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Expert Review of Precision Medicine and DrugDevelopmentPersonalized medicine in drug development and clinical practice
ISSN: (Print) 2380-8993 (Online) Journal homepage: http://www.tandfonline.com/loi/tepm20
Population-level pharmacogenomics for precisiondrug development in dementia
Ramón Cacabelos
To cite this article: Ramón Cacabelos (2018): Population-level pharmacogenomics for precisiondrug development in dementia, Expert Review of Precision Medicine and Drug Development, DOI:10.1080/23808993.2018.1468218
To link to this article: https://doi.org/10.1080/23808993.2018.1468218
Accepted author version posted online: 24Apr 2018.Published online: 08 May 2018.
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Population-level pharmacogenomics for precision drug development in dementiaRamón Cacabelos
EuroEspes Biomedical Research Center, Institute of Medical Science and Genomic Medicine, Bergondo, Corunna, Spain; Chair of Genomic Medicine,Continental University Medical School, Huancayo, Peru
ABSTRACTIntroduction: There is an alarming lack of therapeutic options for dementia (Alzheimer’s disease,vascular/mixed dementia). Despite the enormous effort made by scientists, industry and society, nomedication has been approved for the treatment of dementia in almost two decades. In contrast, theaffected population is a great consumer of pharmaceutical resources for the management of age-related and dementia-associated disorders, with a high risk of suffering adverse drug reactions whichmultiply the cost of the disease and aggravate its clinical course. The implementation of pharmacoge-nomic procedures may help to accelerate drug development and optimize the use of polypharmacyregimes.Areas covered: The areas covered include the following: determinants of pharmacological and phar-macogenomic outcomes (pathogenic, mechanistic, metabolic, transporter, pleiotropic genes), drugdevelopment, pharmacogenomics of dementia (anti-dementia drugs, treatment of cardio-cerebro-vas-cular risk factors, psychotropic drugs), pharmacoepigenomics, and novel drug targets.Expert commentary: Therapeutic strategies in dementia need a profound revision, novel drug targetsshould be urgently identified, and research programs demand a consequent reorientation. Precisionmedicine can be of help in this endeavor by introducing pharmacogenomic tools and satellite tech-nologies into drug development and into safer disease management. Large-scale population studiesand educational programs are necessary; and the practical application of personalized treatmentsshould be simplified with digital devices.
ARTICLE HISTORYReceived 24 January 2018Accepted 19 April 2018
KEYWORDSAlzheimer’s disease;anti-dementia drugs;pharmacogenomics
1. Introduction
Dementia, conceptually defined as premature neuronal deathassociated with progressive, irreversible cognitive decline, isbecoming the third major problem of health in developed coun-tries, after cardiovascular disorders and cancer. Alzheimer’s dis-ease (AD) is the principal cause of dementia, followed by vasculardementia, mixed dementia, Lewy body dementia, and other lessfrequent forms of dementia [1]. Together with depression,dementia is the most prevalent central nervous system (CNS)disorder in this century. Its prevalence ranges from 1.8% at65–69 years to 42.1% at age 95–99 years (annual incidence of34.1 per 1000 persons >60 years), with an age-adjusted deathrate of 25.4 per 100,000 and a global cost of over $700 billionworldwide [2]. About 10–20% of the cost of AD is attributed topharmaceutical expenses, including anti-dementia drugs plusmedication for concomitant disorders and AD-related neuropsy-chiatric disorders. The use of anti-dementia drugs is veryirregular, depending on the country. In Japan [3], 90% of ADpatients are current users of anti-dementia drugs, whereas in theUSA [4] and Europe [5], consumers of these medications repre-sent 50% and 85%, respectively; and in some regions of the EU,less than 20% of the affected population use conventional drugsfor the treatment of dementia [6]. In general, elderly patientstend to be under polypharmacy regimes with potentially inap-propriate prescriptions, and in particular, patients with dementia
are over-medicalized with an excess of drugs which do notbenefit cognitive function [5]. Furthermore, no new drugs fordementia have been approved during the past 15 years [7,8].This historic failure in contemporary medicine needs a profoundrevision on the part of the scientific/medical community, thepharmaceutical industry, and the health authorities.
A promising option for accelerating drug development in theprecision medicine era is pharmacogenomics (PGx) and its satel-lite technologies [9]. However, after six decades of history [10],PGx still remains in a primitive stage, with many obstacles for anefficient implantation as a global strategy in clinical practice [11].Notwithstanding recent developments, many studies documentthat PGx would help to optimize therapeutics (drug efficacy andsafety) and to improve drug development with the incorporationof genomic, proteomic, metabolomic, and epigenomic biomar-kers [12–14].
AD is an optimal paradigm for the implementation ofprecision medicine protocols [15–17], assuming its conditionof complex disorder with an underlying neurodegenerativeprocess which starts 20–30 years before the onset of thedisease, its lack of curative options, and its susceptibility topolypharmacy for the treatment of concomitant age-relateddisorders (i.e. cardio-cerebrovascular problems, hypertension,dyslipidemia, diabetes, and dementia-associated neuropsy-chiatric disorders) [1]. In this context, the characterization of
CONTACT Ramón Cacabelos rcacabelos@euroespes.com EuroEspes Biomedical Research Center, Institute of Medical Science and Genomic Medicine,15165-Bergondo, Corunna, Spain
EXPERT REVIEW OF PRECISION MEDICINE AND DRUG DEVELOPMENT, 2018https://doi.org/10.1080/23808993.2018.1468218
© 2018 Informa UK Limited, trading as Taylor & Francis Group
geno-pheno-markers, the identification of novel drug targets,and the implantation of personalized treatments and preven-tive procedures are imperative needs in the near future [18].
2. Determinants of pharmacological outcome
Major determinants of the pharmacological outcome inhumans include the following: (i) age, (ii) sex, (iii) race, (iv)nutritional status, (v) drug properties (chemistry, pharmaceu-tical category, biopharmaceutical properties, drug source: syn-thetic, natural), (vi) route of administration, (vii) dose, (viii)pharmacokinetics, (ix) pharmacodynamics, (x) drug target(s),(xi) disease stage, (xii) concomitant treatments, (xiii) compli-ance rate, (xiv) PGx, and (xv) pharmacoepigenomics [19].
3. Genetic determinants of pharmacogenomics
The pharmacogenomic network is integrated by pathogenic,mechanistic, metabolic, transporter, and pleiotropic (PMMTP)genes [19–21].
3.1. Pathogenic genes
Pathogenic genes (Table 1) are represented by a series ofdefective genes responsible for neurodegeneration, character-ized by the phenotypic expression of classical neuropathologi-cal hallmarks [extracellular deposits of amyloid-β (Aβ) in neuriticplaques, intracellular neurofibrillary tangles (hyperphosphory-lated Tau protein), dendritic desarborization, neuronal loss,neuroinflammation, excitotoxic reactions, oxidative stress, neu-rotrophic dysfunction, neurotransmitter deficits, and alterations
in the ubiquitin-proteasome system] and clinical manifestations(cognitive deterioration, functional decline, behavioral changes)[1]. Classical gene mutations associated with Mendelian ADcomprise the Aβ precursor protein (APP) gene (21q21)(AD1);the presenilin 1 (PSEN1)(14q24.3)(AD3) and presenilin 2(PSEN2) genes (1q31–q42)(AD4), and the microtubule-asso-ciated protein Tau (MAPT) gene (17q21.1), which confer ADthe dual character of an amyloid-tauopathy [1,22]. However,mutations in these genes are very rare in AD (<1:500). In con-trast, over 600 different genes distributed across the humangenome are potentially associated with AD (Table 1). Thesegenes affect approximately 2% (>40.000 kb) of the humangenome. Among them, the apolipoprotein (APOE) gene is themost important risk factor for dementia, either degenerative orvascular [23,24]. The presence of the APOE-4 allele confers riskwhereas the APOE-2 allele may contribute to partial protectionagainst dementia [1]. The synergistic, epistatic effect of patho-genic genes is likely to be determinant of the age of onset,clinical course, and response to treatment [20].
3.2. Mechanistic genes
Mechanistic genes are those encoding receptor subunits,enzymes, and messengers responsible for the metabolic path-ways and/or neurotransmitter systems on which a drugaddresses a pathogenic target [19].
3.3. Metabolic genes
Metabolic genes encode Phase I–II reaction enzymes respon-sible for drug metabolism, including (i) Phase I enzymes:
Table 1. Pathogenic genes associated with Alzheimer’s disease.
Gene symbol Gene name Gene ID OMIM# Locus dbSNP ID Risk allele MAF
ABCA7 ATP binding cassette subfamily A member 10347 605414 19p13.3 rs3764650 G 0,20 (G)APOE Apolipoprotein E 348 107741 19q13.32 rs429358; rs7412 *4 0,15 /C); 0,08 (T)APP Amyloid beta precursor protein 351 104760 21q21.3 52 SNPs < 0,01BIN1 Bridging integrator 1 274 601248 2q14.3 rs744373 C 0,36 (C)BUB3 BUB3, mitotic checkpoint protein 9184 603719 10q26.13 rs4980270 T 0,10 (T)C9ORF72 Chromosome 9 open reading frame 72 203228 614260 9p21.2 rs3849942 T 0,22 (T)CD2AP CD2-associated protein 23607 604241 6p12.3 rs9349407 C 0,25 (C)CD33 CD33 molecule 945 159590 19q13.41 rs3865444 T 0,01 (T)CLU Clusterin 1191 185430 8p21.1 rs11136000 T 0,38 (T)CPZ Carboxypeptidase Z 8532 603105 4p16.1 rs7436874 C 0,36 (C)CR1 Complement C3b/C4b receptor 1 185430 120620 1q32.2 rs3818361 T 0,25 (T)DISC1 Disrupted in schizophrenia 1 27185 605210 1q42.2 rs16856202 G 0,03 (G)ENPP1 Ectonucleotide pyrophosphatase/phosphodiesterase 1 5167 173335 6q23.2 rs7767170 T 0,02 (T)EXO1 Exonuclease 1 9156 606063 1q43 rs1776148 A 0,27 (A)LAMA3 Laminin subunit alpha 3 64231 606548 11q12.2 rs11082762 A 0,47 (A)LHFP Lipoma HMGIC fusion partner 10186 606710 13q13.3-q14.11 rs7995844 G 0,35 (G)MAPT Microtubule associated protein tau 4137 157140 17q21.31 15 SNPs < 0,01MS4A4E Membrane spanning 4-domains A4E 643680 608401 8p21.1 rs670139 A 0,38 (A)MS4A6A Membrane spanning 4-domains A6A 64231 606548 11q12.2 rs610932 A 0,45 (A)NLRP4 NLR family pyrin domain containing 4 147945 609645 19q13.43 rs12462372 A 0,08 (A)NTNG1 Netrin G1 3909 600805 18q11.2 rs11803905 T 0,32 (T)PICALM Phosphatidylinositol binding clathrin assembly protein 8301 603025 11q14.2 rs3851179 A 0,31 (A)PIWIL2 Piwi-like RNA-mediated gene silencing 2 55124 610312 8p21.3 rs4266653 G 0,47 (G)PSEN1 Presenilin 1 5663 104311 14q24.2 241 SNPs < 0,01PSEN2 Presenilin 2 5664 600759 1q42.13 43 SNPs < 0,01STK36 Serine/threonine kinase 36 27148 607652 2q35 rs2303565 C 0,33 (C)STX17 Syntaxin 17 55014 604204 9q31.1 rs1997368 G 0,32 (G)SUN3 Sad1 and UNC84 domain containing 3 256979 607723 7p12.3 rs2708909 G 0,39 (G)TBC1D5 TBC1 domain family member 5 9779 615740 3p24.3 rs10510480 C 0,11 (C)USP6NL USP6 N-terminal like 9712 605405 10p14 rs3847437 T 0,04 (T)ZSWIM7 Zinc finger SWIM-type containing 7 125150 614535 17p12 rs10491104 T 0,41 (T)
2 R. CACABELOS
alcohol dehydrogenases (ADHs), aldehyde dehydrogenases,aldo-keto reductases, amine oxidases (MAOs), carbonyl reduc-tases (CBRs), cytidine deaminase, cytochrome P450 family(CYPs), cytochrome b5 reductase, dihydropyrimidine dehydro-genase, esterases (AADAC, CEL, CESs, CES1P1, ESD, GZMA,GZMB, PONs, UCHLs), epoxidases, flavin-containing monooxy-genases (FMOs), glutathione reductase/peroxidases, pepti-dases (DPEP, METAP), prostaglandin endoperoxide synthases(PTGSs), short-chain dehydrogenases (DHRS1-2), reductases(DHRSs, HSDs), superoxide dismutases, and xanthine dehydro-genase (XDH); and (ii) Phase II enzymes: amino acid trans-ferases (AGXT, BAAT, CCBL1), dehydrogenases (NQO1, NQO2,XDH), esterases (CESs), glucuronosyl transferases (UGTs), glu-tathione transferases (GSTs, GSTMs, GSTOs, GSTP, GSTTs,GSTZ1, GSTCD, MGSTs, PTGES), methyl transferases (ASMT,COMT, GNMT, GAMT, HNMT, INMT, NNMT, PNMT, TPMT),N-acetyl transferases (ACSLs, ACSMs, AANAT, GLYAT, NAA20,NAT1-2, SAT1), thioltransferase (GLRX), and sulfotransferases(CHST1-13, GAL3ST1, SULT1A1-3, SULT1B1, SULT1C1-4,SULT1E1, SULT2A1, SULT2B1, SULT4A1, SULT6B1) [19,25,26].
Genes encoding metabolic enzymes show a high rate ofethnic variation, which is a fundamental issue to take intoaccount when performing clinical trials in precision medicineor when applying PGx procedures in personalized treatmentswithin a world geographic area [27,28]. CYP enzymes, espe-cially CYP2D6, CYP2C9, CYP2C19, and CYP3A4/5, metabolizeover 60–80% of current drugs [19]. About 900 drugs aremetabolized via CYP2D6 enzymes as substrates (371 drugs),inhibitors (300 drugs), or inducers (18 drugs); 600 drugs (311substrates, 375 inhibitors, 41 inducers) are CYP2C9-related;500 drugs (281 substrates, 263 inhibitors, 23 inducers) areCYP2C19-related; and over 1900 drugs (1,033 substrates, 696inhibitors, 241 inducers) are metabolized via CYP3A4/5
enzymes [19,29,30]. No significant differences have beenfound in the distribution and frequency of polymorphic var-iants of genes encoding Phase I–II enzymes between ADpatients and the healthy population [31] (Figure 1); however,CYP variants leading to the condition of extensive (EM), inter-mediate (IM), poor (PM), or ultra-rapid metabolizer (UM) aremajor determinants of drug efficacy and safety [19,29,30]. Theintegration of CYP2D6, CYP2C9, CYP2C19, and CYP3A4/5 var-iants in tetragenic clusters yields 156 haplotypes of which only20% correspond to extensive metabolizers. This indicates thatapproximately 80% of Caucasians are deficient for the bio-transformation and elimination of current drugs that are meta-bolized via CYP2D6-2C9-2C19-3A4 enzymes [31].
3.4. Transporter genes
Transporter genes encode proteins that regulate the influx–efflux of xenobiotics through cell membranes and biologicalbarriers (blood–brain barrier, placental membranes, tumorbarriers, etc.). Transporter proteins are classified into fourmajor categories, including (i) ATPases: P-type (ATPs), V-type(vacuolar H+-ATPase subunit), and F-type; (ii) 49 ATP-bindingcassette transporters: subfamily A (ABCAs)(ABCA1–13),subfamily B (MDR/TAP)(ABCBs)(ABCB1, TAP1-2, ABCB4–11),subfamily C (CFTR/MRP)(ABCCs)(ABCC1–6, CFTR, ABCC8–13),subfamily D (ALD)(ABCDs)(ABCD1–4), subfamily E (OABP)(ABCEs)(ABCE1), subfamily F (GCN20)(ABCFs)(ABCF1–3), andsubfamily G (WHITE)(ABCGs)(ABCG1–5, ABCG8); (iii) 388 solutecarriers (SLCs); and (iv) a miscellaneous group of transportersrepresented by aquaporins (AQP1, AQP7, AQP9), major vaultprotein, and metallothioneins [19,25,26,32].
Genetic variation in transporter genes affects drug metabo-lism, brain penetrance, and drug resistance [33]. Mutations in
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Figure 1. Distribution and frequency of CYP2D6, CYP2C19, CYP2C19 and CYP3A4/5 geno-phenotypes in the general population and in Alzheimer’s disease.A: Alzheimer; C: Control population.EM: Extensive Metabolizers; IM: Intermediate Metabolizers; PM: Poor Metabolizers; UMs: Ultra-Rapid Metabolizers.
EXPERT REVIEW OF PRECISION MEDICINE AND DRUG DEVELOPMENT 3
ABC transporters are associated with AD pathogenesis. ABCB1 isprobably the most important drug transporter in the CNS. About1270 drugs are metabolized via ABCB1 (490 substrates, 618inhibitors, 182 inducers, 269 modulators) [19]. Genetic variationin ABCB1 contributes to the accumulation and progression of Aβdeposits in the AD brain. Conversely, the cholesterol (CHO)transporter ABCA1 neutralizes Aβ aggregation and facilitates Aβelimination from brain tissues [34]. Other ABCs show associationwith AD, such as ABCA7 or ABCG2 [35,36].
3.5. Pleiotropic genes
Pleiotropic genes encode multifaceted proteins that directly orindirectly participate in the pathogenesis of dementia and/orage-related disorders [23] (Figure 2).
4. Historical drug development
In the decade 1993–2003, conventional anti-AD drugs, four acet-ylcholinesterase inhibitors (AChEIs) (tacrine, donepezil, rivastig-mine, galantamine) and one N-methyl-D-aspartate (NMDA)receptor partial antagonist (Memantine) were introduced in themarket; since then no new drugs for AD have been approved bythe US Food and Drug Administration, European MedicinesAgency, or Koseisho in the USA, EU, or Japan, respectively [7,8].In May 2017, there were 105 drugs in Phase I–III clinical trials,
including disease-modifying therapies (70%), symptomatic cog-nitive enhancers (14%), and symptomatic agents for neuropsy-chiatric disorders (13%) in AD [7]. Over the past decade,thousands of synthetic and natural compounds have beenscreened [7,8,20,37,38], and during the period 2012–2017 8,380 studies on AD treatment have been reported (PubMed,January 2013–24 December 2017) [2]. Major pharmacologicalcategories under development were the following: neurotrans-mitter enhancers (11.38%), multitarget drugs (2.45%), anti-amy-loid agents (13.30%), anti-Tau agents (2.03%), natural productsand derivatives (25.58%), novel drugs (8.13%) based on newtargets (Table 2), other (old) drugs (11.77%), anti-inflammatorydrugs (1.20%), neuroprotective peptides (1.25%), stem cell ther-apy (1.85%), nanocarriers/nanotherapeutics (1.52%), and othercategories and/or therapeutic strategies (polyunsaturated fattyacids, cognitive enhancers/nootropics, neurotrophic factors,hormone therapy, epigenetic drugs, miRNAs, RNAi/gene silen-cing, drug delivery systems, gene therapy, and combinationtreatments) (<1% each) [2]. Research on AD PGx represents0.79% of all scientific production in drug development.
