A human translational model based on neuroplasticity for pharmacological agents potentially effective in Treatment-Resistant Depression: Focus on dopaminergic system

Major Depressive Disorder (MDD) is a common psychiatric condition characterised by two core symptoms, low mood and anhedonia (or lack of pleasure). About 15-30% of people suffering from MDD do not respond to standard-of-care antidepressants, e.g., the serotonin re-uptake inhibitors (SSRI), and are considered affected by Treatment Resistant Depression (TRD). The neurobiology of this condition is presently unknown. Recent attempts of developing novel treatments for TRD have been driven by four major breakthroughs: (1) Increasing dopaminergic neurotransmission improves TRD symptoms; (2) Anhedonia occurs when central dopaminergic neurotransmission is low; (3) Enhanced neuroplasticity is critical for the action of antidepressants; (4) Ketamine shows antidepressant properties in TRD patients and triggers neuroplasticity in preclinical animal models. These breakthroughs are at the basis of a putative human translational cellular model for antidepressant agents that we are proposing in this article. The rationale is briefly described here.