Developments in the field of antidepressants, where do we go now?

Major depression is a severe psychiatric syndrome with very high prevalence and socio-economic impact. Its pathophysiology is poorly known, yet several neurotransmitter systems and brain areas have been implicated. Selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitors (SSRI) and serotonin and norepinephrine reuptake inhibitors (SNRI) are most used antidepressant treatments. However, these drugs show slow onset of action and limited efficacy, making necessary the use of drug augmentation strategies or more aggressive interventions. Two important observations have emerged in recent years indicating that more rapid and effective antidepressant treatments are possible. Hence, the deep brain stimulation (DBS) of ventral anterior (subgenual) cingulate cortex (Cg25) evokes rapid mood improvements in subgroups of treatment-resistant depressive patients, likely mediated by a functional remodelling of cortico-limbic circuits. On the other hand, the non-competitive NDMA receptor antagonist ketamine can also evoke rapid (e.g., 2h) and persistent (up to 1 wk) improvements in some treatment-resistant patients. Moreover, recent preclinical observations indicate the antidepressant capacity of mGluR agents. Overall, this supports the usefulness of glutamatergic transmission as a new area in antidepressant drug development. On the monoamine side, new preclinical and clinical research should clarify the different roles played by 5-HT receptors in depression as well as the brain areas and circuits responsible for therapeutic improvement. This will lead to the synthesis of new agents blocking the serotonin (and possibly norepinephrine) transporter which will also activate or block 5-HT receptors playing respectively positive (e.g., postsynaptic 5-HT1A, 5-HT4) or negative (e.g., presynaptic 5-HT1A,/1B, 5-HT2A, 5-HT2C,5-HT3, etc.) roles in antidepressant effects.