Unraveling the role of the renin-angiotensin system in severe mental illnesses: An insight into psychopathology and cognitive deficits

Severe mental illnesses (SMI), especially schizophrenia and bipolar disorder (BD), are associated with significant distress to patients, reduced life expectancy and a higher cost of care. There is growing evidence that SMI may increase the risk of dementia in later life, posing an additional challenge in the management of these patients. SMI present a complex and highly heterogeneous pathophysiology, which has hampered the understanding of its underlying pathological mechanisms and limited the success of the available therapies. Despite the advances in therapeutic approaches in psychiatry over the past decades, treatment resistance is still a common problem in clinical practice, highlighting the urgent need for novel therapeutic targets for SMI. The discovery that renin-angiotensin system (RAS) components are expressed in the central nervous system opened new possibilities for investigating a potential role for this system in the neurobiology of SMI. The safety and efficacy of AT₁ receptor blockers and angiotensin-converting enzyme inhibitors in cardiovascular and metabolic diseases, common medical comorbidities among SMI patients and well-known risk factors for dementia, suggest the potential scalability of these strategies for the management of SMI outcomes including the risk of subsequent dementia. This review aimed to discuss the available evidence from animal models and human studies of the potential involvement of RAS in the pathophysiology of SMI. We also provided a reflection on drawbacks and perspectives that can foster the development of new related therapeutic strategies.