Sustained antidepressant use reflects clinically meaningful subtypes of major depressive disorder (MDD) and may help to identify patients at risk of difficult-to-treat illness, according to real-world prescribing data from a large retrospective cohort study.
Published in JAMA Psychiatry, the study drew on data from the Australian Genetics of Depression Study (AGDS) and examined whether real-world antidepressant prescription patterns could be used to characterise phenotypic and genetic heterogeneity in MDD, with the aim of informing more precise treatment selection.
A total of 12,074 adults with lifetime MDD who had filled at least one prescription for one of the 10 most commonly used antidepressants in Australia between 2013 and 2017 were included. Of these, 8,898 participants also had genome-wide genotyping data.
The cohort was predominantly female (75%), with a mean age of 41.8 years for women and 47.7 years for men. Prescription records were linked to detailed self-reported phenotypic data collected during AGDS recruitment in 2017/18.
Sustained antidepressant use was defined as 360 or more cumulative days of dispensing for a single drug over a 4.5-year period, encompassing both acute and maintenance treatment phases.
Clinical severity and antidepressant types
Treatment complexity was assessed using cumulative duration, antidepressant diversity and class diversity.
Greater class diversity was linked to 37 of 44 self-reported phenotypes, including recurrent depression, suicidal ideation, atypical and circadian subtypes, chronic pain, smoking and substance use. It was also associated with higher polygenic scores for several psychiatric traits, including MDD (β 0.04; P=1.2×10⁻⁸), attention-deficit hyperactivity disorder (β 0.03; P=2.1×10⁻⁵), bipolar disorder (β 0.03; P=1.2×10⁻⁴) and neuroticism (β 0.02; P=1.3×10⁻³).
By contrast, sustained single-drug use for 360 days or longer defined distinct but clinically interpretable subgroups. Among genotyped participants, 5,246 (59%) met criteria for sustained use of a single antidepressant.
Compared with selective serotonin reuptake inhibitor (SSRI) users, those with sustained serotonin–norepinephrine reuptake inhibitor use had a higher body mass index and greater rates of recurrent MDD and suicidal ideation, while tricyclic antidepressant use was associated with older age and markedly higher chronic pain.
Genome-wide association analysis identified a novel immune-related locus linked to sustained SSRI use. The G allele of rs4656934, located in the SLAMF3/LY9 gene region, was associated with reduced odds of sustained SSRI use (odds ratio 0.81; P=3.5×10⁻⁸). No genome-wide significant variants were identified for self-reported antidepressant efficacy.
The study was limited by the analysis being restricted to a 4.5-year prescribing window and the 10 most commonly prescribed antidepressants, potentially missing lifetime treatment trajectories.
Prescribing patterns may also reflect clinician preference or changing guidelines rather than biological factors, the authors said. Smaller sample sizes in some drug classes also reduced precision, and reliance on self-reported bipolar disorder status further constrained the findings.
Clinical implications for personalised MDD treatment
The findings suggest that sustained antidepressant use is a pragmatic proxy for long-term treatment acceptability and can delineate clinically meaningful MDD subtypes and potentially guide personalised treatment.
While polygenic scores were more informative for identifying treatment complexity than for predicting response to specific drugs, combining genetic markers with phenotypic profiles may help to flag patients at risk of difficult-to-treat depression.
The need for replication in other large, genotyped cohorts and for future studies exploring immune mechanisms implicated by the SLAMF3/LY9 finding was highlighted by the authors, with the longer-term goal of supporting precision psychiatry approaches in routine care.
Reference
Walker A et al. Genotypic and Phenotypic Associations With Sustained Antidepressant Use in Major Depressive Disorder. JAMA Psychiatry 2026;Jan 28:e254372.
