Healthcare (Commonwealth Union) – Australian researchers at the University of Adelaide are optimistic that a recent biological breakthrough could pave the way for more targeted treatments for bipolar disorder (BD).
Roughly 2.2 per cent of Australians live with some form of BD, a mental health condition marked by intense mood swings between depressive lows and manic highs.
Lithium has long been regarded as the gold standard and primary treatment for BD since its mood-stabilising effects were discovered in 1949. Yet, patient responses to lithium vary widely — only about one-third see significant improvement, another 30 per cent respond moderately, and over a quarter derive little to no benefit.
At present, there is no reliable biomarker to predict which individuals will respond well to lithium, leading clinicians to rely on a trial-and-error approach when prescribing it.
Associate Professor Azmeraw Amare, NHMRC Emerging Leadership Fellow at the Adelaide Medical School indicated that genetic differences explain approximately 25 per cent of the variation in how individuals respond to lithium treatment.
He further pointed out that the understanding of how this genetic influence, could open the door to more personalised and effective treatment plans for patients taking lithium.
In recent years genetic links to disease have been in the spotlight. This could be attributed to advances in technology and more indebt knowledge in genetics. A study looking in genetic factos affecting mood disorders in hippocampus saw key genetic differences in the anterior and posterior parts.
As part of his work with the International Consortium on Lithium Genetics (ConLi+Gen) — a team that includes his university collaborators Associate Professors K. Oliver Schubert and Scott Clark — Associate Professor Amare has spearheaded research showing that polygenic scores focused on specific biological pathways can help predict how individuals respond to lithium therapy.
Associate Professor Clark indicated that this research highlights the value of analysing the specific biological pathways linked to lithium response and it marks a major advance that could also steer future investigations toward better understanding the underlying mechanisms and developing new treatment options.
The researchers developed nine pathway-focused polygenic scores (pPGS) by analysing groups of genes associated with bipolar disorder or known to interact with lithium.
PhD candidate Nigussie Sharew pointed out that a pathway-specific polygenic score, or pPGS, is a numerical value that reflects a person’s genetic likelihood of expressing a particular trait or condition it’s calculated by adding up the effects of genetic variants that are active within a particular biological pathway.
“In this instance, we targeted sets of genes including dopamine, glutamate, calcium channel signalling and circadian rhythm, and found pPGSs based on acetylcholine, calcium channel, GABA, and circadian rhythm pathways were associated with favourable lithium response.”
The study, published in Biological Psychiatry Global Open Science, found that individuals with bipolar disorder (BD) who had a higher concentration of genetic variants in pathways related to acetylcholine, calcium channels, GABA, or circadian rhythms were more likely to show a positive response to lithium treatment than those with lower concentrations. In contrast, a greater genetic presence of variants in the mitochondrial pathway was linked to a less favourable lithium response.
Associate Professor Amare indicated that these pathway-based polygenic scores offer biologically meaningful predictions that align closely with how lithium works, unlike conventional genome-wide scoring methods.
“Our pathway-specific scores translate complex genetics into actionable insights, combining these genomic predictors with established clinical and demographic factors brings us closer to a lithium pharmacogenetic score-guided clinical trial and, ultimately, to real-world implementation.”
Scientists consider the results a major step forward in the field of precision psychiatry.
Associate Professor K. Oliver Schubert pointed out that these insights could pave the way for genetic screening tools that more accurately and quickly identify patients likely to benefit from lithium treatment, while also guiding the development of novel therapies for bipolar disorder.
