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

Abstract

Major depressive disorder (MDD) is a common, disabling, and heterogeneous condition that responds unpredictably to current treatments. We previously showed an association between depressive symptoms and plasma concentrations of two cholesterol precursors, desmosterol and 7-dehydrocholesterol (7DHC). Here, we measured total cholesterol and sterol concentrations with mass spectrometry in postmortem brain samples from depressed and control subjects. Mean (±SEM) desmosterol concentration was 8.9 ± 0.97 ng/mg in the depressed versus 10.7 ± 0.72 ng/mg in the control group. The mean of the posterior probability distribution for the difference in desmosterol concentration between the two groups was 2.36 (95% highest density interval [HDI] 0.59–4.17). Mean 7DHC concentrations, 12.5 ± 4.1 ng/mg in the depressed versus 5.4 ± 0.74 ng/mg in the control group, were unlikely to be different (95% HDI, [−1.37–0.34]). We found that presence of trazodone in the peri-mortem toxicology screen accounted for the observed difference in desmosterol concentrations. We also observed extremely high 7DHC levels in all 4 subjects who had taken trazodone. Trazodone has been recently found to inhibit 7-dehydrocholesterol reductase and alter sterol concentrations in rodents, cell culture, human fibroblasts, and blood. In this study, we demonstrate for the first time that trazodone alters human brain sterol composition. Given congenital deficiency of 7-dehydrocholesterol reductase results in Smith-Lemli-Opitz syndrome, our findings support the hypothesis that this commonly used medication may have previously unappreciated risks.

Individual and simultaneous treatment with antipsychotic aripiprazole and antidepressant trazodone inhibit sterol biosynthesis in the adult brain

“…In addition, in the most recent study, Cenik et al. have observed increased 7-DHC in human postmortem brain tissue due to TRZ usage, suggesting that DHCR7 inhibition is an integral part of TRZ action ( 22 ). In follow-up studies on sterol biosynthesis health, we found that multiple CNS-targeting medications are strong inhibitors of post-lanosterol biosynthesis, including (but not limited to) aripiprazole, cariprazine, haloperidol, trazodone, and amiodarone.…”

“…The cross-species translatability of findings is always a concern. This concern is alleviated by the fact that cholesterol biosynthesis across the mammalian species is conserved ( 60 ) and that multiple publications show that ARI and TRZ utilization increases 7-DHC levels in the human plasma ( 31 , 61 ) and brain tissue ( 22 ). In addition, we have shown previously that single drug treatments with ARI and TRZ are strong developmental inhibitors of sterol biosynthesis both in vitro and in vivo, with deleterious consequences on prenatal brain development ( 33 , 34 , 52 , 61 , 62 ).…”

“…The primary use of TRZ is the treatment of depression ( 13 ). However, TRZ has been also extensively utilized for off-label treatment of insomnia ( 14 , 15 ), opioid withdrawal symptoms ( 16 ), alcohol withdrawal ( 17 , 18 , 19 ), dementia ( 15 ), fibromyalgia ( 20 ) and other conditions ( 21 , 22 ).…”

Effects of Psychotropic Medication on Somatic Sterol Biosynthesis of Adult Mice

“…We and others have previously documented the strong sterol biosynthesis inhibitory activity of ARI and TRZ on the developing and adult brain, neurons, and astrocytes [ 19 , 20 , 49 , 68 ] across various in vitro and in vivo models. Furthermore, it is apparent that the same 7-DHC elevating effects of TRZ can be also observed in human blood and postmortem brain [ 18 , 19 , 54 , 69 ]. Our current findings raise the possibility that the 7-DHC elevating effects of ARI and TRZ can impact the development of other tissues beyond the CNS.…”

Chronic Aripiprazole and Trazodone Polypharmacy Effects on Systemic and Brain Cholesterol Biosynthesis

“…Studies in rodents have shown that both ARI and TRZ affect brain tissue through unique signaling pathways and their effects are not always directly related to their binding on dopaminergic and serotonergic receptors [ 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ]. ARI has been shown to have neuroprotective effects in stroke recovery by promoting dopaminergic survival and neuroprotective effects in a mouse model of Alzheimer’s Disease [ 23 , 24 ].…”