Mechanisms Underlying Treatment-Resistant Depression: Exploring Sex-Based Biological Differences

Abstract

Treatment-resistant depression (TRD) represents a severe and complex subtype of major depressive disorder (MDD), affecting approximately 30% of patients who fail to respond adequately to multiple standard antidepressant therapies. While the pathophysiology of TRD remains incompletely understood, emerging evidence suggests that sex-based biological differences might influence its onset, progression, and treatment response. Women are disproportionately affected by depression and are more likely to experience residual symptoms and treatment resistance, potentially due to hormonal fluctuations, immune system differences, and variations in brain circuitry and neuroplasticity. This narrative explores the current literature on the mechanisms underlying TRD, with a particular emphasis on sex-specific biological factors. Key focus areas include dysregulation in neurotransmitters and neurotrophic pathways, inflammation, HPA axis alterations, mitochondrial dysfunction, as well as the influence of sex hormones such as estrogen and progesterone. By highlighting these differences, this review underscores the importance of personalized, sex-informed approaches in the prevention and treatment of TRD and calls for further research to elucidate the biological underpinnings that contribute to sex disparities in treatment outcomes.

Keywords: BDNF: Inflammation; estrogen; metabolism; sex differences; treatment‐resistant depression.

FIGURE 1

Anatomical and functional brain differences associated with treatment‐resistant depression (TRD) and sex‐based differences. (A) Brain regions exhibiting structural and functional alterations associated with TRD, including differences in cortical and subcortical connectivity, gray matter volume, and cortical surface area. (B) Sex‐specific anatomical and functional variations observed in TRD patients. Arrows indicate increased (↑) or decreased (↓) structural volume or functional connectivity in females and males, respectively. Symbols represent alterations in connectivity, volume, and cortical surface area. These sex‐based distinctions highlight differential vulnerabilities and potential mechanisms underlying TRD. L, left (hemisphere/side). Created with BioRender.com.

FIGURE 2

Sex‐based biological differences relevant to treatment‐resistant depression (TRD). This schematic summarizes key molecular, hormonal, immune, and neuroanatomical distinctions between males (left, blue) and females (right, pink) that may contribute to differential risk and expression of TRD. ACC, anterior cingulate cortex; ACTH, adrenocorticotropic hormone; BDNF, brain‐derived neurotrophic factor; GR, glucocorticoid receptor; OXPHOS, oxidative phosphorylation. Created with BioRender.com.