Abstract
Cytochrome P450 2D6 (CYP2D6) is expressed at high levels in the brain and plays a considerable role in the biotransformation and neurotransmission of dopamine. This raises the question of whether CYP2D6 variations and its impact on the brain can confer susceptibility to schizophrenia. We investigated the possible links among the CYP2D6 genotype, white matter (WM) integrity of the hippocampus, and the treatment response to antipsychotic drugs in Korean patients with schizophrenia (n = 106). Brain magnetic resonance imaging and genotyping for CYP2D6 were conducted at baseline. The severity of clinical symptoms and the treatment response were assessed using the Positive and Negative Syndrome Scale (PANSS). After genotyping, 43 participants were classified as intermediate metabolizers (IM), and the remainder (n = 63) were classified as extensive metabolizers (EM). IM participants showed significantly higher fractional anisotropy (FA) values in the right hippocampus compared to EM participants. Radial diffusivity (RD) values were significantly lower in the overlapping region of the right hippocampus in the IM group than in the EM group. After 4 weeks of antipsychotic treatment, the EM group showed more improvements in positive symptoms than the IM group. FAs and RDs in the CYP2D6-associated hippocampal WM region were significantly correlated with a reduction in the positive symptom subscale of the PANSS. Greater improvements in positive symptoms were negatively associated with FAs, and positively associated with RDs in the right hippocampal region. The findings suggest that CYP26D-associated hippocampal WM alterations could be a possible endophenotype for schizophrenia that accounts for individual differences in clinical features and treatment responses.
Highlights
Cytochrome P450 2D6 (CYP2D6), a member of the cytochromeP450 mixed-function oxidase system, is one of the most popular enzymes involved in the metabolism of numerous drugs used in clinical practice
This study examined the genetic influence of CYP2D6 polymorphism on hippocampal white matter (WM) connectivity and treatment response in patients with schizophrenia
We demonstrated that IM patients had significantly higher fractional anisotropy (FA) and lower Radial diffusivity (RD) values in the right hippocampal WM region compared to extensive metabolizers (EM) patients
Summary
Cytochrome P450 2D6 (CYP2D6), a member of the cytochromeP450 mixed-function oxidase system, is one of the most popular enzymes involved in the metabolism of numerous drugs used in clinical practice. Recent evidence shows that CYP2D6 is expressed at high levels in neuronal cells of the brain[2,3], and plays a considerable role in the biotransformation and neurotransmission of central dopamine[4]. This raises the question of whether individual variations in CYP2D6 can confer susceptibility to schizophrenia[5]. CYP2D6 has strong activity for the conversion of dopamine from tyramine that exists in the brain[10], suggesting its intertwining effects on the central dopaminergic system. Previous studies revealed that CYP2D6 activity is associated with conditions, in which dopamine signaling plays a substantial role in pathophysiology, including Parkinson’s disease[11], smoking behavior[12], sexual dysfunction[13], and suicide[14]
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