In an article for BMC Psychiatry, researchers argue that antidepressants (AD) should not be recommended as a first-line treatment for even moderate to severe depression. Martin Plöderl and Michael Hengartner looked at the German S3 guidelines for the treatment of depression to see whether they are in accord with the current evidence about antidepressant effectiveness. They found that the guidelines diverged from the evidence base. The researchers found that the guidelines cited old studies, erroneously cited irrelevant studies, and reported improvements that were not supported by the data in those studies.

According to the researchers, “Most patient-level meta-analyses, especially the more recent and larger ones, reported that AD are not clinically significantly superior to placebo, even for severe depression.”

The German S3 guidelines already recommend against AD use for mild depression. The guidelines state that “antidepressant medication is hardly superior to a placebo condition” for mild depression. Therefore, the risk of harm from adverse effects is higher than the benefit. However, the same guidelines recommend in favor of AD use in cases of severe and moderate depression.

According to the researchers, the primary study cited by the guidelines in support of the idea that antidepressants are more effective in severe depression “is not related to depression at all and is most likely a citation error.”

The guidelines also cite archaic studies that have been disproven by far more recent data. For instance, the guidelines use the example of a 25% improvement over placebo for AD found in two studies from the early 2000s. When the researchers dug into this data, they found multiple meta-analyses that were more recent, all of which show a 10% (or smaller) improvement over placebo for antidepressants.

Worse, when the authors reviewed the studies that the guidelines did cite, they found that even those studies did not report such a large improvement. Instead, both studies reported a smaller improvement than the guidelines referenced.

“AD are indeed hardly superior to placebo in mild depression, but the same holds for moderate and severe depression. This already modest efficacy is most likely an overestimation of the true effect size due to various systematic method biases inherent in clinical trials.”

Plöderl and Hengartner also reviewed the evidence for antidepressant effectiveness. They found that antidepressants do consistently show a small improvement over placebo, which is statistically significant. However, this improvement is so minute that it is considered clinically insignificant. That is, although the statistics show a slight difference, patients and clinicians are unable to notice this difference in real life.

The authors write that “AD do not meet any criterion for clinical significance.”

According to the researchers, even that small difference is likely due to methodological biases. Such biases include only publishing positive results (when unpublished trials are included, 49% of the studies showed no improvement over placebo), and falsely reporting negative results as positive results (according to the authors, 21% of negative studies were misrepresented this way).

Plöderl and Hengartner write that guidelines should consider this evidence. They suggest downgrading the recommendation to make it clear that there is very little evidence for antidepressant effectiveness even in severe depression.

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Plöderl, M., & Hengartner, M. P. (2019). Guidelines for the pharmacological acute treatment of major depression: conflicts with current evidence as demonstrated with the German S3-guidelines. BMC Psychiatry, 19(265). https://doi.org/10.1186/s12888-019-2230-4 (Link)