Consistent superiority of selective serotonin reuptake inhibitors over placebo in reducing depressed mood in patients with major depression

F Hieronymus, J F Emilsson, S Nilsson, E Eriksson, F Hieronymus, J F Emilsson, S Nilsson, E Eriksson

Abstract

The recent questioning of the antidepressant effect of selective serotonin reuptake inhibitors (SSRIs) is partly based on the observation that approximately half of company-sponsored trials have failed to reveal a significant difference between active drug and placebo. Most of these have applied the Hamilton depression rating scale to assess symptom severity, the sum score for its 17 items (HDRS-17-sum) serving as effect parameter. In this study, we examined whether the negative outcomes of many SSRI trials may be partly caused by the use of this frequently questioned measure of response. We undertook patient-level post-hoc analyses of 18 industry-sponsored placebo-controlled trials regarding paroxetine, citalopram, sertraline or fluoxetine, and including in total 6669 adults with major depression, the aim being to assess what the outcome would have been if the single item depressed mood (rated 0-4) had been used as a measure of efficacy. In total, 32 drug-placebo comparisons were reassessed. While 18 out of 32 comparisons (56%) failed to separate active drug from placebo at week 6 with respect to reduction in HDRS-17-sum, only 3 out of 32 comparisons (9%) were negative when depressed mood was used as an effect parameter (P<0.001). The observation that 29 out of 32 comparisons detected an antidepressant signal from the tested SSRI suggests the effect of these drugs to be more consistent across trials than previously assumed. Further, the frequent use of the HDRS-17-sum as an effect parameter may have distorted the current view on the usefulness of SSRIs and hampered the development of novel antidepressants.

Conflict of interest statement

Drs Hieronymus, Emilsson, and Nilsson report no potential conflict of interest. Elias Eriksson has been on advisory boards and/or received speaker's honoraria from Eli Lilly and H Lundbeck.

