Do antidepressants work? Comments on the latest Lancet study On February 21 2018, The Lancet published a large meta-analysis (MA) led by Dr. Andrea Cipriani of the National Institute for Health Research, Oxford, on the efficacy and acceptability of 21 antidepressants (AD). According to the study, all AD’s were superior to placebo (PBO). The results of the MA were hyped by many media outlets. The English newspaper The Guardian called it a «groundbreaking study» that «will put to rest doubts about the medicine». «The drugs do work», so says the title (https://www.theguardian.com/science/2018/feb/21/the-drugs-do-work-antidepressants-are-effective-study-shows). But even the authors of The Lancet article don’t go as far as sharing this kind of «jovialism», of cheerful enthusiasm, when they write: «certainty of evidence is moderate to low», and then again: «the effect sizes were mostly modest» (http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32802-7/fulltext). One of the weakest points of this MA is its failure to report anything on harms, which are numerous and well documented (see among others, « A.F. Carvalho et al., //www.karger.com/Article/Pdf/447034; C. Cartwright, «Long-term antidepressant use: patient perspectives of benefits and adverse effects, Patient Preference and Adherence», 2016, and many articles by psychiatrist David Healy). There are many more weaknesses. First of all the MA says nothing about the Number Needed to Treat (NNT); nothing about difficulty coming off AD’s; 78% of the randomized controlled trials (RCT’s) part of this MA were sponsored by the pharmaceutical industry; four authors declared conflicts of interest (COI), (but we don’t know how many of the authors of the studies included in the MA were in COI?); it was way too short (around 8 weeks); according to The Lancet, 73% had «moderate risk» of bias, 9% «high risk»; no information about run-in periods (which allow to cherry-pick participants and exaggerate efficacy); many trials had no information about randomization and allocation concealment; no evaluation of global functioning; one of the primary outcomes was response rate, a very weak criterion to judge efficacy; likely no active placebo; so-called a «considerable amount of unpublished data»… for 8 drugs out of 21 (were clinical study reports included , how many participants were concerned by these unpublished studies, and can you trust pharma giving negative studies?). Moreover, in AD studies the blind is broken because AD’s are active substances giving rise to adverse events. In a systematic review of 21 trials in a variety of areas that had both blinded and nonblinded assessors, the effect was exaggerated by 36% on average by nonblinded assessors (Hróbjartsson et al, BMJ 2012;344:e1119). Many studies have shown that RCT’s sponsored by industry and/or reported by authors in COI inflate efficacy. A study in the Am. J. of Psychiatry (2005), estimated that articles in four psychiatric journals, by authors in COI were 4.9 times more likely to estimate the drug was superior to PBO than authors who declared no COI (Roy H. Perlis et al., <http://ajppsychiatryonline.org/doi/full/10.1176/appi.ajp.162.10.1957). Sometimes efficacy is purely invented. This is what the famous and manipulated 329 study on paroxetine for depression in adolescents did (J.D. Amsterdam et al., «Industry-corrupted psychiatric trials», https://gallery.mailchimp.com/a6a198ec28f476496d9945891/files/470b3922-de15-4e23-ba5f-7769b2e404f0/Industry_corrupted_trials.pdf ). A MA led by Erik Turner looked at 74 FDA-registered studies of AD’s. Almost half (49%) failed to prove the drugs were superior to PBO (N Engl J Med 2008;PMID: 13199864). We are allowed to hypothesize that those studies were the «best» the makers of AD’s submitted to FDA. The authors of The Lancet article say the «great majority» had MODERATE to severe depression as measured by the Hamilton scale, or HAMD (mean score 25.7, standard deviation 3.97). Whatever criticism can be made about HAMD, this statement seems to be incorrect: according to the American Psychiatric Association, 8-13 is mild depression, 14 to 18 moderate, 19-22 severe, 23 + very severe. So the participants in this MA were very very severely depressed. Many MA’s by independent researchers (I. Kirsch, J.C Fournier, psychiatrist Joanna Moncrieff) show that efficacy for mild to moderate depression is no better than PBO. And the great majority of AD’s are