The neurobiology of depression and antidepressant action

Neurosci Biobehav Rev. 2013 Dec;37(10 Pt 1):2331-71. doi: 10.1016/j.neubiorev.2012.12.007. Epub 2012 Dec 19.


We present a comprehensive overview of the neurobiology of unipolar major depression and antidepressant drug action, integrating data from affective neuroscience, neuro- and psychopharmacology, neuroendocrinology, neuroanatomy, and molecular biology. We suggest that the problem of depression comprises three sub-problems: first episodes in people with low vulnerability ('simple' depressions), which are strongly stress-dependent; an increase in vulnerability and autonomy from stress that develops over episodes of depression (kindling); and factors that confer vulnerability to a first episode (a depressive diathesis). We describe key processes in the onset of a 'simple' depression and show that kindling and depressive diatheses reproduce many of the neurobiological features of depression. We also review the neurobiological mechanisms of antidepressant drug action, and show that resistance to antidepressant treatment is associated with genetic and other factors that are largely similar to those implicated in vulnerability to depression. We discuss the implications of these conclusions for the understanding and treatment of depression, and make some strategic recommendations for future research.

Keywords: Affective neuroscience; Amygdala; Anterior cingulate cortex; Antidepressant drugs; Caudate nucleus; Habenula; Hippocampus; Nucleus accumbens; Stress; Treatment resistance; Unipolar major depression; Ventromedial prefrontal cortex.

Publication types

  • Review

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology*
  • Antidepressive Agents / therapeutic use*
  • Brain / drug effects*
  • Brain / physiopathology*
  • Depression / drug therapy*
  • Depression / physiopathology*
  • Disease Models, Animal
  • Humans
  • Hypothalamo-Hypophyseal System / drug effects
  • Hypothalamo-Hypophyseal System / physiopathology
  • Models, Neurological
  • Pituitary-Adrenal System / drug effects
  • Pituitary-Adrenal System / physiopathology
  • Stress, Psychological / physiopathology


  • Antidepressive Agents