Antidepressant use in relation to long‐term dementia risk and imaging markers of neurodegeneration: a population‐based study of potential adverse effects

Abstract

AbstractBackgroundIn Europe, one in five adults uses antidepressants, with an increase in prescriptions of 20% per year. It has been suggested that antidepressant use might ultimately lead to adverse cognitive outcomes due to their anticholinergic properties. However, this impact remains largely undetermined, as randomised trials have limited follow‐up duration. We aimed to determine the association between antidepressant use and the long‐term risk of dementia in a population‐setting. In addition, we assessed the effect of antidepressant use on change in brain volume as measured with MRI.MethodBetween 2005‐2008, we included 5551 cognitively healthy participants of the population‐based Rotterdam Study (57.6% women, mean age 70.5 years). Detailed information on type of antidepressant (ATC‐coded), number of prescriptions, days of use and daily dose was extracted from pharmacy dispensing records from 1991 until baseline. Participants underwent neuropsychological testing and brain MRI every 2‐4 years. We determined the association of antidepressant use with incident dementia until 2018 using a Cox model, and with change in cognitive performance and brain MRI measures using linear mixed‐effects modelling. Models were adjusted for demographics, lifestyle variables, comorbidity and comedication. Furthermore, we explored the effect of slowed metabolization of antidepressants based on CYP2D6 genotype.ResultDuring a mean follow‐up of 10.2 years, 640 participants developed dementia. Antidepressant use was not associated with risk of all‐cause dementia (hazard ratio (HR) [95% confidence interval (CI)]: 0.87 [0.70;1.08]). This was similar for tricyclic antidepressants and serotonin‐reuptake inhibitors, and regardless of dose and duration. Antidepressant use was not associated with decline in general cognition (mean difference [95% CI] per standard deviation: 0.01 [0.00;0.01], nor with change in brain volume (mean difference [95% CI] per mm3; total volume: 15.19 [‐210.22;240.60], grey matter: ‐52.23 [‐179.45;74.99], white matter: 71.49 [‐93.03;236.01], hippocampus: ‐3.70 [‐8.18;0.78], amygdala: ‐0.60 [‐3.49;2.30], thalamus: 0.87 [‐6.14;7.88]). Similarly, among antidepressant users only, CYP2D6 genotype was not related to dementia risk (HR [95% CI] for amitriptyline users: 0.88 [0.76;1.02], paroxetine users: 0.83 [0.67;1.02]).ConclusionIn this population‐based study, antidepressant use was not associated with long‐term adverse effects on cognition or subclinical brain injury. These results are reassuring regarding safe prescription of antidepressive medication with respect to cognitive decline.