Decoding Treatment Choice: Genetic and Phenotypic Analyses of Long-term Antidepressant Acceptability

ImportanceAntidepressant treatment remains largely trial-and-error, with approximately one-third of patients with major depressive disorder (MDD) reporting inefficacy of first-line medications. Identifying predictors of treatment acceptability is needed to improve prescribing precision and patient outcomes. ObjectiveTo identify phenotypic and genetic signatures associated with antidepressant acceptability and treatment complexity. Design, Setting, and ParticipantsRetrospective cohort study of Australian Genetics of Depression Study participants dispensing [≥]1 prescription of the 10 most commonly used antidepressants, based on linked 4.5-year (2013-2017) prescription data. ExposuresTreatment complexity was assessed as number of antidepressant classes dispensed. Antidepressant acceptability was defined as sustained single-antidepressant use ([≥]360 cumulative days). Participants with genotyping data were classified into mutually exclusive groups based on sustained single-medication use. Main Outcomes and MeasuresAssociations with 40 phenotypes and polygenic scores (PGS) for 15 traits. Genome-wide association studies (GWAS) were conducted for SSRI and SSRI/SNRI antidepressant acceptability. ResultsOf 13,763 participants with [≥]1 antidepressant prescription, 9,844 had genotyping data (mean [SD] age 44.5 [15.0] years; 26% male; 89% lifetime MDD). Treatment complexity was significantly associated with 27 of 40 phenotypes (e.g., smoking, recurrent MDD, suicidal ideation, chronic pain, BMI) and higher PGSs for psychiatric traits (MDD, ADHD, bipolar disorder, neuroticism; {beta} = 0.028- 0.045 per PGS SD unit, p = 9.9 x 10-6 to 2.1 x 10-10). Sixty percent met criteria for an exclusive antidepressant acceptability group. These groups had distinct phenotypic profiles, including associations with BMI, suicidal ideation, and comorbidities. In particular, only SNRI users had higher BMI than SSRI users, but this association was explained by the BMI PGS, indicating genetic rather than treatment-induced differences. GWAS identified novel loci including an immune-related gene LY9, for which the G allele of rs6427545 was associated with reduced SSRI acceptability (frequency = 0.31; OR = 0.82; p = 2.8 x 10-8) Conclusions and RelevanceAntidepressant acceptability and complex treatment patterns correspond to distinct phenotypic and genetic signatures. PGS demonstrate potential for enabling precision psychiatry, and immune-related pathways warrant therapeutic investigation. Key PointsO_ST_ABSQuestionC_ST_ABSCan phenotypic and genetic factors help identify individuals likely to show antidepressant-specific acceptability and treatment complexity, improving treatment precision in major depressive disorder (MDD)? FindingsIn this cohort study of 13,763 individuals with antidepressant prescriptions, treatment complexity was associated with 27 self-reported phenotypic traits and higher polygenic scores (PGS) for psychiatric conditions. Among 9,844 genotyped participants, 60% met criteria for single-antidepressant acceptability, with distinct phenotypic and genetic profiles. Notably, higher BMI among sustained SNRI users was explained by genetic predisposition. A genome-wide association study identified novel loci, including an immune-related gene (LY9), associated with reduced SSRI acceptability. MeaningPhenotypic and genetic factors, including PGS, are associated with both antidepressant acceptability and treatment complexity. These findings support the use of such markers to guide treatment selection and identify patients at risk for more complex courses, informing precision psychiatry and early intervention in MDD.