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May 24, 2019

Evolving Issues in the Treatment of Depression

Author Affiliations
  • 1Psychosis Research Unit, Aarhus University Hospital–Psychiatry, Aarhus, Denmark
  • 2Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark
  • 3Depression Clinic and Research Program, Department of Psychiatry, Massachusetts General Hospital, Boston
  • 4Harvard Medical School, Boston, Massachusetts
  • 5Dauten Family Center for Bipolar Treatment Innovation, Department of Psychiatry, Massachusetts General Hospital, Boston
JAMA. 2019;321(24):2401-2402. doi:10.1001/jama.2019.4990

Major depressive disorder (MDD) has a lifetime incidence of 10% to 15%.1 The main treatment options include pharmacological and psychological interventions, with many patients receiving combination treatment. Although randomized clinical trials (RCTs) have established the efficacy of antidepressants,2 acute and long-term effectiveness is limited, and one-third of patients develop treatment resistance. New interventions are needed in the field and this Viewpoint examines novel interventions, with a specific focus on exercise, nutrition, and ketamine.

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    3 Comments for this article
    Missing Pillar of Mental Health - Sleep
    Jeffrey Durmer |
    Numerous studies demonstrate the impact of treating common sleep disorders like insomnia and obstructive sleep apnea on mental health, and specifically on mood. Of note, recent large scale online CBTi investigations demonstrate the benefits of treating insomnia (1,2) and obstructive sleep apnea (3) on multiple mental health outcomes. Of course, the "chicken and egg" argument persists regarding cause and effect, however, the same could be said for exercise and nutrition. In addition, since sleep is well known to be impacted by both exercise and nutrition, it may be that the benefits in terms of depression symptoms seen with these approaches is primarily due to improvements in sleep. Unfortunately, most large-scale studies omit measures of sleep, which limits our understanding of this very important and often overlooked element of health and wellbeing.


    1. Freeman D et al., The effects of improving sleep on mental health (OAISI): a randomised controlled trial with mediation analysis. Lancet Psych, 2017;4:749-58.

    2. Vedaa Q et al., Long-term effects of an unguided online cognitive behavioral therapy for chronic insomnia. J Clin Sleep Med, 2019;15(1):101-10.

    3. Edwards C et al., Depressive symptoms before and after treatment of obstructive sleep apnea in men and women. J Clin Sleep Med, 2015;11(9):1029-38.
    CONFLICT OF INTEREST: Chief Medical Officer for FusionHealth, a workflow-enabled population sleep healthcare company
    Pathophysiology Understanding is Paramount.
    Edoardo Cervoni, M.D. | Locumdoctor4u Ltd.
    Depression may be the leading cause of disability worldwide, but its pathophysiology is poorly understood. Perhaps unsurprisingly, current management strategies remain sub-optimal. We should know far more about brain changes produced by this disorder and its treatment and how the central nervous system produces neuroplasticity to orchestrate adaptive defensive behaviours. My opinion is that different roots to depression may be identified.
    What is Major Depressive Disorder?
    Ole Thienhaus, MD | University of Arizona College of Medicine Tucson
    The authors competently summarize the support for novel therapies for major depressive disorder (MDD), but neglect to address the critical epistemological conundrum: What is MDD? In 1850, if we had asked for best treatments for dropsy, foxglove preparations would have scored highly on effectiveness if only for less than half the cases. This would have changed only after the syndrome of congestive heart failure would have been introduced as a criterion for assessing treatment response. Today, most treatment studies for MDD indicate some 20 to 30% superiority over placebo -- an efficacy claim that would sink probably any antihypertensive or antibiotic medication. Even so, as clinicians, we have experiential data suggesting excellent responses in anecdotal cases. I propose that the solution to such inconsistency lies in our purely phenomenologic definition of MDD. Unless we have a sound pathophysiologic understanding of a disease we claim to treat, we should be very careful about evaluating comparative treatment effectiveness.