HMN 2026: What are the clues as to why standard antidepressants fail for so many

A study from the University of Sydney’s Brain and Mind Center reveals new clues as to why standard antidepressants fail for many Australians, opening the door for more effective, personalized treatments.

Examining nearly 15,000 Australians with depression in one of the largest studies of its kind, researchers from the Brain and Mind Center’s Youth Mental Health and Technology team identified a clinically distinct “atypical depression” subtype that is strongly linked to other mental and physical illnesses like diabetes.

Published in the journal Biological Psychiatry, the study found that this atypical depression group (21% of the study sample) did not respond well to common antidepressants such as SSRIs and SNRIs.

These common drugs target brain chemistry, but the study’s findings suggest other biological processes, such as a dysregulated body clock, might be behind this type of depression, suggesting a need for alternative treatment strategies.

The study also found the group with atypical depression was more likely to experience side effects from common antidepressants such as weight gain.

“We found people with atypical depression have higher genetic risks for metabolic, immune, inflammatory and circadian markers. This suggests distinct biological pathways could be at play,” lead author Dr. Mirim Shin said.

“By understanding this unique trajectory leading to atypical depression, we can tailor treatments to individuals based on an individual’s biology. This personalized approach would ensure people got help sooner and avoid ineffective and prolonged medication trials that may cause side effects that can be distressing.”

Of the 14,897 participants from the Australian Genetics of Depression study, 75% were female. The 21% classified as having “atypical depression” were identified by specific symptoms, such as self-reported weight gain and prolonged sleep, or hypersomnia, during their worst depressive episodes.

“A significant number of Australians, many of whom are women, are not getting the right treatment they need the first time they seek help. This research makes a strong case for more precise treatment for individuals based on their biology as a vital tool in tackling increasing rates of depression,” Brain and Mind Center Co-Director Professor Ian Hickie said.