Exploring the Renin–Angiotensin System as a Potential Approach for Managing Perimenopausal Depression

Perimenopause is characterised by debilitating psychological symptoms, includinga two- to four-fold increased risk of depressive symptoms during this sensitive time. Current first-line treatment strategies, such as antidepressants and hormonal therapy, are proven to be only moderately effective and linked to severe adverse effects. With the population of perimenopausal women rapidly growing due to rising life expectancy, novel strategies to prevent or mitigate perimenopausal symptoms of depression are of increasing importance.Perimenopause is marked by pronounced sex-hormone changes, primarily declining oestrogen. Both have been linked to increased depression risk. On the other hand, the renin–angiotensin system (RAS), an endocrine system involved in blood pressure regulation, has been linked to depression, with RAS-based pharmacological manipulations having antidepressant effects. Perimenopausal hormonal changes closely interact with the RAS by upregulating the depressogenic Ang II–ACE–AT₁R pathway and downregulating the protective Ang-(1–7)–ACE2–MasR/AT₂R pathway. This narrative review summarises research highlighting the RAS as a potential novel treatment target for depression in perimenopausal women and proposes a hypothesis-generating framework to guide future research.