Benefits From Antidepressants:  Synthesis of 6-Week Patient-Level Outcomes From Double-blind Placebo-Controlled Randomized Trials of Fluoxetine and Venlafaxine

“Benefits from Antidepressants,” (1) is fraught with problems and offers a misrepresentation of available evidence. For example, the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) (2), contrary to the 67% cumulative response rate reported, found that of the 4041 patients who entered the program only 108 (3%) had a sustained remission—all other patients either dropped out or relapsed (3). Moreover, the Treatment for Adolescents with Depression Study (TADS), the largest of the four trials in the current analysis of youth showing a “significant” effect at 6 weeks, demonstrated no differences between placebo and fluoxetine at both 6 and12 weeks (4).

Given the results of studies like the STAR*D and TADS, as well as other meta-analyses showing similarly small and clinically insignificant differences (5,6,7,8), the reported 2.55 point difference on the HAM-D, under the accepted 3 point criterion of clinical significance, and the 4.62 points (even less than the 6 and 12 week non-significant differences in TADS) on the CDRS-R is not front page news. But herein is the authors’ main thrust: these clinically insignificant mean differences translate to large response and remission rate differences. Their analysis reported an “estimated” combined response/remission rate of 32.2% over placebo for adults and a 54.1% combined advantage over placebo for youth. How are we to interpret the findings of small mean discrepancies translating to large response/remission rate differences in the context of the findings of the STAR*D and TADS? For example, what sense do the differential response and remission estimates at 6 weeks make given the TADS reported no difference between medication and placebo at 6 and 12 weeks not only on the CDRS-R but also the Reynolds Adolescent Depression Scale?

Finally, the most dangerous misrepresentation in the study was that these findings of “benefits” should favor a reconsideration of the black box warning for suicidal thinking and antidepressants in children and adolescents. TADS recorded 15 suicidal events in fluoxetine groups compared with 9 in non-fluoxetine groups at 12 weeks, including 6 suicide attempts by fluoxetine takers compared to 1 in the cognitive behavioral therapy (CBT) group (none in placebo). After 36 weeks of treatment, there were 25 suicidal events for those taking fluoxetine compared with 7 in CBT (9). This already troubling risk benefit equation is actually an underestimate of the risk. Following the acute treatment phase, fluoxetine was prescribed to some patients in the placebo and CBT conditions and when those patients had a suicidal event, it was charged against their original non-drug assignment rather that the medication (10).

In sum, this article does not warrant the media hype it has received and certainly does not trump the large body of available evidence about antidepressant efficacy. Its major premise does not make common-sense (extremely small differences at 6 weeks translating to large response and remission differences) and its representation of the available evidence inaccurate. This assertion is only strengthened by consideration of the study’s sole reliance on clinician rated measures and the problems associated with industry affiliation.

References:

1. Gibbons RD, Hur K, Brown CH, Davis JM, Mann J. 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(6):572-579.

2. Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, Niederehe G, Thase ME, Lavori PW, Lebowitz BD, McGrath PJ, Rosenbaum JF, Sackheim HA, Kupfer DJ, Luther J, Fava M. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: A STAR*D report. Am J Psychiatry. 2006;163:1905-1917.

3. Pigott HE, Leventhal AM, Alter GS, Boren JJ. Efficacy and effectiveness of antidepressants: Current status of research. Psychother Psychosom. 2010;79(5):267-279.

4. March J, Silva S, Petrycki S, Curry J, Wells K, Fairbank J, Burns B, Domino M, McNulty S, Vitiello B, Severe J. Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression: Treatment for Adolescents With Depression Study (TADS) randomized controlled trial. JAMA. 2004;292:807–820.

5. Kirsch, I, Moore T, Scoboria A, Nichols, S. The emperor’s new drugs: An analysis of antidepressant medication data submitted to the U.S. Food and Drug Administration. Prev Treat. 2002;5(23):article 33.

6. Kirsch I, Deacon B, Huedo-Medina T, Scoboria A, Moore T, Johnson B. Initial severity and antidepressant benefits: A meta-analysis of data submitted to the Food and Drug Administration. PLoS Medicine. 2008;5(2): 260-268.

7. Fournier JC, DeRubeis RJ, Hollon SD, Dimidjian S, Amsterdam JD, Shelton RC, Fawcett J. Antidepressant drug effects and depression severity: A patient-level meta-analysis. JAMA. 2007;303(1): 47–53.

8. Turner EH, Matthews AM, Eftihia Linardatos BS, Tell RA, Rosenthal R. Selective publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med. 2008;358(3):252-260.

9. March JS, Silva S, Petrycki S, Curry J, Wells K, Fairbank J, Burns B, Domino M, McNulty S, Vitiello B, Severe J. The Treatment for Adolescents With Depression Study (TADS): Long-term effectiveness and safety outcomes. Arch Gen Psychiatry. 2007;64:1132–43.

10. Vitiello B, Silva SG, Rohde P, Kratochvil CJ, Kennard BD, Reinecke MA, Mayes TL, Posner K, May DE, March JS. Suicidal events in the Treatment for Adolescents With Depression Study (TADS). J Clin Psychiatry. 2009;70(5): 741-747.

Duncan and colleagues criticize our paper on “Benefits from Antidepressants” because it reaches different conclusions regarding the efficacy of antidepressants than the STAR*D and TADS studies. They provide no methodologic basis for this criticism. They question how a small mean difference in adults of 2.55 points on the HAM-D and 4.62 on the CDRS-R translate to combined 32.2% and 54.1% response/remission rates over placebo for adults and youth respectively. The logical fallacy is that a change in the mean of the distribution restricts the magnitude of what occurs in the tails of the distribution. “Small” differences on average can translate into quite large differences in more clinically meaningful effects such as response and remission rates which is clearly made evident by our study. Furthermore, our research synthesis made full use of all available data from all subjects from all studies whereas previous meta-analyses have been restricted to end-point analyses for which the treatment of missing data was inconsistent. With respect to the relationship between the length of the studies and the efficacy of treatment, Duncan and colleagues are also mistaken. Comparison of the results from our efficacy paper with the mediator analysis in our safety paper, which covered patient data through 12 weeks, revealed that the improvement for adults and geriatrics was 2.55 HAMD units at 6 weeks and increased to 4.03 at 12 weeks. For youth the gain was 4.62 units at 6 weeks and was only slightly lower at 3.90 units at 12 weeks. These results indicate that the efficacy of treatment does not disappear with time as suggested by Duncan and colleagues.

Finally, Duncan and colleagues take exception with our suggestion that these data provide evidence which contradicts the black box warning. The black box warning was based in part on the purported lack of efficacy of antidepressants in the treatment of depression in youth. The findings of our paper suggest that the benefits were miscalculated in the risk benefit equation that led to the black box warning.