International Journal of Molecular Sciences

Review of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia

Ramon Cacabelos EuroEspes Biomedical Research Center, International Center of and Genomic , 15165 Bergondo, Corunna, Spain; [email protected]

 Received: 12 March 2020; Accepted: 21 April 2020; Published: 26 April 2020 

Abstract: Symptomatic interventions for patients with dementia involve anti-dementia to improve cognition, psychotropic drugs for the treatment of behavioral disorders (BDs), and different categories of drugs for concomitant disorders. Demented patients may take >6–10 drugs/day with the consequent risk for –drug interactions and adverse drug reactions (ADRs >80%) which accelerate cognitive decline. The pharmacoepigenetic machinery is integrated by pathogenic, mechanistic, metabolic, transporter, and pleiotropic redundantly and promiscuously regulated by epigenetic mechanisms. CYP2D6, CYP2C9, CYP2C19, and CYP3A4/5 geno-phenotypes are involved in the metabolism of over 90% of drugs currently used in patients with dementia, and only 20% of the population is an extensive metabolizer for this tetragenic cluster. ADRs associated with anti-dementia drugs, antipsychotics, antidepressants, anxiolytics, hypnotics, sedatives, and antiepileptic drugs can be minimized by means of pharmacogenetic screening prior to treatment. These drugs are substrates, inhibitors, or inducers of 58, 37, and 42 enzyme/ products, respectively, and are transported by 40 different protein transporters. APOE is the reference gene in most pharmacogenetic studies. APOE-3 carriers are the best responders and APOE-4 carriers are the worst responders; likewise, CYP2D6-normal metabolizers are the best responders and CYP2D6-poor metabolizers are the worst responders. The incorporation of pharmacogenomic strategies for a personalized treatment in dementia is an effective option to optimize limited therapeutic resources and to reduce unwanted side-effects.

Keywords: alzheimer’s disease; anxiety; behavioral disorders; depression; epilepsy; neuropsychiatric disorders; personalized medicine; pharmacogenomics; psychosis; sleep disorders

1. Introduction Alzheimer’s disease (AD) is the most prevalent form of dementia (>50%), followed by vascular (VD), mixed dementia (MXD) (30–40%), and other modalities of neurodegenerative disorders (NDDs) (Lewy body dementia (LBD), frontotemporal dementia (FTD), prion dementia, Pick’s dementia, Parkinson–dementia complex (PDC); and comorbid FTD-amyotrophic lateral sclerosis) (5–10%). MXD shows the highest prevalence (>50%) in patients over 70–75 years of age. Genomic defects (Table1), epigenetic aberrations, cerebrovascular dysfunction, and multiple environmental factors are the major risk factors that precipitate pathogenic cascades leading to the clinical phenotype of dementia which is characterized by progressive cognitive deterioration, behavioral changes, functional decline, and classical neuropathological hallmarks (extracellular Aβ deposition in senile plaques, intracellular neurofibrillary tangles with hyperphosphorylated tau, dendritic desarborization, and neuronal loss) [1–6]. The main focus of pharmacological research over the past 50 years has been the identification of cognitive enhancers; however, no US Food and Drug Administration (FDA)-approved drugs for AD have been reported for the past two decades [7]. Behavioral disorders (BDs) (psychotic, depressive, anxiety, sleep disorders, and inappropriate sexual behaviors) are common (10–90%) in

Int. J. Mol. Sci. 2020, 21, 3059; doi:10.3390/ijms21093059 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 3059 2 of 82 patients with dementia and tend to increase in parallel with the cognitive deterioration [8–14]. BDs increase the risk of institutionalization, impair daily functioning, reduce quality of life, and accelerate cognitive deterioration [15,16]. BDs also increase the costs of dementia (e.g., LBD and VD) [17].

Table 1. Prevalent Alzheimer’s disease-related pathogenic genes.

Gene OMIM Risk Gene Name Gene ID Locus dbSNP ID MAF Symbol # Allele ATP binding cassette ABCA7 10347 605414 19p13.3 rs3764650 G 0.20 (G) subfamily A member rs429358; 0.15 (C); APOE Apolipoprotein E 348 107741 19q13.32 *4 rs7412 0.08 (T) Amyloid beta APP 351 104760 21q21.3 52 SNPs <0.01 precursor protein BIN1 Bridging integrator 1 274 601248 2q14.3 rs744373 C 0.36 (C) BUB3, mitotic BUB3 9184 603719 10q26.13 rs4980270 T 0.10 (T) checkpoint protein 9 open C9ORF72 203228 614260 9p21.2 rs3849942 T 0.22 (T) reading frame 72 CD2 associated CD2AP 23607 604241 6p12.3 rs9349407 C 0.25 (C) protein 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) Complement C3b/C4b CR1 185430 120620 1q32.2 rs3818361 T 0.25 (T) 1 Disrupted in DISC1 27185 605210 1q42.2 rs16856202 G 0.03 (G) schizophrenia 1 Ectonucleotide ENPP1 pyrophosphatase/ 5167 173335 6q23.2 rs7767170 T 0.02 (T) phosphodiesterase 1 EXO1 Exonuclease 1 9156 606063 1q43 rs1776148 A 0.27 (A) Laminin subunit LAMA3 64231 606548 11q12.2 rs11082762 A 0.47 (A) alpha 3 Lipoma HMGIC LHFP 10186 606710 13q13.3-q14.11 rs7995844 G 0.35 (G) fusion partner Microtubule MAPT 4137 157140 17q21.31 15 SNPs <0.01 associated protein tau Membrane spanning MS4A4E 643680 608401 8p21.1 rs670139 A 0.38 (A) 4-domains A4E Membrane spanning MS4A6A 64231 606548 11q12.2 rs610932 A 0.45 (A) 4-domains A6A NLR family pyrin NLRP4 147945 609645 19q13.43 rs12462372 A 0.08 (A) domain containing 4 NTNG1 Netrin G1 3909 600805 18q11.2 rs11803905 T 0.32 (T) Phosphatidylinositol PICALM binding clathrin 8301 603025 11q14.2 rs3851179 A 0.31 (A) assembly protein Piwi like PIWIL2 RNA-mediated gene 55124 610312 8p21.3 rs4266653 G 0.47 (G) silencing 2 PSEN1 Presenilin 1 5663 104311 14q24.2 241 SNPs < 0.01 PSEN2 Presenilin 2 5664 600759 1q42.13 43 SNPs < 0.01 Serine/threonine STK36 27148 607652 2q35 rs2303565 C 0.33 (C) kinase 36 STX17 Syntaxin 17 55014 604204 9q31.1 rs1997368 G 0.32 (G) Sad1 and UNC84 SUN3 256979 607723 7p12.3 rs2708909 G 0.39 (G) domain containing 3 TBC1 domain family TBC1D5 9779 615740 3p24.3 rs10510480 C 0.11 (C) member 5 USP6NL USP6 N-terminal like 9712 605405 10p14 rs3847437 T 0.04 (T) finger ZSWIM7 SWIM-type 125150 614535 17p12 rs10491104 T 0.41 (T) containing 7 Int. J. Mol. Sci. 2020, 21, 3059 3 of 82

There is not a prototypical pattern of BDs in different dementia types; however, BDs tend to be more prevalent in FTD, in cases where the compromise of frontotemporal regions is more relevant [18–20], and in cases with mild traumatic brain injury (TBI) [21] where DNA damage-induced cellular senescence pathways have been identified [22]. Apathy, depression, dysphoria, agitation, aggression, hallucinations, and delusions are frequent distressing symptoms in dementia [14]. A current behavioral phenotype is the hyperactivity–impulsivity–irritiability–disinhibition–aggression–agitation complex, with a difficult set of symptoms to manage, causing an important psychological burden for caregivers and hospital staff [23]. Some neuropsychiatric disorders may increase the risk for late-onset dementia, and dementia may increase the risk for delayed-onset BDs in specific cases [24]. The primary causes of BDs in dementia are unclear. APP, MAPT, APOE, and other variants in pathogenic genes (Table1) as well as the presence of schizophrenia- and /or depression-related SNPs [25–27], together with additional metabolic disorders [28], cerebrovascular risk or consolidated vascular damage [4,29–31], premorbid personality [32], and inappropriate management may contribute to BDs in AD. BDs partially correlate with conventional biomarkers of dementia [33,34]; however, agitation/aggression correlates with AD cerebrospinal fluid (CSF) biomarkers, and depression is inversely associated with core AD CSF pathology (low Aβ42, high Tau, and high pTau) [35,36]. Over 50% of AD patients show comorbidities (TDP-43 and Lewy bodies) which associate with frontotemporal lobar degeneration and LBD. Some of these comorbidities might explain BDs in dementia. TDP-43 is associated with aberrant psychomotor activity, and Lewy bodies are associated with anxiety, irritability, sleep disorders, and appetite anomalies [37]. In FTD, C9orf72 hexanucleotide repeat expansion with more than 80 G4C2 repeats has been associated with high frequency of psychotic symptoms [38]. Limbic-predominant age-related TDP-43 encephalopathy with high pTau burden might also predispose to more severe cognitive deterioration and BDs [39]. Most BDs in dementia are susceptible to pharmacological intervention, and though some studies suggest that psychotropic does not accelerate cognitive decline [40], most studies indicate that inappropriate treatments and consequent adverse drug reactions (ADRs) are frequent and deleterious [41–43]. Current ADRs in the elderly population are associated with , neuroleptics, antidepressants, and antihypertensives. These drugs may cause falls; delirium and excess mortality increase with polypharmacy; over-infections are frequent in patients with inappropriate use of broad-spectrum antibiotics; increased risk of stroke is observed in patients with dementia treated with antipsychotics; nonsteroidal anti-inflammatory drugs may cause hypertensive crises, bleeding, and cerebrovascular problems; and other ADRs have been extensively reported worldwide [43–46]. To palliate preventable ADRs, drug information resources have been developed. Some of them are designed for analyzing drug interactions, and others are useful to help physicians for an appropriate drug prescription [47–51]. However, few resources incorporate pharmacogenomics (PGx) as a practical tool for clinical use [45,52–56]. About 80% variability in drug and is attributed to PGx factors [56,57]. Rare variants contribute to approximately 30–40% of functional variability in 146 pharmagenes with clinical relevance. Over 240 pharmagenes are potentially associated with ADRs, and over 400 genes and their products influence drug efficacy and safety [53,54]. Furthermore, the pharmacological outcome is highly influenced by components of the PGx machinery, the chemical properties of each drug, and other diverse factors (e.g., compliance, nutrition, metabolic conditions, and concomitant drugs) [58,59]. The present review explores available information for personalized treatment of dementia in the areas of cognition and BDs based on PGx principles.

