Influence of isotretinoin on hippocampal-based learning in human subjects

Abstract

RationaleThe 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.ObjectivesWe aimed to test the hypothesis that a course of oral isotretinoin therapy would result in declining visuospatial learning and memory.MethodsCANTAB 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.ResultsPerformance 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.ConclusionIsotretinoin 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.

Vitamin A and Cognitive Impairment

“…Recent results show that human supplementation with RA results in improved learning and memory [49] and hint at improvement in executive function [50]. These results are in line with the questioning of the relevancy of current nutritional recommendations and suggest that although the incidence of VAD is low in the Western world, the usual food intake provides suboptimal levels of RA to the normal human brain, perhaps because of its high demand for vitamin A.…”

Akneli Hastalarda İzotretinoin Kullanımı Sırasında Dikkat ve Yürütücü İşlevlerde Düzelme

“…Retinoik asit hücre çoğalması ve farklılaşmasına ek olarak MSS ve özellikle de hipokampus nöronları ile ilişkili nöronal plastisite, uzun süreli nöronal potansiyel artışı (long-term potentiation) ve nöronal viabilite için gereklidir [18][19][20] . Retinoik asitin invivo olumlu fizyolojik etkilerine rağmen izotretinoinin suprafizyolojik dozlarda verilmesi ile hayvanlarda öğrenme ve bellek üzerine olumsuz etkiler yaptığı gösterilmiştir 8,21 .…”

“…Bunlardan ilki ülkemizde gerçekleştirilmiş ve izotretinoin tedavisi sonrası akne hastalarında, sayı uzamı testi, digit symbol, stroop ve kelime çağrışım (KAS) testleriyle ölçülen dikkat, kelime akıcılığı ve yürütücü işlevlerde anlamlı düzelmeler saptanmıştır 24 . Ormerod ve arkadaşlarının 18 hasta ile yaptıkları çalışmada ise CANTAB adı verilen bilişsel test bataryası ile değerlendirilen hastalarda izotretinoin tedavisi ile bellek ve öğrenmede değişiklik saptanmamış, hastaların testteki cevap hızlarında anlamlı bir artış olmuştur 19 . Bizim çalışmamızda ve Ergün ve ark.larının yaptığı çalışmada dikkat ve yürütücü işlevlerde izotretinoin tedavisi ile düzelme olduğu saptanmıştır.…”

The 1,000-Day Window and Cognitive Development

“…Reduced hippocampal sizes and reduced learning abilities have been described in rats with VAD [52] . According to Barth and co-workers [45] , it might be assumed that VAD seldom occurs in the Western world but recent results have pointed to high levels of RA signaling in hippocampus and it has been shown that human supplementation with RA results in improved learning and memory [53]. This suggests that normal human brain may have suboptimal levels of RA, perhaps of its high demand for the vitamin A.…”