We propose several pathways that could be involved in major depression. According to our proposal, noradrenaline hypoactivity could occur through a strong presynaptic GABAergic inhibition, via GABA(B) receptors, and serotonin hypoactivity through a strong glutaminergic inhibition via subreceptor 5 of the metabotropic glutaminergic receptor. In this sense, it is important to know whether the antagonists of such receptors might be able to improve the symptoms observed in major depression. Some neuropeptides are also altered in such states (corticotropin-releasing hormone, neuropeptide Y, galanin). It is also important to know whether in addition to current antidepressants the administration of neuropeptides and their agonists/antagonists could ameliorate depressive symptoms.