2. The Pharmacogenomic Machinery The pharmacogenomic machinery is composed by a network of gene clusters coding for and enzymes responsible for drug targeting and processing as well as critical components of the epigenetic machinery that regulate [60,61]. The pharmagenes involved in the Int. J. Mol. Sci. 2020, 21, 3059 4 of 82 pharmacogenomic response to drugs can be classified into five major categories: (i) Pathogenic genes (Table1) which are associated with disease pathogenesis [ 62]; (ii) mechanistic genes coding for components of enzymes, receptor subunits, transmitters, and messengers associated with the of drugs; (iii) metabolic genes of different categories that encode phase I–II reaction enzymes responsible for . Phase-I reaction enzymes include (in alphabetical order) dehydrogenases, aldehyde dehydrogenases, aldo-keto reductases, amine oxidases, carbonyl reductases, cytidine deaminases, cytochrome P450 family (CYPs) of mono-oxygenases, cytochrome b5 reductase, dihydropyrimidine dehydrogenase, esterases, epoxidases, flavin-containing monooxygenases, glutathione reductase/peroxidases, peptidases, prostaglandin endoperoxide synthases, short-chain dehydrogenases, reductases, superoxide dismutases, and xanthine dehydrogenase. The most relevant Phase-II reaction enzymes include the following: amino acid transferases, dehydrogenases, esterases, glucuronosyl transferases, glutathione transferases, methyl transferases, N-acetyl transferases, thioltransferase, and sulfotransferases; (iv) transporter genes coding for drug transporters. The most relevant categories of transporters include the following: ATPase (P-type subfamily), V-type (vacuolar H+-ATPase subunit), and ATPase (F-type subfamily); ATP-binding cassette transporters (subfamily A) (ABC1), subfamily B (MDR/TAP), subfamily C (CFTR/MRP), subfamily D (ALD), subfamily E (OABP), subfamily F (GCN20), and subfamily G (WHITE); and solute carriers (high-affinity glutamate and neutral amino acid transporter family) (SLC); and (v) pleiotropic genes which encode proteins and enzymes involved in a great variety of metabolic cascades and metabolomic networks [6,43,56,61–63]. The expression or repression of all these genes and their products are regulated in a redundant and promiscuous fashion by the epigenetic machinery (DNA methylation/demethylation, histone/chromatin remodeling, and miRNA regulation), configuring the pharmacoepigenetic apparatus. The same enzyme/protein/transporter can process a multitude of drugs, and the same drug can be processed by a vast array of gene products in an orchestrated manner to operate as a security system against xenobiotic intruders [61–67]. A vast array of polymorphic variants in over 600 defective human genes are potentially involved in AD pathogenesis and drug response. The presence of the ε4 allele in the APOE gene is the most important risk factor among top pathogenic genes (Table1)[ 1]. However, many other SNPs in diverse genes may contribute to AD-related neurodegeneration and premature neuronal death, including genes encoding components of the pharmacogenetic machinery. Polymorphic variants in ABC and SLC transporters may affect AD pathogenesis and response to drugs [3,63,68–73]. SNPs in genes encoding transporter proteins may affect brain penetrance and accessibility to neuronal/glial targets, drug metabolism, and [70,74,75]. Mutations in ABC transporters affect pathogenesis and therapeutics in AD. The ABCB1 transporter protein (P-gp1) and other transporters of this category are located on endothelial cells lining brain vasculature. They play important roles in limiting the movement of substances into and enhancing their efflux from the brain. ABCB1 is a very active drug transporter in the brain. It is estimated that over 1270 drugs are directly or indirectly processed via the ABCB1 transporter protein P-gp. Approximately, 490 drugs are substrates, 618 are inhibitors, and 182 are inducers [55]. In Caucasians and African-Americans, 116 and 127 polymorphic sites, respectively, have been identified with a minor allele frequency greater than 5%. ABCB1 C1236T in exon 12, G2677T/A in exon 21, and C3435T in exon 26 are common variants. The ABCB1*13 haplotype involves 3 intronic SNPs (in intron 9, 13, and 14) and the 1236, 2677, and 3435 (TTT) SNPs. The ABCB1 C1236T, G2677T/A, and C3435T variants participate in the P-gp1 function at the blood–brain barrier (BBB). AD patients carrying T in C1236T, G2677T, and C3435T have exhibited higher binding potential values than T noncarriers. ABCB1 variants might be potential biomarkers and might contribute to the progression of Aβ deposition in AD brains [76,77]. ABCB1 transports Aβ from the brain into the blood stream, and the transporter ABCA1 neutralizes Aβ aggregation in an APOE-dependent manner, facilitating Aβ elimination from the brain [78]. Other ABCs have shown potential association with AD [79]. The ABCA7 (G allele) rs115550680 SNP has been Int. J. Mol. Sci. 2020, 21, 3059 5 of 82 associated with AD in Europeans, with a comparable effect to that of the APOE-ε4 SNP rs429358 [80]. The ABCA7 SNP rs200538373, with altered ABCA7 exon 41 splicing, also shows association with AD risk [81]. ABCA7 methylation might be a biomarker of AD [82]. In AD, ABCA7 mRNA expression is higher than in controls, correlating with disease progression and cognitive decline. Alterations in lipid metabolism associated with APOE-4 and several SNPs in ABCA7 (rs3764650, rs3752246, and rs4147929) and loss-of-function mutations are pathogenic and PGx-dysfunctional in AD [83–85]. An intronic variable number tandem repeat (VNTR) in the ABCA7 locus shows strong association with AD [86]. ABCA7 variants cause accumulation of amyloid peptides and BBB dysfunction. ABCA7 defects decrease APOE secretion and cholesterol exchange across the BBB [87]. Cholesterol-related genes such as APOA5 (rs662799), APOC1 (rs11568822), APOD (rs1568565), CH25H (rs13500), LDLR (rs5930), and SORL1 (rs2282649), which affect lipid metabolism and membrane trafficking, may also be pathogenic and PGx-disruptive [63,88]. Soluble low-density lipoprotein receptor-related protein-1 (sLRP1), soluble receptor of advanced glycation end products (sRAGE), and transport proteins participate in the of plasma Aβ in an APOE-dependent manner [89]. The ATP-binding cassette transporter ABCA2 is an endolysosomal with pleiotropic activities and a critical role in mediating sphingolipids and cholesterol trafficking [90]. ABCA1 (rs2230805 and rs2230806) and ABCA2 variants are associated with AD [91,92]. Upregulation of ABCA2 mRNA expression has been observed in AD. Methylation of specific CpG islands in the ABCA2 gene negatively associates with AD risk. ABCA2 mRNA expression might also be used to differentially diagnose mild cognitive impairment (MCI) from other forms of dementia (i.e., Huntington’s disease) but not AD from MCI [93]. ABCG2 is a transporter of large, hydrophobic, charged molecules and different toxic compounds. Dysfunctional ABCG2 variants may affect absorption, distribution, accumulation, effectiveness, and of xenobiotic compounds and drugs [94]. ABCG2 is upregulated in AD brains and is involved in Aβ transport. The ABCG2-C421A variant (rs2231142) (ABCG2 C/C genotype) is associated with AD. Interaction of the ABCG2 C/C genotype with the APOE ε4 allele may increase AD risk [95]. Aβ alters BBB ABC efflux transporters and BBB permeability; specifically, ABCB1, ABCC5, and ABCG2; pregnane X receptor (PXR); and constitutive androstane receptor (CAR) transcription factors are inhibited by Aβ in brain endothelial cells [96]. Transporters encoded by genes of the solute carrier superfamily (SLC) and solute carrier organic (SLCO) transporter family are also important for AD pharmacogenomics. The human solute carrier (SLC) superfamily of transporters includes several hundred membrane-bound proteins with roles in physiological, pathological, and PGx processes. Over 200,000 exonic single-nucleotide variants (SNVs) have been identified, 99.8% of which are present in <1% of analyzed alleles. In the individual genome, there are about 29.7 variants with putative functional effects, and in specific populations, interethnic variability shows over 80% deleterious SLC variants [97]. In addition to APP, PSEN1, and PSEN2 mutations, SNPs in membrane proteins that alter the transmembrane trafficking of products also influence pathogenesis and PGx. One example of this may be SORL1. SORL1 (LR11) gene variants are associated with AD. SORL1 encodes a type I transmembrane 250-kDa protein (sorLA) that belongs to both the low-density lipoprotein receptor (LDLR) family and the vacuolar protein sorting 10 (VPS10) domain receptor family, acting as a sorting receptor for APP. SorLA, which interacts with ApoE and Tau, is a central regulator of trafficking and processing of APP and of Aβ destruction [98]. Another example might be the sarco/endoplasmic reticulum (SR/ER) calcium (Ca2+)-ATPase (SERCA) pump, an integral endoplasmic reticulum protein which has been associated with neuropsychiatric disorders (NPDs) and NDDs [99]. Translocation of substances across the mitochondrial membranes is required for cellular survival and efficient functioning. Major components of this translocation machinery are the translocase of the outer (TOMM) and inner mitochondrial membrane (TIMM) complexes. Mutations in the TIMM8A (DDP) and DNAJC19 (TIMM14) genes are pathogenic for Mohr–Tranebjærg syndrome and dilated Int. J. Mol. Sci. 2020, 21, 3059 6 of 82 cardiomyopathy syndrome, and polymorphisms in the TOMM40 gene are associated with AD and other NDDs [100]. Transient receptor potential melastatin 2 (TRPM2) is a Ca2+-permeable nonselective cation channel of the TRP family. TRPM2 dysfunction linked to aberrant intracellular Ca2+ accumulation and neuronal death has been implicated in AD. TRPM2 is involved in the induction of N-methyl-D-aspartate (NMDA) receptor-dependent long-term depression, a form of synaptic plasticity at glutamate synapses [101]. Drug transporter expression is altered at the BBB and peripheral tissues in AD. Intestinal expression of multidrug resistance-associated protein 2 (Mrp2), monocarboxylate transporter 1 (Mct1), and UDP-glucuronosyltransferase (Ugt) and liver expression of Cyp51a1 and Cyp2c29 have been found altered in AD transgenic models [102].