Novel procedures for an efficient drug development shouldcontemplate the following items: (i) identification of morespecific pathogenic targets (Table 2); (ii) target-oriented pri-mary screening; (iii) transfected cell models for in vitro studies;(iv) improved transgenic models for in vivo studies; (iv) patientrecruitment for clinical trials based on selected primary
0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%
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AD-APOE
C-APOB
AD-APOB
C-APOC3
AD-APOC3
C-CETP
AD-CETP
C-LPL
AD-LPL
C-NOS3
AD-NOS3
C-ACE
AD-ACE
C-AGT
AD-AGT
C-IL1B
AD-IL1B
C-IL6
AD-IL6
C-IL6R
AD-IL6R
C-TNF
AD-TNF
C-MTHFR
AD-MTHFR
Pleiotropic Genotypes in Alzheimer’s Disease
g1 g2 g3 g4 g5 g6
Apolipoprotein E; APOE rs429358/rs7412 [112T>C/158T>C], APOE-2/2, 2/3, 2/4, 3/3, 3/4, 4/4; A: N=1803; C: N=1096.
Apolipoprotein B; APOB rs693 [7545C>T], APOB-C/C, C/T, T/T; AD: N=376; C: N=255
Apolipoprotein C3; APOC3 rs5128 [3175G>C], S1/S2; APOC3-C/C, C/G, G/G; AD: N=376; C: N=255
Cholesteryl Ester Transfer Protein; CETP rs708272 [+279G>A, B1/B2]; CETP-A/A, A/G, G/G; AD: N=803; C: N=567
Lipoprotein Lipase; LPL [1421C>G, S474X] ; LPL-C/C, C/G, G/G; AD: N=375; C: N=255
Nitric Oxide Synthase 3; NOS3 rs1799983 [894G>T]; NOS3-G/G, G/T, T/T; AD: N=1164; C: N=805
Angiotensin I-Converting Enzyme; ACE rs4332 [547C>T]; ACE-C/C, C/T, T/T; AD: N=379; C: N=265
Angiotensinogen; AGT rs699 [9543A>G, T174M]; AGT-A/A, A/G, G/G; AD: N=1535; C: N=997
Interleukin-1beta; IL1B rs1143634 [3954C>T]; IL1B-C/C, C/T, T/T; AD: N=373; C: N=255
Interleukin-6; IL6 rs1800795 [-174G>C]rs1800796 [-573G>C]; IL6-C/C, C/G, G/G; AD: N=373; C: N=255
Interleukin-6 Receptor; IL6R rs8192284 [1510A>G]; IL6R-A/A, A/G, G/G; AD: N=373; C: N=255
Tumor Necrosis Factor Alpha; TNFA rs1800629 [-308G>A]; TNFA-A/A, A/G, G/G; AD: N=373; C: N=255
5,10-Methylenetetrahydrofolate Reductase; MTHFR rs1801131 [1298A>C]; MTHFR-A/A, A/C, C/C; AD: N=392; C: N=276
p=0.0009 p=0.0001 p=0.006
p=0.02
Figure 2. Distribution and frequency of polymorphic variants of selected pathogenic and pleiotropic genes associated with vascular risk factors in the generalpopulation (C) and in patients with Alzheimer’s disease (A) .g: genotypesAPOE genotypes: (g1) APOE-2/2; (g2) APOE-2/3; (g3) APOE-2/4; (g4) APOE-3/3; (g5) APOE-3/4; (g6) APOE-4/4.APOB genotypes: (g1) APOB-C/C; (g2) APOB-C/T; (g3) APOB-T/T.APOC3 genotypes: (g1) APOC3-C/C; (g2) APOC3-C/G; (g3) APOC3-G/G. CETP genotypes: (g1) CETP-A/A; (g2) CETP-A/G; (g3) CETP-G/G. LPL genotypes: (g1) LPL-C/C; (g2) LPL-C/G; (g3) LPL-G/G.NOS3 genotypes: (g1) NOS3-G/G; (g2) NOS3-G/T; (g3) NOS3-T/T.ACE genotypes: (g1) ACE-C/C; (g2) ACE-C/T; (g3) ACE-T/T. AGT genotypes: (g1) AGT-A/A; (g2) AGT-A/G; (g3) AGT-G/G. IL1B genotypes: (g1) IL1B-C/C; (g2) IL1B-C/T; (g3) IL1B-T/T. IL6 genotypes:(g1) IL6-C/C; (g2) IL6-C/G; (g3) IL6-G/G. IL6R genotypes: (g1) IL6R-A/A; (g2) IL6R-A/G; (g3) IL6R-G/G. TNFA genotypes: (g1) TNFA-A/A; (g2) TNFA-A/G; (g3) TNFA-G/G. MTHFR genotypes: (g1)MTHFR-A/A; (g2) MTHFR-A/C; (g3) MTHFR-C/C.
4 R. CACABELOS
Table 2. Novel pharmacological targets for Alzheimer’s disease treatment.
5-Lipoxygenase activating protein(FLAP) inhibition
12/15-Lipoxygenase (12-15LO)26S Proteasome37/67 kDa Laminin receptor3β-Hydroxysteroid-Δ24 reductase(DHCR24)/selective Alzheimer’sdisease indicator 1 (seladin-1)
ABC transportersAbelson tyrosine kinase inhibitorsACAT1/SOAT1Acid sphingomyelinase (ASM)Activating transcription factor 4(ATF4)
Adaptor protein MyD88Adenosine receptorsAGE and RAGEAldose reductaseAminoacyl-tRNA synthetase complex(ARS)-interacting multifunctionalprotein 1 (AIMP1)
Amylin and Amylin receptorAmyloid-β peptide-specific DARPinsβ-Amyloid precursor protein-bindingfamily B member 2 (APBB2, FE65-like, FE65L1)
Asparagine endopeptidaseAstrocytes’ Calcium-sensingreceptors
ATP-binding cassette transporter A7(ABCA7)
ATP-binding cassette transporter-2(ABCA2)
ATP-sensitive homomeric P2X7receptor (P2X7R)
AutophagyBrain hepatocyte growth factor/c-Met receptor system
BRICHOS domainCalcitonin gene-related peptide(CGRP)
Calcium/calmodulin-dependentprotein kinase II (CaMKII) andcalcium/calmodulin-dependentprotein kinase IV (CaMKIV)
Calcium-activated potassium channelCalpaincAMP response element bindingprotein (CREB)
Cannabinoid receptorsCarbonic anhydrasesCardiotrophin-1Caspase-3 short hairpin RNAsCaspase-6Cathepsin DCdc2-like kinases (CLKs), CMGC(cyclin-dependent kinases (CDKs),mitogen-activated protein kinases(MAP kinases), glycogenChaperones (HSP70, HSP90)
Chemokine CCL11Chitinase-1Cholesterol 24S-hydroxylase(CYP46A1)
Cholesterol ester hydrolasesc-Jun N-terminal Kinase (JNK)Clathrin and Adaptor protein 2
CX3CL1/CX3CR1Cyclin-dependent kinase 5 (CDK5)Cysteinyl leukotrienes
D-Amino acid oxidaseDeoxyribonuclease IDiscoidin domain receptorDisintegrin and metalloproteinase 10(ADAM10),
Disrupted-in-schizophrenia-1DNA-dependent protein kinaseDock GEFsDrebrinDual leucine zipper kinase (DLK) isserine/threonine protein kinase
DYRK1AEctonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2)/autotaxin/ lysophospholipase D
Endothelial nitric oxide synthase(eNOS)
Ephs and ephrinsErythropoietin receptor (EpoR)ExosomesFarnesyl pyrophosphate synthaseFast-acting clade E serine proteaseinhibitor (SERPIN) plasminogenactivator inhibitor type-1 (PAI-1;SERPINE1)
Fyn tyrosine kinaseG protein-coupled receptors (GPCRs)Galanin receptorsGangliosides and glycolipidsGelatinase B/matrix metalloproteinase9 (MMP-9)
GelsolinGlial glutamate transporter EAAT2Glucagon-like peptide-1 (GLP-1)GLT-1 transporterGlutaminyl cyclaseGlycogen synthase kinase-3 beta(GSK3β) kinase
GPR40 receptor/guanine-basedpurinergic system
Heat shock proteins (HSPs)Heme oxygenase-1HeminHeparan sulfate (HS) proteoglycan(PG) glypican-1 (Gpc-1)
HeparanasesHMGB1/NLRP3-Inflammasome andInflamma-miRNAs
Human presequence protease (hPreP)Hypoxia-inducible factor prolylhydroxylases
ImmunoproteasomeIndoleamine 2,3-dioxygenase (IDO)InflammasomeInsulin growth factor bindingprotein 7
Insulin-degrading enzyme (IDE)Intramembrane proteases (IMPs)Ionotropic P2X and metabotropic P2Yreceptors
IRE1 signalingJanus kinase 2 (JAK2)-mediatedsignaling
Kallikrein-8KCa2 or small-conductance Ca2
+-activated K+ channelsKCa3.1KEAP1 and Cul3-based E3 ubiquitinligases
Kinin B1 receptorKlothoKrüppel-like factor 8 (KLF8)Kynurenines
Kynurenine-3-monooxygenase (KMO) andtryptophan-2,3-dioxygenase (TDO)
Lactate receptor, G-protein-coupledreceptor 81/hydroxycarboxylic acidreceptor 1
LeptinLingo-1Lipoxin A4 signalingLiver X receptors (LXRs)Low-density lipoprotein receptor-relatedprotein 1 (LRP1)
Matrix metalloproteinasesMetalloporphyrinsMetalloproteinase 10 (ADAM10)Metalloproteinases (TIMP)-3Metallothionein 3Microglial targetsMicroparticles (MPs), heterogeneous smallcell-derived vesicles (0.1–1 μm)
Midkine (MK) and pleiotrophin (PTN),heparin binding growth
factorsMitochondrial ATP-sensitive potassiumchannels
Mitochondria-Division Inhibitor 1Mitochondrial amyloid-binding alcoholdehydrogenase (ABAD)
Mitochondrial permeability transition poreMitochondrial voltage-dependent anionchannel 1 (VDAC1)
mTORMyeloperoxidaseNecrostatin-1Nectins and nectin-like molecules (Necls)/Cadms), Ca2+-independentimmunoglobulin superfamily celladhesion molecules
NeprilysinNeuronal nitric oxide synthase (nNOS)NeurosteroidsNeurotrophic factorsNLRP3 inflammasomeNOD-like receptor (NLR) family, pyrindomain-containing protein 3 (NLRP3)inflammasome
Nogo/NgR signaling pathwayNrf2 (nuclear factor erythroid 2-relatedfactor 2)- antioxidant response element(ARE) pathway
Nuclear receptorsO-linked β-N-acetylglucosaminylation (O-GlcNAcylation); O-GlcNAcase (OGA)
Orexin receptorsOrphan receptors of rhodopsin (class A)family
P2Y receptorsp53p75NTR receptorPDK1PERK kinase/protein kinase RNA-likeendoplasmic reticulum kinase (PERK)
Peroxisome proliferator-activatedreceptors (PPARs)
P-Glycoprotein (ABCB1)PhosphodiesterasesPhospholipase DPim1Postsynaptic density protein 93 (PSD-93)Potassium channel KCa3.1Pregnane X receptorsProgranulinProkineticin
Proprotein Convertase Subtilisin/kexin type 9 (PCSK9)
Prostaglandin J2Protein kinase CProtein phosphatase 2AProtein tyrosine phosphatase 1B(PTP1B)
Protein-remodeling factorsPurinergic receptorsRAGE-DIAPH1 signal transductionRan-binding protein microtubule-organizing center (RanBPM)
ReelinRegulator of calcineurin 1 (RCAN1)RemyelinationRESTReticulons (RTNs)Retinoic acid receptorRetromer complexRhein lysinateRho GTPasesRho-associated protein kinases(ROCKs)
Rho-guanosine triphosphatasesRibonucleoproteinSecretory protein interleukin-likeepithelial-mesenchymal transitioninducer (ILEI, FAM3 superfamilymember C
Seladin-1 (selective Alzheimer diseaseindicator-1), DHCR24
Sestrin2Serine palmitoyltransferaseSH3-binding protein 5Sigma receptorsSigma-2/PGRMC1 receptorsSignal transducer and activator oftranscription 3 (STAT3)
Soluble epoxide hydrolaseSphingosine kinase-1/2Sphingosine kinases/sphingosine-1-phosphate
sphingosine-1-phosphate (S1P)receptor
STEP (STriatal-Enriched proteintyrosine Phosphatase)
Synaptic GTPase-Activating Protein(SynGAP1)
Synaptic protein α1-takusanTelomeraseThrombinTNFSF10Toll-like receptors (TLRs)TransglutaminaseTransient receptor potential (TRP)channels
Translocator protein (TSPO)TREM and TREM-like receptorsTriggering receptor expressed onmyeloid cells-1/2 (TREM1/2)
Tryptophan-2, 3-dioxygenase (TDO)Tyrosine kinasesUbiquilin-1Ubiquitin C-terminal hydrolase-L1(UCH-L1)
Ubiquitin-Proteasome systemVoltage-dependent anion channel(VDAC) proteins
Wnt signaling, secreted frizzled-related proteins (sFRPs)
β-Arrestinsμ-Opioid receptor
EXPERT REVIEW OF PRECISION MEDICINE AND DRUG DEVELOPMENT 5
genotypes; (v) stratification of patients according to PMMTPclusters; (vi) clear differentiation of trials for (a) prevention, (b)disease-modifying treatments, and (c) disease-associatedsymptoms; and (vii) analysis of results based on sensitivepheno-geno-markers.
5. Pharmacogenomics of the dementia syndrome
The dementia syndrome requires a multifactorial treatmentincluding (i) anti-dementia drugs for halting disease progres-sion (post-symptomatic treatments) and for preventive pur-poses (pre-symptomatic treatments); (ii) specific treatments forconcomitant disorders (cerebrovascular, 60–80%; cardiovascu-lar, 20–40%; hypertension, 20–30%; hypercholesterolemia,30–40%; diabetes, 10–20%; other pathologies, 20–30%); and(iii) psychotropic treatments for CNS disorders associated withdementia (agitation, anxiety, depression, behavioral changes,sleep disorders, epilepsy, psychomotor dysfunction) (>80%)[20,29–31]. Most of the drugs currently used for the treatmentof these ailments may interact, contributing to severe adversedrug reactions (ADRs) in over 40–60% of the cases, 10% ofwhich may require hospitalization with the consequentincrease in health expenditure and further deterioratingconditions.
PGx studies in dementia started in the early 2000s [39].Approximately 200 studies have been performed, mainlyusing APOE and CYPs as reference geno-markers in treatmentswith AChEIs, memantine, and combination therapies. Majorconclusions derived from these studies indicate that (i) APOEis a major determinant of PGx outcomes in dementia, withAPOE-3 carriers acting as the best responders and APOE-4carriers behaving as the worst responders; CYP2D6-EMs andIMs are good responders to conventional drugs, while PMsand UMs tend to be poor responders to different drugs; and(iii) some SNPs in other genes (i.e. ABCB1, TOMM40, ACHE,BCHE) also influence the therapeutic response to drugs,depending upon the pharmacological category and biophar-maceutical properties of each drug [19,20,29–31,40,41].
5.1. Pharmacogenomics of anti-dementia drugs
Conventional anti-dementia drugs are metabolized by CYPenzymes, except rivastigmine. Donepezil is a major substrateof CYP2D6, CYP3A4, ACHE, and UGTs, inhibits ACHE and BCHE,and is transported by ABCB1 [19] (Table 3). CYP2D6 variantsaffect donepezil efficacy and safety. About 50–65% of patientstend to show some response to donepezil, and some studiesindicate that mutant enzymes accumulate in responders[42,43]. However, most studies indicate that CYP2D6-PMsand UMs tend to be worse responders to donepezil thanEMs and IMs [19,20,29–31,40,41,44,45]. ABCB1-T/T/T carriers(haplotypes 1236C/2677G/3435C and 1236T/2677T/3435T)show lower plasma donepezil concentration-to-dose ratiosand better response than patients with other haplotypes [46].
Galantamine is influenced by APOE, APP, ACHE, BCHE,CHRNA4, CHRNA7, CHRNB2 variants; it is a major substrate ofCYP2D6, CYP3A4, and UGT1A1, and an inhibitor of ACHE andBCHE (Table 3). CYP2D6-PMs show higher dose-adjustedgalantamine plasma concentrations than heterozygous and
homozygous CYP2D6-EMs. The co-administration of galanta-mine with CYP2D6 and/or CYP3A4 strong inhibitors may affectits bioavailability [19,20,29–31].
APOE, APP, CHAT, ACHE, BCHE, CHRNA4, CHRNB2, and MAPTvariants modify the pharmacological effects of rivastigmine,with no apparent effect of CYPs, and UGT2B7-PMs exhibit apoor response to treatment [19,20,29–31,47] (Table 3).
Tacrine was the first AChEI introduced in 1993 and discon-tinued years later due to hepatotoxicity. The effects of thisprototype AChEI are influenced by ACHE, ABCB4, BCHE,CHRNA4, CHRNB2, APOE, MTHFR, CES1, LEPR, GSTM1, andGSTT1 variants. Tacrine is a major substrate of CYP1A2 andCYP3A4, a minor substrate of CYP2D6, and is transported viaSCN1A and ABCB4. Tacrine is an inhibitor of ACHE, BCHE, andCYP1A2, and also acts as an inducer of CYP1A1, 2B1, and 3A2.Tacrine-induced transaminase elevation is associated with PGxfactors in up to 50% of patients, especially in vulnerablepatients harboring particular CYP1A and ABCB4 SNPs [19,48](Table 3).
Memantine binds NMDA receptor-operated cation channelsand blocks glutamate, also acting as an antagonist of GRIN2A,GRIN2B, GRIN3A, HTR3A and CHRFAM7A. APOE, PSEN1, MAPT,GRIN2A, GRIN2B, GRIN3A, HTR3A, CHRFAM7A, c-Fos, Homer1b,and PSD-95 variants influence to some extent its pharmacolo-gical effects. Memantine is a strong inhibitor of CYP2B6 andCYP2D6, and a weak inhibitor of CYP1A2, CYP2A6, CYP2C9,CYP2C19, CYP2E1, and CYP3A4 [19,20,29,30,49] (Table 3). Theco-administration of CYP2B6 substrates with memantinereduces its metabolism by 65%. NR1I2 rs1523130 is a geneticcovariate for memantine clearance. NR1I2-CT/TT carriers showa slower elimination of memantine than CC carriers [50].
5.2. Pharmacogenomics of combination treatments
Studies on combination treatments increased by 64% over thepast decade [2]. The most typical combination is donepezil +memantine; however, many other combinations have beenused in basic and clinical trials with apparently superior resultswhen compared to monotherapy. At least 150 different com-binations have been identified from 2013 to 2017 in basic andclinical studies [2].
Combination treatments under PGx scrutiny confirmed thatAPOE-3 carriers are the best responders and APOE-4 carriersare the worst responders [20,40,41,51,52] (Figure 3). Similarly,CYP2D6-PMs are the best responders, CYP2D6-IMs are inter-mediate responders, and both CYP2D6-PMs and UMs tend tobe poor responders to conventional treatments in terms ofcognitive performance or behavioral/emotional effects(depression, anxiety) [51]. The influence of other CYP enzymeshas been shown to be less relevant [20,51]. In contrast, ABCB1and ABCA1 might be important in Aβ clearance from thebrain [34].
APOE variants are also influential in AD immunotherapywith vaccines against Aβ [49]. A potent association betweenAPOE and TOMM40 variants has also been demonstrated incombination treatments [53]. A poly T repeat in an intronicpolymorphism (rs10524523) (intron 6) in the TOMM40 gene,which encodes an outer mitochondrial membrane translocaseinvolved in the transport of Aβ and other proteins into
6 R. CACABELOS
Table3.
Pharmacolog
icalprop
ertiesandph
armacog
enom
icsof
conventio
nalanti-d
ementia
drug
s.
