# Vulnerability of DHCR7+/- mutation carriers to aripiprazole and trazodone treatment

> **NIH NIH R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2021 · $524,246

## Abstract

The last step in the cholesterol biosynthesis pathway is conversion of 7-dehydrocholesterol (7-DHC) to
cholesterol, catalyzed by a single enzyme, 7-dehyrocholesterol reductase (DHCR7). To date, >150 DHCR7
loss-of-function mutations have been identified, with >1% heterozygous carriers in the human population.
Heterozygous carriers have elevated 7-DHC levels. It has been well documented that 7-DHC is toxic, and its
numerous spontaneous oxidative products (oxysterols) have disruptive effects on normal cell division and
differentiation. 7-DHC levels can also markedly increase as a result of drug treatment. We recently performed
a high throughput drug screening and found that aripiprazole (ARI- an atypical antipsychotic) and trazodone
(TRZ - an antidepressant) both strongly increased 7-DHC levels. Further literature review revealed that ARI-
and TRZ-treated patients have elevated 7-DHC levels, misclassifying some them as SLOS patients - even
when they had two intact copies of the Dchr7 gene. In a follow-up experiments we observed that peripheral
dermal fibroblasts from human DHCR7+/- mutation carriers also had elevated 7-DHC levels at baseline, which
worsened as a result of ARI exposure. Our newest data indicate that ARI treatment of pregnant Dhcr7+/- mice
have deleterious effects on the development of the offspring. Based on these data, we hypothesize that
ARI/TRZ exposure and DHCR7+/- mutations potentiate each other, elevating 7-DHC levels into a
pathological range. As a result, the spontaneous, toxic metabolites of 7-DHC will alter neural
development and/or brain function, especially when DHCR7+/- mutation carrier mothers have DHCR7+/-
offspring exposed to ARI or TRZ. We will test this central hypothesis in a patient-derived fibroblast model
(Aim 1) and neurodevelopmental transgenic mouse models (Aims 2-3) at two different time points using a
maternal genotype*offspring genotype*treatment paradigm. Aripiprazole, marketed under the name of Ablilify®
is the most prescribed drug in the US, and the possibility that heterocyclic cationic amphiphile exposure might
be deleterious to >1% of the human DHCR7+/- mutation carriers warrants further investigation. Developing
personalized medicine approaches requires understanding Gene*Treatment interactions, and knowing the
interaction between maternal genotype*offspring genotype*treatment is necessary to precisely define the
population that is potentially vulnerable to ARI/TRZ exposure.

## Key facts

- **NIH application ID:** 10173889
- **Project number:** 5R01MH110636-05
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Karoly Mirnics
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $524,246
- **Award type:** 5
- **Project period:** 2017-06-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10173889

## Citation

> US National Institutes of Health, RePORTER application 10173889, Vulnerability of DHCR7+/- mutation carriers to aripiprazole and trazodone treatment (5R01MH110636-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10173889. Licensed CC0.

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