Autophagy is an evolutionary conserved cellular housekeeping process implicated in the surveillance and recycling of cellular proteins and organelles, thereby maintaining cellular homeostasis, performance and metabolism. Importantly, autophagy has been centrally linked to stress-related disorders and mental health. Especially in the brain, synaptic autophagy has been shown to regulate synapse remodeling and plasticity and mitochondrial turnover, which appears critical to neuronal homeostasis and viability, and is directly linked to neuronal functioning. Consequently, genome-wide and proteome-wide association studies have indicated a significant over-representation of impairments of autophagy-related pathways in multiple brain disorders such as clinical depression. In line with these findings, several antidepressants have been shown to induce autophagic pathways. Even though antidepressants are the most effective treatment for depressive disorders, adequate therapy response to a single antidepressant is only observed in 40-60% of patients. Furthermore, plenty of patients show severe drug-related symptoms, so there is still a high demand for novel methods of treatment. Spermidine is a naturally occurring polyamine, which is known to act as an inducer of autophagy and mitophagy. Hence, our research group is interested in investigating spermidine as a potential treatment for clinical depression and other mental disorders. To verify this hypothesis we use different interdisciplinary approaches from cell culture and mouse model to clinical studies in patients and healthy subjects.