The Candesartan Adjunctive Depression Trials-CADET: Study Protocols for Double-Blind, Randomized, Placebo-Controlled Trials for Bipolar Depression and Major Depressive Disorder.

BACKGROUND

Depression in both bipolar and major depressive disorder remains a major unmet need due to treatment resistance to the existing treatments. Emerging evidence implicates the renin-angiotensin system in regulating the cellular stress response relevant to depression, suggesting it as a novel therapeutic target for depression. Candesartan, a common hypertension medication, decreases neuroinflammation, oxidative and nitrosative pathway activation, and neurotrophic signalling of angiotensin II by predominantly blocking the angiotensin II type 1 receptors (AT1R). Given AT1R-induced activities are implicated in the pathophysiology of bipolar and major depressive disorder and with supportive pharmacoepidemiology data, candesartan may represent a novel antidepressant strategy.

METHODS

The CADET Trials are 2 parallel 16-week double-blind randomized placebo-controlled trials of adjunctive candesartan (or placebo) for the treatment of bipolar depression (CADET-BD) and major depressive disorder (CADET-UD). Each trial aims to recruit 240 adult participants. The primary outcome is the between-group (ie, intervention vs. placebo) differential change from baseline to week 16 in depression symptoms as measured by the Montgomery Åsberg Depression Rating Scale. Secondary outcomes measure depression, mania, anxiety, quality of life, cost-effectiveness, functioning, substance use, cognition, and biological markers.

FINDINGS: Findings are not yet available as the trial is ongoing.

IMPLICATIONS: The CADET Trials examine the efficacy of candesartan in reducing depressive symptoms in both unipolar and bipolar depression, and whether its effects are mediated through the renin-angiotensin system. Candesartan is affordable, accessible, and well-tolerated. If effective, it could quickly be adopted into clinical practice as a new adjunctive medication for the treatment of these disorders.