CYP2D6 variation, behaviour and psychopathology: implications for pharmacogenomics‐guided clinical trials

Abstract

Individual and population differences in polymorphic cytochrome P450 enzyme function have been known for decades. The biological significance of these differences has now been deciphered with regard to drug metabolism, action and toxicity as well as disposition of endogenous substrates, including neuroactive compounds. While the cytochrome P450 enzymes occur abundantly in the liver, they are expressed in most tissues of the body, albeit in varying amounts, including the brain. The latter location of cytochrome P450s is highly pertinent for susceptibility to neuropsychiatric diseases, not to mention local drug metabolism at the site of psychotropic drug action in the brain. In the current era of personality medicine with companion theranostics (i.e. the fusion of therapeutics with diagnostics), this article underscores that such versatile biological roles of cytochrome P450s offer multiple points of entry for personalized medicine and rational therapeutics. We focus our discussion on CYP2D6, one of the most intensively researched drug and endogenous compound metabolism pathways, with a view to relevance for, and optimization of, pharmacogenomic-guided clinical trials. Working on the premise that CYP2D6 is related to human behaviour and certain personality traits such as serotonin and dopamine system function, we further suggest that the motivation of healthy volunteers to participate in clinical trials may in part be influenced by an under-or over-representation of certain CYP2D6 metabolic groups. CYP2D6 genetic polymorphisms and neuroactive endogenous compound metabolismAmong cytochrome P450s, CYP2D6 is one of the most intensively researched and clinically important enzymes involved in the metabolism of a large number of widely used central nervous system (CNS) drugs. CYP2D6 is highly polymorphic. Multiple allelic variants of the CYP2D6 gene have been identified, which are associated with an absent or increased enzyme activity in individuals who are respectively so called poor (PMs) and extensive metabolizers (EMs), including in the latter group a subgroup of ultrarapid metabolizers (UMs). This polymorphic enzyme is involved in the metabolism of many drugs of relevance to psychiatry, neurology and addiction medicine such as antidepressants, antipsychotics and opioids [1, 2]. Moreover, CYP2D6 has also been shown to contribute to endogenous metabolism of neuroactive substrates, which can explain the associations hitherto observed with human behaviour and disease susceptibility (e.g., personality, neurocognition and neuropsychiatric disorders) [3, 4] CYP2D6 was identified in both animal and human brain tissues in the late 1980s [5]. More than a decade later, dextromethorphan to dextrorphan metabolism was demonstrated in human brain microsomes [6]. CYPD6 has been described in neurons in the human cerebral cortex, hippocampus and cerebellum [7], basal ganglia and midbrain [8, 9]. Other studies have provided additional evidence of CYP2D6 expression in these brain regions and the thalamus [10] as well as in glial cel...

CYP2D6 genotype is not associated with survival in breast cancer patients treated with tamoxifen: results from a population-based study

“…The physiological role of CYP2D6 is not well defined as few high-affinity endogenous substrates have been identified. CYP2D6 is responsible for O-demethylation of pinoline[37] and of 6-methoxytryptamine to serotonin[38], which may account for the well-established association between CYP2D6 activity and personality[39,40]. It is unlikely, though possible, that these physiological differences are related to prognosis of ER+ breast cancer.…”

A combined high CYP2D6-CYP2C19 metabolic capacity is associated with the severity of suicide attempt as measured by objective circumstances

“…[5][6][7]20,21 However, an important limiting factor of the present study is the lack of data about the individuals' drug treatment and their drug plasma levels. As most of the available information about these polymorphic genes is related to drug therapeutic failure, the independent relationship between CYP2D6 and CYP2C19 with suicide severity could be expected in the individuals taking drug metabolized by these enzymes.…”

“…6,7 Thus, the effect of CYP2D6 on suicidal behavior can be partially due to drug therapeutic failure during treatment with CYP2D6 substrates and/or to differences in the CNS regulation. In support of the latter hypothesis, variability in CYP2D6 has been linked to differences in personality traits, neurocognitive functions and mental disorders.…”

“…In support of the latter hypothesis, variability in CYP2D6 has been linked to differences in personality traits, neurocognitive functions and mental disorders. 6 Furthermore, several studies have found poor response to antidepressant drugs or early dropout from monotherapy treatment with CYP2D6 antidepressant substrates in ultrarapid metabolizers (UMs). [8][9][10][11][12] Despite above evidence, negative findings have been also reported for the association of CYP2D6 genotypes with either response to drug treatment 13,14 or history of suicidal behaviors.…”

Progress in pharmacogenetics: consortiums and new strategies

“…Furthermore, the recent discovery of a high CYP2D6 hydroxylation capacity by the presence of -1584G allele in the promoter region of the CYP2D6 gene [22] emphasizes the need of an improvement in the genetic analysis in order to take into account other factors apart from gen duplication/multiplication. The effect of UM for CYP2D6 on suicidal behavior has to be highlighted since several studies have found poor response to antidepressant drugs or early dropout from monotherapy treatment with CYP2D6 antidepressant substrates [23,24].…”