1. Main findings

The association between long-term benzodiazepine use and risk of dementia has received significant attention but is still in debate. A most recent systematic review of observational studies (cohort and case-control studies) found that the long-term users of benzodiazepines have a 1.5- to 2-fold increased risk of developing dementia compared with never users [28]. On the basis of nested case-control and prospective cohort studies, our meta-analysis found that compared with never users, long-term benzodiazepine users (ever, recent and past users) were at an elevated risk of dementia when we pooled either unadjusted RRs or adjusted RRs, which was consistent with the findings of previous review [28].

The prodromal symptoms of dementia, including sleep disturbance, anxiety and depression [29–31], can occur around 10 years preceding a clinical diagnosis of dementia [32]. The presence of these psychiatric symptoms may motivate physicians to prescribe benzodiazepines. Thus, some researchers raise concerns that the observed association between benzodiazepine use and dementia may be due to confounding by indication and reverse causation [31, 33]. Nonetheless, the following facts possibly attenuate these concerns. First, it is found that the frequency of prodromes increases when dementia onset is approaching [32]. On the basis of this fact, the strength of the association for recent users should be stronger than that for past users if reverse causation is the case in the association of benzodiazepine use and dementia. However, our review observed similar risk estimates for recent and past users. Second, when we confined our analyses to RRs with adjustment for anxiety or depression, most but not all pooled results persisted. Third, a significant dose-response pattern was observed in the present study, although it was derived from limited numbers of included studies. Such finding supports a causal relationship between benzodiazepine use and dementia. Finally, our results are consistent with findings from an individual study [12] that had a mean follow-up of 22 years. The follow-up length in that study [12] was long enough to overcome the hypothesis of reverse causation.

The prevalence of psychotropic medication use among the elderly is high [34, 35], with a reported prevalence of up to 73% in subjects aged 65 years and over [34]. Use of psychotropic medications except benzodiazepines has been found to be associated with an increased risk of dementia [36, 37]. These facts provide a critical reminder that our findings might be biased by use of other psychotropic medication among included study population. There are two extreme conditions regarding this bias: one is that subjects in the exposure group concurrently use other psychotropic medications but those in the non-exposure group not, another is that subjects in the non-exposure group use other psychotropic medications but those in the exposure group not. The former condition results in an overestimated risk of dementia associated with benzodiazepine use, while the latter condition will underestimate that risk. Due to complex circumstances in the real world, unfortunately, we cannot ascertain the specific effect of use of other psychotropic medications on the magnitude and direction of the association between benzodiazepine use and dementia. Nonetheless, several included studies [13, 14, 27] treated benzodiazepine-related drugs, such as Z-drugs, as benzodiazepines, which produced a possibility of overestimating the risk of dementia in relation to benzodiazepine use.

Of included studies, ever use of benzodiazepines was consistently defined as benzodiazepine use during follow-up, namely use of benzodiazepines at least once before the index date. The consistent definition increased the reliability of our pooled results for the association between ever use of benzodiazepines and dementia. However, we observed that the cut-off points between recent use and past use among included studies varied from 2 years [27] to 12 years [12]. The selection of different cut-off points among included studies may be related to differences in the follow-up duration and interval between two follow-up visits. The different cut-off points represent inconsistent definitions of recent and past use of benzodiazepines among included studies. Under this condition, the exact definitions of recent and past use of benzodiazepines for the pooled results are uncertain. Consequently, the utility value of the findings associated with recent and past use of benzodiazepines may be affected to some extent. Nonetheless, our findings regarding recent and past use of benzodiazepines may provide an important implication that stopping use of benzodiazepines cannot significantly reduce the risk of developing dementia.

In this meta-analysis, we calculated summary RRs from unadjusted and adjusted data. Interestingly, a significantly positive association of benzodiazepine use with risk of dementia was consistently observed in both conditions. Furthermore, on the basis of p values for the difference between two conditions calculated from meta-regression (data not shown), we found that there was no significant difference in magnitude of the pooled effect size between two conditions. Therefore, pooled results from unadjusted and adjusted risk estimates resulted in virtually identical interpretation for the association of benzodiazepine use with risk of dementia. Consequently, calculation of unadjusted and adjusted summary RRs makes our findings more convincing rather than more obscuring.