The hippocampus, neurotrophic factors and depression: Possible implications for the pharmacotherapy of depression

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Abstract

Depression is a prevalent, highly debilitating mental disorder affecting up to 15 of the population at least once in their lifetime, with huge costs for society. Neurobiological mechanisms of depression are still not well known, although there is consensus about interplay between genetic and environmental factors. Antidepressant medications are frequently used in depression, but at least 50 of patients are poor responders, even to more recently discovered medications. Furthermore, clinical response only occurs following weeks to months of treatment and only chronic treatment is effective, suggesting that actions beyond the rapidly occurring effect of enhancing monoaminergic systems, such as adaptation of these systems, are responsible for the effects of antidepressants.Recent studies indicate that an impairment of synaptic plasticity (neurogenesis, axon branching, dendritogenesis and synaptogenesis) in specific areas of the CNS, particularly the hippocampus, may be a core factor in the pathophysiology of depression. The abnormal neural plasticity may be related to alterations in the levels of neurotrophic factors, namely brain-derived neurotrophic factor (BDNF), which play a central role in plasticity. As BDNF is repressed by stress, epigenetic regulation of the BDNF gene may play an important role in depression. The hippocampus is smaller in depressed patients, although it is unclear whether smaller size is a consequence of depression or a pre-existing, vulnerability marker for depression. Environmental stressors triggering activation of the hypothalamic-pituitary- adrenal axis cause the brain to be exposed to corticosteroids, affecting neurobehavioural functions with a strong downregulation of hippocampal neurogenesis, and are a major risk factor for depression. Antidepressant treatment increases BDNF levels, stimulates neurogenesis and reverses the inhibitory effects of stress, but this effect is evident only after 34 weeks of administration, the time course for maturation of new neurons. The ablation of hippocampal neurogenesis blocks the behavioural effects of antidepressants in animal models.The above findings suggest new possible targets for the pharmacotherapy of depression such as neurotrophic factors, their receptors and related intracellular signalling cascades; agents counteracting the effects of stress on hippocampal neurogenesis (including antagonists of corticosteroids, inflammatory cytokines and their receptors); and agents facilitating the activation of gene expression and increasing the transcription of neurotrophins in the brain.

Original languageEnglish
Pages (from-to)913-931
Number of pages19
JournalCNS Drugs
Volume25
Issue number11
DOIs
Publication statusPublished - 2011

Keywords

  • Antidepressants
  • BDNF
  • Depression
  • Hypothalamic-pituitary-adrenal-axis

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Psychiatry and Mental health
  • Clinical Neurology

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