On 2017 Jul 24, Jakob Näslund commented:

For a discussion of this study regarding some outstanding issues relating to methodology, as well as the presence of a number of possible inaccuracies, see our commentary in Acta Neuropsychiatrica entitled "Multiple possible inaccuracies cast doubt on a recent report suggesting selective serotonin reuptake inhibitors to be toxic and ineffective", available at https://doi.org/10.1017/neu.2017.23

On 2017 Jul 24, Konstantinos Fountoulakis commented:

This paper confirms that the overall SMD is around or above 0.30 adding to the literature against the idea that antidepressants do not work (e.g. Kirsch 2008). The question of the magnitude of the effect has been discussed in the literature again and again. The NICE has abandoned since years the 3-point magnitude to define 'clinical relevance' and a SMD of 0.30 is the effect size expected for successful psychiatric treatments and also for treatments elsewhere in medicine. Of course we would like more, but this is the only means we have. All the other options (psychotherapy, alternative therapies etc) do not meet the stringent criteria of this meta-analysis as there are essentially not blinded and not adequately placebo-controlled, not to mention the risk of bias. I strongly disagree with the comment on the HDRS by the authors. Yes, regulatory authorities do recommend the HDRS but this does not constitute an essential argument. It is not correct to double register an event as both a symptom and an adverse event. It is either or (at least in principle). Unfortunately the HDRS is based on an antiquitated model of depression while the MADRS is tailored to the needs of trials. For a review please see Fountoulakis et al J Psychopharmacol. 2014 Feb;28(2):106-17. Concerning the adverse events, yes indeed there is a significant effect of the active drug but the NNH are high and there was no difference in severe adverse events in comparison with placebo. In my opinion, the real SMD of SSRIs are much higher, but not really impressive. This is masked by the properties of the HDRS but also by the possibility that a large number of patients enrolled in these studies are not suitable for a number of reasons. I would love to see US vs, rest of world comparison

On 2017 Jun 08, Christian Gluud commented:

Response to Søren Dinesen Østergaard's critique

Søren Dinesen Østergaard (SDØ) [1] criticizes our systematic review on selective serotonin reuptake inhibitors (SSRI) for patients with major depressive disorder [2] for using Hamilton’s depression rating scale (HDRS)17 instead of HDRS6. SDØ refer to four studies ‘documenting’ his claims [3-6].

Two of the studies relate to duloxetine and desvenlafaxine, which are dual action drugs and not SSRIs [3, 4]. The third study is a meta-analysis assessing fluoxetine versus placebo [5]. The results show a mean effect size of the SSRI of -0.30 (95% confidence interval (CI) -0.39 to -0.21) when using HDRS17 and an effect size of -0.37 (95% CI -0.46 to -0.28) when using HDRS6. The difference of 0.07 corresponds to 0.7 HDRS17 points assuming a standard deviation of 10 points. The fourth study is a patient-level analysis of 18 industry-sponsored placebo-controlled trials regarding paroxetine, citalopram, sertraline, or fluoxetine [6]. The authors report a mean effect size of the SSRIs of -0.27 when using HDRS17 and an effect size of -0.35 when using HDRS6 [6]. The difference of 0.08 corresponds to 0.8 HDRS17 points assuming a standard deviation of 10 points. Hence, the absolute effect size difference between the two scales seems less than 1 HDRS point. The National Institute for Clinical Excellence (NICE) recommended a difference of 3 points on the HDRS17 for 'a minimal effect' [7-9]. However, the required minimal clinical relevant difference is probably much larger than this figure. One study showed that a mirtazapine-placebo mean difference of up to 3.0 points on the HDRS corresponds to ‘no clinical change’ [10]. Another study showed that a SSRI-placebo mean difference of 3.0 points is undetectable by clinicians, and that a mean difference of 7.0 HDRS17 points is required to correspond to a rating of ‘minimal improvement’ [11].

Moreover, none of the meta-analyses [5, 6] take into account risks of systematic errors (‘bias’) [12-14] or risks of random errors [15]. Hence, there are risks that the two meta-analyses may overestimate the beneficial effects of SSRIs.

Other studies have shown that HDRS17 and HDRS6 largely show similar results [16,17]. It cannot be concluded that HDRS6 is a better assessment scale than HDRS17, just considering the psychometric validity of the two scales. If the total score of HDRS17 is affected by some of the adverse effects of SSRIs, then this might in fact better reflect the actual summed clinical effects of SSRIs than HDRS6 ignoring these effects. Until scales are validated against patient-centred clinically relevant outcomes, such scales are merely non-validated surrogate outcomes [18].

National and international medical agencies [19-21] all recommend HDRS17 for assessing depressive symptoms. We need access to all individual patient data from all randomised clinical trials to compare the effects of antidepressants on HDRS6 to HDRS17 [22].

SDØ states “no conflicts of interest“. We are aware that SDØ has received substantial support from ‘Lundbeckfonden’, its main objective being to maintain and expand the activities of the Lundbeck Group, one of the companies producing and selling SSRIs [23]. We think it would have been fair to declare this.

Janus Christian Jakobsen, Kiran Kumar Katakam, Naqash Javaid Sethi, Jane Lindshou, Jesper Krogh, and Christian Gluud.

Conflicts of interest:
 None known.

Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen, Denmark

References 1. Ostergaard SD: Do not blame the SSRIs: blame the Hamilton Depression Rating Scale. Acta Neuropsychiatrica 2017:1-3. 2. Jakobsen JC, Katakam KK, Schou A, et al: Selective serotonin reuptake inhibitors versus placebo in patients with major depressive disorder. A systematic review with meta-analysis and Trial Sequential Analysis. BMC Psychiatr 2017, 17(1):58. 3. Bech P, Kajdasz DK, Porsdal V: Dose-response relationship of duloxetine in placebo-controlled clinical trials in patients with major depressive disorder. Psychopharmacology 2006, 188(3):273-280. 4. Bech P, Boyer P, Germain JM, et al: HAM-D17 and HAM-D6 sensitivity to change in relation to desvenlafaxine dose and baseline depression severity in major depressive disorder. Pharmacopsychiatry 2010, 43(7):271-276. 5. Bech P, Cialdella P, Haugh MC, et al: Meta-analysis of randomised controlled trials of fluoxetine v. placebo and tricyclic antidepressants in the short-term treatment of major depression. Br J Psychiatr 2000, 176:421-428. 6. Hieronymus F, Emilsson JF, Nilsson S, Eriksson E: Consistent superiority of selective serotonin reuptake inhibitors over placebo in reducing depressed mood in patients with major depression. Mol Psychiatr 2016, 21(4):523-530. 7. Fournier JC, DeRubeis RJ, Hollon SD, et al: Antidepressant drug effects and depression severity: a patient-level meta-analysis. JAMA 2010, 303(1):47-53. 8. Mathews M, Gommoll C, Nunez R, Khan A: Efficacy and safety of vilazodone 20 and 40 Mg in major depressive disorder: a randomized, double-blind, placebo-controlled trial. Int Clin Psychopharmacol 2015, 30. 9. Kirsch I, Deacon BJ, Huedo-Medina TB, et al: Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration. PLoS medicine 2008, 5(2):e45. 10. Leucht S, Fennema H, Engel R, et al: What does the HAMD mean? J Affect Disord 2013, 148(2-3):243-248. 11. Moncrieff J, Kirsch I: Empirically derived criteria cast doubt on the clinical significance of antidepressant-placebo differences. Cont Clin Trials 2015, 43:60-62. 12. Hróbjartsson A, Thomsen ASS, Emanuelsson F, et al: Observer bias in randomized clinical trials with measurement scale outcomes: a systematic review of trials with both blinded and nonblinded assessors. CMAJ : Canadian Medical Association Journal = Journal de l'Association Medicale Canadienne 2013, 185(4):E201-211. 13. Lundh A, Lexchin J, Mintzes B, Scholl JB, Bero L: Industry sponsorship and research outcome. Cochrane Database Syst Rev 2017, Art. No.: MR000033. DOI: 10.1002/14651858.MR000033.pub3.(2):MR000033. 14. Savovic J, Jones HE, Altman DG, et al: Influence of reported study design characteristics on intervention effect estimates from randomized, controlled trials. Ann Intern Med 2012, 157(6):429-438. 15. Wetterslev J, Jakobsen JC, Gluud C: Trial Sequential Analysis in systematic reviews with meta-analysis. BMC Medical Research Methodology 2017, 17(1):39. 16. Hooper CL, Bakish D: An examination of the sensitivity of the six-item Hamilton Rating Scale for Depression in a sample of patients suffering from major depressive disorder. J Psychiatry Neurosci 2000, 25(2):178-184. 17. O'Sullivan RL, Fava M, Agustin C, Baer L, Rosenbaum JF: Sensitivity of the six-item Hamilton Depression Rating Scale. Acta psychiatrica Scandinavica 1997, 95(5):379-384. 18. Gluud C, Brok J, Gong Y, Koretz RL: Hepatology may have problems with putative surrogate outcome measures. J Hepatol 2007, 46(4):734-742. 19. Sundhedsstyrelsen (Danish Health Agency): Referenceprogram for unipolar depression hos voksne (Guideline for unipolar depression in adults). http://wwwsstdk/~/media/6F9CE14B6FF245AABCD222575787FEB7ashx 2007. 20. European Medicines Agency: Guideline on clinical investigation of medicinal products in the treatment of depression. EMA/CHMP/185423/2010 Rev 2 previously (CPMP/EWP/518/97, Rev 1) 2013. 21. U.S. Food and Drug Administration: https://www.fda.gov/ohrms/dockets/AC/07/briefing/2007-4273b1_04-DescriptionofMADRSHAMDDepressionR(1).pdf. 22. Skoog M, Saarimäki JM, Gluud C, et al.: Transaprency and Registration in Clinical Research in the Nordic Countries. Nordic Trial Alliance, NordForsk. 2015:1-108. 23. Lundbeck Foundation. http://www.lundbeckfonden.com/about-the-foundation.25.aspx.

On 2017 Mar 03, Søren Dinesen Østergaard commented:

For a comment on this meta-analysis, see the letter to the editor in Acta Neuropsychiatrica "Do not blame the SSRIs: blame the Hamilton Depression Rating Scale": https://doi.org/10.1017/neu.2017.6

SDØ declares no conflicts of interest. Grants received from the Lundbeck foundation (see comment below) were all non-conditional and not given to support studies on antidepressant efficacy.

On 2017 Mar 03, Søren Dinesen Østergaard commented:

For a comment on this meta-analysis, see the letter to the editor in Acta Neuropsychiatrica "Do not blame the SSRIs: blame the Hamilton Depression Rating Scale": https://doi.org/10.1017/neu.2017.6

SDØ declares no conflicts of interest. Grants received from the Lundbeck foundation (see comment below) were all non-conditional and not given to support studies on antidepressant efficacy.

On 2017 Jul 24, Jakob Näslund commented:

For a discussion of this study regarding some outstanding issues relating to methodology, as well as the presence of a number of possible inaccuracies, see our commentary in Acta Neuropsychiatrica entitled "Multiple possible inaccuracies cast doubt on a recent report suggesting selective serotonin reuptake inhibitors to be toxic and ineffective", available at https://doi.org/10.1017/neu.2017.23