Abstract
Several observational studies have found a link between the long-term use of benzodiazepines and dementia, which remains controversial. Our study was designed to assess (i) whether the long-term use of benzodiazepines, at two different doses, has an irreversible effect on cognition, (ii) and whether there is an age-dependent effect. One hundred and five C57Bl/6 male mice were randomly assigned to the 15 mg/kg/day, the 30 mg/kg/day diazepam-supplemented pellets, or the control group. Each group comprised mice aged 6 or 12 months at the beginning of the experiments and treated for 16 weeks. Two sessions of behavioral assessment were conducted: after 8 weeks of treatment and after treatment completion following a 1-week wash-out period. The mid-treatment test battery included the elevated plus maze test, the Y maze spontaneous alternation test, and the open field test. The post-treatment battery was upgraded with three additional tests: the novel object recognition task, the Barnes maze test, and the touchscreen-based paired-associated learning task. At mid-treatment, working memory was impaired in the 15 mg/kg diazepam group compared to the control group (p = 0.005). No age effect was evidenced. The post-treatment assessment of cognitive functions (working memory, visual recognition memory, spatial reference learning and memory, and visuospatial memory) did not significantly differ between groups. Despite a cognitive impact during treatment, the lack of cognitive impairment after long-term treatment discontinuation suggests that benzodiazepines alone do not cause irreversible deleterious effects on cognitive functions and supports the interest of discontinuation in chronically treated patients.
Highlights
Benzodiazepines, allosteric agonists of the γ-aminobutyric acid (GABA) A receptor, are a class of psychotropic drugs commonly prescribed to treat acute anxiety and/or insomnia [1]
Plasma concentrations of diazepam and its metabolites The plasma profiles showed that diazepam was rapidly metabolized to its active metabolites, including nordiazepam and oxazepam (Table 1)
The accumulation of oxazepam was significantly greater in the middle-aged group compared to the mature group, p = 0.002 and greater for both oxazepam and nordiazepam in the diet group at 30 mg/kg/day (D30) group vs the diet group at 15 mg/kg/day (D15) group, p < 0.001
Summary
Benzodiazepines, allosteric agonists of the γ-aminobutyric acid (GABA) A receptor, are a class of psychotropic drugs commonly prescribed to treat acute anxiety and/or insomnia [1]. The major concern arising from observational studies in this population is an increased risk of irreversible cognitive deficits leading to dementia after long-term use of benzodiazepines [8,9,10]. According to these studies, the risk magnitude may be influenced by treatment duration, dosage used, and probably benzodiazepine half-life [11]. First hypothesis: benzodiazepines have no influence on age-related cognitive decline and these conflicting results can be explained by methodological issues such as the protopathic bias, since the main indications for benzodiazepines (anxiety, insomnia) can be prodromes of dementia [12, 13]
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