TY - JOUR
T1 - Effect of psychotropic drug treatment on sterol metabolism
AU - Korade, Željka
AU - Liu, Wei
AU - Warren, Emily B.
AU - Armstrong, Kristan
AU - Porter, Ned A.
AU - Konradi, Christine
N1 - Funding Information:
This work was supported by the National Institutes of Health, NICHD HD064727 (NAP), NIEHS ES024133 (NAP and ZK) and NIMH MH074000 (CK). Recruitment and diagnosis of study participants, and collection of patient data and patient samples used in the study was carried out through the Psychiatric Genotyping-Phenotyping Project at the Vanderbilt Department of Psychiatry. The authors thank the members of the project as well as Dr. Stephan Heckers, Chair of the Vanderbilt Department of Psychiatry and project head.
Publisher Copyright:
© 2017 Elsevier B.V.
PY - 2017/9
Y1 - 2017/9
N2 - Cholesterol metabolism is vital for brain function. Previous work in cultured cells has shown that a number of psychotropic drugs inhibit the activity of 7-dehydrocholesterol reductase (DHCR7), an enzyme that catalyzes the final steps in cholesterol biosynthesis. This leads to the accumulation of 7-dehydrocholesterol (7DHC), a molecule that gives rise to oxysterols, vitamin D, and atypical neurosteroids. We examined levels of cholesterol and the cholesterol precursors desmosterol, lanosterol, 7DHC and its isomer 8-dehydrocholesterol (8DHC), in blood samples of 123 psychiatric patients on various antipsychotic and antidepressant drugs, and 85 healthy controls, to see if the observations in cell lines hold true for patients as well. Three drugs, aripiprazole, haloperidol and trazodone increased circulating 7DHC and 8DHC levels, while five other drugs, clozapine, escitalopram/citalopram, lamotrigine, olanzapine, and risperidone, did not. Studies in rat brain verified that haloperidol dose-dependently increased 7DHC and 8DHC levels, while clozapine had no effect. We conclude that further studies should investigate the role of 7DHC and 8DHC metabolites, such as oxysterols, vitamin D, and atypical neurosteroids, in the deleterious and therapeutic effects of psychotropic drugs. Finally, we recommend that drugs that increase 7DHC levels should not be prescribed during pregnancy, as children born with DHCR7 deficiency have multiple congenital malformations.
AB - Cholesterol metabolism is vital for brain function. Previous work in cultured cells has shown that a number of psychotropic drugs inhibit the activity of 7-dehydrocholesterol reductase (DHCR7), an enzyme that catalyzes the final steps in cholesterol biosynthesis. This leads to the accumulation of 7-dehydrocholesterol (7DHC), a molecule that gives rise to oxysterols, vitamin D, and atypical neurosteroids. We examined levels of cholesterol and the cholesterol precursors desmosterol, lanosterol, 7DHC and its isomer 8-dehydrocholesterol (8DHC), in blood samples of 123 psychiatric patients on various antipsychotic and antidepressant drugs, and 85 healthy controls, to see if the observations in cell lines hold true for patients as well. Three drugs, aripiprazole, haloperidol and trazodone increased circulating 7DHC and 8DHC levels, while five other drugs, clozapine, escitalopram/citalopram, lamotrigine, olanzapine, and risperidone, did not. Studies in rat brain verified that haloperidol dose-dependently increased 7DHC and 8DHC levels, while clozapine had no effect. We conclude that further studies should investigate the role of 7DHC and 8DHC metabolites, such as oxysterols, vitamin D, and atypical neurosteroids, in the deleterious and therapeutic effects of psychotropic drugs. Finally, we recommend that drugs that increase 7DHC levels should not be prescribed during pregnancy, as children born with DHCR7 deficiency have multiple congenital malformations.
KW - (6): Cholesterol
KW - Aripiprazole
KW - Clozapine
KW - Haloperidol
KW - Neurosteroids
KW - Trazodone
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U2 - 10.1016/j.schres.2017.02.001
DO - 10.1016/j.schres.2017.02.001
M3 - Article
C2 - 28202290
AN - SCOPUS:85012027123
SN - 0920-9964
VL - 187
SP - 74
EP - 81
JO - Schizophrenia Research
JF - Schizophrenia Research
ER -