Genetic Variability of Drug-Metabolizing Enzymes: the Dual Impact on Psychiatric Therapy and Regulation of Brain Function

EXPERT REVIEW Genetic variability of drug-metabolizing enzymes: the dual impact on psychiatric therapy and regulation of brain function

JC Stingl1,4, J Brockmo¨ ller2 and R Viviani3

Polymorphic drug-metabolizing enzymes (DMEs) are responsible for the metabolism of the majority of psychotropic drugs. By explaining a large portion of variability in individual drug metabolism, pharmacogenetics offers a diagnostic tool in the burgeoning era of personalized medicine. This review updates existing evidence on the inﬂuence of pharmacogenetic variants on drug exposure and discusses the rationale for genetic testing in the clinical context. Dose adjustments based on pharmacogenetic knowledge are the ﬁrst step to translate pharmacogenetics into clinical practice. However, also clinical factors, such as the consequences on toxicity and therapeutic failure, must be considered to provide clinical recommendations and assess the cost-effectiveness of pharmacogenetic treatment strategies. DME polymorphisms are relevant not only for clinical pharmacology and practice but also for research in psychiatry and neuroscience. Several DMEs, above all the cytochrome P (CYP) enzymes, are expressed in the brain, where they may contribute to the local biochemical homeostasis. Of particular interest is the possibility of DMEs playing a physiological role through their action on endogenous substrates, which may underlie the reported associations between genetic polymorphisms and cognitive function, personality and vulnerability to mental disorders. Neuroimaging studies have recently presented evidence of an effect of the CYP2D6 polymorphism on basic brain function. This review summarizes evidence on the effect of DME polymorphisms on brain function that adds to the well- known effects of DME polymorphisms on pharmacokinetics in explaining the range of phenotypes that are relevant to psychiatric practice.

Molecular Psychiatry (2013) 18, 273--287; doi:10.1038/mp.2012.42; published online 8 May 2012 Keywords: CYP2D6; CYP2C19; DME endogenous substrates; DME in brain; polymorphic DMEs; psychotropic drugs; pharmacogenetic dose adjustments

INTRODUCTION pharmacogenetic testing in psychiatry and highlight clinical Many drug-metabolizing enzymes (DMEs) are affected by genetic situations in which it may be useful. polymorphisms resulting in variations in functional activity.1 Much less is known about the emerging picture of the function These genetic polymorphisms have been subjected to intense of these enzymes in the central nervous system when locally study, as they may be responsible for more than 10-fold expressed. In the second part of this review, we will review differences in drug clearance affecting therapy outcome and evidence suggesting that through their activity in the CNS, DMEs safety.2--5 Gradually, it also became clear that several DMEs are may affect therapy outcome and psychic processes independently expressed throughout the body, including the brain,6 suggesting from their action in the liver. Metabolism of drugs may take place that they may have a role in the regulation of physiological directly in brain tissue, but even more intriguingly, some evidence homeostasis by biotransformation of endogenous compounds.7 suggests that DMEs may be associated with psychological traits of Very different amounts of knowledge have been obtained on clinical significance. The aim of this review is to summarize the the role of DMEs in response to drugs, in vulnerability to the current state of knowledge on both aspects of DME function while effects of other xenobiotics, and in differences in biological considering the implications of their manifold roles. function through the action on endogenous ligands. For what concerns the pharmacogenetics of drug exposure, the impact of DME polymorphisms has been explored in hundreds of studies. PHARMACOGENETIC TESTING IN PSYCHOTROPIC DRUG THERAPY The maturity of the field is reflected by current discussions about Genetic variability of DMEs can affect all phases of drug the possibility of delivering ‘personalized medicine’ by making metabolism (Table 1). In phase I, lipophilic drugs or xenobiotics use of computerized databases to assess the cumulative empirical are transformed by oxidation reactions, reductions or hydrolysis to evidence and rationally justify pharmacogenetic dose adjust- more soluble compounds. Generally, this transformation corres- ments.8,9 In the first part of this review, we will summarize the ponds to detoxification and inactivation and facilitates hepatic or recent data on the influence of DME polymorphisms on renal excretion. However, xenobiotics may at times be activated to psychotropic drug therapy. We will also discuss strengths and toxic or therapeutically active compounds.10 Cytochrome P450 limitations of current assessments of the clinical utility of (CYP450) enzymes are the major family of enzymes mediating the

1Institute of Pharmacology of Natural Products and Clinical Pharmacology, University of Ulm, Ulm, Germany; 2Department of Clinical Pharmacology, University Medical Center, Georg-August-University, Go¨ ttingen, Germany and 3Department of Psychiatry and Psychotherapy III, University of Ulm, Ulm, Germany. Correspondence: Professor JC Stingl, Research Department, Federal Institute for Drugs and Medical Devices (BfArM), Kurt-Georg-Kiesinger-Allee 3, 53175 Bonn, Germany. E-mails: [email protected] and [email protected] 4Current address: Research Department, Federal Institute for Drugs and Medical Devices (BfArM), Bonn, Germany. Received 15 August 2011; revised 28 March 2012; accepted 3 April 2012; published online 8 May 2012 DME polymorphism in research and practice JC Stingl et al 274 Table 1. Polymorphic drug-metabolizing enzymes (DMEs) in psychiatry

DME Phase of liver metabolism Main role Degree of polymorphism References

CYP2D6 I Xenobiotics High 20,166 CYP2C19 I Xenobiotics High 159 CYP1A2 I Endobiotics Medium 167 CYP2C9 I Xenobiotics Medium 39 CYP3A4 I Xenobiotics Low 168 CYP2B6 I Endobiotics Medium 169 CYP2A6 I Endobiotics High 170 CYP2C8 I Xenobiotics Medium 56 CYP2E1 I Endobiotics Low 69 UGT1A4 II Xenobiotics Medium 171 UGT1A6 II Endobiotics Medium 171 UGT2B7 II Endobiotics Medium 171 UGT1A9 II Endobiotics Medium 171 Degree of polymorphism; high, alleles leading to complete enzyme deﬁciency; medium, polymorphic but still residual enzyme activity; low, rare genetic variants but no polymorphic phenotype.18,20

