Oc. Ikonomov et Hk. Manji, Molecular mechanisms underlying mood stabilization in manic-depressive illness: The phenotype challenge, AM J PSYCHI, 156(10), 1999, pp. 1506-1514
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.