Enhancing neuronal plasticity and cellular resilience to develop novel, improved therapeutics for difficult-to-treat depression

Husseini K. Manji, Jorge A. Quiroz, Jonathan Sporn, Jennifer L. Payne, Kirk Denicoff, Neil A. Gray, Carlos A. Zarate, Dennis S. Charney

Research output: Contribution to journalReview articlepeer-review

442 Scopus citations


There is growing evidence from neuroimaging and post-mortem studies that severe mood disorders, which have traditionally been conceptualized as neurochemical disorders, are associated with impairments of structural plasticity and cellular resilience. It is thus noteworthy that recent preclinical studies have shown that critical molecules in neurotrophic signaling cascades (most notably cyclic adenosine monophosphate [cAMP] response element binding protein, brain-derived neurotrophic factor, bcl-2, and mitogen activated protein [MAP] kinases) are long-term targets for antidepressant agents and antidepressant potentiating modalities. This suggests that effective treatments provide both trophic and neurochemical support, which serves to enhance and maintain normal synoptic connectivity, thereby allowing the chemical signal to reinstate the optimal functioning of critical circuits necessary for normal affective functioning. For many refractory patients, drugs mimicking "traditional" strategies, which directly or indirectly alter monoaminergic levels, may be of limited benefit. Newer "plasticity enhancing" strategies that may have utility in the treatment of refractory depression include N-methyl-o-aspartate antagonists, alpha-amino-3-hydroxy-5- methylisoxazole propionate (AMPA) potentiators, cAMP phosphodiesterase inhibitors, and glucocorticoid receptor antagonists. Small-molecule agents that regulate the activity of growth factors, MAP kinases cascades, and the bcl-2 family of proteins are also promising future avenues. The development of novel, nonaminergic-based therapeutics holds much promise for improved treatment of severe, refractory mood disorders.

Original languageEnglish (US)
Pages (from-to)707-742
Number of pages36
JournalBiological psychiatry
Issue number8
StatePublished - Apr 15 2003
Externally publishedYes


  • Bcl-2
  • Brain-derived neurotrophic factor
  • Glutamate
  • Lithium
  • Mitogen activated protein kinase
  • Neuroplasticity

ASJC Scopus subject areas

  • Biological Psychiatry


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