A high genetic load for major depression may predict an unfavorable long term response to lithium in patients with bipolar disorder, according to findings published in Molecular Psychiatry.

Only a third of patients respond adequately to lithium, a first line therapy for bipolar disorder that is generally more effective in preventing manic than depressive episodes. There is no known biological or clinical marker that reliably predicts responsiveness to lithium, and determining objective response markers would allow for more personalized treatments.

Azmeraw T. Amare, MPH, MSc, PhD, of the discipline of psychiatry, School of Medicine, University of Adelaide, South Australia, Australia, and colleagues computed weighted polygenic scores (PGSs) for major depression. They analyzed genetic data from 2586 patients with bipolar disorder who received lithium treatment and participated in the Consortium on Lithium Genetics study. The analysis was performed for the entire patient cohort, as well as European and Asian subgroups. They assessed symptom improvement related to lithium therapy using the Alda scale.

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Overall, 27.2% of the patients had an optimal response to treatment, with an Alda score ≥7. The PGSs for major depression were significantly associated with lithium treatment response across various thresholds. Patients with a low polygenic load for major depression showed a better response to lithium compared to those who had a high polygenic load. This finding was statistically significant for the entire cohort (odds ratio [OR], 1.54; 95% CI, 1.18-2.01) and the European subgroup (OR, 1.75; 95% CI, 1.30-2.36), but not the Asian sample (OR, 1.71; 95% CI, 0.61-4.90).


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The main limitation of the study is that PGSs for major depression account for a small proportion of the variation in response to lithium therapy. Another limitation is the small size of the Asian subsample, which may not have been adequately powered to identify consistent effects.

The researchers noted, “Our study represents the first direct molecular evidence of an association between a genetic predisposition for major depression and poorer response to lithium treatment in patients with [bipolar disorder].”

Reference

Amare AT, Schubert KO, Hou L, et al. Association of polygenic score for major depression with response to lithium in patients with bipolar disorder. Mol Psychiatry. 2020. https://doi.org/10.1038/s41380=020-0689-5.