In this masterclass, Charles L. Raison, MD, returns to the MDedge Psychcast to discuss the risks and benefits of antidepressants. He previously appeared on the Psychcast in episodes 15 and 16.

Dr. Raison is Mary Sue and Mike Shannon Chair for Healthy Minds, Children & Families and professor, School of Human Ecology, and professor, department of psychiatry, School of Medicine and Public Health, University of Wisconsin-Madison.

Later, Renee Kohanski, MD, discusses the need for psychiatrists to take care of and nourish their communities.

Show Notes by Jacqueline Posada, MD, consultation-liaison psychiatry fellow with the Inova Fairfax Hospital/George Washington University program in Falls Church, Va.

Treatment with antidepressants

• The STAR-D trial, a large effectiveness trial (n = 4,000), looked at the effect of SSRIs and other medications for the treatment of depression.
• As an effectiveness trial, STAR-D looked at “real” patients with comorbidities (as opposed to efficacy trials, which use “perfect patients” with no comorbidities to minimize confounding effects).
  • Only 30% of patients went into complete remission with first step of treatment with an SSRI (citalopram) at the highest tolerated dose.
  • Almost 50% experienced a response (a 50% reduction in symptoms of depression on standardized scale).

Cynicism and hope for antidepressants

• To obtain Food and Drug Administration approval, a medication requires two positive studies (showing that the drug beats placebo), and on average, an SSRI requires five to seven studies to get the two positive studies.
  • A meta-analysis of negative SSRI studies that were “filed away” found only a 1.8-point difference on Hamilton Depression Rating Scale score between SSRI vs placebo.
  • The difference between SSRI and placebo in treatment disappeared among patients who were less depressed.
• Geddes et al., presented a more balanced view in a published meta-analysis of 522 trials that included more than 100,000 patients.
  • Antidepressants had a modest benefit, compared with placebo.
  • In head-to-head studies, some antidepressants were better than others, such as amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine, and vortioxetine. 

Predictors of response

• Poor response to antidepressants: Presence of comorbid anxiety disorder, failure of first or subsequent antidepressant trials.
  • Within STAR-D, among those who failed three treatment steps, only 13% responded to the next treatment.
• Good response to antidepressants: An acute response to an antidepressant predicts long-term response.
  • A 20% or greater improvement within 2 weeks of treatment resulted in a higher chance of remission, compared with those who don’t initially respond, who then had a less than 5% chance of remission.

Are antidepressants good for everyone?

• The difference between active antidepressants and placebo is small.
• A latent growth curve analysis of placebo vs. antidepressants for depression showed that there are two separate trajectories with antidepressants: 70% will respond and are vastly improved, while 30% actually do worse.
• A National Institute of Mental Health study from 1980s randomized patients to two types of psychotherapy vs. tricyclic antidepressants (TCAs) vs. waitlist control group. Treatment took place for 16 weeks, and patients were followed for 18 months.
  • People who went into remission on TCAs were more likely to relapse than those who went into remission on psychotherapy.
• Epidemiological Catchment Area (ECA) trial: Prospective data of 92 people from the total 3,500 in the study.
  • Of the 92 with a first major depressive episode, 50% had a second major depressive episode.
  • Of those who were treated into complete remission, even after 5 years, more than 50% had a relapse of their depression.

Conclusion: Relapse of depression is common when patients come off antidepressants

• To stay well, a patient with depression should continue to receive an antidepressant.
• Clinicians must ask: Do the antidepressants increase the risk of relapse of depression?
• Depression is a disabling disease, so treatment is necessary. But clinicians should question for whom and when antidepressants should be used.

References

Turner EH et al. Selective publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med. 2008;358:352-60.

Cipriani A et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: A systematic review and network meta-analysis. Lancet. 2018 Apr 7:391(10128):1357-66.

Penninx BW et al. Two-year course of depressive and anxiety disorders: Results from the Netherlands study of depression and anxiety (NESDA). J Affect Disord. 2011 Sep;133(1-2):76-85.

Perlman K et al. A systematic meta-review of predictors of antidepressant treatment outcome in major depressive disorder. J Affect Disord. 2019 Jan 15;243:503-15.

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