Genetic factors contribute to the phenotype of drug response. We systematically analyzed all available pharmacogenetic data from Medline databases (1970–2003) on the impact that genetic polymorphisms have on positive and adverse reactions to antidepressants and antipsychotics. Additionally, dose adjustments that would compensate for genetically caused differences in blood concentrations were calculated. To study pharmacokinetic effects, data for 36 antidepressants were screened. We found that for 20 of those, data on polymorphic CYP2D6 or CYP2C19 were found and that in 14 drugs such genetic variation would require at least doubling of the dose in extensive metabolizers in comparison to poor metabolizers. Data for 38 antipsychotics were examined: for 13 of those CYP2D6 and CYP2C19 genotype was of relevance. To study the effects of genetic variability on pharmacodynamic pathways, we reviewed 80 clinical studies on polymorphisms in candidate genes, but those did not for the most part reveal significant associations between neurotransmitter receptor and transporter genotypes and therapy response or adverse drug reactions. In addition associations found in one study could not be replicated in other studies. For this reason, it is not yet possible to translate pharmacogenetic parameters fully into therapeutic recommendations. At present, antidepressant and antipsychotic drug responses can best be explained as the combinatorial outcome of complex systems that interact at multiple levels. In spite of these limitations, combinations of polymorphisms in pharmacokinetic and pharmacodynamic pathways of relevance might contribute to identify genotypes associated with best and worst responders and they may also identify susceptibility to adverse drug reactions.
The need for predictive pharmacogenetics-based therapeutic recommendations
Major depressive disorder, schizophrenia, and related disorders are among the most important causes of death and disability worldwide.1 These disorders are highly prevalent, chronic or recurrent conditions with a substantial impact on public health. Antidepressant drugs are the standard of care for clinical depression; likewise, antipsychotics are the standard treatment for schizophrenia. Despite the availability of a wide range of different drug classes, about 30–50% of patients will not respond sufficiently to acute treatment, regardless of the initial choice of standard psychiatric medication.2,3,4,5 For example, in randomized controlled trials in major depressive disorder, after 6–8 weeks, only 35–45% of the patients treated with standard doses of the most commonly prescribed antidepressants return to premorbid levels of functioning without any significant depressive symptoms.6,7 There is consequently a considerable need to increase efforts in maximizing clinical outcomes in major psychiatric disorders. The identification of genetic factors underlying drug response is among the most promising areas of research in molecular medicine.
Large genetic variability has been described in drug metabolism, in drug effects, and genetic modulators of the response to drug treatment. However, it is not yet possible to use genetic tools to identify an individual's likelihood of responding to a treatment and thereby to individualize drug therapy by choosing the best medication and dosage. While faster and more effective methods for genetic testing are being developed, the concept of formally using pharmacogenetics to guide therapy can only be clinical applicable when there is reliable ability to predict clinical outcomes. Blood typing for the A, B, O system may serve as an analogy of how specific therapeutic products are administered after being specifically guided by a laboratory genetic test. Similarly, specific clinical guidelines in psychopharmacology have to be developed to clarify in which situations and with which consequences the results of individual pharmacogenetic tests may be applicable for therapy.
This review covers methods for data extraction from pharmacogenetic studies and for aggregating such information into concise and usable therapeutic recommendations. This concept is nearly established with respect to polymorphisms in pharmacokinetic pathways, but use of genetic testing of neurotransmitter transporter and receptor variants for therapeutic decisions, is still incipient. Rapid advances in molecular analytical tools will soon allow very rapid and inexpensive genotyping; however, pharmacogenetics will only be used as a diagnostic tool in clinical practice, if precise and specific treatment options and guidelines based on genetic testing can be provided.
Methods of pharmacogenetics data extraction and dose calculation
Data on antidepressant and antipsychotic genotype-dependent pharmacokinetics published in Medline and Embase databases were searched using word combinations of ‘cytochrome’, ‘debrisoquine’, ‘sparteine’, ‘dextromethorphan’, ‘mephenytoin’, ‘polymorph*’, ‘metabolizer’, ‘ultrarapid’, ‘antidepressant’, ‘antipsychotic’ in combination with 36 generic names of commonly used antidepressants and 38 antipsychotics. Data on therapeutic response and adverse drug reactions of antidepressants and antipsychotics in relation to genetic parameters were retrieved from current Medline using search combinations ‘antidepressant’, ‘polymorphism’, ‘antipsychotic’, ‘genetic’, ‘response’, ‘tardive dyskinesia’, and ‘adverse drug reactions’. Studies on inherited susceptibility factors for depression and schizophrenia were not included, because the focus of this work was on the phenotype of drug response, not on the elucidation of the genetic basis of disease susceptibility. Data were classified according to gene polymorphisms studied, sample size, time interval for response measurement, clinical outcome parameters, and surrogate parameters (rating scales for response, documentation of adverse drug reactions).
With respect to pharmacokinetically relevant polymorphisms, only data from human studies with healthy volunteers or patients were included. Data on the in vitro biotransformation of antidepressants and antipsychotics have been reviewed elsewhere.8,9,10,11,12
Studies were restricted to those providing data on effects of genetic polymorphisms in CYP2D6, CYP2C19, or CYP2C9. The functional impact of other polymorphisms in drug-metabolizing enzymes including CYP1A2, CYP2A6, CYP2B6, CYP3A4, -5, and -7 or phase-II enzymes in psychopharmacology was considered to be either too moderate or controversial.
The cytochrome P450 enzyme 1A2 partially catalyzes biotransformation of clozapine, olanzapine, and some other antipsychotics;10 however, it remains questionable how much of the interindividual variability in CYP1A2 activity is explained by genetic polymorphisms.13,14,15 Some data exist on higher drug concentrations and higher risks for tardive dyskinesia in schizophrenic patients who are smokers and carriers of CYP1A2 genotypes with reduced inducibility (C/A polymorphism at position 734 in intron 1 and G/A polymorphism at position −2964 in the 5′-flanking region of CYP1A2), but those results have not been fully replicated.16,17,18 Polymorphisms in CYP2B6 might be relevant for the antidepressant bupropion, but the differences due to genotype are small.19 Polymorphisms in the CYP3A enzyme family were not considered, since CYP3A4 genetic variants have little effects on function or are rare in most populations.20 Whether or not the polymorphisms in CYP3A5 and CYP3A7 play a medically relevant role is questionable since expression levels are low and a psychotropic drug selectively metabolized by either CYP3A5 or CYP3A7, but not by CYP3A4, still remains to be identified.21
Studies using CYP inhibiting substances such as quinidine to mimic poor metabolizer status were not included. Studies were classified based on whether they were conducted in patients or healthy volunteers, single or multiple dosage, existence of data on active metabolites/active moiety of the drug, sample size, and available pharmacokinetic parameters. For dose adjustments, dose-related pharmacokinetic parameters such as trough concentrations at steady state (Ctss), area under the concentration–time curve (AUC), or total drug clearance (Cl) were used. Data on metabolic ratios (MR) in urine or plasma could not be used since these parameters are not linearly correlated with dose.
As many psychotropic drugs are metabolized to equally active metabolites,22 some studies provide data on both metabolite and parent drug, and thus the whole active moiety was taken into consideration. In Tables 2 and 3, data of all studies are shown and the substances measured in the respective studies are indicated. In Figures 2, 3 and 4, dose adjustments calculated as the weighted mean from the single studies were depicted for each substance and data of the active moiety were taken if available.
Classification of metabolizer groups
The homozygous carriers of two CYP2D6 genes coding for functional enzymes are termed extensive metabolizers (EM; genotypes: *1/*1, *1/*2, *2/*2) and carriers of one duplication allele (*2 × 2 or *1 × 2) plus one deficient allele (eg *3, *4; *5, *6) were also classified as extensive metabolizers. Heterozygous carriers of only one active allele were termed intermediate metabolizers and homozygous or compound homozygous carriers of two deficient alleles were termed poor metabolizers. Ultrarapid metabolizers identified by genotype were carriers of any combination of one CYP2D6*1 or one CYP2D6*2 gene duplication in combination with another active allele (genotypes: *2 × 2/*1, *1 × 2/*1).23,24 CYP2D6 alleles *9, *10, *17, and *41 were also classified as active alleles but with intermediate to low activity.25 In Africans, the CYP2D6*17 allele is frequent and causes greatly decreased (but not deficient) enzyme activity. This has to be considered if genotyping is used to predict metabolic phenotype in African populations.26 In Orientals, the CYP2D6*10 allele causing decreased (but not deficient) enzyme activity is prevalent with an allele frequency of about 50%. Heterozygous carriers of *10 may be in the higher activity range of the IM group and homozygous carriers (CYP2D6*10/*10) may be at the lower activity range.27 The poor metabolizer genotype with two deficient alleles is very rarely found in Orientals (<1%); therefore, studies in Japanese, Chinese or Korean individuals are mostly focused on intermediate and extensive metabolizers of substrates of CYP2D6. Studies analyzing the impact of the CYP2D6*10 genotypes are marked by a number sign (#) in Table 2, and for these studies PM genotype data are extrapolated from data in IMs and EMs.
For CYP2C19, the following classifications of metabolic phenotype based on genotype were made: extensive metabolizer: genotype *1/*1; intermediate: heterozygous carrier of one inactive CYP2C19 allele (*2, *3) and poor metabolizer as homozygous combination of two deficient CYP2C19 alleles. Most studies did not provide data on intermediate metabolizers. In these cases, a linear gene–dose relationship was assumed and a mean AUC of those of the PMs and EMs was used to calculate dose adjustments for heterozygous carriers of deficient alleles.
Phenotyping with debrisoquine or dextromethorphan for CYP2D6 and S-mephenytoin for CYP2C19 was considered equivalent to genotyping. Classification by phenotype was based on the usual urinary metabolic ratio antimodes of 12.6 for testing with debrisoquine and 0.3 for testing with dextromethorphan.28,29
Data calculation for dose adjustment
To adapt doses according to genotypes, data on clearance (Cl), area under concentration–time curve (AUC) or trough concentrations at steady state (Ctss) in the respective genotype groups were used to calculate internal exposure to the drugs. It was assumed that the average dose recommended for the whole population can be regarded as the weighted mean of subpopulation-specific doses.30 For CYP2D6 about 7–10% of Caucasians are poor metabolizers, 40% are intermediate (heterozygous carriers), and 50% are extensive metabolizers.31 Thus, the average dose (Dav) usually recommended in Caucasian populations can be regarded as
where DPM, DIM and DEM represent the optimal dose for the groups of poor metabolizers, intermediate metabolizers, and extensive metabolizers. The empirically gained average dose (Dav) can be set as 100%. Then, percentages of dose adaptations (reductions or elevations) for each genotype are obtained. The genotype-specific dose differences can be expressed by pharmacokinetic parameters from the patient or volunteer pharmacokinetic/pharmacogenetic studies analyzed here (Tables 1 and 2):
Then, Equations (2) and (3) can be substituted into (1):
When DEM is obtained, DPM and DIM can be calculated from (2) and (3). If no data on intermediate metabolizer are available, linear gene–dose effects were assumed and ClIM was estimated as 0.5 (ClPM+ClEM).
For CYP2D6, gene duplications lead to the so-called ultrarapid metabolizer type (UM). Only few studies were found concerning UMs and these were mostly single case reports. We usually assumed a linear gene–dose effect. Thus, the UM genotype with three active alleles would be correctly dosed with the EM-dose plus (difference between EM and IM doses):
As explained above, in most studies from Asiatic populations only data on CYP2D6 EMs and IMs are available. For calculation of dose recommendations, a linear gene–dose effect was assumed and the AUC in PMs was estimated as follows:
For CYP2C19, genotype frequencies of approximately 3% PM, 27% IM and 70% EM as known in Caucasian populations were used.32 The equation for CYP2C19 corresponding to Equation (1) would be
and Equations (2) and (3) from above were applied accordingly. In the tables, tentative therapeutic recommendations are given as percentual adjustments from the standard dose. Intentionally, no milligram-doses were given since the standard dose may differ depending on factors such as disease severity, age, gender, body weight, and ethnicity. When applying our dose recommendation tables in ethnic groups other than Caucasians, it is advisible to calculate the dose adjustments based on the standard dose used in that population. Ethnic differences in the response to a drug are not only due to differences in the frequencies of drug metabolic enzyme polymorphisms, but also due to differences in nutrition, other lifestyle factors, and the effects of various other genotypes on the pharmacodynamic site of drug action.
Limitations of dose adjustments based on CYP2D6 or CYP2C19 genotype
An approach using the principles of bioequivalence has been described above. However, drug concentration differences due to genotype are not exactly the same as drug concentration differences due to different preparations of a drug because the active metabolites also contribute to the overall drug effect or are responsible for adverse drug reactions.22,33 Whenever possible, we based dose adjustments on the active moiety of drug exposure consisting of parent drug and active metabolites if prevalent in considerable concentrations.
Many psychotropic drugs are administered as racemates and the enantiomers may undergo differential biotransformation, have different receptor binding profiles and different side effects,34,35 but pharmacologic activities of the specific enantiomers are frequently unknown in humans: enantiomers have been in most cases only tested in animals or in vitro. Therefore, dose recommendations might not be able to take the differential activity of enantiomers into account.
Some psychotropic drugs show saturation kinetics in the common dose-range. For clomipramine, desipramine, fluvoxamine, haloperidol, paroxetine, trimipramine, dose adjustments are only applicable in the dose ranges used in research studies, which is often much lower than clinical dosages.
Data from single dose experiments cannot be extrapolated to long-term drug therapy as saturation pharmacokinetics, irreversible enzyme blockade, or enzyme up- or downregulation might change the outcome under multiple dosing.36,37,38 Enzyme inhibition by the substrate itself was described to convert genotypic extensive metabolizers of CYP2D6 substrates to phenotypically poor metabolizers in antidepressant drug therapy.39,40,41
Drug target polymorphisms
We included all available studies concerning response to therapy and adverse drug reactions. We did not include studies on genetic polymorphisms as risk factors for the genetic susceptibility to mental illness. Essential parameters in this meta-analysis were sample size (power of the study), effect size and statistical significance. Effect size was either the odds ratio (if therapy response or adverse events were dichotomized) or the effect ratio (if response was presented on a continuous scale in the respective size). Effect ratio was the ratio of the response criterion in the group with the variant at risk divided by the response criterion in the complementary group. Funnel plots were used to assess for possible publication bias (Figures 5, 6 and 7).42 Such funnel plots illustrate the relationship between sample size of clinical trials and the study outcome. From statistical theory, it is expected that the odds ratio or the effect ratio converging to the true values if sample size of studies becomes larger and individual study data should scatter randomly around the overall mean of all studies, unless there is selective publication.
Pharmacokinetic phase: dose adjustments based on polymorphisms in cytochrome P450 enzymes
Examination of research on metabolism of 36 antidepressants and 38 antipsychotics was conducted (Table 1). For 20 antidepressants, data on CYP2D6 or CYP2C19 polymorphisms from pharmacokinetic studies in humans were found.
For iprindole, isocarboxacid, setiptiline, and viloxazine, no data on polymorphic drug metabolism were found. Elimination mainly via conjugation reactions (glucuronidation, acetylation, sulfatation) and subsequent renal excretion was described for phenelzine and tranylcypromine, and elimination via renal excretion of the unchanged compound was described for milnacipran.
