Lithium-related genetics of bipolar disorder

Lithium is a potent prophylactic medication and mood stabilizer in bipolar disorder. However, clinical outcome is variable. and its therapeutic effect manifests after a period of chronic treatment, implying a progressive and complex biological response process, Signal transduction systems known to b e perturbed by lithium involve phosphoinositide (PI) turnover, activation o f the Wnt pathway via inhibition of glycogen synthase kinase-3 beta (GSK-3 beta), and a growth factor-induced, Akt-mediated signalling that promotes c ell survival. These pathways, acting in synergy. probably prompt the amplif ication of lithium signal causing such immense impact on the neuronal netwo rk. The sequencing of the human genome presents an unparallelled opportunit y to uncover the full molecular repertoire involved in lithium action. Inte rrogation of high-resolution expression micro-arrays and protein profiles r epresents a strategy that should help accomplish this goal. A recent microa rray analysis on lithium-treated versus untreated PC12 cells identified mul tiple differentially altered transcripts. Lithium-perturbed genes, particul arly those that map to susceptibility regions, could be candidate risk-conf erring factors for mood disorders. Transcript and protein profiling in pati ents could reveal a lithium fingerprint for responsiveness or nonresponsive ness, and a signature motif that may be diagnostic of a specific phenotype. Similarly, lithium-sensitive gene products could provide a new generation of pharmacological targets.