Liver CYP450 expression Brain CYP450 expression CYP1A2 CYP1B1 10% 8.0%

CYP2D6 CYP3A4/5/7 CYP2C8/9/19 non-DME DME 6.0% non-DME DME CYP2J2 23% 15% 57.6% 42.4% 23% 77% 20.0% CYP2E1 7.5% CYP2E1 5%

CYP1A1 0.2% CYP2D6 CYP2B6 CYP2A6 2% CYP3A5 0.2% CYP2B6 0.2% 1% 3% CYP2C8 0.3% Figure 1. The relative amount of expression of the CYP450 enzymes in the liver and brain is shown (data from Shimada et al.245 and Dutheil et al.66). One can see that the expression patterns in the brain and liver differ; the only enzymes that are expressed in substantial amounts in both organs are CYP2D6 and CYP2E1. Furthermore, the relative amount of CYP450 enzymes with DME activity varies, being higher in the liver. Furthermore, most of the CYP450 DMEs expressed in the brain possess DME activity only on individual compounds52 and are presumably primarily involved with endogenous substrates. CYP1B1, for example, metabolizes estradiol246 and CYP2J2 metabolizes ebastine and astemizole.247,248

phase I of drug metabolism.11 In the liver, most expressed CYP450 Proportion of psychotropic medications metabolized enzymes are involved in xenobiotic metabolism; in the brain, by individual enzymes however, they may be involved in endobiotic metabolism (that is biosynthesis or deactivation of endogenous compounds) (Figure 1). Locally expressed CYP450 enzymes or local endogenous substrates CYP3A4 may also modulate pharmacodynamics in the brain.12,13 In phase II, solubility of drugs is increased by conjugation CYP2D6 CYP2C19 with hydrophilic residues. The main DMEs involved in phase II metabolism are glucuronyl transferases (UGTs), N-acetyltrans-

ferases, sulfonyltransferases and glutathione S-transferases. Phase CYP2C9 CYP2B6 CYP1A2 II DMEs present polymorphisms of varying functional significance. However, because most psychiatric drugs are extensively metabolized by phase I DMEs, the majority of pharmacogenetic effects of clinical significance are attributable to phase I, with a few notable exceptions like lamotrigine or morphine (Table 1, Figure 2). Among the phase I DMEs, CYP2D6 is particularly notable because Aldehyde Dopa- it is involved in the metabolism of approximately half of the oxidase decarboxylase COMT UGT1A4 commonly prescribed psychotropic drugs.14 Before and after biotransformation, most drugs are excreted or Figure 2. Relative contribution of individual DMEs in the metabolism taken up by transporters (often referred to as phase 0 or phase III of of psychopharmacological drugs estimated from involvement in the main metabolic pathways (based on data from Hiemke et al163). drug metabolism). Functional polymorphisms in drug transporters 15--17 As can be seen in the figure, the most important liver enzymes arebeyondthescopeofthisarticleandarereviewedelsewhere. involved in antidepressant and antipsychotic drug metabolism are DME phenotypes express wide ranges of clinically significant the CYP450 enzymes CYP2D6, CYP3A4, CYP2C19 and CYP1A2, and 18 variation and appear as almost monogenetic traits acting to a lesser extent CYP2C9 and CYP2B6 or DMEs other than CYP450 through major changes in expression and protein structure.19 enzymes.

Molecular Psychiatry (2013), 273 -- 287 & 2013 Macmillan Publishers Limited DME polymorphism in research and practice JC Stingl et al 275 DME phenotypes, as predicted from genotypes, may be classified Pharmacogenetics-based dose adjustments into four major groups: Because differences in plasma concentration due to individual variability in drug clearance can be more than 10-fold, uniform poor metabolizer phenotypes (PMs) are characterized by a dose recommendations as those issued by manufacturers may be complete lack of enzyme activity (two defective alleles); off the mark in specific patients. Dose recommendations based on intermediate metabolizer phenotypes (IMs) are carriers of either DME genotypes may be obtained by systematically collating data one defective allele or two partially functional alleles; from pharmacokinetic studies.22--24 Figure 3 provides an updated extensive metabolizer phenotypes (EMs) are carriers of two version of these data, integrating previous surveys22--24 with the functional alleles; and studies on the pharmacogenetics of psychotropics published to ultrarapid metabolizer phenotypes (UMs) are carriers of alleles date. This figure shows the calculated dose adjustments based on leading to increased enzyme function. pharmacokinetic parameters (oral clearance, area under the concentration time curve and concentration at steady state) observed The functional relevance of a genetic polymorphism in drug in the phenotype groups. Dose adjustments were computed such metabolism depends on several factors influencing the size of its that, when averaged over a reference population, they corre- effect. First, the polymorphism must have a large impact on DME sponded to a mean administered dose that is identical to the activity. As a first approximate guide to their potential influence, recommended dose for the drug in question. For CYP2C19, the genetic polymorphisms of DMEs may be arranged in several degrees 18--20 revisions were substantial due to the newly discovered *17 of functionality. In Table 1, the class ‘high degree of polymorph- 25 allele coding for an ultrafast metabolizer phenotype. The ism’ denotes the existence of the PM and/or the UM phenotypes. In methods and source studies that led to the summary values such cases, the distribution of plasma concentrations of the DME displayed in Figure 3 are detailed in the Supplementary data. substrate in the population is typically bimodal or trimodal, reflecting the large effect of lack of functional enzymes or manifold enhanced activity. At the opposite end of the spectrum, ‘low degree of Integrating pharmacogenetic dose adjustments with clinical polymorphism’ refers to cases where genetic variants may exist but evidence on outcome and toxicity do not explain much of the variance of a typically unimodal The magnitude of pharmacokinetic differences per se may indicate population distribution of plasma concentrations. Most of the variance some clinical impact of appropriate dose adjustments. However, may be here attributable to environmental factors, some of which for pharmacokinetic differences to have an impact on the clinic, affect the regulation of gene expression, gene--gene interactions the therapeutic range of the drug in question and its effect in the and to other implicated genes. Second, the affinity of the drug clinic need be considered also. When large pharmacokinetic for the specific DME must be high. Reflecting the wide net cast effects are accompanied by narrow therapeutic ranges and the bytheDMEenzymestocopewithamultitudeofxenobiotics, ensuing risks of toxicity or therapeutic failure, judicious use of affinities of individual enzymes vary across substrates. Third, the genotypic information to adjust dosing appears rationally DME must constitute the main metabolic pathway in elimination justified. or bioactivation of at least a fraction of about 30% of the drug. Table 2 integrates pharmacokinetic data with information on Finally, the therapeutic range of the drug must be narrow, so that the clinical relevance of inadequate dosing on efficacy and safety deviations from this range may have clinical implications, such as issues. Dose adjustments may be considered for tricyclics, in which therapeutic failure due to inadequate plasma concentrations, or CYP2D6 and CYP2C19 polymorphisms exhibit large effects, and adverse effects and premature interruption of therapy caused by carry a risk of dose-dependent toxicity and for which different high drug exposure.21 target dosages are generally applied in clinical practice with

