Over-adjustment leads to underestimation of hypnotic risks Daniel Kripke, UCSD 14 October 2013 This excellent paper of Jaussent and colleagues is indeed among the best studies which have been reported concerning hypnotic-associated risks. As the manuscript asserts, an outstanding strength of the study is the number of potential confounders which have been included in the model, some of which were measured with excellent methods. An important limitation is the absence of hypnotics dosage and dose-response data. Much of the statistical approach is admirable. Also, as the manuscript emphasizes, the results¿if accurate--do imply that mortality associated with hypnotics consumption might result primarily from confounding factors. Unfortunately, the manuscript seriously underestimated the possibility that overadjustment of intermediate variables could obscure the causal pathway between hypnotics intake and mortality. Several of the covariate measures of morbidity are not independent risk factors, but have been proven by controlled trials to be caused or exacerbated by hypnotics. Prominent among these are depression (and by inference, antidepressant use), impairments of cognition (e.g., Mini Mental State), and excessive daytime sleepiness [1-3]. Depression, impaired cognition, and excessive daytime sleepiness, in turn, are likely contributors to confinement. Considering that 21.7% of participants were taking at least one hypnotic at baseline, the great majority for more than 5 years, it is virtually a certainty that hypnotic usage was a causal factor in these comorbidities at baseline, and that adjustment for these intermediate variables produced a element of over-adjustment. Thus, hypnotic use might have appeared a significant mortality risk if over-adjustment had been avoided. There are several sensitivity analyses which might allow us to appraise the importance of over-adjustment. First, what were the mortality hazard ratios associated with hypnotic usage when participants who had ever used hypnotics at baseline were excluded, so that the hazard estimates were based entirely upon prospective usage of hypnotics after baseline comorbidities had been employed to control for confounding? Second, what were the mortality hazard ratios among participants who used hypnotics at all follow-ups before death? Were participants who only took 1-2 DDD per month included as users? Perhaps the authors could clarify whether the Cox proportional hazard models were time-dependent models in which the timing of incident comorbidities in relationship to the timing of hypnotic usage might be evaluated. Were stepwise models employed, and if so, what were the criteria for entry or removal of each covariate from the stepwise models? Inclusion of excessive covariates which are not independently significant or collinearities could also cause an element of over-adjustment. Incidentally, it is interesting that insomnia complaints were NOT significant predictors of deaths during follow-up, although insomnia has often been claimed to be a confounder of hypnotic mortality studies. Because of the complexity of causal interactions between hypnotics, comorbidities, and various behavioral elements, it will never be possible to be confident that an epidemiologic design is safe both from confounding and from over-control. Obviously, hypnotics manufacturers such as the authors¿ sponsor, Sanofi-Synthélabo, have no intention of doing large enough controlled trials to assure us that their products do not cause excess mortality or cancer. Controlled trials are already available showing that certain hypnotics do cause cancers in experimental animals. Perhaps Mendelian randomization studies will prove the only realistic method of being reasonably certain whether hypnotics do or do not cause excess mortality and cancer. Reference List 1. Kripke DF. Greater incidence of depression with hypnotics than with placebo. BMC Psychiatry 2007, 7:42. 2. Boyle J, Groeger JA, Paska W, et al. A Method to Assess the Dissipation of Residual Hypnotics: Eszopiclone Versus Zopiclone. J Clin Psychopharmacol 2012, 32:704-709. 3. Johnson LC, Chernik DA. Sedative-hypnotics and human performance. Psychopharmacology (Berlin) 1982, 76:101-13. Competing interests DFK is a long-time critic of hypnotic drugs via his web site, www.DarkSideOfSleepingPills.com, now available in Kindle. The Kripke family own shares in a mutual investment corporation which holds a small percentage of its capital in Sanofi-Aventis.