Review
`
`Click here for more articles from the symposium
`
`doi: 10.1111/joim.12317
`
`Polymorphism in CYP2D6 and CYP2C19, members of the
`cytochrome P450 mixed-function oxidase system, in the
`metabolism of psychotropic drugs
`
`J. Stingl1 & R. Viviani2
`From the 1Center for Translational Medicine, University of Bonn Medical School, Bonn; and 2Department of Psychiatry and Psychotherapy III,
`University of Ulm, Ulm, Germany
`
`Abstract. Stingl J, Viviani R (University of Bonn
`Medical Faculty, Bonn; University of Ulm, Ulm;
`Germany).
`Polymorphism in CYP2D6
`and
`CYP2C19, members of
`the cytochrome P450
`mixed-function
`oxidase
`system,
`in
`the
`metabolism of psychotropic drugs
`(Review).
`J Intern Med 2015; 277: 167–177.
`
`Numerous studies in the field of psychopharmaco-
`logical treatment have investigated the possible
`contribution of genetic variability between individ-
`uals to differences in drug efficacy and safety,
`motivated by the wide individual variation in
`treatment response. Genomewide analyses have
`been conducted in several large-scale studies on
`antidepressant drug response. However, no con-
`sistent findings have emerged from these studies.
`In a recent meta-analysis of genomewide data from
`the three studies capturing common variation for
`association with symptomatic improvement and
`remission revealed the absence of any strong
`genetic association and failed to replicate results
`of individual studies in the pooled data. However,
`
`there are good reasons to consider the possible
`importance of pharmacogenetic variants sepa-
`rately. These variants explain a large portion of
`the manifold variability in individual drug metab-
`olism. More than 20 psychotropic drugs have now
`been relabelled by the FDA adding information on
`polymorphic drug metabolism and therapeutic
`recommendations. Furthermore, dose recommen-
`dations for polymorphisms in drug metabolizing
`enzymes, first
`and foremost CYP2D6 and
`CYP2C19, have been issued with the advice to
`reduce the dosage in poor metabolizers to 50% or
`less (in eight cases), or to choose an alternative
`treatment. Beside the well-described role in hepatic
`drug metabolism,
`these
`enzymes
`are
`also
`expressed in the brain and play a role in biotrans-
`formation of endogenous substrates. These poly-
`morphisms may
`therefore modulate
`brain
`metabolism and affect the function of the neural
`substrates of cognition and emotion.
`
`Keywords: antidepressant drugs, CYP2C19, CYP2D6,
`drug metabolism, pharmacogenetics.
`
`Pharmacogenomics of antidepressant drug response: the
`genomewide association study approach
`
`Psychotropic medications belong to the most
`frequently prescribed drugs with more than
`100Mio daily drug doses in Germany in long-term
`therapies [1]. Hence,
`the fact
`that
`individual
`response to the same drug given in the same dose
`varies considerably has large practical
`implica-
`tions.
`In antidepressant treatment, only about
`one-third of patients achieve sufficient long-term
`symptomatic remission with their first-choice
`antidepressant, whilst the remaining 67% do not
`respond and are subsequently switched to different
`antidepressant drugs with the consequence of a
`prolongation of the duration of illness [2].
`
`Evidence for the hypothesis that genetic variation
`may contribute to the variability of drug response
`has been intensively sought. Several large-scale
`genetic association studies on antidepressant drug
`response have been recently performed using the
`genomewide association approach [3–5]. However,
`a consistent picture of replicated findings has so
`far failed to emerge.
`
`In a recent meta-analysis, the results from these
`three studies were combined with the aim to
`increase the power for the detection of effects [6].
`A broader analysis was conducted including all
`patients to reveal general genetic patterns of
`remission, whilst a narrower analysis in patients
`focused on selective serotonin reuptake inhibitors
`
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`
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`J. Stingl & R. Viviani
`
`Review: Pharmacogenetics of psychotropic drugs
`
`(SSRIs), especially escitalopram or citalopram.
`Using a genetic imputation technique, genome-
`wide data pooled from the three studies capturing
`common variation for association with symptom-
`atic improvement and remission were analysed.
