Pharmacogenetics of antipsychotic and antidepressent

Ismail sadek

pharmacogenetics

Determine the sequence of the 3 billion nucleotides that make up human DNA

Characterize variability in the genomeIdentify all the genes in human DNA

The Era of Genomic Medicine: Improve prediction of drug efficacy or toxicity Improve the diagnosis of diseaseEarlier detection of genetic predisposition to disease

Human Genome Project

DNA is InformationDNA

A, T, G, C

Codon

Gene

Chromosome

Genome

ENGLISH

Abcdefg….xyz

Word

Sentence

Chapter

Book

diagnosistrials and errors

effective treatment

TODAY….

TOMORROW….

tailor made

AgeRace/ethnicityWeightGenderConcomitant DiseasesConcomitant DrugsSocial factorsGENETICS

Factors Contributing to Interindividual Variability in Drug Disposition and Action

PERSONALIZEDMEDICINE

PharmacogeneticsStudy of how genetic differences in a SINGLE gene

influence variability in drug response (i.e., efficacy and toxicity)

PharmacogenomicsStudy of how genetic (genome) differences in

MULTIPLE genes influence variability in drug response (i.e., efficacy and toxicity)

Genetics or Genomics?

HypothesisVariability in response, toxicity and adverse effects

following drug treatment is influenced by genetic variation

AdvantagesGenotyping can be done any timeNot influenced by current treatmentCan be measured very reliablyGenome fully sequencedEasy to do – peripheral blood sample

Pharmacogenetics

"Here's my sequence..."

The New Yorker

Maximize drug efficacyMinimize drug toxicityPredict patients who will respond to interventionAid in new drug development

Goals of Pharmacogen(etics)omics

Mutation: difference in the DNA code that occurs in less than 1% of populationOften associated with rare diseases

Cystic fibrosis, sickle cell anemia, Huntington’s disease

Polymorphism: difference in the DNA code that occurs in more than 1% of the populationA single polymorphism is less likely to be the main

cause of a diseasePolymorphisms often have no visible clinical

impact

The Foundation of Pharmacogenomics: Differences in the Genetic Code Between People

Pronounced “snip”Single base pair difference in the DNA sequence

Over 2 million SNPs in the human genomeOther polymorphisms:

Insertion/deletion polymorphismsGene duplicationsGene deletions

Single Nucleotide Polymorphisms (SNP)

Genetics TerminologyAlleles = different DNA

sequences at a locusCodon 389 1-AR

Arg (0.75)Gly (0.25)

Genotype = pair of alleles a person has at a region of the chromosomeCodon 389 1-AR

Arg389Arg Arg389Gly Gly389Gly

Pharmacogenomics

DRUGTARGETS

DRUGMETABOLIZING

ENZYMES

DRUGTRANSPORTERS

PHARMACOKINETICSPHARMACODYNAMICS

Variability in Efficacy/Toxicity

Evidence of an inherited basis for drug response dates back in the literature to the 1950sSuccinylcholine: 1 in 3000 patients developed

prolonged muscle relaxationMonogenicPhenotype to genotype approach

Drug Metabolism Pharmacogenomics

CYP2D6 is responsible for the metabolism of a number of different drugsAntidepressants, antipsychotics, analgesics, cardiovascular drugs

Over 100 polymorphisms in CYP2D6 have been identifiedBased on these polymorphisms, patients are phenotypically classified

as:Ultrarapid metabolizers (UMs)Extensive metabolizers (EMs)Poor metabolizers (PMs)

CYP2D6 Polymorphisms

Increased rate of adverse effects in poor metabolizers due to increased plasma concentrations of drug:Fluoxetine (Prozac) death in child attributed to CYP2D6 poor

metabolizer genotypeSide effects of antipsychotic drugs occur more frequently in CYP2D6

poor metabolizersCYP2D6 poor metabolizers with severe mental illness had more adverse

drug reactions, increased cost of care, and longer hospital stays

CYP2D6 Polymorphisms and Psychiatric Drug Response

Treatment of attention deficit hyperactivity disorderCYP2D6 poor metabolizers have 10-fold higher

plasma concentrations to a given dose of STRATTERA compared with extensive metabolizers

Approximately 7% of Caucasians are poor metabolizers

Higher blood levels in poor metabolizers may lead to a higher rate of some adverse effects of STRATTERA

Strattera® (Atomoxetine)

Roche AmpliChip: FDA-Approved

The Roche AmpliChip CYP450 Test is intended to identify a patient's CYP2D6 and CYP2C19 genotype from genomic DNA extracted from a whole blood sample.