For several tricyclic antidepressants, no data on the specific enzymes involved in hydroxylation or demethylation reactions were available, and apparently the impact of genetic polymorphisms for biotransformation of these drugs has not been studied. However, structural similarity to other tricyclics such as imipramine implicates that CYP2D6 and CYP2C19 might be involved in metabolism of these tricyclics, as well.
Tianeptine as well as reboxetine seem to be mainly metabolized by CYP3A4 in humans and genetic polymorphisms of CYP2D6, CYP2C19 and CYP1A2 enzymes are unlikely to cause relevant pharmacokinetic variability of these antidepressants.9
The new atypical antidepressant duloxetine is a potent inhibitor of CYP2D6 in vivo and a CYP2D6 substrate in vivo.43 It therefore seems probable that CYP2D6 genetic polymorphisms have a major impact on elimination of this drug, but this has not yet been studied in detail.
CYP2D6 or CYP2C19 polymorphisms were studied for the metabolism of 13 antipsychotic drugs (Table 1). Other elimination pathways than cytochrome P450 enzymes are important for following antipsychotics: sulpiride and amisulpride (renal excretion), raclopride (glucuronidation, sulfatation), zotepine (flavin-mono-oxygenases involved). CYP3A4 is the main enzyme involved in the metabolism of bromperidole, iloperidone, perospirone, quetiapine, and ziprasidone.8,44 For chlorpromazine, remoxipride, and sertindole, only in vitro data exist on involvement of CYP2D6.8 Remoxipride and sertindole were withdrawn from the market due to adverse drug reactions (aplastic anemia and arrhythmia). Melperone is described as potent inhibitor of CYP2D6 but studies on impact of CYP2D6 polymorphisms on melperone metabolism are not yet available.45
Studies on polymorphic metabolism by CYP2D6
Table 2 summarizes all human studies found for antidepressants and antipsychotics: information on poor and extensive metabolizers of CYP2D6 are shown and percents of dose adjustments were calculated from AUC, Cl, or Ctss as described above. There is good concordance of the quantitative effects on pharmacokinetic parameters among various studies.
Impact of CYP2D6 polymorphisms on dosing of antidepressants
The group of tricyclic antidepressants undergoes similar biotransformation actions in the liver with CYP2D6 catalyzing hydroxylation reactions,49,50,51,68,121,122 whereas demethylation of the parent drug is mediated by CYP2C19. Both metabolites are pharmacologically active and the demethylated metabolites are partially tricyclic drugs by themselves such as nortriptyline and desipramine, which are desmethyl-metabolites of amitriptyline and imipramine, respectively. For dose adjustments, the active drug moiety consisting of the sum of parent drug+demethylated metabolite was used if available from the studies. The desmethyl-metabolite-drugs nortriptyline and desipramine are mainly hydroxylated to less active or inactive metabolites,63,121 in consequence, dose adjustments were calculated taking the parent drug alone.
Differences in the internal exposure to the drug (AUC) due to genotypes were mostly similar when comparing single-dose or multiple-dose studies (Table 2).
Stereoselective metabolism by CYP2D6 was reported in trimipramine metabolism towards the less active L-trimipramine68 and for doxepin, CYP2D6 polymorphisms had influence only on clearance of the less active E-isomer.59 For these two tricyclics, dose adjustments should be based on the active drug compound (active enantiomers or isomer plus demethylated metabolite).
An extremely high clearance was described for a few CYP2D6 ultrarapid metabolizers from studies with nortriptyline and desipramine. For nortriptyline, one ultrarapid metabolizer carrying 13 active CYP2D6 genes was included, which caused the very high mean of clearance in this group.61,123 However, the 1–10% carriers of a CYP2D6 gene-amplification allele found in Caucasian populations usually carry only one gene duplication and should get moderately higher doses as calculated above and as illustrated in Figures 2 and 3.
In Figure 1, dose adjustments calculated from the data of Table 2 of all studies on tricyclic antidepressants and CYP2D6 polymorphisms are depicted in relation to the number of EMs or PMs studied. As can be seen in the figure, despite small sample sizes, different studies come to very similar results for dose adjustments. CYP2D6 PMs seem to be dosed correctly with approximately half of an average dose of tricyclic antidepressants.
Selective serotonin reuptake inhibitors
Some selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, fluvoxamine, and paroxetine are potent inhibitors of CYP2D6 activity. Therefore, multiple dosing causes decreased CYP2D6-mediated metabolism of the drugs themselves, and conversion from extensive to slow metabolizer phenotype and from ultrarapid to extensive metabolism was described.124,125,126,127 Unfortunately, these studies for fluoxetine and fluvoxamine describing conversion from higher to lower enzyme activity have studied the effect of enzyme inhibition only in one genotype group40,127 and could therefore not be used in our dose calculation approach.
Genotype-based dose adjustments might be necessary for paroxetine (Table 2), but less for fluoxetine and fluvoxamine; moreover, caution has to be paid to drug interactions. These drugs are strong inhibitors of CYP2D6, and therefore, differences in pharmacogenetic parameters are substantially decreasing under multiple dosing conditions72,75 (Table 2). For paroxetine, undetectable drug concentrations are described in one ultrarapid metabolizer carrying at least three functional CYP2D6 genes. For sertraline and citalopram, no influence of CYP2D6 polymorphisms on pharmacokinetic parameters was detected.
For other antidepressants (bupropion, maprotiline, mianserin, mirtazapine, moclobemide, nefazodone, reboxetine, venlafaxine), no general assessment on polymorphic drug metabolism can be made.
Bupropion is a substrate of CYP2B6 and apparently not influenced by CYP2D6 polymorphisms.76 In about 100 subjects, no major effects of CYP2B6 genotypes on bupropion pharmacokinetics were identified.19
There are contradictory data regarding the effects of CYP2D6 polymorphisms on metabolism of the tetracyclic antidepressant maprotiline: while in a patient group receiving monotherapy with 150 mg maprotiline, no differences in steady-state concentrations were detected due to the debrisoquine metabolizer status,77 a study with healthy volunteers receiving 100 mg maprotiline over 7 days, revealed differences similar to those detected in tricyclics.78
For mianserin, CYP2D6 mediates enantioselective hydroxylation of the more active S-(+) mianserin. For dose adjustments, the sum of S-(+)-mianserin and the active desmethylmianserin was taken (Table 2).
For the racemic drug mirtazapine, S-(+)-mirtazapine clearance significantly depends from CYP2D6 genotype, but no CYP2D6 effect on R-(−)-mirtazapine clearance was found.128 Achiral analysis did not reveal CYP2D6 genotype-related differences.82 Further clinical studies are warranted on the impact of CYP2D6 on mirtazapine clinical effects and adverse events, which differ between both enantiomers.
Venlafaxine is a chiral drug with both enantiomers transformed by CYP2D6 to the equipotent O-desmethyl-venlafaxine.88,90,131 Thus, the active drug moiety, sum of parent drug and metabolite is not much changed by the CYP2D6 genotype. However, a higher risk for cardiotoxic events and severe arrhythmia was reported in four patients admitted to a cardiologic unit who all were PMs, according to CYP2D6 function.87 Dose adjustments based on parent drug alone would lead to 60% reduction of the average dose for PMs.
Figure 2 shows the differential doses of antidepressants needed because of polymorphisms of CYP2D6 as the weighted mean (weighted according to the sample sizes in the studies) of single-study data given in Table 2. Dose adjustments are given for poor, intermediate, extensive, and ultrarapid (UM) metabolizers of CYP2D6. For the UM group, extrapolation was made assuming a linear gene–dose effect according to the calculation methods given above. If possible, data on active moiety of the drug (sum of parent drug and active metabolites) after multiple dosing were taken and if more studies exist, mean dose adjustments were calculated. The figure shows that the amount of dose adjustment varies for substrate to substrate, and that clinically relevant differences in dosages are supported by existing data.
Impact of CYP2D6 polymorphisms on dosing of antipsychotics
The influence of CYP2D6 polymorphisms on antipsychotic drug metabolism was studied in humans for aripiprazole, clozapine, flupentixol, haloperidol, levomepromazine, olanzapine, perazine, perphenazine, pimozide, risperidone, thioridazine, and zuclopenthixol.
Differences in pharmacokinetic parameters resulting in dose adjustments are depicted in Table 2, and dose recommendations according to the results from the studies in each substance are expressed in Figure 3.
The recently released antipsychotic drug aripiprazole was studied for polymorphic CYP2D6 metabolism prior to marketing, and 60% higher exposure to the total active moieties (parent drug and dehydroaripiprazole) was detected in PMs compared to EMs (aripiprazole drug information) (Table 2). Similar dose variations were detected for flupentixol as well as for perazine in a naturalistic study with schizophrenic patients receiving different doses.92
For thioridazine, a recent study within patients reports a large difference in pharmacokinetics resulting in 30% of the average dose in PMs,116 which corresponds to the data from a study in healthy volunteers administering single doses,114 but is in contrast to another study in patients where smaller differences were found.115 For dose recommendations, the weighted mean of the dose adjustment was taken from the two studies in patients (with multiple doses) according to the number of PMs (Figure 3).
For haloperidol, differences in drug metabolism lead to 60–70% of the average dose for PMs94,96 and two studies did not report significant differences at all.93,95 However, a significant higher risk for extrapyramidal side effects in PMs was observed, probably due to higher levels of reduced haloperidol. Patients with UM genotype had the worst clinical outcome measured by the positive and negative symptoms scale.96
For perphenazine, thioridazine, and zuclopenthixol, pharmacokinetic differences due to CYP2D6 genotype decreased under steady state compared to single-dose studies (30–40% decrease with PM single dose, and 60–70% with multiple dosing) and risperidone with 20% for PMs according to single dose and no significant differences for multiple doses due to an active CYP2D6-generated metabolite.
For olanzapine, a single-dose study in healthy volunteers failed to show CYP2D6-mediated differences, whereas in a patient study, steady-state concentrations differed according to the CYP2D6 genotype.105 Our own data indicated the same trend (Kirchheiner et al., unpublished).
For zuclopenthixol, the only study evaluating depot medication and CYP2D6 genotype revealed that CYP2D6 PMs should get only 70% of an average dose.120 Consequently, particularly at the beginning of antipsychotic treatment, knowledge about the poor metabolizer status might help to reduce adverse events by initiation therapy with lower doses in this subgroup of the population.
Impact of CYP2C19 polymorphisms
When compared to CYP2D6 polymorphisms, substantially fewer studies were conducted evaluating CYP2C19-mediated differences in drug metabolism (Table 3). Since CYP2C19 poor metabolizers are more frequent in Asiatic populations (13–23% in contrast to 2–5% in Caucasians132,133), several studies of Table 3 were conducted in Japanese individuals.
In general, CYP2C19 seems to be involved in demethylation biotransformation reactions of tricyclic antidepressants as was shown for amitriptyline, clomipramine, doxepin, imipramine, and trimipramine (Table 3 and Figure 4). For these drugs, PMs seem to be adequately adjusted with about 60% of the average dose and EMs with 110%. The same dose adjustments seem to be adequate for moclobemide and citalopram.
Impact of CYP2C9
Carriers of the alleles CYP2C9*2 and *3 have lower enzyme activity compared with carriers of the wild-type allele (CYP2C9*1), and a CYP2C9*4 allele with completely deficient enzyme activity was found in a single African-American subject.143 CYP2C9*2 and *3 alleles have frequencies of about 12 and 8% in Caucasians (our own data on 1010 Caucasians), but CYP2C9*2 is rare in Asian populations.
All currently existing data show only a minor contribution of CYP2C9 polymorphisms for interindividual pharmacokinetic variability of tricyclic antidepressants: data on amitriptyline are based on in vitro studies only, a small difference in kinetics between carriers of CYP2C9*1/*1 and *3/*3 was shown for trimipramine and doxepin.59,67
Clinical impact of pharmacogenetic testing for polymorphic drug metabolism
Although differences in the pharmacokinetic parameters due to polymorphic metabolism are relatively well characterized with a surprisingly good between-study concordance (Tables 2 and 3, and Figure 1), the impact of those variations on therapeutic outcomes and incidence and severity of adverse drug reactions are not as well documented. Few studies provide quantitative data on adverse drug reactions.49,57,80,87,137,144 Higher risk for antidepressant induced seizures was reported in relation to CYP2D6 activity145 and several studies showed a relationship between extrapyramidal side effects of antipsychotic drugs and CYP2D6 polymorphisms.96,146,147,148,149,150,151,152,153,154,155,156 However, compared to the large efforts made to evaluate pharmacokinetic differences due to CYP polymorphisms, few prospective studies on benefit of phenotyping or genotyping for therapeutic outcome have been conducted so far. It was estimated from retrospective assessments that patients with psychiatric disorders who are poor or ultrarapid metabolizer of CYP2D6 cost US$ 4000–6000 more per year than extensive metabolizers.157,158 The next step is to perform prospective controlled analyses on the benefit of genotyping in drug therapy: one group should receive therapeutic recommendations according to genotype, whereas the other group should be treated as usual.
Dose reduction might take place by prolongation of the dosing interval and/or by reducing the single dose. Due to first-pass metabolism, dose adjustments may be smaller in i.v. than in oral doses as shown recently by a study on trimipramine.159 However, the validity of these calculated dose adaptations (Figures 2, 34) for dose recommendations remains to be tested.
Pharmacodynamics: polymorphisms in neurotransmitter transporters, receptors, and other drug targets
As pharmacokinetic factors explain only a small part of the variability in therapeutic response, efforts have to concentrate on variations within target molecules in the brain. Thus far, mostly dopaminergic and serotoninergic receptors and transporters have been studied in patients as predictors of the response to psychotropic drug therapy (Table 4). Systematic exploration of other transmitter systems, of downstream intracellular signaling molecules, of neurotrophic factors and their receptors is a major goal of the next few years.
Role in antidepressant drug therapy
The molecular mechanism of antidepressant drug action involves inhibition of the neuronal serotonin transporter. One apparently functional polymorphism in the 5′-upstream regulatory region of this gene is a 44-base pair (bp) insertion/deletion resulting in a long (l) and a short (s) variant, the latter resulting in two-fold decreased expression and transport activity in vitro.191,192 Several studies have reported a better response to SSRIs in individuals carrying two (l)-alleles of the 44-bp insertion/deletion polymorphism in the regulatory region of the serotonin transporter (SERT).168,169,171,172,173,174,175,193 Two studies had contradictory results.165,170 This discrepancy might be due to ethnic differences: the (s)-allele frequency is much higher in Orientals than in Caucasians (79 vs 42%),194 and both studies showing an association of the (s) allele with better response were conducted in Oriental patients. However, Yu et al,169 who also studied an Asian population, found data similar to the European studies. Thus, ethnicity does not provide a clear explanation of the discrepancies and further studies are required for confirmation.
Increased circulating prolactin levels, used as a surrogate parameter of antidepressant drug action, were reported to be higher in individuals carrying the (l)-allele.166,167 In Figure 5, effect size of the studies is depicted in relation to sample size. One would expect from such plots a symmetric convergence of the effect towards the overall mean with increasing sample size. None of the authors has given a specific solution how the knowledge about differences in response depending on SERT genotype should be used in psychiatric practice. A rational approach would be to prefer primarily noradrenergic agents or tricyclics in carriers of the s/s genotype; however, this requires confirmation in a clinical study.
