Higher levels of plasma Adrenocorticotropic hormone (ACTH) are associated with lower suicidal ideation in depressed patients compared to controls and suicide attempters, independently from depression severity

Introduction: Suicidal ideation, an important risk factor for suicide attempts, has an unclear neurobiological basis and is potentially linked to the dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and immuneinflammatory systems. While inflammatory markers have been associated with suicide attempts and, to a lower extent suicidal ideation, the data on the role of a stress-response system is less robust, with most studies carried out with cortisol showing inconsistent results. The present study extends on the previous studies implicating stress-response and immune-inflammatory systems in suicidal thoughts and behaviours, focusing on the associations of several stress-response (adrenocorticotropic hormone (ACTH), cortisol, and dehydroepiandrosterone (DHEA)) and immune-inflammatory (C-reactive protein (CRP),interle ukin-6 (IL-6), and tumour necrosis factor-alpha (TNF-alpha)) with suicidal ideation severity in recent suicide attempters, patients with major depressive disorder, and non-psychiatric controls. Methods: This observational study included 156 adults from three Vilnius hospitals, recruited into one of the three groups in equal parts: recent suicide attempters, patients with major depressive disorder in current depressive episode, and non-psychiatric controls. Measures included the Hamilton Depression Rating Scale (HDRS-17) and the Beck Scale for Suicide Ideation/Suicide Severity Index (BSS/SSI), alongside sociodemographic data, alcohol, tobacco use, and morning blood samples, measuring plasma ACTH, cortisol, DHEA, CRP, and IL-6. Data were analysed with non-parametric tests, Kendall's tau correlation, and multivariate linear regression adjusted for confounders. Results: We found a negative correlation between the plasma ACTH levels and suicidal ideation severity (tau = -0.130, p = 0.033), which was driven by the patients with major depressive disorder (tau = -0.237, p = 0.031). Suicidal ideation severity was also negatively correlated with TNF-alpha (tau = -0.231; p < 0.001), positively correlated with IL-6 (tau = 0.154, p = 0.015), and CRP levels (tau = 0.153, p = 0.015), but no differences were observed in group-stratified analyses. The association between plasma ACTH levels and suicidal ideation severity in patients with major depressive disorder remained robust to adjustment for major confounders (adjusted for age, sex, education years, body mass index, smoking status, plasma CRP and PEth concentration (measuring chronic alcohol exposure), and antidepressant use) in the linear regression model (t = -2.71, p = 0.011), as well as additionally adjusting for depression severity (t = -2.99, p = 0.006). Discussion: The present study shows an association between plasma ACTH levels and suicidal ideation severity in patients with major depressive disorder, robust to adjustment for antidepressant use and depression severity. This finding highlights the potential role of ACTH, in elucidating the effects of stress and mental health disorders. Our findings underscore the importance of the HPA axis in the diagnosis and treatment of suicidal ideation in major depressive disorder and invite further research on interventions targeting this pathway.