Information about CYP2D6 and CYP2C19 genotype may be used as an aid to clinicians in determining therapeutic strategy and treatment dose for therapeutics that are metabolized by the CYP2D6 or CYP2C19 gene product.

Roche AmpliChip P450 Test

Drug Target Pharmacogenomics

Direct protein target of drug ReceptorEnzyme

Proteins involved in pharmacologic response Signal transduction proteins or downstream proteins

Polymorphisms associated with disease risk “Disease-modifying” polymorphisms“Treatment-modifying” polymorphisms

POLYGENIC

Drug Target Pharmacogenomics

Complexity of Drug Effect

Depression—Symptom rating scalesIndirect measure of drug responseInter-rater reliability

Hypertension—Blood pressureMinute to minute and diurnal variabilityInfluence of environmental factors (e.g. lack of rest before

measurement)Diabetes—Blood glucose

Diurnal variation in blood glucoseInfluence of environmental factors (e.g. diet/exercise)

Assessing Phenotype in Drug Target Pharmacogenomics

It required a shift in clinician attitude and beliefs “not one dose fits all”

Paucity of studies demonstrating improved clinical benefit from use of pharmacogenomic dataStill much to be learned

Even some of the black block warnings currently on drug labels may be overcalls of importance

Genome wide interrogation will likely be important to get the entire picture

Why is pharmacogenomics not widely utilized in the clinic

Larry Lesko, Director of the FDA Office of Clinical Pharmacology and Biopharmaceutics

“Personalized medicine: elusive dream or imminent reality?

In summary: it is both.”

Pharmacogenetics of antidepressant drugs:

a way towards personalized treatment of major depressive disorder

Despite the enormous progress made in the understanding of the neurobiology of MDD, treatment outcomes have improved only slightly in the past few decades in spite of the broadening of the target spectrum of antidepressants (ADs).

The recent Sequence Treatment Alternatives to Relieve Depression (STAR*D) study indicate that even with systematic measurement-based treatment, only approximately 50% of patients show response to treatment after one treatment trial, and only 30% of patients reach full remission.

There is a significant decrease in remission rate after two failed trials, with only 60% reaching full remission after four treatment trials

The long duration required to conclude treatment success or failure (eight to twelve weeks) can prove to be a difficult and frustrating experience for the patient and the family and may even increase the risk of suicide,

Besides failure to reach remission, relapse rate is also over 40%, especially in patients who did not achieve full remission.

Treatment resistant depression (TRD) is an extremely common problem, affecting a large proportion of all patients suffering from major depressive episodes

Since genetic factors contribute for about 50% of the Adverse response, pharmacogenetic researchers have assumed that in order to minimize disorder duration and re-duce the occurrence of Adverse response it would be useful to be able to predict the pharmacological intervention likely to be effective and tolerable for each patient according to the patient’s specific genetic makeup.

PharmacoKinetics

The cytochrome P450s (CYPs) are members of a superfamily of oxidative enzymes, and act as the major system for phase I oxidative metabolism of approximately 80% of the commonly used therapeu-tic substances

This important endogenous system has received the most attention by pharmacogenetic researchers, leading to the discovery of 58 different human CYP genes with various polymorphisms that affect drug metabolism

Cytochrome P450 enzyme system

The variations of DNA within the coding genes may contribute to excessive metabolism as well as diminished or absent metabolism of a drug, leading to the prolonged presence of a toxic dose or failure to reach therapeutic dose of the given medication.

The clinically most important isoenzymes of he-patic CYPs, regarding AD metabolism, are CYP1A2, CYPC9/19, CYP2D6, CYP3A4 and CYP2B6

The majority of ADs (fluoxetine; fluvoxamine; paroxetine; venlafaxine; mirtazapine; amitriptyline; imipramine; trimipramine; desipramine; nortriptyline) are metabolized primarily by CYP2D6

CYP2D6 is the most researched gene in the field of pharmacogenetics, and more than 100 different alleles were identified which determine the level of activity of the enzyme

According to the number of gene copies inherited, individuals are classified as :poor (PM), intermediate (IM), extensive (EM), or ultrarapid metabolizers (UM).

