# Genetic and Phenotypic Associations With Sustained Antidepressant Use in Major Depressive Disorder

## TL;DR

This study explores how antidepressant use patterns in major depressive disorder can reveal distinct subtypes and inform personalized treatment strategies.

## Contribution

The study identifies immune-related genetic variants and phenotypic profiles linked to sustained antidepressant use, offering new insights for precision psychiatry.

## Key findings

- MDD subgroups defined by sustained antidepressant use had distinct phenotypic profiles.
- A genome-wide significant variant in SLAMF3/LY9 was associated with sustained SSRI use.
- Polygenic scores for psychiatric traits were linked to treatment complexity but not sustained-use subgroups.

## Abstract

Can real-world antidepressant prescription patterns identify biologically meaningful subtypes of major depressive disorder (MDD) and inform precision psychiatry approaches?

In this cohort study of 12 074 participants, MDD subgroups defined by sustained single-drug antidepressant use (≥360 days) had distinct phenotypic profiles; polygenic scores for psychiatric disorders differentiated individuals with greater class diversity but not single-drug sustained-use 360 groups. One genome-wide significant immune-related variant in SLAMF3/LY9 was associated with sustained selective serotonin reuptake inhibitor use.

The findings suggest that real-world antidepressant prescription patterns have the potential to identify phenotypically distinct MDD subtypes that may guide personalized treatment selection, and polygenic scores may help identify which patients are at risk of difficult-to-treat depression.

This cohort study evaluates phenotypic and genetic heterogeneity in major depressive disorder.

Antidepressant treatment remains a trial-and-error process: one-third of people with major depressive disorder (MDD) report inefficacy of first-line medications. Predictors of prescription patterns are needed to improve prescribing precision.

To investigate phenotypic and genetic heterogeneity of MDD subgroups defined by antidepressant prescription patterns.

This was a retrospective cohort study of Australian Genetics of Depression Study (2017-2018) adult participants (aged ≥18 years) with lifetime MDD who filled 1 or more prescriptions of the 10 most commonly used antidepressants across 4.5 years (2013-2017). Data were analyzed from August 2024 to October 2025.

Treatment complexity was assessed as number of different antidepressant classes in prescriptions filled in 4.5 years. Sustained-use 360 groups were defined as 360 or more cumulative days (in 4.5 years) of a single antidepressant. Participants with genome-wide genotypes were contrasted across mutually exclusive sustained-use 360 groups.

Associations of 44 self-reported phenotypes and polygenic scores (PGSs) for 15 traits with sustained-use 360 subgroups. Genome-wide association studies (GWASs) were conducted for selective serotonin reuptake inhibitor (SSRI) or SSRI/serotonin-norepinephrine reuptake inhibitor sustained use contrasted to other participants.

Of 12 074 participants (9041 [75%] female with a mean [SD] age of 41.8 [14.6] years; 3022 [25%] male with a mean [SD] age of 47.7 [14.6] years) with 1 or more prescriptions and lifetime MDD, 8898 had genotyping data. High treatment complexity was significantly associated with 37 of 44 self-reported phenotypes (eg, higher rates of smoking, recurrent MDD, suicidal ideation, chronic pain, and circadian and atypical depression subtypes) and higher PGSs for psychiatric traits (MDD PGS: β, 0.04; 95% CI, 0.03-0.06; P = 1.2 × 10−8; ADHD PGS: β, 0.03; 95% CI, 0.02-0.05; P = 2.1 × 10−5 ; bipolar disorder PGS: β, 0.03; 95% CI, 0.01-0.04. P = 1.2 × 10−4 ; neuroticism PGS: β, 0.02; 95% CI, 0.01-0.04; P = 1.3 × 10−3). A total of 5453 (61%) met criteria for an exclusive antidepressant sustained-use 360 group. These groups had distinct phenotypic profiles, including associations with body mass index, suicidal ideation, and co-occurring conditions. GWASs identified novel loci, including an immune-related gene SLAMF3/LY9, for which single-nucleotide variant rs4656934 was associated with reduced odds of sustained SSRI use (G allele; odds ratio, 0.81; 95% CI, 0.75-0.87; P = 3.5 × 10−8).

This study found that phenotypic factors were associated with sustained antidepressant use and treatment complexity. PGSs for traits studied were associated with treatment complexity but showed little association with sustained-use 360 groups. These findings support further research to guide treatment selection and to identify patients at risk of difficult-to-treat depression, informing precision psychiatry and early intervention in MDD.