Another polymorphism is located in intron 2 of the SERT gene. It is a variable number of tandem repeats (VNTR) polymorphism resulting in three frequent alleles containing 9, 10, and 12 copies of the VNTR element. The VNTR was shown to act as strong positive transcriptional regulatory element for SERT in mouse embryonic rostral hindbrain and the (l)-allele containing 12 copies had the strongest transcriptional inducing ability.195 Two studies assessed the predictive value on antidepressant response of this VNTR, but an initially described association with an odds ratio of 32 of the (l) 12 allele with better response to SSRIs165 was not replicated.164 Studies on the association of adverse drug reactions and SERT polymorphisms show that there is a positive association with the risk of switching to mania, but no correlation to antidepressant-caused nausea.196,197 Fluoxetine-induced insomnia appeared to be greater in carriers of the s/s genotype.198
Role in antipsychotic drug therapy
Newer antipsychotics appear to exert their effects partially through the serotoninergic systems making the SERT a logical candidate gene for prediction of antipsychotic drug response. One study showed a better response to clozapine in carriers of the (l)-allele (Table 5). For various typical antipsychotics, in 684 patients, no differences in drug response were observed in relation to SERT genotype.199
Adverse effects of antipsychotics have also been related to SERT polymorphisms. A slightly higher frequency of the SERT l/l genotype was observed in patients suffering from tardive dyskinesia with an odds ratio of 1.9; however, differences were not statistically significant.200 Clozapine-induced weight gain was not associated with the SERT promoter polymorphism either.201
Role in antidepressant drug therapy
Serotonin (5-HT) receptor genes are further candidate genes for the prediction of antidepressant response. Several studies have shown that paroxetine induces downregulation of the 5-HT2A receptor,202,203 which has been reported to be overexpressed in depressed patients.204
Three polymorphisms have been described in the 5-HT2A gene: a silent point mutation 102T>C that is completely linked to a −1438G>A promoter polymorphism, and a polymorphism in the coding region causing a His452Tyr amino-acid substitution. A better treatment response to antidepressants in patients with one or two C-alleles of the 102T>C polymorphism was reported as compared to T/T homozygotes.160 In contrast, no significant association between the completely linked −1438G>A polymorphism and therapeutic response to fluvoxamine was observed.162
A severe adverse drug effect related to the serotonin system is the serotonin syndrome characterized by serotonin-related side effects with symptoms such as mental status changes, agitation, myoclonus, hyper-reflexia, tremor, and diarrhea.205 Impaired drug metabolism of serotonergic drugs caused by genetic deficiency of drug-metabolizing enzyme activity, as well as genetic factors in serotonergic neurotransmission, might be involved, but serotonin receptor polymorphisms have not been systematically analyzed in this context.
Role in antipsychotic drug therapy
Even though the mechanisms of action of clozapine are incompletely elucidated, it appears that in comparison to typical neuroleptics, this atypical antipsychotic drug has more effects at the level of serotoninergic systems and less on dopaminergic systems.206 Serotonin receptor (5-HT2A, 5-HT2C, 5-HT3A, 5-HT5A, 5-HT6) polymorphisms were studied as predictors of the therapeutic response to clozapine. In Figure 6, studies on serotonin receptor polymorphisms as predictors of clozapine response are depicted in relation to effect size and sample sizes. In cases where ≥3 studies on the same polymorphism have been performed, studies are ordered by sample size. The true impact of a polymorphism as a predictor for response is dependent, if this result is reproduced in several independent studies. Nevertheless, a possibility of publication bias has to be considered. A first hint for possible publication bias is deviation from the theoretically expected pattern in the funnel plots where studies should converge with increasing sample size. The weighted mean of the odds ratios of all studies on 5-HT2A receptor genotypes was 1.7, thus predicting only a minor influence of this gene on clozapine response (Table 5).
For 5-HT receptor subtype 2C, one study reported significant better clozapine response in individuals carrying the Ser allele of the Cys23Ser variant,229 but subsequent studies failed to reproduce this observation.220,225,230,231 The 5-HT receptor variants have also been studied as predictors of antipsychotic drug adverse events including tardive dyskinesia, weight gain, and malignant neuroleptic syndrome, but mostly without significant results (Table 6).
Tryptophan hydroxylase is the rate-limiting enzyme of serotonin biosynthesis.185,186 One polymorphism (218A>C) located in a possible transcription factor-binding site may influence gene expression.280 Significant associations with response to SSRIs were reported in individuals carrying the C variant of the A218C polymorphism.185,186 Recently, it has been elucidated that tryptophan hydroxylase expressed in the brain is coded by a gene (TPH2) different from that coding for peripherally expressed tryptophan hydroxylase (TPH1)281 and animals in which TPH1 was knocked out had normal central tryptophan hydroxylase. Thus, the older polymorphisms data will have to be reanalyzed and an analysis of the TPH2 gene regarding medically relevant polymorphisms has to be performed. Regeneration of serotonin from 5-methoxytryptamine is mediated by polymorphic human CYP2D6; this drug-metabolizing enzyme is therefore also directly involved in serotonin homeostasis.282
Dopamine receptors are classified according to their signal transduction pathways and sequence homology into the dopamine D1-like receptors (DRD1 and DRD5) and the dopamine D2-like receptors (DRD2, DRD3, and DRD4). Numerous polymorphisms have been described in all five receptors,283,284 but functional effects of most variants appear to be moderate. Variants resulting in completely deficient expression of DRD4285 are very rare.
Role in antidepressant drug therapy
Dopamine receptor genes might be less involved in antidepressant drug action, and so far, all studies resulted in odds ratios around 1 when testing the predictive value for antidepressant treatment response of dopamine receptor variants (Table 4).
Role in antipsychotic drug therapy
For dopamine receptor D2 (DRD2), two alleles A1 and A2 exist, of which allele A1 appeared to be associated with lower dopamine D2 receptor density in the brain and with diminished dopaminergic activity.286,287 However, data on the medical impact of these polymorphisms are controversial. Three amino-acid substitutions in the DRD2 are apparently functionally relevant288 but these are rare, and conclusive clinical data are missing. Numerous other noncoding polymorphisms have been identified including two promoter polymorphisms (−241A>G and deletion −141C) but again, consistent data indicating a clinical impact are missing (Table 6).
One recently performed meta-analysis on pharmacogenetics of tardive dyskinesia involved data from 780 patients from different populations (mostly Caucasian, but also African American and Ashkenazi) confirmed contribution of the dopamine receptor D3 (DRD3) Ser9Gly polymorphism with an odds ratio of 1.33 for carriers of the Gly variant;252 however, in epidemiology, such small odds ratios are usually interpreted with caution. In Figure 7, the odds ratio or effect sizes of the studies on the role of the DRD3 Ser9Gly polymorphism in tardive dyskinesia are depicted in relation to sample sizes. As illustrated in Figure 7, the biggest effects were seen in the small studies and these effects were apparently not replicated in the larger studies. One explanation for this trend may be publication bias meaning that small studies with the opposite effect might also exist but have never been submitted for publication.42
Dopamine D4 receptor (DRD4) polymorphisms have been studied as predictors of the response to the DRD4 ligand clozapine, but the results on a 16-amino-acid VNTR polymorphism were contradictory (Table 5).214,215,216,217,218
For typical (ie predominantly dopamine D-2 antagonistic) antipsychotics, only few studies were found on dopamine receptor genes (DRD2, DRD3, and DRD4).210,289,290,291,292,293 Most results were negative findings for response prediction. One study observed a slight over-representation of the DRD3 Ser9Gly amino-acid exchange (allele *2) in patients with poor response to antipsychotics, particularly in the non-Ashkenazi, Israeli schizophrenics.290
Antidepressant efficacy is mediated not only by serotonin reuptake inhibition, but also by inhibition of the norepinephrine uptake. Norepinephrine reuptake inhibitors (NRIs) with variable selectivity are desipramine, lofepramine, viloxazine, maprotiline, oxaprotiline, and reboxetine. Several genetic variants have been identified in the human norepinephrine transporter gene; however, no association has been found so far between those polymorphisms and either bipolar disorder and schizophrenia.294 It has not yet been studied if genetic polymorphisms in the norepinephrine transporter gene have influence on antidepressant drug response especially of the NRIs.
Candidate genes beyond the neurotransmitter axes
Associations with response to various antidepressant drugs were observed with the ACE 287-bp insertion/deletion polymorphism,176,177 with the G-protein β3 subunit (GNB3).182 Both genes play an important role in regulation of blood pressure, and there is a well-known relationship between depression and cardiovascular disease. In turn, depression is a major risk factor for the development of coronary artery disease. In fact, it was shown recently by the authors, that the same allelic combination of ACE and GNB3 that have been shown to increase the risk for myocardial infarction295 increase the vulnerability for depressive disorder.296
The reason why most genetic variability within pharmacodynamic elements did not turn out to be highly predictive of favorable antidepressant treatment response might be that most studies focused on short-time effects of antidepressants such as changes in the serotonin- or noradrenaline-pathways. There is growing evidence that long-term antidepressant treatment enhances structural changes in neuroplasticity, and genes involved in neurotrophic signaling cascades, might act as antidepressant targets.297 Future studies on genetic variability in antidepressant treatment response should focus on these systems, which in fact could be the common final pathway of different antidepressant strategies (irrespective of whether the drug used is primarily serotonergic or noradrenergic).
Methylenetetrahydrofolate reductase (MTHFR) gene was studied in relation to antipsychotic drug therapy.298 A missense mutation (677C>T) in the MTHFR gene was previously found to be associated with schizophrenia,299 and a significant over-representation of the T allele in responders to antipsychotic therapy was found compared to nonresponders.298
Catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO) enzymes are involved in metabolic inactivation of several neurotransmitters. Within the COMT gene, a G to A transition at codon 158 resulting in a Val158Met amino-acid exchange is responsible for 3–4-fold lower enzyme activity in Met/Met carriers compared to wild type.300 For the MAO gene, a VNTR located in the upstream regulatory region was described to affect enzyme activity with lower activity in carriers of only three repeat elements in comparison to four.301 Both functional polymorphisms were studied with regard to antipsychotic drug response, and the Met/Met genotype of the COMT gene was found to be associated with nonresponse to at least two antipsychotic drugs. The MAO gene promoter polymorphism showed an additional synergistic effect with a six-fold higher risk to be a nonresponder found in patients with genotypes predicting low activity of both enzymes than in patients with the wild-type genotype combination (COMT Met/Met and MAO 3/3 vs COMT Val/Val and MAO 4/4, odds ratio 6.1).302
BDNF is involved in the neurodevelopment of dopaminergic-related systems. A dinucleotide repeat polymorphism is located 1040 bp upstream of the transcriptional site.303 Allele distribution differed significantly in treatment-responding patients compared to refractory patients with an excess of (l)-alleles (172–176 bp) in the treatment responders.304 Another polymorphism is located in the coding region and causes a Val166Met amino-acid substitution. In human subjects, the Met allele was associated with poorer episodic memory, and abnormal hippocampal activation.305 The response to clozapine was studied in patients with regard to the Val166Met polymorphism but no association was found.238
Polymorphisms in free radical detoxification might be particularly relevant for adverse events caused by haloperidol, which has reactive metabolites. An association of a polymorphism in manganese superoxide dismutase (SOD2) was found to be associated with tardive dyskinesia,265 but replication failed.266
Hypersalivation is a common side effect of clozapine, which might be caused by its β2-adrenoceptor-blocking effects.306 Thus, genetic polymorphisms within the β2-adrenoceptor gene might be associated with altered susceptibility to hypersalivation; however, no association has been observed so far.208
There are several additional adverse drug reactions, for which susceptibility caused by genetic mechanisms are not yet elucidated. A variety of psychotropic drugs are associated with cardiac side effects, in particular with iatrogenic prolongation of the QT interval of the electrocardiogram, which in turn is associated with torsade-de-pointes arrhythmia. Tricyclic antidepressants, such as imipramine and amitriptyline, and phenothiazine antipsychotics, such as thioridazine, inhibit cardiac potassium channels.307 Individual risk for drug-induced prolongation of the QT interval was shown to be related to genetic variants in genes encoding cardiac K+-channels, such as the HERG gene encoding for a K+ channel subunit.308
Several recently published studies on schizophrenia focus on susceptibility genes for schizophrenia, which have shared effects on synapses, such as glutamatergic, GABAergic, cholinergic, and monoaminergic synapses.309 Polymorphisms in these genes (eg neuregulin, dysbindin, COMT, D-amino acid oxides (DAAO), regulator of G-protein signaling 4 (RGS4), and proline dehydrogenase (PRODH) may be candidates for prediction of antipsychotic therapeutic response, and will certainly be addressed in future studies.
Integrated multigene and multifactorial approaches
Promising efforts have been made to test for the best predictive value of combinations of polymorphisms in context of genetic prediction of response to clozapine. A set of six from 19 genetic polymorphisms was extracted showing the strongest association with clozapine response in a sample of 200 patients;310 however, the exciting finding of 76% success in the prediction of clozapine response could not be replicated by others in a sample of 163 schizophrenic patients.225 This illustrates the major problem of type I error adjustment in pharmacogenomic studies. Usually, it is a rational and necessary approach to consider multiple candidate genes and to consider their gene–gene and gene–environment interactions, but this exploratory approach results in substantial increases in the type I error.
As drug response is just as complex a phenotype as disease susceptibility, it is probable that genetic variability will derive not only from genotypes in the translated gene regions, but also from variability in gene expression and regulation. Genetic mechanisms on the level of drug metabolism and transport as well as in drug target structures such as neurotransmitter receptors and transporter molecules have to be systematically studied for their predictive value in terms of antidepressant drug response. This is a necessary foundation for the development of clearcut therapeutic strategies. Individualized medicine is the overall goal of pharmacogenetic research. A systematic pharmacogenomic approach for optimization of antidepressant drug treatment is based on several levels: (1) identifying and validating the candidate genes involved in drug response, (2) developing a commercially viable pharmacogenetic test system for bedside-testing of patients’ individual response profiles, and (3) providing guidelines for pharmacogenetic-based individualized drug therapy in the form of therapeutic strategy flow-charts and genotypic specific dose recommendations.
Pharmacogenetic knowledge will only be translated into daily clinical decision-making when it becomes scientifically possible to provide relatively specific therapeutic recommendations. Therefore, this review intended to integrate pharmacogenetic results from clinical studies on drug response and pharmacokinetic variability into dose adjustments and therapeutic strategies. In terms of pharmacokinetic variability, quantitative dose adjustments based on genotypes can already be calculated for many antidepressants and antipsychotics. However, the actual outcome and benefit of pharmacogenetic individualization of drug therapy will have to be supported by future prospective studies, leading to dose recommendations that will then have to be validated.
The pharmacodynamic aspects of psychotropic drug action, including the functional consequences of polymorphisms in neurotransmitter receptors, transporters, and molecules involved in signal transduction, cannot yet be easily translated into treatment recommendations. This is partly due to difficulties in replication of findings from association studies in prospective trials from diverse populations, and also might be due to the key problem of multigenetic influences. Rather than large effects given by single polymorphisms, multigenic interactions and gene–environment interactions will have to be considered. Therefore, in the future, haplotype analyses and multigenetic analyses with sufficient power (adequate sample size and high quality of phenotypic data) might reveal the genotypes that predict clinical responses, including susceptibility to adverse drug reactions. We are optimistic that progress in this field will integrate excellence in clinical research and phenotypic characterization, genomic science, and bioinformatics to yield in the not-too-distant future a body of reliable data that will eventually guide clinical pharmacology and medical practice.
Murray CJ, Lopez AD . Global mortality, disability, and the contribution of risk factors: Global Burden of Disease Study. Lancet 1997; 349: 1436–1442.
