Assessing the neuroendocrine and psychological effects of acute everolimus administration in healthy male participants

Abstract

Previous experimental studies have shown that immunosuppressive mechanistic target of rapamycin inhibitors can induce neuropsychological changes, such as anxiety and depression, in healthy rodents. Furthermore, psychiatric conditions including anxiety have been reported in transplant patients and healthy subjects receiving the mechanistic target of rapamycin inhibitor everolimus. Thus, the present study aimed to further investigate the potentially dose-dependent neuroendocrine and psychological adverse side effects of acute everolimus intake in healthy male subjects. To this end, P70S6 kinase and Akt expression and phosphorylation in peripheral mononuclear blood cells as well as plasma and saliva cortisol, plasma noradrenaline and plasma dehydroepiandrosterone sulfate have been evaluated via western blotting and ELISA. State anxiety and depression have been assessed using questionnaires. Administering 2.5 mg of everolimus four times significantly increased blood peak levels. Additionally, acute everolimus intake led to decreased P70S6 kinase and slightly increased Akt phosphorylation, while protein expression remained unregulated. However, no effects on neuroendocrine parameters including cortisol, noradrenaline and dehydroepiandrosterone sulfate have been reported. Consistent with these findings, acute everolimus administration had no impact on psychological parameters, such as anxiety and depression. Overall, the present study demonstrated that the acute administration of 2.5 mg everolimus in healthy men does not lead to neuroendocrine or psychological adverse side effects. However, as other studies have reported neuroendocrine alterations as well as anxiety- and depression-like symptoms at lower everolimus doses, these findings should be further verified to determine whether everolimus induces psychiatric side effects in a dose-dependent manner.