The Renin-Angiotensin System: a fresh new direction in the treatment of depression

A recent review article published in BMC Medicine explores the potential positive effects that angiotensin blockers, acting on the renin-angiotensin system, may have on depression. The authors hope that filling gaps between serendipitous observations and targeted molecular observations can contribute to antidepressant development in a new era in depression treatment.

Depression is a tough enemy to patients, to friends or family and to doctors. It gnaws away something at the core of being alive, the ability to feel pleasure. Depression is unfortunately fairly common and a leading cause of disability worldwide. The best treatments we have are limited as only about a third of people with depression fully respond after the first treatment, making use of multiple treatments common and residual symptoms the rule, not the exception.

Untreated depression can culminate in suicide. Therefore a need for innovative options is evident; ‘precision psychiatry’ aims to extend advanced diagnostic and therapeutic technologies already fundamental in other clinical specialties to psychiatry.

The first antidepressants were discovered in the 1950’s by serendipity. Tuberculosis patients treated with Iproniazid suddenly showed a new vitality and even began dancing in the hospital halls. Imipramine, another early antidepressant, was first tested as an antihistamine, and unexpected effects on mood were observed.

Early research found that these all were targeting the monoamine system, and these findings ushered in a new era in the treatment of depression. An era we are still living in to a large extent.

The message from these stories is that an advance in one given area can carry secrets and new information relevant to another area. Its sadly true that this has been a far more fruitful avenue for the discovery of the psychiatric therapies that we use today than approaches primarily developed from the molecular level.

However, contrary to the monoamine system case, the idea that drugs targeting the renin-angiotensin system can treat depression has deep roots in both worlds. It has a serendipity component, with case reports that date from the 1980’s showing that drugs that target the renin-angiotensin system may have effects on mood. And this story also began with a strong molecular argument, with a solid rationale based on effects on the stress response system and inflammation. A recent large epidemiological study suggested a protective effect of these agents on the development of depression [12].

Several anti-inflammatory drugs such as celecoxib, aspirin or statins may exhibit antidepressant properties.

One exciting direction regarding these drugs that we explore in this review is the stress response and inflammatory hypothesis of depression. Inflammatory markers are elevated during a depressive episode and at least some tend to normalize after it remits.

Drugs that target the renin-angiotensin system like the angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) are well established in the treatment of hypertension, but they also have anti-inflammatory properties. Several anti-inflammatory drugs such as celecoxib, aspirin or statins may exhibit antidepressant properties.

Furthermore, drugs that target the renin-angiotensin system have been studied and tested in large samples and for long periods of time and have been compared to other antihypertensive drugs without the anti-inflammatory properties [345]. The anti-depressant action appears unrelated to the lowering of blood pressure as other anti-hypertensive drugs such as beta-blockers or calcium channel blockers do not lower the risk of depression.

By filling the gaps between serendipitous observations and a targeted molecular explanation, we hope to contribute to the start of a new era in the treatment of depression and inspire new clinical trials and biomarker research. Because these drugs are relatively safe and already in wide use, they could be quickly repurposed and provide relief in an area plagued by a heavy morbidity burden and underwhelming therapy developments.

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