PT  - JOURNAL ARTICLE
AU  - F. Caraci
AU  - F. Calabrese
AU  - R. Molteni
AU  - L. Bartova
AU  - M. Dold
AU  - G. M. Leggio
AU  - C. Fabbri
AU  - J. Mendlewicz
AU  - G. Racagni
AU  - S. Kasper
AU  - M. A. Riva
AU  - F. Drago
ED  - Ohlstein, Eliot H.
TI  - International Union of Basic and Clinical Pharmacology CIV: The Neurobiology of Treatment-resistant Depression: From Antidepressant Classifications to Novel Pharmacological Targets
AID  - 10.1124/pr.117.014977
DP  - 2018 Jul 01
TA  - Pharmacological Reviews
PG  - 475--504
VI  - 70
IP  - 3
4099  - http://pharmrev.aspetjournals.org/content/70/3/475.short
4100  - http://pharmrev.aspetjournals.org/content/70/3/475.full
SO  - Pharmacol Rev2018 Jul 01; 70
AB  - Major depressive disorder is one of the most prevalent and life-threatening forms of mental illnesses and a major cause of morbidity worldwide. Currently available antidepressants are effective for most patients, although around 30% are considered treatment resistant (TRD), a condition that is associated with a significant impairment of cognitive function and poor quality of life. In this respect, the identification of the molecular mechanisms contributing to TRD represents an essential step for the design of novel and more efficacious drugs able to modify the clinical course of this disorder and increase remission rates in clinical practice. New insights into the neurobiology of TRD have shed light on the role of a number of different mechanisms, including the glutamatergic system, immune/inflammatory systems, neurotrophin function, and epigenetics. Advances in drug discovery processes in TRD have also influenced the classification of antidepressant drugs and novel classifications are available, such as the neuroscience-based nomenclature that can incorporate such advances in drug development for TRD. This review aims to provide an up-to-date description of key mechanisms in TRD and describe current therapeutic strategies for TRD before examining novel approaches that may ultimately address important neurobiological mechanisms not targeted by currently available antidepressants. All in all, we suggest that drug targeting different neurobiological systems should be able to restore normal function but must also promote resilience to reduce the long-term vulnerability to recurrent depressive episodes.