
Hooked on Hype? A Critical Examination of Recent Anti-Antidepressant Reporting
Here’s why most of the claims recently made about antidepressants in Newsweek are wrong.
COMMENTARY
Regular reports are published in the lay media regarding the alleged lack of efficacy of antidepressants. This time, it was Newsweek’s turn, with Adam Piore1 highlighting, amongst other reports, a new analysis by Stone et al,2 in which it was found that antidepressants work better than placebo only 15% of the time.
As usual in this type of reporting, “critical” voices are heard mostly unopposed, and little room is made for actual evidence-based interpretation of the data presented. In this article, I will review some of the claims made, provide evidence that the statistic 15% is most likely an underestimation of real-world antidepressant effects, and cast doubt on some other claims made about the (lack of) efficacy of
No Stone Unturned
In their analysis, Stone et al included all antidepressants and possible age groups. Thus, their estimate represents the average effects across all antidepressant trials submitted to the US Food and Drug Administration (FDA), but not necessarily one of the average antidepressants used. The 5 worst drugs, according to their analysis, are very rarely used for
The main outcome measure in the Stone et al analysis is the sum score of the 17 items of the Hamilton Depression Rating Scale (HDRS-17-sum). The use of this measure has been widely criticized for many reasons: it lacks one-dimensionality,4 it might reflect factors other than depressive symptoms,4 and the majority of the measured symptoms are not present in many individuals with depression.5 Drug-placebo differences were found to be substantially larger when the sum score of 6 core depressive symptoms included in the unidimensional HDRS-6 scale were used.5,6 It was also found that drug-placebo differences for this subscale are similar in those with severe and nonsevere depression,7 although the Newsweek article made a contrary claim against antidepressants.
HDRS items not included in the HDRS-6 are prone to pick up
Dosing and Other Issues
Dosing is also an important issue. Drug-placebo differences are about twice as large at doses above the common starting one for the most frequently prescribed SSRIs compared.9 Yet, in the Stone et al analysis, all possible doses were included, including those shown to not be significantly more effective than placebo. In a recent publication,6 for example, a 22.3% drug-placebo difference was found for optimal SSRI doses in adults when using response (50% score reduction from baseline) on the HDRS-6 sum score as outcome measure; however, this number is more likely an underestimation than an overestimation.
Other issues in clinical trials include difficulties in finding drug-placebo separation, noncompliance to randomized drugs,10 high drop-out rates,11 patient recruitment difficulties,12 and substantial placebo response rates.13 Further difficulties are presented by the diagnosis itself,
Although only company-sponsored trials were analyzed in most papers cited here, as well as in the Stone et al paper, unsponsored trials were found to show about 50% higher drug-placebo differences.15 It is possible that the studied populations in the latter more accurately reflect patients receiving treatment in clinical practice. This is another issue not reflected in most critical opinions about antidepressants, where it is instead stressed that trials are funded by pharmaceutical companies, with the results thus being inflated and untrustworthy.
Psychotherapy
Another treatment highlighted in the Newsweek article is
Discussing the 15%
Understandably, the first author of the Stone et al paper—Marc B. Stone, MD, of the Center for Drug Evaluation and Research, US Food and Drug Administration—declined to comment in the Newsweek article, perhaps because media discussion lies beyond the obligations of FDA employees. My personal primary take-away point from this analysis is not the 15% number itself, but the finding of a subgroup of patients with
In all, it might be that only 15% of those with depression experience significantly positive effects from antidepressant treatment compared to placebo, if the material studied was indeed representative of the average treatment, setting, and patient group. In real-world practice, the actual number might instead substantially differ depending on the drug used, the drug dose, the patient group treated, and the efficacy measure used. Effect estimates in clinical trials are more likely to underestimate than overestimate treatment effects.