CYP2C19 UM 200 EM CYP2D6 175 IM 225 UM PM 150 EM

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in d in 87 0 50 67 68 69 71 74 77 59 50 51 55 86 25 74 34 66 28 58 61 66 Venlafaxine Etizolam 25 56 Doxepin 45 Trimipramine 42 Diazepam Sertraline 0 e e 31 Moclobemide Citalopram Clozapine in in Escitalopram yline ine Imipramine ipramDoxepin ine ClomipramineAmitriptyline DesipramIm am yline ine NortriptParoxetineipramipr ine rin lom itript ram C TrimAm Duloxetineianse ate FluvoxamMirtazapM enlafaxineitalop zinezine ne V C Bupropionecano thixol Thiorida azole e erphenaRisperido thixol P Olanzapineripipraloperidol Zuclopen A H Perazin HaloperidolD Flupen Figure 3. Percentual dose adjustments according to the CYP2D6 and CYP2C19 phenotypes. The dose recommended by the manufacturer was taken as an average dose of 100% in a population consisting of 10% PM, 40% intermediate metabolizer (IM) and 50% extensive metabolizer (EM) (in the case of CYP2D6), and 3% PM, 27% IM and 70% EM (in the case of CYP2C19). Dose adjustments were based on differences in pharmacokinetic parameters (oral clearance, area under the concentration time curve and concentration at steady state) observed between the phenotype groups. The homozygous carriers of the CYP2C19*17 allele were considered ultrafast metabolizers of this enzyme. In the studies where no data on the CYP2C19*17 allele were available, we extrapolated the estimated UM dose based on the differences between EM and IM, assuming a similar magnitude of difference between EM and UM (marked with # in the Supplementary tables).

& 2013 Macmillan Publishers Limited Molecular Psychiatry (2013), 273 -- 287 276 oeua scity(03,23- 287 -- 273 (2013), Psychiatry Molecular Table 2. Systematic assessment of DME genotype on dose and clinical effects by substance

PK differences caused by genotype Clinical Pharmacokinetic corresponding to dose adjustments Pharmacokinetic implications Clinical-based evidence: evidence: Substance class Substance DME (toxicity or efﬁcacy) evidence studies Action to be undertaken references references PM IM EM UM

Tricyclic anti- Toxicity/side-effect risk Limited evidence for For all tricyclics below: 45,46,48,172,173 depressant in PM, risk for therapeutic efﬁcacy and toxicity monitor plasma failure in UMs concentrations (P+M),

consider dose adjustment practice and research in polymorphism DME Separate Amitriptyline CYP2D6 67% 90% 114% 138% 8,24,174,175 studies CYP2C19 70% 87% 105 141% Clomipramine CYP2D6 55% 87% 119% 152% 8,24,175 CYP2C19 69% 87% 106% 125% Desipramine CYP2D6 25% 76% 136% 207% 24 Doxepin CYP2D6 34% 77% 131% 204% 8,24,89 Imipramine CYP2D6 28% 79% 131% 183% 8,24,176 CYP2C19 77% 86% 106% 128% Nortriptyline CYP2D6 50% 72% 133% 195% 8,24 Trimipramine CYP2D6 59% 88% 118% 147% 24 CYP2C19 45% 76% 107% 154% SSRIs 45,46,48,172,173 35,177 8,24,36,175,178--180 Citalopram CYP2C19 59% 87% 107% 130% Large therapeutic range; no Conﬂicting evidence on Monitor plasma Stingl JC response effect observed response and toxicity concentrations, consider except UMs carrying the risk dose adjustment of therapeutic failure

Escitalopram CYP2C19 60% 86% 104% 155% Large therapeutic range; Clinical evidence Monitor plasma 36,181 182,183 al et no response effect observed for response concentrations, consider except UMs carrying the risk dose adjustment of therapeutic failure

Fluoxetine CYP2D6 Substrate and strong No clinical evidence for Alertness for drug 184 24,185 inhibitor, P+M equal for important genotype interactions with CYP2D6 CYP2D6 genotypes, no effect substrates data on safety risk for PMs

Fluvoxamine CYP2D6 68% 89% 117% 147% Preliminary PK data only Clinical evidence for Consider monitoring 186,187 24,188 response and toxicity plasma concentrations, dose adjustments Paroxetine CYP2D6 51% 81% 125% 169% Substrate and inhibitor No clinical evidence for Select alternative drug in 189--192 8,24 response, clinical evidence UMs, consider dose for adverse effects adjustment in PM

