Depression is the leading cause of disability worldwide. Psychotherapy is an integral part of depression treatment, however rates of response and remission remain limited. Research on the neurobiological mechanisms involved in depression may contribute to a better understanding of recovery processes and inform a more targeted use of treatments. To date, critical gaps in the knowledge of the neurobiology of depression remain and the neurobiological mechanisms involved in its psychotherapeutic treatment are poorly understood. The aim of this study is to identify specific neurofunctional and neurochemical brain alterations in depression and the effects of psychotherapy on these alterations. We employed functional magnetic resonance imaging and magnetic resonance spectroscopy in two samples: A) 56 depressed participants compared to 52 healthy controls were assessed once; and B) 32 depressed patients were assessed before and after six months of once a week psychotherapy and compared to 30 healthy controls.