title: Common effect of antipsychotics on the biosynthesis and regulation of fatty acids and cholesterol supports a key role of lipid homeostasis in schizophrenia.
abstract: For decades, the dopamine hypothesis has gained the most attention in an attempt to explain the origin and the symptoms of schizophrenia. While this hypothesis offers an explanation for the relationship between psychotic symptoms and dopamine kinetics, it does not provide a direct explanation of the etiology of schizophrenia which remains poorly understood. Consequently, current antipsychotics that target neurotransmitter receptors, have limited and inconsistent efficacy. To gain insights into the mechanism of action of these drugs, we studied the expression profile of 12,490 human genes in a cell line treated with 18 antipsychotics, and compared it to that of a library of 448 other compounds used in a variety of disorders. Analysis reveals a common effect of antipsychotics on the biosynthesis and regulation of fatty acids and cholesterol, which is discussed in the context of a lipid hypothesis where alterations in lipid homeostasis might underlie the pathogenesis of schizophrenia. This finding may help research aimed at the development of novel treatments for this devastating disease.
authors.affiliation: Vanda Pharmaceuticals Inc., 9605 Medical Center Drive, Rockville, Maryland 20850, USA.
authors.forename: Mihael H
authors.initials: MH
authors.lastname: Polymeropoulos
authors.forename: Louis
authors.initials: L
authors.lastname: Licamele
authors.forename: Simona
authors.initials: S
authors.lastname: Volpi
authors.forename: Kendra
authors.initials: K
authors.lastname: Mack
authors.forename: Shruti N
authors.initials: SN
authors.lastname: Mitkus
authors.forename: Eugene D
authors.initials: ED
authors.lastname: Carstea
authors.forename: Lise
authors.initials: L
authors.lastname: Getoor
authors.forename: Andrew
authors.initials: A
authors.lastname: Thompson
authors.forename: Christian
authors.initials: C
authors.lastname: Lavedan
mesh_terms: D014150:Antipsychotic Agents / Q000494:pharmacology*; D002461:Cell Line, Transformed; D002784:Cholesterol / Q000378:metabolism*; D004847:Epithelial Cells / Q000187:drug effects*; D005227:Fatty Acids / Q000378:metabolism*; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D046228:Microarray Analysis / Q000379:methods; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000166:cytology; D018709:Statistics, Nonparametric
chemical_list: D014150:Antipsychotic Agents; D005227:Fatty Acids; D011960:Receptors, Estrogen; D002784:Cholesterol