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Reports of antidepressant harms largely unsupported

October 10, 2019

By Marilynn Larkin

NEW YORK (Reuters Health) - Adverse health outcomes associated with antidepressant use may be exaggerated and not supported by evidence, according to the authors of a systematic umbrella review.

"No absolute contraindication" emerged in the study, the researchers say.

"Our analysis shows that there is no convincing evidence for the association of antidepressants with most severe adverse outcomes, and in cases where there seems to be some evidence - i.e., autism, suicidality - probably the underlying disease is the factor that interferes," Dr. Elena Dragioti of Linkoping University in Sweden told Reuters Health.

"Of course, a variety of adverse outcomes exists in daily practice - some of them severe - and although a clear association has not been proven, it is something which should be considered, and every case should be individualized," she said by email.

"The existing literature about the adverse effects of the antidepressants is already controversial," she added. "We hope that our study elucidates the field even though we do not have enough evidence from randomized clinical trials about long-term adverse health outcomes."

Dr. Dragioti and colleagues graded evidence from meta-analyses of observational studies with a cohort or case-control design that assessed the association between antidepressant use or exposure and adverse health outcomes.

As reported online October 2 in JAMA Psychiatry, 45 selected meta-analyses and 252 full-text articles described 120 associations, including data from 1,012 individual effect size estimates.

Seventy-four (61.7%) of the 120 associations were nominally statistically significant using random-effects models. Fifty-two associations (43.4%) had large heterogeneity (estimated fraction of variance due to heterogeneity > 50%). Small-study effects were found for 17 associations (14.2%) and nine associations (7.5%) had excess significance bias.

Convincing evidence emerged from both main and sensitivity analyses for links between antidepressant use and risk of suicide attempt or completion among children and adolescents; between maternal antidepressant exposure before and during pregnancy and autism spectrum disorders in offspring; and between antidepressant use and preterm birth or low Apgar scores. None of these associations remained supported by convincing evidence after adjustment for confounding by indication.

The authors state, "This study's findings suggest that most putative adverse health outcomes associated with antidepressant use may not be supported by convincing evidence, and confounding by indication may alter the few associations with convincing evidence."

Dr. Myrna Weissman an epidemiologist in psychiatry at Vagelos College of Physicians and Surgeons and Chief, Division of Translational Epidemiology at New York State Psychiatric Institute, commented by email, "The authors have done an amazing amount of answer a question that always remains after even the best of clinical trials: What are the effects of any drug out in the real world of clinical practice after the investigators have gone home?"

"The compilation of studies in the tables in the text and appendix alone will be a reference source for researchers and clinicians," she told Reuters Health.

"However, the final conclusion...that 'no absolute contraindication to antidepressants emerged from this umbrella review' seems a bit out of step with all that preceded in the analysis," she said.

"I focus on pregnancy as I know this literature best," she noted. "The observational studies included in this paper had a median duration of follow-up of two to five years. There is reasonable evidence based on mouse and human studies that the effects on offspring of in utero exposure to SSRI can be seen well after that median period of observation." ( and

Nonetheless, she added, "these data offer some strong further reassurance that antidepressants are safe for the most part, but nothing in clinical care is absolute. This paper provides a new piece of data to add to clinical judgment."


JAMA Psychiatry 2019.

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