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-HT receptor 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.

Effect of cytochrome CYP2C19 metabolizing activity on antidepressant response and side effects: Meta-analysis of data from genome-wide association studies

“…In addition to pharmacokinetic mechanisms, pharmacodynamic mechanisms may be involved in the association between CYP2C19 and antidepressant response, since CYP2C19 activity was reported to influence central neurotransmitters and neurotrophins relevant to antidepressant mechanisms of action (Jukić et al, 2016).…”

“…2) Pharmacodynamic mechanisms may modulate the association between CYP2C19 metabolic phenotypes and citalopram/escitalopram efficacy and some side effects, confounding the association between pharmacokinetic parameters and treatment outcomes (Jukić et al, 2016);…”

Genetic insight into cytochrome P450 in Chinese from the Chinese Millionome Database

“…Genetic variations in CYP genes participate in the pathogenesis of susceptibility to diseases such as depression and colon cancer and, more importantly, the inter‐individual differences in drug response . Clinical pharmacogenetic tests, such as CYP2C19*2 , *3 and clopidogrel; CYP2D6*4 , *5 , *10 and codeine; and CYP2C9*3 and warfarin, have benefitted genotyped patients.…”

Effect of cytochrome CYP2C19 metabolizing activity on antidepressant response and side effects: meta-analysis of data from genome-wide association studies

“…Inconsistent associations between CYP2C19 phenotypes and citalopram/escitalopram outcomes have been observed, and several factors may have led to the contradictory results (Mrazek et al, 2011) (Hodgson et al, 2014) (Hodgson et al, 2015): 1) Only a weak correlation exists between SSRI dose and efficacy and drug plasma levels may not be associated with either efficacy or side effects (Jakubovski et al, 2016) (Hodgson et al, 2014) (Hodgson et al, 2015); 2) Pharmacodynamic mechanisms may modulate the association between CYP2C19 phenotypes and citalopram/escitalopram efficacy and some side effects, weakening the association between pharmacokinetic parameters and treatment outcomes (Jukić et al, 2016);…”