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Lithium Response in Bipolar Disorder Linked to Schizophrenia-Related Variants

NEW YORK (GenomeWeb) – For individuals with bipolar disorder, response to lithium treatment may be affected by genetic risk for another psychiatric condition: schizophrenia.

Members of the International Consortium on Lithium Genetics, including investigators from the University of Adelaide and elsewhere, compared genotyping profiles for nearly 2,600 individuals with bipolar disorder who were treated with lithium. Their results, appearing online today in JAMA Psychiatry, suggest variations in schizophrenia-, human leukocyte antigen-, and inflammation-related genes.

"We found that patients clinically diagnosed with bipolar disorder who showed a poor response to lithium treatment all shared something in common: a high number of genes previously identified for schizophrenia," corresponding author Bernhard Baune, an Adelaide psychiatry researcher, said in a statement. "In conjunction with other biomarkers and clinical variables, our findings will help to advance the highly needed ability to predict the response to treatment prior to an intervention. This research also provides new clues as to how patients with bipolar disorder and other psychiatric disorders should be treated in the future."

Lithium has been employed as a mood stabilizer in individuals with bipolar disorder for decades, the researchers wrote, often dialing down mania, easing depressive episodes, and significantly reducing suicide risk. But the drug is not effective for all individuals: up to one-third of bipolar disorder patients do not respond to the drug and others show a partial response.

With that in mind, Baune and his colleagues focused on genetic factors that might influence or predict lithium response. They conducted a cross-trait GWAS meta-analysis involving 2,586 individuals with bipolar disorder, including nearly 1,500 women and more than 1,100 men. The set represented 2,043 cases of type I bipolar disorder and 543 type II bipolar disorder cases.

When they considered genotyping profiles and polygenic schizophrenia risk scores for these individuals in relation to lithium treatment response, the researchers found that the 704 patients with the good lithium response tended to have fewer genetic risk factors for schizophrenia than those with poorer response to lithium treatment.

While the individuals are not necessarily affected by schizophrenia itself, the presence of these schizophrenia-associated risk variants did seem to dial down response to lithium treatment for bipolar disorder.

"[I]f a bipolar patient has a high 'gene load' of schizophrenia risk genes, our research shows they are less likely to respond to mood stabilizers such as lithium," Baune explained. "In addition, we identified new genes within the immune system that may play an important biological role in the underlying pathways of lithium and its effect on treatment response."

Likewise, the analysis highlighted lithium-responder and non-responder differences when it came to HLA antigens, genes involved in antigen presentation, and inflammatory cytokine genes. 

"These results suggest the potential for translational research aimed at personalized prescribing of lithium," the authors concluded.