`The results revealed the lack of strong genetic
`associations, and failed to replicate the single
`study results in the pooled analysis. The broader
`analysis in the entire sample resulted in one
`genomewide effect of a SNP located in the intronic
`region of the myosin X (MYO10) gene at 5p15.1,
`but the result could not be validated in confir-
`matory follow-up genotyping because of
`the
`absence of this effect in the STAR*D study [6].
`The narrow analysis focusing on SSRI-treated
`individuals identified a variant associated with
`early SSRI response (within 2 weeks of
`treat-
`ment), a SNP in an intergenic region on chromo-
`some 5. This association awaits replication in
`future studies [6].
`
`The failure to replicate findings and the poor
`predictive value of genetic variants in genomewide
`association studies raises the issue of the real
`prospects of success of approaches that wager on
`exploratory analyses to compensate for our limited
`current understanding of how neurobiological
`mechanisms and molecular changes contribute to
`the genesis of psychiatric disorders. This issue will
`likely take a prominent position in research in
`psychopharmacology and treatment of psychiatric
`disorders in the years to come.
`
`Pharmacogenetics: Psychotropic drugs and polymorphic drug
`metabolism
`
`A different approach focuses on the genetic vari-
`ability in drug metabolizing enzymes (DMEs) [7].
`These genetic polymorphisms have large effects,
`extensively documented in studies of individual
`differences in drug clearance affecting therapy
`outcome and safety [8].
`
`DME phenotypes, as predicted from genotypes,
`may be classified into four major groups:
`
`1 poor metabolizers (PM phenotype) are charac-
`terized by a complete lack of enzyme activity (two
`defective alleles);
`
`2 intermediate metabolizers (IM phenotype) are
`carriers of either one defective allele or two partially
`functional alleles;
`
`168 ª 2014 The Association for the Publication of the Journal of Internal Medicine
`Journal of Internal Medicine, 2015, 277; 167–177
`
`3 extensive metabolizers (EM phenotype) are car-
`riers of two functional alleles;
`
`4 ultrarapid metabolizers (UM phenotype) are car-
`riers of alleles leading to increased enzyme func-
`tion.
`
`As differences in plasma concentration due to
`individual variability in drug clearance in these
`phenotypes can be more than 10-fold, the possi-
`bility of delivering ‘personalized medicine’ through
`dose adjustments based on pharmacokinetic data
`has a sound rationale [9–11]. Most psychiatric
`drugs are extensively metabolized by these poly-
`morphic DMEs, with CYP2D6 being involved in the
`metabolism of approximately half of the commonly
`prescribed psychotropic drugs [12].
`
`dose-adjustment
`pharmacokinetic-based
`The
`approach is now being integrated with a formal
`assessment of the degree of evidence justifying a
`clinical recommendation for specific drug–geno-
`type pairs (Clinical Pharmacogenetics Implemen-
`tation consortium, CPIC) [10, 13]. Evidence-based
`dosing guidelines have now been issued for 27
`drugs and made available in the PharmGKB data-
`base [14]. Of all genes involved in these evalua-
`tions, CYP2C19 and CYP2D6 have been shown to
`be the most important DMEs for dose adjustments
`of psychotropic drugs.