Entsuah AR, Huang H, Thase ME . Response and remission rates in different subpopulations with major depressive disorder administered venlafaxine, selective serotonin reuptake inhibitors, or placebo. J Clin Psychiatry 2001; 62: 869–877.
Thase ME . New approaches to managing difficult-to-treat depressions. J Clin Psychiatry 2003; 64 (Suppl 1): 3–4.
Thase ME . Effectiveness of antidepressants: comparative remission rates. J Clin Psychiatry 2003; 64 (Suppl 2): 3–7.
Bauer M, Whybrow PC, Angst J, Versiani M, Moller HJ . World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Unipolar Depressive Disorders, Part 1: Acute and continuation treatment of major depressive disorder. World J Biol Psychiatry 2002; 3: 5–43.
Thase ME . Overview of antidepressant therapy. Manag Care 2001; 10: 6–9, discussion 18–22.
Thase ME, Entsuah AR, Rudolph RL . Remission rates during treatment with venlafaxine or selective serotonin reuptake inhibitors. Br J Psychiatry 2001; 178: 234–241.
Caccia S . Biotransformation of post-clozapine antipsychotics: pharmacological implications. Clin Pharmacokinet 2000; 38: 393–414.
Caccia S . Metabolism of the newer antidepressants. An overview of the pharmacological and pharmacokinetic implications. Clin Pharmacokinet 1998; 34: 281–302.
Dahl ML . Cytochrome P450 phenotyping/genotyping in patients receiving antipsychotics: useful aid to prescribing? Clin Pharmacokinet 2002; 41: 453–470.
Bertilsson L, Dahl ML, Dalen P, Al-Shurbaji A . Molecular genetics of CYP2D6: clinical relevance with focus on psychotropic drugs. Br J Clin Pharmacol 2002; 53: 111–122.
Rendic S . Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev 2002; 34: 83–448.
Nakajima M, Yokoi T, Mizutani M, Kinoshita M, Funayama M, Kamataki T . Genetic polymorphism in the 5′-flanking region of human CYP1A2 gene: effect on the CYP1A2 inducibility in humans. J Biochem (Tokyo) 1999; 125: 803–808.
Sachse C, Brockmöller J, Bauer S, Roots I . Functional significance of a C → A polymorphism in intron 1 of the cytochrome P450 CYP1A2 gene tested with caffeine. Br J Clin Pharmacol 1999; 47: 445–449.
Sachse C, Bhambra U, Smith G, Lightfoot TJ, Barrett JH, Scollay J et al. Polymorphisms in the cytochrome P450 CYP1A2 gene (CYP1A2) in colorectal cancer patients and controls: allele frequencies, linkage disequilibrium and influence on caffeine metabolism. Br J Clin Pharmacol 2003; 55: 68–76.
Basile VS, Ozdemir V, Masellis M, Walker ML, Meltzer HY, Lieberman JA et al. A functional polymorphism of the cytochrome P450 1A2 (CYP1A2) gene: association with tardive dyskinesia in schizophrenia. Mol Psychiatry 2000; 5: 410–417.
Shimoda K, Someya T, Morita S, Hirokane G, Yokono A, Takahashi S et al. Lack of impact of CYP1A2 genetic polymorphism (C/A polymorphism at position 734 in intron 1 and G/A polymorphism at position −2964 in the 5′-flanking region of CYP1A2) on the plasma concentration of haloperidol in smoking male Japanese with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2002; 26: 261–265.
Schulze TG, Schumacher J, Muller DJ, Krauss H, Alfter D, Maroldt A et al. Lack of association between a functional polymorphism of the cytochrome P450 1A2 (CYP1A2) gene and tardive dyskinesia in schizophrenia. Am J Med Genet 2001; 105: 498–501.
Kirchheiner J, Klein C, Meineke I, Sasse J, Zanger UM, Murdter TE et al. Bupropion and 4-OH-bupropion pharmacokinetics in relation to genetic polymorphisms in CYP2B6. Pharmacogenetics 2003; 13: 619–626.
Lamba JK, Lin YS, Thummel K, Daly A, Watkins PB, Strom S et al. Common allelic variants of cytochrome P4503A4 and their prevalence in different populations. Pharmacogenetics 2002; 12: 121–132.
Koch I, Weil R, Wolbold R, Brockmöller J, Hustert E, Burk O et al. Interindividual variability and tissue-specificity in the expression of cytochrome P450 3A mRNA. Drug Metab Dispos 2002; 30: 1108–1114.
Sanchez C, Hyttel J . Comparison of the effects of antidepressants and their metabolites on reuptake of biogenic amines and on receptor binding. Cell Mol Neurobiol 1999; 19: 467–489.
Johansson I, Lundqvist E, Dahl ML, Ingelman-Sundberg M . PCR-based genotyping for duplicated and deleted CYP2D6 genes. Pharmacogenetics 1996; 6: 351–355.
Lovlie R, Daly AK, Matre GE, Molven A, Steen VM . Polymorphisms in CYP2D6 duplication-negative individuals with the ultrarapid metabolizer phenotype: a role for the CYP2D6*35 allele in ultrarapid metabolism? Pharmacogenetics 2001; 11: 45–55.
Raimundo S, Fischer J, Eichelbaum M, Griese E, Schwab M, Zanger U . Elucidation of the genetic basis of the common ‘intermediate metabolizer’ phenotype for drug oxidation by CYP2D6. Pharmacogenetics 2000; 10: 577–581.
Masimirembwa C, Persson I, Bertilsson L, Hasler J, Ingelman-Sundberg M . A novel mutant variant of the CYP2D6 gene (CYP2D6*17) common in a black African population: association with diminished debrisoquine hydroxylase activity. Br J Clin Pharmacol 1996; 42: 713–719.
Yokota H, Tamura S, Furuya H, Kimura S, Watanabe M, Kanazawa I et al. Evidence for a new variant CYP2D6 allele CYP2D6J in a Japanese population associated with lower in vivo rates of sparteine metabolism. Pharmacogenetics 1993; 3: 256–263.
Steiner E, Bertilsson L, Sawe J, Bertling I, Sjoqvist F . Polymorphic debrisoquin hydroxylation in 757 Swedish subjects. Clin Pharmacol Ther 1988; 44: 431–435.
Sachse C, Brockmöller J, Bauer S, Roots I . Cytochrome P450 2D6 variants in a Caucasian population: allele frequencies and phenotypic consequences. Am J Hum Genet 1997; 60: 284–295.
Kirchheiner J, Brøsen K, Dahl ML, Gram LF, Kasper S, Roots I et al. CYP2D6 and CYP2C19 genotype-based dose recommendations for antidepressants: a first step towards subpopulation-specific dosages. Acta Psychiatr Scand 2001; 104: 173–192.
Bradford LD . CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants. Pharmacogenomics 2002; 3: 229–243.
Xie HG, Stein CM, Kim RB, Wilkinson GR, Flockhart DA, Wood AJ . Allelic, genotypic and phenotypic distributions of S-mephenytoin 4′-hydroxylase (CYP2C19) in healthy Caucasian populations of European descent throughout the world. Pharmacogenetics 1999; 9: 539–549.
Rudorfer MV, Potter WZ . Metabolism of tricyclic antidepressants. Cell Mol Neurobiol 1999; 19: 373–409.
Lane RM, Baker GB . Chirality and drugs used in psychiatry: nice to know or need to know? Cell Mol Neurobiol 1999; 19: 355–372.
Baumann P, Eap CB . Enantiomeric antidepressant drugs should be considered on individual merit. Hum Psychopharmacol 2001; 16: S85–S92.
Venkatakrishnan K, Greenblatt DJ, von Moltke LL, Schmider J, Harmatz JS, Shader RI . Five distinct human cytochromes mediate amitriptyline N-demethylation in vitro: dominance of CYP 2C19 and 3A4. J Clin Pharmacol 1998; 38: 112–121.
Gram LF, Guentert TW, Grange S, Vistisen K, Brøsen K . Moclobemide, a substrate of CYP2C19 and an inhibitor of CYP2C19, CYP2D6, and CYP1A2: a panel study. Clin Pharmacol Ther 1995; 57: 670–677.
Sindrup SH, Brøsen K, Gram LF, Hallas J, Skjelbo E, Allen A et al. The relationship between paroxetine and the sparteine oxidation polymorphism. Clin Pharmacol Ther 1992; 51: 278–287.
Christensen M, Tybring G, Mihara K, Yasui-Furokori N, Carrillo JA, Ramos SI et al. Low daily 10-mg and 20-mg doses of fluvoxamine inhibit the metabolism of both caffeine (cytochrome P4501A2) and omeprazole (cytochrome P4502C19). Clin Pharmacol Ther 2002; 71: 141–152.
Laine K, Tybring G, Hartter S, Andersson K, Svensson JO, Widen J et al. Inhibition of cytochrome P4502D6 activity with paroxetine normalizes the ultrarapid metabolizer phenotype as measured by nortriptyline pharmacokinetics and the debrisoquin test. Clin Pharmacol Ther 2001; 70: 327–335.
Sindrup SH, Brøsen K, Gram LF . Pharmacokinetics of the selective serotonin reuptake inhibitor paroxetine: nonlinearity and relation to the sparteine oxidation polymorphism. Clin Pharmacol Ther 1992; 51: 288–295.
Song F, Khan KS, Dinnes J, Sutton AJ . Asymmetric funnel plots and publication bias in meta-analyses of diagnostic accuracy. Int J Epidemiol 2002; 31: 88–95.
Skinner MH, Kuan HY, Pan A, Sathirakul K, Knadler MP, Gonzales CR et al. Duloxetine is both an inhibitor and a substrate of cytochrome P4502D6 in healthy volunteers. Clin Pharmacol Ther 2003; 73: 170–177.
Caccia S . New antipsychotic agents for schizophrenia: pharmacokinetics and metabolism update. Curr Opin Investig Drugs 2002; 3: 1073–1080.
Grozinger M, Dragicevic A, Hiemke C, Shams M, Muller MJ, Hartter S . Melperone is an inhibitor of the CYP2D6 catalyzed O-demethylation of venlafaxine. Pharmacopsychiatry 2003; 36: 3–6.
Mellström B, Bertilsson L, Lou YC, Säwe J, Sjöqvist F . Amitriptyline metabolism: relationship to polymorphic debrisoquine hydroxylation. Clin Pharmacol Ther 1983; 34: 516–520.
Mellström B, Säwe J, Bertilsson L, Sjöqvist F . Amitriptyline metabolism: association with debrisoquin hydroxylation in nonsmokers. Clin Pharmacol Ther 1986; 39: 369–371.
Balant Gorgia AE, Schulz P, Dayer P, Balant L, Kubli A, Gertsch C et al. Role of oxidation polymorphism on blood and urine concentrations of amitriptyline and its metabolites in man. Arch Psychiatr Nervenkr 1982; 232: 215–222.
Baumann P, Jonzier Perey M, Koeb L, Küpfer A, Tinguely D, Schopf J . Amitriptyline pharmacokinetics and clinical response: II. Metabolic polymorphism assessed by hydroxylation of debrisoquine and mephenytoin. Int Clin Psychopharmacol 1986; 1: 102–112.
Nielsen KK, Brøsen K, Hansen MG, Gram LF . Single-dose kinetics of clomipramine: relationship to the sparteine and S-mephenytoin oxidation polymorphisms. Clin Pharmacol Ther 1994; 55: 518–527.
Nielsen KK, Brøsen K, Gram LF . Steady-state plasma levels of clomipramine and its metabolites: impact of the sparteine/debrisoquine oxidation polymorphism. Danish University Antidepressant Group. Eur J Clin Pharmacol 1992; 43: 405–411.
DUAG. Clomipramine dose–effect study in patients with depression: Clinical end points and pharmacokinetics. Clin Pharmacol Ther 1999; 66: 152–165.
Steiner E, Spina E . Differences in the inhibitory effect of cimetidine on desipramine metabolism between rapid and slow debrisoquin hydroxylators. Clin Pharmacol Ther 1987; 42: 278–282.
Spina E, Steiner E, Ericsson O, Sjöqvist F . Hydroxylation of desmethylimipramine: dependence on the debrisoquin hydroxylation phenotype. Clin Pharmacol Ther 1987; 41: 314–319.
Brøsen K, Otton SV, Gram LF . Imipramine demethylation and hydroxylation: impact of the sparteine oxidation phenotype. Clin Pharmacol Ther 1986; 40: 543–549.
Bergmann TK, Bathum L, Brosen K . Duplication of CYP2D6 predicts high clearance of desipramine but high clearance does not predict duplication of CYP2D6. Eur J Clin Pharmacol 2001; 57: 123–127.
Spina E, Gitto C, Avenoso A, Campo GM, Caputi AP, Perucca E . Relationship between plasma desipramine levels, CYP2D6 phenotype and clinical response to desipramine: a prospective study. Eur J Clin Pharmacol 1997; 51: 395–398.
Shimoda K, Morita S, Hirokane G, Yokono A, Someya T, Takahashi S . Metabolism of desipramine in Japanese psychiatric patients: the impact of CYP2D6 genotype on the hydroxylation of desipramine. Pharmacol Toxicol 2000; 86: 245–249.
Kirchheiner J, Meineke I, Muller G, Roots I, Brockmöller J . Contributions of CYP2D6, CYP2C9 and CYP2C19 to the biotransformation of E- and Z-doxepin in healthy volunteers. Pharmacogenetics 2002; 12: 571–580.
Brøsen K, Klysner R, Gram LF, Otton SV, Bech P, Bertilsson L . Steady-state concentrations of imipramine and its metabolites in relation to the sparteine/debrisoquine polymorphism. Eur J Clin Pharmacol 1986; 30: 679–684.
Dalén P, Dahl ML, Ruiz ML, Nordin J, Bertilsson L . 10-Hydroxylation of nortriptyline in white persons with 0, 1, 2, 3, and 13 functional CYP2D6 genes. Clin Pharmacol Ther 1998; 63: 444–452.
Mellström B, Bertilsson L, Säwe J, Schulz HU, Sjöqvist F . E- and Z-10-hydroxylation of nortriptyline: relationship to polymorphic debrisoquine hydroxylation. Clin Pharmacol Ther 1981; 30: 189–193.
Bertilsson L, Eichelbaum M, Mellström B, Säwe J, Schulz HU, Sjöqvist F . Nortriptyline and antipyrine clearance in relation to debrisoquine hydroxylation in man. Life Sci 1980; 27: 1673–1677.
Dahl ML, Bertilsson L, Nordin C . Steady-state plasma levels of nortriptyline and its 10-hydroxy metabolite: relationship to the CYP2D6 genotype. Psychopharmacology (Berlin) 1996; 123: 315–319.
Yue QY, Zhong ZH, Tybring G, Dalén P, Dahl ML, Bertilsson L et al. Pharmacokinetics of nortriptyline and its 10-hydroxy metabolite in Chinese subjects of different CYP2D6 genotypes. Clin Pharmacol Ther 1998; 64: 384–390.
Morita S, Shimoda K, Someya T, Yoshimura Y, Kamijima K, Kato N . Steady-state plasma levels of nortriptyline and its hydroxylated metabolites in Japanese patients: impact of CYP2D6 genotype on the hydroxylation of nortriptyline. J Clin Psychopharmacol 2000; 20: 141–149.
