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Reducing the Burden of Difficult-to-Treat Major Depressive Disorder: Revisiting Monoamine Oxidase Inhibitor Therapy

Larry Culpepper, MD, MPH

Published: October 31, 2013

Article Abstract

Objective: Difficult-to-treat depression (eg, depression with atypical or anxious symptoms, treatment-resistant depression, or depression with frequent recurrence) is a challenging real-world health issue. This critical review of the literature focuses on monoamine oxidase inhibitor (MAOI) therapy and difficult-to-treat forms of depression.

Data Sources: A PubMed literature search was performed in November 2012 and refreshed through January 2013 with no date restrictions using key search terms including MAO inhibitor therapy or MAOI and depression and anxiety, atypical, treatment-resistant, recurrent, relapse, or refractory.

Study Selection: Articles were selected to summarize the current needs in difficult-to-treat depression as well as the use of MAOI therapies in this area.

Results: Two strategies have fallen out of favor in the care of patients with major depressive disorder. The first is the use of MAOI therapy and the second is the proactive recognition of difficult-to-treat depression that may not respond as well to more frequently used antidepressants. The infrequent use of MAOIs stems from the perception that other oral therapies for depression are safer and easier to use than oral MAOIs; however, transdermal delivery is one potential strategy to improve the safety of this class of agents. Although food-related interactions with transdermal delivery of MAOI therapy can be lessened, clinicians still need to be vigilant for drug-drug interactions and serotonin syndrome.

Conclusions: Clinicians should consider MAOIs for patients who have had several unsuccessful trials of antidepressants. Guidelines generally reserve MAOIs as third- and fourth-line treatments due to concerns over safety and tolerability; however, transdermal delivery of an MAOI may allay some of the safety and tolerability concerns. Patients should be provided education about MAOIs and their risks.

Prim Care Companion CNS Disord 2013;15(5):doi:10.408/PCC.13r01515

Submitted: March 13, 2013; accepted July 22, 2013.

Published online: October 31, 2013.

Corresponding author: Larry Culpepper, MD, Department of Family Medicine, Boston University School of Medicine, Boston Medical Center, 1 Boston Medical Center Place,
Dowling 5, Boston, MA 02118 (

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