3. CNS Drugs According to data available in the World Guide for Drug Use and Pharmacogenomics [55] and the EuroPharmaGenics (EPG) database [56] concerning central nervous system (CNS) drugs (Figure1), the best-known genes of the pharmacogenetic machinery involved in the processing of antiepileptic, antidepressant, anxiolytic, hypnotic, sedative, antiparkinsonian, and antipsychotic drugs are mechanistic and metabolic genes, and poorly investigated genes are those involved in pathogenic mechanisms, transporters, and pleiotropic genes (Figure1). Globally, 74% pathogenic, 97% mechanistic, 94% metabolic, 68% transporter, and 40% pleiotropic genes have so far been associated with CNS drug efficacy and safety [103]. CNS drugs can act as substrates, inhibitors, or inducers of enzymes encoded by metabolic genes (Figure2). Among the 307 most frequently used CNS drugs, antiepileptics represent 14.66%, antiparkinsonians represent 10.42%, antipsychotics represent 21.82%, anxiolytics represent 11.40%, hypnotics and sedatives represent 21.17%, antidepressants represent 20.53%, and anti-dementia drugs represent 1%–2% (Figure1 and Table2). About 90% of these drugs use CYP enzymes as major metabolic pathways. CNS drugs are substrates, inhibitors, or inducers of 58, 37, and 42 enzyme/protein gene products, respectively, and are transported by 40 different protein transporters (Figure3). CNS drugs are major substrates of CYP3A4 (71%), CYP3A5 (37%), CYP2D6 (60%), CYP2C19 (45%), and CYP1A2 enzymes (44%); inhibitors of CYP3A4 (22%), CYP2D6 (23%), CYP2C19 (20%), CYP1A2 (17%), and CYP2C9 (15%); and inducers of CYP2C9 (9%), CYP2D6 (7%), CYP3A4 (5%), CYP1A2 (4.5%), CYP2A6 (4.5%), and CYP2B6 (3.7%). Major transporters of CNS drugs are ABCB1 (29%), SLCA1 (20%), SLC6A4 (20%), CLCNs (15%), SLC6A3 (12%), and SLC6A2 (11%) (Figure3)[103]. Approximately 80% of patients are deficient metabolizers for the tetrategic cluster integrated by CYP2D6, 2C19, 2C9, and 3A4/4 variants which encode enzymes responsible for the metabolism of 60–80% of drugs of current use, showing ontogenic-, age-, sex-, circadian- and ethnic-related differences. CYP geno-phenotypes differentiate extensive (EM; normal, NM), intermediate (IM), poor (PM), or ultra-rapid metabolizers (UM) with great geographic and ethnic variability worldwide [4,43,63]. The integration of CYP2D6, CYP2C9, CYP2C19, and CYP3A4/5 variants into tetragenic haplotypes yields 156 geno-phenotypes. H3 (1/1-1/1-1/1-3/3) (20.87%) is the most frequent haplotype, representing full extensive metabolizers. Only 17 haplotypes exhibit a frequency higher than 1% in the Caucasian population. According to this, it is very likely that about 80% of individuals are deficient for the biotransformation of current drugs metabolized via CYP2D6-2C9-2C19-3A4 enzymes [4,43,63]. Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 7 of 87 Int.Int. J. J. Mol. Mol. Sci. Sci. 20202020, ,2121, ,x 3059 FOR PEER REVIEW 7 7 of of 87 82

Figure 1. Pharmacogenetic machinery-related pathogenic, mechanistic, metabolic, transporter, and FigureFigure 1. 1. PharmacogeneticPharmacogenetic machinery-related machinery-related pathogenic pathogenic,, mechanistic, mechanistic, metabolic, metabolic, transporter, transporter, and and pleiotropic genes of antiepileptics, antidepressants,antidepressants, anxiolytics,anxiolytics, andand antipsychotics.antipsychotics. pleiotropic genes of antiepileptics, antidepressants, anxiolytics, and antipsychotics.

Figure 2. SubstratesSubstrates of antiepileptics, antipsycho antipsychotics,tics, anxiolytics, and antidepressants. Figure 2. Substrates of antiepileptics, antipsychotics, anxiolytics, and antidepressants.

Int. J. Mol. Sci. 2020, 21, 3059 8 of 82 Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 8 of 87

Figure 3. Substrates, inhibitors, inducers, and transporters of 307 CNS drugs (antidepressants, anxiolitics, Figurehipnotics, 3. sedatives,Substrates, antipsychotics, inhibitors, inducers, antiepileptics, and antiparkinsonian,transporters of 307 and CNS anti-dementia drugs (antidepressants, drugs). anxiolitics, hipnotics, sedatives, antipsychotics, antiepileptics, antiparkinsonian, and anti-dementia 4. Pharmacogenomicsdrugs). of Cognition Four acetylcholinesterase inhibitors have been approved for the treatment of AD. Tacrine was introducedApproximately in 1993 and80% discontinuedof patients are years deficient later metabo due tolizers hepatoxicity; for the tetrategic Donepezil cluster was introducedintegrated by in CYP2D6,1996; Galantamine 2C19, 2C9, wasand introduced3A4/4 variants in 2001;which and encode Rivastigmine enzymes resp wasonsible introduced for the in metabolism 2002. Memantine, of 60– 80%an NMDA of drugs partial of current antagonist, use, showing was approved ontogenic-, by age-, the FDAsex-, circadian- in 2003 [104 and,105 ethnic-related]. Over the pastdifferences. decade, CYPthe mostgeno-phenotypes prevalent pharmacological differentiate extensive categories (EM; currently normal, investigatedNM), intermediate as candidate (IM), poor strategies (PM), foror ultra-rapidthe treatment metabolizers of AD included (UM) with great geographic enhancers and ethnic (11.38%), variability anti-Amyloid worldwide agents [4,43,63]. (13.30%), multi-targetThe integration drugs (2.45%), of CYP2D6, anti-Tau CYP2C9, agents (2.03%), CYP2C19 and, and diverse CYP3A4/5 natural productsvariants (25.58%).into tetragenic Some haplotypesnovel drugs yields (8.13%), 156 geno-phenotypes. novel targets (5.66%), H3 (1/1-1/1-1/1-3/3) revised old drugs (20.87%) (11.77%), is the most anti-inflammatory frequent haplotype, drugs representing(1.20%), neuroprotective full extensive peptides metabolizers. (1.25%), Only stem 17 cell haplotypes therapy (1.85%),exhibit a nanocarriers frequency higher/nanotherapeutics than 1% in the(1.52%), Caucasian and others population. (combination According treatments, to this, cognitive it is very enhancers likely that/nootropics, about 80% neurotrophic of individuals factors, are deficientpolyunsaturated for the fattybiotransformation acids, hormone therapy,of current epigenetic drugs drugs,metabolized RNAi /genevia CYP2D6-2C9-2C19-3A4 silencing, miRNAs, and enzymesgene therapy) [4,43,63]. (<1% each) have also been investigated in exploratory studies for the treatment of AD [6]. However, no new drugs have been FDA-approved for the past 20 years. Consequently, most 4.PGx Pharmacogenomics studies concentrate of onCognition acetylcholinesterase inhibitors (AChEIs) (Donepezil, Galantamine, and Rivastigmine),Four acetylcholinesterase Memantine, and inhibitors combination have treatments been approved [2,3,106 for–108 the]. treatment of AD. Tacrine was introducedAPOE ingene 1993 variation and discontinued is associated years with later major due pathogenic to hepatoxicity; events in Donepezil AD [109,110 was], andintroducedAPOE has in 1996;been usedGalantamine as a reference was introduced gene in many in 2001; clinical and trials Rivastigmine as a PGx marker, was introduced followed byin metabolic2002. Memantine, genes (CYP an NMDAgeno-phenotypes) partial antagonist, [1,2,4,56 ,106was,107 approved,111–118 by]. APOE-4the FDAcarriers in 2003 exhibit [104,105]. differential Over the phenotypic past decade, patterns the mostof acetylcholinesterase prevalent pharmacological and butyrylcholinesterase categories currently activities investigated as well as CYP as candidate enzyme activities strategies with for strong the treatmentinfluence inof PGxAD included outcomes neurotransmitter [119]. SNP variation enhancer in CYP2D6s (11.38%),, acetylcholinesterase, anti-Amyloid agents butyrylcholinesterase, (13.30%), multi- targetcholine drugs acetyltransferase, (2.45%), anti-Tau and paraoxonase agents (2.03%), is associated and diverse with natural better clinicalproducts response (25.58%). to AChEIs Some novel [120]. drugs (8.13%), novel targets (5.66%), revised old drugs (11.77%), anti-inflammatory drugs (1.20%), 4.1. Donepezil neuroprotective peptides (1.25%), stem cell therapy (1.85%), nanocarriers/nanotherapeutics (1.52%), and Donepezilothers (combination is the most prescribed treatments, AChEI cognitive for the treatment enhancers/nootropics, of AD worldwide neurotrophic [107,121]. Donepezil factors, is polyunsaturateda major substrate fatty of CYP2D6, acids, hormone CYP3A4, therapy, ACHE, and epig UGTs;enetic inhibits drugs, ACHERNAi/gene and BCHE; silencing, and miRNAs, is transported and geneby ABCB1 therapy) [120 (<1%,122 ]each) (Table have2). Severalalso beenCYP2D6 investigatvariantsed in exploratory may modify studies donepezil for the effi treatmentcacy and of safety AD [6].in ADHowever, [55], and no APOEnew drugsand haveCYP2D6 beenvariants FDA-approved are determinant for the past in 20 the years. effects Consequently, of donepezil. mostAPOE-4 PGx studiescarriers concentrate tend to be the on worst acetylcholinesterase responders, and APOE-3inhibitorscarriers (AChEIs) are the(Donepezil, best responders Galantamine, to donepezil and Rivastigmine), Memantine, and combination treatments [2,3,106–108].