Kirchheiner J, Muller G, Meineke I, Wernecke KD, Roots I, Brockmoller J . Effects of polymorphisms in CYP2D6, CYP2C9, and CYP2C19 on trimipramine pharmacokinetics. J Clin Psychopharmacol 2003; 23: 459–466.
Eap CB, Bender S, Gastpar M, Fischer W, Haarmann C, Powell K et al. Steady state plasma levels of the enantiomers of trimipramine and of its metabolites in CYP2D6-, CYP2C19- and CYP3A4/5-phenotyped patients. Ther Drug Monit 2000; 22: 209–214.
Sindrup SH, Brøsen K, Hansen MG, Aaes Jorgensen T, Overo KF, Gram LF . Pharmacokinetics of citalopram in relation to the sparteine and the mephenytoin oxidation polymorphisms. Ther Drug Monit 1993; 15: 11–17.
Fjordside L, Jeppesen U, Eap CB, Powell K, Baumann P, Brøsen K . The stereoselective metabolism of fluoxetine in poor and extensive metabolizers of sparteine. Pharmacogenetics 1999; 9: 55–60.
Hamelin BA, Turgeon J, Vallee F, Belanger PM, Paquet F, LeBel M . The disposition of fluoxetine but not sertraline is altered in poor metabolizers of debrisoquin. Clin Pharmacol Ther 1996; 60: 512–521.
Eap CB, Bondolfi G, Zullino D, Savary-Cosendai L, Powell-Golay K, Kosel M et al. Concentrations of the enantiomers of fluoxetine and norfluoxetine after multiple doses of fluoxetine in cytochrome P4502D6 poor and extensive metabolizers. J Clin Psychopharmacol 2001; 21: 330–334.
Spigset O, Granberg K, Hagg S, Norstrom A, Dahlqvist R . Relationship between fluvoxamine pharmacokinetics and CYP2D6/CYP2C19 phenotype polymorphisms. Eur J Clin Pharmacol 1997; 52: 129–133.
Carrillo JA, Dahl ML, Svensson JO, Alm C, Rodriguez I, Bertilsson L . Disposition of fluvoxamine in humans is determined by the polymorphic CYP2D6 and also by the CYP1A2 activity. Clin Pharmacol Ther 1996; 60: 183–190.
Spigset O, Granberg K, Hagg S, Soderstrom E, Dahlqvist R . Non-linear fluvoxamine disposition. Br J Clin Pharmacol 1998; 45: 257–263.
Pollock BG, Sweet RA, Kirshner M, Reynolds III CF . Bupropion plasma levels and CYP2D6 phenotype. Ther Drug Monit 1996; 18: 581–585.
Gabris G, Baumann P, Janzier-Perey MPB, Woggon B, Küpfer A . N-methylation of maprotiline in debrisoquine/mephenytoin-phenotyped depressive patients. Biochem Pharmacol 1985; 34: 409–410.
Firkusny L, Gleiter CH . Maprotiline metabolism appears to co-segregate with the genetically-determined CYP2D6 polymorphic hydroxylation of debrisoquine. Br J Clin Pharmacol 1994; 37: 383–388.
Mihara K, Otani K, Tybring G, Dahl ML, Bertilsson L, Kaneko S . The CYP2D6 genotype and plasma concentrations of mianserin enantiomers in relation to therapeutic response to mianserin in depressed Japanese patients. J Clin Psychopharmacol 1997; 17: 467–471.
Dahl ML, Tybring G, Elwin CE, Alm C, Andreasson K, Gyllenpalm M et al. Stereoselective disposition of mianserin is related to debrisoquin hydroxylation polymorphism. Clin Pharmacol Ther 1994; 56: 176–183.
Eap CB, Lima CA, Macciardi F, Woggon B, Powell K, Baumann P . Steady state concentrations of the enantiomers of mianserin and desmethylmianserin in poor and in homozygous and heterozygous extensive metabolizers of debrisoquine. Ther Drug Monit 1998; 20: 7–13.
Dahl ML, Voortman G, Alm C, Elwin CE, Delbressine L, Vos R et al. In vitro and in vivo studies on the disposition of mirtazapine in humans. Clin Drug Invest 1997; 13: 37–46.
Härtter S, Dingemanse J, Baier D, Ziegler G, Hiemke C . The role of cytochrome P450 2D6 in the metabolism of moclobemide. Eur Neuropsychopharmacol 1996; 6: 225–230.
Schoerlin MP, Blouin RA, Pfefen JP, Guentert TW . Comparison of the pharmacokinetics of moclobemide in poor and efficient metabolizers of debrisoquine. Acta Psychiatr Scand Suppl 1990; 360: 98–100.
Barbhaiya RH, Buch AB, Greene DS . Single and multiple dose pharmacokinetics of nefazodone in subjects classified as extensive and poor metabolizers of dextromethorphan. Br J Clin Pharmacol 1996; 42: 573–581.
Mihara K, Otani K, Suzuki A, Yasui N, Nakano H, Meng X et al. Relationship between the CYP2D6 genotype and the steady-state plasma concentrations of trazodone and its active metabolite m-chlorophenylpiperazine. Psychopharmacology (Berlin) 1997; 133: 95–98.
Lessard E, Yessine M, Hamelin B, O'Hara G, LeBlanc J, Turgeon J . Influence of CYP2D6 activity on the disposition and cardiovascular toxicity of the antidepressant agent venlafaxine in humans. Pharmacogenetics 1999; 9: 435–443.
Fukuda T, Yamamoto I, Nishida Y, Zhou Q, Ohno M, Takada K et al. Effect of the CYP2D6*10 genotype on venlafaxine pharmacokinetics in healthy adult volunteers. Br J Clin Pharmacol 1999; 47: 450–453.
Eap CB, Lessard E, Baumann P, Brawand-Amey M, Yessine MA, O'Hara G et al. Role of CYP2D6 in the stereoselective disposition of venlafaxine in humans. Pharmacogenetics 2003; 13: 39–47.
Veefkind AH, Haffmans PM, Hoencamp E . Venlafaxine serum levels and CYP2D6 genotype. Ther Drug Monit 2000; 22: 202–208.
Dahl ML, Llerena A, Bondesson U, Lindstrom L, Bertilsson L . Disposition of clozapine in man: lack of association with debrisoquine and S-mephenytoin hydroxylation polymorphisms. Br J Clin Pharmacol 1994; 37: 71–74.
Walter S . Bedeutung der erblichen Polymorphismen von Cytochrom-P450-2D6 für den Metabolismus und die Pharmakokinetik von Antipsychotika. Dissertation. Humboldt Universität zu Berlin, Berlin, 2000.
Young D, Midha KK, Fossler MJ, Hawes EM, Hubbard JW, McKay G et al. Effect of quinidine on the interconversion kinetics between haloperidol and reduced haloperidol in humans: implications for the involvement of cytochrome P450IID6. Eur J Clin Pharmacol 1993; 44: 433–438.
Llerena A, Dahl ML, Ekqvist B, Bertilsson L . Haloperidol disposition is dependent on the debrisoquine hydroxylation phenotype: increased plasma levels of the reduced metabolite in poor metabolizers. Ther Drug Monit 1992; 14: 261–264.
Gram LF, Debruyne D, Caillard V, Boulenger JP, Lacotte J, Moulin M et al. Substantial rise in sparteine metabolic ratio during haloperidol treatment. Br J Clin Pharmacol 1989; 27: 272–275.
Brockmöller J, Kirchheiner J, Schmider J, Walter S, Sachse C, Müller-Oerlinghausen B et al. The impact of the CYP2D6 polymorphism on haloperidol pharmacokinetics and outcome. Clin Pharmacol Ther 2002; 72: 438–452.
Suzuki A, Otani K, Mihara K, Yasui N, Kaneko S, Inoue Y et al. Effects of the CYP2D6 genotype on the steady-state plasma concentrations of haloperidol and reduced haloperidol in Japanese schizophrenic patients. Pharmacogenetics 1997; 7: 415–418.
Roh HK, Chung JY, Oh DY, Park CS, Svensson JO, Dahl ML et al. Plasma concentrations of haloperidol are related to CYP2D6 genotype at low, but not high doses of haloperidol in Korean schizophrenic patients. Br J Clin Pharmacol 2001; 52: 265–271.
Mihara K, Suzuki A, Kondo T, Yasui N, Furukori H, Nagashima U et al. Effects of the CYP2D6*10 allele on the steady-state plasma concentrations of haloperidol and reduced haloperidol in Japanese patients with schizophrenia. Clin Pharmacol Ther 1999; 65: 291–294.
Shimoda K, Someya T, Morita S, Hirokane G, Noguchi T, Yokono A et al. Lower plasma levels of haloperidol in smoking than in nonsmoking schizophrenic patients. Ther Drug Monit 1999; 21: 293–296.
Someya T, Suzuki Y, Shimoda K, Hirokane G, Morita S, Yokono A et al. The effect of cytochrome P4502D6 genotypes on haloperidol metabolism: a preliminary study in a psychiatric population. Psychiatry Clin Neurosci 1999; 53: 593–597.
Ohara K, Tanabu S, Yoshida K, Ishibashi K, Ikemoto K, Shibuya H . Effects of smoking and cytochrome P450 2D6*10 allele on the plasma haloperidol concentration/dose ratio. Prog Neuropsychopharmacol Biol Psychiatry 2003; 27: 945–949.
Bagli M, Hoflich G, Rao ML, Langer M, Baumann P, Kolbinger M et al. Bioequivalence and absolute bioavailability of oblong and coated levomepromazine tablets in CYP2D6 phenotyped subjects. Int J Clin Pharmacol Ther 1995; 33: 646–652.
Hagg S, Spigset O, Lakso HA, Dahlqvist R . Olanzapine disposition in humans is unrelated to CYP1A2 and CYP2D6 phenotypes. Eur J Clin Pharmacol 2001; 57: 493–497.
Carrillo JA, Herraiz AG, Ramos SI, Gervasini G, Vizcaino S, Benitez J . Role of the smoking-induced cytochrome P450 (CYP)1A2 and polymorphic CYP2D6 in steady-state concentration of olanzapine. J Clin Psychopharmacol 2003; 23: 119–127.
Dahl Puustinen ML, Liden A, Alm C, Nordin C, Bertilsson L . Disposition of perphenazine is related to polymorphic debrisoquin hydroxylation in human beings. Clin Pharmacol Ther 1989; 46: 78–81.
Linnet K, Wiborg O . Steady-state serum concentrations of the neuroleptic perphenazine in relation to CYP2D6 genetic polymorphism. Clin Pharmacol Ther 1996; 60: 41–47.
Desta Z, Kerbusch T, Flockhart DA . Effect of clarithromycin on the pharmacokinetics and pharmacodynamics of pimozide in healthy poor and extensive metabolizers of cytochrome P450 2D6 (CYP2D6). Clin Pharmacol Ther 1999; 65: 10–20.
Huang ML, Van Peer A, Woestenborghs R, De Coster R, Heykants J, Jansen AA et al. Pharmacokinetics of the novel antipsychotic agent risperidone and the prolactin response in healthy subjects. Clin Pharmacol Ther 1993; 54: 257–268.
Nyberg S, Dahl ML, Halldin C . A PET study of D2 and 5-HT2 receptor occupancy induced by risperidone in poor metabolizers of debrisoquin and risperidone. Psychopharmacology (Berlin) 1995; 119: 345–348.
Olesen OV, Licht RW, Thomsen E, Bruun T, Viftrup JE, Linnet K . Serum concentrations and side effects in psychiatric patients during risperidone therapy. Ther Drug Monit 1998; 20: 380–384.
Roh HK, Kim CE, Chung WG, Park CS, Svensson JO, Bertilsson L . Risperidone metabolism in relation to CYP2D6*10 allele in Korean schizophrenic patients. Eur J Clin Pharmacol 2001; 57: 671–675.
Yasui-Furukori N, Mihara K, Kondo T, Kubota T, Iga T, Takarada Y et al. Effects of CYP2D6 genotypes on plasma concentrations of risperidone and enantiomers of 9-hydroxyrisperidone in Japanese patients with schizophrenia. J Clin Pharmacol 2003; 43: 122–127.
von Bahr C, Movin G, Nordin C, Liden A, Hammarlund Udenaes M, Hedberg A et al. Plasma levels of thioridazine and metabolites are influenced by the debrisoquin hydroxylation phenotype. Clin Pharmacol Ther 1991; 49: 234–240.
Eap CB, Guentert TW, Schaublin Loidl M, Stabl M, Koeb L, Powell K et al. Plasma levels of the enantiomers of thioridazine, thioridazine 2-sulfoxide, thioridazine 2-sulfone, and thioridazine 5-sulfoxide in poor and extensive metabolizers of dextromethorphan and mephenytoin. Clin Pharmacol Ther 1996; 59: 322–331.
Berecz R, de la Rubia A, Dorado P, Fernandez-Salguero P, Dahl ML, Llerena A . Thioridazine steady-state plasma concentrations are influenced by tobacco smoking and CYP2D6, but not by the CYP2C9 genotype. Eur J Clin Pharmacol 2003; 59: 45–50.
Dahl ML, Ekqvist B, Widen J, Bertilsson L . Disposition of the neuroleptic zuclopenthixol cosegregates with the polymorphic hydroxylation of debrisoquine in humans. Acta Psychiatr Scand 1991; 84: 99–102.
Linnet K, Wiborg O . Influence of Cyp2D6 genetic polymorphism on ratios of steady-state serum concentration to dose of the neuroleptic zuclopenthixol. Ther Drug Monit 1996; 18: 629–634.
Jerling M, Dahl ML, Aberg Wistedt A, Liljenberg B, Landell NE, Bertilsson L et al. The CYP2D6 genotype predicts the oral clearance of the neuroleptic agents perphenazine and zuclopenthixol. Clin Pharmacol Ther 1996; 59: 423–428.
Jaanson P, Marandi T, Kiivet RA, Vasar V, Vaan S, Svensson JO et al. Maintenance therapy with zuclopenthixol decanoate: associations between plasma concentrations, neurological side effects and CYP2D6 genotype. Psychopharmacology (Berlin) 2002; 162: 67–73.
Spina E, Birgersson C, von Bahr C, Ericsson O, Mellström B, Steiner E et al. Phenotypic consistency in hydroxylation of desmethylimipramine and debrisoquine in healthy subjects and in human liver microsomes. Clin Pharmacol Ther 1984; 36: 677–682.
Haritos V, Ghabrial H, Ahokas J, Ching M . Role of cytochrome P450 2D6 (CYP2D6) in the stereospecific metabolism of E- and Z-doxepin. Pharmacogenetics 2000; 10: 591–603.
Johansson I, Lundqvist E, Bertilsson L, Dahl ML, Sjoqvist F, Ingelman Sundberg M . Inherited amplification of an active gene in the cytochrome P450 CYP2D locus as a cause of ultrarapid metabolism of debrisoquine. Proc Natl Acad Sci USA 1993; 90: 11825–11829, (see comments).
Lam YW, Gaedigk A, Ereshefsky L, Alfaro CL, Simpson J . CYP2D6 inhibition by selective serotonin reuptake inhibitors: analysis of achievable steady-state plasma concentrations and the effect of ultrarapid metabolism at CYP2D6. Pharmacotherapy 2002; 22: 1001–1006.
Jeppesen U, Gram LF, Vistisen K, Loft S, Poulsen HE, Brosen K . Dose-dependent inhibition of CYP1A2, CYP2C19 and CYP2D6 by citalopram, fluoxetine, fluvoxamine and paroxetine. Eur J Clin Pharmacol 1996; 51: 73–78.
