Tetrahydrocurcumin for Major Depressive Disorder with Therapeutic Potential and Mechanistic Insights from Clinical and Preclinical Studies.

Major depressive disorder (MDD) remains a leading cause of disability worldwide, and while selective serotonin reuptake inhibitors (SSRIs) are standard treatments, they have limited efficacy and adverse effects. Tetrahydrocurcumin (THC), a bioactive metabolite of curcumin, shows anti-inflammatory and neuroprotective properties that may augment antidepressant therapy. This study aimed to evaluate the efficacy and mechanisms of THC in treating MDD. A randomized, open-label, parallel-group pilot trial enrolled 19 patients with major depressive disorder (MDD) who received either escitalopram (ESC, 10 mg/day) or ESC plus tetrahydrocurcumin (ESC + THC, 10 mg ESC + 200 mg THC per day) for 29 days. Participants were randomized 1:1, with blinded raters assessing depressive severity using the 17-item Hamilton Depression Rating Scale (HAMD-17) at baseline and Day 29. Sixteen participants completed the primary endpoint assessment. Serum underwent data-independent acquisition (DIA-PASEF) proteomics, molecular docking, and ELISA. In parallel, chronic restraint stress (CRS) mice received THC (80 mg/kg) and were evaluated by behavior, immunofluorescence, and serum biomarkers. THC augmentation improved gastrointestinal symptoms in patients (p = 0.025), though total HAMD scores showed no significant group differences. Proteomic analysis identified 32 differentially expressed serum proteins, with THC modulating neurodegenerative pathways. In CRS mice, THC administration reversed anxiety- and depressive-like behaviors (open field, tail suspension, and forced swim tests), normalized prefrontal cortex (HSP90, KRT6A, P4HB, C1QA, APOM, CDH13) and hippocampal (HSP90, P4HB, CDH13) protein expression in mice, and restored serum levels of P4HB, C1QA, and CDH13 in both humans and mice, while additionally modulating LTF, TNF-α, IL-1β, cAMP, and DA in mice serum. These findings demonstrate that THC exerts multimodal antidepressant effects through coordinated anti-inflammatory and neuroprotective mechanisms. THC demonstrates antidepressant potential through anti-inflammatory and neuroprotective mechanisms, supporting its use as a safe augmentation strategy in MDD treatment. Further trials are warranted to validate its clinical efficacy and molecular targets.