Int. J. Mol. Sci. 2020, 21, 3059 9 of 82 in either monotherapy or drug combination regimes; CYP2D6-EMs are the best responders, and CYP2D6-PMs are the worst responders [1,2,4,56,106,111–118]. CYP2D6 geno-phenotypes influence donepezil clearance. CYP2D6-PMs show a 32% slower elimination, and CYP2D6-UMs show a 67% faster elimination [123]. AD carriers of the common variant rs1080985 of CYP2D6 show poor response to donepezil [122,124]. In Chinese patients, CYP2D6-EMs and PMs show a similar response to donepezil; however, EMs are better responders than UMs. Patients harboring the rs1080985 G allele are poor responders to donepezil, and the worst responders accumulate in carriers of the bigenic APOE-4/rs1080985-G genotype [125]. The mutated CYP2D6 allele *2A is more frequent in responder than in nonresponder patients (75.38% vs. 43.48%). In Italian patients, 67% of the cases were responders, in whom abnormal enzymes accumulate, and 33% were nonresponders [126]. In Chinese and Thai AD cases, carriers of the mutant CYP2D6*10 allele responded better (58% responders) than carriers of the wild-type CYP2D6*1 allele [127]. The CYP2D6*10 variant strongly affects steady-state plasma concentration of donepezil and therapeutic outcome in Asian populations [128]. A recent study in China showed that CYP2D6*10 carriers treated with donepezil/galantamine have less side effects and that CYP2D6*10 carriers respond better to ChEIs [129]. Lower plasma donepezil concentration-to-dose ratios and better clinical response to donepezil have been reported in patients homozygous for the T/T/T genotype in the ABCB1 haplotypes 1236C/2677G/3435C (46%) and 1236T/2677T/3435T (41%) [130]. There is also a better response to donepezil in ABCA1 rs2230806 GG carriers than in AA or AG carriers [131]. APOE-ε4/BCHE-K* carriers show an earlier age of onset, an accelerated cognitive decline, and a differential response to donepezil therapy [132]. Donepezil is not recommended in BChE-K and APOE-4 carriers [133]. Donepezil is also used for the treatment of BDs in AD, LBD, and other dementia types [14,107,134]. Some reports indicate that AChEIs may also be beneficial in vascular dementia and cardiovascular disorders [135]. Donepezil might also ameliorate oxaliplatin-induced peripheral neuropathy [136] and confer protection against induced seizures in a mouse model (Scn1a+/-) of Dravet syndrome, an encephalopathy caused by de novo loss-of-function mutations in the SCN1A gene [137].

Table 2. Pharmacogenetics of conventional anti-dementia drugs. Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 10 of 87 Drug Properties Pharmacogenetics

Name:IUPAC Donepezil Name: 2-[(1-benzylpiperidin- hydrochloride, Aricept,ACHE, BCHE 120011-70-3, Donepezil HCl, BNAG, E-2020, 4-yl)methyl]-5,6-dimethoxy-2,3- Metabolic genes: E2020 dihydroinden-1-one;hydrochloride Substrate: CYP2D6 IUPAC Name: (major), CYP3A4 (major), 2-[(1-benzylpiperidin-4-yl)methyl]-5,6-Molecular Formula: C24H30ClNO3 UGTs,Pathogenic ACHE genes: APOE CHAT dimethoxy-2,3-dihydroinden-1-one; , Inhibitor:Mechanistic ACHE genes:, BCHE CHAT ACHE hydrochlorideMolecular Weight: 415.9529 g/mol , , TransporterBCHE genes: ABCB1 Molecular Formula: C24H30ClNO3 Metabolic genes: Category: Cholinesterase inhibitor Molecular Weight: 415.9529 g/mol Substrate: CYP2D6 (major), Mechanism: Centrally active, CYP3A4 (major), UGTs, ACHE Category: Cholinesterase inhibitor Inhibitor: ACHE BCHE reversible acetylcholinesterase , Transporter genes: ABCB1 Mechanism:inhibitor; increasesCentrally the active, acetylcholine reversible acetylcholinesteraseavailable for synaptic inhibitor; transmission increases in the acetylcholine available for synaptic the CNS transmission in the CNS Effect: Nootropic agent, cholinesterase Einhibitor,ffect: Nootropic parasympathomimetic agent, cholinesterase effect inhibitor, parasympathomimetic effect Name: Galantamine hydrobromide

IUPAC Name: (1S,12S,14R)-9- methoxy-4-methyl-11-oxa-4- azatetracyclo[8.6.1.0^{1,12}.0^{6,17}]he ptadeca-6,8,10(17),15-tetraen-14-ol

Molecular Formula: C17H22BrNO3 Pathogenic genes: APOE, APP Mechanistic genes: ACHE, Molecular Weight: 368.26548 g/mol BCHE, CHRNA4, CHRNA7, CHRNB2 Category: Cholinesterase inhibitor Metabollic genes: Substrate: CYP2D6 Mechanism: Reversible and (major), CYP3A4 (major), competitive acetylcholinesterase UGT1A1 inhibition leading to an increased Inhibitor: ACHE, BCHE concentration of acetylcholine at cholinergic synapses; modulates nicotinic ; may increase glutamate and serotonin levels Effect: Nootropic agent, cholinesterase inhibitor, parasympathomimetic effect Name: Memantine Hydrochloride, 41100-52-1, Namenda, Memantine Pathogenic genes: APOE, HCL, Axura, 3,5-Dimethyl-1- MAPT, PSEN1 adamantanamine hydrochloride, 3,5- Mechanistic genes: dimethyladamantan-1-amine CHRFAM7A, DLGAP1, hydrochloride FOS, GRIN2A, GRIN2B, IUPAC Name: 3,5- GRIN3A, HOMER1, HTR3A dimethyladamantan-1- Metabolic genes: amine;hydrochloride Inhibitor: CYP1A2 (weak), CYP2A6 Molecular Formula: C12H22ClN (weak), CYP2B6 (strong), CYP2C9 (weak), CYP2C19 (weak), CYP2D6 (strong), Molecular Weight: 215.76278 g/mol CYP2E1 (weak), CYP3A4

(weak), NR1I2 Category: N-Methyl-D-Aspartate Transporter genes: NR1I2;

Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 10 of 87

Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEWIUPAC Name: 2-[(1-benzylpiperidin- ACHE, BCHE 10 of 87 4-yl)methyl]-5,6-dimethoxy-2,3- Metabolic genes: dihydroinden-1-one;hydrochlorideIUPAC Name: 2-[(1-benzylpiperidin- ACHE Substrate:, BCHE CYP2D6 4-yl)methyl]-5,6-dimethoxy-2,3- (major),Metabolic CYP3A4 genes: (major), Molecular Formula: C24H30ClNO3 dihydroinden-1-one;hydrochloride UGTs Substrate:, ACHE CYP2D6 (major), Inhibitor: CYP3A4 ACHE (major),, BCHE MolecularMolecular Weight:Formula: 415.9529 C24H30ClNO g/mol3 TransporterUGTs, ACHE genes: ABCB1 Inhibitor: ACHE, BCHE Category:Molecular Cholinesterase Weight: 415.9529 inhibitor g/mol Transporter genes: ABCB1

Mechanism:Category: Cholinesterase Centrally inhibitor active, reversible acetylcholinesterase inhibitor;Mechanism: increases Centrally the acetylcholine active, availablereversible for synapticacetylcholinesterase transmission in theinhibitor; CNS increases the acetylcholine Effectavailable: Nootropic for synaptic agent, transmission cholinesterase in inhibitor,the CNS parasympathomimetic effect Int. J. Mol. Sci. 2020, 21, 3059 Effect: Nootropic agent, cholinesterase 10 of 82 Nameinhibitor,: Galantamine parasympathomimetic hydrobromide effect

