Emerging targets for antidepressant therapies

Curr Opin Chem Biol. 2009 Jun;13(3):291-302. doi: 10.1016/j.cbpa.2009.04.617. Epub 2009 Jun 6.


Despite adequate antidepressant monotherapy, the majority of depressed patients do not achieve remission. Even optimal and aggressive therapy leads to a substantial number of patients who show minimal and often only transient improvement. In order to address this substantial problem of treatment-resistant depression, a number of novel targets for antidepressant therapy have emerged as a consequence of major advances in the neurobiology of depression. Three major approaches to uncover novel therapeutic interventions are: first, optimizing the modulation of monoaminergic neurotransmission; second, developing medications that act upon neurotransmitter systems other than monoaminergic circuits; and third, using focal brain stimulation to directly modulate neuronal activity. We review the most recent data on novel therapeutic compounds and their antidepressant potential. These include triple monoamine reuptake inhibitors, atypical antipsychotic augmentation, and dopamine receptor agonists. Compounds affecting extra-monoamine neurotransmitter systems include CRF(1) receptor antagonists, glucocorticoid receptor antagonists, substance P receptor antagonists, NMDA receptor antagonists, nemifitide, omega-3 fatty acids, and melatonin receptor agonists. Focal brain stimulation therapies include vagus nerve stimulation (VNS), transcranial magnetic stimulation (TMS), magnetic seizure therapy (MST), transcranial direct current stimulation (tDCS), and deep brain stimulation (DBS).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Biogenic Monoamines / antagonists & inhibitors*
  • Depression / drug therapy*
  • Depression / therapy
  • Drug Delivery Systems*
  • Electric Stimulation Therapy
  • Humans
  • Magnetic Field Therapy
  • Neurotransmitter Uptake Inhibitors / pharmacology*
  • Neurotransmitter Uptake Inhibitors / therapeutic use
  • Receptors, Glucocorticoid / antagonists & inhibitors
  • Receptors, Neuropeptide / antagonists & inhibitors*


  • Biogenic Monoamines
  • Neurotransmitter Uptake Inhibitors
  • Receptors, Glucocorticoid
  • Receptors, Neuropeptide