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".

TL;DR

A historical comment highlights that valproic acid (VPA) demonstrated antidepressant-like effects in rodent models as early as the 1980s, predating the systematic review by Goudarzi et al. (2007–2024) and strengthening the evidence base for VPA's antidepressant profile.

Key findings

• Early 1988 studies first demonstrated VPA's antidepressant-like effects in the forced swim test in rats, with effects partially antagonized by GABA-A receptor antagonists (bicuculline and picrotoxin), suggesting GABA-A enhancement as a mechanism
• VPA effects were confirmed in mice by 1989, establishing a consistent antidepressant-like phenotype across rodent species in the forced swim test
• Goudarzi et al.'s meta-analysis of 19 studies (2007–2024) showed VPA improves multiple depression-like behaviors including sucrose preference, immobility in FST, activity in open field, and novel object recognition memory
• The 1980s precedents provide relevant historical context that strengthens the profile of VPA's antidepressant effects demonstrated in contemporary systematic reviews

Why this matters at the bedside

Establishes the historical foundation and extended evidence base for valproic acid as a potential antidepressant agent, suggesting long-standing and reproducible antidepressant-like effects across methodologies and rodent models. Mechanistic insights involving GABA-A neurotransmission may inform understanding of VPA's antidepressant action.