IUPACName: GalantamineName: hydrobromide(1S,12S,14R)-9- methoxy-4-methyl-11-oxa-4-Table 2. Cont. azatetracyclo[8.6.1.0^{1,12}.0^{6,17}]heIUPAC Name: (1S,12S,14R)-9- Drug Properties Pharmacogenetics ptadeca-6,8,10(17),15-tetraen-14-olmethoxy-4-methyl-11-oxa-4- Name:azatetracyclo[8.6.1.0^{1,12}.0^{6,17}]he Galantamine hydrobromide IUPACMolecularptadeca-6,8,10(17),15-tetraen-14-ol Name: Formula:(1S,12S,14R)-9-methoxy-4- C17H22BrNO3 Pathogenic genes: APOE, methyl-11-oxa-4-azatetracyclo[8.6.1.0ˆ{1,12}.APP 0ˆ{6,17}]heptadeca-6,8,10(17),15-tetraen-14-olMolecular Formula: C17H22BrNO3 MechanisticPathogenic genes:: ACHE,APOE, Molecular Weight: 368.26548 g/mol BCHE,APP CHRNA4, CHRNA7, Molecular Formula: C17H22BrNO3 CHRNB2MechanisticPathogenic genes genes:: ACHE,APOE, APP Molecular Weight: 368.26548 g/mol MolecularCategory: Cholinesterase Weight: 368.26548 inhibitor g/mol MetabollicBCHE,Mechanistic CHRNA4, genes: CHRNA7, genes: ACHE, BCHE, Category: Cholinesterase inhibitor CHRNB2 SubstrateCHRNA4, : CHRNA7,CYP2D6 CHRNB2 MechanismCategory: Cholinesterase: Reversible inhibitor and (major),MetabollicMetabollic CYP3A4 genes: genes: (major), Mechanism: Reversible and competitive competitive acetylcholinesterase SubstrateSubstrate:: CYP2D6CYP2D6(major), acetylcholinesterase inhibition leading to anUGT1A1 inhibitionMechanism leading: Reversible to an increased and CYP3A4 (major), UGT1A1 increased concentration of acetylcholine at (major), Inhibitor CYP3A4: ACHE, BCHE(major), concentrationcompetitive of acetylcholinesteraseacetylcholine at Inhibitor: ACHE, BCHE cholinergic synapses; modulates nicotinic UGT1A1 inhibition leading to an increased acetylcholinecholinergic receptor;synapses; may increasemodulates Inhibitor: ACHE, BCHE glutamatenicotinicconcentration acetylcholine and serotoninof acetylcholine receptor; levels may at increasecholinergic glutamate synapses; and modulatesserotonin Effect: Nootropic agent, cholinesterase levelsnicotinic acetylcholine receptor; may inhibitor, parasympathomimetic effect Effect:increase Nootropic glutamate agent, and cholinesterase serotonin Name: Memantine Hydrochloride, inhibitor,levels parasympathomimetic effect 41100-52-1, Namenda, Memantine HCL, Effect: Nootropic agent, cholinesterase Axura,Name: 3,5-Dimethyl-1-adamantanamineMemantine Hydrochloride, hydrochloride,41100-52-1,inhibitor, parasympathomimetic Namenda, Memantine effect Pathogenic genes: APOE, 3,5-dimethyladamantan-1-amineHCL,Name: MemantineAxura, 3,5-Dimethyl-1-Hydrochloride, MAPT,Pathogenic PSEN1 genes: APOE, MAPT, hydrochlorideadamantanamine41100-52-1, Namenda, hydrochloride, Memantine 3,5- MechanisticPathogenicPSEN1 genes: genesAPOE,: IUPACdimethyladamantan-1-amineHCL, Name:Axura, 3,5-Dimethyl-1- CHRFAM7A,MAPT,Mechanistic PSEN1 DLGAP1, genes: CHRFAM7A, DLGAP1, FOS, GRIN2A, GRIN2B, 3,5-dimethyladamantan-1-amine;hydrochloridehydrochlorideadamantanamine hydrochloride, 3,5- FOS,Mechanistic GRIN2A, GRIN2B,genes: GRIN3A, HOMER1, HTR3A Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEWIUPACdimethyladamantan-1-amine Name: 3,5- GRIN3A,CHRFAM7A, HOMER1, DLGAP1, HTR3A 11 of 87 Molecular Formula: C12H22ClN Metabolic genes: hydrochloride MetabolicFOS, GRIN2A, genes: GRIN2B, dimethyladamantan-1- Inhibitor :CYP1A2 (weak), Molecular Weight: 215.76278 g/mol GRIN3A, Inhibitor HOMER1,: HTR3A amine;hydrochlorideMechanism:IUPAC BindsName: preferentially 3,5-to PleiotropicCYP2A6 genes:(weak), APOE,CYP2B6 (strong), Metabolic genes: Category:NMDAdimethyladamantan-1- N-Methyl-D-Aspartatereceptor-operated cation receptor MAPT,CYP1A2CYP2C9 MT-TK, (weak),(weak), PSEN1 CYP2A6CYP2C19 (weak), antagonistMolecularchannels;amine;hydrochloride may Formula: act by C blocking12H22ClN actions (weak), InhibitorCYP2D6 CYP2B6: (strong), (strong),CYP2E1 (weak), CYP1A2 (weak), CYP2A6 Mechanism:of glutamate,Binds mediated preferentially in part to NMDAby CYP2C9CYP3A4 (weak),(weak), CYP2C19NR1I2 NMDAMolecular receptors Formula: C12H22ClN (weak),(weak),Transporter CYP2D6CYP2B6 genes:(strong),(strong),NR1I2 ; receptor-operatedMolecular Weight: cation 215.76278 channels; g/mol may act by CYP2E1CYP2C9Pleiotropic (weak), genes:CYP2C19CYP3A4APOE, MAPT, blockingEffect: Dopamine actions of agent, glutamate, antiparkinson mediated in part by NMDA receptors (weak),(weak),MT-TK, NR1I2CYP2D6PSEN1 (strong), agent,Molecular excitatory Weight: 215.76278amino g/mol acid Category: N-Methyl-D-Aspartate CYP2E1 (weak), CYP3A4 Eantagonist,ffect: Dopamine antidyskinetic agent, antiparkinson agent,Transporter genes: NR1I2; receptor antagonist (weak), NR1I2 excitatoryNameCategory:: Rivastigmine amino N-Methyl-D-Aspartate acid antagonist,tartrate, 129101- Transporter genes: NR1I2; antidyskinetic54-8,receptor SDZ-ENA antagonist 713, Rivastigmine Name:hydrogentartrate, Rivastigmine tartrateRivastigmine, 129101-54-8, SDZ-ENAHydrogen 713,Tartrate, Rivastigmine ENA 713, ENA- hydrogentartrate,713 Rivastigmine Hydrogen Tartrate,IUPAC ENA 713,Name: ENA-713 (2R,3R)-2,3- IUPACdihydroxybutanedioic Name: acid;[3-[(1S)-1- Pathogenic genes: APOE, (2R,3R)-2,3-dihydroxybutanedioic(dimethylamino)ethyl]phenyl] N- APP, CHATPathogenic genes: APOE, APP, acid;[3-[(1S)-1-(dimethylamino)ethyl]phenyl]ethyl-N-methylcarbamate MechanisticCHAT genes: ACHE, N-ethyl-N-methylcarbamate BCHE, CHAT, CHRNA4, Molecular Formula: C18H28N2O8 Mechanistic genes: ACHE, BCHE, Molecular Formula: C18H28N2O8 CHRNB2CHAT, CHRNA4, CHRNB2 Molecular Weight: 400.42352 g/mol MetabolicMetabolic genes: genes: Molecular Weight: 400.42352 g/mol Inhibitor:Inhibitor: ACHE,ACHE, BCHE BCHE Category: Cholinesterase inhibitor PleiotropicPleiotropic genes: genes: APOE,APOE, MAPT Mechanism:Category: CholinesteraseIncreases acetylcholine inhibitor in CNSMAPT through reversible inhibition of its hydrolysis byMechanism: cholinesterase Increases acetylcholine in CNS through reversible inhibition of Effect: Neuroprotective agent, cholinesterase its hydrolysis by cholinesterase inhibitor, cholinergic agent Effect: Neuroprotective agent, cholinesterase inhibitor, cholinergic agent Name: Tacrine Hydrochloride, Tacrine HCl, 1684-40-8, Hydroaminacrine, tacrine.HCl, 9- AMINO-1,2,3,4- TETRAHYDROACRIDINE Pathogenic genes: APOE HYDROCHLORIDE, Tenakrin Mechanistic genes: ACHE, IUPAC Name: 1,2,3,4- BCHE, CHRNA4, CHRNB2 tetrahydroacridin-9- Metabolic genes: amine;hydrochloride Substrate: CYP1A2 (major), CYP2D6 (minor), Molecular Formula: C13H15ClN2 CYP3A4 (major) Inhibitor: ACHE, BCHE, Molecular Weight: 234.7246 g/mol CYP1A2 (weak) Transporter genes: SCN1A Category: Cholinesterase inhibitor Pleiotropic genes: APOE, CES1, GSTM1, GSTT1, Mechanism: Elevates acetylcholine in LEPR, MTHFR cerebral cortex by slowing degradation of acetylcholine Effect: Nootropic agent, cholinesterase inhibitor, Parasympathomimetic effect AADAC: arylacetamide deacetylase; AANAT: aralkylamine N-acetyltransferase; ABAT: 4-aminobutyrate aminotransferase; ABCB1: ATP-binding cassette, sub-family B (MDR/TAP), member 1; ABCB11: ATP- binding cassette, sub-family B (MDR/TAP), member 11; ABCC1: ATP-binding cassette, sub-family C (CFTR/MRP), member 1; ABCC2: ATP-binding cassette, sub-family C (CFTR/MRP), member 2; ABCC3: ATP-binding cassette, sub-family C (CFTR/MRP), member 3; ABCC4: ATP-binding cassette, sub-family C (CFTR/MRP), member 4; ABCC6: ATP-binding cassette, sub-family C (CFTR/MRP), member 6; ABCC8: ATP-binding cassette, sub-family C (CFTR/MRP), member 8; ABCG2: ATP-binding cassette, sub-family G

