Full Terms & Conditions of access and use can be found athttp://www.tandfonline.com/action/journalInformation?journalCode=tepm20

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.

Submit your article to this journal

Article views: 2

View related articles

View Crossmark data

REVIEW

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

A C A C A C A C0%

20%

40%

60%

80%

100%

CYP2D6 CYP2C9 CYP2C19 CYP3A4/5

)4

48

=N(

C;)

11

01

=N(

A%

27.

95

:C-

ME

;%

84.

65

:A-

ME

%6

1.1

3:

C-MI

;%

58.

13

:A-

MI%

19.

3:

C-M

P;

%4

3.5

:A-

MP

%1

2.5

:C-

MU

;%

33.

6:

A-M

U

)4

38

=N(

C;)

19

9=

N(A

%9

1.3

6:

C-M

E;

%4

6.9

5:

A-M

E%

77.

13

:C-

MI;

%2

5.5

3:

A-MI

%4

0.5

:C-

MP

;%

48.

4:

A-M

P

)9

48

=N(

C;)

10

01

=N(

A%

62.

37

:C-

ME

;%

38.

27

:A-

ME

%1

6.2

2:

C-MI

;%

84.

42

:A-

MI%

45.

1:

C-M

P;

%0

9.0

:A-

MP

%9

5.2

:C-

MU

;%

97.

1:

A-M

U

)7

36

=N(

C;)

52

7=

N(A

%5

9.1

8:

C-M

E;

%6

7.2

8:

A-M

E%

72.

71

:C-

MI;

%9

5.5

1:

A-MI

%8

7.0

:C-

MR

;%

56.

1:

A-M

R

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%

C-APOE

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.

References

Papers of special note have been highlighted as either of interest (•) or ofconsiderable interest (••) to readers.

1. Cacabelos R, Fernández-Novoa L, Lombardi V, et al. Moleculargenetics of Alzheimer’s disease and aging. Meth Find Exp ClinPharmacol. 2005;27(Suppl. A):1–573.

2. Cacabelos R. Have there been improvements in Alzheimer’s diseasedrug discovery over the past 5 years? Expert Opin Drug Dis. 2018.DOI:10.1080/17460441.2018.1457645

• Extensive review on Alzheimer’s disease (AD) drug discoveryduring the period 2013–2017.

3. Kadohara K, Sato I, Doi Y, et al. Prescription patterns of medicationsfor Alzheimer’s disease in Japan from 2010 to 2015: a descriptivepharmacy claims database study. Neurol Ther. 2017;6(1):25–37.

4. Koller D, Hua T, Bynum JP. Treatment patterns with antidementiadrugs in the United States: medicare cohort study. J Am GeriatrSoc. 2016;64(8):1540–1548.

5. Tsolaki M, Papaliagkas V, Frisoni G, et al. MCI patients in Europe:medication and Comorbidities. The DESCRIPA study. Curr AlzheimerRes. 2016;13(12):1407–1413.

6. Allegri N, Rossi F, Del Signore F, et al. Drug prescription appropri-ateness in the elderly: an Italian study. Clin Interv Aging.2017;12:325–333.

7. Cummings J, Lee G, Mortsdorf T, et al. Alzheimer’s disease drugdevelopment pipeline: 2017. Alzheimers Dement (N Y). 2017;3(3):367–384.

EXPERT REVIEW OF PRECISION MEDICINE AND DRUG DEVELOPMENT 23

• Overview of clinical trials in AD (updated information).8. Cacabelos R, Teijido O, Carril JC. Can cloud-based tools accelerate

Alzheimer’s disease drug discovery? Expert Opin Drug Discov.2016;11(3):215–223.

9. Dickmann LJ, Ware JA. Pharmacogenomics in the age of persona-lized medicine. Drug Discov Today Technol. 2016;21-22:11–16.

10. Meyer UA. Pharmacogenetics - five decades of therapeutic lessonsfrom genetic diversity. Nat Rev Genet. 2004;5(9):669–676.

• Seminal review on the history of pharmacogenetics.11. Relling MV, Evans WE. Pharmacogenomics in the clinic. Nature.

2015;526(7573):343–350.12. Lauschke VM, Milani L, Ingelman-Sundberg M. Pharmacogenomic

biomarkers for improved drug therapy-recent progress and futuredevelopments. Aaps J. 2017;20(1):4.

