Irving Kirsch; Brett J Deacon; Tania B Huedo-Medina; Alan Scoboria; Thomas J Moore; Blair T Johnson

“ Specifically, a meta-analysis of clinical trial data submitted to the US Food and Drug Administration (FDA) revealed a mean drug–placebo difference in improvement scores of 1.80 points on the Hamilton Rating Scale of Depression (HRSD) [ [2] , whereas the National Institute for Clinical Excellence (NICE) used a drug–placebo difference of three points as a criterion for clinical significance when establishing guidelines for the treatment of depression in the United Kingdom [ [1] . Mean improvement scores can obscure differences in improvement within subsets of patients. ”

“ By that criterion, the differences between drug and placebo were not clinically significant in clinical trials involving either moderately or very severely depressed patients, but did reach the criterion for trials involving patients whose mean initial depression scores were at the upper end of the very severe depression category (mean HRSD baseline ≈ 28; Figures 2–4) . Given these data, there seems little evidence to support the prescription of antidepressant medication to any but the most severely depressed patients, unless alternative treatments have failed to provide benefit. ”

“ The first analysis permitted a determination of the absolute magnitude of change in both the placebo and treatment groups. Results permitted a determination of overall trends, analyses of baseline scores in relation to change, and for both types of models, tests of model specification, which assess the extent to which only sampling error remains unexplained. The results in raw metric are presented comparing both groups, but because of the variation of the SDcs, the standardized mean difference was used in moderator analyses in order to attain better-fitting models [12] . ”

“ Had groups with a wider array of baseline depression scores been assessed, the curvilinear pattern might have been more obvious; in which case, clinically significant benefits for severely depressed patients might have been obtained. To perform this task in an unbiased way, it would be necessary for data for all approved medications to be available, even those gathered after the medication is approved. ”

“ The solid blue regression line represents the trend across all 35 trials; the dashed red line represents the trend excluding the left-most observation. A visual inspection of Figure 4 suggests that studies' effects are fairly evenly distributed above and below the NICE criterion (3) but that most small studies have high baselines and show large effects. Although sample size (N) was negatively linked to the drug-versus-placebo differences (β = −0.34, p = 0.003) , when mean baseline severity values are controlled, this effect disappears and the baseline effect remains significant. ”

“ The answers to each question are given a score and a total score for the questionnaire of more than 18 indicates severe depression. Mild depression is often treated with psychotherapy or talk therapy (for example, cognitive–behavioral therapy helps people to change negative ways of thinking and behaving) . For more severe depression, current treatment is usually a combination of psychotherapy and an antidepressant drug, which is hypothesized to normalize the brain chemicals that affect mood. ”

“ Both Q [15] and I2 [16] indices were used to assess inconsistencies from the models, not only to infer the presence or absence of homogeneity, but also (in the case of I2) to assess the degree of inconsistencies among trials [17] . ”

“ However, this difference seems to result from a poorer response to placebo amongst more depressed patients.==Abstract== Editors' Summary
Background.
Everyone feels miserable occasionally. But for some people—those with depression—these sad feelings last for months or years and interfere with daily life. Depression is a serious medical illness caused by imbalances in the brain chemicals that regulate mood. It affects one in six people at some time during their life, making them feel hopeless, worthless, unmotivated, even suicidal. ”