`
`This empirical evidence is starting to have an
`impact on regulatory agencies such as the FDA
`and the EMA. Information on the genetic polymor-
`phism in DMEs is now being inserted in drug
`labels, where it is given in the respective sections of
`the product information (Dosage and Administra-
`tion, Warnings and Precautions, Drug Interactions,
`Clinical Pharmacology) [15]. To date, more than
`150 drug labels have been updated with pharma-
`cogenetic information by the FDA and more than
`70 by the EMA [16] (http://www.pharmgkb.org/
`view/drug-labels.do), alerting physicians
`that
`genetic factors may influence therapeutic outcome
`or adverse reactions. Of these pharmacogenetic
`labels, 24 involve drugs used in psychiatry. In 23
`cases, alertness is recommended due to major
`metabolism via CYP2D6, whilst four cases involve
`CYP2C19. For most drugs in psychiatric use, there
`are no explicit dose adjustments for the different
`phenotype groups, but rather general recommen-
`dations to watch out for and adopt a cautious
`stance about drug interactions. In Table 1, we have
`
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`

`J. Stingl & R. Viviani
`
`Review: Pharmacogenetics of psychotropic drugs
`
`Table 1 Pharmacokinetic based dose adjustments for psychotropic drugs for which pharmacogenetic information is provided
`in the drug label
`
`PK differences caused by
`
`genotype corresponding to
`
`Pharmacokinetic
`
`Clinical-based
`
`dose adjustments
`
`implications (toxicity
`
`evidence
`
`Substance
`
`DME
`
`PM
`
`IM
`
`EM
`
`UM
`
`or efficacy)
`
`studies
`
`Action to be
`
`undertaken
`
`Antidepressants
`
`Amitriptyline
`
`CYP2D6
`
`CYP2C19 70% 87% 105
`
`67% 90% 114% 138%a Toxicity/side effect
`risk in PM, risk for
`
`141%
`
`therapeutic failure in
`
`efficacy and
`
`UMs
`
`toxicity
`
`Limited
`
`Monitor plasma
`
`evidence for
`
`concentrations
`(P+M),
`Consider dose
`
`adjustment
`
`Clomipramine CYP2D6
`
`55% 87% 119% 152% Toxicity/side effect
`
`Limited
`
`Monitor plasma
`
`CYP2C19 69% 87% 106% 125%
`
`risk in PM, risk for
`
`evidence for
`
`therapeutic failure in
`
`efficacy and
`
`UMs
`
`toxicity
`
`concentrations
`(P+M),
`Consider dose
`
`adjustment
`
`Desipramine
`
`CYP2D6
`
`25% 76% 136% 207% Toxicity/side effect
`
`Limited
`
`Monitor plasma
`
`risk in PM, risk for
`
`evidence for
`
`therapeutic failure in
`
`efficacy and
`
`UMs
`
`toxicity
`
`concentrations
`(P+M),
`Consider dose
`
`adjustment
`
`Doxepin
`
`CYP2D6
`
`34% 77% 131% 204% Toxicity/side effect
`
`Limited
`
`Monitor plasma
`
`risk in PM, risk for
`
`evidence for
`
`therapeutic failure in
`
`efficacy and
`
`UMs
`
`toxicity
`
`concentrations
`(P+M),
`Consider dose
`
`adjustment
`
`Imipramine
`
`CYP2D6
`
`28% 79% 131% 183% Toxicity/side effect
`
`Limited
`
`Monitor plasma
`
`CYP2C19 77% 86% 106% 128%
`
`risk in PM, risk for
`
`evidence for
`
`therapeutic failure in
`
`efficacy and
`
`UMs
`
`toxicity
`
`concentrations
`(P+M),
`Consider dose
`
`adjustment
`
`Nortriptyline
`
`CYP2D6
`
`50% 72% 133% 195% Toxicity/side effect
`
`Limited
`
`Monitor plasma
`
`risk in PM, risk for
`
`evidence for
`
`therapeutic failure in
`
`efficacy and
`
`UMs
`
`toxicity
`
`concentrations
`(P+M),
`Consider dose
`
`adjustment
`
`Trimipramine CYP2D6
`
`59% 88% 118% 147% Toxicity/side effect
`
`Limited
`
`Monitor plasma
`
`CYP2C19 45% 76% 107% 154%
`
`risk in PM, risk for
`
`evidence for
`
`therapeutic failure in
`
`efficacy and
`
`UMs
`
`toxicity
`
`concentrations
`(P+M),
`Consider dose
`
`adjustment
`
`ª 2014 The Association for the Publication of the Journal of Internal Medicine
`Journal of Internal Medicine, 2015, 277; 167–177
`
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`

`J. Stingl & R. Viviani
`
`Review: Pharmacogenetics of psychotropic drugs
`
`Table 1 (Continued )
`
`PK differences caused by
`
`genotype corresponding to
`
`Pharmacokinetic
`
`Clinical-based
`
`dose adjustments
`
`implications (toxicity
`
`evidence
`
`Substance
`
`Citalopram
`
`DME
`
`UM
`EM
`IM
`PM
`or efficacy)
`CYP2C19 59% 87% 107% 130% Large therapeutic
`
`studies
`
`Action to be
`
`undertaken
`
`Conflicting
`
`Monitor plasma
`
`Fluoxetine
`
`CYP2D6
`
`–
`
`–
`
`–
`
`–
`
`range; no response
`
`evidence on
`
`concentrations,
`
`effect observed except
`
`response and
`
`Consider dose
`
`UMs carrying the risk
`
`toxicity
`
`adjustment
`
`of therapeutic failure
`
`Substrate and strong
`inhibitor, P+M equal
`for CYP2D6
`
`No clinical
`
`Alertness for drug
`
`evidence for
`
`interactions with
`
`important
`
`CYP2D6
`
`genotypes, no data on
`
`genotype
`
`substrates
`
`safety risk for PMs
`
`effect
`
`Fluvoxamine
`
`CYP2D6
`
`68% 89% 117% 147% Preliminary PK data
`
`Clinical
`
`Consider
`
`only
`
`evidence for
`
`monitoring
`
`response and
`
`plasma
`
`toxicity
`
`concentrations,
`
`Paroxetine
`
`CYP2D6
`
`51% 81% 125% 169% Substrate and
`
`No clinical
`
`Select alternative
`
`dose adjustments
`
`inhibitor
`
`evidence for
`
`drug in UMs,
`
`response,
`
`consider dose
`
`clinical
`
`adjustment in PM
`
`Venlafaxine
`
`CYP2D6
`
`77% 92% 109% 172% Active metabolites.
