Antidepressant-like effects of valproic acid in rodents go back to the 1980s: a comment to enrich the reviewed evidence by Goudarzi et al. (2026) "Valproic acid effects on stress-induced depression-like behavior in rodent models: a systematic review and meta-analysis".

In a recent review and meta-analysis, Goudarzi et al. (Stress, 2026 Dec 31; 29(1):2641561) show that valproic acid (VPA) exhibits antidepressant (AD)-like effects in several procedures involving the induction of depression-like symptoms by prior sub-chronic or chronic stress in laboratory rats or mice. In their review, the authors included reports of experimental studies (covering only from 2007 to 2024), using several validated depression-like behaviors, such as decreased sucrose preference, increased immobility in the forced swim test (FST), decreased activity in the open field test, and/or impaired novel object recognition memory. The meta-analysis of the 19 included studies showed that sub-chronic/chronic VPA treatment improves most of these depression-like symptoms. The present "Comment" article aims to highlight that the first demonstrations of VPA AD-like and passive coping-reducing effects date back to the 1980s. Our group was the first to demonstrate AD-like effects of sub-acute and chronic VPA treatments in the forced swim test in rats (in 1988). These effects were partially antagonized by pre-test injections of the GABA-A receptor complex antagonists bicuculline and picrotoxin, thus suggesting that VPA-induced passive coping reduction was at least partly mediated by enhancement of GABA-A neurotransmission. Shortly thereafter (1989), the AD-like effects of VPA were confirmed in the FST in mice. These reports from the late 1980s, showing positive effects of VPA on the FST in rats and mice, constitute relevant precedents that further strengthen the profile of AD-like effects of VPA reported by Goudarzi et al.