Treatment-resistant depression. From classification to new therapies.

Aims. This paper aims to investigate the advances in recent years in the recognition and therapy of treatment-resistant depression starting from the concepts of: depressive disorder, resistance and pseudoresistance to drug treatment in depression, and appropriate treatments of treat-ment-resistant depression. Methods. An extensive research was carried out on scientific databases such as: PubMed, PsychInfo and Cochrane Library, until May 2022, using the keywords "major depression ", "treatment-resistant depression ", "staging ", "instrumental therapies for resistant depres-sion ", "esketamine " and "psilocybin ". Results. Subjects who do not respond to antidepressants show a form of treatment resistance that requires an approach with additional pharma-cological and/or instrumental therapies. Recently, esketamine and psilocybin are of particular interest among clinicians, and instrumental treatments such as: vagus nerve stimula-tion, deep brain stimulation, repetitive transcranial magnetic stimulation, transcranial direct current stimulation, epidural cortical stimulation, and electro convulsive therapy, are being added to them. Discussion and conclusions. Treatment -resistant depression has increasingly become a public health problem due to the significant number of relapses, hospital-izations and mortality it entails, with increased demand for the use of more drugs, therapeutic resources by health servic-es, and loss of quality of life for patients. Treatment-resistant depression needs to be addressed through the creation of dedicated study protocols. Future research should focus on the need to establish operational, valid and appropriate crite-ria, both on the psychopathological, clinical governance and therapeutic levels, focusing on the latest therapies in order to provide reliable data on the benefits, risks and costs associated with their use.