Abstract
Recent neuroimaging studies have demonstrated regional central nervous system volume
reductions in mood disorders, findings that are complemented by postmortem observations
of cell atrophy and loss. It is thus noteworthy that lithium and valproate have recently
been demonstrated to robustly increase the expression of the cytoprotective protein
bcl-2 in the central nervous system. Chronic lithium not only exerts neuroprotective
effects in several preclinical paradigms but also enhances hippocampal neurogenesis.
Valproate robustly promotes neurite outgrowth and activates the ERK mitogen-activated
protein kinase pathway, a signaling pathway utilized by many endogenous neurotrophic
factors. Consistent with its preclinical neurotrophic/neuroprotective effects, chronic
lithium treatment of patients with manic–depressive illness increases brain N-acetylaspartate (a putative marker of neuronal viability and function) levels, an
effect that is localized almost exclusively to gray matter. To determine if lithium
was producing neuropil increases, quantitative three-dimensional magnetic resonance
imaging studies were undertaken, which revealed that chronic lithium significantly
increases total gray matter volume in the human brain of patients with manic–depressive illness. Together, these results
suggest that a reconceptualization about the optimal long-term treatment of recurrent
mood disorders is warranted. Optimal long-term treatment for these severe illnesses
may only be achieved by the early use of agents with neurotrophic/neuroprotective
effects, irrespective of the primary, symptomatic treatment.
Keywords
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Article info
Publication history
Accepted:
June 23,
2000
Received in revised form:
June 15,
2000
Received:
February 18,
2000
Identification
Copyright
© 2000 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
