1. Introduction
2. Accutane Reduces Activity in The Orbitofrontal Cortex
3. Retinoic Acid Drives GABA Interneuron Differentiation
4. Could Increased GABAergic Interneurons Trigger Anhedonia?
5. Blocking GABA-A Has Pro-Cognitive Effects
6. Restoring Glutamate Signalling
7. References

Introduction:

In previous articles I’ve explored the diverse and concerning effects of Accutane on the brain. This evidence spans from in vitro experiments showing Isotretinoin directly triggering the death of neurons, to changes to the expression of genes involved in serotonin signalling. [29][30] However, of all the evidence of Accutane’s neurological effects, the most damning of all comes from a 2005 study by Bremner et al. where it was determined that 4 months of Accutane treatment was sufficient to dramatically reduce metabolism in the prefrontal cortex called the Orbitofrontal cortex. [1]

In the years since this study evidence has come to light that makes sense of this striking discovery and in this article, I’ll present a mechanism that makes sense of this finding. Furthermore, I’ll present how and if it is possible to enhance activity in the orbitofrontal cortex with aim of improving mood, cognition and decision making.

Accutane Reduces Activity in The Orbitofrontal Cortex

Of all the evidence for Accutane’s troubling effects on the brain, the most damning comes from a 2005 study by Bremner et al. In this study, PET scans were performed on 28 men and women to compare changes in brain metabolism following either four months of Accutane or antibiotic treatment. The results were shocking: the Isotretinoin group experienced a 21% decrease in activity in the orbitofrontal cortex, compared to a 2% increase in the antibiotic group. [1]

Effects on Regional Brain Metabolism in a Representative Patient Receiving Isotretinoin Treatment for Acne (J. Douglas Bremner, M.D., Negar Fani, M.S., Ali Ashraf, M.D., John R. Votaw, Ph.D., Marijn E. Brummer, Ph.D., Thomas Cummins, M.D., Viola Vaccarino, M.D., Ph.D., Mark M. Goodman, Ph.D., Lai Reed, M.B.A., Sajid Siddiq, M.D., and Charles B. Nemeroff, M.D., Ph.D. Functional Brain Imaging Alterations in Acne Patients Treated With Isotretinoin, American Journal of Psychiatry https://doi.org/10.1176/appi.ajp.162.5.983)

The orbitofrontal cortex is a region within the prefrontal cortex involved in higher cognitive functions, such as reward-based decision-making. This finding strongly supports the link between depressive symptoms and prior Accutane use. The researchers also identified an intriguing connection between reports of headaches during treatment and the relative degree of suppression of brain metabolism, with those reporting more severe headaches also showing greater reductions in orbitofrontal cortex activity.

The orbitofrontal cortex (OFC) evaluates decisions and choices based on expected rewards and punishments. For this reason, abnormalities in OFC activity can be linked to disorders of reward perception, such as obsessive-compulsive behaviour or hypersexuality. [2]

Damage to the prefrontal cortex often leaves individuals unable to consider the long-term consequences of decision-making, resulting in choices that prioritize immediate gratification. [3] Functional neuroimaging has found that the orbitofrontal cortex is one of the brain regions most implicated in depression. Patients with depression were found to have a 32% smaller orbitofrontal cortex compared to controls. [34]

Whilst Retinoic Acid is highly relevant to neuronal differentiation in embryonic tissues, into adulthood RA-synthesising enzymes are restricted to cortical regions involved in executive functioning. [4] This narrow band of the cortex is characterised by the presence of RALDH3, with slower maturation compared to surrounding cortical tissue.

The finding that 4 months of isotretinoin treatment reduces the activity of the orbitofrontal cortex therefore has a strong neuro-anatomical basis. [5] The fact that this region has slower maturation compared to surrounding cortical regions supports the role of Retinoic Acid signalling during adulthood. In opposition to CYP26b1 is ALDH1A3, which is present on the superficial layer of the PFC, and is involved in synthesising RA.