CYP2D6

A gene x environment effect has been shown concerning the CYP1A2 izoenzyme, in which the presence of an exogenous inducer, tobacco smoke affects transcription and translation and may contribute to an UM phenotype, resulting in an up to 50% reduction in plasma concentration of Ads

Some CYP1A2 polymorphisms (rs4646425; rs2472304; rs2470890) may also influence treatment response to paroxetine

CYP1A2

P-glycoprotein (P-gp) is a member of the ATP-binding cassette superfamily of membrane transport proteins encoded by the ABCB1 gene also known as the multidrug resistance protein 1 (MDR1) gene.

P-glyco-protein 1 is found in various human tissues, including the endothelial cells of the blood-brain barrier (BBB) and is responsible for the efflux of many exogenous and endogenous substances against a concentration gradient influencing antidepressant concentrations in the brain as well.

P-Glycoprotein

Pharmacodynamics

Monoamine transporters Serotonin Transporter (SLC6A4) The human serotonin transporter (5-HTT) gene is potentially involved in mood regulation and the great majority of currently used ADs influences the activity of 5-HTT, making it an ideal candidate for pharmacogenetic studies.

A 44-bp insertion/deletion poly-morphism with 2 allelic forms within the serotonin transporter gene promoter region (5-HTTLPR) that could affect SLC6A4 expression was shown to have functional significance with the long allele (l) associated with two times higher 5-HTT expression in the basal state compared to the s allele according to in vitro studies

Caucasian subjects report that presence of the s allele is associated with lower response and remission

According to the results of a recent GWAS study cer-tain genetic variations of the noradrenalin transporter may be associated with the risk of MDD. In addition, the noradrenalin transporter is the principal site of action of some ADs

Noradrenalin Transporter (SLC6A2)

It is assumed that dopaminergic mechanisms play an important role in AD drug action, since AD drugs, in particular dopamine/norepinephrine reuptake inhibitor bupropion and specific members of SSRIs (mainly sertraline) modulate activity of the dopamine transporter.

A 40-base pair VNTR polymorphism in the SLC6A3 gene, encoding for the dopamine transporter (DAT) has been associated with expression levels of the transporter.

Dopamine Transporter (SLC6A3)

Tryptophan hydroxylaseThe tryptophan hydroxylase (TPH) gene encoding

the rate-limiting enzyme in serotonin synthesis has been studied intensively in psychiatric disorders, yielding mixed results.

Monoamine Metabolic Enzymes

The COMT enzyme is responsible for the inactiva-tion of various catecholamines including dopamine, adrenalin and noradrenalin.

The COMT gene has several allelic variants, including the most extensively studied rs4680 variant.

A functional G to A SNP at codon 158 leading to a Val to Met substitution was identified contributing to a high activity Val/Val, intermediate activity Val/Met, low activity in Met/Met genotype

Catechol-O-Methyltransferase (COMT)

MAO-A is one of the enzymes responsible for the degradation of monoamine neurotransmitters. One polymorphism in the promoter region of the MAO-A gene consisting of a repetitive sequence (VNTR) has been linked to variations in the biological activity and consequentially serotonin concentrations.

Variants with 3.5 or 4 copies of the repeat sequence (“MAO-A High”) are expressed 2-10 times more efficiently than those with 2, 3 or 5 copies of the repeat

Monoamine Oxidase A (MAO-A)

Monoamine receptors are among the most plausible candidates for modulation of AD response, since most ADs act to increase monoamine concentration in the synaptic cleft.

Monoamine Receptors

About 50 known SNPs have been described regarding the 5-HT1A autoreceptor. One of the most intensively investigated functional polymorphism (rs6295; a.k.a. 1019C/G) is in the promoter region of the gene for 5-HT1A receptor (Stahl, 1994). The majority of results suggests an effect of the rs6295 on treatment outcome with several classes of ADs,

5-HT1A

Three important common SNPs of the 5HTR2A gene are 102T/C (rs6313), 1438A/G (rs6311) and 452His/Tyr (rs6314).

Overall, several studies have found that rs6313, rs6311 and rs6314 SNPs are associated with response to AD treatment,

Another genetic variant of the 5HTR2A gene (rs7997012) is also associated with success of AD treatment.