13. Weinshilboum RM, Wang L. Pharmacogenomics: precision medi-cine and drug response. Mayo Clin Proc. 2017;92(11):1711–1722.

• Interesting perspective of pharmacogenomics in precisionmedicine.

14. Angelbello AJ, Chen JL, Childs-Disney JL, et al. Using genomesequence to enable the design of medicines and chemical probes.Chem Rev. Forthcoming 2018. DOI:10.1021/acs.chemrev.7b00504.

15. Castrillo JI, Lista S, Hampel H, et al. Systems biology methods forAlzheimer’s disease research toward molecular signatures, sub-types, and stages and precision medicine: application in cohortstudies and trials. Methods Mol Biol. 2018;1750:31–66.

16. Hampel H, O’Bryant SE, Durrleman S, et al. A precision medicine initia-tive for Alzheimer’s disease: the road ahead to biomarker-guided inte-grative disease modeling. Climacteric. 2017;20(2):107–118.

17. Hampel H, Toschi N, Babiloni C, et al. Revolution of Alzheimerprecision neurology. passageway of systems biology and neuro-physiology. J Alzheimers Dis. 2018. DOI:10.3233/JAD-179932.

18. Cacabelos R. Impact of genomic medicine on the future of neu-ropsychopharmacology. J Neuropsychopharmacol Mental Health.2015;1:1.

19. World Guide for Drug Use and Pharmacogenomics. In: Cacabelos R,Ed. EuroEspes Publishing: Corunna, Spain; 2012.

•• This is the World Guide of Pharmacogenomics (3000 pages)with over 50,000 entries (drugs, genes, diseases).

20. Cacabelos R, Cacabelos P, Torrellas C, et al. Pharmacogenomics ofAlzheimer’s disease: novel therapeutic strategies for drug develop-ment. Methods Mol Biol. 2014;1175:323–556.

• Extensive review on AD pharmacogenomics, including conven-tional drugs and novel products.

21. Cacabelos R, Goldgaber D, Roses AD, et al. Gene interactions in thepharmacogenomics of Alzheimer’s disease. Sciforschen Geneticsand Gene Therapy. 2015;1(1). DOI:10.16966/sggt.102

22. Karch CM, Cruchaga C, Goate A, et al. Alzheimer’s disease genetics:from the bench to the clinic. Neuron. 2014;83:11–26.

23. Carril JC, Cacabelos R. Genetic risk factors in cerebrovascular disordersand cognitive deterioration. Cur Genomics. 2017;18:416–429.

24. Teijido O, Carril JC, Cacabelos R. Population-based study of riskpolymorphisms associated with vascular disorders and dementia.Cur Genomics. 2017;18:430–441.

25. Cacabelos R, Torrellas C. Epigenetics of aging and Alzheimer’sdisease: implications for pharmacogenomics and drug response.Int J Mol Sci. 2015;16:30483–30543.

• Extensive review of AD epigenetics and introduction topharmacoepigenetics.

26. Cacabelos R. Pleiotropy and promiscuity in pharmacogenomics forthe treatment of Alzheimer’s disease and related disorders. FutureNeurol. 2018. DOI:10.2217/fnl-2017-0038

27. Shah RR, Gaedigk A. Precision medicine: does ethnicity informationcomplement genotype-based prescribing decisions? Ther AdvDrug Saf. 2018;9(1):45–62.

• Interesting paper about the importance of ethnic variation onprecision medicine.

28. Zhou Y, Ingelman-SundbergM, LauschkeVM.Worldwidedistributionofcytochrome p450 alleles: a meta-analysis of population-scale sequen-cing projects. Clin Pharmacol Ther. 2017;102(4):688–700.

• Study on the geographic distribution of cytochrome P450 inthe world.

29. Cacabelos R, Torrellas C, Teijido O, et al. Pharmacogenetic consid-erations in the treatment of Alzheimer’s disease.Pharmacogenomics. 2016;17(9):1041–1074.

30. Cacabelos R, Torrellas C, Carrera I. Opportunities in pharmacoge-nomics for the treatment of Alzheimer’s disease. Future Neurol.2015;10(3):229–252.

