Subchronic administration of creatine produces antidepressant-like effect by modulating hippocampal signaling pathway mediated by FNDC5/BDNF/Akt in mice.
Level 5 - mechanism / opinion, no new human data
Preclinical animal study
PubMed 30005372 · doi:10.1016/j.jpsychires.2018.07.001
What was done
Mice were administered oral creatine daily for 21 days and tested in the tail suspension test (TST) across doses of 1 to 10 mg/kg alongside locomotor activity assessments. In mice given 1 mg/kg oral creatine, researchers measured hippocampal gene expression (mRNA) for creatine kinase isoforms (uCK, CK-B), PGC-1α, FNDC5, BDNF, BAD, Bcl2, and Bcl-xL, as well as BDNF protein immunocontent, Akt phosphorylation (Ser 473), and Bcl2 protein levels.
What was found
Creatine (1–10 mg/kg) reduced immobility time in the TST without altering locomotor activity. At 1 mg/kg, creatine increased hippocampal mRNA levels of uCK, CK-B, PGC-1α, FNDC5, BDNF, Bcl2, and Bcl-xL, elevated BDNF protein and Akt phosphorylation (Ser 473), increased Bcl2 protein levels, and decreased BAD mRNA. Quantitative values and effect sizes were not reported in the abstract.
Why it matters
This study outlines a neurobiological pathway—involving PGC-1α/FNDC5/BDNF signaling, Akt activation, and antiapoptotic modulation in the hippocampus—that may explain the antidepressant-like behavioral actions of creatine observed in preclinical models.
Limits
The study was conducted entirely in mice, limiting direct translation to human depression. The abstract does not disclose sample sizes, animal sex, strain, or numerical effect sizes with confidence intervals, and the tail suspension test is an acute behavioral screen rather than a complete model of major depressive disorder.
Cited by
- supports Creatine supplementation has been shown in animal models to increase levels of brain-derived neurotrophic factor (BDNF).