Genetics could hold the key to personalized treatment for late life depression
Late-life depression (LLD) is one of the most common mental disorders among older adults. Affecting those over sixty, it is characterized by ongoing or episodic sadness, loss of interest in pleasurable activities, and disruptions of sleep and cognitive abilities. It can drastically decrease quality of life.
Treating LLD is complicated by the fact that many older adults have other health problems and are on medications that may interfere with common treatments. The effectiveness of a particular treatment for LLD can be hard to predict, meaning care providers frequently end up relying on trial-and-error. This is difficult for patients who must endure multiple rounds of treatments and side-effects.
Dr. Daniel Mueller and his team are confronting this challenge by exploring the role of genetics in determining how patients respond to LLD treatments. Their research has revealed that polygenetic risk scores (PRS) may offer insight that will help clinicians predict what treatments have the best chance of helping patients with LLD.
What is a polygenic risk score (PRS)?
DM: PRSs are measurements used to estimate an individual's risk of developing a specific trait or condition based on their genetic profile. Specifically, a PRS is calculated using the frequency of genetic risk variants in the entire gene set (genome) weighted by the effect of that variant on a specific trait of interest.
What motivated this research?
DM: This study was motivated by the challenges in treating LLD. People with LLD often have other medical conditions and are on a unique combination of medications, making treatment more complex and leading to poor outcomes. Identifying genetic risk factors that influence how a patient responds to antidepressants could help us use treatments more effectively and avoid the trial-and-error approach commonly used.
Previous research in adults indicated that the risk of not responding to any antidepressant medication is higher for those with a higher genetic risk load (PRS) for attention deficit hyperactivity disorder (ADHD). Our study aimed to confirm this finding in LLD.
What was the most important finding of this study, in your opinion?
DM: We found an association between PRSs and the outcomes experienced by older adults who were treated with venlafaxine, an antidepressant medication. Specifically, we observed that those with a high PRS for ADHD had a higher chance of experiencing improvement in their symptoms, while those with a high PRS score for bipolar disorder had a lower chance of experiencing improvement. This suggests that having a higher genetic risk of developing ADHD or bipolar disorder influences response to antidepressants in LLD. However, there is an unmet need for more studies to see if we can produce the same results.
How does this change treatment in the future?
DM: This research highlights the potential of PRS to predict antidepressant treatment outcomes and allow us to personalize treatment strategies for LLD. If these results are confirmed by larger studies, these findings could lead to: 1) tailored antidepressant prescriptions based on genetic profiles, 2) improved identification of individuals at higher risk of poor response to specific treatments, and, 3) reduced trial-and-error prescribing, leading to faster and more effective management of LLD.
Any next steps?
DM: As our next steps, we plan to attempt to replicate our findings in a larger and more diverse group of older adults. Ultimately, this could lead to the integration of PRS into routine care for depression.
What is the major take-home message for the public?
DM: The study highlights the potential role of genetics in improving the treatment of LLD. As such, this work represents an important step toward personalized medicine in mental health care for older adults. However, while genetics may influence how individuals respond to antidepressants, more research is needed before these findings can be applied clinically.
Read this month's impact paper.
Elsheikh, S.S.M., Marshe, V.S., Men, X. et al. Polygenic score analyses on antidepressant response in late-life depression, results from the IRL-GRey study. Pharmacogenomics J 24, 38 (2024). https://doi.org/10.1038/s41397-024-00351-0