- Email: [email protected]
Novel melatonin-based treatments for major depression
Correspondence
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Hickie IB, Rogers NL. Novel melatonin-based therapies: potential advances in the treatment of major depression. Lancet 2011; 378: 621–31. Howland RH. A risk-benefit assessment of agomelatine in the treatment of depression. Drug Saf 2011; 34: 709–31. Howland RH. Publication bias and outcome reporting bias: agomelatine as a case example. J Psychosoc Nurs Ment Health Serv 2011; 49: 11–14.
In their paper on new antidepressant treatment strategies that target the circadian system,1 Ian Hickie and Naomi Rogers review five distinct melatonin analogues. Four of these analogues are briefly presented on a single page (Circadin, ramelteon, tasimelteon, and PD-6735), whereas agomelatine, Servier’s analogue, is described over four pages, including three tables. We have several concerns about Hickie and Rogers’s statements about the efficacy and safety of agomelatine. Of the ten placebo-controlled trials involving various doses (1–25 mg/day) of agomelatine, half of them were negative and one (NCT00411242) gave inconclusive results with respect to the primary endpoints. Additionally, none of the active comparator trials presented in Hickie and Rogers’s table 4 was significantly in favour of agomelatine with respect to the two primary endpoints. Considering the small sample size of the various trials presented, these trials were too weak to allow a non-inferiority statement with respect to the effect of agomelatine (25–50 mg/day) with at least 80% statistical power. Melatonin analogues, including agomelatine, are being developed with a view to achieving a better safety profile than the currently available antidepressant strategies.1 However, despite agomelatine producing no increase in serotonin concentrations, it did not seem to have a better safety profile than sertraline, venlafaxine, and fluoxetine, as shown in Hickie and Rogers’s table 4. These results do not support the statement that agomelatine is “unique” and displays a “significant antidepressant effect” and a “favourable safety profile”.1 216
Readers should be aware of Hickie and Rogers’s numerous conflicts of interest with Servier. Clinical trials and audit sponsored by Servier, unrestricted educational grants, consultancy fees, and honoraria for lectures might explain the subjective nature and inappropriateness of Hickie and Rogers’s conclusions. We declare that we have no conflicts of interest.
Celia Lloret-Linares, Jean-François Bergmann, *Stéphane Mouly [email protected] Assistance Publique-Hôpitaux de Paris, Université Paris Cité-Diderot, Clinique Thérapeutique, Hôpital Lariboisière, 75010 Paris, France 1
Hickie IB, Rogers NL. Novel melatonin-based therapies: potential advances in the treatment of major depression. Lancet 2011; 378: 621–31.
conception and writing of this article and have seen and approved the final version.” That careful parsing leaves a lot unsaid and might be viewed as dissembling. Did employees of Servier Laboratories participate in shaping the misleading manner of reporting the clinical trials data? Did they review the manuscript or request changes? This paper seems to break new ground for sponsored writing in medical journals, with conflicts of interest hidden in plain sight while bias continues.3 I declare that I have no conflicts of interest.
Bernard J Carroll [email protected] Pacific Behavioral Research Foundation, Carmel, CA 93923, USA 1
The New Drug Class paper by Ian Hickie and Naomi Rogers1 does not adequately address the weak efficacy of agomelatine in depression and seems biased for promotional effect. Where is a pooled analysis of all the listed placebo-controlled trials? Listing the negative studies but then excluding those data from analyses is disingenuous.2 Where are the data for categorical outcome (response vs nonresponse) in all the trials, not just the three registration trials? The hidden data are needed to estimate the composite number needed to treat. And where are categorical outcomes (relapse vs non-relapse) to support the claim of prevention (table 4)? Why are these data hidden? The financial arrangements are not transparent. Was this review commissioned? Was it proposed by Hickie and Rogers to Servier? Was the “unrestricted educational grant” from Servier Laboratories to Rogers effectively an honorarium to them? Who paid how much to whom, and where did the money go? Who paid the three acknowledged assistants? Was the paper drafted by the assistants? Did the corporation supply content? Hickie and Rogers declare that “Both authors participated in the
2
3
Hickie IB, Rogers NL. Novel melatonin-based therapies: potential advances in the treatment of major depression. Lancet 2011; 378: 621–31. Turner EH, Matthews AM, Linardatos E, Tell RA, Rosenthal R. Selective publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med 2008; 358: 252–60. Horton R. The dawn of McScience. New York Review of Books 2004; March 11. http://www.nybooks.com/articles/ archives/2004/mar/11/the-dawn-ofmcscience/ (accessed Dec 16, 2011).
Ian Hickie and Naomi Rogers’s paper1 illustrates substantial problems prevalent in reviews of psychotropic drugs: unjustified and misleading conclusions in the summary (abstract), withholding of information about serious adverse effects, citation misrepresentation, and possible conflicts of interest. First, there is a serious discrepancy between the summary and the body of the paper. The summary claims that “fewer patients on agomelatine relapse (23·9%) than do those receiving placebo (50·0%)”. But that was only one trial. The body of the paper admits that two other trials did not find lower relapse with agomelatine. Unfortunately, many will only read the summary, and will be misled. Second, Hickie and Rogers selectively emphasise agomelatine’s lower risk of common side-effects but do not cite authoritative sources that raise www.thelancet.com Vol 379 January 21, 2012
1
2
3
Hickie IB, Rogers NL. Novel melatonin-based therapies: potential advances in the treatment of major depression. Lancet 2011; 378: 621–31. Howland RH. A risk-benefit assessment of agomelatine in the treatment of depression. Drug Saf 2011; 34: 709–31. Howland RH. Publication bias and outcome reporting bias: agomelatine as a case example. J Psychosoc Nurs Ment Health Serv 2011; 49: 11–14.
