Trazodone effects on developing brain

Zeljka Korade,Allison Anderson,Luke B Allen,Karoly Mirnics,Keri A Tallman,Thiago C Genaro-Mattos,Ned A Porter

doi:10.1038/s41398-021-01217-w

Zeljka Korade, Allison Anderson + Show 5 more

Open Access

https://doi.org/10.1038/s41398-021-01217-w

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Abstract

Trazodone (TRZ) is a commonly prescribed antidepressant with significant off-label use for insomnia. A recent drug screening revealed that TRZ interferes with sterol biosynthesis, causing elevated levels of sterol precursor 7-dehydrocholesterol (7-DHC). Recognizing the well-documented, disruptive effect of 7-DHC on brain development, we designed a study to analyze TRZ effects during pregnancy. Utilizing an in vivo model and human biomaterial, our studies were designed to also account for drug interactions with maternal or offspring Dhcr7 genotype. In a maternal exposure model, we found that TRZ treatment increased 7-DHC and decreased desmosterol levels in brain tissue in newborn pups. We also observed interactions between Dhcr7 mutations and maternal TRZ exposure, giving rise to the most elevated toxic oxysterols in brains of Dhcr7+/− pups with maternal TRZ exposure, independently of the maternal Dhcr7 genotype. Therefore, TRZ use during pregnancy might be a risk factor for in utero development of a neurodevelopmental disorder, especially when the unborn child is of DHCR7+/− genotype. The effects of TRZ on 7-DHC was corroborated in human serum samples. We analyzed sterols and TRZ levels in individuals with TRZ prescriptions and found that circulating TRZ levels correlated highly with 7-DHC. The abundance of off-label use and high prescription rates of TRZ might represent a risk for the development of DHCR7 heterozygous fetuses. Thus, TRZ use during pregnancy is potentially a serious public health concern.

Highlights

The inhibition of 7-dehydrocholesterol reductase (DHCR7) enzyme, a key enzyme in the cholesterol biosynthesis pathway, leads to elevated levels of 7dehydrocholesterol (7-DHC) and decreased levels of desmosterol and cholesterol[1]
We found markedly increased circulating 7-DHC levels in patients treated with TRZ, suggesting that TRZ is a strong inhibitor of DHCR721
We report concentrations of cholesterol, desmosterol, 7-DHC, and lanosterol (Fig. 1) in WT and Dhcr7+/− pups born to either WT or Dhcr7+/− mothers

Summary

Introduction

The inhibition of 7-dehydrocholesterol reductase (DHCR7) enzyme, a key enzyme in the cholesterol biosynthesis pathway, leads to elevated levels of 7dehydrocholesterol (7-DHC) and decreased levels of desmosterol and cholesterol[1]. Inhibition of DHCR7 is a side effect of multiple widely-used pharmaceuticals[2,3,4] These compounds produce changes in sterol profiles that mimic biochemical changes arising from genetic mutations in humans (Supplemental Fig. 1)[5,6]. Nonapproved uses include treatment and/or self-treatment of opioid withdrawal symptom[10], complex regional pain syndrome[11], obsessive–compulsive disorder[12], alcohol withdrawal[13,14,15], schizophrenia[16], dementia in Alzheimer’s disease, eating disorders, fibromyalgia, and erectile dysfunction[17] Considering this extensive off-label use, it is not surprising that for the period from 2007 to 2017 there were a total of 226,057,791 TRZ prescriptions (Supplemental Fig. 2)[18]. The total number of TRZ prescriptions is almost twice as high as the number of oxycodone prescriptions

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