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Mechanism: Binds preferentially to Pleiotropic genes: APOE, NMDA receptor-operated cation MAPT, MT-TK, PSEN1 channels; may act by blocking actions of glutamate, mediated in part by NMDA receptors Effect: Dopamine agent, antiparkinson agent, excitatory amino acid antagonist, antidyskinetic Name: Rivastigmine tartrate, 129101- 54-8, SDZ-ENA 713, Rivastigmine hydrogentartrate, Rivastigmine Hydrogen Tartrate, ENA 713, ENA- 713 IUPAC Name: (2R,3R)-2,3- dihydroxybutanedioic acid;[3-[(1S)-1- Pathogenic genes: APOE, (dimethylamino)ethyl]phenyl] N- APP, CHAT ethyl-N-methylcarbamate Mechanistic genes: ACHE, BCHE, CHAT, CHRNA4, Molecular Formula: C18H28N2O8 CHRNB2 Metabolic genes: Molecular Weight: 400.42352 g/mol Inhibitor: ACHE, BCHE Pleiotropic genes: APOE, Category: Cholinesterase inhibitor MAPT Mechanism: Increases acetylcholine in CNS through reversible inhibition of its hydrolysis by cholinesterase Int. J. Mol. Sci. 2020, 21, 3059 Effect: Neuroprotective agent, 11 of 82 cholinesterase inhibitor, cholinergic agent Name: TacrineTable 2.HydrochlorideCont. , Tacrine HCl, 1684-40-8, Drug Properties Pharmacogenetics Hydroaminacrine, tacrine.HCl, 9- Name:AMINO-1,2,3,4- Tacrine Hydrochloride, Tacrine HCl, 1684-40-8, Hydroaminacrine, tacrine.HCl, TETRAHYDROACRIDINE Pathogenic genes: APOE 9-AMINO-1,2,3,4-TETRAHYDROACRIDINE HYDROCHLORIDE, Tenakrin Mechanistic genes: ACHE, HYDROCHLORIDE, Tenakrin Pathogenic genes: APOE IUPAC Name: 1,2,3,4- BCHE,Mechanistic CHRNA4, CHRNB2 genes: ACHE, BCHE, IUPACtetrahydroacridin-9- Name: MetabolicCHRNA4, genes: CHRNB2 1,2,3,4-tetrahydroacridin-9-amine;hydrochloride amine;hydrochloride SubstrateMetabolic: genes:CYP1A2 Molecular Formula: C13H15ClN2 (major),Substrate: CYP2D6CYP1A2 (minor), (major), Molecular Formula: C13H15ClN2 CYP3A4CYP2D6 (major) (minor), CYP3A4 (major) Molecular Weight: 234.7246 g/mol InhibitorInhibitor:: ACHE,ACHE, BCHE, BCHE, CYP1A2 Category:MolecularCholinesterase Weight: 234.7246 inhibitor g/mol CYP1A2(weak) (weak) Transporter genes: SCN1A Mechanism: Elevates acetylcholine in Transporter genes: SCN1A Pleiotropic genes: APOE, CES1, cerebral cortex by slowing degradation of Pleiotropic genes: APOE, Category: Cholinesterase inhibitor GSTM1, GSTT1, LEPR, MTHFR acetylcholine CES1, GSTM1, GSTT1, Mechanism: Elevates acetylcholine in Effect: Nootropic agent, cholinesterase LEPR, MTHFR cerebral cortex by slowing degradation inhibitor, Parasympathomimetic effect of acetylcholine AADAC: arylacetamide deacetylase;Effect:AANAT Nootropic: aralkylamine agent, cholinesterase N-acetyltransferase; ABAT: 4-aminobutyrate inhibitor, Parasympathomimetic effect aminotransferase; ABCB1: ATP-binding cassette, sub-family B (MDR/TAP), member 1; ABCB11: ATP-binding AADAC: arylacetamide deacetylase; AANAT: aralkylamine N-acetyltransferase; ABAT: 4-aminobutyrate cassette, sub-family B (MDR/TAP), member 11; ABCC1: ATP-binding cassette, sub-family C (CFTR/MRP), member 1; aminotransferase; ABCB1: ATP-binding cassette, sub-family B (MDR/TAP), member 1; ABCB11: ATP- bindingABCC2: cassette,ATP-binding sub-family cassette, B sub-family (MDR/TAP), C (CFTR member/MRP), 11; member ABCC1 2;: ABCC3:ATP-bindingATP-binding cassette, cassette, sub-family sub-family C C (CFTR/MRP),(CFTR/MRP), membermember 3; 1;ABCC4: ABCC2:ATP-binding ATP-binding cassette, cassette, sub-family sub-family C (CFTR C (CFTR/MRP),/MRP), member member 4; ABCC6: 2; ABCC3:ATP-binding ATP-bindingcassette, sub-family cassette, C (CFTRsub-family/MRP), C member(CFTR/MRP), 6; ABCC8: memberATP-binding 3; ABCC4: cassette, ATP-binding sub-family cassette, C (CFTR sub-family/MRP), memberC (CFTR/MRP),8; ABCG2: ATP-binding member 4; cassette,ABCC6: sub-familyATP-binding G (WHITE),cassette, sub-family member 2 C (Junior (CFTR/MRP), blood group); memberACACA 6; ABCC8:: acetyl-CoA ATP-bindingcarboxylase alpha;cassette,ACADSB: sub-familyacyl-CoA C (CFTR/MRP), dehydrogenase member short 8; ABCG2:/branched ATP-binding chain; ACHE: cassette,acetylcholinesterase sub-family G (Yt blood group); ACSL1: acyl-CoA synthetase long-chain family member 1; ACSL3: acyl-CoA synthetase long-chain family member 3; ACSL4: acyl-CoA synthetase long-chain family member 4; ACSM1: acyl-CoA synthetase medium-chain family member 1; ACSM2B: acyl-CoA synthetase medium-chain family member 2B; ACSM3: acyl-CoA synthetase medium-chain family, member 3; ADCY1: adenylate cyclase 1 (brain); ADH1A: alcohol dehydrogenase 1A (class I), alpha polypeptide; ADH1B: alcohol dehydrogenase 1B (class I), beta polypeptide; ADH1C: alcohol dehydrogenase 1C (class I), gamma polypeptide; ADH4: alcohol dehydrogenase 4 (class II), pi polypeptide; ADH5: alcohol dehydrogenase 5 (class III), chi polypeptide; ADH6: alcohol dehydrogenase 6 (class V); ADH7: alcohol dehydrogenase 7 (class IV), mu or sigma polypeptide; ADHs: alcohol dehydrogenases; ADHFE1: alcohol dehydrogenase, iron containing, 1; ADIPOQ: adiponectin, C1Q and collagen domain containing; ADRA1A: adrenoceptor alpha 1A; ADRA1B: adrenoceptor alpha 1B; ADRA1D: adrenoceptor alpha 1D; ADRA1s: alpha 1- family; ADRA2A: adrenoceptor alpha 2A; ADRA2B: adrenoceptor alpha 2B; ADRA2C: adrenoceptor alpha 2C; ADRA2s: alpha 2-adrenergic receptor family; ADRAs: alpha-adrenergic receptor family; ADRB1: adrenoceptor beta 1; ADRB2: adrenoceptor beta 2, Surface; ADRB3: adrenoceptor beta 3; ADRBs: beta-adrenergic receptor family; ADRs: adrenoceptors; AGXT: alanine-glyoxylate aminotransferase; AHR: aryl hydrocarbon receptor; AKR1A1: aldo-keto reductase family 1, member A1 (aldehyde reductase); AKR1B1: aldo-keto reductase family 1, member B1 (aldose reductase); AKR1C1: aldo-keto reductase family 1, member C1; AKR1D1: aldo-keto reductase family 1, member D1; ALB: albumin; ALDH1A1: aldehyde dehydrogenase 1 family, member A1; ALDH1A2: aldehyde dehydrogenase family 1, subfamily A2; ALDH1A3: aldehyde dehydrogenase family 1, subfamily A3; ALDH1B1: aldehyde dehydrogenase 1 family, member B1; ALDH2: aldehyde dehydrogenase 2 family (mitochondrial); ALDH3A1: aldehyde dehydrogenase 3 family, member A1; ALDH3A2: aldehyde dehydrogenase 3 family, member A2; ALDH3B1: aldehyde dehydrogenase 3 family, member B1; ALDH3B2: aldehyde dehydrogenase 3 family, member B2; ALDH4A1: aldehyde dehydrogenase 4 family, member A1; ALDH5A1: aldehyde dehydrogenase 5 family, member A1; ALDH6A1: aldehyde dehydrogenase 6 family, member A1; ALDH7A1: aldehyde dehydrogenase 7 family, member A1; ALDH8A1: aldehyde dehydrogenase 8 family, member A1; ALDH9A1: aldehyde dehydrogenase 9 family, member A1; ANKK1: ankyrin repeat and kinase domain containing 1; AOX1: aldehyde oxidase 1; APOA1: apolipoprotein A-I; APOA5: apolipoprotein A-V; APOC3: apolipoprotein C-III; APOD: apolipoprotein D; APOE: apolipoprotein E; APP: amyloid beta (A4) precursor Int. J. Mol. Sci. 2020, 21, 3059 12 of 82