Drug
Prop
erties
Pharmacog
enetics
Nam
e:Don
epezilhydrochloride,Aricept,120011-70-3,
Don
epezilHCl,B
NAG
,E-2020,
E2020
IUPA
Cname:2-[(1
-benzylpiperidin-4-yl)m
ethyl]-5,6-dimetho
xy-2,3-dihydroinden-1-on
e;hydrochloride
Molecular
form
ula:C 2
4H30ClNO3
Molecular
weigh
t:415.9529
g/mol
Catego
ry:C
holinesterase
inhibitor
Mechanism
:centrallyactive,reversibleacetylcholinesterase
inhibitor;increasestheacetylcholineavailableforsynaptic
transm
ission
intheCN
SEffect:N
ootrop
icagent,cholinesterase
inhibitor,parasympathom
imeticeffect
Pathog
enicgenes:APOE,CH
ATMechanisticgenes:CH
AT,A
CHE,BCHE
Drugmetabolism-related
genes:
–Substrate:CYP2D6(m
ajor),CYP3A4
(major),UGTs,A
CHE
–Inhibitor:AC
HE,BCHE
Transportergenes:AB
CB1
Nam
e:Galantaminehydrob
romide,Galantham
inehydrob
romide,1953-04-4,
Nivalin,R
azadyne,UNII-MJ4PTD2VVW
,Nivaline
IUPA
Cname:(1S,12S,14R)-9-m
etho
xy-4-m
ethyl-11-oxa-4-azatetracyclo[8.6.1.0^
{1,12}.0^{6,17}]heptadeca-6,8,10
(17),15-tetraen-14-ol
Molecular
form
ula:C 1
7H22BrNO3
Molecular
weigh
t:368.26548g/mol
Catego
ry:C
holinesterase
inhibitor
Mechanism
:Reversibleandcompetitiveacetylcholinesterase
inhibitio
nleadingto
anincreasedconcentrationof
acetylcholineat
cholinergicsynapses;m
odulates
nicotin
icacetylcholinereceptor;m
ayincrease
glutam
ateand
serotoninlevels
Effect:N
ootrop
icagent,cholinesterase
inhibitor,parasympathom
imeticeffect
Pathog
enicgenes:APOE,APP
Mechanisticgenes:AC
HE,BCHE,CH
RNA4,C
HRN
A7,C
HRN
B2Drugmetabolism-related
genes:
–Substrate:CYP2D6(m
ajor),CYP3A4
(major),UGT1A1
–Inhibitor:AC
HE,BCHE
Nam
e:Mem
antin
ehydrochloride,41100-52-1,N
amenda,M
emantin
eHCL,A
xura,3
,5-dimethyl-1-adamantanamine
hydrochloride,3,5-dimethyladamantan-1-am
inehydrochloride
IUPA
Cname:3,5-dimethyladamantan-1-am
ine;hydrochloride
Molecular
form
ula:C 1
2H22ClN
Molecular
weigh
t:215.76278g/mol
Catego
ry:N
-methyl-D-aspartate
receptor
antago
nist
Mechanism
:Binds
preferentially
toNMDAreceptor-operatedcatio
nchannels;m
ayactby
blocking
actio
nsof
glutam
ate,mediatedin
partby
NMDAreceptors
Effect:D
opam
ineagent,antip
arkinson
agent,excitatory
aminoacid
antago
nist,antidyskinetic
Pathog
enicgenes:APOE,MAPT,PSEN
1Mechanisticgenes:CH
RFAM
7A,D
LGAP1,FO
S,GRIN2A,G
RIN2B,G
RIN3A,
HOMER1,HTR3A
Drugmetabolism-related
genes:
–Inhibitor:CYP1A2
(weak),C
YP2A6(weak),C
YP2B6(stron
g),C
YP2C9(weak),
CYP2C19(weak),C
YP2D
6(stron
g),C
YP2E1(weak),C
YP3A4(weak),N
R1I2
Transportergenes:NR1I2
Pleiotropicgenes:APOE,MAPT,MT-TK,P
SEN1
Nam
e:Rivastigminetartrate,1
29101-54-8,SDZ-EN
A713,
Rivastigminehydrog
entartrate,R
ivastig
mineHydrogen
Tartrate,ENA713,
ENA-713
IUPA
Cname:(2R,3R)-2,3-dihydroxybutanedioicacid;[3-[(1S)-1-(dimethylamino)ethyl]p
henyl]N-ethyl-N-
methylcarbamate
Molecular
form
ula:C 1
8H28N2O
8
Molecular
weigh
t:400.42352g/mol
Catego
ry:C
holinesterase
inhibitor
Mechanism
:Increases
acetylcholinein
CNSthroug
hreversible
inhibitio
nof
itshydrolysisby
cholinesterase
Effect:N
europrotectiveagent,cholinesterase
inhibitor,cholinergicagent
Pathog
enicgenes:APOE,APP,
CHAT
Mechanisticgenes:AC
HE,BCHE,CH
AT,C
HRN
A4,C
HRN
B2Drugmetabolism-related
genes:
–Inhibitor:AC
HE,BCHE
Pleiotropicgenes:APOE,MAPT
Nam
e:Tacrinehydrochloride,TacrineHCl,1
684-40-8,H
ydroam
inacrin
e,tacrine.HCl,9
-amino-1,2,3,4-
tetrahydroacrid
inehydrochloride,Tenakrin
IUPA
Cname:1,2,3,4-tetrahydroacrid
in-9-amine;hydrochloride
Molecular
form
ula:C 1
3H15ClN2
Molecular
weigh
t:234.7246
g/mol
Catego
ry:C
holinesterase
inhibitor
Mechanism
:Elevatesacetylcholinein
cerebral
cortex
byslow
ingdegradationof
acetylcholine
Effect:N
ootrop
icagent,cholinesterase
inhibitor,parasympathom
imeticeffect
Pathog
enicgenes:APOE
Mechanisticgenes:AC
HE,BCHE,CH
RNA4,C
HRN
B2Drugmetabolism-related
genes:
–Substrate:CYP1A2
(major),CYP2D6(m
inor),CYP3A4
(major)
–Inhibitor:AC
HE,BCHE,CYP1A2
(weak)
Transportergenes:SCN1A
Pleiotropicgenes:APOE,CES1,G
STM1,GSTT1,LEPR,
MTH
FR
ABCB1:
ATPbind
ingcassette
subfam
ilyBmem
ber1;
ACHE:
Acetylcholinesterase
(Ytbloodgrou
p);A
POE:
Apolipop
rotein
E;APP
:Amyloidbeta
precursorprotein;
BCHE:
butyrylcho
linesterase;C
ES1:
Carboxylesterase
1;CHAT:
CholineO-acetyltransferase;
CHRFA
M7A
:CH
RNA7
(exons
5-10)andFA
M7A
(exons
A-E)
fusion
;CHRNA4:
Cholinergicreceptor
nicotin
icalph
a4subu
nit;CHRNA7:
Cholinergicreceptor
nicotin
icalph
a7subu
nit;
CHRNB2:
Cholinergicreceptor
nicotin
icbeta
2subu
nit;CYP1
A2:
CytochromeP450,fam
ily1,subfam
ilyA,
polypeptide2;CYP2
A6:
CytochromeP450,fam
ily2,subfam
ilyA,
polypeptide6;CYP2
B6:
CytochromeP450,fam
ily2,
subfam
ilyB,
polypeptide6;
CYP2
C9:
CytochromeP450,family
2,subfam
ilyC,
polypeptide9;
CYP2
C19
:CytochromeP450,family
2,subfam
ilyC,
polypeptide19;CYP2
D6:
CytochromeP450,family
2,subfam
ilyD,
polypeptide6;
CYP2
E1:CytochromeP450,family
2,subfam
ilyE,
polypeptide1;
CYP3
A4:
CytochromeP450,family
3,subfam
ilyA,
polypeptide4;
DLG
AP1
:Discs
largeho
molog
associated
protein1;
FOS:
FBJmurine
osteosarcomaviralo
ncog
eneho
molog
;GRIN2A
:glutamateiono
trop
icreceptor
NMDAtype
subu
nit2A
;GRIN2B
:glutamateiono
trop
icreceptor
NMDAtype
subu
nit2B;G
RIN3A
:glutamateiono
trop
icreceptor
NMDAtype
subu
nit3A
;GST
M1:
Glutathione
S-transferasemu1;
GST
T1:Glutathione
S-transferasetheta1;
HOMER
1:Hom
erho
molog
1(Drosoph
ila);HTR
3A:5-Hydroxytryptaminereceptor
3A;LE
PR:Leptin
receptor;MAPT
:Microtubu
leassociated
proteintau;
MT-TK
:thymidinekinase
2,mito
chon
drial;MTH
FR:M
ethylenetetrahydrofolate
redu
ctase(NAD
(P)H);NR1/2:
Nuclear
receptor
1/2;
PSEN
1:Presenilin1;
SCN1A
:Sod
ium
voltage-gated
channelalpha
subu
nit1;
UGT1
A1:
UDPglucuron
osyltransferase1family,p
olypeptid
eA1
;UGTs:U
DPglucuron
osyltransferases.
EXPERT REVIEW OF PRECISION MEDICINE AND DRUG DEVELOPMENT 7
mitochondria, has been implicated in AD [54]. APOE-TOMM40genotypes have been shown to modify disease risk and age atonset of symptoms [54]. The first pharmacogenetic study ofthe APOE-TOMM40 region in AD patients receiving a multi-factorial treatment revealed that (i) TOMM40 poly T-S/S carriersare the best responders, VL/VL and S/VL carriers are intermedi-ate responders, and L/L carriers are the worst responders totreatment (Figure 4); (ii) patients harboring a large (L) numberof poly T repeats in intron 6 of the TOMM40 gene (L/L or S/Lgenotypes) in haplotypes associated with APOE-4 are theworst responders to treatment; (iii) patients with short (S)TOMM40 poly T variants (S/S genotype), and to a lesser extentS/VL and VL/VL carriers, in haplotypes with APOE-3 are thebest responders to treatment; and (iv) in 100% of the cases,the L/L genotype is exclusively associated with the APOE-4/4genotype, and this haplotype (4/4-L/L) is probably responsiblefor early onset of the disease, a faster cognitive decline, and apoor response to different treatments [29,31,53].
5.3. Pharmacogenomics of cardio-cerebro-vascular riskfactors
The cerebrovascular component of AD has been extensivelystudied at the phenotypic and genotypic levels[23,24,26,31,55]. AD patients present concomitant disordersincluding hypertension (20–30%), overweightness or obesity(20–40%), diabetes (20–25%), hypercholesterolemia (>40%),anemia (>20%), metabolic deficiencies (>15%), atherosclerosis(>60%), cardiovascular disease (>40%), and cerebrovasculardamage (60%), which require additional treatments [31,55].
The appropriate therapeutic intervention on these vascularrisk factors may be beneficial for brain function; however,routine treatments with conventional drugs for the treatmentof most of these concomitant ailments can be deleterious forpatients with dementia.
5.3.1. Hypercholesterolemia and dyslipidemiaAlterations in CHO metabolism are very frequent in dementia(>40%) [56]. Under certain PGx conditions, statins may bebeneficial in AD, though clinical evidence is conflicting [57].The potential beneficial effect of statins and reduction in ADrisk varied across statin molecules, sex, race/ethnicity, and PGx[58,59]. Statins might facilitate Aβ-protein degradation, regu-lation of CHO in lipid rafts, suppression of inflammation, andinhibition of oxidative stress [60]. The pleiotropic effects ofstatins (simvastatin, atorvastatin, cerivastatin, fluvastatin, pra-vastatin, rosuvastatin) are apparently APOE-independent;however, APOE is a fundamental factor in the regulation oflipid metabolism, and APOE variants influence the therapeuticeffect of most hypolipemic compounds, including statins[20,31,55]. In combination studies [atorvastatin (10 mg/day)+ LipoFishins (LipoEsar, 500 mg/day) for 1 month] [31,55,61],the response rate (RR) was 78.96% responders (CHO < baselinelevels) and 21.04% non-responders (CHO ≥ baseline levels)after 1 month of treatment. The stratification of patientsaccording to their APOE, APOB, APOC3, CETP, and LPL geno-types (Figure 2) showed no genotype-related differences atbasal CHO levels, except in the case of APOE-4 carriers, wherethe highest baseline levels of CHO were found [31].Pentagenic haplotypes integrating all possible variants of the
Figure 3. APOE-related therapeutic response to a multifactorial treatment in patients with Alzheimer’s disease.MMSE: Mini-Mental State Examination.AD patients were stratified according to their APOE genotypes (APOE-2/3, APOE-2/4, APOE-3/3, APOE-3/4, APOE-4/4). Patients received a multifactorialtreatment as specified [53] and their cognitive function was assessed with the MMSE test at baseline (BL), and after 1 month (1M), 3 months (3M), 6 months (6M), 9 months (9M) and12 months (12M) after treatment.
8 R. CACABELOS
APOE + APOB + EPOC3 + CETP + LPL genes identified 111haplotypes with differential basal CHO levels. About 75% ofthese haplotypes have a frequency below 1%, and only 4% ofthe haplotypes are present in more than 5% of AD patients[31]. The results of APOE-related CHO response to hypolipemictreatment in hypercholesterolemic AD patients revealed thatin absolute terms all APOE variants respond similarly (RR >70%) to treatment, with a significant reduction in CHO levels;however, individual genotype-related correlation analysis andcomparative correlation analyses of APOE variants show aclear differential APOE-related pattern of CHO response totreatment [31]. A similar effective response (RR > 80%) wasfound among APOB-C/C, APOB-C/T, and APOB-T/T carriers,APOC3-C/C, APOC3-C/G, and APOC3-G/G carriers, CETP-A/A,CETP-A/G, and CETP-G/G carriers, and LPL-C/C, LPL-C/G, andLPL-G/G carriers, with very mild variation among differentgenotypes, except in the case of LPL-C/C carriers, who behaveas the best responders, whereas LPL-C/G patients showed anintermediate response, and LPL-G/G patients exhibited themost uneven response to hypolipemic treatment [31,55].
CYP haplotype-related blood total CHO levels are very hetero-geneous. Basal CHO levels are higher in AD patients harboringthe CYP2D6-*1/*1 and *1xN/*1 genotypes than in the generalpopulation, but no differences have been found according to theEM, IM, PM, or UM condition [31,55]. The therapeutic responseaccording to SNPs of metabolic genes (CYP2D6, CYP2C9,CYP2C19, CYP3A4/4) in hypercholesterolemic patients is variableand geno-phenotype-dependent. Although all CYP2D6 variantsexhibit a positive response to treatment, significant differenceshave only been detected in 2D6-*1/*1, 2D6-*1/*4, and 2D6-*1/*6
carriers. CYP2D6 EMs, IMs, PMs, and UMs behave in a similarmanner, with a significant reduction in CHO levels. Carriers ofmutant enzymes (PMs > UMs) tend to display a more efficientresponse to hypolipemic treatment [31]. EMs also show a sig-nificant reduction in transaminase activity, reflecting an improve-ment in liver function, as compared to PMs (Figure 5). Nodifferences are present in basal CHO levels between the generalpopulation and AD patients related to CYP2C9 genotypes.CYP2C9-EMs, IMs, and PMs show a similar response, with lowerRR (75%) in PMs as compared with EMs (81%) and IMs (82%).CYP2C9-EMs are also very efficient in reducing transaminaseactivity (Figure 5). AD cases harboring the CYP2C19-*1/*2 geno-type, corresponding to CYP2C19-IMs, exhibit higher basal CHOlevels than their homologs in the general population. The CHOresponse among CYP2C19-EMs, IMs, PMs, and UMs is more vari-able, with PMs showing a deficient response in comparison toEMs, IMs, and UMs, and a clearly different behavioral profile,especially in PMs and UMs [31]. CYP3A4/5 geno-phenotypes inAD and the general population show similar basal CHO levels.CYP3A4/5-RMs respond poorly to hypolipemic treatment, withthe worst RR (66%), whereas CYP3A4/5-EMs and IMs exhibit anexcellent response (RR>80%)[31].
Statin metabolism is regulated by CYP3A4/5, CYP2C8/9,CYP2C19, CYP2D6, UGT1A1, UGT1A3, and UGT2B7 enzymes[62]. In the case of Atorvastatin, pathogenic (ACE, APOA1,APOA5, APOB, APOC3, APOE, CETP, FGB, GNB3, LIPC, MMP3,MTTP, NOS3, PON), mechanistic (ABCB1, ABCC1, APOA1,APOA5, APOB, APOC3, APOE, CRP, CYP11B2, HMGCR, IL10,IL6, LDLR, MMP3, PON1, TNF), metabolic, transporter(ABCA1, ABCB1, ABCB11, ABCC1, ABCC2, ABCC3, ABCG2,
Figure 4. TOMM40-Poly-T-related therapeutic response to a multifactorial therapy in patients with Alzheimer’s disease.MMSE: Mini-Mental State Examination. AD patients were stratified according to their TOMM40-Poly T genotypes (TOMM40-S/S, S/L, S/VL, L/L, L/VL, VL/VL). Patients received a multifactorialtreatment as specified [53] and their cognitive function was assessed with the MMSE test at baseline (BL), and after 1 month (1M), 3 months (3M), 6 months (6M), 9 months (9M) and12 months (12M) after treatment.
EXPERT REVIEW OF PRECISION MEDICINE AND DRUG DEVELOPMENT 9
SLCO1B1, SLCO1B3), and pleiotropic genes (APOA1, APOE,CRP, CYP11B2, ESR1, GNB3, HTR3B, IL6, IL10, ITGB3, MMP3,TNF, USP5) are involved in its pharmacological effects.Atorvastatin is a major substrate of CYP2C8 and CYP3A4/5;it is a strong inhibitor of CYP2C19, a moderate inhibitor ofABCB1, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6,CYP3A4, and HMGCR, and an inducer of CYP2B6 andCYP7A1 [19,20,31]. The deficient CYP3A4 enzyme inCYP3A4*22 (rs35599367) carriers alters the pharmacokineticsand pharmacodynamics of simvastatin, atorvastatin, andlovastatin [63], and the CYP3A5*3 (rs776746) variant (loss-of-function allele) causes a high increase in the bioavailabil-ity of simvastatin [64]. The powerful effect of atorvastatin inCYP3A4/5-IMs is the result of a poor metabolization ofatorvastatin by mutant CYP3A4/5 enzymes since atorvasta-tin is a major substrate of CYP3A4/5. In contrast, the lack ofeffect in CYP3A4/5-RMs results from a rapid destruction ofthe drug in the liver mediated by excessive CYP3A4/5 enzy-matic activity.
HMGCR variants (rs17244841, rs3846662, rs17238540) (H7haplotype) are responsible for an attenuated lipid-loweringresponse to statins [62]. HMGCR alternative splicing may
explain 22–55% of the variance in statin response in hyperch-olesterolemic patients [65].
SLCO1B1 gene variants alter transport of statins into theliver. SLCO1B1-521C (rs4149056) is associated with diminishedeffects of statins [66]. ABCB1-1236T (rs1128503), 2677T(rs2032582), and 3435T (rs1045642) variants (TTT haplotype),and SNPs of other transporters (ABCC2, ABCG2, ABCB11,SLC15A1, SLC22A6, SLC22A8, SLCO2B1, SCLO1B3, SLCO1B3)potentially affect statin transport and metabolism [62]. TheLILRB5 (leukocyte immunoglobulin-like receptor subfamily-B)variant (rs12975366: T > C: Asp247Gly) is associated with lowercreatine phosphokinase and lactate dehydrogenase levels andwith statin intolerance and statin-induced myopathy [67].
