Vol. 22, No. 4 / November 2010

Introduction

Rush University Medical Center, Chicago, Illinois 

The World Health Organization (WHO) estimates that major depression will be the leading cause of disability by the year 2020.¹ Based on data from the National Comorbidity Survey Replication, it is estimated that each year approximately 14 million adults in the United States experience a major depressive episode.² Further, only about half receive a proper diagnosis and less than half adequately benefit from existing first-line therapies (eg, psychotherapy; antidepressant medication).

Results from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study provide insight into several important issues clinicians struggle with in managing these patients.³ For example, the primary endpoint chosen by investigators of this landmark National Institute of Mental Health-sponsored trial was remission (ie, minimal to absent symptoms with treatment). The distinction between remission and response is crucial: response often leaves patients with substantial residual symptoms and is more likely to culminate in relapse or recurrence in the months after an acute treatment episode.⁴

Another important observation was that as the number of treatment trials required increased, the chances of achieving remission diminished, and the likelihood of discontinuing treatment because of adverse events increased steadily.⁵ Further, as the number of trials needed to achieve remission increased, the risk of relapse rose and the time to relapse shortened.⁵ In the second phase of STAR*D, switching or augmenting produced remission in only an additional 25% of patients who did not adequately benefit from an initial aggressive trial of citalopram.^6-8

What options are available to clinicians for patients with major depression who do not adequately benefit from standard initial treatments? Presently, if a patient is not adequately responsive to or cannot tolerate a first-line antidepressant trial (eg, selective serotonin reuptake inhibitor monotherapy), there are limited FDA-approved options—second-generation antipsychotic (SGA) augmentation or transcranial magnetic stimulation (TMS)—and several approaches supported by clinical studies and experience, such as switching to an alternate antidepressant or augmentation with a second antidepressant. Ironically, the two FDA-approved options were not included in STAR*D because at the time SGA augmentation was not a recognized viable approach and TMS was not yet clinically available.

The disappointing remission rates (approximately 25% to 30%) achieved in both the first and second phases of STAR*D, coupled with the substantial drop off in both the subsequent chances of remission and attenuated durability of effect, argue for an earlier consideration of SGA augmentation or TMS. In this context, the approved indication for TMS is in patients who fail one adequate antidepressant trial during the current episode. Although studies of aripiprazole, quetiapine, and olanzapine augmentation demonstrated efficacy, these agents carry substantial safety and tolerability concerns (eg, neuro-motor symptoms; weight and metabolic complications). By contrast, the efficacy and excellent safety and tolerability of TMS argue for its earlier introduction.^9,10 Presently, a variety of factors—such as cost, adverse effects with SGAs, and limited clinical experience with TMS—usually relegate these therapies to third- or fourth-line strategies in most treatment settings.

References

1. Moussavi S, Chatterji S, Verdes E, et al. Depression, chronic diseases, and decrements in health: results from the World Health Surveys. Lancet. 2007;370(9590):851–858.
2. Kessler RC, Berglund P, Demler O, et al, National Comorbidity Survey Replication. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA. 2003;289(23):3095–3105.
3. Gilmer WS, Kemp DE. STAR*D: What have we learned thus far? Int Drug Ther Newsl. 2006;41(10):75–82.
4. Zajecka JM. Treating depression to remission. J Clin Psychiatry. 2003;64(suppl 15):7–12.
5. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed out-patients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163: 1905–1917.
6. Rush AJ, Trivedi MH, Wisniewski SR, et al, the STAR*D Study Team. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med. 2006;354:1231–1242.
7. Trivedi MM, Fava M, Wisniewski SR, et al, the STAR*D Study Team. Medication augmentation after the failure of SSRIs for depression. N Engl J Med. 2006;354(12):1243–1252.
8. Thase ME, Friedman ES, Biggs MM, et al. Cognitive therapy versus medication in augmentation and switch strategies as second-step treatments: a STAR*D report. Am J Psychiatry. 2007;164:739–752.
9. Janicak PG, O’Reardon JP, Sampson SM, et al. Transcranial magnetic stimulation in the treatment of major depressive disorder: a comprehensive summary of safety experience from acute exposure, extended exposure, and during reintroduction treatment. J Clin Psychiatry. 2008;69: 222–232.
10. Janicak PG, Marder S, Pavuluri M. Principles and Practice of Psychopharmacotherapy. 5^th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2011 (in press):324.

Dr. Janicak receives research/grant support from and is consultant to and speaker for Bristol-Myers Squibb/Otsuka and Neuronetics, Inc.

Annals of Clinical Psychiatry ©2010 Quadrant HealthCom Inc.