protein; AQP1: aquaporin-1; AS3MT: arsenic (+3 oxidation state) methyltransferase; ASMT: acetylserotonin O-methyltransferase; BAAT: bile acid CoA: amino acid N-acyltransferase (glycine N-choloyltransferase); BCHE: butyrylcholinesterase; BCL2: B-cell CLL/lymphoma 2; BCL2L1: BCL2-like 1; BDNF: brain-derived neurotrophic factor; BLK: BLK proto-oncogene, Src family tyrosine kinase; CA1: 1; CA2: carbonic anhydrase 2; CA3: carbonic anhydrase 3; CA4: ; CA7: ; CA12: ; CA14: ; CACNA1C: calcium channel, voltage-dependent, L type, alpha 1C subunit; CACNs: calcium channel, voltage-dependent family; CALM1: calmodulin 1 (phosphorylase kinase, delta); CALMs: calmodulins; CALY: Calcyon neuron specific vesicular protein; CASR: calcium-sensing receptor; CAT: catalase; CBR1: carbonyl reductase 1; CBR3: carbonyl reductase 3; CBR4: carbonyl reductase 4; CBS: cystathionine-beta-synthase; CCBL1: cysteine conjugate-beta lyase, cytoplasmic; CCND1: cyclin D1; CDA: cytidine deaminase; CEL: carboxyl ester lipase; CELF4: CUGBP, Elav-like family member 4; CERKL: ceramide kinase-like; CES1: carboxylesterase 1; CES1P1: carboxylesterase 1 pseudogene 1; CES2: carboxylesterase 2; CES3: carboxylesterase 3; CES5A: carboxylesterase 5A; CFTR: cystic fibrosis transmembrane conductance regulator (ATP-binding cassette sub-family C, member 7); CHRM1: cholinergic receptor, muscarinic 1; CHRM2: cholinergic receptor, muscarinic 2; CHRM3: cholinergic receptor, muscarinic 3; CHRM4: cholinergic receptor, muscarinic 4; CHRM5: cholinergic receptor, muscarinic 5; CHRMs: muscarinic cholinergic receptor family; CHRNA2: Cholinergic receptor nicotinic alpha 2 subunit; CHRNA3: Cholinergic receptor nicotinic alpha 3 subunit; CHRNA4: cholinergic receptor, nicotinic, alpha 4 (neuronal); CHRNA7: cholinergic receptor, nicotinic, alpha 7 (neuronal); CHRNAs: nicotinic cholinergic receptors, alpha type; CHRNB2: cholinergic receptor, nicotinic, beta 2 (neuronal); CHRNB4: cholinergic receptor nicotinic beta 4 subunit; CHRNs: nicotinic cholinergic receptor family; CHST1: carbohydrate (keratan sulfate Gal-6) sulfotransferase 1; CHST2: carbohydrate (N-acetylglucosamine-6-O) sulfotransferase 2; CHST3: carbohydrate (chondroitin 6) sulfotransferase 3; CHST4: carbohydrate (N-acetylglucosamine 6-O) sulfotransferase 4; CHST5: carbohydrate (N-acetylglucosamine 6-O) sulfotransferase 5; CHST6: carbohydrate (N-acetylglucosamine 6-O) sulfotransferase 6; CHST7: carbohydrate (N-acetylglucosamine 6-O) sulfotransferase 7; CHST8: carbohydrate (N-acetylgalactosamine 4-0) sulfotransferase 8; CHST9: carbohydrate (N-acetylgalactosamine 4-0) sulfotransferase 9; CHST10: carbohydrate sulfotransferase 10; CHST11: carbohydrate (chondroitin 4) sulfotransferase 11; CHST12: carbohydrate (chondroitin 4) sulfotransferase 12; CHST13: carbohydrate (chondroitin 4) sulfotransferase 13; CKS1B: CDC28 protein kinase regulatory subunit 1B; CLCNs: voltage-sensitive chloride channel family; CNR1: 1 (brain); CNTF: ciliary neurotrophic factor; COMT: Catechol-O-methyltransferase; CREB1: cAMP responsive element binding protein 1; CRHR1: corticotropin releasing hormone receptor 1; CRHR2: corticotropin releasing hormone receptor 2; CXCR2: chemokine (C-X-C motif) receptor 2; CYB5R3: cytochrome b5 reductase 3; CYP1A1: cytochrome P450, family 1, subfamily A, polypeptide 1; CYP1A2: cytochrome P450, family 1, subfamily A, polypeptide 2; CYP1B1: cytochrome P450, family 1, subfamily B, polypeptide 1; CYP2A6: cytochrome P450, family 2, subfamily A, polypeptide 6; CYP2A7: cytochrome P450, family 2, subfamily A, polypeptide 7; CYP2A13: cytochrome P450, family 2, subfamily A, polypeptide 13; CYP2B6: cytochrome P450, family 2, subfamily B, polypeptide 6; CYP2C8: cytochrome P450, family 2, subfamily C, polypeptide 8; CYP2C9: cytochrome P450, family 2, subfamily C, polypeptide 9; CYP2C18: cytochrome P450, family 2, subfamily C, polypeptide 18; CYP2C19: cytochrome P450, family 2, subfamily C, polypeptide 19; CYP2D6: cytochrome P450, family 2, subfamily D, polypeptide 6; CYP2D7P1: cytochrome P450, family 2, subfamily D, polypeptide 7 pseudogene 1; CYP2E1: cytochrome P450, family 2, subfamily E, polypeptide 1; CYP2F1: cytochrome P450, family 2, subfamily F, polypeptide 1; CYP2J2: cytochrome P450, family 2, subfamily J, polypeptide 2; CYP2R1: cytochrome P450, family 2, subfamily R, polypeptide 1; CYP2S1: cytochrome P450, family 2, subfamily S, polypeptide 1; CYP2W1: cytochrome P450, family 2, subfamily W, polypeptide 1; CYP3A4: cytochrome P450, family 3, subfamily A, polypeptide 4; CYP3A4/5: cytochrome P450, family 3, subfamily A, polypeptide 4/5; CYP3A5: cytochrome P450, family 3, subfamily A, polypeptide 5; CYP3A7: cytochrome P450, family 3, subfamily A, polypeptide 7; CYP3A43: cytochrome P450, family 3, subfamily A, polypeptide 43; CYP3As: cytochrome P450, family 3, subfamily A; CYP4A11: cytochrome P450, family 4, subfamily A, polypeptide 11; CYP4A22: cytochrome P450, family 4, subfamily A, polypeptide 22; CYP4B1: cytochrome P450, family 4, subfamily B, polypeptide 1; CYP4F2: cytochrome P450, family 4, subfamily F, polypeptide 2; CYP4F3: cytochrome P450, family 4, subfamily F, polypeptide 3; CYP4F8: cytochrome P450, family 4, subfamily F, polypeptide 8; CYP4F11: cytochrome P450, family 4, subfamily F, polypeptide 11; CYP4F12: Int. 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cytochrome P450, family 4, subfamily F, polypeptide 12; CYP4Z1: cytochrome P450, family 4, subfamily Z, polypeptide 1; CYP7A1: cytochrome P450, family 7, subfamily A, polypeptide 1; CYP7B1: cytochrome P450, family 7, subfamily B, polypeptide 1; CYP8B1: cytochrome P450, family 8, subfamily B, polypeptide 1; CYP11A1: cytochrome P450, family 11, subfamily A, polypeptide 1; CYP11B1: cytochrome P450, family 11, subfamily B, polypeptide 1: CYP11B2: cytochrome P450, family 11, subfamily B, polypeptide 2; CYP17A1: cytochrome P450, family 17, subfamily A, polypeptide 1; CYP19A1: cytochrome P450, family 19, subfamily A, polypeptide 1; CYP20A1: cytochrome P450, family 20, subfamily A, polypeptide 1; CYP21A2: cytochrome P450, family 21, subfamily A, polypeptide 2; CYP24A1: cytochrome P450, family 24, subfamily A, polypeptide 1; CYP26A1: cytochrome P450, family 26, subfamily A, polypeptide 1; CYP26B1: cytochrome P450, family 26, subfamily B, polypeptide 1; CYP26C1: cytochrome P450, family 26, subfamily C, polypeptide 1; CYP27A1: cytochrome P450, family 27, subfamily A, polypeptide 1; CYP27B1: cytochrome P450, family 27, subfamily B, polypeptide 1; CYP39A1: cytochrome P450, family 39, subfamily A, polypeptide 1; CYP46A1: cytochrome P450, family 46, subfamily A, polypeptide 1; CYP51A1: cytochrome P450, family 51, subfamily A, polypeptide 1; DAO: D-amino-acid oxidase; DDC: dopa decarboxylase (aromatic L-amino acid decarboxylase); DDOST: dolichyl-diphosphooligosaccharide–protein glycosyltransferase subunit (non-catalytic); DHRS1: dehydrogenase/reductase (SDR family) member 1; DHRS2: dehydrogenase/reductase (SDR family) member 2; DHRS3: dehydrogenase/reductase (SDR family) member 3; DHRS4: dehydrogenase/reductase (SDR family) member 4; DHRS7: dehydrogenase/reductase (SDR family) member 7; DHRS9: dehydrogenase/reductase (SDR family) member 9; DHRS12: dehydrogenase/reductase (SDR family) member 12; DHRS13: dehydrogenase/reductase (SDR family) member 13; DHRSX: dehydrogenase/reductase (SDR family) X-linked; DIO2: deiodinase, iodothyronine, type II; DLGAP1: discs, large (Drosophila) homolog-associated protein 1; DPEP1: dipeptidase 1 (renal); DPP4: dipeptidyl-peptidase 4; DPYD: dihydropyrimidine dehydrogenase; DRD1: D1; DRD2: ; DRD3: ; DRD4: ; DRD5: ; DRDs: dopamine receptors; DTNBP1: dystrobrevin binding protein 1; EPHX1: Epoxide hydrolase 1, microsomal (xenobiotic); EPHX2: epoxide hydrolase 2, microsomal (xenobiotic); ESD: esterase D; FABP1: fatty acid binding protein 1, liver; FGB: fibrinogen beta chain; FKBP5: binding protein 5; FMO1: flavin containing monooxygenase 1; FMO2: flavin containing monooxygenase 2; FMO3: flavin containing monooxygenase 3; FMO4: flavin containing monooxygenase 4; FMO5: flavin containing monooxygenase 5; FMO6P: flavin containing monooxygenase 6 pseudogene; FMOs: flavin containing monooxygenases; FOS: FBJ murine osteosarcoma viral oncogene homolog; GABBRs: gamma-aminobutyric acid (GABA) A receptors, beta; GABRA1: gamma-aminobutyric acid (GABA) A receptor, alpha 1; GABRA2: gamma-aminobutyric acid (GABA) A receptor, alpha 2; GABRA3: gamma-aminobutyric acid (GABA) A receptor, alpha 3; GABRA4: gamma-aminobutyric acid (GABA) A receptor, alpha 4; GABRA5: gamma-aminobutyric acid (GABA) A receptor, alpha 5; GABRA6: gamma-aminobutyric acid (GABA) A receptor, alpha 6; GABRAs: gamma-aminobutyric acid (GABA) A receptors; GABRB1: gamma-aminobutyric acid type A receptor beta1 subunit; GABRB2: gamma-aminobutyric acid type A receptor beta2 subunit; GABRB3: gamma-aminobutyric acid (GABA) A receptor, beta 3; GABRBs: gamma-aminobutyric acid (GABA) A receptors, beta subtype; GABRD: gamma-aminobutyric acid (GABA) A receptor, delta; GABRE: gamma-aminobutyric acid (GABA) A receptor, épsilon; GABRG1: gamma-aminobutyric acid type A receptor gamma1 subunit; GABRG2: gamma-aminobutyric acid (GABA) A receptor, gamma 2; GABRG3: gamma-aminobutyric acid type A receptor pi subunit; GABRGs: gamma-aminobutyric acid (GABA) A receptors, gamma subtype; GABRP: gamma-aminobutyric acid (GABA) A receptor, pi; GABRQ: gamma-aminobutyric acid (GABA) A receptor, theta; receptor rho1 subunit; GABRR2: gamma-aminobutyric acid type A receptor rho2 subunit; GABRR3: gamma-aminobutyric acid type A receptor rho3 subunit; GABRs: gamma-aminobutyric acid (GABA) receptors; GAL3ST1: galactose-3-O-sulfotransferase 1; GAMT: guanidinoacetate N-methyltransferase; GFRA2: GDNF family receptor alpha 2; GH1: growth hormone 1; GLRs: glycine receptors; GLRX: glutaredoxin (thioltransferase); GLYAT: glycine-N-acyltransferase; GNAS: GNAS complex locus; GNB3: guanine nucleotide binding protein (G protein), beta polypeptide 3; GNMT: glycine N-methyltransferase; GPX1: glutathione peroxidase 1; GPR35: G protein-coupled receptor 35; GPX2: glutathione peroxidase 2 (gastrointestinal); GPX3: glutathione peroxidase 3 (plasma); GPX4: glutathione peroxidase 4; GPX5: glutathione peroxidase 5; GPX6: glutathione peroxidase 6 (olfactory); GPX7: glutathione peroxidase 7; GRIA1: , ionotropic, AMPA 1; GRIA2: glutamate receptor, ionotropic, AMPA 2; GRIA3: glutamate Int. J. Mol. Sci. 2020, 21, 3059 14 of 82

