Clinical Edge

Summaries of Must-Read Clinical Literature, Guidelines, and FDA Actions

MDD: What drives specific adverse events with antidepressants?

Key clinical point: Antidepressants may produce adverse events (AEs) above and beyond nocebo effects in patients with major depressive disorder (MDD), and many specific AEs are not likely to result from the direct effects of antidepressants.

Major finding: Numerous AEs did not differ statistically between antidepressant classes and placebo, including worsening psychiatric symptoms, all forms of pain, weight gain, and respiratory symptoms. AEs that were predominantly neurological, sexual, or anticholinergic were significantly more common in antidepressants than placebos. Negative thoughts, emotions, and behavior, pain including headaches, respiratory, and infectious as well as some neurological symptoms appear to be driven by the nocebo effects.

Study details: A systematic review of 56 placebo-controlled, randomized controlled trials, which characterized the magnitude of AEs across antidepressant classes, including the potential contribution of nocebo effects.

Disclosures: This study was partly funded by Academic Scholars Awards from the Departments of Psychiatry at the University of Toronto and Sunnybrook Health Sciences Centre. Dr. Krista L. Lanctôt is supported by the National Institutes of Health, the Alzheimer Association, and the Alzheimer Drug Discovery Foundation. Dr. Mark Sinyor reported grant support from the American Foundation for Suicide Prevention, the Ontario Ministry of Research and Innovation, the Innovation Fund of the Alternative Funding Plan from the Academic Health Sciences Centres of Ontario, the University of Toronto, Department of Psychiatry Excellence Fund, and the Dr. Brenda Smith Bipolar Fund. Dr. Krista L. Lanctôt and Dr. Ayal Schaffer have reported ties with 1 or more pharmaceutical companies. The remaining authors declared no conflict of interest.


“This study by Sinyor et al. reviewed 56 studies of antidepressants versus placebo and found that active drugs physiologically generated more neurological, sexual and anticholinergic side effects. No differences between drug and placebo were found for generating more psychic symptoms, pain symptoms, or weight gain suggesting that if remarkable complaints exist post dosing that these may be nocebo in origin. A nocebo effect occurs when negative expectations in the patient’s mindset creates artificial or psychic-based side effects.

Interestingly in large psychotropic trials, up to a quarter of subject will discontinue the placebo treatment due to side effects. In clinical practice, this also means that many of our patients may quit their medications early or we may discontinue them early allowing for poor dosing and likely poor outcomes. More interventional research about anti-nocebo interventions (identifying those at nocebo risk, tailoring information during informed consent, positive framing of side effect percentages, etc.) are warranted and could lead to more days on drug per patient and ideally better outcomes for them as well.”

Thomas L. Schwartz, MD

Senior Associate Dean of Education, Interim Chair/Professor of Psychiatry

SUNY Upstate Medical University


Sinyor M et al. J Affect Disord. 2020 Feb 4. doi: 10.1016/j.jad.2020.02.013.