Do not blame the SSRIs: blame the Hamilton Depression Rating Scale

Dear Editor, In their recent paper entitled ‘Selective serotonin reuptake inhibitors versus placebo in patients with major depressive disorder. A systematic review with meta-analysis and Trial Sequential Analysis’ (1), Jakobsen et al. conclude that ‘The observed harmful effects seem to outweigh the potential small beneficial clinical effects of SSRIs, if they exist’ (1). In a follow-up article in a Danish popular science journal (Videnskab.dk), Jakobsen is quoted for the following statement on the selective serotonin reuptake inhibitors (SSRIs) (freely translated from Danish): ‘We are dealing with medicine that affects important neurotransmitters in the brain and has severe side effects. To justify giving this to people, we have to be sure that it works against depression. But it doesn’t’ (2). This message was broadly disseminated via the Danish news media in the days following the publication of the meta-analysis. It is very important to communicate research findings to the general public. However, when making as blunt a statement as the one outlined above, which is likely to affect both the opinion and behaviour of individuals (for instance, the adherence to SSRI treatment or the likelihood of accepting SSRI treatment when indicated), researchers are ethically obliged to ensure that their interpretation of their results is completely unchallengeable. Below, I will make the argument that the interpretation made by Jakobsen et al. is far from unchallengeable, and that the statements in the paragraph above are therefore highly questionable. Jakobsen et al. have performed a very extensive systematic search of both published and unpublished results of randomised clinical trials (RCTs) comparing the effect of SSRIs with that of placebo (1). They are to be complimented for that effort. Most of the RCTs included in the meta-analysis used the total score on the 17-item or the 21-item Hamilton Depression Rating Scale (HDRS) (3) as the outcome measure, and the primary results in the article by Jakobsen et al. (1) therefore also refer to the HDRS. The results of their meta-analyses ‘showed that SSRIs versus placebo significantly reduced the HDRS score (mean difference −1.94 points; 95% CI −2.50 to −1.37; p<0.00001)’ (1). Jakobsen et al. consider this ‘numerical’ superiority of the SSRIs over placebo on the HDRS to be below the threshold for clinical significance (3 points on the HDRS), which was suggested by the National Institute for Clinical Excellence (NICE) from the United Kingdom. Thus, the difference between 1.94 and 3 is essentially what leads Jakobsen et al. to the conclusion that there are only ‘small beneficial clinical effects of SSRIs, if they exist’ (1). The rationale for this conclusion may seem bulletproof, but there is a fundamental problem with the HDRS as outcome measure, which Jakobsen et al. do not take into consideration. The HDRS was developed in 1960 (3) and consists of 17 symptom items in the original version (the 21-item version was never intended to be used for severity measurement in depression according to the scale’s developer Max Hamilton (4)). In the RCTs included in the meta-analysis by Jakobsen et al., the total score of these items is used as a measure for the overall severity of depression – and reduction in the HDRS total score over time is used as a measure of clinical improvement. In order for the total score to actually contain this clinical information, the HDRS must meet two fundamental criteria: (I) the total score of the items must correlate with evaluations of depressive severity made by clinical experts (gold standard), and (II) each of the items must convey unique information regarding the severity of the latent syndrome being measured, that is, depression (this is commonly referred to as ‘unidimensionality’ or ‘scalability’ (5)). In two landmark studies from 1975 (6) and 1981 (7), respectively, Bech et al. demonstrated that the original HDRS met none of these two criteria. This lack of psychometric validity of the HDRS has been confirmed in a large number of studies since then (8–15). Therefore, the total score of the HDRS cannot be considered as a clinically valid measure of the severity of depression (5,16). As the conclusions made by Jakobsen et al. (1) are based on the results of analyses of HDRS total scores, it entails that they are not clinically valid either.