Neuropsychological mechanism underlying antidepressant effect: a systematic meta-analysis

Mol Psychiatry. 2015 Mar;20(3):311-9. doi: 10.1038/mp.2014.24. Epub 2014 Mar 25.


Antidepressants are widely used in clinical practice for the treatment of depression and other mood disorders. Numerous neuroimaging studies have recently examined how antidepressants influence emotional processes. However, both clinical trials and neuroimaging studies have reported inconsistent responses to antidepressants. Moreover, the neuropsychological mechanisms by which antidepressants act to improve depressive features remain underspecified. This systematic meta-analysis summarizes pharmacological neuroimaging studies (before February 2013) and the antidepressant effects on human brain activity underlying emotional processes. Sixty fMRI studies (involving 1569 subjects) applying antidepressants vs control were included in the current quantitative Activation Likelihood Estimation (ALE) meta-analysis. Pooling of results by ALE meta-analyses was stratified for population (mood disorder patients/healthy volunteers), emotional valence (positive/negative emotions) and treatment effects (increased/decreased brain activity). For both patients and healthy volunteers, the medial prefrontal and core limbic parts of the emotional network (for example, anterior cingulate, amygdala and thalamus) were increased in response to positive emotions but decreased to negative emotions by repeated antidepressant administration. Moreover, selective antidepressant effects were uncovered in patients and healthy volunteers, respectively. Antidepressants increased activity in the dorsolateral prefrontal (dlPFC), a key region mediating emotion regulation, during both negative and positive emotions in patients. Repeated antidepressant administration decreased brain responses to positive emotions in the nucleus accumbens, putamen, medial prefrontal and midbrain in healthy volunteers. Antidepressants act to normalize abnormal neural responses in depressed patients by increasing brain activity to positive stimuli and decreasing activity to negative stimuli in the emotional network, and increasing engagement of the regulatory mechanism in dlPFC.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Animals
  • Antidepressive Agents / therapeutic use*
  • Cognition Disorders / etiology*
  • Humans
  • Mood Disorders / complications*
  • Mood Disorders / drug therapy*
  • Neuroimaging
  • Neuropsychological Tests
  • Prefrontal Cortex / pathology*


  • Antidepressive Agents