Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants

Nat Med. 2016 Mar;22(3):238-49. doi: 10.1038/nm.4050.


Depression is a common, devastating illness. Current pharmacotherapies help many patients, but high rates of a partial response or no response, and the delayed onset of the effects of antidepressant therapies, leave many patients inadequately treated. However, new insights into the neurobiology of stress and human mood disorders have shed light on mechanisms underlying the vulnerability of individuals to depression and have pointed to novel antidepressants. Environmental events and other risk factors contribute to depression through converging molecular and cellular mechanisms that disrupt neuronal function and morphology, resulting in dysfunction of the circuitry that is essential for mood regulation and cognitive function. Although current antidepressants, such as serotonin-reuptake inhibitors, produce subtle changes that take effect in weeks or months, it has recently been shown that treatment with new agents results in an improvement in mood ratings within hours of dosing patients who are resistant to typical antidepressants. Within a similar time scale, these new agents have also been shown to reverse the synaptic deficits caused by stress.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antidepressive Agents / therapeutic use*
  • Brain-Derived Neurotrophic Factor / metabolism
  • Cytokines / immunology
  • Depressive Disorder / drug therapy*
  • Depressive Disorder / immunology
  • Depressive Disorder / metabolism
  • Diabetes Mellitus / metabolism
  • Excitatory Amino Acid Antagonists / therapeutic use*
  • Female
  • Glucocorticoids / metabolism
  • Humans
  • Hypothalamo-Hypophyseal System / metabolism
  • Inflammation
  • Ketamine / therapeutic use*
  • Male
  • Neuronal Plasticity*
  • Pituitary-Adrenal System / metabolism
  • Selective Serotonin Reuptake Inhibitors / therapeutic use
  • Sex Factors
  • Signal Transduction
  • Stress, Psychological / immunology
  • Stress, Psychological / metabolism*
  • Time Factors


  • Antidepressive Agents
  • Brain-Derived Neurotrophic Factor
  • Cytokines
  • Excitatory Amino Acid Antagonists
  • Glucocorticoids
  • Serotonin Uptake Inhibitors
  • Ketamine