Preclinical evidence for the efficacy of angiotensin receptor antagonism in a rodent model of vulnerability to comorbid depression and cardiovascular disease

摘要

Major depressive disorder and cardiovascular disease are highly comorbid, and the presence of one disorder greatly increases the likelihood of the other. Remarkably, depressed but otherwise healthy patients with no history of cardiovascular disease are as likely to have a heart attack as patients with established cardiovascular disease. Experimental studies have used chronic mild stress (CMS), a rodent model of depression that uses a series of unpredictable, intermittent, and variable mild stressors to induce anhedonia, one of the core diagnostic criteria for major depression. CMS also induces a constellation of behavioral, physiological, and neuroendocrine responses that closely resemble those observed in depressed patients, including alterations in autonomic control of the heart marked by decreased heart rate variability (HRV). Commonly prescribed antidepressants might not improve cardiovascular alterations associated with depression, even when depressive signs are ameliorated. There is evidence, however, that candesartan, an angiotensin type 1 receptor (AT1R) antagonist (ARB) often prescribed for cardiovascular disorders, has anxiolytic and possibly antidepressant effects in animal models. To study the possible antidepressant effects of candesartan, we first established a robust rodent model of vulnerability to depression, since severity of depression is correlated with severity of cardiovascular changes in humans. We found that rats selectively-bred for low locomotor responses to a novel environment (bLR) were especially vulnerable to CMS-induced anhedonia and cardiovascular changes. Conversely, selectively-bred high-responder rats (bHR) were resilient to the behavioral and cardiovascular changes induced by CMS. Finally, we compared the effects of candesartan and the SSRI fluoxetine on CMS-induced anhedonia and cardiovascular changes. We found that candesartan has profound antidepressant effects, including rapid reversal of anhedonia, and attenuated anxiety-like behavior. Furthermore, candesartan reversed cardiovascular changes, including clinically relevant markers of risk for cardiac mortality. Thus the major findings of these studies are twofold: (1) bHR/bLR rats exposed to CMS offer a robust model of the interactions of predisposition and environmental stress that may contribute to depression and comorbid cardiovascular disease and (2) candesartan and other ARBs may be novel therapies for the treatment of comorbid depression and cardiovascular disease, and may be more effective than traditionally-prescribed antidepressants such as SSRIs.