`
`evidence for
`
`adverse
`
`effects
`
`Clinical
`
`Select alternative
`
`Safety concern in PMs
`
`evidence for
`
`drug in PM, UM,
`
`response and
`
`and IM
`
`toxicity
`
`CYP2C19 (44% 89% 107% 124%) Preliminary PK data
`
`No clinical
`
`Consider dose
`
`only, Safety concern
`
`evidence
`
`adjustment
`
`in PMs
`
`Antipsychotics
`
`Perphenazine CYP2D6
`
`(45% 67% 116% 164%) Only preliminary PK
`
`No evidence on
`
`No
`
`data available
`
`toxicity
`
`recommendations
`
`Pimozide
`
`(CYP2D6)
`
`Only minor role of
`
`No clinical
`
`No actions
`
`polymorphic DMEs
`
`evidence data
`
`necessary
`
`Thioridazine
`
`CYP2D6
`
`42% 83% 125% 153% Only PK data available
`
`Limited
`
`Consider dose
`
`evidence on
`
`adjustment
`
`toxicity
`
`170 ª 2014 The Association for the Publication of the Journal of Internal Medicine
`Journal of Internal Medicine, 2015, 277; 167–177
`
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`

`J. Stingl & R. Viviani
`
`Review: Pharmacogenetics of psychotropic drugs
`
`Table 1 (Continued )
`
`PK differences caused by
`
`genotype corresponding to
`
`Pharmacokinetic
`
`Clinical-based
`
`dose adjustments
`
`implications (toxicity
`
`evidence
`
`Substance
`
`DME
`
`Aripiprazole
`
`CYP2D6
`
`UM
`EM
`IM
`PM
`or efficacy)
`66% 90% 115% 139% Large therapeutic
`
`studies
`
`Limited
`
`Action to be
`
`undertaken
`
`Consider dose
`
`range; no response
`
`clinical
`
`adjustment in
`
`effect expected except
`
`evidence
`
`UMs
`
`UMs carrying the risk
`
`of therapeutic failure
`
`Clozapine
`
`(CYP1A2)
`
`Not metabolized by
`
`No clinical
`
`No actions
`
`Risperidone
`
`CYP2D6
`
`polymorphic DMEs
`
`evidence for
`
`necessary
`
`56% 88% 119% 146%a Safety concern in PMs,
`P+M equally effective
`across CYP2D6
`
`an effect
`
`Clinical
`
`Select alternative
`
`evidence on
`
`drug in PM, UM
`
`response and
`
`and IM
`
`genotypes
`
`toxicity
`
`Diazepam
`
`CYP2C19 (51% 81% 109% 138%) Preliminary PK data
`
`No clinical
`
`No
`
`Atomoxetine
`
`CYP2D6
`
`–
`
`–
`
`–
`
`–
`
`Preliminary PK data
`
`No clinical
`
`Standard dose in
`
`only
`
`evidence data
`
`recommendations
`
`only; insufficient data
`
`evidence data
`
`PM, IM; Be alert
`
`to allow calculation of
`
`dose adjustment
`
`to reduced
`
`efficacy or select
`
`alternative drug
`
`in UM
`
`aBased on sum of pharmacologically active parent drug and active metabolite.
