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September 10, 2025

Investigating the Role of Vitamin D in Enhancing Duloxetine and Fluoxetine Efficacy: Mechanistic Insights Into NRF2 Activation, Oxidative Stress, and Neurochemical Modulation

Key Points

Vitamin D significantly improved antidepressant effects when combined with duloxetine and fluoxetine.
Increased nrf2 expression and reduced oxidative stress markers were observed in treatment groups with vitamin D.
Vitamin D elevated serotonin and norepinephrine levels, key neurotransmitters involved in mood regulation.
The study highlights the importance of antioxidant mechanisms in the potential treatment of depression.

Abstract

ABSTRACT Depression is a major psychiatric disorder with limited treatment efficacy. Oxidative stress plays a key role in its pathogenesis, and emerging evidence suggests that vitamin D may reduce oxidative damage in neurological conditions. However, its role in modulating antioxidant enzymes and Nrf2 expression in depression remains unclear. This study investigates the effects of vitamin D in a cortisol‐induced depression model, focusing on its impact on the antioxidant defense system and Nrf2 activation. Depression was induced in male Wistar rats via intraperitoneal cortisol injection (20 mg/kg). Animals were divided into six groups ( n = 5/group), including control, cortisol‐only, vitamin D (5 µg/kg) with cortisol, and standard antidepressant (fluoxetine or duloxetine) with or without vitamin D. Depression‐like behaviors were assessed using the forced swim and sucrose consumption tests. Nrf2 binding interactions with vitamin D and fluoxetine were analyzed in silico using Pyrex, Drug Studio, and LigPlus. Post‐treatment, hippocampal tissues were collected for analysis of antioxidant enzymes, monoamine neurotransmitters (via HPLC), and Nrf2 mRNA expression. Vitamin D showed a better binding energy (−9.3 kcal/mol) compared to fluoxetine (−6.6 kcal/mol). Similarly, vitamin D significantly ( p < 0.0001) enhanced the level of enzymatic antidefense markers (catalase, superoxide dismutase, glutathione) and decreased the level of malondialdehyde. The Nrf2 mRNA level was elevated ( p < 0.0001) in vitamin D‐treated groups compared to positive control groups. Moreover, the mRNA level of the Nrf2 gene was the same as that of the standard groups. Vitamin D also increases the levels of serotonin and norepinephrine in depression. Vitamin D displayed a significant ( p < 0.0001) antidepressant effect, as evidenced by behavioral studies during co‐therapy with duloxetine and fluoxetine. Altogether, this study reveals that vitamin D helps in ameliorating depression by mediating the antioxidant enzymatic system and increasing the Nrf2 expression during co‐therapy with duloxetine and fluoxetine. Moreover, vitamin D also increased the serotonin and norepinephrine levels.

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