressive increase in the number of available antidepressants, many patients with depression continue to be symptomatic. For example, it was reported recently that as many as half of the patients enrolled in 2 academic-based depression specialty clinics did not achieve remission despite receiving numerous antidepressant treatment trials.1 To complicate matters further, residual symptoms among remitters are common and are associated with poorer psychosocial functioning as well as increased relapse rates. In light of the challenge that treatment-resistant major depressive disorder (TRD) poses for clinicians and patients alike, there is an urgent need to develop novel treatment strategies for resistant depression that are safer and more effective than those currently in use.
In 2006, there have been two areas of important development with regard to TRD: the Sequential Treatment Alternatives to Relieve Depression (STAR*D) trial and the use of the atypical antipsychotic agents as an adjunct to standard antidepressant treatment. In this article, I will provide an overview of the definition, prevalence, and staging of TRD and then discuss published findings from the STAR*D study as well as recent developments regarding the use of atypical antipsychotics in TRD.
Definition, prevalence, and staging of TRD
TRD typically refers to an inadequate response to at least one antidepressant trial of adequate dosage and duration in patients with unipolar depressive disorders. Adequate duration is often defined as a minimum of 6 weeks, stemming from the observation that fewer than 7% of patients who show little improvement following 6 weeks of treatment with fluoxetine eventually respond (ie, show a 50% decrease in symptom severity) following an additional 2 weeks of treatment.2 Although similar analyses of clinical trials of longer duration (12 weeks) have provided evidence that 6 weeks may be too short a duration to declare an antidepressant trial ineffective,3 it is important to remember that spontaneous remission can occur over time. The definition of adequate dosing varies widely from agent to agent, with values deriving from double-blind placebo-controlled trials or dose-comparator studies (ie, the lowest dosage at which efficacy was demonstrated in double-blind placebo-controlled trials).
Definitions of "adequate response" have varied throughout the past few decades, ranging from the more traditional view in which treatment resistance is defined as strict nonresponse (25% or less improvement in symptoms following treatment) to the broadest definition (failure to achieve full remission of the depressive episode). Nowadays, most experts agree for several reasons, that inadequate response is the failure to achieve full symptom remission.4 First of all, patients presenting with moderate to severe depression may still be quite symptomatic despite a 25% to 50% improvement in depressive symptoms. In addition, residual symptoms have been associated with poorer psychosocial functioning,5 as well as increased relapse rates.6 Finally, incomplete response (defined as a 25% or greater improvement in depressive symptoms while failing to achieve remission) appears to be more than twice as common as strict nonresponse in naturalistic treatment settings.7
In recent years, increasing attention has also been paid to developing methods to stage the degree of resistance in patients with unipolar depressive disorders. Thase and Rush8 first proposed a 5-stage model that provides a categoric assignment of degree of resistance. According to this model, failure of a trial of one major class of antidepressants constitutes stage 1 antidepressant resistance; failure of an additional antidepressant trial from a different class constitutes stage 2 resistance; failure of an additional tricyclic antidepressant (TCA) trial, stage 3 resistance; and failure of an additional monoamine oxidase inhibitor (MAOI) trial, stage 4 resistance. Failing a trial of electroconvulsive therapy (ECT) in addition to those treatments cited in stages 1 through 4 has been defined as stage 5 treatment resistance, according to this model.
Several methodologic issues have been raised concerning these stages: (1) that the degree of intensity of each trial in terms of dosing and duration is not accounted for, (2) that the model assumes that depression that does not respond to 2 agents of different classes is more difficult to treat than depression that fails to respond to 2 agents of the same class, and (3) that the role of augmentation or combination strategies is not considered. An additional limiting factor is the implicit hierarchy of treatments, with MAOIs considered superior to TCAs.
