title: Elevated CYP2C19 expression is associated with depressive symptoms and hippocampal homeostasis impairment.
abstract: The polymorphic CYP2C19 enzyme metabolizes psychoactive compounds and is expressed in the adult liver and fetal brain. Previously, we demonstrated that the absence of CYP2C19 is associated with lower levels of depressive symptoms in 1472 Swedes. Conversely, transgenic mice carrying the human CYP2C19 gene (2C19TG) have shown an anxious phenotype and decrease in hippocampal volume and adult neurogenesis. The aims of this study were to: (1) examine whether the 2C19TG findings could be translated to humans, (2) evaluate the usefulness of the 2C19TG strain as a tool for preclinical screening of new antidepressants and (3) provide an insight into the molecular underpinnings of the 2C19TG phenotype. In humans, we found that the absence of CYP2C19 was associated with a bilateral hippocampal volume increase in two independent healthy cohorts (N=386 and 1032) and a lower prevalence of major depressive disorder and depression severity in African-Americans (N=3848). Moreover, genetically determined high CYP2C19 enzymatic capacity was associated with higher suicidality in depressed suicide attempters (N=209). 2C19TG mice showed high stress sensitivity, impaired hippocampal Bdnf homeostasis in stress, and more despair-like behavior in the forced swim test (FST). After the treatment with citalopram and 5-HT1Areceptor agonist 8OH-DPAT, the reduction in immobility time in the FST was more pronounced in 2C19TG mice compared with WTs. Conversely, in the 2C19TG hippocampus, metabolic turnover of serotonin was reduced, whereas ERK1/2 and GSK3β phosphorylation was increased. Altogether, this study indicates that elevated CYP2C19 expression is associated with depressive symptoms, reduced hippocampal volume and impairment of hippocampal serotonin and BDNF homeostasis.
authors.affiliation: Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: M M
authors.initials: MM
authors.lastname: Jukić
authors.affiliation: Department of Psychiatry, University of Münster, Münster, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Opel
authors.affiliation: Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Ström
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Carrillo-Roa
authors.affiliation: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Department of Psychiatry, University of Toronto, Toronto, ON, Canada.|Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Miksys
authors.affiliation: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Department of Psychiatry, University of Toronto, Toronto, ON, Canada.|Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Novalen
authors.affiliation: Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Renblom
authors.affiliation: Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: S C
authors.initials: SC
authors.lastname: Sim
authors.affiliation: CICAB Clinical Research Center, Extremadura University Hospital and Medical School, Badajoz, Spain.|CIBERSAM, Madrid, Spain.
authors.forename: E M
authors.initials: EM
authors.lastname: Peñas-Lledó
authors.affiliation: CHU Montpellier, Hôpital Lapeyronie, Psychiatric Emergency and Post-Acute Care Department, Pole Urgence, Montpellier, France.
authors.forename: P
authors.initials: P
authors.lastname: Courtet
authors.affiliation: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Department of Psychiatry, University of Toronto, Toronto, ON, Canada.|Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Llerena
authors.affiliation: Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, SA, Australia.
authors.forename: B T
authors.initials: BT
authors.lastname: Baune
authors.affiliation: Transfaculty Research Platform, Department of Psychology, University Psychiatric Clinics, University of Basel, Basel, Switzerland.
authors.forename: D J
authors.initials: DJ
authors.lastname: de Quervain
authors.affiliation: Transfaculty Research Platform, Department of Psychology, University Psychiatric Clinics, University of Basel, Basel, Switzerland.|Life Sciences Training Facility, Department Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Papassotiropoulos
authors.affiliation: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Department of Psychiatry, University of Toronto, Toronto, ON, Canada.|Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
authors.forename: R F
authors.initials: RF
authors.lastname: Tyndale
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: E B
authors.initials: EB
authors.lastname: Binder
authors.affiliation: Department of Psychiatry, University of Münster, Münster, Germany.|Department of Psychiatry, University of Marburg, Marburg, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Dannlowski
authors.affiliation: Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Ingelman-Sundberg
mesh_terms: D001741:Black or African American / Q000235:genetics; D000818:Animals; D001007:Anxiety / Q000000981:diagnostic imaging / Q000235:genetics; D001008:Anxiety Disorders / Q000235:genetics*; D001522:Behavior, Animal / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D015283:Citalopram / Q000494:pharmacology; D065731:Cytochrome P-450 CYP2C19 / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*; D003863:Depression / Q000188:drug therapy / Q000235:genetics; D003865:Major Depressive Disorder / Q000000981:diagnostic imaging / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D006706:Homeostasis / Q000235:genetics / Q000502:physiology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D055495:Neurogenesis / Q000235:genetics; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D058825:Serotonin 5-HT1 Receptor Agonists; D015283:Citalopram; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; C579455:BDNF protein, human; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19