Sertraline CYP2C19 56% 84% 108% 117% Side effect concern Limited evidence for Be alert to side effects, 193 8,24,194,195 in PMs and IMs response or toxicity consider dose adjustment Other anti- Agomelatine (CYP1A2) No difference No clinical evidence data No recommendations 196

& depressants 197

03McilnPbihr Limited Publishers Macmillan 2013 Bupropion (CYP2B6, Only minor role of No clinical evidence data No recommendations CYP2D6) polymorphic DMEs Duloxetine CYP2D6 (69% 91% 113% 136%) Preliminary PK data only No clinical evidence data No recommendations 198,199 Maprotiline CYP2D6 (68% 91% 114% 136%) Preliminary PK data only No clinical evidence data No recommendations 200,201 Mianserin CYP2D6 (74% 90% 114% 138%) Preliminary PK data only No clinical evidence data No recommendations 24 Mirtazapine CYP2D6 (71% 94% 94% 126%) Only minor role, only No clinical evidence data No recommendations 24,202,203 S-enantiomer affected Moclobemide CYP2C19 54% 82% 110% 138% Only PK data available No clinical evidence data Consider dose adjustment 8,24 Trazodone (CYP2D6) Only minor role of No recommendations 24 polymorphic DMEs Venlafaxine CYP2D6 77% 92% 109% 172% Active metabolites. Safety Clinical evidence for Select alternative drug in 30,204 8,204--206 concern in PMs response and toxicity PM, UM and IM CYP2C19 (44% 89% 107% 124%) Preliminary PK data only, No clinical evidence Consider dose adjustment 207,208 safety concern in PMs &

03McilnPbihr Limited Publishers Macmillan 2013 Table 2 (Continued )

PM IM EM UM

Antipsychotics 139,209--215 Typical Haloperidol CYP2D6 66% 92% 113% 139% Safety concern in PMs Clinical evidence on Select alternative drug 147 8,24 antipsychotics, response and toxicity in PM and UM, consider highly potent dose adjustments Haloperidol CYP2D6 31% 90% 122% 188% PK inﬂuences stronger Clinical evidence on Select alternative drug in 216 216 Decanoate than for oral formulation response and toxicity PM and UM, consider dose adjustments Perphenazine CYP2D6 45% 67% 116% 164% Only PK data available No evidence on toxicity Consider dose adjustments 217 92 Pimozide (CYP2D6) Only minor role of No clinical evidence data No recommendations 24 polymorphic DMEs Flupenthixol CYP2D6 74% 86% 116% 146% Safety concern in PMs No clinical evidence data No recommendations 24 and IMs Zuclopenthixol CYP2D6 58% 88% 119% 150% Safety concern in PMs Limited evidence on toxicity Select alternative drug in 218 8,24 and IMs PM, UM and IM or consider dose adjustment Typical Levomepromazine (CYP2D6) Only minor role of No clinical evidence data No recommendations 8,24 antipsychotics, polymorphic DMEs low potency Perazine (CYP2D6) Only minor role of No clinical evidence data No recommendations 24 polymorphic DMEs Thioridazine CYP2D6 42% 83% 125% 153% Only PK data available Limited evidence on toxicity Consider dose adjustment 219 24

Atypical Aripiprazole CYP2D6 66% 90% 115% 139% Large therapeutic range Limited clinical evidence Consider dose adjustment 220 221 antipsychotics in UMs Clozapine CYP2C19 62% 91% 105% 119% Only PK data available No clinical evidence for No recommendations 222,223 8,24 (CYP1A2) an effect Olanzapine CYP2D6, 61% 105% 122% 139% Only minor role of Limited evidence on toxicity No recommendations 224 8,24 practice Stingl and JC research in polymorphism DME CYP1A2 polymorphic DMEs UGT1A4*3 (100% 137%)* - No recommendations 225 Risperidone CYP2D6 56% 88% 119% 146% Safety concern in PMs, Clinical evidence on Select alternative 32--34 226--228 P+M equally effective across response and toxicity drug in PM, UM and IM al et CYP2D6 genotypes