`
`collected recommendations of pharmacokinetic
`dose adjustments for the psychotropic drugs in
`common use, and for which such labelling have
`been issued by the regulatory agencies (for more
`detailed information, see FDA website and [11]).
`
`The overall impact of dose adjustments on clinical
`decisions also depends on considerations about
`the clinical utility of equalizing pharmacokinetic
`differences. For example, at one extreme of the
`range of clinical consequences of DME polymor-
`phisms, inadequate exposure to a drug may con-
`stitute a risk to life due to nonresponse or toxicity.
`At the other extreme, imprecise dosing may have
`little or no clinical consequences, because of a wide
`therapeutic range. When the drug is safe and/or
`effective within a plasma concentration range,
`genetic information may be used together with
`therapeutic drug monitoring to ensure adequate
`treatment
`(a resource
`giving
`evidence-based
`
`plasma concentration ranges for psychotropic
`drugs is [17]). Evidence on the clinical relevance
`of DME polymorphism and inadequate dosing in
`antidepressant drug treatment comes from clinical
`data or epidemiological and safety data, showing
`and association of the CYP2D6 poor metabolizer
`phenotype with increased times to settle on the
`appropriate drug and more frequent drug switches
`during antidepressant treatment [18]. These data
`also suggest that poor metabolizers suffer more
`frequently from adverse drug reactions than exten-
`sive metabolizers and register longer hospital
`stays, whereas ultrarapid metabolizers have a
`higher risk of therapeutic failure [18–22].
`
`Expression of DMEs in the brain
`
`Several DMEs are expressed throughout the body,
`including the brain [23], suggesting that they may
`be metabolically active locally and play a role in the
`
`ª 2014 The Association for the Publication of the Journal of Internal Medicine
`Journal of Internal Medicine, 2015, 277; 167–177
`
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`

`J. Stingl & R. Viviani
`
`Review: Pharmacogenetics of psychotropic drugs
`
`regulation of physiological homoeostasis by bio-
`transformation of endogenous compounds [24].
`Brain-expressed DMEs are distributed to specific
`brain regions and different cell types [25–29]. Most
`studies have investigated CYP2D6, which is
`expressed in both neuronal and in glial cells [26,
`30–35]. In the brain, DME gene expression appears
`to be regulated differently than in the liver. Higher
`CYP2D6 protein levels have been reported in brain
`
`of smokers and alcoholics with unchanged hepatic
`enzyme levels [26, 36].
`
`Polymorphisms in CYP2C19 as well as CYP2D6
`may have effects on brain function with conse-
`quences on affect and affective disorders [37, 38].
`In man, there is evidence of a direct association of
`CYP2C19 polymorphism and depression [37].
`Interestingly, CYP2C19 seems to be expressed only
`
`Genotype
`
`Brain DME
`activity
`
`Brain endogenous
`substrate activity
`
`(a)
`
`Comedication/other
`DME substrates
`
`Liver DME
`activity
`
`Brain function
`
`Treatment success
`neurotoxicity
`behavioral effect
`
`Drug of
`interest/xenobiotic
`
`Blood concentration
`drug/xenobiotic
`
`Genotype
`
`Brain
`morphogenesis
`
`CYP2D6
`
`CYP2C19
`
`(b)
`
`Comedication/other
`DME substrates
`
`Liver DME
`activity
`
`Brain function
`
`Treatment success
`behavioral effect
`
`Drug of
`interest/xenobiotic
`
`Blood concentration
`drug/xenobiotic
`
`Legend:
`
`Induction/inhibition
`
`Fig. 1 Graph illustrating causal paths considered in the literature linking genotype variants, xenobiotic exposures, and
`effects with individual differences in treatment efficacy, cognitive function, vulnerability to neurotoxins or behavioural
`disorders. These causal paths need to be considered when inferring in observational studies the effect of genotype on
`behaviour or vulnerability to disorder [61]. The drug of interest here may also be any xenobiotic, such as a neurotoxin, or a
`substance of abuse, that is a substrate of the drug metabolizing enzyme in question. a, top: effects of genetic polymorphism
`in CYP2D6. This complex graph reflects the manifold effects due to the activity of CYP2D6 in the liver and in the brain, where
`it may simultaneously affect brain function and act on endogenous and exogenous substrate. b, bottom: effects of genetic
`polymorphism in CYP2C19. Current evidence suggests that the effect on brain function of CYP2C19 is mediated by
`morphological differences emerging during development.
