Plasminogen Activator Inhibitor-1 in the Pathophysiology of Late Life Depression

Late life depression (LLD) is characterized by specific clinical features including a high frequency of vascular form and frequent antidepressant treatment resistance. The expression and functions of the serine protease inhibitor, Plasminogen Activator Inhibitor-1 (PAI-1) is known to be altered by aging, vascular damage, insulin levels associated with a sedentary lifestyle, chronic stress leading to hypercortisolemia, and inflammatory changes linked to stress responses. These phenomena would be implicated in LLD like vascular depression. This article thus aims to review the existing literature regarding the association between LLD and plasmatic levels of PAI-1, a marker of hypofibrinolysis. We hypothesize that increased age would be associated with changes in PAI-1 plasma level and function which influence LLD pathogenesis and its treatment.

Although a large number of studies on PAI-1 changes in the elderly exist, studies about its implications in LLD are sparse. Despite heterogeneous findings regarding the direction of variation in plasmatic PAI-1 levels among elderly participants with LLD, all studies demonstrated an association between PAI-1 levels and current or remitted depressive symptoms. Moreover, disruptions in the concentrations of other biological markers influencing PAI-1 expression, such as cytokines or adipokines, were also observed, notably an increase in the levels of interleukins 6 and 8.

LLD genesis appears to be influenced by PAI-1 regulatory loops which are implicated in senescence or cell death. The resistance to antidepressant treatment appears to be linked to distinct biological profiles involving inflammatory and fibrinolytic factors. Taken together these data suggest that PAI-1 pathway may be a promising target of treatment development efforts for LLD, and depression in general.