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The brain renin–angiotensin system: a target for novel antidepressants and anxiolytics

The renin–angiotensin system is best known for its role in the control of blood pressure, but a separate brain renin–angiotensin system exists that influences behaviour and affect. Since the development of drugs designed to reduce renin–angiotensin system activity for treatment of cardiovascular disorders, it has become increasingly apparent that these drugs also have central effects and thus may be of use in the treatment of affective disorders. Animal studies indicate that angiotensin‐converting enzyme (ACE) inhibitors and AT1 receptor antagonists exhibit antidepressant activity; furthermore, clinically proven antidepressants appear to reduce angiotensin function. In humans, the evidence suggests that depression may be weakly associated with an abnormality of the renin–angiotensin system and that these drugs may be able to alleviate depression in hypertensive patients. They have yet to be tested in normotensive depressed patients, although they are without psychological effect in healthy volunteers. In the case of anxiety, similar findings exist. Animal models indicate an anxiolytic effect of ACE inhibitors and AT1 receptor antagonists, and a reduction in the response to stress. In humans, the use of these drugs in hypertensive patients has been shown to be accompanied by a reduction in anxiety scores, but they have not been tested in normotensive, anxious patients and they have no effect in healthy volunteers. If these drugs are to be further developed for use in the treatment of affective disorders, the potential for hypotensive adverse effects needs to be addressed and the possibility of specific genotype differences in responses to therapy needs to be recognised. Drug Dev. Res. 65:270–277, 2005. © 2005 Wiley‐Liss, Inc.