Factors Associated with Lithium Efficacy in Bipolar Disorder

About one-third of lithium-treated, bipolar patients are excellent lithium responders; that is, lithium monotherapy totally prevents further episodes of bipolar disorder for ten years and more. These patients are clinically characterized by an episodic clinical course with complete remission, a bipolar family history, low psychiatric comorbidity, mania-depression episode sequences, a moderate number of episodes, and a low number of hospitalizations in the pre-lithium period. Recently, it has been found that temperamental features of hypomania (a hyperthymic temperament) and a lack of cognitive disorganization predict the best results of lithium prophylaxis. Lithium exerts a neuroprotective effect, in which increased expression of brain-derived neurotrophic factor (BDNF) and inhibition of the glycogen synthase kinase-3 (GSK-3) play an important role. The response to lithium has been connected with the genotype of the BDNF gene and serum BDNF levels. A better response to lithium is connected with the Met allele of the BDNF Val/Met polymorphism, as is a hyperthymic temperament. Excellent lithium responders have normal cognitive functions and serum BDNF levels, even after long-term duration of the illness. The preservation of cognitive functions in long-term lithium-treated patients may be connected with the stimulation of the BDNF system, with the resulting prevention of affective episodes exerting deleterious cognitive effects, and possibly also with lithium's antiviral effects. A number of candidate genes that are related to neurotransmitters, intracellular signaling, neuroprotection, circadian rhythms, and other pathogenic mechanisms of bipolar disorder were found to be associated with the lithium prophylactic response. The Consortium on Lithium Genetics (ConLiGen) has recently performed the first genome-wide association study on the lithium response in bipolar disorder.