Antidepressants Are Safe: Final Word?

Megan Brooks

October 03, 2019

There is no convincing evidence to support claims that antidepressants are associated with adverse health outcomes, new research suggests.

Results from a large systematic review of 45 meta-analyses that included more than 1000 observational studies show the evidence does not support such assertions.

"The main take-home message from our study is that the antidepressants appear to be generally safe in clinical terms and there is no absolute contraindication for the prescriptions of these agents when a clear clinical indication exists," study investigator Elena Dragioti, PhD, adjunct senior lecturer in the Department of Medicine and Health Sciences at Linköping University, Sweden, told Medscape Medical News.

"Our analysis shows that there is no convincing evidence for the association of antidepressants with most severe adverse outcomes, and in cases where it seems to be some evidence — as in autism, suicidality — probably the underlying disease is the factor that interferes," she added.

The study was published online yesterday in JAMA Psychiatry.

Hot Debate

Antidepressants are the third most frequently prescribed medications in the US, with an estimated 10% of American adults taking at least one antidepressant.

However, the safety of antidepressants has been hotly debated. Meta-analyses provide conflicting evidence on their safety and the credibility of these findings has not been quantified, the authors note.

To that end, they systematically assessed the evidence from 45 meta-analyses comprising more than 1000 observational studies that covered different age groups, underlying psychiatric conditions, and possible adverse health outcomes.

Two independent reviewers recorded the data and assessed the methodological quality of the meta-analyses. Evidence of association was ranked according to established criteria as convincing, highly suggestive, suggestive, weak, or not significant.

Investigators found convincing evidence for a link between selective serotonin reuptake inhibitor (SSRI) use and suicide attempt or completion among children and adolescents, and SSRI or antidepressant use during pregnancy and an increased risk of autism in offspring.

"However, none of these associations remained at the convincing evidence level after a sensitivity analysis that adjusted for confounding by indication," the authors note.

The results showed suggestive evidence for 21 additional associations between antidepressant use and adverse health outcomes, weak evidence for 39, and no evidence for 46 associations. 

Eleven associations had highly suggestive evidence of the association between any antidepressant use and increased risk of adverse health outcomes, including attention deficit hyperactivity disorder (ADHD) in children, cataract development, severe bleeding at any site, upper gastrointestinal tract bleeding, postpartum hemorrhage, preterm birth, lower Apgar score at 5 minutes, osteoporotic fractures, and risk of hip fracture.

Dragioti pointed out that "although a clear association has not [been] proven it is something which should be considered, and every case should be individualized. It is important to note that we do not have evidence from randomized clinical trials about long-term adverse health outcomes and we were not able to assess several newer antidepressants due to limited available data."

Interpret With Caution

However, the authors of an editorial published with the study urge caution in interpreting the results.

"While the methods of this review are sound, the presentation of data is accurate, and the discussion of these meta-analyses is balanced, an important limitation of meta-analysis and umbrella reviews is the risk of reductionism," write Michael Bloch, MD, Victor Avila-Quintero, MD, and Jose Flores, MD, PhD, all from from Yale University School of Medicine, New Haven, Connecticut.

No matter how well conducted, meta-analyses, systematic reviews, and umbrella reviews can't control for systematic bias or confounding present in the underlying studies, they point out.

The editorialists say determining the risks of medication exposure during pregnancy is "important and of great concern" to families, physicians, and children. "Both the costs of untreated psychiatric illness during pregnancy and the possible unknown risks of medication during pregnancy may be profound."

"However, the commonly prevailing experimental methods designed to evaluate the risks of (psychiatric) medication exposure during pregnancy are highly likely to be compromised by biased and confounded associations.

"Systematic reviews, meta-analyses, and the umbrella reviews that summarize them will then report more precise estimates of associations that are subject to confounding and bias, leading to false accuracy and certainty," they conclude.

The study was funded by the NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. Disclosures for authors and editorial writers are listed with the original article.

JAMA Psychiatry. Published online October 2, 2019. Abstract, Editorial

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