Circulating Creatine Concentrations in Adults with Major Depressive Disorder: A Cross-Sectional Exploratory Study from the All of Us Research Program
Dragana Zanini, Sergej M. OstojicBackground:
Major depressive disorder (MDD) is a prevalent psychiatric condition with limited biological markers to guide diagnosis and treatment. While reduced brain creatine concentrations have been implicated in MDD pathophysiology, the role of circulating creatine remains unclear.
Objective:
To examine whether circulating creatine concentrations differ between individuals with MDD and non-MDD comparators in a large, population-based cohort, and to explore demographic correlates of systemic creatine status.
Methods:
We conducted a cross-sectional exploratory analysis within the All of Us Research Program, an NIH-led cohort of U.S. adults. MDD cases were identified from electronic health records using standardized OMOP concept identifiers. Circulating creatine concentrations were extracted from curated laboratory data, and participants with end-stage renal disease were excluded. Group comparisons were performed using Welch’s t-test, and associations with age and sex were evaluated.
Results:
Circulating creatine concentrations did not differ significantly between individuals with MDD and non-MDD participants. Of the 63,162 individuals diagnosed with MDD, creatine measurements were available for 94, and 81 participants were included in the final analysis after excluding those with renal pathology (mean age: 53.7 ± 13.8 years; 54% male). Mean creatine concentrations in the MDD group (1.02 ± 0.36 mg/dL) were similar to those in the non-MDD reference group (n = 121; mean age: 52.4 ± 15.4 years; 1.01 ± 0.40 mg/dL; P = 0.86). Within the MDD group, creatine concentrations were not significantly correlated with age (r = 0.18, P = 0.12). However, serum creatine levels were significantly higher in men than in women (1.16 ± 0.36 mg/dL vs. 0.81 ± 0.24 mg/dL; P < 0.0001).
Conclusions:
In this population-based exploratory analysis, circulating creatine concentrations were comparable between individuals with and without MDD but showed pronounced sex-related differences. These findings highlight the importance of considering sex as a biological variable in creatine research and underscore the need for longitudinal and mechanistic studies to clarify the relationship between peripheral and central creatine homeostasis in depression.