5.3.2. HypertensionOver 20% of AD patients are hypertensive and receive differ-ent modalities of hypotensive agents [i.e. central α-adrenergicagonists, vasodilators, diuretics, nitrates, nitrites, phosphodies-terase inhibitors, calcium channel blockers, angiotensin-con-verting enzyme inhibitors (ACEIs), angiotensin II receptorantagonists, mineralocorticoid (aldosterone) receptor antago-nists, renin inhibitors]. Hypertension is associated with the
CYP2D6-Related ASAT Response to Atorvastatin+LipoEsar
CYP2D6-Related ASAT Levels in Alzheimer's disease
CYP2D6-EM-B CYP2D6-EM-T CYP2D6-IM-B CYP2D6-IM-T CYP2D6-PM-B CYP2D6-PM-T CYP2D6-UM-B CYP2D6-UM-T0
10
20
30
40
50
60ASAT (IU/L)
meansd
N=149
N=29
CYP2D6-UM
N=308
N=31
CYP2D6-EM CYP2D6-IM CYP2D6-PM
p=0.006CYP2D6 (N=517)EMs: 308 (59.57%)IMs: 149 (28.82%)PMs: 29 (5.61%)UMs: 31 (6.00%)
CYP2D6-Related ALAT Response to Atorvastatin+LipoEsar
CYP2D6-Related ALAT Levels in Alzheimer's disease
CYP2D6-EM-B CYP2D6-EM-T CYP2D6-IM-B CYP2D6-IM-T CYP2D6-PM-B CYP2D6-PM-T CYP2D6-UM-B CYP2D6-UM-T0
10
20
30
40
50
60
70ALAT (IU/L)
meansdN=149
N=29
CYP2D6-UM
N=308 N=31
CYP2D6-EM CYP2D6-IM CYP2D6-PM
p=0.01
CYP2D6 (N=517)EMs: 308 (59.57%)IMs: 149 (28.82%)PMs: 29 (5.61%)UMs: 31 (6.00%)
N=308
N=149
ME
sv10.0
=p
MIsv
20.0=
p
CYP2C9-Related ASAT Response to Atorvastatin+LipoEsar
CYP2C9-Related ASAT Levels in Alzheimer's disease
CYP2C9-EM-B CYP2C9-EM-T CYP2C9-IM-B CYP2C9-IM-T CYP2C9-PM-B CYP2C9-PM-T0
10
20
30
40
50
60
ASAT (IU/L)
meansd
N=178
N=297
N=27
CYP2C9-EM
CYP2C9 (N=502)EMs: 297 (59.16%)IMs: 178 (35.46%)PMs: 27 (5.38%)
CYP2C9-IM CYP2C9-PM
p=0.01
p=0.05p=0.99
CYP2C9-Related ALAT Response to Atorvastatin+LipoEsar
CYP2C9-Related ALAT Levels in Alzheimer's disease
CYP2C9-EM-B CYP2C9-EM-T CYP2C9-IM-B CYP2C9-IM-T CYP2C9-PM-B CYP2C9-PM-T0
10
20
30
40
50
60
ALAT (IU/L)
meansd
N=178
N=297
N=27
CYP2C9-EM
CYP2C9 (N=502)EMs: 297 (59.16%)IMs: 178 (35.46%)PMs: 27 (5.38%)
CYP2C9-IM CYP2C9-PM
p=0.05
CYP2C9-Related GGT Response to Atorvastatin+LipoEsar
CYP2C9-Related GGT Levels in Alzheimer's disease
CYP2C9-EM-B CYP2C9-EM-T CYP2C9-IM-B CYP2C9-IM-T CYP2C9-PM-B CYP2C9-PM-T0
20
40
60
80
GGT (IU/L)
meansd
N=178
N=297N=27
CYP2C9-EM
CYP2C9 (N=502)EMs: 297 (59.16%)IMs: 178 (35.46%)PMs: 27 (5.38%)
CYP2C9-IM CYP2C9-PM
p=0.05
CYP2D6-Related GGT Response to Atorvastatin+LipoEsar
CYP2D6-Related GGT Levels in Alzheimer's disease
CYP2D6-EM-B CYP2D6-EM-T CYP2D6-IM-B CYP2D6-IM-T CYP2D6-PM-B CYP2D6-PM-T CYP2D6-UM-B CYP2D6-UM-T0
20
40
60
80
100
120GGT (IU/L)
meansd
N=149 N=29
CYP2D6-UM
N=308
N=31
CYP2D6-EM CYP2D6-IM CYP2D6-PM
p=0.05
CYP2D6 (N=517)EMs: 308 (59.57%)IMs: 149 (28.82%)PMs: 29 (5.61%)UMs: 31 (6.00%)
N=308 N=149
Figure 5. CYP2D6- and CYP2C9-related response of transaminase activity (ASAT, ALAT, GGT) to a hypolipemic treatment with Atorvastatin + LipoEsar inhypercholesterolemic patients with Alzheimer’s disease.B: Basal values; T: Treatment; EM: Extensive Metabolizers; IM: Intermediate Metabolizers; PM: Poor Metabolizers; UM: Ultra-Rapid Metabolizers.Patients received Atorvastatin (10 mg/day)and LipoEsar (500 mg/day) for one month. ASAT, ALAT and GGT values were analyzed according to the condition of CYP2D6-EM, IM, PM and UM; and CYP2C9-EM, IM and PM.
10 R. CACABELOS
worsening of cognitive function [68] and is a potentially mod-ifiable risk factor for AD [69]. Both hypotension and hyperten-sion may induce deleterious effects on brain function,cognition, and psychomotor praxis. Therefore, the persona-lized treatment of hypertension is a worthwhile interventionin dementia. Systolic blood pressure (SBP) tends to be higherin AD than in the control population with no family history ofdementia; in contrast, diastolic blood pressure (DBP) does notshow differences between both groups. Among AD cases,15.81% of patients are hypotensive (SBP < 120 mm Hg),57.60% are normotensive (SBP: 120–150 mm Hg), and26.59% are hypertensive (SBP > 150 mm Hg). Regarding DBP,9.80% are hypotensive (DBP < 70 mm Hg), 65.47% normoten-sive (DBP: 70–85 mm Hg), and 24.73% hypertensive (DBP >85 mm Hg). Hypertension is almost 50% less frequent in thecontrol population than in the AD cohort [55].
Basic and clinical studies suggest that some hypotensiveagents may affect AD neuropathology and cognition [70].ACEIs and angiotensin receptor blockers are common antihy-pertensive treatments, but have differential effects on corticalamyloid [70]. Moreover, these agents may improve cognitionin an APOE-dependent fashion [71] and their effects can beoptimized with PGx [72].
A recent PGx study in hypertensive AD patients withenalapril (10–20 mg/day) for 1 month revealed that APOE,NOS3, ACE, AGT (Figure 2), and CYP2D6, 2C19, 2C9, and 3A4/5 variants (Figure 1) differentially influence the effect of thisACE inhibitor. APOE-3/3 and APOE-3/4 carriers respondedwith significant reductions in SBP and DBP values; andAPOE-4 carriers tended to show higher hypertensive levelsthan APOE-4 non-carriers. NOS3-G/G carriers responded bet-ter than NOS3-G/T>NOS3-T/T carriers. Polymorphic variantsof the ACE rs4332 (547C>T) SNP did not show any effect;however, ACE-I/D carriers of the Alu 287 bp Indel I/D exhib-ited a better response than ACE-D/D and ACE-I/I carriers inSBP, and ACE-I/I carriers responded better in DBP than ACE-D/D and ACE-I/D. The clearest response was observedamong AGT-A/A and AGT-A/G carriers, who responded sig-nificantly better than AGT-G/G carriers. CYP2D6-, CYP2C19-,and CYP2C9-EMs and IMs were better responders that PMsor UMs. CYP3A4/5 variants did not show any effect onblood pressure changes [55]. To date, 48 genes show evi-dence of involvement in blood pressure regulation [73].
5.3.3. Cardiovascular functionNearly 50% of AD patients show cardiovascular disorders suscep-tible to pharmacological treatment. In population studies, cleardifferences have been found in the electrocardiogram (EKG) ofAD patients as compared with that of age-matched apparentlyhealthy controls. AD patients show a normal EKG in 48.56% ofthe cases, borderline EKG in 8.00%, and abnormal EKG in 43.44%.In the control population, EKG is normal in 60% of the subjects,borderline in 11.47%, and abnormal in 25.33% [55].
Cardiovascular drugs are frequently given to elderly sub-jects and demented patients. However, the use of PGx proce-dures in cardiovascular disorders is very limited and thecombination of cardiotonics, antihypertensives, lipid-loweringdrugs, and anti-dementia drugs may bring about severe
complications that might be preventable with a PGx-guidedprescription [74].
5.4. Pharmacogenomics of dementia-relatedneuropsychiatric disorders
The prescription of psychotropic drugs (i.e. antipsychotics, antide-pressants, benzodiazepines, hypnotics, sedatives) to patients withdementia is very frequent (>80%) for the treatment of behavioralchanges, agitation, depression, anxiety, and alterations in circadianrhythms (Tables 4 and 5). All neuroleptic drugs (Table 4) exertdeleterious effects on cognitive and psychomotor function,increasing lipid levels and weight gain, cardio- and cerebrovascu-lar risk, movement disorders, and mortality [75,76]. This is particu-larly important in the case of typical antipsychotics. Atypicalantipsychotic drugs (Table 4) show some advantages and tendto be less detrimental for cognitive impairment and psychomotoractivity [77,78]. There is an increasing interest in the use of PGxprocedures for personalized treatment with antipsychotics in thepsychiatric and psychogeriatric community, though the routineuse of PGx in schizophrenics and demented patients is very scarce[77,78]. PGx would contribute to reduce the inappropriate use ofneuroleptics in demented patients, as well as to diminishunwanted side effects, domestic accidents such as falls, and car-dio-cerebro-vascular damage [78,79].
About 70% of depressive patients taking antidepressants(Table 5) by trial and error, according to conventional prescrip-tion protocols, receive an inappropriate medication with unsa-tisfactory results [80]. Rectification of the prescription accordingto the PGx profile of the patients enables the obtaining of anefficacy ratio over 80% [80]. Available PGx tools can effectivelyhelp physicians to improve prescription accuracy, with substan-tial benefits for patients with mood disorders [19,80–83].
6. Pharmacoepigenomics
PGx alone does not explain in full all phenotypic variations indrug response [25,84,85]. The PMMTP cluster of genes poten-tially involved in the pharmacogenomic network are under theregulatory control of the epigenetic machinery (DNA methyla-tion, histone/chromatin modifications, miRNA regulation), thisconfiguring the pharmacoepigenomic apparatus [25,85–88].Epigenetics involves heritable alterations of gene expressiontranscriptionally and post-transcriptionally without changes inDNA sequence. Methylation varies spatially across the genome,with a majority of the methylated sites mapping to intragenicregions. About 70% of CpG dinucleotides within the humangenome are methylated. Not only nuclear DNA (nDNA), but alsomitochondrial DNA (mtDNA) may be subjected to epigeneticmodifications related to disease development, environmentalexposure, drug treatment, and aging [25,88].
Epigenetic aberrations participate in AD pathogenesis.Alterations in DNA methylation, chromatin/histone function, andmiRNA regulation have been found in several genes associatedwith AD [89,90]. Epigenetic regulation is responsible for the tissue-specific expression of genes involved in pharmacogenetic pro-cesses, and epigenetics plays a key role in the development ofdrug efficacy, safety, and resistance. Variable methylation patternshave been detected in genes encoding Phase I–III enzymes.
EXPERT REVIEW OF PRECISION MEDICINE AND DRUG DEVELOPMENT 11
Table4.
Pharmacolog
icalprofile
andph
armacog
enom
icsof
atypical
antip
sychoticsandtypicalb
utyrop
heno
nes.
Atypical
antip
sychotics
Drug
Prop
erties
Pharmacog
enetics
Nam
e:Aripiprazole;1
29722-12-9;A
bilify;Ab
ilitat;Ab
ilify
Discm
elt;OPC
-1459
IUPA
Cname:7-{4-[4-(2,3-dichlorop
henyl)p
iperazin-1-yl]b
utoxy}-1,2,3,4-tetrahydroq
uino
lin-2-
one
Molecular
form
ula:448.38538g/mol
Molecular
weigh
t:C 2
3H27Cl2N
3O2
Mechanism
:Partialago
nistat
theD2and5-HT 1
Areceptors,andas
anantago
nistat
the5-HT 2
A
receptor.
Effect:A
ntipsychoticagent;H1-receptor
antago
nist;seroton
ergicagon
ist.
Pathog
enicgenes:DRD
2,DRD
3,HTR1A,H
TR2A,H
TR2C
Mechanisticgenes:AD
RA1A,D
RD2,DRD
3,DRD
4,HRH
s,HTR1A,H
TR2A,H
TR2B,H
TR2C,H
TR7
Metabolicgenes:
Substrate:CYP2D6(m
ajor),CYP3A4
(major),CYP3A5
Transportergenes:AB
CB1
Nam
e:Asenapinemaleate;Saphris;O
rg5222
maleate;85650-56-2;Org
5222
maleate;O
rg-5222
maleate
IUPA
Cname:(2Z)-but-2-enedioicacid;1
7-chloro-4-m
ethyl-13-oxa-4-azatetracyclo
[12.4.0.02
,6.07,12]octadeca-1(14),7,9,11,15,17-hexaene
Molecular
form
ula:C 2
1H20ClNO5
Molecular
weigh
t:401.8402
g/mol
Mechanism
:Itsmainactivity
isassociated
tocombinatio
nof
antago
nisticactio
nsat
D2and5-
HT 2
Areceptors.
Effect:A
ntipsychoticagent;do
paminergicantago
nist;seroton
ergicantago
nist;alpha-
adrenergicantago
nist;b
eta-adrenergicantago
nist.
Pathog
enicgenes:AD
RA2A,D
RD1,DRD
2,DRD
3,DRD
4,HTR1A,H
TR2A,H
TR2C,H
TR7
Mechanisticgenes:AD
RA1A,A
DRA
2A,A
DRA
2B,A
DRA
2C,D
RD1,DRD
2,DRD
3,DRD
4,HRH
1,HRH
2,HTR1A,H
TR1B,H
TR2A,H
TR2B,H
TR2C,H
TR5A,H
TR6,HTR7
Metabolicgenes:
Substrate:CYP1A1,C
YP1A2(m
ajor),CYP2D6(m
inor),CYP3A4
(minor),UGT1A4
Inhibitor:CYP2D6(weak)
Nam
e:Clozapine;Lepo
nex;Fazaclo;
Iprox;CLOZA
RIL;Clozapin
IUPA
Cname:6-chloro-10-(4-m
ethylpiperazin-1-yl)-2,9-diazatricyclo[9.4.0.03,8 ]pentadeca-1
(15),3,5,7,9,11,13-heptaene
Molecular
form
ula:C 1
8H19ClN4
Molecular
weigh
t:326.82326g/mol
Mechanism
:Itshow
sserotonergic,adrenergic,andcholinergicneurotransmitter
system
sin
additio
nto
moreselective,region
allyspecificeffectson
themesolimbicdo
paminergic
system
.Italso
displays
antago
nisticactivity
atH1-receptors
Effect:D
opam
inergicantago
nist;seroton
ergicantago
nist;h
istamineantago
nist;m
uscarin
icantago
nist;G
ABAantago
nist;G
ABAmod
ulator;antipsychoticagent.
Pathog
enicgenes:AD
RA2A,D
RD1,DRD
2,DRD
3,DRD
4,DTN
BP1,HTR2A,LPL,N
RXN1,TN
FMechanisticgenes:AD
RAs,CH
RMs,DRD
1,DRD
2,DRD
3,DRD
4,HRH
1,HTR1F,H
TR2A,H
TR2C,
HTR3A,H
TR6,NRXN1
Metabolicgenes:
Substrate:CYP1A2
(major),CYP2A6
(minor),CYP2C8
(minor),CYP2C9
(minor),CYP2C19(m
inor),
CYP2D6(m
inor),CYP3A4/5
(major),FM
O3,UGT1A1,U
GT1A3,U
GT1A4
Inhibitor:CYP1A2
(weak),C
YP2C9(m
oderate),C
YP2C19
(mod
erate),C
YP2D
6(m
oderate),
CYP2E1
(weak),C
YP3A4(weak)
Transportergenes:AB
CB1
Pleiotropicgenes:APOA5,A
POC3,A
POD,C
NR1,FAB
P1,G
NB3,G
SK3B,LPL,R
GS2,TNF
Nam
e:Iloperid
one;Zomaril;133454-47-4;
Fanapt;Fanapta;H
P873
IUPA
Cname:1-(4-{3-[4-(6-fluoro-1,2-benzoxazol-3-yl)p
iperidin-1-yl]p
ropo
xy}-3-metho
xyph
enyl)
ethan-1-on
eMolecular
form
ula:C 2
4H27FN
2O4
Molecular
weigh
t:426.480583
g/mol
Mechanism
:Ithasmixed
D2/5-HT 2
antago
nistactivity.Itexhibitshigh
affin
ityfor5-HT 2
A,D
2,andD3receptors,lowto
mod
erateaffin
ityforD1,D4,H1,5-HT 1
A,5-HT 6,5HT 7,and
ADR α
1/α2C
receptors,andno
affin
ityformuscarin
icreceptors.Ithaslow
affin
ityforhistam
ineH1
receptors.
Effect:A
ntipsychoticagent;do
paminergicantago
nist;seroton
ergicantago
nist;antidepressant
effects;anxiolyticactivity;reductio
nof
riskforweigh
tgain;cog
nitivefunctio
nimproved.
Pathog
enicgenes:AD
RA2A,C
NTF,D
RD1,DRD
2,DRD
3,DRD
4,HTR2A,H
TR7,NRG
3Mechanisticgenes:AD
RA1A,A
DRA
2A,A
DRA
2B,A
DRA
2C,A
DRB1,AD
RB2,DRD
1,DRD
2,DRD
3,DRD
4,DRD
5,GFRA2,G
RIA4,H
RH1,HTR1A,H
TR2A,H
TR2C,H
TR6,HTR7,NPAS3,N
UDT9P1,TNR,
XKR4
Metabolicgenes:
Substrate:CYP1A2,C
YP2E1,CYP2D6(m
ajor),CYP3A4
(major)
Transportergenes:SLC6A2,SLCO3A1
Pleiotropicgenes:AD
RB2,CELF4,CERKL,DRD
5,HTR1F,N
PAS3,N
RG3,NUBPL,PALLD (C
ontin
ued)
12 R. CACABELOS
Table4.
(Con
tinued).
Atypicalantip
sychotics
Drug
Prop
erties
Pharmacog
enetics
Nam
e:Lurasido
ne;Latud
a;(3aR,4S,7R,7aS)-2-((1
R,2R)-2-(4-(1,2-Benzothiazol-3-yl)p
iperazin-1-
ylmethyl)cyclohexylmethyl)h
exahydro-4,7-m
ethano
-2H-isoind
ole-1,3-dion
e;UNII-
22IC88528T;C
HEBI:70735;3
67514-87-2
IUPA
Cname:(1R,2S,6R,7S)-4-{[(1R,2R)-2-{[4-(1,2-benzothiazol-3-yl)p
iperazin-1-yl]m
ethyl}
cycloh
exyl]m
ethyl}-4-azatricyclo[5.2.1.0²,⁶]decane-3,5-dion
eMolecular
form
ula:C 2
8H36N4O
2SMolecular
weigh
t:492.67604g/mol
Mechanism
:Com
binatio
nof
centrald
opam
inetype
2(D
2)andserotonintype
2(5HT 2
A)
receptor
antago
nism
s.Inadditio
n,thisagentisan
antago
nistwith
high
affin
ityat
dopamine
5-HT 7,isan
antago
nistwith
mod
erateaffin
ityat
human
α 2C-adrenergicreceptors,isapartial
agon
istat
serotonin5-HT 1
Areceptors,andisan
antago
nist
atα 2
A-adrenergicreceptors.It
exhibitslittle
orno
affin
ityforhistam
ineH1andmuscarin
icM1receptors.
