Guidelines for the pharmacological acute treatment of major depression: conflicts with current evidence as demonstrated with the German S3-guidelines

Several international guidelines for the acute treatment of moderate to severe unipolar depression recommend a first-line treatment with antidepressants (AD). This is based on the assumption that AD obviously outperform placebo, at least in the case of severe depression. The efficacy of AD for severe depression can only be definitely clarified with individual patient data, but corresponding studies have only been available recently. In this paper, we point out discrepancies between the content of guidelines and the scientific evidence by taking a closer look at the German S3-guidelines for the treatment of depression. Based on recent studies and a systematic review of studies using individual patient data, it turns out that AD are marginally superior to placebo in both moderate and severe depression. The clinical significance of this small drug-placebo-difference is questionable, even in the most severe forms of depression. In addition, the modest efficacy is likely an overestimation of the true efficacy due to systematic method biases. There is no related discussion in the S3-guidelines, despite substantial empirical evidence confirming these biases. In light of recent data and with their underlying biases, the recommendations in the S3-guidelines are in contradiction with the current evidence. The risk-benefit ratio of AD for severe depression may be similar to the one estimated for mild depression and thus could be unfavorable. Downgrading of the related grade of recommendation would be a logical consequence.