title: Methylenetetrahydrofolate reductase gene variants and antipsychotic-induced weight gain and metabolic disturbances.
abstract: Weight gain and metabolic disturbances represent serious side-effects in antipsychotic (AP) treatment, particularly with clozapine and olanzapine. The methylenetetrahydrofolate reductase (MTHFR) gene is a key determinant in the folate metabolism and previous studies reported a significant effect on AP-induced weight gain and related metabolic abnormalities. Thus, we investigated MTHFR gene variants and changes in several important metabolic parameters in AP-treated patients. In this study, two functional MTHFR polymorphisms, rs1801133 (C677T) and rs1801131 (A1298C), were investigated for changes in weight and metabolic parameters. Genotypic associations were evaluated in a large population (n = 347 including 66 first episode psychosis, FEP patients) treated mostly with clozapine and olanzapine. We did not detect any genotypic association with weight changes (p > 0.05) in our total sample and in the sample refined for ancestry and medication. In our allelic analyses, we observed a trend for the 677-C allele to be associated with weight gain in the total sample (p = 0.03). This effect appeared to be driven by the FEP patients where those carrying the C-allele gained, on average, twice as much weight. Exploratory analyses revealed a significant association between the C677T and the A1298C polymorphism with HDL cholesterol serum levels in patients (p = 0.031). Overall we did not detect a major effect of two functional MTHFR gene variants and AP-induced weight gain. However, our findings suggest an effect of the C677T polymorphism in FEP patients and changes in weight and cholesterol levels. Further investigations in a larger sample are required.
authors.affiliation: Pharmacogenetics Research Clinic, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Biological Sciences, University of Toronto, Scarborough, ON, Canada.
authors.forename: A C C
authors.initials: AC
authors.lastname: Kao
authors.affiliation: Department of Psychiatry, University Hospital Centre Zagreb, Zagreb School of Medicine, Croatia.
authors.forename: M
authors.initials: M
authors.lastname: Rojnic Kuzman
authors.affiliation: Pharmacogenetics Research Clinic, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
authors.forename: A K
authors.initials: AK
authors.lastname: Tiwari
authors.affiliation: Psychiatric Clinic Vrapce, Zagreb, Croatia.
authors.forename: M V
authors.initials: MV
authors.lastname: Zivkovic
authors.affiliation: Pharmacogenetics Research Clinic, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors.forename: N I
authors.initials: NI
authors.lastname: Chowdhury
authors.affiliation: Department of Psychiatry, University Hospital Centre Zagreb, Zagreb School of Medicine, Croatia.
authors.forename: V
authors.initials: V
authors.lastname: Medved
authors.affiliation: Department of Psychiatry, University Hospital Centre Zagreb, Zagreb School of Medicine, Croatia.
authors.forename: I
authors.initials: I
authors.lastname: Kekin
authors.affiliation: Pharmacogenetics Research Clinic, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
authors.forename: C C
authors.initials: CC
authors.lastname: Zai
authors.affiliation: Department of Psychiatry, College of Physicians and Surgeons, Columbia University and the New York State Psychiatric Institute, New York City, NY, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Lieberman
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: H Y
authors.initials: HY
authors.lastname: Meltzer
authors.affiliation: Department of Laboratory Diagnostics, University Hospital Centre Zagreb, Zagreb School of Medicine, Croatia.
authors.forename: T
authors.initials: T
authors.lastname: Bozina
authors.affiliation: Department of Laboratory Diagnostics, University Hospital Centre Zagreb, Zagreb School of Medicine, Croatia.
authors.forename: N
authors.initials: N
authors.lastname: Bozina
authors.affiliation: Pharmacogenetics Research Clinic, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
authors.forename: J L
authors.initials: JL
authors.lastname: Kennedy
authors.affiliation: Department of Laboratory Diagnostics, University Hospital Centre Zagreb, Zagreb School of Medicine, Croatia.
authors.forename: J
authors.initials: J
authors.lastname: Sertic
authors.affiliation: Pharmacogenetics Research Clinic, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada. Electronic address: daniel.mueller@camh.ca.
authors.forename: D J
authors.initials: DJ
authors.lastname: Müller
mesh_terms: D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D014150:Antipsychotic Agents / Q000009:adverse effects*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008659:Metabolic Diseases / Q000139:chemically induced*; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011569:Psychiatric Status Rating Scales; D011618:Psychotic Disorders / Q000188:drug therapy / Q000235:genetics; D012559:Schizophrenia / Q000188:drug therapy / Q000235:genetics; D015430:Weight Gain / Q000187:drug effects* / Q000235:genetics; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; D042965:Methylenetetrahydrofolate Reductase (NADPH2)
keywords: A1298C; Antipsychotic; C677T; MTHFR; Weight gain