Biobank analysis suggests genetic links to side effects in antidepressants

Researchers at the University of Tartu Institute of Genomics have reported on the insights they discovered into why some individuals are more susceptible to side effects from antidepressant medication. Drawing on genetic and clinical data from more than 13,000 participants in the Estonian Biobank, the study examined the relationship between common genetic variants and adverse effects from 16 widely prescribed antidepressants.

The findings highlighted a significant role for the CYP2C19 gene, which is involved in metabolising many antidepressants. Individuals identified as slow metabolisers – those whose genetic variants cause the medication to be processed more slowly – were found to be 49% more likely to report side effects such as nausea, weight gain, sleepiness, headaches and heart palpitations. By contrast, those with ultra-rapid metabolism experienced a 17% lower risk of side effects.

Dr Hanna Maria Kariis, lead author for the study, stated that understanding the genetic mechanisms behind adverse drug reactions could help clinicians tailor treatments more effectively.

“This means that the same medication may affect individuals very differently depending on their genetic profile. And depending on how quickly the drug is metabolised, a doctor may recommend a dosage adjustment or an alternative antidepressant,” she said.

For the first time, the team also investigated a previously unstudied CYP2C19 gene deletion present in over 3% of the Estonian population. This deletion, which removes a significant part of the gene, has not been documented in other populations. The researchers found it to have a strong association with increased risk of side effects, suggesting it should be included in pharmacogenetic screening in Estonia.

Kariis noted that adding this variant to clinical tests could help reduce the burden of adverse effects among patients.

The study also explored the role of genetic predisposition to psychiatric disorders. A higher polygenic risk for depression or schizophrenia was associated with more frequent side effects across several classes of antidepressants. Additionally, participants with a genetic predisposition to higher body mass index were more likely to gain weight while taking antidepressants. A meta-analysis comparing these findings with data from a cohort in Australia confirmed the link between polygenic risk for obesity and antidepressant-induced weight gain. People with a genetic susceptibility to headaches also experienced more frequent headaches when treated with sertraline.

The research team used anonymised questionnaire data, clinical notes and medical records, applying data mining and natural language processing techniques to identify adverse reactions.

The findings underscore the growing potential of population-wide genomic data to inform personalised medicine. By tailoring antidepressant treatment to an individual’s genetic profile, it may be possible to reduce side effects, improve therapeutic outcomes and support long-term adherence to mental health treatments.

For further reading please visit: 10.1038/s41431-025-01894-x