The Effects of Cognitive Therapy Versus ‘Treatment as Usual’ in Patients with Major Depressive Disorder Janus Christian Jakobsen 1,2 *, Jane Lindschou Hansen 2 , Ole Jakob Storebø 1 , Erik Simonsen 1 , Christian Gluud 2 1 Psychiatric Research Unit, Copenhagen University Hospital, Region Zealand, Roskilde, Denmark, 2 Copenhagen Trial Unit, Department 3344 Rigshospitalet, Centre for Clinical Intervention Research, Copenhagen University Hospital, Copenhagen, Denmark Abstract Background: Major depressive disorder afflicts an estimated 17% of individuals during their lifetimes at tremendous suffering and costs. Cognitive therapy may be an effective treatment option for major depressive disorder, but the effects have only had limited assessment in systematic reviews. Methods/Principal Findings: Cochrane systematic review methodology, with meta-analyses and trial sequential analyses of randomized trials, are comparing the effects of cognitive therapy versus ‘treatment as usual’ for major depressive disorder. To be included the participants had to be older than 17 years with a primary diagnosis of major depressive disorder. Altogether, we included eight trials randomizing a total of 719 participants. All eight trials had high risk of bias. Four trials reported data on the 17-item Hamilton Rating Scale for Depression and four trials reported data on the Beck Depression Inventory. Meta- analysis on the data from the Hamilton Rating Scale for Depression showed that cognitive therapy compared with ‘treatment as usual’ significantly reduced depressive symptoms (mean difference 22.15 (95% confidence interval 23.70 to 20.60; P,0.007, no heterogeneity)). However, meta-analysis with both fixed-effect and random-effects model on the data from the Beck Depression Inventory (mean difference with both models 21.57 (95% CL 24.30 to 1.16; P = 0.26, I 2 = 0) could not confirm the Hamilton Rating Scale for Depression results. Furthermore, trial sequential analysis on both the data from Hamilton Rating Scale for Depression and Becks Depression Inventory showed that insufficient data have been obtained. Discussion: Cognitive therapy might not be an effective treatment for major depressive disorder compared with ‘treatment as usual’. The possible treatment effect measured on the Hamilton Rating Scale for Depression is relatively small. More randomized trials with low risk of bias, increased sample sizes, and broader more clinically relevant outcomes are needed. Citation: Jakobsen JC, Hansen JL, Storebø OJ, Simonsen E, Gluud C (2011) The Effects of Cognitive Therapy Versus ‘Treatment as Usual’ in Patients with Major Depressive Disorder. PLoS ONE 6(8): e22890. doi:10.1371/journal.pone.0022890 Editor: Josef Priller, Charite ´-Universita ¨tsmedizin Berlin, Germany Received February 23, 2011; Accepted June 30, 2011; Published August 4, 2011 Copyright: ß 2011 Jakobsen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: These authors have no support or funding to report. Competing Interests: The authors have declared that no competing interests exist. * E-mail: janusjakobsen@mac.com Introduction According to the WHO, major depressive disorder is the second largest healthcare problem worldwide in terms of disability caused by illness [1]. It afflicts an estimated 17% of individuals during their lifetimes at tremendous cost to the individual and society [2,3], and roughly a third of all depressive disorders take a chronic course [4,5]. Compared to other medical disorders, major depres- sive disorder causes the most significant deterioration in individual life quality [6]. Approximately 15% of depressive patients will commit suicide over a 10 to 20 year period [7]. Antidepressant medication remains the mainstay in the treat- ment of depression [8]. However, meta-analyses have shown that newer antidepressants presumably only obtain beneficial effect in severely depressed patients, and this effect seems to be clinically small [9,10]. Antidepressants might, however, decrease the risk of relapse [11]. The therapeutic benefits of antidepressants seem to be limited and this raises the question if there are other effective treatments for this serious illness? Aaron T. Beck originally developed cognitive therapy for depression [12]. Beck believed that critical life events could accentuate hidden negative beliefs, which could generate nega- tive automatic thoughts. These negative thoughts could lead to symptoms of depression, which then could reinforce more negative automatic thoughts. The main goal of the ‘cognitive model of depression’ is to correct these negative beliefs and thoughts in order to treat the depressive symptoms [12]. A Cochrane review shows that cognitive therapy has a preventive effect against recur- rent depression, and that this effect clearly surpasses the preventive effects of antidepressant medication [13]. Furthermore, cognitive therapy appears to be an effective treatment for major depressive disorder [14], but we were unable to find any meta-analysis with Cochrane methodology [15] examining the effect of cognitive therapy versus ‘treatment as usual’ for major depressive disorder. Methods We conducted our systematic review of randomized clinical trials involving meta-analysis [15] and trial sequential analysis [16,17] to answer the question: what are the beneficial and harmful effects of cognitive therapy versus ‘treatment as usual’ in the treatment of major depressive disorder? We used assessment of PLoS ONE | www.plosone.org 1 August 2011 | Volume 6 | Issue 8 | e22890