`
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`

`J. Stingl & R. Viviani
`
`Review: Pharmacogenetics of psychotropic drugs
`
`Fig. 2 With copyright permission from [51]. Top half: Regression of resting brain perfusion values on the CYP2D6 activity
`score over the whole brain. Left: hypothalamus and occipital/calcarine cortex; Centre: hippocampus and adjacent occipito/
`temporal cortex (lingual and fusiform gyrus); Right: thalamus and occipital/calcarine cortex. Bottom half: cerebral blood flow
`perfusion in the hypothalamus and occipital/calcarine region divided by CYP2D6 activity scores. Individuals with activity 0
`in this plot are poor metabolizers.
`
`during brain development in the foetus. However,
`in mice, this expression has morphological and
`functional effects on the brain in adult life [39]. A
`decreased hippocampal volume, an altered neuro-
`nal composition in the hippocampal dentate gyrus,
`and behaviour indicative of increased stress and
`anxiety based on four different tests were observed
`[39]. These results indicate that CYP2C19 metab-
`olizes critical compounds for brain development
`during foetal life, potentially affecting brain devel-
`opment. A number of independent studies have
`also associated the CYP2D6 polymorphism with
`the risk of suicide. Forensic studies originally
`reported an increased frequency of the ultrarapid
`
`metabolizer type in suicide victims [40–43]. Two
`further studies in depressives [38] and eating
`disorders [44] showed higher suicidality and sui-
`cidal ideation in carries of the ultrarapid metabo-
`lizer phenotype.
`
`No conclusive evidence identifies the possible
`endogenous substrates of CYP2D6 or other DMEs
`that may underlie these effects on brain function.
`Plausible candidates include monoamines, neu-
`rosteroids and endorphins [45, 46]. However, evi-
`dence on an effect of CYP2D6 genotype on
`serotonergic or dopaminergic function in vivo
`remains sparse [47, 48].
`
`ª 2014 The Association for the Publication of the Journal of Internal Medicine
`Journal of Internal Medicine, 2015, 277; 167–177
`
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`

`J. Stingl & R. Viviani
`
`Review: Pharmacogenetics of psychotropic drugs
`
`(a)
`
`PAROXETINE
`
`(b)
`
`BUPROPION
`
`(c)
`
`PAROXETINE
`vs. BUPROPION
`
`x = 5 mm
`
`x = 5 mm
`
`x = 5 mm
`
`(d)
`
`(e)
`
`(f)
`
`t
`
`−4.0
`
`−3.5
`
`−2.9
`
`−1.75
`1.75
`
`z = −30 mm
`
`z = −30 mm
`
`z = −30 mm
`
`Fig. 3 With copyright permission to be reproduced from
`[58]. Effects of paroxetine (a, d) and bupropion (b, e) versus
`placebo and of the comparison paroxetine versus bupro-
`pion (c, f) in the brainstem. In the paroxetine and bupro-
`pion versus placebo comparisons, light blue and magenta
`colours refer to decrements of perfusion under medication.
`In the comparison paroxetine versus bupropion, light blue
`and magenta colours are compatible with larger perfusion
`decrements under paroxetine, whilst yellow colour is
`compatible with larger perfusion decrements under bupro-
`pion. Threshold for visualization purposes: P < 0.005 (full
`colours) and P < 0.05 (light blue, yellow), uncorrected.
`
`Because of the potential simultaneous effect of
`CYP2D6 on the metabolism of both xenobiotics
`and endobiotics and its localization in the liver
`and in the brain, the overall effect of its poly-
`morphism can be due to a set of alternative or
`concurrent
`causal paths affecting
`individual
`treatment or behavioural effects (Fig. 1). An
`example is given by the possible association
`between the ultrarapid metabolizer phenotype
`and suicide. A possible, and perhaps most obvi-
`ous, explanation of this association is therapeutic
`failure due to insufficient plasma levels of an-
`tidepressants metabolized by CYP2D6 [49]. How-
`ever, alternative conceivable explanations rely on
`influences of CYP2D6 on the local brain metab-
`olism of the drug or endogenous substrates such
`as 5-methoxytryptamine [45]. This example high-
`lights the complementarities of research on liver-
`and brain-mediated effects of CYP2D6 genotypes.