Anxiolytics Etizolam CYP2C19 (45% 52% 121% 190%) Preliminary PK data only No clinical evidence data No recommendations 229 Diazepam CYP2C19 (51% 81% 109% 138%) Preliminary PK data only No clinical evidence data No recommendations 230 Lorazepam UGT2B7*2 Preliminary PK data only No clinical evidence data No recommendations 231 UGT2B15*2 (58% 100%)* Preliminary PK data only No clinical evidence data No recommendations 232 Oxazepam UGT2B15*2 (48% 70% 100%)* Preliminary PK data only No clinical evidence data No recommendations 233 Mood Lamotrigine UGT2B7*2 (56% 100%)* Preliminary PK data only No clinical evidence data No recommendations 234 stabilizers UGT1A4*3 (100% 200%)* Preliminary PK data only No recommendations 235 Valproic acid UGT2B7*2 (67% 76% 100%)* Preliminary PK data only No clinical evidence data No recommendations 232 oeua scity(03,23- 287 -- 273 (2013), Psychiatry Molecular Abbreviations: DME, drug-metabolizing enzyme; EM, extensive metabolizer; IM, intermediate metabolizer; PM, poor metabolizer; UM, ultrarapid metabolizer. P+M: when monitoring plasma concentrations, add parent drug (P) and metabolite (M) to the active drug fraction. The asterisk * denotes dose adjustment in UGT alleles, in which the reference dose 100% refers to the wild type, and the deviations in percentage points to the presence of one or more variant alleles. Preliminary PK data: dose adjustments are in brackets if PK data were only from one single study and the sample size was small in the genotype groups. Clinical evidence: evidence was judged to be limited if the sample size was small in the genotype groups, if replication is lacking or if evidence was based on single case reports. 277 DME polymorphism in research and practice JC Stingl et al 278 different indications. In contrast, typical doses of selective old age, comorbidity or comedication, which in combination with serotonin-transporter inhibitors apply more uniformly. In addition, DME polymorphisms may produce complex clinical pictures. In an important issue is the capacity of some selective serotonin- polytherapy, UM/EM phenotypes can turn into IM/PM phenotypes transporter inhibitors to inhibit DMEs, making individual dose due to enzyme inhibition by comedication,37 and DME induction titration more difficult. Hence, when clinical issues arise in the use can produce a UM phenotype depending on the susceptibility for of selective serotonin-transporter inhibitors, recommendations are induction of specific genes and their alleles.38,39 rather to switch to another drug than to adjust dose. In the case of A related issue discussed in the literature is that of the cost venlafaxine, the parent and the metabolized compound are both effectiveness and clinical utility of genetic testing, which is also equally active but with different side-effect profiles.26--29 The few relevant to the question of its routine use and reimbursement. The described cases of CYP2D6 PMs suggest an increased incidence clinical utility of pharmacogenetic testing can be assessed either of cardiovascular side effects.30,31 Here, the way to avoid these in its effects on therapeutic response or safety, or in how often it side effects in PMs and maintain adequate exposure is to switch to influences a clinical decision, such as adjusting the dose according an alternative medication. to the genotype.40 Few studies have formally addressed the issue In antipsychotics, the effect of DME polymorphisms on of the clinical utility of pharmacogenetic testing in psychiatry pharmacokinetic parameters is variable. Clinically relevant issues using cost-benefit analysis.41,42 Under the concept of routine pre- arise for the typical neuroleptics haloperidol, thioridazine and treatment genetic testing, every patient considered for pharma- zuclopenthixol. In the case of risperidone, the parent compound cological treatment is tested for DME polymorphisms prior to and its main metabolite are both active but carry different toxicity institution of therapy. Two meta-analyses have been conducted risks, resulting in the recommendation in PMs to switch to another over studies reporting data on the association between DME medication.32--34 Only preliminary data are available for anxiolytics polymorphisms and clinical response or adverse drug effects in and mood stabilizers (Table 2). selective serotonin-transporter inhibitor or antipsychotic drug Few studies have empirically assessed the influence of DME therapy. Both have come to the conclusion that data available to genotype on therapeutic response or adverse effects. The two date are insufficient to assess clinical utility of pre-treatment large pharmacogenetic studies, the Star*D trial in the United testing in depression or schizophrenia.41,42 States and the GenDep cohort in Europe assessed the relation- Routine pre-treatment genetic testing, however, is only one ship between CYP2C19 polymorphisms and antidepressant possible application of pharmacogenetic diagnostics, and one that drug response. In the context of the Star*D trial, Mrazek et al.35 arguably suffers from several drawbacks a priori. Genetic screening reported an effect of the CYP2C19 genotypes on the outcome of is likely to be inefficient when, as typically the case for DME citalopram treatment. In the GenDep study, this polymorphism polymorphisms, about 90% of the population is constituted by was associated with escitalopram blood concentrations, but not intermediate or extensive metabolizers. In these patients, the with significant outcome effects.36 These sources of evidence on information delivered by the test merely confirms these cases to clinical outcomes have also been integrated in Table 2, and fall within the bulk of the expected population distribution. together with formal assessments of the degree of evidence Because of the relatively small number of patients detected by for pharmacokinetic data, clear clinical recommendations for generalized screening as worthy of pharmacogenetic adjustment, pharmacogenetic testing have been formulated. the results of cost-effectiveness analyses may be expected to be unfavorable. Utility and effectiveness of pharmacogenetic testing may be Clinical utility of pharmacogenetic testing much higher in the clinical context of therapeutic failure or Although the data reviewed so far show the large influence of adverse effects. In this case, the rationale of pharmacogenetic DME polymorphisms on drug exposure, safety and efficacy, it is testing is uncovering the cause of a clinical problem, and the the clinical context that should alert the clinician to the probability of detecting an extreme metabolizer genotype are opportunity of obtaining genetic testing. Table 3 lists common higher than in routine pre-treatment testing.43 Evidence suggests situations in which the pharmacogenetic test can be understood that PMs are more difficult to treat, switch antidepressant drugs as a guiding diagnostic instrument that helps to identify reasons more often,44 are more at risk of adverse drug effects45--47 and that for therapeutic failure or adverse drug reactions, and in which the UMs are more frequently represented among treatment-resistant clinical utility of testing may therefore be particularly high. Most patients.48 Therefore, even if the clinical utility of routine obvious among these situations are those where abnormal plasma pharmacogenetic testing in the general population has not been concentrations, non-response or adverse effects have been empirically demonstrated, judicious application of pharmaco- observed. Other situations where testing may be indicated are genetic diagnostics in individual patients may be justified.49

Table 3. Common situations in which pharmacogenetic testing may have clinical utility

Situation Background Translation of genetic testing into clincial practice References

History of non-response Extreme DME phenotypes (PM or UM) Rationality of individually high dosing (even off label) 48 or toxicity/adverse effects Abnormal plasma Extreme DME phenotypes (PM or UM) Rational choice of drug, circumventing the problem or 236 concentrations rationality of individually high dosing (even off label) Suicidality CYP2D6 UM phenotype, treatment Accurate evaluation of risk with respect to adequacy 154,156,157,155 resistance of medication Drug intolerance in Extreme DME phenotypes (PM or UM) Reduce the number of interacting drugs 237 patients with comedication and drug interactions lead to therapeutic failure or adverse drug reactions Abbreviations: DME, drug-metabolizing enzyme; PM, poor metabolizer; UM, ultrarapid metabolizer.

