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Treatment-resistant depression: role of genetic factors in the perspective of clinical stratification and treatment personalisation

Molecular Psychiatry volume 30, pages 2210–2218 (2025) Cite this article

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Abstract

Treatment-resistant depression (TRD) is associated with chronic depression, suicidal behaviours, and reduced quality of life. TRD has a demonstrated genetic component, estimated around 8% based on common genetic variation in unrelated individuals. However, only six genome-wide association studies of TRD were published, and no replicated signals at locus or gene level have been identified; furthermore, apparently opposite results were reported in terms of genetic overlap between TRD and other traits. Other than limited power, an important issue of previous studies was the scarce consideration of TRD heterogeneity, as TRD likely comprises different groups and talking about TRDs could be more appropriate. This review points out important issues in the definition of TRD and differences across samples included in previous studies, which can be partly responsible for the inconsistency across results. Different definitions of TRD should not be expected to have similar genetic profiles, and the whole TRD group can partitioned into subgroups, based on clinical and biological features, to increase reproducibility, as exemplified by recent findings. This can be a key factor to develop/repurpose targeted treatments, or simply to aid a more personalised prescription of available medications compared to current clinical practice, that is largely concentrated on the prescription of a limited number of antidepressants compared to those available.

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Fig. 1: Manhattan plot showing the loci with p < 5e−4 from genome-wide association studies (GWASs) of TRD.
The alternative text for this image may have been generated using AI.
Fig. 2: Possible approaches to address the heterogeneity of TRDs (treatment-resistant depressions).
The alternative text for this image may have been generated using AI.

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  1. Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy

    Chiara Fabbri

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Fabbri, C. Treatment-resistant depression: role of genetic factors in the perspective of clinical stratification and treatment personalisation. Mol Psychiatry 30, 2210–2218 (2025). https://doi.org/10.1038/s41380-025-02899-0

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