title: Effect of psychotropic drug treatment on sterol metabolism.
abstract: 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.
authors.affiliation: Department of Pediatrics and Department of Biochemistry and Molecular Biology, UNMC, Omaha, NE 68198, United States.
authors.forename: Željka
authors.initials: Ž
authors.lastname: Korade
authors.affiliation: Department of Chemistry and Vanderbilt Institute of Chemical Biology, Nashville, TN 37235, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, Vanderbilt University, Nashville, TN 37240, United States.
authors.forename: Emily B
authors.initials: EB
authors.lastname: Warren
authors.affiliation: Department of Psychiatry, Vanderbilt University, Nashville, TN 37212, United States.
authors.forename: Kristan
authors.initials: K
authors.lastname: Armstrong
authors.affiliation: Department of Chemistry and Vanderbilt Institute of Chemical Biology, Nashville, TN 37235, United States.
authors.forename: Ned A
authors.initials: NA
authors.lastname: Porter
authors.affiliation: Department of Pharmacology, Vanderbilt University, Nashville, TN 37240, United States; Department of Psychiatry, Vanderbilt University, Nashville, TN 37212, United States. Electronic address: Christine.konradi@vanderbilt.edu.
authors.forename: Christine
authors.initials: C
authors.lastname: Konradi
mesh_terms: D000328:Adult; D000818:Animals; D000928:Antidepressive Agents / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use*; D014150:Antipsychotic Agents / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use*; D015992:Body Mass Index; D002775:Cholestadienols / Q000097:blood*; D003024:Clozapine / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D003684:Dehydrocholesterols / Q000097:blood*; D005260:Female; D006220:Haloperidol / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D001523:Mental Disorders / Q000097:blood / Q000188:drug therapy; D011569:Psychiatric Status Rating Scales; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D015430:Weight Gain / Q000187:drug effects
chemical_list: D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D002775:Cholestadienols; D003684:Dehydrocholesterols; C026359:cholesta-5,8-dien-3 beta-ol; C016705:7-dehydrocholesterol; D003024:Clozapine; D006220:Haloperidol
keywords: (6): Cholesterol; Aripiprazole; Clozapine; Haloperidol; Neurosteroids; Trazodone