Molecular Psychiatry (2013), 273 -- 287 & 2013 Macmillan Publishers Limited DME polymorphism in research and practice JC Stingl et al 279 POLYMORPHIC DMES IN THE BRAIN that there is an interplay between DMEs and transporters at the Although the data reviewed so far concern their effects on blood--brain barrier, predicting exposure of xenobiotics within the 84 pharmacokinetics, DME polymorphisms may also be relevant to brain. psychiatric research and practice because of their possible effect on endogenous substrates in the brain. In this section, we review Endogenous substrates of polymorphic DMEs data that speak for the existence of such effects and discuss their Prompted by the evidence of brain expression of DMEs, a line of possible future relevance in devising personalized medicine. inquiry has attempted to identify their possible endogenous substrates, focusing on regulatory substances such as mono- Expression of DMEs in the brain amines, neurosteroids and endorphins (Table 4). Here, most The distribution of brain-expressed DMEs is cell type and studies concern CYP2D6. regionally specific.50--54 One group of DMEs is expressed at brain This DME has been reported to be involved in neurotransmitter vessels. CYP2C8/CYP2C9s are expressed in the endothelium55,56 biotransformation85,86 suggesting the existence of a direct link and are presumably involved in the regulation of vascular to brain function. The metabolism of methoxyphenylethylamine supply.57 In the vascular endothelia, CYP enzymes like CYP2C19 to tyramine (hydroxyphenylethylamine), and in turn of tyramine may also contribute to the functionality of the blood--brain barrier to dopamine, can be catalyzed by CYP2D6,86 which has been through local metabolism.51,55 shown to be expressed in dopaminergic neurons.87 In the Most DMEs found in the brain are detectable in neurons. serotonergic pathway, CYP2D6 has been shown to be active as Evidence for the expression of CYP1A2 has been reported for the an endogenous 5-methoxyindolethylamine O-demethylase, trans- cerebellum, cortex and mesencephalon.58 Low levels of CYP2A6 forming 5-methoxytryptamine into serotonin.85 Studies that mRNA have been detected in subcortical structures.50 CYP2B6 has document the effect of CYP2D6 genotype on serotonergic or been located in the hippocampus, caudate and putamen.59--62 dopaminergic function in vivo, however, are few.88,89 An indirect CYP2D6 is expressed in neuronal and glial cells51,63--66 with effect of CYP2D6 on dopaminergic function may also ensue from CYP2D6 protein levels being the highest in basal ganglia and the interaction between the serotonergic and dopaminergic substantia nigra,67 but present also in the hippocampal cortex, systems90,91 in the nigrostriatal pathway92 or the hypothalamus,93 thalamus, hypothalamus, substantia nigra, cerebellum and layers influencing suppression of prolactin of antidopaminergic agents. III and V of neocortex.68 CYP2E1 is among the CYPs with the An alternative interaction mechanism postulates the synthesis highest levels of observed mRNA, both in cortical and subcortical of serotonin in dopaminergic neurons, interfering with their structures;50 the protein has been detected with immunoreactivity function.94 methods.69 Among the phase II DMEs, UGT1A6 and 2B7 have been Other DMEs in the brain have also been shown to participate in 70 detected in the cerebellum. monoamine metabolism. Of particular interest may be the observation of the inactivation of serotonin by UGT enzymes.70 Brain drug metabolism However, the degree of functional polymorphism of the involved It has been shown that DMEs are not only expressed but also enzymes (UGT1A6 and 2B7) is intermediate, and therefore, the functionally active in the brain.71 Codeine is metabolized to genetic modulation of neurotransmitter signaling might not be 70 morphine in the brain, as has been shown in rats and man.72,73 In large. man, the concomitant administration of codeine and quinidine, a Another class of endogenous substrates in the brain where the CYP2D6 inhibitor that does not cross the blood--brain barrier and role of DME has been investigated is given by the endocanna- therefore only affects hepatic function, still produces the central binoids and endorphins. CYP2D6 and CYP2B6 have been reported 95,96 pharmacological effects of morphine, suggesting the existence of to mediate the biotransformation of anandamide. UGT2B7 is 97 a brain-based metabolism of codeine to morphine.74 the main enzyme for 6-glucuronidation of morphine. In animals, Brain-specific drug metabolism has also been demonstrated for CYP2D has been shown to be important for endogenous 98 other CYP450 enzymes such as CYP2B6, which can be induced by morphine synthesis, but in man, the CYP2D6 genotype does 99 nicotine.75 Propofol is an anesthetic agent whose effect on not appear to influence endogenous morphine levels. sleeping times was increased by locally inhibiting its homolog DMEs may also participate in the metabolism of neuroster- 100 CYP2B in the brain of rats. Brain-specific induction of CYP2B by oids. CYP2D6 has been shown to mediate progesterone 2ß- and 101 nicotine treatment had the opposite effect, decreasing sleeping 21-hydroxylation, and CYP1A2 is the main enzyme involved in 102 times even without changes in propofol plasma concentrations.76 hydroxylation of 17-beta-estradiol. However, data on the The regulation of gene expression may differ in the brain and influence of genetic polymorphisms on these pathways are scarce. liver. The transcriptional factors mediating induction of DMEs in Notwithstanding the considerable efforts directed at uncover- the liver (PXR and CAR) are found only at low levels in the human ing the role of DMEs on the biosynthesis of metabolism of specific brain.77 Furthermore, it has been shown that hepatic CYP2D6 is candidate endogenous substrates, several caveats must be not affected by enzyme inducers that act via transcriptional mentioned in this respect. First, the concentration of substrates regulation by nuclear receptors.78 However, higher levels of brain used in these studies was rather high, raising the issue of the CYP2D6 have been observed in smokers and alcoholics, whereas physiological relevance of the described mechanisms. In this in the liver, the levels were unchanged.51,79 In rat brain, CYP2D respect, however, it has been noted that the concentration of protein induction was also observed under treatment with substrates in specific subcellular compartment may be much clozapine and ethanol.80,81 In these studies, no changes in mRNA higher than the one observed in plasma or tissue homoge- levels were observed, suggesting that the regulatory mechanism nates.103 Second, the relevance of the involved metabolic path- may rather be posttranscriptional, thus differing from the ways is uncertain, because the high-capacity alternative pathways common mechanisms of enzyme induction by nuclear transcrip- are generally available.77 It is possible, however, that important tion factors.67,82 Brain CYP2E1 has also been shown to be higher endogenous DME substrates exist that have so far escaped in smokers and alcoholics, suggesting that it can be locally detection. Third, evidence from the functional studies in vivo on induced.69 gene function in the brain is lacking. Such information is usually The local drug exposure not only depends on the activity of gained from the studies in genetically modified mice. In the case DMEs but also on the influence of transporter activity at the of DMEs, however, this kind of evidence is difficult to obtain blood--brain barrier. It has been shown that genetic polymorph- because animal DMEs differ substantially in substrate specificity isms of transporters affect local brain-drug concentrations83 and and affinity from their human homologs. Humanized mouse

