Mechanisms Underlying Treatment-Resistant Depression: Exploring Sex-Based Biological Differences.
Francisco E R da Silva1,2, Atakan Yucel2, Antonio P M Menezes2
1Translational Psychiatry Program, Faillace Department of Psychiatry and Behavioral Sciences at McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, Texas, USA.
Journal of Neurochemistry
|September 4, 2025
Summary
Treatment-resistant depression (TRD) affects many, with women experiencing it more. Sex-based biological differences, like hormones and brain activity, are key to understanding and treating TRD effectively.
Area of Science:
- Neuroscience
- Psychiatry
- Endocrinology
Background:
- Treatment-resistant depression (TRD) affects ~30% of major depressive disorder (MDD) patients.
- Women exhibit higher depression rates and are more prone to treatment resistance.
- Sex-based biological variations may underlie TRD onset, progression, and treatment response.
Purpose of the Study:
- To review current literature on TRD mechanisms.
- To emphasize sex-specific biological factors in TRD.
- To highlight the need for sex-informed, personalized TRD treatments.
Main Methods:
- Narrative review of existing research.
- Focus on sex-specific biological mechanisms.
- Analysis of neurotransmitter, neurotrophic, immune, and hormonal pathways.
Main Results:
- Sex differences influence TRD pathophysiology.
- Hormonal fluctuations, immune responses, and brain circuitry variations are implicated.
- Dysregulation in neurotransmitters, neurotrophic factors, HPA axis, and mitochondria contribute to TRD.
Conclusions:
- Sex-specific factors are crucial in TRD.
- Personalized, sex-informed approaches are needed for TRD prevention and treatment.
- Further research is required to address sex disparities in TRD outcomes.
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