31. Cacabelos R, Carril JC, Cacabelos P, et al. Pharmacogenomics ofAlzheimer’s disease: genetic determinants of phenotypic variationand therapeutic outcome. J Genomic Med Pharmacogenomics.2016;1(2):151–209.

• Study on AD pharmacogenomics considering genetic determi-nants of therapeutic response to conventional treatments andage-related disorders in dementia.

32. Kovacsics D, Patik I, Özvegy-Laczka C. The role of organic aniontransporting polypeptides in drug absorption, distribution, excre-tion and drug-drug interactions. Expert Opin Drug Metab Toxicol.2017;13(4):409–424.

33. Marquez B, Van Bambeke F. ABC multidrug transporters: target formodulation of drug pharmacokinetics and drug-drug interactions.Curr Drug Targets. 2011;12(5):600–620.

34. Elali A, Rivest S. The role of ABCB1 and ABCA1 in beta-amyloidclearance at the neurovascular unit in Alzheimer’s disease. FrontPhysiol. 2013;4:45.

35. Cascorbi I, Flüh C, Remmler C, et al. Association of ATP-bindingcassette transporter variants with the risk of Alzheimer’s disease.Pharmacogenomics. 2013;14(5):485–494.

36. Reitz C, Jun G, Naj A, et al. Variants in the ATP-binding cassettetransporter (ABCA7), apolipoprotein E ϵ4, and the risk of late-onset Alzheimer disease in African Americans. Jama. 2013;309(14):1483–1492.

37. Hung SY, Fu WM. Drug candidates in clinical trials for Alzheimer’sdisease. J Biomed Sci. 2017;24(1):47.

38. Cacabelos R, Torrellas C, Carrera I, et al. Novel therapeutic strate-gies for dementia. CNS Neurol Disord Drug Targets. 2016;15(2):141–241.

39. Cacabelos R, Álvarez XA, Lombardi V, et al. Pharmacological treatmentof Alzheimer disease: from psychotropic drugs and cholinesteraseinhibitors to pharmacogenomics. Drugs Today. 2000;36:415–499.

40. Cacabelos R, Llovo R, Fraile C, et al. Pharmacogenetic aspects oftherapy with cholinesterase inhibitors: the role of CYP2D6 inAlzheimer’s disease pharmacogenetics. Cur Alzheimer Res.2007;4:479–500.

41. Cacabelos R. Pharmacogenomics in Alzheimer’s disease. Meth MolBiol. 2008;448:213–357.

42. Noetzli M, Eap CB. Pharmacodynamic, pharmacokinetic and phar-macogenetic aspects of drugs used in the treatment of Alzheimer’sdisease. Clin. Pharmacokinet. 2013;52:225–241.

43. Seripa D, Bizzarro A, Pilotto G, et al. Role of cytochrome P4502D6functional polymorphisms in the efficacy of donepezil in patientswith Alzheimer’s disease, pharmacogenet. Genomics. 2011;21:225–230.

44. Cacabelos R, Martínez R, Fernández-Novoa L, et al. Genomics ofdementia: APOE- and CYP2D6-related pharmacogenetics. Intern JAlzheimer Dis. 2012. DOI:10.1155/2012/518901.

45. Chianella C, Gragnaniello D, MaisanoDelser P, et al. BCHE andCYP2D6 genetic variation in Alzheimer’s disease patients treatedwith cholinesterase inhibitors. Eur J Clin Pharmacol. 2011;67(11):1147–1157.

46. Magliulo L, Dahl ML, Lombardi G, et al. Do CYP3A and ABCB1genotypes influence the plasma concentration and clinical out-come of donepezil treatment? Eur J Clin Pharmacol. 2011;67:47–54.

47. Noetzli M, Guidi M, Ebbing K, et al. Relationship of CYP2D6, CYP3A,POR, and ABCB1 genotypes with galantamine plasma concentra-tions. Ther Drug Monit. 2013;35:270–275.

48. Alfirevic A, Mills T, Carr D, et al. Pirmohamed, Tacrine-induced liverdamage: an analysis of 19 candidate genes. PharmacogenetGenomics. 2017;17:1091–1100.

24 R. CACABELOS

49. Yang Z, Zhou X, Zhang Q. Effectiveness and safety of memantinetreatment for Alzheimer’s disease. J Alzheimers Dis. 2013;36:445–458.