Alfaro CL, Lam YW, Simpson J, Ereshefsky L . CYP2D6 inhibition by fluoxetine, paroxetine, sertraline, and venlafaxine in a crossover study: intraindividual variability and plasma concentration correlations. J Clin Pharmacol 2000; 40: 58–66.
Alfaro CL, Lam YW, Simpson J, Ereshefsky L . CYP2D6 status of extensive metabolizers after multiple-dose fluoxetine, fluvoxamine, paroxetine, or sertraline. J Clin Psychopharmacol 1999; 19: 155–163.
Timmer CJ, Ad Sitsen JM, Delbressine LP . Clinical pharmacokinetics of mirtazapine. Clin Pharmacokinet 2000; 38: 461–474.
Faucette SR, Hawke RL, Lecluyse EL, Shord SS, Yan B, Laethem RM et al. Validation of bupropion hydroxylation as a selective marker of human cytochrome P450 2B6 catalytic activity. Drug Metab Dispos 2000; 28: 1222–1230.
Dostert P, Benedetti MS, Poggesi I . Review of the pharmacokinetics and metabolism of reboxetine, a selective noradrenaline reuptake inhibitor. Eur Neuropsychopharmacol 1997; 7 (Suppl 1): S23–S35, discussion S71–S73.
Otton SV, Ball SE, Cheung SW, Inaba T, Rudolph RL, Sellers EM . Venlafaxine oxidation in vitro is catalysed by CYP2D6. Br J Clin Pharmacol 1996; 41: 149–156.
Kaneko A, Lum JK, Yaviong L, Takahashi N, Ishizaki T, Bertilsson L et al. High and variable frequencies of CYP2C19 mutations: medical consequences of poor drug metabolism in Vanuatu and other Pacific islands. Pharmacogenetics 1999; 9: 581–590.
Shimoda K, Someya T, Yokono A, Morita S, Hirokane G, Takahashi S et al. The impact of CYP2C19 and CYP2D6 genotypes on metabolism of amitriptyline in Japanese psychiatric patients. J Clin Psychopharmacol 2002; 22: 371–378.
Jiang ZP, Shu Y, Chen XP, Huang SL, Zhu RH, Wang W et al. The role of CYP2C19 in amitriptyline N-demethylation in Chinese subjects. Eur J Clin Pharmacol 2002; 58: 109–113.
Yokono A, Morita S, Someya T, Hirokane G, Okawa M, Shimoda K . The effect of CYP2C19 and CYP2D6 genotypes on the metabolism of clomipramine in Japanese psychiatric patients. J Clin Psychopharmacol 2001; 21: 549–555.
Skjelbo E, Brøsen K, Hallas J, Gram LF . The mephenytoin oxidation polymorphism is partially responsible for the N-demethylation of imipramine. Clin Pharmacol Ther 1991; 49: 18–23.
Morinobu S, Tanaka T, Kawakatsu S, Totsuka S, Koyama E, Chiba K et al. Effects of genetic defects in the CYP2C19 gene on the N-demethylation of imipramine, and clinical outcome of imipramine therapy. Psychiatry Clin Neurosci 1997; 51: 253–257.
Koyama E, Tanaka T, Chiba K, Kawakatsu S, Morinobu S, Totsuka S et al. Steady-state plasma concentrations of imipramine and desipramine in relation to S-mephenytoin 4′-hydroxylation status in Japanese depressive patients. J Clin Psychopharmacol 1996; 16: 286–293.
Liu ZQ, Cheng ZN, Huang SL, Chen XP, Ou-Yang DS, Jiang CH et al. Effect of the CYP2C19 oxidation polymorphism on fluoxetine metabolism in Chinese healthy subjects. Br J Clin Pharmacol 2001; 52: 96–99.
Jan MW, ZumBrunnen TL, Kazmi YR, VanDenBerg CM, Desai HD, Weidler DJ et al. Pharmacokinetics of fluvoxamine in relation to CYP2C19 phenotype and genotype. Drug Metabol Drug Interact 2002; 19: 1–11.
Wang JH, Liu ZQ, Wang W, Chen XP, Shu Y, He N et al. Pharmacokinetics of sertraline in relation to genetic polymorphism of CYP2C19. Clin Pharmacol Ther 2001; 70: 42–47.
Kondo T, Tanaka O, Otani K, Mihara K, Tokinaga N, Kaneko S et al. Possible inhibitory effect of diazepam on the metabolism of zotepine, an antipsychotic drug. Psychopharmacology (Berlin) 1996; 127: 311–314.
Kidd RS, Curry TB, Gallagher S, Edeki T, Blaisdell J, Goldstein JA . Identification of a null allele of CYP2C9 in an African-American exhibiting toxicity to phenytoin. Pharmacogenetics 2001; 11: 803–808.
Koyama E, Chiba K, Tani M, Ishizaki T . Identification of human cytochrome P450 isoforms involved in the stereoselective metabolism of mianserin enantiomers. J Pharmacol Exp Ther 1996; 278: 21–30.
Spigset O, Hedenmalm K, Dahl ML, Wiholm BE, Dahlqvist R . Seizures and myoclonus associated with antidepressant treatment: assessment of potential risk factors, including CYP2D6 and CYP2C19 polymorphisms, and treatment with CYP2D6 inhibitors. Acta Psychiatr Scand 1997; 96: 379–384.
Lane HY, Hu OY, Jann MW, Deng HC, Lin HN, Chang WH . Dextromethorphan phenotyping and haloperidol disposition in schizophrenic patients. Psychiatry Res 1997; 69: 105–111.
Spina E, Ancione M, Di Rosa AE, Meduri M, Caputi AP . Polymorphic debrisoquine oxidation and acute neuroleptic-induced adverse effects. Eur J Clin Pharmacol 1992; 42: 347–348.
Meyer JW, Woggon B, Baumann P, Meyer UA . Clinical implications of slow sulphoxidation of thioridazine in a poor metabolizer of the debrisoquine type. Eur J Clin Pharmacol 1990; 39: 613–614, (letter).
Arthur H, Dahl ML, Siwers B, Sjöqvist F . Polymorphic drug metabolism in schizophrenic patients with tardive dyskinesia. J Clin Psychopharmacol 1995; 15: 211–216.
Pollock BG, Mulsant BH, Sweet RA, Rosen J, Altieri LP, Perel JM . Prospective cytochrome P450 phenotyping for neuroleptic treatment in dementia. Psychopharmacol Bull 1995; 31: 327–331.
Scordo MG, Spina E, Romeo P, Dahl ML, Bertilsson L, Johansson I et al. CYP2D6 genotype and antipsychotic-induced extrapyramidal side effects in schizophrenic patients. Eur J Clin Pharmacol 2000; 56: 679–683.
Spina E, Sturiale V, Valvo S, Ancione M, Di Rosa AE, Meduri M et al. Debrisoquine oxidation phenotype and neuroleptic-induced dystonic reactions. Acta Psychiatr Scand 1992; 86: 364–366.
Vandel P, Haffen E, Vandel S, Bonin B, Nezelof S, Sechter D et al. Drug extrapyramidal side effects. CYP2D6 genotypes and phenotypes. Eur J Clin Pharmacol 1999; 55: 659–665.
Schillevoort I, de Boer A, van der Weide J, Steijns LS, Roos RA, Jansen PA et al. Antipsychotic-induced extrapyramidal syndromes and cytochrome P450 2D6 genotype: a case–control study. Pharmacogenetics 2002; 12: 235–240.
Armstrong M, Daly AK, Blennerhassett R, Ferrier N, Idle JR . Antipsychotic drug-induced movement disorders in schizophrenics in relation to CYP2D6 genotype. Br J Psychiatry 1997; 170: 23–26.
Andreassen OA, MacEwan T, Gulbrandsen AK, McCreadie RG, Steen VM . Non-functional CYP2D6 alleles and risk for neuroleptic-induced movement disorders in schizophrenic patients. Psychopharmacology (Berlin) 1997; 131: 174–179.
Chen S, Chou WH, Blouin RA, Mao Z, Humphries LL, Meek QC et al. The cytochrome P450 2D6 (CYP2D6) enzyme polymorphism: screening costs and influence on clinical outcomes in psychiatry. Clin Pharmacol Ther 1996; 60: 522–534.
Chou WH, Yan FX, de Leon J, Barnhill J, Rogers T, Cronin M et al. Extension of a pilot study: impact from the cytochrome P450 2D6 polymorphism on outcome and costs associated with severe mental illness. J Clin Psychopharmacol 2000; 20: 246–251.
Kirchheiner J, Sasse J, Meineke I, Roots I, Brockmöller J . Trimipramine pharmacokinetics after intravenous and oral administration in carriers of CYP2D6 genotypes predicting poor, extensive and ultra-high activity. Pharmacogenetics 2003; 13: 721–728.
Minov C, Baghai TC, Schule C, Zwanzger P, Schwarz MJ, Zill P et al. Serotonin-2A-receptor and -transporter polymorphisms: lack of association in patients with major depression. Neurosci Lett 2001; 303: 119–122.
Cusin C, Serretti A, Zanardi R, Lattuada E, Rossini D, Lilli R et al. Influence of monoamine oxidase A and serotonin receptor 2A polymorphisms in SSRI antidepressant activity. Int J Neuropsychopharmacol 2002; 5: 27–35.
Sato K, Yoshida K, Takahashi H, Ito K, Kamata M, Higuchi H et al. Association between −1438G/A promoter polymorphism in the 5-HT(2A) receptor gene and fluvoxamine response in Japanese patients with major depressive disorder. Neuropsychobiology 2002; 46: 136–140.
Wu WH, Huo SJ, Cheng CY, Hong CJ, Tsai SJ . Association study of the 5-HT(6) receptor polymorphism (C267T) and symptomatology and antidepressant response in major depressive disorders. Neuropsychobiology 2001; 44: 172–175.
Ito K, Yoshida K, Sato K, Takahashi H, Kamata M, Higuchi H et al. A variable number of tandem repeats in the serotonin transporter gene does not affect the antidepressant response to fluvoxamine. Psychiatry Res 2002; 111: 235–239.
Kim DK, Lim SW, Lee S, Sohn SE, Kim S, Hahn CG et al. Serotonin transporter gene polymorphism and antidepressant response. Neuroreport 2000; 11: 215–219.
Whale R, Quested DJ, Laver D, Harrison PJ, Cowen PJ . Serotonin transporter (5-HTT) promoter genotype may influence the prolactin response to clomipramine. Psychopharmacology (Berlin) 2000; 150: 120–122.
Reist C, Mazzanti C, Vu R, Tran D, Goldman D . Serotonin transporter promoter polymorphism is associated with attenuated prolactin response to fenfluramine. Am J Med Genet 2001; 105: 363–368.
Rausch JL, Johnson ME, Fei YJ, Li JQ, Shendarkar N, Hobby HM et al. Initial conditions of serotonin transporter kinetics and genotype: influence on SSRI treatment trial outcome. Biol Psychiatry 2002; 51: 723–732.
Yu YW, Tsai SJ, Chen TJ, Lin CH, Hong CJ . Association study of the serotonin transporter promoter polymorphism and symptomatology and antidepressant response in major depressive disorders. Mol Psychiatry 2002; 7: 1115–1119.
Yoshida K, Ito K, Sato K, Takahashi H, Kamata M, Higuchi H et al. Influence of the serotonin transporter gene-linked polymorphic region on the antidepressant response to fluvoxamine in Japanese depressed patients. Prog Neuropsychopharmacol Biol Psychiatry 2002; 26: 383–386.
Smeraldi E, Zanardi R, Benedetti F, Di Bella D, Perez J, Catalano M . Polymorphism within the promoter of the serotonin transporter gene and antidepressant efficacy of fluvoxamine. Mol Psychiatry 1998; 3: 508–511.
Zanardi R, Serretti A, Rossini D, Franchini L, Cusin C, Lattuada E et al. Factors affecting fluvoxamine antidepressant activity: influence of pindolol and 5-HTTLPR in delusional and nondelusional depression. Biol Psychiatry 2001; 50: 323–330.
Pollock BG, Ferrell RE, Mulsant BH, Mazumdar S, Miller M, Sweet RA et al. Allelic variation in the serotonin transporter promoter affects onset of paroxetine treatment response in late-life depression. Neuropsychopharmacology 2000; 23: 587–590.
Zanardi R, Benedetti F, Di Bella D, Catalano M, Smeraldi E . Efficacy of paroxetine in depression is influenced by a functional polymorphism within the promoter of the serotonin transporter gene. J Clin Psychopharmacol 2000; 20: 105–107.
Benedetti F, Serretti A, Colombo C, Campori E, Barbini B, di Bella D et al. Influence of a functional polymorphism within the promoter of the serotonin transporter gene on the effects of total sleep deprivation in bipolar depression. Am J Psychiatry 1999; 156: 1450–1452.
Baghai TC, Schule C, Zwanzger P, Minov C, Schwarz MJ, de Jonge S et al. Possible influence of the insertion/deletion polymorphism in the angiotensin I-converting enzyme gene on therapeutic outcome in affective disorders. Mol Psychiatry 2001; 6: 258–259.
Hong CJ, Wang YC, Tsai SJ . Association study of angiotensin I-converting enzyme polymorphism and symptomatology and antidepressant response in major depressive disorders. J Neural Transm 2002; 109: 1209–1214.
Serretti A, Zanardi R, Cusin C, Rossini D, Lilli R, Lorenzi C et al. No association between dopamine D(2) and D(4) receptor gene variants and antidepressant activity of two selective serotonin reuptake inhibitors. Psychiatry Res 2001; 104: 195–203.
Schumann G, Benedetti F, Voderholzer U, Kammerer N, Hemmeter U, Travers HW et al. Antidepressive response to sleep deprivation in unipolar depression is not associated with dopamine D3 receptor genotype. Neuropsychobiology 2001; 43: 127–130.
Serretti A, Benedetti F, Colombo C, Lilli R, Lorenzi C, Smeraldi E . Dopamine receptor D4 is not associated with antidepressant activity of sleep deprivation. Psychiatry Res 1999; 89: 107–114.
Zill P, Baghai TC, Zwanzger P, Schule C, Minov C, Behrens S et al. Association analysis of a polymorphism in the G-protein stimulatory alpha subunit in patients with major depression. Am J Med Genet 2002; 114: 530–532.
Zill P, Baghai TC, Zwanzger P, Schule C, Minov C, Riedel M et al. Evidence for an association between a G-protein beta3-gene variant with depression and response to antidepressant treatment. Neuroreport 2000; 11: 1893–1897.
Serretti A, Lorenzi C, Cusin C, Zanardi R, Lattuada E, Rossini D et al. SSRIs antidepressant activity is influenced by G beta 3 variants. Eur Neuropsychopharmacol 2003; 13: 117–122.
Yoshida K, Naito S, Takahashi H, Sato K, Ito K, Kamata M et al. Monoamine oxidase: a gene polymorphism, tryptophan hydroxylase gene polymorphism and antidepressant response to fluvoxamine in Japanese patients with major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry 2002; 26: 1279–1283.
Serretti A, Zanardi R, Rossini D, Cusin C, Lilli R, Smeraldi E . Influence of tryptophan hydroxylase and serotonin transporter genes on fluvoxamine antidepressant activity. Mol Psychiatry 2001; 6: 586–592.