More recently, the Massachusetts General Hospital staging method was proposed.4 According to this model, nonresponse to each adequate trial increases the overall degree of resistance by 1 point, while optimization of dosage and duration, augmentation, or combination increases the degree of resistance by 0.5 points. ECT was proposed to increase the degree of resistance by 3 points according to this model. Recently, empiric testing of these 2 models with the use of outcome data from outpatients receiving treatment for depression in 1 of 2 hospital-based, academically affiliated depression specialty clinics revealed that, although highly correlated, the latter model demonstrated significantly greater ability to predict remission status than the Thase-Rush model did.7
1. Petersen T, Papakostas GI, Posternak MA. Empirical testing of two models for staging antidepressant treatment resistance. J Clin Psychopharmacol. 2005;25: 336-341.
2. Nierenberg AA, McLean NE, Alpert JE, et al. Early nonresponse to fluoxetine as a predictor of poor 8-week outcome. Am J Psychiatry. 1995;152:1500-1503.
3. Quitkin FM, Petkova E, McGrath PJ, et al. When should a trial of fluoxetine for major depression be declared failed? Am J Psychiatry. 2003;160:734-740.
4. Fava M. Diagnosis and definition of treatment-resistant depression. Biol Psychiatry. 2003;53:649-659.
5. Papakostas GI, Petersen T, Denninger JW, et al. Psychosocial functioning during the treatment of major depressive disorder with fluoxetine. J Clin Psychopharmacol. 2004;24:507-511.
6. Paykel ES, Ramana R, Cooper Z, et al. Residual symptoms after partial remission: an important outcome in depression. Psychol Med. 1995;25:1171-1180.
7. Petersen T, Papakostas GI, Posternak MA, et al. Empirical testing of two models for staging antidepressant treatment resistance. J Clin Psychopharmacol. 2005; 25:336-341.
8. Thase ME, Rush AJ. When at first you don't succeed: sequential strategies for antidepressant nonresponders. J Clin Psychiatry. 1997;58(suppl 13):23-29.
9. Fava M, Davidson KG. Definition and epidemiology of treatment-resistant depression. Psych Clin North Am. 1996;19:179-200.
10. Corey-Lisle PK, Nash R, Stang P, Swindle R. Response, partial response, and nonresponse in primary care treatment of depression. Arch Intern Med. 2004;164: 1197-1204.
11. Rush AJ, Trivedi M, Carmody TJ, et al. One-year clinical outcomes of depressed public sector outpatients: a benchmark for subsequent studies. Biol Psychiatry. 2004;56:46-53.
12. 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.
13. 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.
14. Ballesteros J, Callado LF. Effectiveness of pindolol plus serotonin uptake inhibitors in depression: a meta-analysis of early and late outcomes from randomised controlled trials. J Affect Disord. 2004;79:137-147.
15. Carpenter LL, Yasmin S, Price LH. A double-blind, placebo-controlled study of antidepressant augmen- tation with mirtazapine. Biol Psychiatry. 2002;51: 183-188.
16. Ferreri M, Lavergne F, Berlin I, et al. Benefits from mianserin augmentation of fluoxetine in patients with major depression non-responders to fluoxetine alone. Acta Psychiatr Scand. 2001;103:66-72.
17. 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.
18. Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry. 2006;163:28-40.
19. 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.
20. Trivedi MH, Fava M, Wisniewski SR, et al. Medication augmentation after the failure of SSRIs for depression. N Engl J Med. 2006;354:1243-1252.
21. 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.
22. Papakostas GI, Petersen TJ, Nierenberg AA, et al. Ziprasidone augmentation of selective serotonin reuptake inhibitors (SSRIs) for SSRI-resistant major depressive disorder. J Clin Psychiatry. 2004;65:217-221.
23. Papakostas GI. Augmentation of standard antidepressants with atypical antipsychotic agents for treatment-resistant major depressive disorder. Essent Psychopharmacol. 2005;6:209-220.