50. Noetzli M, Guidi M, Ebbing K, et al. Population pharmacokineticstudy of memantine: effects of clinical and genetic factors. ClinPharmacokinet. 2013;52:211–223.

• Interesting study on the pharmacogenetics of memantine.51. Cacabelos R. Molecular pathology and pharmacogenomics in

Alzheimer’s disease: polygenic-related effects of multifactorialtreatments on cognition, anxiety, and depression. Meth FindExper Clin Pharmacol. 2007;29(Supp. A):1–91.

52. Pankiewicz JE, Baquero-Buitrago J, Sanchez S, et al. APOE genotypedifferentially modulates effects of anti-aβ, passive immunization inapp transgenic mice. Mol Neurodegener. 2017;12(1):12.

53. Cacabelos R, Goldgaber D, Vostrov A, et al. APOE-TOMM40 in thepharmacogenomics of demetia. J PharmacogenomicsPharmacoproteomics. 2014;5:135.

• First paper demonstrating the influence of TOMM40 variantson AD pharmacogenetics.

54. Roses AD. An inherited variable poly-T repeat genotype inTOMM40 in Alzheimer disease. Arch Neurol. 2010;67:536–541.

55. Cacabelos R, Meyyazhagan A, Carril JC, et al. Pharmacogenetics ofvascular risk factors in Alzheimer’s disease. J Pers Med. 2018;8(1).pii: E3. DOI:10.3390/jpm8010003

56. Appleton JP, Scutt P, Sprigg N, et al. Hypercholesterolaemia andvascular dementia. Clin Sci (Lond). 2017;131:1561–1578.

57. Samara K, Brodaty H, Sachdev PS. Does statin use cause memorydecline in the elderly? Trends Cardiovasc Med. 2016;26:550–565.

58. Zissimopoulos JM, Barthold D, Brinton RD, et al. Sex and racedifferences in the association between statin use and the incidenceof Alzheimer disease. JAMA Neurol. 2016. DOI:10.1001/jamaneurol.2016.3783.

59. Maxwell WD, Ramsey LB, Johnson SG, et al. Impact of pharmaco-genetics on efficacy and safety of statin therapy for dyslipidemia.Pharmacotherapy. 2017;37(9):1172–1190. Epub 2017 Aug 23.

60. Zhou X, Li Y, Shi X, et al. An overview on therapeutics attenuatingamyloid β level in Alzheimer’s disease: targeting neurotransmis-sion, inflammation, oxidative stress and enhanced cholesterollevels. Am J Transl Res. 2016;8:246–269.

61. Cacabelos R, Carril JC, Teijido O. Pharmacogenomics and epigenomicsof age-related neurodegenerative disorders: strategies for drug devel-opment. In: vaiserman, A.M. (Ed). anti-aging drugs: from basicresearch to clinical practice. RSC Drug Discov Ser. 2017;57:75–141.

62. Kitzmiller JP, Mikulik EB, Dauki AM, et al. Pharmacogenomics ofstatins: understanding susceptibility to adverse effects.Pharmgenomics Pers Med. 2016;9:97–106.

63. Wang D, Guo Y, Wrughton SA, et al. Intronic polymorphism inCYP3A4 affects hepatic expression and response to statin drugs.Pharmacogenomics J. 2011;11:274–286.

64. Kim KA, Park PW, Lee OJ, et al. Effect of polymorphic CYP3A5genotype on the single-dose simvastatin pharmacokinetics inhealthy subjects. J Clin Pharmacol. 2007;47:87–93.

65. Leduc V, Bourque L, Poirier J, et al. Role of rs3846662 and HMGCRalternative splicing in statin efficacy and baseline lipid levels in familialhypercholesterolemia. Pharmacogenet Genomics. 2016;26:1–11.

66. Peters BJ, Rodin AS, Klungel OH, et al. Pharmacogenetic interac-tions between ABCB1 and SLCO1B1 tagging SNPs and the effec-tiveness of statins in the prevention of myocardial infarction.Pharmacogenomics. 2010;11:1065–1076.

67. Siddiqui M, Maroteau C, Veluchamy A, et al. PREDICTION-ADR con-sortium. A common missense variant of LILRB5 is associated withstatin intolerance and myalgia. Eur Heart J. 2017;38(48):3569–3575.

