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The Use of Mood Stabilizers as Plasticity Enhancers in the Treatment of Neuropsychiatric Disorders

Neil A. Gray, BA; Rulun Zhou, MD; Jing Du, MD, PhD; Gregory J. Moore, PhD; and Husseini K. Manji, MD, FRCPC

Published: April 1, 2003

Article Abstract

Mood disorders have traditionally been conceptualized as neurochemical disorders, but there is now evidencefrom 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 suggest that severe mood disorders are associated with impairments of structural plasticity and cellular resilience. It is thus noteworthy that lithium and valproate have recently been demonstrated to robustly increase the expression of the cytoprotective protein bcl-2 (an abbreviation for the B-cell lymphoma/leukemia-2 gene) in the CNS in vivo and in cells of human neuronal origin. Lithium and valproate also robustly activate a signaling cascade utilized by endogenous growth factors—the extracellular signal-regulated kinase (ERK) mitogen-activated protein (MAP) kinase pathway. Complementary human studies have shown that chronic lithium administration significantly increases gray matter content in a regionally selective manner, suggesting a reversal of illness-related atrophy and an increase in the volume of the neuropil. These unique and unexpected properties of lithium and valproate suggest that they may have broader utility as adjunctive agents in the treatment of a variety of neuropsychiatric disorders associated with cell atrophy or loss. The adjunctive use of these agents—at low doses—may provide the trophic support necessary to restore, enhance, and maintain normal synaptic connectivity, thereby allowing the chemical signal to reinstate the optimal functioning of critical circuits necessary for normal functioning.

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