Depression is a leading cause of disability, with often chronic course of illness and high treatment resistance in a large proportion of patients. In the current short perspective paper, we present evidence supporting the presence of synaptic-based chronic stress pathology (CSP) in depression and across a number of psychiatric disorders. We summarize the synaptic connectivity model of CSP, and briefly review related preclinical and clinical evidence, while providing appropriate references for more comprehensive reviews and alternative models. We then underscore some gaps in the literature and provide various tips for future directions.