Influence of isotretinoin on hippocampal-based learning in human subjects

The acne drug isotretinoin has 13-cis retinoic acid as its active agent. Adverse effects that have been described include severe depression. Animal studies indicate that the hippocampus is particularly sensitive to retinoic acid. Changes induced by isotretinoin to hippocampal function could contribute to depression but may be more evident in altered visuospatial learning and memory, the primary function of the hippocampus. We aimed to test the hypothesis that a course of oral isotretinoin therapy would result in declining visuospatial learning and memory. CANTAB tasks designed to assess visuospatial memory were performed repeatedly on 14 males and 3 females in an open prospective observational study of patients with severe acne undergoing isotretinoin therapy. Beck's Depression Inventory and Global Acne Grade were also administered. Performance stayed unchanged for DMS, SRM and PRM tasks, while surprisingly participants improved their speed on the PRM task. Performance improved across sessions on the PAL task, and moreover the dose of isotretinoin correlated with improvement in the total trial score, reduction in total error rate and stage completed at the first trial. Isotretinoin does not reduce learning and memory and our study suggests that it may instead lead to a dose-related improvement in specific aspects of hippocampal learning and memory. Retinoic acid functions in the hippocampus as the active metabolite of vitamin A, suggesting that this may be a limiting factor in the human hippocampus and addition of exogenous retinoic acid brings levels closer to an optimal state.