Several months ago, Lancet Psychiatry published a study, led by Gemma Lewis, that found sertraline (brand name Zoloft) ineffective for treating depression, even for people with severe symptoms. However, despite this finding, the researchers went on to suggest the drug be prescribed to people who do not have a diagnosis of depression or anxiety. Mad in America covered that article at the time.
After some controversy, Lancet Psychiatry has decided to spend an issue addressing the criticisms of that article. In it are three new re-assessments of the study by other researchers.
Michael P. Hengartner led the first group at the Zurich University of Applied Sciences, Switzerland. His article provides an overview of the study results:
The results were “negative regarding the effects of sertraline on the primary outcome of depressive symptoms at week 6 (effect size 0.09), and there was only a marginal effect at week 12 (effect size 0.18). There was no interaction between sertraline and baseline severity, indicating that sertraline did not lead to a clinically meaningful reduction in depressive symptoms in patients with mild and severe depression.”
Hengartner and his co-authors write that the results have been spun by “the media and various experts” who argued that the drug would still be helpful to those with severe symptoms.
However, Hengartner notes that the original article belies this assumption. The authors of the original article wrote: “Many people in our sample had very severe depression, suggesting that there is uncertainty about the prescription of antidepressants in primary care at all levels of severity.”
The original study also found some slight improvements in anxiety and overall well-being. Of note, these were secondary outcomes, and the participants did not have diagnoses of anxiety disorders. This became a major “positive finding” of the study. Hengartner and his co-authors suggest that this is misleading, as it is a “very small” effect “of questionable practical relevance to patients.” Hengartner also indicates that the result could be due to unblinding in the placebo group—a whopping 81% of the participants in the placebo group figured out that they weren’t taking the active drug.
A second re-analysis of the study was conducted by Asger Sand Paludan-Müller and Klaus Munkholm at the Nordic Cochrane Center. They found that even the positive outcomes on anxiety and overall mental health were slight—far below the minimum clinically meaningful improvement. They also took issue with the use of secondary outcomes, which were added to the study at a later date. Finally, they suggested that the methods used for reporting adverse events might have underestimated the harms of sertraline use.
Bruce Arroll wrote the third re-appraisal of the study at the University of Auckland, New Zealand. His analysis of the data demonstrated that improvement classified as “response” at the 12-week time point was “3.25 times more likely to be a placebo response than a medication response.” That means that a large number of those who receive the medication would have improved anyway. This group of people is exposed to the harms of the drug unnecessarily. Hengartner and his co-authors agree:
“It is unknown whether minimal short-term benefits might outweigh the drugs’ potential for severe long-term harm.”
Gemma Lewis and Glyn Lewis, two of the original authors of the study from several months ago, were also given space to reply to these criticisms. In their rebuttal, they take issue with the statistical methods used by Paludan-Müller and Munkholm and defend their use of secondary analyses, as well as their methods for reporting adverse events.
However, in contrast to their previously published statements—in which they suggested that even people without depression or anxiety should also receive sertraline—Lewis and Lewis took a more nuanced view at this time. They write:
“We agree with Bruce Arroll that many people with depression might recover without antidepressants or through talking therapies, and that watchful waiting and careful review is often appropriate.”
Hengartner, M. P., Plöderl, M., Braillon, A., Jakobsen, J. C., & Gluud, C. (2020). Sertraline in primary care: comments on the PANDA trial. Lancet Psychiatry, 7(1), P17. DOI: https://doi.org/10.1016/S2215-0366(19)30381-5
Arroll, B. (2020). Sertraline in primary care: comments on the PANDA trial. Lancet Psychiatry, 7(1), P17-18. DOI: https://doi.org/10.1016/S2215-0366(19)30438-9
Paludan-Müller, A. S., & Munkholm, K. (2020). Sertraline in primary care: comments on the PANDA trial. Lancet Psychiatry, 7(1), P18-19. DOI: https://doi.org/10.1016/S2215-0366(19)30441-9
Lewis, G., & Lewis, G. (2020). Sertraline in primary care: comments on the PANDA trial – Authors’ reply. Lancet Psychiatry, 7(1), P19. DOI: https://doi.org/10.1016/S2215-0366(19)30480-8