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Managing Partial Response or Nonresponse: Switching, Augmentation, and Combination Strategies for Major Depressive Disorder

J Clin Psychiatry 2009;70(suppl 6):16-25
10.4088/JCP.8133su1c.03

Despite the multitude of agents approved for the treatment of major depressive disorder, approximately 50% of patients experience no response to treatment with a first-line antidepressant. Clinicians have4 broad pharmacologic strategies to choose from for treating antidepressant non responders: increasing the dose of the antidepressant, switching to a different antidepressant, augmenting the treatment regimen with a non antidepressant agent, and combining the original antidepressant with a second antidepressant. To date, the most comprehensively studied treatment strategy for non response or partial response to antidepressants is augmentation with atypical antipsychotic agents, including aripiprazole, olanzapine, quetiapine, andrisperidone. However, augmentation or combination with other agentssuch as mirtazapine, mianserin, and omega-3 fatty acids is alsosupported by considerable efficacy data. Lithium, desipramine, triiodothyronine, and modafinil have mixed data. While more studies areneeded, agents such as bupropion, desipramine, mecamylamine, and testosterone look promising. Switching antidepressants, especially tothe newer agents, including selective serotonin reuptake inhibitors,bupropion, mirtazapine, and venlafaxine, is also supported by considerable efficacy data. Clinicians should carefully reevaluate patients with major depressive disorder who are nonresponders to treatment, particularly those who have had several adequate trials.When choosing the best treatment strategy for antidepressant nonresponders, clinicians should take into account the efficacy andtolerability of treatment as well as patient preference and treatment history. Finally, the risk of potential loss of partial therapeutic benefit from the first-line antidepressant, as well as the risk of withdrawal symptoms, should be taken into account when considering switching antidepressants, while the risk of drug interactions and poor adherence should be taken into account when considering combination and augmentation treatments.


From the Department of Psychiatry, Harvard Medical School and Massachusetts General Hospital, Boston.

This article is derived from the planning teleconference series “Tackling Partial Remission to Depression Treatment,” which was held in March and April 2009 and supported by an educational grant from Bristol-Myers Squibb Company and Otsuka America Pharmaceutical, Inc.

Lifetime financial disclosure as of September 23, 2009: Dr Papakostas has served as an advisor/consultant for AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Eli Lilly, Evotec, Inflabloc, Jazz, Shire, Otsuka, Pfizer, Pierre Fabre, Wyeth, and Pamlab; has received grant/research support from the National Institute of Mental Health, Pamlab, Pfizer, Forest, Ridge Diagnostics, and Bristol-Myers Squibb; has received honoraria from AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Eli Lilly, Evotec, Inflabloc, Jazz, Shire, Otsuka, Pierre Fabre, Pfizer, Pamlab, Titan, Wyeth, and Lundbeck; and has been a member of the speaker’s bureau for Bristol-Myers Squibb and Pfizer.

Corresponding author: George I. Papakostas, MD, Massachusetts General Hospital, 15 Parkman St WACC #812, Boston, MA 01224 (gpapakostas@partners.org).