Trazodone effects on developing brain

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.

Medication effects on developmental sterol biosynthesis

“…Three drugs, aripiprazole, haloperidol and trazodone were associated with increased circulating 7DHC and 8DHC levels, while five other drugs, clozapine, escitalopram/citalopram, lamotrigine, olanzapine, and risperidone, were not. In separate biobank sample studies, we found that 7-DHC levels were also higher in patients with detectable levels of CAR and TRZ in their blood ( 111 , 113 ). While these findings are only minimally informative about the sterol synthesis events in the brain (as brain and body sterol synthesis are distinct and separated by the blood-brain barrier), they lead us to the conclusion that drugs can possess sterol-inhibiting function both in the brain and the body.…”

“…Hall et al made a critical observation of cholesterol biosynthesis interference by medications, noting that some patients who used aripiprazole and trazodone were misidentified as SLOS patients based on their blood 7-DHC levels ( 109 ). Following up on these observations, over the last seven years we validated that haloperidol, aripiprazole, trazodone, and cariprazine are all strong inhibitors of sterol biosynthesis, and that they have profound biochemical effects on the fetal brain in rodent models ( 110 – 113 ). It is also important to point out that the above-mentioned compounds appears to inhibit directly the DHCR7 enzyme, as it occurs in the cell systems without the receptors targeted by the drugs.…”

“…We tested if medications given to pregnant mice affect cholesterol biosynthesis in developing brain of WT and Dhcr7 +/− embryos. Embryos were maternally exposed to aripiprazole, cariprazine, trazodone or vehicle from E12 to E19 ( 110 , 111 , 113 ). This exposure time was chosen based on developmental closure of blood-brain-barrier, and allowed us to examine endogenous brain sterol synthesis.…”

Desmosterol and 7-dehydrocholesterol concentrations in post mortem brains of depressed people: The role of trazodone

“…Next, we investigated whether the differences in brain sterol concentrations could be explained by medication use, based on recent reports of inhibition of key cholesterol synthesis enzymes by psychotropic medications [ 17 – 19 , 35 , 36 ]. We considered data from both medication use history and toxicology reports, and identified morphine, ethanol, trazodone, escitalopram, alprazolam, diphenhydramine, hydrocodone, aspirin, atropine, insulin, and lisinopril as the only medications used by or found in >2 subjects.…”

“…Changes in brain cholesterol concentrations have long been associated with suicide and depression. More recently, four psychotropic medications, aripiprazole, cariprazine, haloperidol, and trazodone have been shown to be inhibitors of 7-dehydrocholesterol reductase, leading to increased 7DHC and reduced desmosterol levels in cell culture, rodents (including in utero models), human dermal fibroblasts, and human blood [ 17 , 19 , 20 , 35 , 36 , 38 ]. In these models, the magnitude of 7-DHC elevation was comparable to levels seen in Smith-Lemli-Opitz syndrome, a severe congenital syndrome caused by mutations in the DHCR7 gene encoding 7-dehydrocholesterol reductase.…”