Effect:A
ntipsychoticagent;adrenergicantago
nist;d
opam
inergicantago
nist;seroton
ergic
antago
nist.
Pathog
enicgenes:AD
RA2A,D
RD2,HTR2A,H
TR7
Mechanisticgenes:AD
RA2A,A
DRA
2C,B
DNF,DRD
2,HRH
1,CH
RM1,HTR1A,H
TR2A,H
TR7
Metabolicgenes:
Substrate:CYP3A4
(major)
Nam
e:Olanzapine;Zyprexa;132539-06-1;
ZyprexaZydis;Olansek;Sym
byax
IUPA
Cname:5-methyl-8-(4-methylpiperazin-1-yl)-4-thia-2,9-diazatricyclo[8.4.0.0³,⁷]tetradeca-1
(14),3(7),5,8,10,12-hexaene
Molecular
form
ula:C 1
7H20N4S
Molecular
weigh
t:312.4325
g/mol
Mechanism
:Itdisplays
potent
antago
nism
ofserotonin5-HT 2
Aand5-HT 2
C,d
opam
ineD1-4,
histam
ineH1andα 1-adrenergicreceptors.Itshow
smod
erateantago
nism
of5-HT 3
and
muscarin
icM1-5receptors,andweakbind
ingto
GAB
A-A,
BZD,and
β-adrenergicreceptors.
Effect:A
ntipsychoticagent;GAB
Amod
ulator;m
uscarin
icantago
nist;seroton
inup
take
inhibitor;
dopaminergicantago
nist;seroton
ergicantago
nist;h
istamineantago
nist;antiemeticactivity.
Pathog
enicgenes:CO
MT,DRD
1,DRD
2,DRD
3,DRD
4,GRM
3,HTR2A,H
TR2C,LPL
Mechanisticgenes:AB
CB1,AD
RA1A,A
DRB3,AH
R,BD
NF,CH
RM1,CH
RM2,CH
RM3,CH
RM4,
CHRM
5,CO
MT,DRD
1,DRD
2,DRD
3,DRD
4,GAB
Rs,G
RIN2B,H
RH1,HTR2A,H
TR2C,H
TR3A,H
TR6,
LEP,
RGS2,R
GS7,SLC6A4,STAT3,TM
EM163
Metabolicgenes:
Substrate:CO
MT,CYP1A2
(major),CYP2C9,C
YP2D
6(m
ajor),CYP3A43,CYP3A5,FMO1,FM
O3,
GSTM3,TPMT,UGT1A1,U
GT1A4,U
GT2B10
Inhibitor:AB
CB1,CYP1A2
(weak),C
YP2C9(weak),C
YP2C19
(weak),C
YP2D
6(weak),C
YP3A4
(weak)
Indu
cer:GSTM1,MAO
B,SLCO
3A1
Transportergenes:KCNH2,SLC6A2,SLC6A4,SLCO
3A1
Pleiotropicgenes:APOA5,A
POC3,G
NB3,LEP,LEPR,
LPL
Nam
e:Paliperidon
e;Paliperidon
e;9-Hydroxyrisperid
one;Invega;1
44598-75-4;9
-OH-
risperid
one;Invega
Sustenna
IUPA
Cname:3-{2-[4-(6-fluoro-1,2-benzoxazol-3-yl)p
iperidin-1-yl]ethyl}-9-hydroxy-2-methyl-
4H,6H,7H,8H,9H-pyrido[1,2-a]pyrim
idin-4-one
Molecular
form
ula:C 2
3H27FN
4O3
Molecular
weigh
t:426.483883
g/mol
Mechanism
:Mixed
centralseroton
ergicanddo
paminergicantago
nism
.Dem
onstrateshigh
affin
ityto
α 1,D
2,H1,and5-HT 2
Creceptors,andlow
affin
ityformuscarin
icand5-HT 1
A
receptors.
Effect:A
ntipsychoticagent;neurop
rotectiveagent;H1-receptor
antago
nist;alpha-adrenergic
antago
nist;seroton
ergicantago
nist;d
opam
inergicantago
nist.
Pathog
enicgenes:AD
RA2A,D
RD2,HTR2A
Mechanisticgenes:AD
RA1A,A
DRA
1B,A
DRA
1D,A
DRA
2s,B
DNF,DRD
2,HRH
1,HTR1A,H
TR2A,
HTR2C
Metabolicgenes:
Substrate:AD
H,C
YP2D
6(minor),CYP3A4/5
(major),UGTs
Inhibitor:AB
CB1,CYP2D6(m
oderate),C
YP3A4/5(m
oderate)
Transportergenes:AB
CB1
Nam
e:Quetiapine
fumarate;Seroqu
el;Q
uetiapine
hemifumarate;111974-72-2;
Seroqu
elXR
;UNII-2S3PL1B6UJ
IUPA
Cname:2-[2-(4-{2-thia-9-azatricyclo[9.4.0.0³,⁸]pentadeca-1(15),3,5,7,9,11,13-heptaen-10-yl}
piperazin-1-yl)ethoxy]ethan-1-ol
Molecular
form
ula:C 4
6H54N6O
8S2
Molecular
weigh
t:883.08636g/mol
Mechanism
:Antagon
istat
multip
leneurotransmitter
receptors:serotonin5-HT 1
Aand5-HT 2,
dopamineD1andD2,histam
ineH1,andadrenergicα 1-andα 2-receptors.
Effect:A
ntipsychoticagent;adrenergicantago
nist;h
istamineantago
nist;seroton
ergic
antago
nist;d
opam
inergicantago
nist;sedativeactivity;o
rtho
statichypo
tension.
Pathog
enicgenes:AD
RA2A,D
RD1,DRD
2,DRD
4,HTR1A,H
TR2A,R
GS4
Mechanisticgenes:AD
RA1s,ADRA
2s,BDNF,CH
RM1,CH
RM3,CH
RM5,DRD
1,DRD
2,DRD
4,HRH
1,HTR1A,H
TR1E,H
TR2A,H
TR2B,H
TR7
Metabolicgenes:
Substrate:CYP2D6(m
inor),CYP3A4/5
(major),CYP3A7,C
YP2C19
Inhibitor:AB
CB1,SLC6A2
Transportergenes:AB
CB1,KCNE1,K
CNE2,K
CNH2,KCNQ1,SCN5A,SLC6A2
(Con
tinued)
EXPERT REVIEW OF PRECISION MEDICINE AND DRUG DEVELOPMENT 13
Table4.
(Con
tinued).
Atypicalantip
sychotics
Drug
Prop
erties
Pharmacog
enetics
Nam
e:Risperidon
e;Risperdal;Risperidal;1
06266-06-2;R
isperdalCo
nsta;R
ispo
lept
IUPA
Cname:3-{2-[4-(6-fluoro-1,2-benzoxazol-3-yl)p
iperidin-1-yl]ethyl}-2-methyl-
4H,6H,7H,8H,9H-pyrido[1,2-a]pyrim
idin-4-one
Molecular
form
ula:C 2
3H27FN
4O2
Molecular
weigh
t:410.484483
g/mol
Mechanism
:Antagon
istat
multip
leneurotransmitter
receptors:serotonin5-HT 1
Aand5-HT 2,
dopamineD1andD2,histam
ineH1,andadrenergicα 1-andα 2-receptors.
Effect:A
ntipsychoticagent;H1-receptor
antago
nist;dop
aminergicantago
nist;alpha-adrenergic
antago
nist;seroton
ergicantago
nist;som
nolence;orthostatic
hypo
tension.
Pathog
enicgenes:AD
RA2A,B
DNF,CO
MT,DRD
1,DRD
2,DRD
3,DRD
4,GRM
3,HTR2A,H
TR2C,
HTR7,PO
N1,RG
S4Mechanisticgenes:AD
RA1A,A
DRA
1B,A
DRA
2s,D
RD1,DRD
2,DRD
3,DRD
4,FO
S,HTR2A,H
TR2C,
HTR3A,H
TR3C,H
TR6,HTR7,NR1I2,STAT3
Metabolicgenes:
Substrate:CO
MT,CYP2D6(m
ajor),CYP3A4/5
(minor)
Inhibitor:AB
CB1,CYP2D6(weak),C
YP3A4(weak)
Indu
cer:MAO
BTransportergenes:AB
CB1,KCNH2,SLC6A4
Pleiotropicgenes:APOA5,B
DNF,RG
S2
Nam
e:Ziprasidon
e;Geodo
n;146939-27-7;
Zeldox;Z
iprazido
ne;Z
iprasido
nehydrochloride
IUPA
CNam
e:5-{2-[4-(1,2-benzothiazol-3-yl)p
iperazin-1-yl]ethyl}-6-chloro-2,3-dihydro-1H-in
dol-
2-on
eMolecular
form
ula:C 2
1H21ClN4OS
Molecular
weigh
t:412.93564g/mol
Mechanism
:Ithashigh
affin
ityforD2,D3,5-HT 2
A,5
-HT 1
A,5
-HT 2
C,5
-HT 1
D,and
α1-adrenergic,
andmod
erateaffin
ityforhistam
ineH1receptors.Itfunctio
nsas
antago
nistat
D2,5-HT 2
A,
and5-HT 1
Dreceptorsandas
agon
istat
5-HT 1
Areceptor.Itmod
eratelyinhibits
reup
take
ofserotoninandno
repineph
rine.
Effect:A
ntipsychoticagent;histam
ineantago
nist;d
opam
inergicantago
nist;seroton
ergic
antago
nist;m
uscarin
icantago
nist;seroton
in–n
orepinephrinereup
take
inhibitor.
Pathog
enicgenes:DRD
2,DRD
3,DRD
4,HTR1A,H
TR2A,H
TR2C,R
GS4
Mechanisticgenes:AD
RA1A,D
RD2,DRD
3,HRH
1,HTR1A,H
TR1B,H
TR1D
,HTR2A,H
TR2C
Metabolicgenes:
Substrate:AO
X1(m
ajor),CYP1A2
(minor),CYP3A4
(major)
Inhibitor:CYP2D6(m
oderate),C
YP3A4(m
oderate),SLC6A2,SLC6A4
Transportergenes:KCNH2,SLC6A2,SLC6A4
Pleiotropicgenes:CH
RM1,RRAS2
Typicalan
tipsycho
tics
(butyrop
heno
nes)
Nam
e:Benp
eridol;Frenactil;Glianimon
;Con
cilium;Frenactyl;2
062-84-2
IUPA
Cname:3-[1-[4-(4-fluorop
henyl)-4-oxob
utyl]piperidin-4-yl]-1H
-benzimidazol-2-one
Molecular
form
ula:C 2
2H24FN
3O2
Molecular
weigh
t:381.443263
g/mol
Mechanism
:Blockspo
stsynapticmesolimbicdo
paminergicD1andD2receptorsin
thebrain.It
depressesthereleaseof
hypo
thalam
icandhypo
physealh
ormon
es.Itisbelievedto
depress
thereticular
activatingsystem
.Effect:A
ntipsychoticagent;do
pamineantago
nist;libido-redu
cing
effects;antiemesis.
Mechanisticgenes:DRD
1,DRD
2,KCNH2
Pleiotropicgenes:DRD
2
Nam
e:Brom
perid
ol;Improm
en;B
romop
eridol;Tesop
rel;10457-90-6;A
zurene
IUPA
Cname:4-[4-(4-brom
ophenyl)-4-hydroxypiperidin-1-yl]-1-(4-fluorop
henyl)b
utan-1-one
Molecular
form
ula:C 2
1H23BrFN
O2
Molecular
weigh
t:420.315223
g/mol
Mechanism
:Potentdo
paminergicD2antago
nist.H
asweakα 1-adrenoliticactivity.Itisa
mod
erateserotonin5-HT 2
antago
nist.H
asno
antih
istaminicor
anticho
linergiceffects.Itacts
onthemesocortex,lim
bicsystem
,and
basalg
anglia
(nigrostriate
pathway).
Effect:A
ntipsychoticagent;do
pamineantago
nist;α
1-adreno
liticactivity.
Pathog
enicgenes:DRD
2,HTR2A
Mechanisticgenes:DRD
2,HTR2A
Metabolicgenes:
Substrate:CYP2D6(m
inor),CYP3A4
(major),UGTs
Inhibitor:CYP2D6(m
oderate)
Transportergenes:AB
CB1
(Con
tinued)
14 R. CACABELOS
Table4.
(Con
tinued).
Atypicalantip
sychotics
Drug
Prop
erties
Pharmacog
enetics
Nam
e:Halop
eridol;H
aldo
l;Eukystol;Serenace;Alop
eridin;A
loperid
olIUPA
Cname:4-[4-(4-chloroph
enyl)-4-hydroxypiperidin-1-yl]-1-(4-fluorop
henyl)b
utan-1-one
Molecular
form
ula:C 2
1H23ClFN
O2
Molecular
weigh
t:375.864223
g/mol
Mechanism
:Halop
eridol
isabu
tyroph
enon
eantip
sychoticwhich
blocks
postsynaptic
mesolimbicdo
paminergicD1andD2receptorsin
brain.
Depresses
releaseof
hypo
thalam
icandhypo
physealh
ormon
es.B
elievedto
depressreticular
activatingsystem
.Effect:A
ntipsychoticagent;serotonergicantago
nist;d
opam
inergicantago
nist;antiemetic;
antid
yskinesiaagent;sedativeeffects;hypo
tension.
Pathog
enicgenes:AD
RA2A,B
DNF,DRD
1,DRD
2,DRD
4,DTN
BP1,GRIN2B,H
TR2A
Mechanisticgenes:AN
KK1,BD
NF,CO
MT,DRD
1,DRD
2,DTN
BP1,GRIN2A,G
RIN3B,G
RIN2C,
GRIN2B,SLC6A3
Metabolicgenes:
Substrate:CBR1,C
YP1A1(m
inor),CYP1A2
(minor),CYP2A6,C
YP2C8(m
inor),CYP2C9
(minor),
CYP2C19(m
inor),CYP2D6(m
ajor),CYP3A4/5
(major),GSTP1,U
GTs
Inhibitor:AB
CB1,CYP2D6(m
oderate),C
YP3A4(m
oderate)
Transportergenes:AB
CB1,AB
CC1,KCNE1,K
CNE2,K
CNH2,KCNJ11,KCNQ1,SLC6A3
Pleiotropicgenes:CH
RM2,FO
S,GSK3B,H
RH1,HTR2A,H
TT,IL1RN
ABCB1:
ATP-bind
ingcassette,sub
-fam
ilyB(M
DR/TA
P),m
ember1
;ABCC1:
ATP-bind
ingcassette,sub
-fam
ilyC(CFTR/MRP),mem
ber1
;ADHs:Alcoho
ldehydrogenases;ADRA1A
:adrenoceptora
lpha
1A;A
DRA1B
:adrenoceptor
alph
a1B;A
DRA1D
:adrenoceptoralph
a1D
;ADRA1s:alpha
1-adrenergicreceptor
family;A
DRA2A
:adrenoceptoralph
a2A
;ADRA2B
:adrenoceptoralph
a2B;A
DRA2C
:adrenoceptoralph
a2C;A
DRA2s:alpha
2-adrenergic
receptor
family;A
DRAs:alph
a-adrenergicreceptor
family;A
DRB1:
adreno
ceptor
beta
1;ADRB2:
adreno
ceptor
beta
2,Surface;
ADRB3:
adreno
ceptor
beta
3;AHR:arylh
ydrocarbon
receptor;A
NKK1:
ankyrin
repeat
and
kinase
domaincontaining
1;AOX1
:aldehydeoxidase1;
APO
A5:
apolipop
rotein
A-V;
APO
C3:
apolipop
rotein
C-III;A
POD:apo
lipop
rotein
D;B
DNF:
brain-derived
neurotroph
icfactor;C
BR1:
carbon
ylredu
ctase1;
CEL
F4:
CUGBP,Elav-like
family
mem
ber4;
CER
KL:
ceramidekinase-like;CHRM1:
cholinergicreceptor,muscarin
ic1;
CHRM2:
cholinergicreceptor,muscarin
ic2;
CHRM3:
cholinergicreceptor,muscarin
ic3;
CHRM4:
cholinergic
receptor,muscarin
ic4;
CHRM5:
cholinergicreceptor,muscarin
ic5;
CHRMs:
muscarin
iccholinergicreceptor
family;CNR1:
cann
abinoid
receptor
1(brain);
CNTF
:ciliary
neurotroph
icfactor;COMT:
catechol-O-
methyltransferase;
CYP1
A1:
cytochromeP450,family
1,subfam
ilyA,
polypeptide1;
CYP1
A2:
cytochromeP450,family
1,subfam
ilyA,
polypeptide2;
CYP2
A6:
cytochromeP450,family
2,subfam
ilyA,
polypeptide6;
CYP2
C8:
cytochromeP450,fam
ily2,subfam
ilyC,po
lypeptide8;CYP2
C9:
cytochromeP450,fam
ily2,subfam
ilyC,po
lypeptide9;CYP2
D6:
cytochromeP450,fam
ily2,subfam
ilyD,polypeptid
e6;CYP2
E1:cytochrom
eP450,
family
2,subfam
ilyE,po
lypeptide1;CYP3
A4:
cytochromeP450,fam
ily3,subfam
ilyA,
polypeptide4;CYP3
A4/5:
cytochromeP450,fam
ily3,subfam
ilyA,
polypeptide4/5;CYP3
A5:
cytochromeP450,fam
ily3,subfam
ilyA,
polypeptide5;
CYP3
A7:
cytochromeP450,fam
ily3,
subfam
ilyA,
polypeptide7;
CYP3
A43
:cytochrom
eP450,fam
ily3,
subfam
ilyA,
polypeptide43;D
RD1:
dopaminereceptor
D1;
DRD2:
dopaminereceptor
D2;
DRD3:
dopaminereceptor
D3;DRD4:
dopaminereceptor
D4;DRD5:
dopaminereceptor
D5;DTN
BP1
:dystrob
revinbind
ingprotein1;FA
BP1
:fatty
acid
bind
ingprotein1,liver;F
MO1:
flavincontaining
mon
ooxygenase
1;FM
O3:
flavincontaining
mon
ooxygenase
3;FO
S:FBJmurineosteosarcomaviralo
ncog
eneho
molog
;GABRs:gamma-am
inob
utyricacid
(GAB
A)receptors;GFR
A2:
GDNFfamily
receptor
alph
a2;GNB3:
guaninenu
cleotid
ebind
ing
protein(G
protein),b
etapo
lypeptide3;GRIA4:
glutam
atereceptor,ion
otropic,AM
PA4;GRIN2A
:glutamatereceptor,ion
otropic,N-m
ethylD
-aspartate
2A;G
RIN2B
:glutamatereceptor,ion
otropic,N-m
ethylD
-aspartate
2B;
GRIN2C
:glutamatereceptor,ion
otropic,N-m
ethylD
-aspartate
2C;G
RIN3B
:glutamatereceptor,ion
otropic,N-m
ethyl-D
-aspartate
3B;G
RM3:
glutam
atereceptor,m
etabotropic3;
GSK
3B:g
lycogensynthase
kinase
3beta;
GST
M1:
glutathion
eS-transferasemu1;GST
M3:
glutathion
eS-transferasemu3(brain);GST
P1:glutathione
S-transferasepi
1;HRH1:
histam
inereceptor
H1;HRH2:
histam
inereceptor
H2;HRHs:histam
inereceptor
family;
HTR
1A:5
-hydroxytryptamine(seroton
in)receptor
1A,G
protein-coup
led;
HTR1B;5
-hydroxytryptamine(seroton
in)receptor
1B,G
protein-coup
led;
HTR
1D:5
-hydroxytryptamine(seroton
in)receptor
1D,G
protein-coup
led;
HTR
1E:5
-hydroxytryptamine(seroton
in)receptor
1E,G
protein-coup
led;
HTR
1F:5
-hydroxytryptamine(seroton
in)receptor
1F,G
protein-coup
led;
HTR
2A:5
-hydroxytryptamine(seroton
in)receptor
2A,G
protein-coup
led;
HTR
2B:5-hydroxytryptamine(seroton
in)receptor2B,G
protein-coup
led;HTR
2C:5-hydroxytryptamine(seroton
in)receptor2C,G
protein-coup
led;HTR
3A:5-hydroxytryptamine(seroton
in)receptor3A
,ion
otropic;HTR
3C:5-
hydroxytryptam
ine(seroton
in)receptor
3C,iono
trop
ic;HTR
5A:5-hydroxytryptam
ine(seroton
in)receptor
5A,G
protein-coup
led;
HTR
6:5-hydroxytryptam
ine(seroton
in)receptor
6,G
protein-coup
led;
HTR
7:5-hydro-
xytryptamine(seroton
in)receptor7,adenylatecyclase-coup
led;HTT
:hun
tingtin;IL1
RN:interleukin
1receptor
antago
nist;K
CNE1
:potassium
channel,voltage
gatedsubfam
ilyEregu
latory
beta
subu
nit1;KCNE2
:potassium
channel,voltage
gatedsubfam
ilyEregu
latory
beta
subu
nit2;KCNH2:
potassium
channel,voltage
gatedeagrelatedsubfam
ilyH,m
ember2;KCNJ11:
potassium
channel,inwardlyrectifyingsubfam
ilyJ,mem
ber11;K
CNQ1:
potassium
channel,voltage
gatedKQ
T-likesubfam
ilyQ,m
ember1;LE
P:leptin;LEP
R:leptin
receptor;LPL
:lipop
rotein
lipase;MAOB:m
onoamineoxidaseB;NPA
S3:neuronalPAS
domainprotein3;NR1I2:
nuclearreceptor
subfam
ily1,
grou
pI,mem
ber2;
NRG3:
neuregulin
3;NRXN
1:neurexin
1;NUBPL
:nucleotidebind
ingprotein-like;NUDT9
P1:n
udix(nucleosidediph
osph
atelinkedmoietyX)-typemotif9pseudo
gene
1;PA
LLD:alladin,
cytoskeletalassociated
protein;
PON1:
paraoxon
ase1;RGS2
:regulator
ofG-protein
sign
aling2;RGS4
:regulator
ofG-protein
sign
aling4;RGS7
:regulator
ofG-protein
sign
aling7;RRAS2
:related
RASviral(r-ras)on
cogene
homolog
2;SC
N5A
:sod
ium
channel,voltage
gated,type
Valph
asubu
nit;SLC6A
2:solute
carrierfamily
6(neurotransm
itter
transporter),m
ember2;SLC6A
3:solute
carrierfamily
6(neurotransm
itter
transporter),m
ember3;
SLC6A
4:solute
carrierfamily
6(neurotransm
itter
transporter),mem
ber4;
SLCO3A
1:solute
carrierorganicaniontransporterfamily,mem
ber3A
1;ST
AT3
:sign
altransducer
andactivator
oftranscrip
tion3(acute-phase
respon
sefactor);TM
EM16
3:transm
embraneprotein163;TN
F:tumor
necrosisfactor;TNR:
tenascin
R;TP
MT:
thiopu
rineS-methyltransferase;UGT1
A1:
UDPglucuron
osyltransferase1family,p
olypeptid
eA1
;UGT1
A3:
UDP
glucuron
osyltransferase1family,p
olypeptid
eA3
;UGT1
A4:
UDPglucuron
osyltransferase1family,p
olypeptid
eA4
;UGT2
B10
:UDPglucuron
osyltransferase2family,p
olypeptid
eB10;
UGTs:g
lucurono
syltransferasefamily;
XKR4:
XK,K
ellb
lood
grou
pcomplex
subu
nit-relatedfamily,m
ember4.
