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.