Serretti A, Zanardi R, Cusin C, Rossini D, Lorenzi C, Smeraldi E . Tryptophan hydroxylase gene associated with paroxetine antidepressant activity. Eur Neuropsychopharmacol 2001; 11: 375–380.
Yu YW, Chen TJ, Wang YC, Liou YJ, Hong CJ, Tsai SJ . Association analysis for neuronal nitric oxide synthase gene polymorphism with major depression and fluoxetine response. Neuropsychobiology 2003; 47: 137–140.
Zill P, Baghai TC, Engel R, Zwanzger P, Schule C, Minov C et al. Beta-1-adrenergic receptor gene in major depression: influence on antidepressant treatment response. Am J Med Genet 2003; 120B: 85–89.
Yu YW, Chen TJ, Hong CJ, Chen HM, Tsai SJ . Association study of the interleukin-1 beta (C-511T) genetic polymorphism with major depressive disorder, associated symptomatology, and antidepressant response. Neuropsychopharmacology 2003; 28: 1182–1185.
Tsai SJ, Cheng CY, Yu YW, Chen TJ, Hong CJ . Association study of a brain-derived neurotrophic-factor genetic polymorphism and major depressive disorders, symptomatology, and antidepressant response. Am J Med Genet 2003; 123B: 19–22.
Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 1996; 274: 1527–1531.
Heils A, Teufel A, Petri S, Stober G, Riederer P, Bengel D et al. Allelic variation of human serotonin transporter gene expression. J Neurochem 1996; 66: 2621–2624.
Ozdemir V, Kalow W, Okey AB, Lam MS, Albers LJ, Reist C et al. Treatment-resistance to clozapine in association with ultrarapid CYP1A2 activity and the C → A polymorphism in intron 1 of the CYP1A2 gene: effect of grapefruit juice and low-dose fluvoxamine. J Clin Psychopharmacol 2001; 21: 603–607.
Kunugi H, Hattori M, Kato T, Tatsumi M, Sakai T, Sasaki T et al. Serotonin transporter gene polymorphisms: ethnic difference and possible association with bipolar affective disorder. Mol Psychiatry 1997; 2: 457–462.
MacKenzie A, Quinn J . A serotonin transporter gene intron 2 polymorphic region, correlated with affective disorders, has allele-dependent differential enhancer-like properties in the mouse embryo. Proc Natl Acad Sci USA 1999; 96: 15251–15255.
Mundo E, Walker M, Cate T, Macciardi F, Kennedy JL . The role of serotonin transporter protein gene in antidepressant-induced mania in bipolar disorder: preliminary findings. Arch Gen Psychiatry 2001; 58: 539–544.
Takahashi H, Yoshida K, Ito K, Sato K, Kamata M, Higuchi H et al. No association between the serotonergic polymorphisms and incidence of nausea induced by fluvoxamine treatment. Eur Neuropsychopharmacol 2002; 12: 477–481.
Perlis RH, Mischoulon D, Smoller JW, Wan YJ, Lamon-Fava S, Lin KM et al. Serotonin transporter polymorphisms and adverse effects with fluoxetine treatment. Biol Psychiatry 2003; 54: 879–883.
Kaiser R, Tremblay PB, Schmider J, Henneken M, Dettling M, Muller-Oerlinghausen B et al. Serotonin transporter polymorphisms: no association with response to antipsychotic treatment, but associations with the schizoparanoid and residual subtypes of schizophrenia. Mol Psychiatry 2001; 6: 179–185.
Chong SA, Tan EC, Tan CH, Mahendren R, Tay AH, Chua HC . Tardive dyskinesia is not associated with the serotonin gene polymorphism (5-HTTLPR) in Chinese. Am J Med Genet 2000; 96: 712–715.
Hong CJ, Lin CH, Yu YW, Yang KH, Tsai SJ . Genetic variants of the serotonin system and weight change during clozapine treatment. Pharmacogenetics 2001; 11: 265–268.
Maj J, Bijak M, Dziedzicka-Wasylewska M, Rogoz R, Rogoz Z, Skuza G et al. The effects of paroxetine given repeatedly on the 5-HT receptor subpopulations in the rat brain. Psychopharmacology (Berlin) 1996; 127: 73–82.
Meyer JH, Kapur S, Eisfeld B, Brown GM, Houle S, DaSilva J et al. The effect of paroxetine on 5-HT(2A) receptors in depression: an [(18)F]setoperone PET imaging study. Am J Psychiatry 2001; 158: 78–85.
Stanley M, Mann JJ . Increased serotonin-2 binding sites in frontal cortex of suicide victims. Lancet 1983; 1: 214–216.
Sternbach H . The serotonin syndrome. Am J Psychiatry 1991; 148: 705–713.
Meltzer HY . Action of atypical antipsychotics. Am J Psychiatry 2002; 159: 153–154, author reply 154–155.
Bolonna AA, Arranz MJ, Munro J, Osborne S, Petouni M, Martinez M et al. No influence of adrenergic receptor polymorphisms on schizophrenia and antipsychotic response. Neurosci Lett 2000; 280: 65–68.
Tsai SJ, Wang YC, Yu Younger WY, Lin CH, Yang KH, Hong CJ . Association analysis of polymorphism in the promoter region of the alpha2a-adrenoceptor gene with schizophrenia and clozapine response. Schizophr Res 2001; 49: 53–58.
Potkin SG, Basile VS, Jin Y, Masellis M, Badri F, Keator D et al. D1 receptor alleles predict PET metabolic correlates of clinical response to clozapine. Mol Psychiatry 2003; 8: 109–113.
Arranz MJ, Li T, Munro J, Liu X, Murray R, Collier DA et al. Lack of association between a polymorphism in the promoter region of the dopamine-2 receptor gene and clozapine response. Pharmacogenetics 1998; 8: 481–484.
Scharfetter J, Chaudhry HR, Hornik K, Fuchs K, Sieghart W, Kasper S et al. Dopamine D3 receptor gene polymorphism and response to clozapine in schizophrenic Pakistani patients. Eur Neuropsychopharmacol 1999; 10: 17–20.
Malhotra AK, Goldman D, Buchanan RW, Rooney W, Clifton A, Kosmidis MH et al. The dopamine D3 receptor (DRD3) Ser9Gly polymorphism and schizophrenia: a haplotype relative risk study and association with clozapine response. Mol Psychiatry 1998; 3: 72–75.
Shaikh S, Collier DA, Sham PC, Ball D, Aitchison K, Vallada H et al. Allelic association between a Ser-9-Gly polymorphism in the dopamine D3 receptor gene and schizophrenia. Hum Genet 1996; 97: 714–719.
Kohn Y, Ebstein RP, Heresco-Levy U, Shapira B, Nemanov L, Gritsenko I et al. Dopamine D4 receptor gene polymorphisms: relation to ethnicity, no association with schizophrenia and response to clozapine in Israeli subjects. Eur Neuropsychopharmacol 1997; 7: 39–43.
Rietschel M, Naber D, Oberlander H, Holzbach R, Fimmers R, Eggermann K et al. Efficacy and side-effects of clozapine: testing for association with allelic variation in the dopamine D4 receptor gene. Neuropsychopharmacology 1996; 15: 491–496.
Rao PA, Pickar D, Gejman PV, Ram A, Gershon ES, Gelernter J . Allelic variation in the D4 dopamine receptor (DRD4) gene does not predict response to clozapine. Arch Gen Psychiatry 1994; 51: 912–917.
Shaikh S, Collier DA, Sham P, Pilowsky L, Sharma T, Lin LK et al. Analysis of clozapine response and polymorphisms of the dopamine D4 receptor gene (DRD4) in schizophrenic patients. Am J Med Genet 1995; 60: 541–545.
Shaikh S, Collier D, Kerwin RW, Pilowsky LS, Gill M, Xu WM et al. Dopamine D4 receptor subtypes and response to clozapine. Lancet 1993; 341: 116.
Tsai SJ, Hong CJ, Yu YW, Lin CH, Song HL, Lai HC et al. Association study of a functional serotonin transporter gene polymorphism with schizophrenia, psychopathology and clozapine response. Schizophr Res 2000; 44: 177–181.
Masellis M, Basile V, Meltzer HY, Lieberman JA, Sevy S, Macciardi FM et al. Serotonin subtype 2 receptor genes and clinical response to clozapine in schizophrenia patients. Neuropsychopharmacology 1998; 19: 123–132.
Arranz MJ, Munro J, Owen MJ, Spurlock G, Sham PC, Zhao J et al. Evidence for association between polymorphisms in the promoter and coding regions of the 5-HT2A receptor gene and response to clozapine. Mol Psychiatry 1998; 3: 61–66.
Malhotra AK, Goldman D, Ozaki N, Breier A, Buchanan R, Pickar D . Lack of association between polymorphisms in the 5-HT2A receptor gene and the antipsychotic response to clozapine. Am J Psychiatry 1996; 153: 1092–1094.
Arranz MJ, Collier DA, Munro J, Sham P, Kirov G, Sodhi M et al. Analysis of a structural polymorphism in the 5-HT2A receptor and clinical response to clozapine. Neurosci Lett 1996; 217: 177–178.
Nöthen MM, Rietschel M, Erdmann J, Oberlander H, Moller HJ, Nober D et al. Genetic variation of the 5-HT2A receptor and response to clozapine. Lancet 1995; 346: 908–909.
Schumacher J, Schulze TG, Wienker TF, Rietschel M, Nöthen MM . Pharmacogenetics of the clozapine response. Lancet 2000; 356: 506–507.
Lin CH, Tsai SJ, Yu YW, Song HL, Tu PC, Sim CB et al. No evidence for association of serotonin-2A receptor variant (102T/C) with schizophrenia or clozapine response in a Chinese population. Neuroreport 1999; 10: 57–60.
Arranz M, Collier D, Sodhi M, Ball D, Roberts G, Price J et al. Association between clozapine response and allelic variation in 5-HT2A receptor gene. Lancet 1995; 346: 281–282.
Masellis M, Paterson AD, Badri F, Lieberman JA, Meltzer HY, Cavazzoni P et al. Genetic variation of 5-HT2A receptor and response to clozapine. Lancet 1995; 346: 1108.
Sodhi MS, Arranz MJ, Curtis D, Ball DM, Sham P, Roberts GW et al. Association between clozapine response and allelic variation in the 5-HT2C receptor gene. Neuroreport 1995; 7: 169–172.
Malhotra AK, Goldman D, Ozaki N, Rooney W, Clifton A, Buchanan RW et al. Clozapine response and the 5HT2C Cys23Ser polymorphism. Neuroreport 1996; 7: 2100–2102.
Rietschel M, Naber D, Fimmers R, Moller HJ, Propping P, Nöthen MM . Efficacy and side-effects of clozapine not associated with variation in the 5-HT2C receptor. Neuroreport 1997; 8: 1999–2003.
Gutierrez B, Arranz MJ, Huezo-Diaz P, Dempster D, Matthiasson P, Travis M et al. Novel mutations in 5-HT3A and 5-HT3B receptor genes not associated with clozapine response. Schizophr Res 2002; 58: 93–97.
Birkett JT, Arranz MJ, Munro J, Osbourn S, Kerwin RW, Collier DA . Association analysis of the 5-HT5A gene in depression, psychosis and antipsychotic response. Neuroreport 2000; 11: 2017–2020.
Yu YW, Tsai SJ, Lin CH, Hsu CP, Yang KH, Hong CJ . Serotonin-6 receptor variant (C267T) and clinical response to clozapine. Neuroreport 1999; 10: 1231–1233.
Masellis M, Basile VS, Meltzer HY, Lieberman JA, Sevy S, Goldman DA et al. Lack of association between the T → C 267 serotonin 5-HT6 receptor gene (HTR6) polymorphism and prediction of response to clozapine in schizophrenia. Schizophr Res 2001; 47: 49–58.
Mancama D, Arranz MJ, Munro J, Osborne S, Makoff A, Collier D et al. Investigation of promoter variants of the histamine 1 and 2 receptors in schizophrenia and clozapine response. Neurosci Lett 2002; 333: 207–211.
Hong CJ, Yu YW, Lin CH, Cheng CY, Tsai SJ . Association analysis for NMDA receptor subunit 2B (GRIN2B) genetic variants and psychopathology and clozapine response in schizophrenia. Psychiatr Genet 2001; 11: 219–222.
Hong CJ, Yu YW, Lin CH, Tsai SJ . An association study of a brain-derived neurotrophic factor Val66Met polymorphism and clozapine response of schizophrenic patients. Neurosci Lett 2003; 349: 206–208.
Hong CJ, Yu YW, Lin CH, Song HL, Lai HC, Yang KH et al. Association study of apolipoprotein E epsilon4 with clinical phenotype and clozapine response in schizophrenia. Neuropsychobiology 2000; 42: 172–174.
Nimgaonkar VL, Zhang XR, Brar JS, DeLeo M, Ganguli R . 5-HT2 receptor gene locus: association with schizophrenia or treatment response not detected. Psychiatr Genet 1996; 6: 23–27.
Jonsson E, Nöthen MM, Bunzel R, Propping P, Sedvall G . 5HT 2a receptor T102C polymorphism and schizophrenia. Lancet 1996; 347: 1831.
Chen CH, Wei FC, Koong FJ, Hsiao KJ . Association of TaqI A polymorphism of dopamine D2 receptor gene and tardive dyskinesia in schizophrenia. Biol Psychiatry 1997; 41: 827–829.
Hori H, Ohmori O, Shinkai T, Kojima H, Nakamura J . Association between three functional polymorphisms of dopamine D2 receptor gene and tardive dyskinesia in schizophrenia. Am J Med Genet 2001; 105: 774–778.
Chong SA, Tan EC, Tan CH, Mythily, Chan YH . Polymorphisms of dopamine receptors and tardive dyskinesia among Chinese patients with schizophrenia. Am J Med Genet 2003; 116: 51–54.
Kaiser R, Tremblay PB, Klufmoller F, Roots I, Brockmöller J . Relationship between adverse effects of antipsychotic treatment and dopamine D(2) receptor polymorphisms in patients with schizophrenia. Mol Psychiatry 2002; 7: 695–705.
Lovlie R, Daly AK, Blennerhassett R, Ferrier N, Steen VM . Homozygosity for the Gly-9 variant of the dopamine D3 receptor and risk for tardive dyskinesia in schizophrenic patients. Int J Neuropsychopharmacol 2000; 3: 61–65.
Basile VS, Masellis M, Badri F, Paterson AD, Meltzer HY, Lieberman JA et al. Association of the MscI polymorphism of the dopamine D3 receptor gene with tardive dyskinesia in schizophrenia. Neuropsychopharmacology 1999; 21: 17–27.
Rietschel M, Krauss H, Muller DJ, Schulze TG, Knapp M, Marwinski K et al. Dopamine D3 receptor variant and tardive dyskinesia. Eur Arch Psychiatry Clin Neurosci 2000; 250: 31–35.
Steen VM, Lovlie R, MacEwan T, McCreadie RG . Dopamine D3-receptor gene variant and susceptibility to tardive dyskinesia in schizophrenic patients. Mol Psychiatry 1997; 2: 139–145.
Garcia-Barcelo MM, Lam LC, Ungvari GS, Lam VK, Tang WK . Dopamine D3 receptor gene and tardive dyskinesia in Chinese schizophrenic patients. J Neural Transm 2001; 108: 671–677.
Liao DL, Yeh YC, Chen HM, Chen H, Hong CJ, Tsai SJ . Association between the Ser9Gly polymorphism of the dopamine D3 receptor gene and tardive dyskinesia in Chinese schizophrenic patients. Neuropsychobiology 2001; 44: 95–98.