`
`An approach to the investigation of the interplay of
`pharmacological and genetic effects on human
`brain function and behaviour is given by neuroi-
`maging techniques, where the brain correlates of
`genetic polymorphisms are assessed by functional
`tasks activating key networks [50]. Recently,
`
`174 ª 2014 The Association for the Publication of the Journal of Internal Medicine
`Journal of Internal Medicine, 2015, 277; 167–177
`
`neuroimaging approaches have detected differ-
`ences in healthy individuals in vivo, thus providing
`direct evidence of a functional effect of CYP2D6
`polymorphism in man. In a first study, an effect of
`CYP2D6 polymorphism was detected on rest per-
`fusion levels in the thalamus, hypothalamus, in
`the posterior cerebral cortex, and in isolated parts
`of the orbitofrontal cortex and the medial temporal
`lobe [51] (Fig. 2).
`
`In the second study [52], the effect of the CYP2D6
`polymorphism was detected on the signal elicited
`by a standard working memory task [53], and by a
`recognition of facial expressions task [54]. In both
`paradigms, the association with CYP2D6 genetic
`polymorphism affected visual areas in the posterior
`cerebral cortex. The fact that these two tasks have
`little in common suggests functional involvement
`with a basic brain function such as the capacity to
`sustain vigilance levels, which is required for
`prolonged performance [55]. These studies, how-
`ever, may have provided evidence on only one
`aspect of CYP2D6 activity, whose full role in local
`brain metabolism is yet to be precisely character-
`ized.
`
`Studies of brain perfusion at rest have shown
`that psychoactive substances may affect
`the
`brain according to different regional patterns.
`Antipsychotics, for example, have been shown to
`increase of metabolism and perfusion in the
`basal ganglia, and at a variable degree to
`decrease them in the cortex, especially in the
`frontal
`lobes [56, 57]. Likewise, comparative
`studies of brain perfusion at rest of antidepres-
`sants with different profiles show different perfu-
`sion patterns dependent on drug-target profile
`(Fig. 3,
`[58]). However, neuroimaging studies
`attempting to use neuroimaging quantitative
`assays of brain function to predict response and
`assist clinical decision-making have been few
`[50]. One recent study combined genotyping and
`neuroimaging techniques to identify reduced
`antidepressant response in carriers of a polymor-
`phism in the cannabinoid receptor gene [59]. As
`in studies of associations with outcome variables,
`careful study designs will be needed in the future
`to validate neuroimaging techniques as predictors
`of therapeutic interventions. Furthermore, beyond
`the use of endophenotypic biological markers,
`data on long-term parameters such as hospital-
`ization time, quality of life, disability or survival
`are warranted to finally estimate the cost–benefit
`ratio of pharmacogenetic testing.
`
`Vanda Exhibit 2042 - Page 8
`
`

`

`J. Stingl & R. Viviani
`
`Review: Pharmacogenetics of psychotropic drugs
`
`Conclusion
`
`Despite the efforts put in genomewide association
`studies based on data from large clinical trials,
`genotyping for CYP2D6 and CYP2C19 in psychi-
`atric patients is the only pharmacogenetic test
`whose use in clinical practice is justified by the
`available evidence. However,
`it allows only the
`prediction of
`individual differences
`in drug
`metabolism for the optimization of dosage to
`prevent drug toxicity. Accurate prediction of
`treatment response in complex psychiatric disor-
`ders is likely to require a suite of tools repre-
`senting intermediate phenotypes, as they may
`emerge from renewed efforts to understand the
`fundamental mechanisms from which psychiatric
`symptoms originate. Neuroimaging approaches
`are also at the centre of a research thrust to
`identify biological markers that may differentiate
`between similar manifestations of mental disor-
`ders
`[60]. Functional neuroimaging
`studies
`amongst other
`intermediate phenotypes show
`promise for the detection of endophenotype mark-
`ers but have not yet reached the stage where they
`can be applied in clinical practice.
`
`Conflict of interest statement
`
`The authors have no conflict of interest connected
`to this paper.
`
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`J. Stingl & R. Viviani
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