24. Papakostas GI, Petersen TJ, Kinrys G, et al. Aripiprazole augmentation of selective serotonin reuptake inhibitors for treatment-resistant major depressive disorder. J Clin Psychiatry. 2005;66:1326-1330.
25. Shelton RC, Tollefson GD, Tohen M, et al. A novel augmentation strategy for treating resistant major depression. Am J Psychiatry. 2001;158:131-134.
26. Sanjay Dube S, Andersen SW, Sanger TM, et al. Olanzapine-fluoxetine combination for psychotic major depression. Presented at: American Psychiatric Association Annual Meeting; May 18-23, 2002; Philadelphia.
27. Dube S, Andersen SW, Paul S, et al. Meta-analysis of olanzapine-fluoxetine in treatment-resistant depression. Presented at: American Psychiatric Association Annual Meeting; May 18-23, 2002; Philadelphia.
28. Thase ME, McCoy R, Chang W, Macfadden W. Efficacy of quetiapine monotherapy in bipolar depression: a confirmatory double-blind, placebo-controlled study (the BOLDER II study). Presented at: American Psychiatric Association Annual Meeting; May 20-25, 2006; Toronto.
29. Thase ME, Osuntokun O, Sanger T, et al. Olanzapine/fluoxetine combination, olanzapine, and fluoxetine in treatment-resistant major depressive disorder. Presented at: American Psychiatric Association Annual Meeting; May 20-25, 2006; Toronto.
30. Keitner GI, Garlow SJ, Ryan CE, et al. Risperidone augmentation for patients with difficult-to-treat major depression. Presented at: American Psychiatric Association Annual Meeting; May 20-25, 2006; Toronto.
31. Gharabawi G, Canuso C, Pandina G. A double-blind, placebo-controlled study of risperidone augmentation for major depressive disorder suboptimally responsive to antidepressant treatment. Presented at: Collegium Internationale Neuropsychopharmacologicum Meeting; July 9-13, 2006; Chicago.
32. McIntyre RS, Konarski JZ, Kennedy SH. Antidepressant effectiveness in primary-care settings. Presented at: American Psychiatric Association Annual Meeting; May 20-25, 2006; Toronto.
33. Khullar A, Chokka P, Fullerton D, et al. Quetiapine as treatment of non-psychotic unipolar depression with residual symptoms: double blind, randomized, placebo controlled study. Presented at: American Psychiatric Association Annual Meeting; May 20-25, 2006; Toronto.
34. Mattingly GW, Ilivicky HJ, Canale JP, Anderson RH. Quetiapine augmentation for treatment-resistant depression. Presented at: American Psychiatric Association Annual Meeting; May 20-25, 2006; Toronto.
35. Barbui C, Cipriani A, Brambilla P, Hotopf M. "Wish bias" in antidepressant drug trials? J Clin Psychopharmacol. 2004;24:126-130.
36. Perlis RH, Perlis CS, Wu Y, et al. Industry sponsorship and financial conflict of interest in the reporting of clinical trials in psychiatry. Am J Psychiatry. 2005; 162:1957-1960.
37. Healy D, Cattell D. Interface between authorship, industry and science in the domain of therapeutics. Br J Psychiatry. 2003;183:22-27.
38. Fountoulakis KN, Nimatoudis I, Iacovides A, Kaprinis G. Off-label indications for atypical antipsychotics: a systematic review. Ann Gen Hosp Psychiatry. 2004;3:4.
39. Shelton RC, Williamson DJ, Corya SA, et al. Olanzapine/fluoxetine combination for treatment-resistant depression: a controlled study of SSRI and nortriptyline resistance. J Clin Psychiatry. 2005;66:1289-1297.
40. Corya SA, Williamson D, Sanger TM, et al. A randomized, double-blind comparison of olanzapine/fluoxetine combination, olanzapine, fluoxetine, and venlafaxine in treatment-resistant depression. Depress Anxiety. 2006; May 18 [E-pub ahead of print].