In their paper on new antidepressant treatment strategies that target the circadian system,1 Ian Hickie and Naomi Rogers review five distinct melatonin analogues. Four of these analogues are briefly presented on a single page (Circadin, ramelteon, tasimelteon, and PD-6735), whereas agomelatine, Servier’s analogue, is described over four pages, including three tables. We have several concerns about Hickie and Rogers’s statements about the efficacy and safety of agomelatine. Of the ten placebo-controlled trials involving various doses (1–25 mg/day) of agomelatine, half of them were negative and one (NCT00411242) gave inconclusive results with respect to the primary endpoints. Additionally, none of the active comparator trials presented in Hickie and Rogers’s table 4 was significantly in favour of agomelatine with respect to the two primary endpoints. Considering the small sample size of the various trials presented, these trials were too weak to allow a non-inferiority statement with respect to the effect of agomelatine (25–50 mg/day) with at least 80% statistical power. Melatonin analogues, including agomelatine, are being developed with a view to achieving a better safety profile than the currently available antidepressant strategies.1 However, despite agomelatine producing no increase in serotonin concentrations, it did not seem to have a better safety profile than sertraline, venlafaxine, and fluoxetine, as shown in Hickie and Rogers’s table 4. These results do not support the statement that agomelatine is “unique” and displays a “significant antidepressant effect” and a “favourable safety profile”.1 216
Readers should be aware of Hickie and Rogers’s numerous conflicts of interest with Servier. Clinical trials and audit sponsored by Servier, unrestricted educational grants, consultancy fees, and honoraria for lectures might explain the subjective nature and inappropriateness of Hickie and Rogers’s conclusions. We declare that we have no conflicts of interest.
Celia Lloret-Linares, Jean-François Bergmann, *Stéphane Mouly [email protected] Assistance Publique-Hôpitaux de Paris, Université Paris Cité-Diderot, Clinique Thérapeutique, Hôpital Lariboisière, 75010 Paris, France 1
Hickie IB, Rogers NL. Novel melatonin-based therapies: potential advances in the treatment of major depression. Lancet 2011; 378: 621–31.
conception and writing of this article and have seen and approved the final version.” That careful parsing leaves a lot unsaid and might be viewed as dissembling. Did employees of Servier Laboratories participate in shaping the misleading manner of reporting the clinical trials data? Did they review the manuscript or request changes? This paper seems to break new ground for sponsored writing in medical journals, with conflicts of interest hidden in plain sight while bias continues.3 I declare that I have no conflicts of interest.
Bernard J Carroll [email protected] Pacific Behavioral Research Foundation, Carmel, CA 93923, USA 1
The New Drug Class paper by Ian Hickie and Naomi Rogers1 does not adequately address the weak efficacy of agomelatine in depression and seems biased for promotional effect. Where is a pooled analysis of all the listed placebo-controlled trials? Listing the negative studies but then excluding those data from analyses is disingenuous.2 Where are the data for categorical outcome (response vs nonresponse) in all the trials, not just the three registration trials? The hidden data are needed to estimate the composite number needed to treat. And where are categorical outcomes (relapse vs non-relapse) to support the claim of prevention (table 4)? Why are these data hidden? The financial arrangements are not transparent. Was this review commissioned? Was it proposed by Hickie and Rogers to Servier? Was the “unrestricted educational grant” from Servier Laboratories to Rogers effectively an honorarium to them? Who paid how much to whom, and where did the money go? Who paid the three acknowledged assistants? Was the paper drafted by the assistants? Did the corporation supply content? Hickie and Rogers declare that “Both authors participated in the
2
3
Hickie IB, Rogers NL. Novel melatonin-based therapies: potential advances in the treatment of major depression. Lancet 2011; 378: 621–31. Turner EH, Matthews AM, Linardatos E, Tell RA, Rosenthal R. Selective publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med 2008; 358: 252–60. Horton R. The dawn of McScience. New York Review of Books 2004; March 11. http://www.nybooks.com/articles/ archives/2004/mar/11/the-dawn-ofmcscience/ (accessed Dec 16, 2011).
Ian Hickie and Naomi Rogers’s paper1 illustrates substantial problems prevalent in reviews of psychotropic drugs: unjustified and misleading conclusions in the summary (abstract), withholding of information about serious adverse effects, citation misrepresentation, and possible conflicts of interest. First, there is a serious discrepancy between the summary and the body of the paper. The summary claims that “fewer patients on agomelatine relapse (23·9%) than do those receiving placebo (50·0%)”. But that was only one trial. The body of the paper admits that two other trials did not find lower relapse with agomelatine. Unfortunately, many will only read the summary, and will be misled. Second, Hickie and Rogers selectively emphasise agomelatine’s lower risk of common side-effects but do not cite authoritative sources that raise www.thelancet.com Vol 379 January 21, 2012