EXPERT REVIEW OF PRECISION MEDICINE AND DRUG DEVELOPMENT 15
Table5.
Pharmacolog
icalprofile
andph
armacog
eneticsof
selected
antid
epressants.
Tricyclics(TCA
)andotherno
repineph
rine-reup
take
inhibitors
Drug
Prop
erties
Pharmacog
enetics
Nam
e:Am
itriptylinehydrochloride;An
noyltin
;AmitriptylineHCl;5
49-18-8;
Tryptizol;D
omical
IUPA
Cname:dimethyl(3-{tricyclo[9.4.0.0³,⁸]pentadeca-1(15),3,5,7,11,13-hexaen-2-ylidene}prop
yl)amine
Molecular
form
ula:C 2
0H24ClN
Molecular
weigh
t:313.86426g/mol
Catego
ry:Tricyclics
Mechanism
:Increases
synapticconcentrationof
serotoninand/or
norepineph
rinein
thecentraln
ervous
system
byinhibitin
gtheirreup
take
inthepresynaptic
neuron
almem
brane.
Effect:A
drenergicup
take
inhibitio
n;antim
igraineactivity;analgesic(non
-narcotic)activity;antidepressant
actio
n.
Pathog
enicgenes:AB
CB1,GNB3,H
TRs,NTRK2,SLC6A4,TN
FMechanisticgenes:AD
RA1A,H
TRs,NTRK1,N
TRK2
Metabolicgenes:
Substrate:AB
CB1,CYP1A2
(minor),CYP2B6
(minor),CYP2C9
(minor),CYP2C19
(minor),CYP2D6(m
ajor),CYP3A4/5
(major),GSTP1,U
GT1A3,U
GT1A4,U
GT2B10
Inhibitor:AB
CB1,AB
CC2,AB
CG2,CYP1A2
(mod
erate),C
YP2C9(m
oderate),
CYP2C19(m
oderate),C
YP2D
6(m
oderate),C
YP2E1(weak)
Transportergenes:AB
CB1,AB
CC2,AB
CG2,KCNE2,KCN
H2,KCNQ1,SCN5A,SLC6A4
Pleiotropicgenes:FABP1,GNAS,G
NB3,N
TRK1,TNF
Nam
e:Am
oxapine;Asendin;
Dem
olox;1
4028-44-5;
Asendis;Moxadi
IUPA
Cname:13-chloro-10-(piperazin-1-yl)-2-oxa-9-azatricyclo[9.4.0.0³,⁸]pentadeca-1(11),3,5,7,9,12,14-
heptaene
Molecular
form
ula:C 1
7H16ClN3O
Molecular
weigh
t:313.78144g/mol
Catego
ry:Tricyclics
Mechanism
:Reduces
reup
take
ofserotoninandno
repineph
rine.Themetabolite,7
-OH-amoxapine,has
sign
ificant
dopaminereceptor-blockingactivity.
Effect:Seroton
inup
take
inhibitio
n;adrenergicup
take
inhibitio
n;do
pamineantago
nism
;neurotransm
itter
uptake
inhibitio
n;antid
epressantactio
n;anti-anxietyactivity.
Pathog
enicgenes:GNB3,SLC6A4
Mechanisticgenes:AD
RA1A,A
DRA
2A,C
HRM
s,DRD
1,DRD
2,GAB
Rs,G
ABBRs,HTRs
Metabolicgenes:
Substrate:CYP2D6(m
ajor)
Transportergenes:SLC6A2,SLC6A4
Pleiotropicgenes:DRD
2,GNAS,G
NB3
Nam
e:Clom
ipraminehydrochloride;An
afranil;Clom
ipramineHCL;1
7321-77-6;
Anaphranil;3-(3-chloro-
10,11-dihydro-5H
-dibenzo[b,f]azepin-5-yl)-N,N-dimethylpropan-1-am
inehydrochloride
IUPA
Cname:(3-{14-chloro-2-azatricyclo[9.4.0.0³,⁸]pentadeca-1(11),3,5,7,12,14-hexaen-2-yl}propyl)
dimethylamine
Molecular
form
ula:C 1
9H24Cl2N
2
Molecular
weigh
t:351.31326g/mol
Catego
ry:Tricyclics
Mechanism
:Itisastrong
,but
notcompletelyselectiveserotoninreup
take
inhibitor;as
itsactivemain
metabolite
desm
ethylclomipramineactspreferablyas
aninhibitorof
noradrenalinereup
take.α
1-receptor
blockage
andβ-dow
n-regu
latio
nhave
been
notedandmostlikelyplay
arolein
itsshortterm
effects.Ablockade
ofsodium
-chann
elsandNDMA-receptors.
Effect:Seroton
inup
take
inhibitio
n;antid
epressantactio
n;anti-anxietyactivity;antiobsession
aleffects;
analgesiceffects.
Pathog
enicgenes:HTR2A,SLC6A4
Mechanisticgenes:AD
RA1s,C
HRM
s,CH
RNs,HRH
1,HTR2s,H
TR3
Metabolicgenes:
Substrate:CYP1A2
(major),CYP2A6,C
YP2B6,CYP2C19(m
ajor),CYP2D6(m
inor),
CYP3A4
(major),CYP3A5
(major),UGT1A4
Inhibitor:CYP2C9
(mod
erate),C
YP2C19
(stron
g),C
YP2D
6(m
oderate),G
STP1,
SLC6A4
Transportergenes:SLC6A4
Pleiotropicgenes:FABP1,PTGS2
Nam
e:Desipraminehydrochloride;Norpram
in;D
esipramineHCl;D
MIh
ydrochlorid
e;Pertofrane;P
ertofran
IUPA
Cname:(3-{2-azatricyclo[9.4.0.0³,8]pentadeca-1(15),3,5,7,11,13-hexaen-2-yl}propyl)(methyl)amine
Molecular
form
ula:C 1
8H23ClN2
Molecular
weigh
t:302.84162g/mol
Catego
ry:Tricyclics
Mechanism
:Increases
thesynapticconcentrationof
norepineph
rineintheCN
Sby
inhibitio
nof
itsreup
take
bythepresynaptic
neuron
almem
brane.Ad
ditio
nalreceptoreffectsinclud
ingdesensitizatio
nof
adenyl
cyclase,do
wn-regu
latio
nof
β-adrenergicreceptors,anddo
wn-regu
latio
nof
serotoninreceptors.
Effect:Enzym
einhibitio
n;adrenergicup
take
inhibitio
n;antid
epressantactio
n;analgesicactivity.
Pathog
enicgenes:AB
CB1,CRHR1,C
RHR2,FKBP5,H
TR1A,IL1B,
NR3C1,N
TRK2,
PDE5A,
SLC6A4,TBX21
Mechanisticgenes:AD
CY1,AD
RA1A,ADRBs,CH
RMs,HTR1A,IFN
A1,PDE1C,PSMD9,
PRKCSH
,STAT3
Metabolicgenes:
Substrate:CYP1A2
(minor),CYP2C9,C
YP2D
6(m
ajor)
Inhibitor:AB
CB1,CYP2A6
(mod
erate),C
YP2B6(m
oderate),C
YP2C19
(mod
erate),
CYP2D6(m
oderate),C
YP2E1(weak),C
YP3A4(m
oderate),SLC6A2,SLC22A3
Transportergenes:AB
CB1,SLC6A2,SLC6A3,SLC6A4,SLC22A3
Pleiotropicgenes:NTRK2,FOS
(Con
tinued)
16 R. CACABELOS
Table5.
(Con
tinued).
Tricyclics(TCA
)andotherno
repineph
rine-reup
take
inhibitors
Drug
Prop
erties
Pharmacog
enetics
Nam
e:Doxepin
hydrochloride;Sileno
r;Ad
apin;N
ovoxapin;Toruan;
Curatin
IUPA
Cname:dimethyl(3-{9-oxatricyclo[9.4.0.0³,⁸]pentadeca-1(15),3,5,7,11,13-hexaen-2-ylidene}prop
yl)
amine
Molecular
form
ula:C 1
9H22ClNO
Molecular
weigh
t:315.83708g/mol
Catego
ry:Tricyclics
Mechanism
:Itincreasesthesynapticconcentrationof
serotoninandno
repineph
rinein
theCN
Sby
inhibitio
nof
theirreup
take
bythepresynaptic
neuron
almem
brane.
Effect:A
drenergicup
take
inhibitio
n;histam
ineantago
nism
;antidepressantactio
n;analgesiceffects;
pruritu
sredu
ction.
Pathog
enicgenes:AB
CB1,SLC6A4
Mechanisticgenes:AD
RBs,CH
RMs,HRH
1,HRH
2,HTRs
Metabolicgenes:
Substrate:CYP1A1
(minor),CYP1A2
(minor),CYP2C9
(minor),CYP2C19(m
ajor),
CYP2D6(m
ajor),CYP3A4/5
(minor),GSTP1,U
GT1A3,U
GT1A4
Inhibitor:CYP2C19(stron
g),C
YP2D
6(m
oderate)
Transportergenes:AB
CB1,KCNH2,SLC6A2,SLC6A4
Nam
e:Imipraminehydrochloride;Tofranil;ImipramineHCl;1
13-52-0;
Chimoreptin
;Feinalmin
IUPA
Cname:(3-{2-azatricyclo[9.4.0.0³,⁸]pentadeca-1(15),3,5,7,11,13-hexaen-2-yl}propyl)d
imethylamine
Molecular
form
ula:C 1
9H25ClN2
Molecular
weigh
t:316.8682
g/mol
Catego
ry:Tricyclics
Mechanism
:Itbind
sthesodium
-dependent
serotonintransporterandsodium
-dependent
norepineph
rine
transporterpreventin
gor
redu
cing
thereup
take
ofno
repineph
rineandserotoninby
nervecells.It
causes
down-regu
latio
nof
cerebralcorticalbeta-adrenergicreceptors.
Effect:A
drenergicup
take
inhibitio
n;antid
epressantactio
n;antienu
retic
effects;analgesicactivity;attentio
nenhancer.
Pathog
enicgenes:AB
CB1,BD
NF,HTR2A,SLC6A4
Mechanisticgenes:AD
RB2,DRD
2,CH
RMs,HTR2A,SCN
sMetabolicgenes:
Substrate:CYP1A2
(minor),CYP2B6
(minor),CYP2C19(m
ajor),CYP2D6(m
ajor),
CYP3A4
(minor),CYP3A7,G
STP1,U
GT1A3,U
GT1A4,U
GT2B10
Inhibitor:CYP1A2
(weak),C
YP2C9(m
oderate),C
YP2C19
(weak),C
YP2D
6(m
oderate),C
YP2E1(weak),C
YP3A4(m
oderate),FMO1,SLC22A2,SLC22A3
Transportergenes:AB
CB1,SLC6A2,SLC6A4,SLC22A2,SLC22A3
Pleiotropicgenes:AD
RB2,BD
NF,FABP1,FO
S,ORM
1
Nam
e:Maprotilinehydrochloride;Ludiom
il;Psym
ion;
MaprotilineHCl;1
0347-81-6;
MaprotilineHCl
IUPA
Cname:methyl(3-{tetracyclo[6.6.2.0²,⁷.0⁹,¹⁴]hexadeca-2,4,6,9,11,13-hexaen-1-yl}propyl)amine
Molecular
form
ula:C 2
0H24ClN
Molecular
weigh
t:313.86426g/mol
Catego
ry:Tetracyclics
Mechanism
:Inh
ibits
presynaptic
uptake
ofcatecholam
ines,thereby
increasing
theirconcentrationat
the
synapticcleft.Acts
asan
antago
nist
atcentralp
resynapticα2-adrenergicinhibitory
autoreceptorsand
hetero-receptors.Itisalso
amod
erateperip
heralα
1adrenergicantago
nistanditisastrong
inhibitorof
thehistam
ineH1receptor.Italso
inhibitstheam
inetransporter,delaying
thereup
take
ofno
radrenaline
andno
repineph
rine.
Effect:A
drenergicup
take
inhibitio
n;antid
epressantactio
n;sedativeactio
n;anxiolyticeffects;hypo
tensive
effects.
Pathog
enicgenes:AB
CB1
Mechanisticgenes:AD
RA2s,A
DRA
1s,C
HRM
4,CH
RM5,HRH
1Metabolicgenes:
Substrate:CYP1A2
(minor),CYP2C19,CYP2D6(m
ajor),CYP3A4
Inhibitor:MAO
B,SLC6A2
Transportergenes:AB
CB1,SLC6A2
Nam
e:Mianserin
hydrochloride;21535-47-7;A
thym
il;Mianserinehydrochloride;Mianserin
HCl;B
olvido
nIUPA
Cname:5-methyl-2,5-diazatetracyclo[13.4.0.0²,⁷.0⁸,¹³]non
adeca-1(19),8,10,12,15,17-hexaene
Molecular
form
ula:C 1
8H21ClN2
Molecular
weigh
t:300.82574g/mol
Catego
ry:Tetracyclics
Mechanism
:Increases
centraln
oradrenergicneurotransmission
byα2-autoreceptor
blockade
and
noradrenaline-reup
take
inhibitio
n.In
additio
n,interactions
with
serotoninreceptorsin
CNShave
been
foun
d.Effect:Seroton
inantago
nism
;histamineH1antago
nism
(antihistaminicactio
n);adrenergicalph
a-antago
nism
;antidepressantagent;hypn
osedativeactivity.
Pathog
enicgenes:HTR2A
Mechanisticgenes:AD
RA2A,H
RH1,HTR2s
Metabolicgenes:
Substrate:CYP1A2,C
YP2B6,CYP2D6(m
ajor),CYP3A4
(major),UGTs
Inhibitor:SLC6A2
Transportergenes:SLC6A2
(Con
tinued)
EXPERT REVIEW OF PRECISION MEDICINE AND DRUG DEVELOPMENT 17
Table5.
(Con
tinued).
Tricyclics(TCA
)andotherno
repineph
rine-reup
take
inhibitors
Drug
Prop
erties
Pharmacog
enetics
Nam
e:Nortriptylinehydrochloride;Pamelor;A
llegron
;Altilev;Nortrilen;
894-71-3
IUPA
Cname:methyl(3-{tricyclo[9.4.0.0³,⁸]pentadeca-1(15),3,5,7,11,13-hexaen-2-ylidene}prop
yl)amine
Molecular
form
ula:C 1
9H22ClN
Molecular
weigh
t:299.83768g/mol
Catego
ry:Tricyclics
Mechanism
:Inh
ibits
thereup
take
oftheneurotransmitter
serotoninat
theneuron
almem
braneor
actsat
beta-adrenergicreceptors.Ithasadditio
nalreceptoreffectsinclud
ingdesensitizatio
nof
adenylcyclase,
down-regu
latio
nof
β-adrenergicreceptors,anddo
wn-regu
latio
nof
serotoninreceptors.
Effect:A
drenergicup
take
inhibitor;antid
epressantagent;analgesicactivity;h
ypno
sedativeactivity.