5HT2A

According to our current knowledge, among the different adrenergic receptor subtypes, the β1 and α2a receptors seem to play a role in response to AD treatment

A recently identified functional polymorphism G(1165)C (a.k.a. rs1801253) in the ADRβ1 gene (encoding adrenergic β1 receptor), resulting in the amino acid variation Gly389Arg, has been linked to enhanced coupling to the stimulatory Gs protein and increased adenylate cyclase activation. This SNP might be responsible for faster response to AD treatment

Adrenoreceptors

G Protein β3 subunitThe β3 subunit of the G protein is present in all cells of the body and has a key role in the downstream signaling cascade following monoamine receptor activation.The C825T (a.k.a. rs5443) functional polymorphism is the most

investigated variant within the GNβ3 gene in this field. It was associated with AD treatment response; particularly the T variant seems to predict better AD response.

Intracellular Signal Transduction Pathways

CRH Receptors (CRHR1 and CRHR2)Corticotropin releasing hormone (CRH) is a potent mediator of endocrine, autonomic, behavioral, and immune responses to stress.An association between the rs242941 G/G geno-type and

homozygous GAG haplotype of the 3 SNPs (rs1876828, rs242939, and rs242941) and therapeutic response to fluoxetine

Another study did not find associations between some other variants of CRHR1 gene (rs110402; rs242937) and treatment response to citalopram

Hypothalamic-Pituitary-Adrenal Axis and Stress Hormones

The GENDEP study identified three SNPs (rs852977, rs10482633 and rs10052957) which may predict response to both ADs used in the study (nortriptyline and escitalopram)

Glucocorticoid Receptor (GR)

Despite of expectations fuelled by the role of CREB in the pathogenesis of depression, the role of CREB1 variants in AD response was not verified .

Furthermore, two SNPs (rs4675690; rs7569963) were found to have a role in treatment-emergent suicidal ideation in patients with MDD during citalopram treatment, but only in males, suggesting a significant gene x sex interaction

c-AMP Response-Element Binding protein (CREB)

Chronic stress leads to decreased levels of BDNF in the brain, and serum/plasma BDNF levels of patients with mood disorders are decreased.

Brain-Derived Neurotrophic Factor (BDNF)

Results of the GENDEP study have raised the possibility that that there is an association between rs10835210 variation in the BDNF gene and response to escitalopram and a strong association between rs962369 in the BDNF gene and an increase in suicidal ideation during AD treatment (the same study identified some other suicidality related regions in the BDNF gene

Brain-Derived Neurotrophic Factor (BDNF)

According to results of the STAR*D study an SNP (rs1954787) of the GRIK4 gene encoding kainate receptor subunit 1 (KA1; a.k.a. GluK4) was associated with treatment response to citalopram

Glutamatergic system

Despite the impressive potential of pharmacogenetics and the great progress in the understanding of the pathomechanism of MDD and the genetic influence both on emergence of depression and on response to AD treatment, the use of pharmacogenetics in current clinical practice is still very limited,

Limitations in application of Pharmacogenetic achievements in clinical Practice

in part due to inconsistent results and failure to replicate several associations.

Another problematic issue is the complexity and ultifactorial nature of the genetics underlying psychiatric disorders and medication response. Since the therapeutic mechanism of ADs is not well understood, it is difficult for pharmacogenetic researchers to select “candidate” genes.

Limitations in application of Pharmacogenetic achievements in clinical Practice

PHARMACOGENETICS

OF ANTIPSYCHOATICS

Since chlorpromazine was first introduced into clinical psychiatry, various kinds of antipsychotics have been developed and used for schizophrenia.

Clinicians, however, still have considerable difficulty in choosing an appropriate antipsychotic for certain patients due to the inter-individual diversities of drug response.

Most antipsychotics are extensively metabolized by cytochrome (CYP) P450s that are members of a super-family of oxidative enzymes and that constitute a major system for the oxida-tive metabolism of therapeutic substances.

Pharmacokinetics of antipsychotics

The CYP2D6 has been most extensively investigated in the field of psychiatry, since this enzyme is involved in the metabolism of many antipsychotics and has many genetic polymorphisms that influence the function of the enzyme.

There are more than 70 variant alleles at the CYP2D6 gene locus, including the two most common variants, CYP2D6*4 and CYP2D6*45, encoding non-functional products.1 Other variants that reduce activity, alter substrate specificity or increase activity have also been described

Compared with efficient metabolizers (EM), poor metabolizers (PM) show no or reduced CYP2D6 activity bypolymorphisms resulting in potentially increased concentrations of metabolized drugs.

On the other hand, ultra rapid metabolizers (UM) that can be found in 1% of Caucasians often do not reach therapeutic concentrations and require an increased dose. Pronounced ethnic differences in the prevalence of both PM and UM have been reported; e.g., the frequency of PM is 5 to 10% among Caucasians, about 2% in Asians, and 7–8% in Africans.