References

    1. U.S. Food and Drug Administration CfDEaR. Guidance for Industry: Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products, May. 1998. (Accessed 15 August, 2014, at ).
    1. Kirsch I. The emperor's new drugs: exploding the antidepressant myth. Basic Books: New York, NY, 2010.
    1. Melander H, Ahlqvist-Rastad J, Meijer G, Beermann B. Evidence b(i)ased medicine—selective reporting from studies sponsored by pharmaceutical industry: review of studies in new drug applications. BMJ 2003; 326: 1171–1173.
    1. 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: 252–260.
    1. Moncrieff J. Are antidepressants as effective as claimed? No, they are not effective at all. Can J Psychiatry 2007; 52: 96–97.
    1. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960; 23: 56–62.
    1. Gelenberg AJ, Thase ME, Meyer RE, Goodwin FK, Katz MM, Kraemer HC et al. The history and current state of antidepressant clinical trial design: a call to action for proof-of-concept studies. J Clin Psychiatry 2008; 69: 1513–1528.
    1. Bagby RM, Ryder AG, Schuller DR, Marshall MB. The Hamilton Depression Rating Scale: has the gold standard become a lead weight? Am J Psychiatry 2004; 161: 2163–2177.
    1. Bech P, Gram LF, Dein E, Jacobsen O, Vitger J, Bolwig TG. Quantitative rating of depressive states. Acta Psychiatr Scand 1975; 51: 161–170.
    1. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry 1979; 134: 382–389.
    1. Isacsson G, Adler M. Randomized clinical trials underestimate the efficacy of antidepressants in less severe depression. Acta Psychiatr Scand 2012; 125: 453–459.
    1. Bech P, Allerup P, Gram LF, Reisby N, Rosenberg R, Jacobsen O et al. The Hamilton depression scale. Evaluation of objectivity using logistic models. Acta Psychiatr Scand 1981; 63: 290–299.
    1. Gibbons RD, Clark DC, Kupfer DJ. Exactly what does the Hamilton Depression Rating Scale measure? J Psychiatr Res 1993; 27: 259–273.
    1. Maier W, Philipp M. Improving the assessment of severity of depressive states - a reduction of the Hamilton Depression Scale. Pharmacopsychiatry 1985; 18: 114–115.
    1. Demyttenaere K, De Fruyt J. Getting what you ask for: on the selectivity of depression rating scales. Psychother Psychosom 2003; 72: 61–70.
    1. Cicchetti DV, Prusoff BA. Reliability of depression and associated clinical symptoms. Arch Gen Psychiatry 1983; 40: 987–990.
    1. Zimmerman M, Martinez J, Attiullah N, Friedman M, Toba C, Boerescu DA. Why do some depressed outpatients who are not in remission according to the hamilton depression rating scale nonetheless consider themselves to be in remission? Depress Anxiety 2012; 29: 891–895.
    1. Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, Johnson BT. Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration. PLoS Med 2008; 5: e45.
    1. Fournier JC, DeRubeis RJ, Hollon SD, Dimidjian S, Amsterdam JD, Shelton RC et al. Antidepressant drug effects and depression severity: a patient-level meta-analysis. JAMA 2010; 303: 47–53.
    1. Fountoulakis KN, Veroniki AA, Siamouli M, Moller HJ. No role for initial severity on the efficacy of antidepressants: results of a multi-meta-analysis. Ann Gen Psychiatry 2013; 12: 26.
    1. Gibbons RD, Hur K, Brown CH, Davis JM, Mann JJ. Benefits from antidepressants: synthesis of 6-week patient-level outcomes from double-blind placebo-controlled randomized trials of fluoxetine and venlafaxine. Arch Gen Psychiatry 2012; 69: 572–579.
    1. Khan A, Leventhal RM, Khan SR, Brown WA. Severity of depression and response to antidepressants and placebo: an analysis of the Food and Drug Administration database. J Clin Psychopharmacol 2002; 22: 40–45.
    1. U.S. Food and Drug Administration CfDEaR. Celexa NDA 20-822 approval letter, statistical review (part 2). 17 July. 1998. (Accessed August 15, 2014, at ).
    1. U.S. Food and Drug Administration CfDEaR. Paxil NDA 020031 approval letter, statistical review. December 1992.
    1. U.S. Food and Drug Administration CfDEaR. Paxil CR NDA 20-982 & 20-936/S008 approval letter, statistical review. 12 February. 2002. (Accessed August 15, 2014, at ).
    1. U.S. Food and Drug Administration CfDEaR. Zoloft NDA 019839 approval letter, statistical review. December 1991.
    1. Faries D, Herrera J, Rayamajhi J, DeBrota D, Demitrack M, Potter WZ. The responsiveness of the Hamilton Depression Rating Scale. J Psychiatr Res 2000; 34: 3–10.
    1. Mallinckrodt CH, Meyers AL, Prakash A, Faries DE, Detke MJ. Simple options for improving signal detection in antidepressant clinical trials. Psychopharmacol Bull 2007; 40: 101–114.
    1. Ruhe HG, Dekker JJ, Peen J, Holman R, de Jonghe F. Clinical use of the Hamilton Depression Rating Scale: is increased efficiency possible? A post hoc comparison of Hamilton Depression Rating Scale, Maier and Bech subscales, Clinical Global Impression, and Symptom Checklist-90 scores. Compr Psychiatry 2005; 46: 417–427.
    1. Entsuah R, Shaffer M, Zhang J. A critical examination of the sensitivity of unidimensional subscales derived from the Hamilton Depression Rating Scale to antidepressant drug effects. J Psychiatr Res 2002; 36: 437–448.
    1. Ferguson JM. SSRI Antidepressant Medications: Adverse Effects and Tolerability. Prim Care Companion J Clin Psychiatry 2001; 3: 22–27.
    1. Richelson E. Tricyclic antidepressants and histamine H1 receptors. Mayo Clinic Proc 1979; 54: 669–674.
    1. Ferguson JM, Feighner JP. Fluoxetine-induced weight loss in overweight non-depressed humans. Int J Obes 1987; 11: 163–170.
    1. Montgomery SA, Baldwin DS, Riley A. Antidepressant medications: a review of the evidence for drug-induced sexual dysfunction. J Affect Disord 2002; 69: 119–140.
    1. Klein DF, Fink M. Multiple Item Factors as Change Measures in Psychopharmacology. Psychopharmacologia 1963; 4: 43–52.
    1. Kobak KA, Leuchter A, DeBrota D, Engelhardt N, Williams JB, Cook IA et al. Site versus centralized raters in a clinical depression trial: impact on patient selection and placebo response. J Clin Psychopharmacol 2010; 30: 193–197.
    1. Engelhardt N, Feiger AD, Cogger KO, Sikich D, DeBrota DJ, Lipsitz JD et al. Rating the raters: assessing the quality of Hamilton rating scale for depression clinical interviews in two industry-sponsored clinical drug trials. J Clin Psychopharmacol 2006; 26: 71–74.
    1. Landin R, DeBrota DJ, DeVries TA, Potter WZ, Demitrack MA. The impact of restrictive entry criterion during the placebo lead-in period. Biometrics 2000; 56: 271–278.
    1. Liu KS, Snavely DB, Ball WA, Lines CR, Reines SA, Potter WZ. Is bigger better for depression trials? J Psychiatr Res 2008; 42: 622–630.
    1. Parker G. Antidepressants on trial: how valid is the evidence? Br J Psychiatry 2009; 194: 1–3.
    1. Horder J, Matthews P, Waldmann R. Placebo, prozac and PLoS: significant lessons for psychopharmacology. J Psychopharmacol 2011; 25: 1277–1288.
    1. Mallinckrodt CH, Clark WS, David SR. Accounting for dropout bias using mixed-effects models. J Biopharm Stat 2001; 11: 9–21.

Source: PubMed

Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence

3
Předplatit