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

Area of Science:

• Psychiatry and Genetics
• Pharmacogenomics
• Computational Biology

Background:

• Major depressive disorder (MDD) treatment is often trial-and-error, with many patients unresponsive to initial antidepressant prescriptions.
• Identifying predictors for antidepressant prescription patterns is crucial for enhancing prescribing precision and patient outcomes.
• Understanding the heterogeneity within MDD patient subgroups based on treatment response is a significant clinical challenge.

Purpose of the Study:

• To investigate the phenotypic and genetic heterogeneity among major depressive disorder (MDD) subgroups defined by antidepressant prescription patterns.
• To identify patient characteristics and genetic factors associated with complex and sustained antidepressant use in MDD.

Main Methods:

• Retrospective cohort study of adult participants with lifetime MDD from the Australian Genetics of Depression Study.
• Analysis of antidepressant prescription data over 4.5 years to define treatment complexity and sustained-use groups.
• Genome-wide association studies (GWASs) and polygenic score (PGS) analyses contrasting phenotypic and genetic data across treatment groups.

Main Results:

• High treatment complexity in MDD was significantly associated with 37 out of 44 self-reported phenotypes, including smoking, recurrent depression, suicidal ideation, chronic pain, and specific depression subtypes.
• Polygenic scores for psychiatric traits (MDD, ADHD, bipolar disorder) and neuroticism were associated with treatment complexity.
• Genome-wide association studies identified a novel immune-related gene (SLAMF3/LY9) associated with selective serotonin reuptake inhibitor (SSRI) sustained use.

Conclusions:

• Phenotypic factors significantly influence antidepressant use patterns and treatment complexity in major depressive disorder (MDD).
• Polygenic scores are linked to treatment complexity but show limited association with specific sustained-use antidepressant groups.
• Findings support further research into guiding treatment selection and identifying patients with difficult-to-treat depression, advancing precision psychiatry.