Impairments of neuroplasticity and cellular resilience in severe mood disorders: implications for the development of novel therapeutics

Psychopharmacol Bull. Spring 2001;35(2):5-49.


Mood disorders have traditionally been conceptualized as neurochemical disorders, but there is now evidence from a variety of sources demonstrating regional reductions in central nervous system (CNS) volume, as well as reductions in the numbers and/or sizes of glia and neurons in discrete brain areas. Although the precise cellular mechanisms underlying these morphometric changes remain to be fully elucidated, the data suggests that mood disorders are associated with impairments of structural plasticity and cellular resilience. Recent preclinical and clinical studies have shown that signaling pathways involved in regulating cell survival and cell death are long-term targets for the actions of antidepressants and mood stabilizers. Antidepressants, lithium, and valproate indirectly regulate a number of factors involved in cell survival pathways, including CREB, BDNF, Bcl-2, and MAP kinases, and may thus bring about some of their delayed long term beneficial effects via underappreciated neurotrophic effects. The future development of treatments that more directly target molecules involved in critical CNS cell survival and cell death pathways thus hold promise as novel, improved long-term treatments for mood disorders.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Atrophy
  • Bipolar Disorder / pathology
  • Brain / pathology
  • Cell Membrane / drug effects
  • Cell Membrane / pathology
  • Cell Membrane / physiology
  • Cell Survival / drug effects
  • Glycogen Synthase Kinases / physiology
  • Hippocampus / pathology
  • Humans
  • Lithium / pharmacology
  • Magnetic Resonance Imaging
  • Mood Disorders / drug therapy*
  • Mood Disorders / pathology*
  • Neuronal Plasticity / physiology*
  • Neuroprotective Agents / pharmacology
  • Psychotropic Drugs / pharmacology*
  • Psychotropic Drugs / therapeutic use
  • Signal Transduction / drug effects
  • Stress, Psychological / pathology


  • Antidepressive Agents
  • Neuroprotective Agents
  • Psychotropic Drugs
  • Lithium
  • Glycogen Synthase Kinases