Molecular mechanisms underlying mood stabilization in manic-depressive illness: The phenotype challenge

Objective: The authors critically examine the evidence supporting the hypot hesis that lithium's therapeutic effects in bipolar affective disorder are mediated by alterations in the expression of specific genes in critical neu ronal circuits. Method: Using the heuristic "initiation and adaptation para digm," the authors appraise the biological effects and underlying molecular and cellular mechanisms of lithium's action. The evidence is critically re viewed, with special attention to the reductive and integrative approaches necessary for identifying lithium's clinically relevant cellular and molecu lar targets. Results: Lithium's acute effects are mediated through inhibiti on of specific enzymes involved in two distinct but interacting signaling p athways-the protein kinase C and glycogen synthase kinase 3 beta signaling cascades-that converge at the level of gene transcriptional regulation. The expression of different genes, including transcription factors, is markedl y altered by chronic lithium administration, Chronic lithium treatment also robustly increases the expression of the neuroprotective protein Bcl-2, ra ising the intriguing possibility that some of lithium's effects are mediate d through underappreciated neurotrophic/neuroprotective effects. The import ance of lithium's effect on circadian rhythms and the related methodologica l problems in validating the role of specific genes in lithium's therapeuti c effects are discussed. Conclusions: Despite the plethora of lithium effec ts at the genomic level, direct evidence that the genes identified thus far are responsible for phenotypic changes associated with chronic lithium tre atment is still lacking. The combination of sensitive molecular technologie s, appropriately designed paradigms, better behavioral analysis, and a chro nobiologic approach seems necessary for the future identification of one or more clinically relevant lithium-target genes.