PMs have higher plasma concentrations of and suffer more adverse effects from antipsychotics. The incidence of the acute side effects of these drugs, including postural hy-potension, excess sedation, or extrapyramidal symptoms, is disproportionately in PMs.

On the other hand, it is not clear whether the development of chronic side effects such as tardive dyskinesia is associated with a reduced metabolizing capacity of CYP2D6.

Pharmacodynamics of antipsychotics

All receptor and transporter genes for neurotransmitters as well as genes located down-stream of the intracellular signaling pathways can be considered candidate genes for the pharmacodynamics of antipsychotics.

It is difficult to select a good candidate gene, since the true mechanism of therapeutic action of antipsychotics has not been clarified yet.

genetic polymorphisms in serotonin (5-HT) and dopamine (DA) systems have been extensively investigated in the pharmacodynamics of antipsychotics

The first candidate gene examined with regard to clozapine response was the DA4 receptor gene (DRD4) because in addition to its high affinity for clozapine, the DA4 receptor is abundant in the prefrontal cortex, (a brain region thought to be related to the cognitive dysfunction of schizophrenia), and the DRD4 gene itself is highly polymorphic.

DA system

Among polymorphisms in the DRD4, the 48 bp variable number of tandem repeats (VNTR) has been the most extensively investigated, since the VNTR was shown an in vitro study to influence the sodium chloride sensitivity of clozapine-binding and inhibition of c-AMP synthesis.

DA system

The DA3 receptor, which shares homologies with both the DA4 and DA2 receptors, has generated interest, since the DA3 receptor gene (DRDA3) has a known functional polymorphism,Ser9Gly, that influences dopamine binding. However, the association between the Ser9Gly and clozapine response remains controversial.

The DA3 receptor

The DA2 receptor is a major site of the action of conventional antipsychotics such as chlorpromazine and haloperidol, and of some atypical antipsychotics such as risperidone. One functional polymorphism (-141 Ins/Del) in the promoter region, as well as missense variants including Ser311Cer and an intronic variant (Taq 1 A), have been identified in the DA2 receptor gene (DRD2).

The DA2 receptor

The -141 Ins/Del polymorphism that influences the expression of the DRD2 was reported to be associated with anxiolytic and antidepressive effects during treatment with two conventional antipsychotics,

The DA2 receptor

Although theSer311Cer was shown to influence c-AMP synthesis, it has not been associated with clozapine or with a typical antipsychotic response. The Taq 1A that is located in the intron of DRD2 and has been reported to influence the density of the receptor was shown to have an association with the acute effects of a selective DA2 receptor antagonist, nemonapride, and haloperidol.

The 5-HT receptor genes have been regarded as good candidates for pharmacodynamic stud-ies of antipsychotics, since 5-HT mediated mechanisms seem crucial to atypical antipsychotic drug action, including that of clozapine.

5-HT system

An association between the silent polymorphism 102T/C in the 5-HT2A receptor gene (HTR2A) and clozapine has been reported.

Hys452Tyr12 was shown to influence the intracellular signal transduction of the 5-HT2A receptor, as measured by Ca2+ mobilization induced by 5-HT stimulation.

In addition to the 5-HT2A receptor, other 5-HT receptors, such as 5-HT 2C and 5-HT 6, have also been investigated in psychopharmacognetic studies because atypical antipsychotics also have high affinity for these receptors.

The Ser23 in the 5-HT2C receptor gene influences m-chlorophenylpiperazine (m-CPP), a nonse-lective5-HT2C agonist, binding, in comparison with Cys23. Therefore, the Ser23 may be consti-tutively more active and tends to be more desensitized.

Not just one gene but multiple genes play a role in complex phenotypes, including the clini-cal response to medication. Arranz et al. published the most comprehensive study to date of a pharmacogenetics screening strategy: a combination of 6 out of 19 candidate gene variants (in 5-HT2A, 2C, 5-HT transporter and Histamin 2 receptor genes) predicted response to clozapine with a prediction level of 76.9%

Future direction: Multiple candidate genes

Interindividual Variability in Clozapine Pharmacokinetics and Response: A Focus on Cytochrome P450-1A2 (CYP1A2)-Mediated Enzyme Metabolism

Pharmacogenetics of Antipsychotic Treatment: Lessons Learned from Clozapine

PERSONALIZED MEDICINE OR

PERSONAL PRESCRIPTION IN PSYCHIATRY

Clinicians almost always initiate antipsychotic drugs in schizophrenia “a priori” . However, this may lead to ineffective treatment, to the use of an additional antipsychotic or multiple antipsychotics, to different adverse effects, and result in increased morbidity and mortality.

