Neurosteroids as emerging therapeutics for treatment-resistant depression: Mechanisms and clinical potential

Treatment-resistant depression (TRD) is a severe and persistent subset of major depressive disorder (MDD) that remains unresponsive to at least two different classes of antidepressants. Given the limitations of conventional treatments, neurosteroids have emerged as promising alternatives due to their rapid and multi-faceted mechanisms of action. Neurosteroids such as allopregnanolone, pregnenolone, and dehydroepiandrosterone (DHEA) modulate key neurotransmitter systems, including gamma-aminobutyric acid (GABA_A) and N-methyl-D-aspartate (NMDA) receptors, enhancing inhibitory transmission and promoting synaptic plasticity. They regulate the hypothalamic–pituitary–adrenal (HPA) axis, mitigating stress-related neurotoxicity and restoring neurochemical balance. Preclinical studies have demonstrated the efficacy of neurosteroids in reversing depressive-like behaviors in rodent models of chronic stress, while clinical trials highlight their potential for rapid and sustained antidepressant effects. Notably, the FDA approval of brexanolone for postpartum depression underscores the translational potential of neurosteroid-based therapies. However, challenges such as limited bioavailability, long-term safety concerns, and regulatory hurdles must be addressed to optimize their clinical application. This review explores the therapeutic potential of neurosteroids in TRD, discussing their mechanisms, clinical evidence, and future directions. The findings support the integration of neurosteroid-based treatments into TRD management, offering new hope for patients unresponsive to conventional antidepressants. This review uniquely highlights the paradigm shift offered by neurosteroids, moving beyond the traditional monoamine hypothesis, and positions them as novel, multi-target therapeutics capable of addressing the complex neurobiology of TRD.