Depression and antidepressant drugs: Beyond a purely neurotransmitter approach

Previously proposed mechanisms of action of antidepressants have involved effects on biogenic amines, and glutamic acid systems to explain their clinically beneficial effects. These models of neurotransmission have also attempted to explain the pathophysiology of depression. These approaches, however, have failed to explain the long latency of clinical actions of classic antidepressants or provide a convincing explanation for the pathophysiology of depression. There is a need for a paradigm shift to understand the mechanism of action of antidepressants and pathophysiology of depression. Translational research on cerebral structures that are involved in depression and short-latency antidepressant actions of N-methyl-D-aspartate receptor antagonists have provided some insights on: (1) Neuroinflammatory processes in depression; (2) The participation of neuroglia and neurotrophic factors; (3) Alterations of the functional activity of corticolimbic structures; and (4) Common antiinflammatory actions among both old and new antidepressants. Our hypothetical model consists of the following: When there is a need to cope with adversity, allostatic processes allow natural functional recovery (resilient individuals), whereas allostatic overload results in a neuroinflammatory process that leads to anxiety and depression (vulnerable individuals). Such a model encourages the development of modulators of antiinflammatory processes that involve microglia, astrocytes, and neurotrophic factors.