prescribed to people who have mild to moderate depression. According to Kirsch, for very very severe depression (28 +), the mean difference on HAMD between AD and PBO is 4.36, slightly more than the 3 considered clinically significant by the National Institute of Clinical Excellence (NICE) (Kirsch, I., Zeitschrift für Psychologie, 222(3), https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4172306/, 2014). J. Undurraga and well known psychiatrist Ross Baldessarini (107 RCT’s) found, for second-generation antidepressants an NNT of 8.7 for SSRI’s, 10.2 for SNRI’s, and 6.2 for first-generation antidepressants called TCA’s (deadly in overdose and likely to cause heart rhythm disturbances that may be fatal )–(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3280655/, 2012, Table 2). Of course, these are means. The MA points out correctly that depressive symptoms tend to improve spontaneously. Industry sponsored RCT’s of fluoxetine and venlafaxine show no significant difference by week 8 between AD and PBO (Gibbons et al, Arch Gen Psychiatry, doi:10.1001/archgenpsychiatry.2011.2044). Moreover, a study comparing the efficacy of psychotherapy assigned 340 persons to a wait list (10 weeks). They gained 4 points on HAMD (Rutherford, B.R., Roose, S. P., https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3628961/, July 2013). Furthermore, a 3-year study carried in the US showed that 50.7% of people with depression, anxiety and drug abuse remit without any treatment (Sareen, J., et al., http://jamanetwork.com/journals/jamapsychiatry/fullarticle/211213, 2013, 43). Of course, it does not mean they don’t need help. Some of the same researchers did another study (1 year) in the Netherlands and found a greater number of remitters (some had residual symptoms). Moreover, AD’s may worsen depression. In this MA, the relapse rate for PBO is 24.7% versus 48.7 for SSRI’s (Andrews, P. et al., https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3133866). And what about overdiagnosis, which does not seem to be the case for this MA (see Thombs, B. D., et al., (2018). «Addressing overestimation of the prevalence of depression based on self-report screening questionnaires», Canadian Medical Association Journal. DOI: 10.1503/cmaj.170691, and R. Mojtabai who determined that 61,4% of people, almost all on AD’s, did not meet DSM so-called «criteria» (R. Mojtabai, Psychother Psychosom, 2013). The Guardian article quotes one of the authors, Dr. Geddes: «we don’t have very precise treatments for depression». True for AD’s; false for psychotherapy, at least for mild to moderate depression, and no side effects as long as you don’t end up in the hands of a charlatan. The Guardian piece quotes Dr. Cipriani saying that 80% stop their AD within one month. How do you reconcile this with the fact that those who defend their efficacy declare that it takes a few weeks (more or less 6 to 8) before AD’s show efficacy. But, unfortunately it takes just a few days for adverse events to manifest in many users, including suicidality and homicidal thoughts in a small percentage. As Joanna Moncrieff points out, media coverage of AD’s focusses on people who say they were helped by those molecules and this question is important to address. As Dr. Moncrieff says, if they decide that AD’s are worth trying, they should be aware that they will have to put up with the risks of side effects, understand that the difference between drug and PBO is very small (clinically null for mild to moderate depression) and the idea that the chemical imbalance theory, is not at all supported by research (https://www.madinamerica.com/2018/03/dr-joanna-moncrieff-challenging-new-hype-antidepressants/). I would add that alternatives exist (psychotherapy, peer and community support, exercise, acupuncture, etc.). If antidepressants show some efficacy in a minority, it is most likely not by virtue of their antidepressive qualities. It is by virtue of their activation effect (some clinicians adjust the dose to «create a controlled hypomania»), or the opposite, their sedative effects. They numb emotions, bad and in many instances good, as a New Zealand study has shown (C. Cartwright, op. cit.). This MA may look impressive with 522 RCT’s, but adds nothing new, just more smoke and mirrors. Including more biased studies in a MA does not make it better. J.-C. St-Onge, author: Tous fous? L’influence de l’industrie pharmaceutique sur la psychiatrie.