The GABAergic deficit hypothesis of major depressive disorder

Mol Psychiatry. 2011 Apr;16(4):383-406. doi: 10.1038/mp.2010.120. Epub 2010 Nov 16.


Increasing evidence points to an association between major depressive disorders (MDDs) and diverse types of GABAergic deficits. In this review, we summarize clinical and preclinical evidence supporting a central and causal role of GABAergic deficits in the etiology of depressive disorders. Studies of depressed patients indicate that MDDs are accompanied by reduced brain concentration of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) and by alterations in the subunit composition of the principal receptors (GABA(A) receptors) mediating GABAergic inhibition. In addition, there is abundant evidence that suggests that GABA has a prominent role in the brain control of stress, the most important vulnerability factor in mood disorders. Furthermore, preclinical evidence suggests that currently used antidepressant drugs (ADs) designed to alter monoaminergic transmission and nonpharmacological therapies may ultimately act to counteract GABAergic deficits. In particular, GABAergic transmission has an important role in the control of hippocampal neurogenesis and neural maturation, which are now established as cellular substrates of most if not all antidepressant therapies. Finally, comparatively modest deficits in GABAergic transmission in GABA(A) receptor-deficient mice are sufficient to cause behavioral, cognitive, neuroanatomical and neuroendocrine phenotypes, as well as AD response characteristics expected of an animal model of MDD. The GABAergic hypothesis of MDD suggests that alterations in GABAergic transmission represent fundamentally important aspects of the etiological sequelae of MDDs that are reversed by monoaminergic AD action.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antidepressive Agents / therapeutic use
  • Brain / drug effects
  • Brain / metabolism
  • Depressive Disorder, Major / drug therapy
  • Depressive Disorder, Major / genetics*
  • Depressive Disorder, Major / pathology
  • Disease Models, Animal
  • Gene Expression Regulation / genetics
  • Genetic Predisposition to Disease*
  • Humans
  • Mice
  • Mutation / genetics
  • Receptors, GABA / deficiency
  • Receptors, GABA / genetics
  • Risk Factors
  • gamma-Aminobutyric Acid / deficiency*
  • gamma-Aminobutyric Acid / genetics*


  • Antidepressive Agents
  • Receptors, GABA
  • gamma-Aminobutyric Acid