& 2013 Macmillan Publishers Limited Molecular Psychiatry (2013), 273 -- 287 DME polymorphism in research and practice JC Stingl et al 280 models have been developed and used successfully to study the kinetics of CYP2D6 endobiotics and xenobiotics in transgenic mice.104--106 However, functionality of DME enzymes in humans may differ from the functionality in such mouse models, for example, transgenic animals may express DME mostly in the liver and not necessarily in the brain.107 85,86,96,98,101,238,239 95,240 240,241 102,239,242 70,243 70,244

Neuroimaging investigations of DME polymorphism ),

M Although these studies support the notion of a modulation of m )

M brain function by DMEs by providing evidence of the afﬁnity of m these enzymes with regulatory endogenous substrates, demon- strating the existence of the corresponding phenotypes remains technically challenging. A complementary research strategy focuses on the identiﬁcation of intermediate phenotypes asses- sing the genetic modulation of the involved enzymes in the context of brain function.108 This is the approach followed by )

) Harmaline, harmine genetic neuroimaging, where the brain correlates of genetic M M m

m polymorphisms are investigated within clinically relevant neural circuitry-behavior models.109 Because of the large sample sizes that may be required, genetic (Km 1.4 Beta-carboline, pinoline (Km 1.8 Harmaline, harmine (Km 13.3 5-methoxyindolethylamines (Km 28 neuroimaging studies often rely on data acquired during the execution of well-known tasks activating fundamental psychological processes. These prototypical tasks are suited for initial systematic explorative studies, leading to a second phase of more speciﬁc testing. For example, executive function, a crucial

) component of all effortful attentional processing, may be studied M

) 110 m

M with a standard working memory task. Another kind of a m ) standard data set is provided by the quantitative measures of M brain activity at rest, which were common in the early studies of brain correlates of mental disorders.111 Quantitative indices of (19 m 21-hydroxylation (Km 22.1 4-hydroxy-estrone (Km 45 brain activity at rest, such as blood perfusion, glucose consump- tion or fraction of extracted oxygen in blood, are closely correlated.112 In the past, these studies required costly positron ) M emission tomography techniques, which also involved exposure to ionizing radiation. Advances in magnetic resonance imaging techniques that allow cost-efﬁcient, noninvasive and reliable acquisitions of perfusion estimates113,114 have recently made the collection of large samples of perfusion data feasible, facilitating 115 116 (Km 0.47--1.0 m Morphine synthesis Progesterone 2ß- and their use in pharmacological and genetic imaging studies. Data on the effect of genetic polymorphism on brain function

) exist for CYP2D6, the most extensively studied brain-expressed ) M M

m DME. Two genetic neuroimaging studies on separate samples m reported an association between speciﬁc brain areas and CYP2D6 genotypes. Kirchheiner et al.108 tested the existence of such an )

M association in rest perfusion levels in healthy participants, m detecting an effect of CYP2D6 polymorphism on rest perfusion in the thalamus, hypothalamus, posterior cerebral cortex and isolated parts of the medial temporal lobe and orbitofrontal cortex, with PMs having higher perfusion levels (see Figure 4). cannabinol (Km 2.13 Anandamide (Km 1.3--2.8 This pattern suggested an association with brain circuits involved in vigilance.117 The second study118 tested the effect of the CYP2D6

), polymorphism on two functional paradigms, focusing on the M ) 17-beta-estradiol

m areas affected by this polymorphism in the perfusion study. The M m ﬁrst paradigm involved a standard working-memory task,110 investigated with conventional blood oxygenation level-dependent (BOLD)-functional magnetic resonance imaging techni-

) 119 )

M ques. The second functional paradigm involved recognition of M m

m facial expressions, a task eliciting neural circuits related with the detection of emotionally arousing stimuli.120 In both paradigms,

-acetylserotonin, the effect of the CYP2D6 polymorphism was detected in visual N 5-hydroxytryptamine (Km 165 5-methoxytryptamine (Km 17 tyramine (Km 87--121 areas in the posterior cerebral cortex (shaded circles in Figure 4). No effect could be detected in areas outside of those staked out Putative endogenous substrates of polymorphic DMEs in the brain by the perfusion study. The fact that an association was detected in experimental conditions that have little in common suggests functional CYP2B6CYP2C9 Hydroxytryptamine (Km n.d.) HydroxytryptamineCYP2E1 (Km n.d.) AnandamideCYP1A2 (1.2--3.6 Cannabinol, Tetrahydro- MelatoninUGT1A6 (Km 19.2 5-hydroxytryptophol and UGT2B7 Cannabinol(Km n.d.) Morphine DMECYP2D6 Monoamines Methoxyphenylethyl-amine, Endocannabinoids Endogenous opioids Steroids Other trace amines References Table 4. Abbreviations: DME, drug-metabolizing enzyme; Km n.d., Km value was not determined in the studies. involvement of CYP2D6 with a basic brain function. If manifested