68. Moonga I, Niccolini F, Wilson H, et al. Alzheimer’s disease neuroi-maging initiative. Hypertension is associated with worse cognitivefunction and hippocampal hypometabolism in Alzheimer’s disease.Eur J Neurol. 2017;24:1173–1182.

69. Norton S, Matthews FE, Barnes DE, et al. Potential for primaryprevention of Alzheimer’s disease: an analysis of population-based data. Lancet Neurol. 2014;13:788–794.

70. Jd E, Ramirez J, Callahan BL, et al. Alzheimer’s disease neuroimaginginitiative. antihypertensive treatment is associated with mri-derivedmarkers of neurodegeneration and impaired cognition: a propensity-weighted cohort study. J Alzheimers Dis. 2017;59:1113–1122.

71. De Oliveira FF, Chen ES, Smith MC, et al. Pharmacogenetics ofangiotensin-converting enzyme inhibitors in patients withAlzheimer’s disease dementia. Curr Alzheimer Res. Forthcoming2017. DOI:10.2174/1567205014666171016101816

72. Danilov SM, Tovsky SI, Schwartz DE, et al. ACE phenotyping asa guide toward personalized therapy with ACE Inhibitors. JCardiovasc Pharmacol Ther. 2017;22(4):374–386. Epub 2017Jan 10.

73. Wain LV, Vaez A, Jansen R, et al. Novel blood pressure locus andgene discovery using genome-wide association study and expres-sion data sets from blood and the kidney. Hypertension. 2017.DOI:10.1161/HYPERTENSIONAHA.117.09438.

74. Berinstein E, Levy A. Recent developments and future directions forthe use of pharmacogenomics in cardiovascular disease treat-ments. Expert Opin Drug Metab Toxicol. 2017;13(9):973–983.

75. Nielsen RE, Lolk A, Rodrigo-Domingo M, et al. Antipsychotic treat-ment effects on cardiovascular, cancer, infection, and intentionalself-harm as cause of death in patients with Alzheimer’s dementia.Eur Psychiatry. 2017;42:14–23.

76. Delacrétaz A, Vandenberghe F, Gholam-Rezaee M, et al. Early changesof blood lipid levels during psychotropic drug treatment as predictorsof long-term lipid changes and of new onset dyslipidemia. J ClinLipidol. Forthcoming 2017. DOI:10.1016/j.jacl.2017.10.002.

77. Meltzer HY. New trends in the treatment of schizophrenia. CNSNeurol Disord Drug Targets. Forthcoming 2017. DOI:10.2174/1871527316666170728165355

78. Cacabelos R, Cacabelos P, Aliev G. Genomics and pharmacoge-nomics of antipsychotic drugs. Open J Psychiatry. 2013;3:46–139.

79. Seripa D, Lozupone M, Stella E, et al. Psychotropic drugs andCYP2D6 in late-life psychiatric and neurological disorders. Whatdo we know? Expert Opin Drug Saf. 2017;16(12):1373–1385.

80. Torrellas C, Carril JC, Cacabelos R. Optimization of antidepressantuse with pharmacogenetic strategies. Curr Genomics. 2017;18(5):442–449.

81. Bousman CA, Forbes M, Jayaram M, et al. Antidepressant prescrib-ing in the precision medicine era: a prescriber’s primer on pharma-cogenetic tools. BMC Psychiatry. 2017;17(1):60.

82. Bradley P, Shiekh M, Mehra V, et al. Improved efficacy with targetedpharmacogenetic-guided treatment of patients with depressionand anxiety: a randomized clinical trial demonstrating clinical uti-lity. J Psychiatr Res. 2018;96:100–107.

83. Cacabelos R, Torrellas C. Pharmacogenomics of antidepressants.HSOA J Psychiatry Depress Anxiety. 2015;1:001.

84. Majchrzak-Celińska A, Baer-Dubowska W. Pharmacoepigenetics: anelement of personalized therapy? Expert Opin Drug Metab Toxicol.2017;13(4):387–398.