Pathog
enicgenes:AB
CB1,GNB3,H
TR1B,N
R3C1,SLC6A4
Mechanisticgenes:AD
CY1,AD
RA2s,A
DRBs,GNB3,H
RH1,HTRs
Metabolicgenes:
Substrate:CYP1A2
(minor),CYP2C19(m
inor),CYP2D6(m
ajor),CYP3A4
(minor),
UGTs
Inhibitor:CYP2C8
(mod
erate),C
YP2C9(m
oderate),C
YP2C19
(mod
erate),C
YP2D
6(weak),C
YP2E1(weak),C
YP3A4(m
oderate)
Transportergenes:AB
CB1,SLC6A2,SLC6A4
Pleiotropicgenes:HTR1B
Nam
e:Protrip
tylinehydrochloride;Protrip
tylineHCl;C
oncordin;M
aximed;Trip
tyl;Triptil
hydrochloride
IUPA
Cname:methyl(3-{tricyclo[9.4.0.0³,⁸]pentadeca-1(15),3,5,7,9,11,13-heptaen-2-yl}p
ropyl)amine
Molecular
form
ula:C 1
9H22ClN
Molecular
weigh
t:299.83768g/mol
Catego
ry:Tricyclics
Mechanism
:Increases
synapticconcentrationof
serotoninand/or
norepineph
rinein
CNSby
inhibitio
nof
theirreup
take
bypresynaptic
neuron
almem
brane.
Effect:A
drenergicup
take
inhibitor;antid
epressantagent;analgesicactivity;anti-m
igraineeffect.
Mechanisticgenes:SLC6A2,SLC6A4
Metabolicgenes:
Substrate:CYP1A2
(minor),CYP2C19(m
inor),CYP2D6(m
ajor),CYP3A4
(minor)
Inhibitor:CYP1A2
(mod
erate),C
YP2C9(m
oderate),C
YP2C19
(mod
erate),C
YP2D
6(m
oderate),C
YP3A4(m
oderate)
Transportergenes:SLC6A2,SLC6A4
Pleiotropicgenes:AD
RA1A,G
NAS,ITGB3
Nam
e:Trimipramine;Sapilent;Surmon
til;B
eta-Methylim
ipramine;Trimeprim
ina
IUPA
Cname:(3-{2-azatricyclo[9.4.0.0³,8]pentadeca-1(15),3,5,7,11,13-hexaen-2-yl}-2-methylpropyl)
dimethylamine
Molecular
form
ula:C 2
0H26N2
Molecular
weigh
t:294.43384g/mol
Catego
ry:Tricyclics
Mechanism
:Increases
synapticconcentrationof
serotoninand/or
norepineph
rinein
CNSby
inhibitio
nof
theirreup
take
bypresynaptic
neuron
almem
brane
Effect:A
drenergicup
take
inhibitio
n;antid
epressantactio
n;antih
istaminicactivity;sedativeeffect.
Pathog
enicgenes:AB
CB1,SLC6A4
Mechanisticgenes:SLC6A2,SLC6A4,SLC22A1,SLC22A2
Metabolicgenes:
Substrate:CYP2C19(m
ajor),CYP2D6(m
ajor),CYP3A4/5
(major)
Inhibitor:AB
CB1
Transportergenes:SLC6A2,SLC6A4,SLC22A1,SLC22A2
Selectiveserotoninan
dno
repine
phrine
reup
take
inhibitors
(SSN
RI)
Nam
e:Desvenlafaxine;O-Desmethylvenlafaxine;93413-62-8;4-(2-(Dimethylamino)-1-(1-hydroxycyclohexyl)
ethyl)p
heno
l;4-[2-(Dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]pheno
l;Desvenlafaxine(IN
N)
IUPA
Cname:4-[2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]pheno
lMolecular
form
ula:C 1
6H25NO2
Molecular
weigh
t:263.3752
g/mol
Mechanism
:Itisapo
tent
andselectiveserotoninandno
repineph
rinereup
take
inhibitor.
Effect:Seroton
inup
take
inhibitio
n;no
repineph
rineup
take
inhibitio
n;antid
epressantactivity.
Pathog
enicgenes:AB
CB1,SLC6A4
Mechanisticgenes:HTR1A,SLC6A2,SLC6A3,SLC6A4
Metabolicgenes:
Substrate:CYP3A4
(minor),UGTs
Inhibitor:CYP2D6(weak),SLC6A2,SLC6A4
Transportergenes:AB
CB1,SLC6A2,SLC6A4
Nam
e:Duloxetinehydrochloride;136434-34-9;
DuloxetineHCl;C
ymbalta;(S)-N-M
ethyl-3-(naph
thalen-1-
yloxy)-3-(thioph
en-2-yl)p
ropan-1-am
inehydrochloride;(S)-DuloxetineHCl
IUPA
CNam
e:methyl[(3S)-3-(naphthalen-1-yloxy)-3-(thioph
en-2-yl)p
ropyl]amine
Molecular
form
ula:C 1
8H20ClNOS
Molecular
weigh
t:333.8755
g/mol
Mechanism
:Itisaselectiveserotonin-
andno
repineph
rine-reup
take
inhibitorandaweakinhibitorof
dopaminereup
take.
Effect:A
ntidepressantactivity;anti-anxiety
activity;seroton
inup
take
inhibitio
n;no
repineph
rineup
take
inhibitio
n;anti-fib
romyalgiaagent;analgesicactivity;U
rinarycontinence
improvem
ent.
Pathog
enicgenes:AB
CB1,SLC6A4
Mechanisticgenes:CO
MT,HTR1A,SLC6A2,SLC6A4
Metabolicgenes:
Substrate:CYP1A2
(major),CYP2D6(m
ajor)
Inhibitor:AB
CB1,CYP1A2
(mod
erate),C
YP2B6(m
oderate),C
YP2C19
(mod
erate),
CYP2D6(m
oderate),C
YP3A4/5(m
oderate),SLC6A2,SLC6A4
Transportergenes:AB
CB1,SLC6A2,SLC6A4
(Con
tinued)
18 R. CACABELOS
Table5.
(Con
tinued).
Tricyclics(TCA
)andotherno
repineph
rine-reup
take
inhibitors
Drug
Prop
erties
Pharmacog
enetics
Nam
e:Levomilnacipram;U
NII-UGM0326TXX;
UGM0326TXX;
Fetzima;(1S,2R)-2-(aminom
ethyl)-N,N-diethyl-
1-ph
enylcyclop
ropane-1-carbo
xamide;F2695
IUPA
Cname:(1S,2R)-2-(aminom
ethyl)-N,N-diethyl-1-phenylcycloprop
ane-1-carboxam
ide
Molecular
form
ula:C 1
5H22N2O
Molecular
weigh
t:246.34798g/mol
Mechanism
:Potentiatio
nof
serotoninandno
reph
inephrinein
thecentraln
ervous
system
throug
hinhibitio
nof
reup
take
atserotoninandno
repineph
rinetransporters.
Effect:Seroton
inup
take
inhibitio
n;no
repineph
rineup
take
inhibitio
n;antid
epressantactivity.
Pathog
enicgenes:SLC6A4
Mechanisticgenes:HCRTR1,HCRTR2,HDC,
HRH
1,SLC6A2,SLC6A4
Metabolicgenes:
Substrate:AB
CB1(m
inor),CYP2C19(m
inor),CYP2C8
(minor),CYP2D6(m
inor),
CYP2J2
(minor),CYP3A4
(major)
Transportergenes:SLC6A2,SLC6A4
Nam
e:Milnacipranhydrochloride;Toledo
min;M
idalcipran;Ixel;Savella;M
ilnacipranu
mIUPA
CNam
e:(1R,2S)-2-(aminom
ethyl)-N,N-diethyl-1-phenylcycloprop
ane-1-carboxam
ide
Molecular
form
ula:C 1
5H22N2O
Molecular
weigh
t:246.34798g/mol
Mechanism
:Itisapo
tent
inhibitorof
neuron
alno
repineph
rineandserotoninreup
take.Itinhibits
norepineph
rineup
take
with
approximatelythreefoldhigh
erpo
tencyin
vitrothan
serotoninwith
out
directlyaffectingtheup
take
ofdo
pamineor
otherneurotransmitters.
Effect:A
nalgesicactio
n;anti-fib
romyalgiaactio
n;serotoninup
take
inhibitio
n;adrenergicup
take
inhibitio
n;antid
epressantactivity.
Pathog
enicgenes:BD
NF
Mechanisticgenes:AD
RA2A,B
DNF,SLC6A2,SLC6A4
Metabolicgenes:
Substrate:CO
MT,CYP1A2
(minor),CYP2A6
(minor),CYP2B6
(minor),CYP2C8,
CYP2C9
(minor),CYP2C19(m
inor),CYP2D6(m
inor),CYP2E1
(minor),CYP3A4/5
(minor),UGTs
Inhibitor:CYP3A4/5
(mod
erate)
Indu
cer:CYP1A2,C
YP2B6,CYP2C8,C
YP2C9,CYP2C19,CYP3A4/5
Transportergenes:SLC6A2,SLC6A4
Nam
e:Venlafaxinehydrochloride;99300-78-4;V
ENLAFA
XINEHCl;Effe
xorXR
;Dob
upal;Trevilor
IUPA
Cname:1-[2-(dimethylamino)-1-(4-metho
xyph
enyl)ethyl]cyclohexan-1-ol
Molecular
form
ula:C 1
7H28ClNO2
Molecular
weigh
t:313.86272g/mol
Mechanism
:Itandits
activemetabolite,O
-desmethylvenlafaxine
(ODV),are
potent
inhibitorsof
neuron
alserotoninandno
repineph
rinereup
take
andweakinhibitorsof
dopaminereup
take.
Effect:Seroton
inup
take
inhibitio
n;no
repineph
rineup
take
inhibitio
n;antid
epressantactivity;anti-anxiety
activity,analgesiceffects.
Pathogenicgenes:AB
CB1,BD
NF,CREB1,FKBP5,HTR1A,H
TR2A,N
R3C1,SLC6A3,
SLC6A4,TPH
2Mechanisticgenes:BD
NF,FKBP5
Metabolicgenes:
Substrate:AB
CB1,CYP2C9
(minor),CYP2C19(m
inor),CYP2D6(m
ajor),CYP3A4
(major)
Inhibitor:AB
CB1,CYP1A2
(weak),C
YP2B6(weak),C
YP2D
6(weak),C
YP3A4(weak),
SLC6A2,SLC6A3,SLC6A4
Transportergenes:AB
CB1,AB
CC1,AB
CG2,SLC6A2,SLC6A3,SLC6A4
Pleiotropicgenes:DRD
2,HTR2A,TPH
2
Selectiveserotoninreup
take
inhibitors
(SSR
I)Nam
e:Citalopram
hydrob
romide;Nitalapram
;Cipram;C
elexa;Celapram
;Ciprapine
IUPA
Cname:1-[3-(dimethylamino)prop
yl]-1-(4-fluorop
henyl)-1,3-dihydro-2-benzofuran-5-carbo
nitrile
Molecular
form
ula:C 2
0H21FN
2OMolecular
weigh
t:324.391943
g/mol
Mechanism
:Selectivelyinhibitsserotoninreup
take
inthepresynaptic
neuron
sandhasminimaleffectson
norepineph
rineor
dopamine.
Effect:Seroton
inup
take
inhibitio
n;serotonergicneurotransmission
enhancer;antidepressiveactivity,
agitatio
nredu
ction,
anti-anxietyactivity.
Pathog
enicgenes:AB
CB1,BD
NF,CREB1,CRHR1,C
RHR2,FKBP5,G
RIA3,G
RIK2,
GRIK4,G
SK3B,H
TR1A,H
TR1B,H
TR2A,M
AOA,
SLC6A4,TPH
1,TPH2
Mechanisticgenes:AD
Rs,C
HRM
s,DRD
s,FKBP5,GAB
Rs,G
RIK4,H
RHs,HTR1A,
HTR1B,H
TR1D
,HTR2A,SLC6A4,TPH1
Metabolicgenes:
Substrate:AB
CC1,CO
MT,CYP2C19(m
ajor),CYP2D6(m
inor),CYP3A4
(major),
CYP3A5
Inhibitor:AB
CB1,CYP1A2
(weak),C
YP2B6(weak),C
YP2C19
(weak),C
YP2D
6(weak),M
AOA,
MAO
BTransportergenes:AB
CB1,SLC6A4
Pleiotropicgenes:BD
NF
(Con
tinued)
EXPERT REVIEW OF PRECISION MEDICINE AND DRUG DEVELOPMENT 19
Table5.
(Con
tinued).
Tricyclics(TCA
)andotherno
repineph
rine-reup
take
inhibitors
Drug
Prop
erties
Pharmacog
enetics
Nam
e:Escitalopram
oxalate;Lexapro;
Cipralex;2
19861-08-2;U
NII-5U
85DBW
7LO;Esertia
IUPA
Cname:(1S)-1-[3-(dimethylamino)prop
yl]-1-(4-fluorop
henyl)-1,3-dihydro-2-benzofuran-5-carbo
nitrile
Molecular
form
ula:C 2
2H23FN
2O5
Molecular
weigh
t:414.426823
g/mol
Mechanism
:Inh
ibits
thereup
take
ofserotoninwith
little
tono
effect
onno
repineph
rineor
dopamine
reup
take.Ithasvery
lowaffin
ityfor5-HT 1
–7,α-
andβ-adrenergic,D1–5,H1–3,M1–5,andbenzod
iazepine
receptors.
Effect:Seroton
inup
take
inhibitio
n;serotonergicneurotransmission
enhancer;antidepressiveactivity;anti-
anxietyactivity.
Pathog
enicgenes:AB
CB1,CREB1,FKBP5,GRIA3,G
RIK2,G
RIK4,N
R3C1,SLC6A4
Mechanisticgenes:AD
RAs,AD
RBs,DDC,
DRD
s,CH
RMs,GAB
Rs,H
RHs,HTRs,IL6
Metabolicgenes:
Substrate:AB
CB1,CYP2C9
(minor),CYP2C19(m
ajor),CYP2D6(m
ajor),CYP3A4
(major)
Inhibitor:AB
CB1,CYP1A2
(weak),C
YP2C9(weak),C
YP2C19
(weak),C
YP2D
6(m
oderate),C
YP2E1(weak),C
YP3A4(weak),SLC6A4
Transportergenes:AB
CB1,SLC6A4
Pleiotropicgenes:IL6
Nam
e:Fluo
xetin
ehydrochloride;Prozac;FluoxetineHCl;5
9333-67-4;
Sarafem;Fluctin
IUPA
Cname:methyl({3-ph
enyl-3-[4-(trifluorom
ethyl)p
heno
xy]propyl})am
ine
Molecular
form
ula:C 1
7H19ClF 3NO
Molecular
weigh
t:345.78707g/mol
Mechanism
:Potentiatesserotonergicactivity
inCN
Sresulting
from
itsinhibitio
nof
CNSneuron
alreup
take
ofserotonin.
Effect:Seroton
inup
take
inhibitio
n;serotoninagent;antid
epressiveactivity;anti-o
bsessive
activity;anti-
anxietyactivity;ano
rexigeniceffects.
Pathog
enicgenes:AB
CB1,BD
NF,CREB1,FKBP5,GSK3B,H
TR1A,H
TR2A,M
AOA,
NR3C1,N
TRK2,SLC6A4,TBX21,TPH1,TPH2
Mechanisticgenes:BD
NF,CH
RMs,CREB1,DRD
3,GSK3B,H
TRs,MAO
A,SLC6A4,
TPH2
Metabolicgenes:
Substrate:CYP1A2
(major),CYP2B6
(major),CYP2C8
(major),CYP2C9
(major),
CYP2C19(m
ajor),CYP2D6(m
ajor),CYP2E1
(minor),CYP3A4/5
(major),PO
RInhibitor:AB
CB1,CYP1A2
(mod
erate),CYP2B6(weak),CYP2C8(m
oderate),CYP2C9
(weak),C
YP2C19
(mod
erate),C
YP2D
6(stron
g),C
YP3A4(m
oderate),M
AOA,
SLC6A4
Transportergenes:AB
CB1,KCNH2,SLC6A4
Pleiotropicgenes:DRD
3,FABP1,HTR2A,IFN
A1,N
TRK2,P
DE5A,
TPH1
Nam
e:Fluvoxam
inemaleate;Luvox;6
1718-82-9;
Fevarin
;Faverin;Floxyfral
IUPA
Cname:(2-aminoethoxy)({5
-metho
xy-1-[4-(trifluorom
ethyl)p
henyl]p
entylidene})amine
Molecular
form
ula:C 1
9H25F 3N2O
6
Molecular
weigh
t:434.40681g/mol
Mechanism
:Inh
ibits
CNSneuron
serotoninup
take.
Effect:A
ntidepressiveactivity;anti-anxiety
activity;seroton
inup
take
inhibitio
n.
Pathog
enicgenes:BD
NF,HTR2A,SIGMAR
1,TPH1
Mechanisticgenes:BD
NF,HTRs,SLC6A4,SIGMAR
1Metabolicgenes:
Substrate:CYP1A2
(major),CYP2C19(m
ajor),CYP2D6(m
ajor),CYP3A4
(major)
Inhibitor:AB
CB1,CYP1A2
(stron
g),C
YP2B6(weak),C
YP2C9(m
oderate),C
YP2C19
(mod
erate),C
YP2D
6(m
oderate),C
YP3A4(weak),M
AOA,
SLC6A4
Transportergenes:AB
CB1,KCNH2,SCL6A4
Pleiotropicgenes:CREB1,TPH1
Nam
e:Paroxetin
e;Paxil;Arop
ax;P
axilCR
;Seroxat;P
exeva
IUPA
Cname:(3S,4R)-3-[(2
H-1,3-benzodioxol-5-yloxy)m
ethyl]-4-(4-fluorop
henyl)p
iperidine
Molecular
form
ula:C 1
9H20FN
O3
Molecular
weigh
t:329.365403
g/mol
Mechanism
:Itisan
SSRI.Presumablyactsby
inhibitin
gserotoninreup
take
from
brainsynapsestimulating
itsactivity
inthebrain.
Effect:Seroton
inup
take
inhibitio
n;serotonergicneurotransmission
enhancer;antidepressantactivity;anti-
anxietyactivity;anti-o
bsessive
activity.
Pathog
enicgenes:AB
CB1,CREB1,HTR1B,H
TR2A,H
TR3B,M
AOA,
SLC6A3,SLC6A4,
TNF,TPH1,TPH2
Mechanisticgenes:CREB1,HTR2A,H
TR3A,SLC6A4,STAT3,TN
FMetabolicgenes:
Substrate:AB
CB1,CO
MT,CYP1A2
(minor),CYP2C19(m
inor),CYP2D6(m
ajor),
CYP3A4
(major),MAO
A,MAO
BInhibitor:AB
CB1,CYP1A2
(weak),C
YP2B6(m
oderate),C
YP2C9(weak),C
YP2C19
(weak),C
YP2D
6(stron
g),C
YP3A4(weak),SLC6A3,SLC6A4
Transportergenes:AB
CB1,SLC6A3,SLC6A4
Pleiotropicgenes:HTR1D
,HTR3C,H
TR6,HTT,TPH
1,TPH2
(Con
tinued)
20 R. CACABELOS
Table5.
(Con
tinued).
Tricyclics(TCA
)andotherno
repineph
rine-reup
take
inhibitors
Drug
Prop
erties
Pharmacog
enetics
Nam
e:Sertralinehydrochloride;79559-97-0;SertralineHCl;Z
oloft;Lustral;Gladem
IUPA
CNam
e:(1S,4S)-4-(3,4-dichlorop
henyl)-N-m
ethyl-1,2,3,4-tetrahydron
aphthalen-1-am
ine
Molecular
form
ula:C 1
7H18Cl3N
Molecular
weigh
t:342.69052g/mol
Mechanism
:Ithasselectiveinhibitory
effectson
presynaptic
serotoninreup
take
andon
lyvery
weakeffects
onno
repineph
rineanddo
pamineneuron
alup
take.
