A new study published in Frontiers in Psychiatry concludes that “antidepressants are largely ineffective and potentially harmful.” The researcher, Michael P. Hengartner at the Zurich University of Applied Sciences in Switzerland, conducted a thorough literature review focusing on randomized, controlled trials—the gold standard of evidence-based recommendation.

According to Hengartner, “Due to several flaws such as publication and reporting bias, unblinding of outcome assessors, concealment and recoding of serious adverse events, the efficacy of antidepressants is systematically overestimated, and harm is systematically underestimated.”

Hengartner questioned why the “massive increase in antidepressant prescription rates over the last three decades did not translate into measurable public health benefits” in the treatment of depression. Although meta-analyses tend to find a small difference between placebo and antidepressant effect, Hengartner argues that it comes nowhere near the “clinically significant” threshold of at least 7 points on the Hamilton Depression Scale. Instead, a difference of 1 or 2 points is a meaningless numerical difference that would not be considered an improvement to a clinician or the person diagnosed with depression.

Additionally, even this small difference could be due to the side effects of antidepressants effectively unblinding researchers or research participants, which casts doubt on the conclusions of any study that does not use an active placebo.

Further, Hengartner argues that “Naturalistic long-term studies suggest that maintenance therapy has no clear benefit, and non-drug users do not show increased recurrence rates.” That is, there is no benefit to continuing antidepressant use. The research demonstrates that those who discontinue the medication are not at higher risk of relapse than those who continue.

In fact, Hengartner cites evidence that likelihood of relapse is correlated with duration of treatment. That is, the more one takes an antidepressant, the likelier one is to have another episode of depression. Hengartner writes that neurochemical sensitization could make someone who takes antidepressants more susceptible to relapse. He cites the STAR*D trial, which is usually cited as evidence of antidepressant efficacy. At 12-month follow-up, he writes, “only 5.8% of all patients who entered continuation therapy were still in remission.” That is, almost every single patient on medication had relapsed within a year.

Hengartner also questions financial conflicts of interest and the bias of industry-supported research.

“The estimated efficacy of pharmaceutical products is significantly higher when the research was funded by the industry compared to non-industry funding, but this difference is not attributable to differences in the study quality.”

According to Hengartner, research funded by the National Institute of Mental Health found no differences between antidepressant efficacy and placebo—and this was despite robust research design using randomized controlled trials, the gold-standard method. Hengartner calls attention to industry-supported research biases in which trials that showed no effect were never published and studies that inaccurately described negative findings as positive. He also notes that harms are systematically not reported or underreported in industry-supported publications.

Regarding harms, Hengartner writes:

“A growing body of evidence from hundreds of randomized controlled trials suggests that antidepressants cause suicidality, but this risk is underestimated because data from industry-funded trials are systematically flawed. Unselected, population-wide observational studies indicate that depressive patients who use antidepressants are at an increased risk of suicide and that they have a higher rate of all-cause mortality than matched controls.”

Also, antidepressants increase the risk of death from other sources as well. Hengartner writes that “In a study with over 60,000 patients with MD aged 65 years and older, it was shown that over a mean follow-up of 5.0 years, prescription of tricyclics increase the relative mortality rate by 16%, SSRI by 54%, and other antidepressants (mostly SNRI) by 66%.”

Hengartner concludes that “As concerns treatment recommendations, my reading of the literature is that some patients may benefit from acute pharmacotherapy, but on average clinical benefits are debatable and should be weighed against adverse side effects. Continuation and maintenance therapy is not recommended due to an apparent lack of clear clinical benefits, coupled with a possibly increased vulnerability to chronic depression, increased suicide risk, and, in particular in older adults, higher all-cause mortality.”

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Hengartner, M. P. (2017). Methodological flaws, conflicts of interest, and scientific fallacies: Implications for the evaluation of antidepressants’ efficacy and harm. Frontiers in Psychiatry, 8(275). https://doi.org/10.3389/fpsyt.2017.00275 (Link)