This represents a real concern and calls for accurate scientific methods that could be used to predict a reasonable therapeutic response and also drug-induced side effects.

Personalized prescription or “tailoring drugs to a patient’s genetic makeup” would be more than beneficial (de Leon 2009b). In the context of personalized prescription, clinicians need to consider environmental, personal and genetic variables when prescribing any medication. According to de Leon, personalized prescription in the clinical practice may be described as personalized selection of the drug and as personalized dosing

In personalized dosing the knowledge of pharmacodynamic and pharmacokinetic dosing properties should be applied.

At the present, in psychiatry there are five pharmacogenomic tests that are currently available on the market or are ready to be introduced.

However, three of the five tests have not published complete details concerning the genes used in them

PHARMACOGENETIC TESTING IN CLINICAL PSYCHIATRIC PRACTICE

CYP 450 Test employs microarray technology for cytochrome P450 (CYP) 2D6 and CYP 2C19 genotyping (de Leon et al. 2009c).

Genomic DNA is extracted from a whole-blood sample to identify 27 alleles in CYP2D6 that are associated with four CYP2D6 phenotypes, and to identify three alleles in CYP2C19 that are associated with two CYP2C19 phenotypes (de Leon et al. 2009c).

The genotypes are then translated with software algorithms into a predicted phenotype, which is indicative of the CYP2D6 and CYP2C19 enzymatic activity.

AmpliChip

One company offers a genetic test for the determination of high (1,5%) or low (0,5%) risk of drug-induced agranulocytosis.

The test can make a valuable prediction in the treatment with clozapine, but does not obviate the need for regular monitoring and has not a significant impact on routine practice.

A new system, called PhyzioType System uses an ensemble of DNA markers from several genes to predict an individual’s risk of developing some adverse drug reactions. The clinical applica-bility of this array is still under investigation.

A recent study describes an array containing probes to identify genetic variants for the risk of hyperlipidemia.

PhyzioType System usesArranz et al. tried to combine genetic information on the prediction of response to clozapine. The prediction level in British Caucasian patients on long-term treatment was 76%, but the results were not replicated in German cohort.

Pharmacogenomics of Neuroleptics (examples)

Category: Atypical antipsychotic; Arilpiperazine Mechanism: Full agonist: 5-HT1A, 5-HT1B, 5-HT1D, 5-

HT6, 5-HT receptors; partial agonist: D2 and 5-HT1A receptors;

antagonist: 5-HT2A receptor Genes: ABCB1, ADRA1A, CYP2D6, CYP3A4, DRD2,

DRD3, HRH1, HTR1A, HTR1B, HTR1D, HTR2A, HTR2C, HTR7

Substrate: CYP2D6 (major), CYP3A4 (major)

Aripiprazole

Clozapine Category: Atypical antipsychotic; Dibenzodiazepine Mechanism: Antagonist of histamine H1, cholinergic and α1-adrenergic

receptors; antagonist: 5-HT1A, 5-HT2B; full agonist: 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1F; inverse agonist: 5-HT6, 5-HT7

Genes: ABCB1, ADRA1A, ADRA1B, ADRA1D, ADRB3, APOA5, APOC3, APOD, CNR1, CYP1A2, CYP2A6, CYP2C8/9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, DRD1, DRD2, DRD3, DRD4, DTNBP1, FABP1, GNAS1, GNB3, GSK3B, HLAA, HRH1, HRH2, HRH4, HTR1A, HTR1B, HTR1D, HTR1E, HTR1F, HTR2A, HTR2B, HTR2C, HTR3A, HTR6, HTR7, LPL, RGS2, SLC6A2, SLC6A4, TNF, UGT1A3, UGT1A4

Substrate: ABCB1, CYP1A2 (major), CYP2A6 (minor), CYP2C8/9 (minor), CYP2C19 (minor), CYP2D6 (minor), CYP3A4 (major), FMO3, UGT1A3, UGT1A4

Inhibitor: CYP1A2 (weak), CYP2C8/9 (moderate), CYP2C19 (moderate), CYP2D6 (moderate), CYP2E1 (weak), CYP3A4 (weak)

Thanks for your mental

effort