Effect:Seroton
inup
take
inhibitio
n;serotonergicneurotransmission
enhancer;antidepressantactivity;anti-
anxietyactivity;anti-o
bsessive
activity.
Pathog
enicgenes:AB
CB1,CREB1,GNB3,H
TR1B,M
AOA,
SIGMAR
1,SLC6A4,TNF,
TPH1,TPH2
Mechanisticgenes:HTR1B,H
TR1D
,SIGMAR
1,SLC6A2,SLC6A3,SLC6A4,TNF
Metabolicgenes:
Substrate:CYP2A6,C
YP2B6(m
inor),CYP2C9
(minor),CYP2C19(m
ajor),CYP2D6
(minor),CYP3A4
(minor),MAO
A,MAO
B,UGT1A1,U
GT2B7
Inhibitor:AB
CB1,AC
HE,CYP1A1,C
YP1A2(weak),C
YP2B6(m
oderate),C
YP2C8
(weak),C
YP2C9(weak),C
YP2C19
(mod
erate),C
YP2D
6(m
oderate),C
YP3A4
(mod
erate),SLC6A4
Transportergenes:AB
CB1,SLC6A2,SLC6A3,SLC6A4
Pleiotropicgenes:FABP1,FO
S,GNB3,TPH
1,TPH2
ABCB1:
ATP-bind
ingcassette,sub
-fam
ilyB(M
DR/TA
P),m
ember1;ABCC1:
ATP-bind
ingcassette,sub
-fam
ilyC(CFTR/MRP),mem
ber1;ABCC2:
ATP-bind
ingcassette,sub
-fam
ilyC(CFTR/MRP),mem
ber2;ABCG2:
ATP-bind
ing
cassette,sub-family
G(W
HITE),mem
ber2(Jun
iorbloodgrou
p);ACHE:
acetylcholinesterase
(Ytbloodgrou
p);ADCY1:
adenylatecyclase1(brain);ADRA1A
:adreno
ceptor
alph
a1A
;ADRA1s:adreno
ceptorsalph
a1;
ADRA2A
:adrenoceptoralph
a2A
;ADRA2s:adrenoceptorsalph
a2;ADRAs:adreno
ceptorsalph
a;ADRB2:
adreno
ceptor
beta
2,surface;ADRBsadreno
ceptorsbeta;A
DRs:adreno
ceptors;BDNF:brain-derived
neurotroph
icfactor;CHRM4:
cholinergicreceptor,muscarin
ic4;
CHRM5:
cholinergicreceptor,muscarin
ic5;
CHRMs:
cholinergicreceptors,
muscarin
ictype;CHRNs:
cholinergicreceptors,
nicotin
ictype;COMT:
catechol-O-
methyltransferase;
CREB
1:cAMPrespon
sive
elem
entbind
ingprotein1;
CRHR1:
corticotropinreleasingho
rmon
ereceptor
1;CRHR2:
corticotropinreleasingho
rmon
ereceptor
2;CYP1
A1:
cytochromeP450,family
1,subfam
ilyA,
polypeptide1;CYP1
A2:cytochromeP450,fam
ily1,subfam
ilyA,
polypeptide2;CYP2
A6:cytochromeP450,fam
ily2,subfam
ilyA,
polypeptide6;CYP2
B6:cytochromeP450,fam
ily2,subfam
ilyB,po
lypeptide6;
CYP2
C19
:cytochrom
eP450,fam
ily2,subfam
ilyC,
polypeptide19;C
YP2
C8:
cytochromeP450,fam
ily2,subfam
ilyC,
polypeptide8;CYP2
C9:
cytochromeP450,fam
ily2,subfam
ilyC,
polypeptide9;CYP2
D6:
cytochrome
P450,fam
ily2,subfam
ilyD,polypeptid
e6;CYP2
E1:cytochrom
eP450,fam
ily2,subfam
ilyE,po
lypeptide1;CYP2
J2:cytochrom
eP450,fam
ily2,subfam
ilyJ,po
lypeptide2;CYP3
A4/5:
cytochromeP450,fam
ily3,subfam
ilyA,
polypeptide4/5;CYP3
A4:
cytochromeP450,fam
ily3,subfam
ilyA,
polypeptide4;CYP3
A5:
cytochromeP450,fam
ily3,subfam
ilyA,
polypeptide5;CYP3
A7:
cytochromeP450,fam
ily3,subfam
ilyA,
polypeptide7;DDC:
dopa
decarboxylase(aromaticL-am
inoaciddecarboxylase);D
RD1:do
paminereceptor
D1;DRD2:do
paminereceptor
D2;DRD3:do
paminereceptor
D3;DRDs:do
paminereceptors;FA
BP1
:fattyacidbind
ingprotein1,liver;
FKBP5
:binding
protein5;FM
O1:
flavincontaining
mon
ooxygenase
1;FO
S:FBJmurineosteosarcomaviralo
ncog
eneho
molog
;GABBRs:gamma-am
inob
utyricacid
(GAB
A)Areceptors,beta;G
ABRs:gamma-am
inob
utyric
acid
(GAB
A)Areceptors;GNAS:
GNAS
complex
locus;GNB3:
guaninenu
cleotid
ebind
ingprotein(G
protein),b
etapo
lypeptide3;
GRIA3:
glutam
atereceptor,ion
otropic,AM
PA3;
GRIK2:
glutam
atereceptor,ion
otropic,
kainate2;GRIK4:
glutam
atereceptor,ion
otropic,kainate4;GSK
3B:glycogensynthase
kinase
3beta;G
STP1
:glutathione
S-transferasepi1;HCRTR
1:hypo
cretin(orexin)
receptor
1;HCRTR
2:hypo
cretin(orexin)
receptor
2;HDC:histid
inedecarboxylase;HRH1:histam
inereceptor
H1;HRH2:histam
inereceptor
H2;HRHs:histam
inereceptors;HTR
1A:5-hydroxytryptamine(seroton
in)receptor1
A,Gprotein-coup
led;HTR
1B:5-hydroxytryptamine
(seroton
in)receptor
1B,G
protein-coup
led;
HTR
1D:5-hydroxytryptamine(seroton
in)receptor
1D,G
protein-coup
led;
HTR
2A:5-hydroxytryptamine(seroton
in)receptor
2A,G
protein-coup
led;
HTR
2s:5-hydroxytryptamine
(seroton
in)receptors2;
HTR
3:histon
eH3;
HTR
3A:5-hydroxytryptam
ine(seroton
in)receptor
3A,iono
trop
ic;HTR
3B:5-hydroxytryptam
ine(seroton
in)receptor
3B,iono
trop
ic;HTR
3C:5-hydroxytryptam
ine(seroton
in)
receptor
3C,ion
otropic;HTR
6:5-hydroxytryptam
ine(seroton
in)receptor
6,Gprotein-coup
led;
HTR
s:5-hydroxytryptam
ine(seroton
in)receptors;HTT
:hun
tingtin;IFN
A1:
interferon
,alpha
1;IL1B
:interleukin
1,beta;IL6
:interleukin
6;ITGB3:
integrin,beta
3(plateletglycop
rotein
IIIa,
antig
enCD
61);KCNE2
:po
tassium
channel,voltage
gatedsubfam
ilyEregu
latory
beta
subu
nit2;
KCNH2:
potassium
channel,voltage
gatedeagrelated
subfam
ilyH,m
ember2
;KCNQ1:po
tassium
channel,voltage
gatedKQ
T-likesubfam
ilyQ,m
ember1
;MAOA:m
onoamineoxidaseA;
MAOB:m
onoamineoxidaseB;MTN
R1A
:melaton
inreceptor
1A;N
R3C
1:nu
clearreceptor
subfam
ily3,grou
pC,
mem
ber1(glucocorticoidreceptor);NTR
K1:
neurotroph
ictyrosine
kinase,receptor,type
1;NTR
K2:
neurotroph
ictyrosine
kinase,receptor,type
2;ORM1:
orosom
ucoid1;PD
E1C:p
hospho
diesterase
1C,calmod
ulin-dependent
70kD
a;PD
E5A:pho
spho
diesterase
5A,cGMP-specific;PO
R:P450(cytochrom
e)oxidoreductase;P
RKCSH
:proteinkinase
Csubstrate80K-H;P
SMD9:
proteasome(prosome,macropain)26S
subu
nit,
non-AT
Pase,9;P
TGS2
:prostagland
in-end
operoxidesynthase
2(prostagland
inG/H
synthase
andcyclooxygenase);SC
L6A4:
solute
carrierfamily
6(neurotransm
itter
transporter),m
ember4;SC
N5A
:sod
ium
channel,voltage
gated,
type
Valph
asubu
nit;SC
Ns:sodium
channels,voltage
gated;
SIGMAR1:
sigm
ano
n-op
ioid
intracellularreceptor
1;SLC22
A1:
solute
carrierfamily
22(organiccatio
ntransporter),m
ember1;SLC22
A2:
solute
carrier
family
22(organiccatio
ntransporter),m
ember2;SLC22
A3:
solute
carrierfamily
22(organiccatio
ntransporter),m
ember3;SLC6A
2:solute
carrierfamily
6(neurotransm
itter
transporter),m
ember2;SLC6A
3:solute
carrier
family
6(neurotransm
itter
transporter),m
ember3;SLC6A
4:solute
carrierfamily
6(neurotransm
itter
transporter),m
ember4;ST
AT3
:signaltransdu
cerandactivator
oftranscrip
tion3(acute-phase
respon
sefactor);TB
X21:
T-bo
x21;T
NF:
tumor
necrosisfactor;T
PH1:
tryptoph
anhydroxylase1;
TPH2:
tryptoph
anhydroxylase2;
UGT1
A1:
UDPglucuron
osyltransferase1family,p
olypeptid
eA1
;UGT1
A3:
UDPglucuron
osyltransferase1family,
polypeptideA3
;UGT1
A4:
UDPglucuron
osyltransferase1family,p
olypeptid
eA4
;UGT2
B10
:UDPglucuron
osyltransferase2family,p
olypeptid
eB10;UGT2
B7:
UDPglucuron
osyltransferase2family,p
olypeptid
eB7;U
GTs:
UDPglucuron
osyltransferasefamily.
EXPERT REVIEW OF PRECISION MEDICINE AND DRUG DEVELOPMENT 21
Although this is a still poorly explored field, epigenetic regulationof genes involved in the pharmacogenomic network has beendocumented in several studies that contributed to the configura-tion of the emerging field of pharmacoepigenomics [25,85–91].
Epigenetic modifications are also associated with drug resis-tance [25,92]. In the complex cascade of pharmacoepigeneticevents, the epigenetic factory may act as a promiscuous, redun-dant security system in which several miRNAs target genesencoding epigenetic regulators. Furthermore, epigenetic drugsreverse epigenetic changes in gene expression and might opennew avenues in the treatment of complex disorders [25,84–88].
7. Conclusions
For an effective implementation of personalized treatments inneurocognitive disorders, the characterization of geno-pheno-markers, identification of novel drug targets (Table 2), anincorporation of precision medicine procedures to drug devel-opment are urgently needed. Genomic determinants of PGxoutcomes include PMMTP genes (PMMTP gene cluster)(Table 1) under the regulatory control of the epigeneticmachinery. Conventional anti-dementia drugs (AChEIs, mem-antine) are not cost-effective, and no new drugs have beenapproved for almost two decades. PGx studies with anti-dementia drugs (Table 3) revealed that major determinantsof therapeutic outcome are APOE, CYPs, and some other genes(TOMM40, ACHE, ABC transporters); APOE-4 carriers are theworst responders and APOE-3 carriers are the best responders(Figures 3 and 4); CYP2D6-EMs and IMs are better respondersthan PMs and UMs (Figure 5). Only 20% of Caucasians areextensive metabolizers for the tetragenic CYP2D6-2C9-2C19-3A4 cluster, with relevant consequences for personalized treat-ments. Cardio-cerebro-vascular risk factors (dyslipidemia,hypertension, cardiovascular disorders) (Figure 2) and neurop-sychiatric disorders are prevalent concomitant ailments thatrequire polypharmacy intervention (Tables 4 and 5). The appli-cation of PGx procedures by trained professionals can sub-stantially contribute to improve accurate prescription anddrug efficacy and safety, and to reduce unnecessary costsassociated with inappropriate medications in the elderlypopulation with dementia.
8. Expert commentary
History demonstrates that PGx has been neglected in CNS disor-ders and dementia. The PGx field is still immature, PGx studieswithmost drugs are insufficient, the professional interest for PGx is verylimited, and many barriers preclude an efficient introduction ofPGx in the clinical practice in the short term. However, PGx studiesin over 400 drugs of common use are proving the utility of PGx inpersonalized treatments; PGx cost-effectiveness is gaining credibil-ity among health professionals; users of PGx procedures applied tochronic, expensive treatments are loyal believers in the benefitsprovided by PGx in terms of efficacy and safety; timid recommen-dations from the regulatory agencies are encouraging the phar-maceutical industry to incorporate PGx in drug development andPhase I–II clinical trials; and some professional guidelines are con-tributing to the gradual implementation of PGx in R&D and in theclinical setting [19,93].
The introduction of PGx in drug development is an impera-tive need in order to reduce R&D costs and to improve efficacyand safety issues. Based on PGx principles, by trial and errorthe efficacy of any conventional drug is below 30% [80]. Thestratification of patients according to their pharmacogenomicprofile would allow the development of drugs for responderswith an efficacy rate >80%; and novel targets should beaddressed for non-responders to be converted into effectiveresponders [31,55,94].
Unfounded barriers are being created to delay the imple-mentation of PGx as a routine strategy in clinical practice. Inthe USA, the payer’s decisions are highly influential, and theirconcerns (clinical utility, preference for outcomes from rando-mized trials, guideline development, impact on clinical deci-sion-making, downstream costs and benefit predictability,impact of public stakeholders) are limiting the applicabilityof PGx [95,96]. Pharmacoeconomic studies and formal PGxstudies are necessary for dismantling the negative forum ofvoices questioning the benefits of PGx; and much education isneeded for health professionals and payers to be convinced ofthe virtues, limitations, opportunities, and challenges of PGx indrug development and in clinical practice [97].
For the efficient implementation of PGx in precision med-icine, PGx testing should be simplified, and bioinformaticstools should be created to help physicians to optimize drugprescription in a personalized manner [98]. Information book-lets should contain PGx data for physicians and users. Thisimplies that the pharmaceutical industry organizes clinicaltrials with a stratification of patients according to their PGx-PMMTP profile [19].
Approximately 60% of the patients with CNS disorders arereceiving an inappropriate medication. After PGx-guided rec-tification of drug/dose, efficacy improves by about 40% andunwanted effects are reduced by 58%; additionally, over a 2-year period, pharmaceutical expenditure can be cut down by18–36%, depending on disease stage. These results are moresignificant in patients taking poly-medication (>4 drugs)(unpublished results). These preliminary results and datafrom theoretical pharmacoeconomic studies elsewhere indi-cate that PGx-guided treatment is cost-effective and cost-sav-ing for society [99].
At the present time, it is impossible to know with absoluteprecision how many genes are involved in the PGx of aparticular drug; however, there is substantial information ona structured basis for the practical application of PGx in manycurrent treatments [19] (Tables 3–5).
9. Five-year view
For the coming years, relevant progress in the precision med-icine of dementia and other CNS disorders is expected in thefollowing areas:
● Fine-tuning characterization of PMMTP genes in CNSdisorders for the implementation of effective PGx strate-gies in drug development and monitoring [19,29,31,55].
● Mapping of specific drug targets essential for drug devel-opment [94,100].
22 R. CACABELOS
● Strategic changes in CNS drug development, shifting thefocus of attention from neurotransmitter-modulatingrepressive drugs to neuroprotective agents [18,77].
● Identification of specific geno- and pheno-markers forthe early detection of disease and assessment of dis-ease-modifying treatments [2].
● Standardization of PGx criteria, allele nomenclature, andguidelines for PGx studies [19,101].
● Incorporation of micro-physiological systems technologyand biopharmachips into drug discovery, primary screen-ing, and early pharmacogenomic assessment in drugdevelopment [102].
● Use of stem cell technology and tissue cloning in pre-clinical PGx.
● Methylomics of brain degeneration and cerebrovasculardamage for the implementation of epigenetic proce-dures in disease prevention and treatment.
● Introduction of pharmacoepigenetics in drug develop-ment and discovery of prototype epigenetic drugs forprophylactic neuroprotection and miRNA therapeutics[25,85,86].
● Development of PMMTP-sensitive smart PGx cards anddigital devices with PGx information for personalizedtreatments in a simplified manner [98,103].
Key issues
● About 10–20% of the cost of AD is attributed to pharma-ceutical expenses, including anti-dementia drugs plus med-ication for concomitant disorders and AD-relatedneuropsychiatric disorders.
● Major pharmacological categories under development forAD are the following: neurotransmitter enhancers (11.38%),multi-target drugs (2.45%), anti-Amyloid agents (13.30%),anti-Tau agents (2.03%), natural products and derivatives(25.58%), novel drugs (8.13%) based on new targets, other(old) drugs (11.77%), anti-inflammatory drugs (1.20%), neu-roprotective peptides (1.25%), stem cell therapy (1.85%),nanocarriers/nanotherapeutics (1.52%), and other cate-gories and/or therapeutic strategies (<1% each).
● For an effective implementation of personalized treatmentsin neurocognitive disorders, the characterization of geno-pheno-markers, identification of novel drug targets, anincorporation of precision medicine procedures to drugdevelopment are urgently needed.
● Genomic determinants of PGx outcomes include patho-genic, mechanistic, metabolic, transporter and pleiotropicgenes (PMMTP gene cluster).
● Genes involved in the pharmacogenetic outcome are underthe regulatory control of the epigenetic machinery (DNAmethylation, histone modifications, miRNA regulation).
● PGx studies with anti-dementia drugs revealed that majordeterminants of therapeutic outcome are APOE, CYPs, andsome other genes (TOMM40, ACHE, ABC transporters).
● APOE-4 carriers are the worst responders and APOE-3 car-riers are the best responders to conventional drugs.
● CYP2D6-EMs and IMs are better responders than PMsand UMs.
● Only 20% of Caucasians are extensive metabolizers for thetetragenic CYP2D6-2C9-2C19-3A4 cluster, with relevantconsequences for personalized treatments.
● Cardio-cerebro-vascular risk factors (dyslipidemia, hyperten-sion, cardiovascular disorders) and neuropsychiatric disor-ders are prevalent concomitant ailments which requirepolypharmacy intervention.
● The application of PGx procedures by trained profes-sionals can substantially contribute to improve accurateprescription and drug efficacy and safety, and to reduceunnecessary costs associated with inappropriate medica-tions in the elderly population with dementia.
Acknowledgments
The author would like to thank his collaborators Juan C. Carril, Iñaki López,Pablo González, Adam McKay, and Pablo Cacabelos for technicalassistance.
Funding
This article was funded by EuroEspes Biomedical Research Center, Instituteof Medical Science and Genomic Medicine, and IABRA (InternationalAgency for Brain Research and Aging).
Declaration of interest
The author is President and stockholder of EuroEspes (BiomedicalResearch Center), EuroEspes Biotechnology, IABRA, and EuroEspesPublishing Co. The author has no other relevant affiliations or financialinvolvement with any organization or entity with a financial interest in orfinancial conflict with the subject matter or materials discussed in themanuscript apart from those disclosed. Peer reviewers on this manuscripthave no relevant financial or other relationships to disclose.
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26 R. CACABELOS
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