A major study from the University of Sydney’s Brain and Mind Centre has uncovered important clues explaining why standard antidepressants fail for a significant number of Australians with depression. Importantly, the findings open the door to more effective and personalised treatment approaches.
Identifying a Distinct Subtype of Depression
By analysing data from nearly 15,000 Australians with depression, researchers from the Brain and Mind Centre’s Youth Mental Health and Technology team identified a clinically distinct subtype known as “atypical depression.” Published in Biological Psychiatry, the study represents one of the largest investigations of its kind.
Notably, this atypical depression group accounted for 21% of participants and showed a strong association with other mental and physical conditions, including diabetes and metabolic disorders.
Poor Response to Common Antidepressants
Crucially, the study found that individuals with atypical depression responded poorly to commonly prescribed antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-noradrenaline reuptake inhibitors (SNRIs). While these medications target brain chemistry, the findings suggest that alternative biological mechanisms may drive this form of depression.
Beyond Brain Chemistry: A Biological Shift
Specifically, researchers observed that atypical depression may involve dysregulated circadian rhythms, along with metabolic, immune, and inflammatory pathways. As a result, standard antidepressants may fail to address the underlying biology in these patients. Moreover, individuals in this group experienced a higher burden of side effects, including weight gain, when treated with conventional medications.
Genetic and Symptom-Based Clues
As reported by medicalxpress, according to lead author Dr. Mirim Shin, people with atypical depression carry higher genetic risks linked to metabolic, immune, inflammatory, and circadian markers. Clinicians identified this group based on hallmark symptoms such as increased weight gain and hypersomnia during severe depressive episodes.
Implications for Personalised Mental Healthcare
Of the 14,897 participants in the Australian Genetics of Depression study, 75% were women, highlighting a significant gender impact. Brain and Mind Centre Co-Director Professor Ian Hickie emphasised that many Australians, particularly women, do not receive effective treatment at first contact.
Ultimately, the findings strengthen the case for biologically informed, personalised depression treatments, which could shorten time to recovery, reduce distressing side effects, and improve long-term outcomes.