Who benefits from antidepressants? Using medication switching as a measure of non-response

Switching from one selective serotonin reuptake inhibitor (SSRI) to another antidepressant could be used to measure antidepressant non-response, according to new research from the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) at King’s College London.

In the UK, current clinical practice is to move patients with major depressive disorder from first-line SSRI treatment to a different antidepressant if they don’t respond to the treatment. Measuring antidepressant ‘switching’ harnesses this information, which can be found in electronic health records, to identify non-responders and better understand why antidepressants work for some people and not for others.

The study, published in Biological Psychiatry Global Open Science, suggests that switching patterns can capture antidepressant response. Using switching as a measure could allow researchers to conduct larger studies investigating the factors which influence antidepressant response, rather than relying on clinical studies of small sample sizes.

The researchers analysed data from UK Biobank and Generation Scotland on more than 40,000 participants who had been prescribed antidepressants (5,133 SSRI ‘switchers’ and 33,630 ‘non-switchers’ in UK Biobank, and 498 switchers and 1,279 non-switchers in Generation Scotland).

Participants who switched from an SSRI to another antidepressant within a 90-day period were classified as ‘switchers’, and participants who had more than three consecutive prescriptions of the same SSRI were ‘non-switchers’.

The characteristics of participants who switched were similar to those seen in clinical trials which assess the effectiveness of antidepressants, affirming that switching is a good indication that the initial antidepressant didn’t work for that user.

Chris Lo, PhD Student at King’s IoPPN and first author of the study, said:

"We were able to trace the switching pattern of over 5,000 UK Biobank participants, which gave us a much bigger sample size than any clinical trials normally have. Our study found that switching is a valid measure of antidepressant non-response. This provides a new way for researchers to investigate why antidepressants work for some but not others."

Professor Cathryn Lewis, Professor of Genetic Epidemiology & Statistics at King’s IoPPN and Co-Deputy Lead of the Trials, Genomics and Prediction theme at the National Institute for Health and Care Research (NIHR) Maudsley Biomedical Research Centre and senior author of the study, said:

"Antidepressants are some of the most widely prescribed drugs, but we have little idea of who is likely to respond favourably, and to which drug. This work is a first step in using health records to define and predict SSRI drug responses. From this we can explore what factors might be instrumental in determining who antidepressants might work for."

The researchers used the switching patterns to identify factors that were linked with non-response. They found that participants were more likely to switch if they had a lower annual income and educational level. Those with a university degree were around 25 per cent less likely to switch than those who did not complete secondary education.

Those with a higher genetic risk of not recovering from depression, as indicated by their polygenic risk score, were also more likely to switch. In contrast, genetic risk of developing depression was not linked with switching, suggesting that the genetics of treatment response differs from the genetics of susceptibility to depression.

These demographic and genetic factors linked with switching were also similar to those seen in clinical trials, providing further support for the validity of switching as a measure of non-response.

Professor Andrew McIntosh, Professor of Biological Psychiatry at the University of Edinburgh and co-author on the study, said:

"We still don’t understand the genetics of antidepressant treatment response, in large part because the available studies are too small. This recent work provides us with a new approach to identifying people who respond to antidepressants that may result in much larger genetic studies in the future. We hope that this approach will ultimately lead to genetic tests that can help identify which antidepressant drugs work best for whom."

The researchers note a limitation of the study is that patients could switch antidepressants for a variety of reasons, for example due to side effects or availability, which isn’t a reflection of treatment non-response.

The study was funded by Wellcome and the National Institute for Health and Care Research (NIHR) Maudsley Biomedical Research Centre. The research is part of the ‘Antidepressant Medications: Biology, Exposure & Response (AMBER)’ study, a larger programme of work led by Professor Cathryn Lewis and funded by a Wellcome Mental Health Award.

“Antidepressant switching as a proxy phenotype for drug non-response: investigating clinical, demographic and genetic characteristics” (Chris Wai Hang Lo, Alexandra C. Gillett, Matthew H. Iveson, Michelle Kamp, Chiara Fabbri, Win Lee Edwin Wong, Dale Handley, Oliver Pain, Evangelos Vassos, Naomi R. Wray, Heather C. Whalley, Danyang Li, Allan H. Young, Andrew M. McIntosh, Cathryn M. Lewis) was published in Biological Psychiatry Global Open Science. Doi: 10.1016/j.bpsgos.2025.100502