The 15% number is then contrasted with 56%—the percentage of patients who apparently experience withdrawal effects. The author leaves us with a take-away that more people have withdrawal effects than antidepressant effects. Unfortunately, the 56% estimate was taken from a flawed19 review based mostly on survey studies20 that were uncontrolled and thus disregarded potential nocebo effects. Tapering was often abrupt—which is against guidelines—and again no difference was made between different drugs, even though drugs with short half-life (eg, paroxetine, venlafaxine) were driving the results. Ignoring these issues and contrasting estimates from uncontrolled surveys to drug-placebo differences from randomized controlled trials is nothing short of a woeful misuse of statistics. A more honest view could have been obtained by contrasting the withdrawal estimate to an efficacy estimate from the largest survey study, which showed that 83% of those taking antidepressants believed the drugs had reduced their depression.21
Contrary Claims
Unfortunately, even more factual inaccuracies were presented in the Newsweek article. It was stated that antidepressants do not aid loss of energy, loss of interest, nor motivation, all being common symptoms in depression. In item-based analyses of SSRIs and the SNRI duloxetine, the opposite was revealed to be true, with small but replicable effects on all these symptoms.22,23 To the best of my knowledge, no better evidence exists on the contrary, thus rendering these statements by Joanna Moncrieff, MD, in the Newsweek article untrue.
Another statement by the same author claims that the superiority of antidepressants can be attributed not to actual antidepressant effects, but to emotional numbing. A recent article in Psychiatric Times™ by Dawson and Pies rebutted this claim,24 and even more evidence was found in a recent analysis of SSRI trials using the Montgomery-Åsberg Depression Rating Scale (MADRS) as outcome measure.25 Here, an opposite effect to what was stated by the Newsweek interviewees was found, with a significant and positive drug effect against
Concluding Thoughts
The Newsweek article is just another unfortunate example of one-sided media reporting, ignoring evidence contradicting claims of those critical to drug treatment, and casting unnecessary doubt on drugs that, while not perfect, are more than useful in alleviating symptoms of major depression, as well as many other disorders (eg, anxiety syndromes, obsessive compulsive disorder, and premenstrual dysphoric disorder). Unfortunately, I expect this tradition of antidepressant bashing will continue. Lay media seem disinterested in correcting their claims (neither the journalist in question nor Newsweek themselves responded when I shared my concerns) and instead will likely continue to seek sensationalist headlines and short-term profit.
The opinions expressed in the interviews are those of the participants and do not necessarily reflect the opinions of Psychiatric Times™.
Dr Lisinski is in the Department of pharmacology at the Institute of Neuroscience and Physiology, Sahlgrenska Academy, at the University of Gothenburg, Sweden.
References
1. Piore A. Antidepressants work better than sugar pills only 15 percent of the time. Newsweek. September 9, 2022. Accessed November 29, 2022.
2. Stone MB, Yaseen ZS, Miller BJ, et al.
3. Zhou X, Teng T, Zhang Y, et al.
4. Fried EI, van Borkulo CD, Epskamp S, et al.
5. Bech P, Gram LF, Dein E, et al.
6. Lisinski A, Hieronymus F, Nilsson S, Eriksson E.
7. Hieronymus F, Lisinski A, Nilsson S, Eriksson E.
8. Hieronymus F, Lisinski A, Eriksson E, Ostergaard SD.
9. Hieronymus F, Nilsson S, Eriksson E.
10. Reis M, Aberg-Wistedt A, Agren H, et al.
11. Cipriani A, Furukawa TA, Salanti G, et al.
12. Brody B, Leon AC, Kocsis JH.
13. Hieronymus F, Lisinski A, Hieronymus M, et al.
14. Fried EI, Nesse RM.
15. Munkholm K, Paludan-Muller AS, Boesen K.
16. Cuijpers P, Turner EH, Mohr DC, et al.
17. Hieronymus F, Lisinski A, Nilsson S, Eriksson E.
18. Kirsch I.
19. Jauhar S, Hayes J.
20. Davies J, Read J.
21. Read J, Cartwright C, Gibson K.
22. Lisinski A, Hieronymus F, Naslund J, et al.
23. Hieronymus F, Emilsson JF, Nilsson S, Eriksson E.
24. Dawson G, Pies RW. Antidepressants do not work by numbing emotions. Psychiatric Times. September 26, 2022.
25. Hieronymus F, Lisinski A, Ostergaard SD, Eriksson E.
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