Valproic acid effects on stress-induced depression-like behavior in rodent models: a systematic review and meta-analysis

Depression is one of the most common health concerns all around the globe. Valproic acid (VPA) is an anticonvulsant agent, with neuroprotective, anti-apoptotic, anti-inflammatory, and antidepressant effects in animal models. We carried out a systematic review of articles that reported the effect of VPA on stress-related depression in animal models. A search of databases was conducted with keywords related to valproic acid (VPA) and stress-induced depression. Data from the Forced Swimming Test (FST), Open Field Test (OFT), Novel Object Recognition (NOR), and Sucrose Preference Test (SPT) were extracted. Meta-analysis was conducted using Stata 14, and standardized mean differences (SMD) were calculated. Quality control and subgroup analysis were carried out. Meta-analysis of FST results obtained from 16 separate experiments showed that VPA had a strong effect in reducing the percentage immobility, signifying lower stress compared to the untreated group (SMD = −0.93; 95% CI = –1.66 to –0.21; p = 0.012). When administered via injection for four consecutive weeks, VPA at a dosage of 300 mg/kg/day significantly decreased depressive symptoms. Results from the vertical OFT in seven studies and the horizontal OFT in six studies indicated that VPA increased movement scores. SPT results in nine separate experiments showed that VPA significantly increased the animals' desire to drink sucrose water. Analysis of the NOR test demonstrated that VPA had no significant effects on the ability of animals to identify a new object. Our findings suggest that VPA can exert antidepressant-like effects in rat models of stress-induced depression, but heterogeneity and potential publication bias suggests caution is required.