Journal
BIOLOGICAL PSYCHIATRY
Volume 53, Issue 8, Pages 707-742Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/S0006-3223(03)00117-3
Keywords
neuroplasticity; lithium; glutamate; brain-derived neurotrophic factor; bcl-2; mitogen activated protein kinase
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There is growing evidence from neuroimaging and postmortem 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 synaptic 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-D-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.
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