Molecular Psychiatry (2013), 273 -- 287 & 2013 Macmillan Publishers Limited DME polymorphism in research and practice JC Stingl et al 281

Figure 4. Medial surface of the right hemisphere modified to display regions inside sulci.249 In blue-green, maximum intensity cortical projection of parametric maps of the effects of CYP2D6 activity score on rest perfusion levels (based on data from Kirchheiner et al.108), affecting the occipital/calcarine/lingual cortex (Occ) and the thalamus (Thal), with the respective boxplots of regional CBF values by CYP2D6 activity score. Also shown are the projected peaks of activation in the working memory (WM, yellow spheres) and facial-expression recognition (FR, red sphere) studies (drawn after Stingl et al.118). at the level of a cognitive process, it must be one obligatorily To date, CYP2D6 remains the most extensively studied DME recruited in a wide variety of settings. Vigilance is a possible with respect to possible genetic effects on personality and candidate for such a functional process, because sustained mental disorders. In the Japanese, associations were reported vigilance levels are also required for prolonged performance in between the functional polymorphism of the CYP2C19 gene all attentional tasks (sustained attention121). The hypothesis of and personality traits, but the findings were not entirely involvement of a basic attentional process, such as vigilance, is consistent.135,136 also supported by an independent behavioral study, which formally tested the existence of an association between CYP2D6 genetic polymorphism and cognitive function with a systematic Mental disorders battery of cognitive tests.122 Even if providing evidence of an Prompted by the early reports of shared affinity for ligands of the influence of CYP2D6 polymorphism on brain function, existing dopamine transporter,6,137 several studies investigated the asso- neuroimaging studies have probably tapped only one aspect of ciation of the CYP2D6 polymorphism with schizophrenia, mostly CYP2D6’s involvement, and the affected processes await a more obtaining null results.138--146 Vallada et al.146 originally hypothe- precise characterization. sized that PMs may be more prone to the effects of enhanced plasma levels of psychostimulants, whose psychotoxicity would favor the development of a psychosis. Other studies, however, found an association in the opposite direction, providing evidence INDIVIDUAL DIFFERENCES IN BEHAVIOR AND PSYCHIATRIC for a decreased occurrence of the PM phenotype among DISORDERS schizophrenic patients.147--150 Personality Perhaps the most consistent data associating the CYP2D6 The first study to explore the genetic polymorphism of DMEs polymorphism and behavioral abnormalities are those linking it to in personality investigated the effects of CYP2D6 variants on suicide. Originally, an incidental observation in forensic studies the Karolinska Personality Index, reporting lower scores in the aimed at evaluating the effect of poor metabolism on fatal PM phenotype on the psychasthenia subscale.123 The relevant intoxication;151,152 this finding was replicated in two independent construct of psychasthenia124 involves the degree of ‘psychic studies explicitly designed to test the association153,154 and in energy’ available to the individual, the capacity to keep up with a further three independent databases of patients in treatment for task, and, at the other extreme, affective lability and fatigability.125 depression155,156 and eating disorders.157 In the recent studies, the Similar traits were also observed in a sample of depressive association is driven by a higher incidence and severity of suicidal patients.126 This trait was further investigated in Spanish and behavior in the UM group.155,156 Of possible significance to this Cuban healthy participants,127,128 where PMs scored higher in association are data suggesting increased frequency of the the psychasthenia score. There may be difficulties in replicating CYP2D6 UM phenotype in depression more generally.158 the earlier findings due to the problems with extending this In a recent study of a large Swedish twins cohort, Sim et al.159 personality construct to other scales129--131 and the existence identified an association of the CYP2C19 functional polymorphism of ethnical factors affecting both the measurement of the with depressive symptoms, more marked in males. The sexual psychasthenic trait132 and CYP2D6 variants.133,134 Note, how- dimorphism observed in this study is consistent with its dimorphic ever, that persistence at a task or low fatigability is a trait, not sexual expression in a humanized mice model.160 An association inconsistent with the capacity to sustain basic attentional between depression and genotype has also been reported for processes discussed in the neuroimaging studies. CYP2C9.161

& 2013 Macmillan Publishers Limited Molecular Psychiatry (2013), 273 -- 287 DME polymorphism in research and practice JC Stingl et al 282 Although these findings may point to the possible vulnerability implications. Therefore, an important task of future research is to of certain DME phenotypes for psychiatric morbidity, an effect on identify endogenous substrates, to elucidate the impact of these medication plasma levels is also possible. Recruitment of cases polymorphisms on psychological function and to assess their among a special population (suicides or hospitalized patients) may implications on mental illness and its risk. To address these issues, introduce a selection bias. For example, it seems possible that it will be essential to harness the new capabilities afforded by the differences in the effectiveness of medication (through the failure modern research technologies such as brain imaging, next- to reach therapeutic exposure levels in the UM phenotype) or generation genetic analyses and high-throughput metabolomics occurrence of adverse side effects (in the PM phenotype) may techniques. contribute to hospitalization, inflating the sample frequency of the respective genotypes relative to population levels. The study of Bijl et al.162 is of particular interest in this respect, because it CONFLICT OF INTEREST investigated the occurrence of depression and anxiety according The authors declare no conflict of interest. to the CYP2D6 genotype in a large community cohort. This study found no increased prevalence of depression and anxiety among PMs.162 This study, however, did not assay the variants leading to ACKNOWLEDGEMENTS the UM phenotype, whose possible association with morbidity, We thank Ms Baerbel Reiser for her helpful assistance in the preparation of the independent of effects of medication exposure, remains an open manuscript. issue.

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