85. Cacabelos R, Torrellas C.Pharmacoepigenomics.In: Tollefsbol T, Ed.Medical epigenetics. Elsevier. 2016. p. 585-617. DOI:10.1016/B978-0-12-803239-8.00032-6

86. Cacabelos R, Teijido O. Epigenetic drug discovery for Alzheimer’s dis-ease. In: Moskalev A, Vaiserman A, Eds. Epigenetics of aging and long-evity. Vol. 1. London, UK: Elsevier/Academic Press; 2018. p. 453–495.

87. Cacabelos R. Epigenomic networking in drug development: frompathogenic mechanisms to pharmacogenomics. Drug Dev Res.2014;75(6):348–365.

88. Cacabelos R, Torrellas C. Epigenetic drug discovery for Alzheimer’sdisease. Expert Opin Drug Discov. 2014;9(9):1059–1086.

89. Tang X, Chen S. Epigenetic regulation of cytochrome P450enzymes and clinical implication. Curr Drug Metab. 2015;16:86–96.

90. Kim IW, Han N, Burckart GT, et al. Epigenetic changes in geneexpression for drug-metabolizing enzymes and transporters.Pharmacotherapy. 2014;34:140–150.

91. Lauschke VM, Barragan I, Ingelman-Sundberg M.Pharmacoepigenetics and toxicoepigenetics: novel mechanistic

EXPERT REVIEW OF PRECISION MEDICINE AND DRUG DEVELOPMENT 25

insights and therapeutic opportunities. Annu Rev PharmacolToxicol. 2018;58:161–185.

92. Kang H, Kim C, Lee H, et al. Post-transcriptional controls by ribo-nucleoprotein complexes in the acquisition of drug resistance. Int JMol Sci. 2013;14:17204–17220.

93. O’Donnell PH, Wadhwa N, Danahey K, et al. Pharmacogenomics-basedpoint-of-care clinical decision support significantly alters drug prescrib-ing. Clin Pharmacol Ther. 2017;102(5):859–869.

94. Stitziel NO, Kathiresan S. Leveraging human genetics to guide drugtarget discovery. Trends Cardiovasc Med. 2017;27(5):352–359.

95. Nj K, Mm R, West-Strum D, et al. Preemptive pharmacogenetictesting: exploring the knowledge and perspectives of US payers.Genet Med. Forthcoming 2017. DOI:10.1038/gim.2017.181.

96. Klein ME, Parvez MM, Shin JG. Clinical implementation of pharma-cogenomics for personalized precision medicine: barriers and solu-tions. J Pharm Sci. 2017;106(9):2368–2379.

97. Nelson MR, Johnson T, Warren L3, et al. The genetics of drug efficacy:opportunities and challenges. Nat Rev Genet. 2016;17(4):197–206.

98. Danahey K, Borden BA, Furner B, et al. Simplifying the use of pharma-cogenomics in clinical practice: building the genomic prescribing sys-tem. J Biomed Inform. 2017;75:110–121.

99. Verbelen M, Weale ME, Lewis CM. Cost-effectiveness of pharmaco-genetic-guided treatment: are we there yet? Pharmacogenomics J.2017;17(5):395–402.

100. Santos R, Ursu O, Gaulton A, et al. A comprehensive map ofmolecular drug targets. Nat Rev Drug Discov. 2017;16(1):19–34.

101. Kalman LV, Agúndez J, Appell ML, et al. Pharmacogenetic allelenomenclature: international workgroup recommendations for testresult reporting. Clin Pharmacol Ther. 2016;99(2):172–185.

102. Ewart L, Dehne EM, Fabre K, et al. Application of microphysiologicalsystems to enhance safety assessment in drug discovery. Annu RevPharmacol Toxicol. 2018;58:65–82.

103. Hicks JK, Dunnenberger HM, Gumpper KF, et al. Integrating phar-macogenomics into electronic health records with clinical decisionsupport. Am J Health Syst Pharm. 2016;73(23):1967–1976.

26 R. CACABELOS

本文献由“学霸图书馆-文献云下载”收集自网络，仅供学习交流使用。

学霸图书馆（www.xuebalib.com）是一个“整合众多图书馆数据库资源，

提供一站式文献检索和下载服务”的24 小时在线不限IP

图书馆。

图书馆致力于便利、促进学习与科研，提供最强文献下载服务。

图书馆导航：

图书馆首页 文献云下载 图书馆入口 外文数据库大全 疑难文献辅助工具