Medication-induced disruption of sterol biosynthesis poses serious risks to brain development and function.
At the center is the cholesterol molecule, essential for neurobiological integrity, flanked by haloperidol—one of over 30 FDA-approved drugs known to inhibit DHCR7. These medications, many administered orally and processed through the gastrointestinal–hepatic axis, begin altering sterol homeostasis at the stage of first-pass metabolism, before reaching the brain.
This leads to the buildup of 7-dehydrocholesterol (7-DHC), a toxic precursor, and its conversion into highly reactive, neurotoxic oxysterols (top right).
A DNA strand on the left indicates genetic vulnerabilities that can exacerbate these effects, particularly during neurodevelopmentally sensitive periods (lower right).
The wide range of implicated medications (upper left) highlights the potential for additive or synergistic toxicity, especially under conditions of polypharmacy.
Once overlooked, this off-target mechanism is now recognized as an urgent public health concern for developing brains and genetically at-risk individuals.
Credit: Julio Licinio
An editorial in Brain Medicine calls for urgent action to address the often-overlooked toxicity of commonly prescribed drugs.
A compelling editorial published in Brain Medicine highlights an emerging concern for brain development and public health: the interference of sterol biosynthesis by widely used prescription drugs.
Written by Editor-in-Chief Julio Licinio, the editorial responds to recent findings by Korade and Mirnics. Their research identified more than 30 FDA-approved medications, including commonly prescribed psychiatric drugs such as aripiprazole, trazodone, haloperidol, and cariprazine, that inhibit DHCR7, a key enzyme involved in cholesterol biosynthesis. Disrupting this enzyme’s function may have significant implications for neurodevelopment and mental health.
“This inhibition raises the levels of 7-dehydrocholesterol (7-DHC), suppresses cholesterol synthesis, and generates a sterol profile indistinguishable from that seen in congenital metabolic disorders,” Dr. Licinio explains in the editorial. “This is not a hypothetical concern—it is empirically validated in cell lines, rodent models, and human blood samples.”
The editorial highlights that these disruptions are particularly concerning during pregnancy and other developmental stages, but may have been systematically overlooked in drug safety evaluations. Even more alarming is that combinations of these medications—a common reality in clinical settings—can produce synergistic effects, elevating toxic metabolites to levels 15 times above normal.
“What Korade and Mirnics reveal is especially disturbing in this context,” notes Dr. Licinio. “If individual drugs can mimic a metabolic disorder, what are we to make of their interactions? We are prescribing molecular cocktails with no empirical knowledge of how they alter developmental neurochemistry.”
The editorial points out that approximately 1-3% of the general population carries single-allele DHCR7 mutations that may make them particularly vulnerable to these medications. A single prescription could potentially tip their biochemical balance, with two or more medications sending them into a state resembling Smith-Lemli-Opitz Syndrome, a serious developmental disorder.
Key Implications
Widely used psychiatric medications and other drugs may disrupt sterol biosynthesis, potentially causing developmental harm
Current drug approval processes fail to account for polypharmacy effects, despite their prevalence
Genetic vulnerability in a significant portion of the population increases risk
Developmental vulnerability extends beyond pregnancy to include infancy, childhood, and adolescence
Regulatory changes and clinical practice adjustments are urgently needed
Recommendations for Action
The editorial issues specific recommendations for immediate changes in clinical practice:
Pregnant women with DHCR7± genotype should avoid medications with 7-DHC-elevating side effects
Genetic testing should be considered for women of childbearing age who require these medications
Polypharmacy involving drugs that disrupt sterol synthesis should be avoided during pregnancy
Patients with Smith-Lemli-Opitz Syndrome should never receive medications with 7-DHC-elevating effects
For regulatory bodies and the pharmaceutical industry, Dr. Licinio calls for mandatory sterol biosynthesis screening in developmental safety assessments, abandoning “the fiction of monotherapy testing,” and developing evaluation methods that reflect real-world prescribing patterns.
“This is a call to action. Not someday. Now,” concludes Dr. Licinio.
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