Lerer B, Segman RH, Fangerau H, Daly AK, Basile VS, Cavallaro R et al. Pharmacogenetics of tardive dyskinesia: combined analysis of 780 patients supports association with dopamine D3 receptor gene Ser9Gly polymorphism. Neuropsychopharmacology 2002; 27: 105–119.
Segman R, Neeman T, Heresco-Levy U, Finkel B, Karagichev L, Schlafman M et al. Genotypic association between the dopamine D3 receptor and tardive dyskinesia in chronic schizophrenia. Mol Psychiatry 1999; 4: 247–253.
Woo SI, Kim JW, Rha E, Han SH, Hahn KH, Park CS et al. Association of the Ser9Gly polymorphism in the dopamine D3 receptor gene with tardive dyskinesia in Korean schizophrenics. Psychiatry Clin Neurosci 2002; 56: 469–474.
Zhang ZJ, Zhang XB, Hou G, Yao H, Reynolds GP . Interaction between polymorphisms of the dopamine D3 receptor and manganese superoxide dismutase genes in susceptibility to tardive dyskinesia. Psychiatr Genet 2003; 13: 187–192.
Segman RH, Heresco-Levy U, Yakir A, Goltser T, Strous R, Greenberg DA et al. Interactive effect of cytochrome P450 17alpha-hydroxylase and dopamine D3 receptor gene polymorphisms on abnormal involuntary movements in chronic schizophrenia. Biol Psychiatry 2002; 51: 261–263.
Basile VS, Ozdemir V, Masellis M, Meltzer HY, Lieberman JA, Potkin SG et al. Lack of association between serotonin-2A receptor gene (HTR2A) polymorphisms and tardive dyskinesia in schizophrenia. Mol Psychiatry 2001; 6: 230–234.
Tan EC, Chong SA, Mahendran R, Dong F, Tan CH . Susceptibility to neuroleptic-induced tardive dyskinesia and the T102C polymorphism in the serotonin type 2A receptor. Biol Psychiatry 2001; 50: 144–147.
Segman RH, Heresco-Levy U, Finkel B, Goltser T, Shalem R, Schlafman M et al. Association between the serotonin 2A receptor gene and tardive dyskinesia in chronic schizophrenia. Mol Psychiatry 2001; 6: 225–229.
Zhang ZJ, Zhang XB, Sha WW, Reynolds GP . Association of a polymorphism in the promoter region of the serotonin 5-HT2C receptor gene with tardive dyskinesia in patients with schizophrenia. Mol Psychiatry 2002; 7: 670–671.
Segman RH, Heresco-Levy U, Finkel B, Inbar R, Neeman T, Schlafman M et al. Association between the serotonin 2C receptor gene and tardive dyskinesia in chronic schizophrenia: additive contribution of 5-HT2Cser and DRD3gly alleles to susceptibility. Psychopharmacology (Berlin) 2000; 152: 408–413.
Ohmori O, Shinkai T, Hori H, Nakamura J . Genetic association analysis of 5-HT(6) receptor gene polymorphism (267C/T) with tardive dyskinesia. Psychiatry Res 2002; 110: 97–102.
Segman RH, Shapira Y, Modai I, Hamdan A, Zislin J, Heresco-Levy U et al. Angiotensin converting enzyme gene insertion/deletion polymorphism: case-control association studies in schizophrenia, major affective disorder, and tardive dyskinesia and a family-based association study in schizophrenia. Am J Med Genet 2002; 114: 310–314.
Ohmori O, Shinkai T, Hori H, Kojima H, Nakamura J . Polymorphisms of mu and delta opioid receptor genes and tardive dyskinesia in patients with schizophrenia. Schizophr Res 2001; 52: 137–138.
Hori H, Ohmori O, Shinkai T, Kojima H, Okano C, Suzuki T et al. Manganese superoxide dismutase gene polymorphism and schizophrenia: relation to tardive dyskinesia. Neuropsychopharmacology 2000; 23: 170–177.
Zhang Z, Zhang X, Hou G, Sha W, Reynolds GP . The increased activity of plasma manganese superoxide dismutase in tardive dyskinesia is unrelated to the Ala-9Val polymorphism. J Psychiatr Res 2002; 36: 317–324.
Lai IC, Liao DL, Bai YM, Lin CC, Yu SC, Chen JY et al. Association study of the estrogen receptor polymorphisms with tardive dyskinesia in schizophrenia. Neuropsychobiology 2002; 46: 173–175.
Hong CJ, Lin CH, Yu YW, Chang SC, Wang SY, Tsai SJ . Genetic variant of the histamine-1 receptor (glu349asp) and body weight change during clozapine treatment. Psychiatr Genet 2002; 12: 169–171.
Tsai SJ, Hong CJ, Yu YW, Lin CH . −759C/T genetic variation of 5HT(2C) receptor and clozapine-induced weight gain. Lancet 2002; 360: 1790.
Reynolds GP, Zhang Z, Zhang X . Polymorphism of the promoter region of the serotonin 5-HT(2C) receptor gene and clozapine-induced weight gain. Am J Psychiatry 2003; 160: 677–679.
Reynolds GP, Zhang ZJ, Zhang XB . Association of antipsychotic drug-induced weight gain with a 5-HT2C receptor gene polymorphism. Lancet 2002; 359: 2086–2087.
Eichhammer P, Albus M, Borrmann-Hassenbach M, Schoeler A, Putzhammer A, Frick U et al. Association of dopamine D3-receptor gene variants with neuroleptic induced akathisia in schizophrenic patients: a generalization of Steen's study on DRD3 and tardive dyskinesia. Am J Med Genet 2000; 96: 187–191.
Murphy Jr GM, Kremer C, Rodrigues HE, Schatzberg AF . Pharmacogenetics of antidepressant medication intolerance. Am J Psychiatry 2003; 160: 1830–1835.
Suzuki A, Kondo T, Otani K, Mihara K, Yasui-Furukori N, Sano A et al. Association of the TaqI A polymorphism of the dopamine D(2) receptor gene with predisposition to neuroleptic malignant syndrome. Am J Psychiatry 2001; 158: 1714–1716.
Kishida I, Kawanishi C, Furuno T, Matsumura T, Hasegawa H, Sugiyama N et al. Lack of association in Japanese patients between neuroleptic malignant syndrome and the TaqI A polymorphism of the dopamine D2 receptor gene. Psychiatr Genet 2003; 13: 55–57.
Mihara K, Kondo T, Suzuki A, Yasui-Furukori N, Ono S, Sano A et al. Relationship between functional dopamine D2 and D3 receptors gene polymorphisms and neuroleptic malignant syndrome. Am J Med Genet 2003; 117B: 57–60.
Kawanishi C, Hanihara T, Shimoda Y, Suzuki K, Sugiyama N, Onishi H et al. Lack of association between neuroleptic malignant syndrome and polymorphisms in the 5-HT1A and 5-HT2A receptor genes. Am J Psychiatry 1998; 155: 1275–1277.
Rybakowski JK, Borkowska A, Czerski PM, Hauser J . Eye movement disturbances in schizophrenia and a polymorphism of catechol-O-methyltransferase gene. Psychiatry Res 2002; 113: 49–57.
Rybakowski JK, Borkowska A, Czerski PM, Hauser J . Dopamine D3 receptor (DRD3) gene polymorphism is associated with the intensity of eye movement disturbances in schizophrenic patients and healthy subjects. Mol Psychiatry 2001; 6: 718–724.
Jonsson EG, Goldman D, Spurlock G, Gustavsson JP, Nielsen DA, Linnoila M et al. Tryptophan hydroxylase and catechol-O-methyltransferase gene polymorphisms: relationships to monoamine metabolite concentrations in CSF of healthy volunteers. Eur Arch Psychiatry Clin Neurosci 1997; 247: 297–302.
Walther DJ, Peter JU, Bashammakh S, Hortnagl H, Voits M, Fink H et al. Synthesis of serotonin by a second tryptophan hydroxylase isoform. Science 2003; 299: 76.
Yu AM, Idle JR, Byrd LG, Krausz KW, Kupfer A, Gonzalez FJ . Regeneration of serotonin from 5-methoxytryptamine by polymorphic human CYP2D6. Pharmacogenetics 2003; 13: 173–181.
Scharfetter J . Dopamine receptor polymorphisms and drug response in schizophrenia. Pharmacogenomics 2001; 2: 251–261.
Wong AH, Buckle CE, Van Tol HH . Polymorphisms in dopamine receptors: what do they tell us? Eur J Pharmacol 2000; 410: 183–203.
Nothen MM, Cichon S, Hemmer S, Hebebrand J, Remschmidt H, Lehmkuhl G et al. Human dopamine D4 receptor gene: frequent occurrence of a null allele and observation of homozygosity. Hum Mol Genet 1994; 3: 2207–2212.
Noble EP, Gottschalk LA, Fallon JH, Ritchie TL, Wu JC . D2 dopamine receptor polymorphism and brain regional glucose metabolism. Am J Med Genet 1997; 74: 162–166.
Pohjalainen T, Rinne JO, Nagren K, Lehikoinen P, Anttila K, Syvalahti EK et al. The A1 allele of the human D2 dopamine receptor gene predicts low D2 receptor availability in healthy volunteers. Mol Psychiatry 1998; 3: 256–260.
Cravchik A, Sibley DR, Gejman PV . Analysis of neuroleptic binding affinities and potencies for the different human D2 dopamine receptor missense variants. Pharmacogenetics 1999; 9: 17–23.
Ohara K, Nagai M, Tani K, Nakamura Y, Ino A . Functional polymorphism of −141C Ins/Del in the dopamine D2 receptor gene promoter and schizophrenia. Psychiatry Res 1998; 81: 117–123.
Ebstein RP, Macciardi F, Heresco-Levi U, Serretti A, Blaine D, Verga M et al. Evidence for an association between the dopamine D3 receptor gene DRD3 and schizophrenia. Hum Hered 1997; 47: 6–16.
Cohen BM, Ennulat DJ, Centorrino F, Matthysse S, Konieczna H, Chu HM et al. Polymorphisms of the dopamine D4 receptor and response to antipsychotic drugs. Psychopharmacology (Berlin) 1999; 141: 6–10.
Jonsson E, Lannfelt L, Sokoloff P, Schwartz JC, Sedvall G . Lack of association between schizophrenia and alleles in the dopamine D3 receptor gene. Acta Psychiatr Scand 1993; 87: 345–349.
Kaiser R, Konneker M, Henneken M, Dettling M, Muller-Oerlinghausen B, Roots I et al. Dopamine D4 receptor 48-bp repeat polymorphism: no association with response to antipsychotic treatment, but association with catatonic schizophrenia. Mol Psychiatry 2000; 5: 418–424.
Leszczynska-Rodziewicz A, Czerski PM, Kapelski P, Godlewski S, Dmitrzak-Weglarz M, Rybakowski J et al. A polymorphism of the norepinephrine transporter gene in bipolar disorder and schizophrenia: lack of association. Neuropsychobiology 2002; 45: 182–185.
Naber CK, Husing J, Wolfhard U, Erbel R, Siffert W . Interaction of the ACE D allele and the GNB3 825T allele in myocardial infarction. Hypertension 2000; 36: 986–989.
Bondy B, Baghai TC, Zill P, Bottlender R, Jaeger M, Minov C et al. Combined action of the ACE D- and the G-protein beta3 T-allele in major depression: a possible link to cardiovascular disease? Mol Psychiatry 2002; 7: 1120–1126.
Manji HK, Quiroz JA, Sporn J, Payne JL, Denicoff K, Gray N et al. Enhancing neuronal plasticity and cellular resilience to develop novel, improved therapeutics for difficult-to-treat depression. Biol Psychiatry 2003; 53: 707–742.
Joober R, Benkelfat C, Lal S, Bloom D, Labelle A, Lalonde P et al. Association between the methylenetetrahydrofolate reductase 677C → T missense mutation and schizophrenia. Mol Psychiatry 2000; 5: 323–326.
Kunugi H, Fukuda R, Hattori M, Kato T, Tatsumi M, Sakai T et al. C677T polymorphism in methylenetetrahydrofolate reductase gene and psychoses. Mol Psychiatry 1998; 3: 435–437.
Lachman HM, Papolos DF, Saito T, Yu YM, Szumlanski CL, Weinshilboum RM . Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics 1996; 6: 243–250.
Sabol SZ, Hu S, Hamer D . A functional polymorphism in the monoamine oxidase A gene promoter. Hum Genet 1998; 103: 273–279.
Illi A, Mattila KM, Kampman O, Anttila S, Roivas M, Lehtimaki T et al. Catechol-O-methyltransferase and monoamine oxidase A genotypes and drug response to conventional neuroleptics in schizophrenia. J Clin Psychopharmacol 2003; 23: 429–434.
Hawi Z, Straub RE, O’Neill A, Kendler KS, Walsh D, Gill M . No linkage or linkage disequilibrium between brain-derived neurotrophic factor (BDNF) dinucleotide repeat polymorphism and schizophrenia in Irish families. Psychiatry Res 1998; 81: 111–116.
Krebs MO, Guillin O, Bourdell MC, Schwartz JC, Olie JP, Poirier MF et al. Brain derived neurotrophic factor (BDNF) gene variants association with age at onset and therapeutic response in schizophrenia. Mol Psychiatry 2000; 5: 558–562.
Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A et al. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 2003; 112: 257–269.
Corrigan FM, MacDonald S, Reynolds GP . Clozapine-induced hypersalivation and the alpha 2 adrenoceptor. Br J Psychiatry 1995; 167: 412.
Witchel HJ, Hancox JC, Nutt DJ . Psychotropic drugs, cardiac arrhythmia, and sudden death. J Clin Psychopharmacol 2003; 23: 58–77.
Yang P, Kanki H, Drolet B, Yang T, Wei J, Viswanathan PC et al. Allelic variants in long-QT disease genes in patients with drug-associated torsades de pointes. Circulation 2002; 105: 1943–1948.
Harrison PJ, Owen MJ . Genes for schizophrenia? Recent findings and their pathophysiological implications. Lancet 2003; 361: 417–419.
Arranz MJ, Munro J, Birkett J, Bolonna A, Mancama D, Sodhi M et al. Pharmacogenetic prediction of clozapine response. Lancet 2000; 355: 1615–1616.
The support for this work has been provided by grants from the German Ministry of Education and Research, BMBF Grant No. 01 GG 9845/5 and from the National Institutes of Health: GM61394, K30HL04526, RR16996, HG002500, RR017611, DK063240, DK58851 (JL), RR017365, MH062777, RR000865 (M-LW), and by awards from the Dana Foundation, Amgen, Inc. (JL), and NARSAD (M-LW).
About this article
Pharmacogenomic Next-Generation DNA Sequencing: Lessons from the Identification and Functional Characterization of Variants of Unknown Significance in CYP2C9 and CYP2C19
Drug Metabolism and Disposition (2019)
International Clinical Psychopharmacology (2019)
Implementation of Pharmacogenetics at Cincinnati Children's Hospital Medical Center: Lessons Learned Over 14 Years of Personalizing Medicine
Clinical Pharmacology & Therapeutics (2019)
Does obtaining CYP2D6 and CYP2C19 pharmacogenetic testing predict antidepressant response or adverse drug reactions?
Psychiatry Research (2019)
Frontiers in Psychiatry (2019)