Oxidative Stress in Treatment-Resistant and Refractory Depression: A Hidden Therapeutic Target?

Treatment-resistant depression (TRD) poses a serious challenge to psychopharmacology, as many patients do not achieve remission despite available therapies. The persistence and recurrence of the disease in the absence of response to antidepressant treatment highlight the complex and multifactorial nature of the disease, including the dysregulation of biological processes such as oxidative stress (OS). Although the role of OS in the pathogenesis of depressive disorders has been well documented, a growing body of evidence also points to its potential significance as a biomarker of persistence and symptom severity in TRD. Furthermore, growing evidence suggests that the severity of OS may be a measure of treatment resistance in depressive disorders, shedding light on OS as a potential biomarker of symptom persistence and a therapeutic target in TRD. This article presents the current state of knowledge on the importance of OS as a modifiable risk factor for the severity, chronicity, and persistence of TRD symptoms. Integrating the latest scientific evidence, this review describes the mechanisms linking OS to the development of TRD and discusses fast-acting antidepressants extended by a non-pharmacological nutraceutical approach, which appears to fill a therapeutic gap and increase the chances of recovery for chronically ill individuals. An integrated approach aimed at reducing OS may be a key point of leverage in overcoming treatment resistance in the most severe forms of TRD, thereby contributing to modifying the course of the disease and improving prognosis, which makes this approach the most clinically useful.