Impact of Antidepressant Use on the Trajectory of Alzheimer's Disease: Evidence, Mechanisms, and Therapeutic Implications.

The relationship between antidepressants and Alzheimer's disease (AD) is very complex, and the literature is mixed regarding the effect of these medications on the trajectory of the disease. This paper reviews findings from relevant clinical studies that have assessed the impact of antidepressants on AD onset and disease progression. To date, these medications seem to attenuate the risk of developing the disease without affecting the rate of progression. However, most evidence stems from observational studies that are subject to methodological bias. Serotonergic antidepressants are thought to affect AD pathophysiology by reducing β-amyloid (Aβ) plaque formation and promoting hippocampal neurogenesis. However, the mechanisms underlying their effect need to be examined further, especially in humans. Moreover, more robust clinical studies in terms of design (randomized controlled trials) and longer duration of follow-up are needed. Variables, including depression timeline/onset and its clinical course, apolipoprotein E4 (APOE4) genotype status, sex, dose/duration of antidepressant treatment, and AD biomarkers need to be incorporated in future trials to better elucidate the effect of antidepressants on AD risk.