Clinical and preclinical evidence for the neurotrophic effects of mood stabilizers: Implications for the pathophysiology and treatment of manic-depressive illness

Recent neuroimaging studies have demonstrated regional central nervous syst em volume reductions in mood disorders, findings that are complemented by p ostmortem 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-activate d protein kinase pathway, a signaling pathway utilized by many endogenous n eurotrophic factors. Consistent with its preclinical neurotrophic/neuroprot ective effects, chronic lithium treatment of patients with manic-depressive illness increases brain N-acetylaspartate (a putative marker of neuronal v iability and function) levels, an effect that is localized almost exclusive ly to gray matter. To determine if lithium was producing neuropil increases quantitative three-dimensional magnetic resonance imaging studies were und ertaken, which revealed that chronic lithium significantly increases total gray matter volume in the human brain of patients with manic-depressive ill ness. Together, these results suggest that a reconceptualization about the optimal long-term treatment of recurrent mood disorders is warranted. Optim al long-term treatment for these severe illnesses may only be achieved by t he early use of agents with neurotrophic/neuroprotective effects, irrespect ive of the primary, symptomatic treatment. Biol Psychiatry 2000;48:740-754 (C) 2000 Society of Biological Psychiatry.