Treatment-resistant depression (TRD) represents one of the most complex challenges in mental health care, affecting millions of individuals worldwide who fail to respond to conventional antidepressants. A recent review, led by Chiara Fabbri and published in Molecular Psychiatry, dives deep into the genetic underpinnings of TRD and highlights the critical role of personalized treatment strategies.
TRD is defined as the lack of adequate response to at least two different antidepressant treatments. It contributes significantly to the global burden of mental illness, often accompanied by chronic symptoms, suicidal behaviors, and diminished quality of life. While the role of genetics in depression has been recognized, the genetic component of TRD is particularly elusive. Studies suggest that approximately 8% of TRD variability can be attributed to genetic factors, but pinpointing specific genes has proven difficult due to the complexity of the condition.
Genome-wide association studies (GWAS) have provided mixed results, with few replicated genetic signals. Factors such as the heterogeneity of TRD and varying definitions used across studies have likely contributed to these inconsistencies. For instance, TRD may encompass multiple subtypes (or “TRDs”) with distinct genetic and biological profiles. This highlights the need for more refined approaches to studying the condition.
Fabbri emphasizes the importance of stratifying patients into subgroups based on their clinical and biological characteristics. Such stratification could lead to more targeted treatments. For example, patients with atypical symptoms (e.g., weight gain and fatigue) might respond better to therapies addressing immune-metabolic dysfunctions, while those with cognitive or anhedonic symptoms might benefit from interventions targeting different neural pathways.
One promising avenue is pharmacogenomics, which uses genetic data to predict individual responses to specific antidepressants. Although still in its infancy for TRD, pharmacogenomic tools hold the potential to revolutionize how clinicians tailor treatments, offering a move away from the current “one-size-fits-all” approach.
The review underscores the need for more extensive, more diverse genetic studies and consensus definitions of TRD to enhance the reproducibility of findings. Additionally, integrating genetic data with electronic health records and clinical assessments could help bridge the gap between research and real-world application.
While much remains to be discovered, the insights from this review mark a significant step toward unraveling the complexities of TRD. By focusing on its genetics and embracing personalized treatment strategies, we are edged closer to improving outcomes for those living with this challenging condition.
Fabbri, C. (2025). Treatment-resistant depression: Role of genetic factors in the perspective of clinical stratification and treatment personalization. Molecular Psychiatry. https://doi.org/10.1038/s41380-025-02899-0
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