receptor, ionotropic, AMPA 3; GRIA4: glutamate receptor, ionotropic, AMPA 4; GRIAs: ionotropic glutamate receptors; GRIK2: glutamate receptor, ionotropic, kainate 2; GRIK4: glutamate receptor, ionotropic, kainate 4; GRK5: G protein-coupled receptor kinase 5; GRIN1: glutamate ionotropic receptor NMDA type subunit 1; GRIN2A: glutamate receptor, ionotropic, N-methyl D-aspartate 2A; GRIN2B: glutamate receptor, ionotropic, N-methyl D-aspartate 2B; GRIN2C: glutamate receptor, ionotropic, N-methyl D-aspartate 2C; GRIN2D: glutamate ionotropic receptor NMDA type subunit 2D; GRIN3A: glutamate ionotropic receptor NMDA type subunit 3A; GRIN3B: glutamate receptor, ionotropic, N-methyl-D-aspartate 3B; GRM3: glutamate receptor, metabotropic 3; GSK3B: glycogen synthase kinase 3 beta; GSR: glutathione reductase; GSTA1: glutathione S-transferase alpha 1; GSTA2: glutathione S-transferase alpha 2; GSTA3: glutathione S-transferase alpha 3; GSTA4: glutathione S-transferase alpha 4; GSTA5: Glutathione S-transferase alpha 5; GSTCD: glutathione S-transferase, C-terminal domain containing; GSTK1: glutathione S-transferase kappa 1; GSTM1: glutathione S-transferase mu 1; GSTM2: glutathione S-transferase mu 2 (muscle); GSTM3: glutathione S-transferase mu 3 (brain); GSTM4: glutathione S-transferase mu 4; GSTM5: glutathione S-transferase mu 5; GSTO1: glutathione S-transferase omega 1; GSTO2: glutathione S-transferase omega 2; GSTP1: glutathione S-transferase pi 1; GSTs: glutathione S-transferases; GSTT1: glutathione S-transferase theta 1; GSTT2: glutathione S-transferase theta 2; GSTZ1: glutathione S-transferase zeta 1; GZMA: granzyme A (granzyme 1, cytotoxic T-lymphocyte-associated serine esterase 3; GZMB: granzyme B (granzyme 2, cytotoxic T-lymphocyte-associated serine esterase 1); HCRTR1: hypocretin (orexin) receptor 1; HCRTR2: hypocretin (orexin) receptor 2; HDAC2: histone deacetylase 2; HDAC9: histone deacetylase 9; HDC: histidine decarboxylase; HLA-B: major histocompatibility complex, class I, B; HNF4A: hepatocyte nuclear factor 4, alpha; HNMT: histamine N-methyltransferase; HOMER1: homer homolog 1 (Drosophila); HRH1: H1; HRH2: histamine receptor H2; HRH4: histamine receptor H4; HRHs: histamine receptor family; HSD11B1: hydroxysteroid (11-beta) dehydrogenase 1; HSD17B10: hydroxysteroid (17-beta) dehydrogenase 10; HSD17B11: hydroxysteroid (17-beta) dehydrogenase 11; HSD17B14: hydroxysteroid (17-beta) dehydrogenase 14; HTR1A: 5-hydroxytryptamine (serotonin) receptor 1A, G protein-coupled; HTR1B; 5-hydroxytryptamine (serotonin) receptor 1B, G protein-coupled; HTR1D: 5-hydroxytryptamine (serotonin) receptor 1D, G protein-coupled; HTR1E: 5-hydroxytryptamine (serotonin) receptor 1E, G protein-coupled; HTR1F: 5-hydroxytryptamine (serotonin) receptor 1F, G protein-coupled; HTR1s: 5-hydroxytryptamine (serotonin) receptors, family 1; HTR2A: 5-hydroxytryptamine (serotonin) receptor 2A, G protein-coupled; HTR2B: 5-hydroxytryptamine (serotonin) receptor 2B, G protein-coupled; HTR2C: 5-hydroxytryptamine (serotonin) receptor 2C, G protein-coupled; HTR2s: 5-hydroxytryptamine (serotonin) receptors, family 2; HTR3: histone H3; HTR3A: 5-hydroxytryptamine (serotonin) receptor 3A, ionotropic; HTR3B: 5-hydroxytryptamine (serotonin) receptor 3B, ionotropic; HTR3C: 5-hydroxytryptamine (serotonin) receptor 3C, ionotropic; HTR5A: 5-hydroxytryptamine (serotonin) receptor 5A, G protein-coupled; HTR6: 5-hydroxytryptamine (serotonin) receptor 6, G protein-coupled; HTR7: 5-hydroxytryptamine (serotonin) receptor 7, adenylate cyclase-coupled; ); HTRs: 5-hydroxytryptamine (serotonin) receptors; HTT: huntingtin; ICAM1: intercellular adhesion molecule 1; IDO1: indoleamine 2,3-dioxygenase 1; IFNA1: interferon, alpha 1; IGF1: insulin-like growth factor 1 (somatomedin C); IL1B: interleukin 1, beta; IL1RN: interleukin 1 receptor antagonist; IL6: interleukin 6; IL12B: interleukin 12B; INMT: indolethylamine N-methyltransferase; ITGB3: integrin, beta 3 (platelet glycoprotein IIIa, antigen CD61); KCNE1: potassium channel, voltage gated subfamily E regulatory beta subunit 1; KCNE2: potassium channel, voltage gated subfamily E regulatory beta subunit 2; KCNH2: potassium channel, voltage gated eag related subfamily H, member 2; KCNH6: potassium channel, voltage gated eag related subfamily H, member 6; KCNJ11: potassium channel, inwardly rectifying subfamily J, member 11; KCNKs: potassium channel, subfamily K; KCNQ1: potassium channel, voltage gated KQT-like subfamily Q, member 1; KRAS: Kirsten rat sarcoma viral oncogene homolog; LEP: leptin; LEPR: leptin receptor; LIPC: lipase, hepatic; LPL: lipoprotein lipase; MAO: monoamine oxidase; MAOA: Monoamine oxidase A; MAOB: monoamine oxidase B; MCHR1: Melanin concentrating hormone receptor 1; MET: MET proto-oncogene, receptor tyrosine kinase; METAP1: Methionyl aminopeptidase 1; MGST1: Microsomal glutathione S-transferase 1; MGST2: Microsomal glutathione S-transferase 1; MGST3: Microsomal glutathione S-transferase 3; MTNR1A: receptor 1A; MTNR1B: 1B; NAA20: N(alpha)-acetyltransferase 20, NatB catalytic subunit; NAT1: N-acetyltransferase 1 (arylamine N-acetyltransferase); NAT2: N-acetyltransferase 2 (arylamine N-acetyltransferase); NDUFs: NADH dehydrogenase (ubiquinone) family; NNMT: N-methyltransferase; NPAS3: neuronal PAS domain Int. J. Mol. Sci. 2020, 21, 3059 15 of 82

protein 3; NPPA: natriuretic peptide A; NPY: neuropeptide Y; NQO1: NAD(P)H dehydrogenase, quinone 1; NQO2: NAD(P)H dehydrogenase, quinone 2; NR1I2: nuclear receptor subfamily 1, group I, member 2; NR1I3: nuclear receptor subfamily 1, group I, member 3; NR3C1: nuclear receptor subfamily 3, group C, member 1 (glucocorticoid receptor); NRG3: neuregulin 3; NRXN1: neurexin 1; NTRK1: neurotrophic tyrosine kinase, receptor, type 1; NTRK2: neurotrophic tyrosine kinase, receptor, type 2; NUBPL: nucleotide binding protein-like; NUDT9P1: nudix (nucleoside diphosphate linked moiety X)-type motif 9 pseudogene 1; OGDH: Oxoglutarate dehydrogenase; ORM1: orosomucoid 1; ORM2: orosomucoid 2; PALLD: alladin, cytoskeletal associated protein; PARK2: parkin RBR E3 ubiquitin protein ligase; PDE1C: phosphodiesterase 1C, calmodulin-dependent 70kDa; PDE5A: phosphodiesterase 5A, cGMP-specific; PNMT: Phenylethanolamine N-methyltransferase; POMC: ; PON1: Paraoxonase 1; PON2: Paraoxonase 2; PON3: Paraoxonase 3; POR: P450 (cytochrome) oxidoreductase; PPARA: Peroxisome proliferator activated receptor alpha; PPARD: Peroxisome proliferator activated receptor delta; PPARG: Peroxisome proliferator activated receptor gamma; PPARGC1A: peroxisome proliferator-activated receptor gamma, coactivator 1 alpha; PRKAB1: protein kinase, AMP-activated, beta 1 non-catalytic subunit; PRKCSH: protein kinase C substrate 80K-H; PRL: prolactin; PRLH: prolactin releasing hormone; PSEN1: presenilin 1; PSEN2: presenilin 2; PSMD9: proteasome (prosome, macropain) 26S subunit, non-ATPase, 9; PTGES: Prostaglandin E synthase; PTGS1: Prostaglandin-endoperoxide synthase 1 (prostaglandin G/H synthase and cyclooxygenase); PTGS2: Prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase); RB1: retinoblastoma 1; RGS2: regulator of G-protein signaling 2; RGS4: regulator of G-protein signaling 4; RGS7: regulator of G-protein signaling 7; RRAS2: related RAS viral (r-ras) oncogene homolog 2; RXRA: retinoid X receptor, alpha; SAT1: spermidine/spermine N1-acetyltransferase 1; SCL6A4: solute carrier family 6 (neurotransmitter transporter), member 4; SCN1A: sodium channel, voltage gated, type I alpha subunit; SCN3A: Sodium voltage-gated channel alpha subunit 3; SCN5A: sodium channel, voltage gated, type V alpha subunit; SCNA: synuclein, alpha (non A4 component of amyloid precursor); SCN1B: sodium voltage-gated channel beta subunit 1; SCNs: sodium channels, voltage gated; SIGMAR1: sigma non- intracellular receptor 1; SLC6A2: solute carrier family 6 (neurotransmitter transporter), member 2; SLC6A3: solute carrier family 6 (neurotransmitter transporter), member 3; SLC6A4: solute carrier family 6 (neurotransmitter transporter), member 4; SLC10A1: solute carrier family 10 (sodium/bile acid cotransporter), member 1; SLC16A1: solute carrier family 16 member 1; SLC18A2: solute carrier family 18 member 2; SLC22A1: solute carrier family 22 (organic cation transporter), member 1; SLC22A2: solute carrier family 22 (organic cation transporter), member 2; SLC22A3: solute carrier family 22 (organic cation transporter), member 3; SLC22A4: solute carrier family 22 member 4; SLC22A5: solute carrier family 22 member 5; SLC22A6: solute carrier family 22 member 6; SLC22A7: solute carrier family 22 member 7; SLC22A8: solute carrier family 22 member 8; SLCO1B1: solute carrier organic anion transporter family, member 1B1; SLCO1B3: solute carrier organic anion transporter family, member 1B3; SLCO1C1: Solute carrier organic anion transporter family member 1C1; SLCO2A1: Solute carrier organic anion transporter family member 2A1; SLCO2B1: solute carrier organic anion transporter family, member 2B1; SLCO3A1: solute carrier organic anion transporter family, member 3A1; SMOX: spermine oxidase; SOD1: Superoxide dismutase 1, soluble; SOD2: superoxide dismutase 2, mitochondrial; SPG7: spastic paraplegia 7 (pure and complicated autosomal recessive); STAT3: signal transducer and activator of transcription 3 (acute-phase response factor); SULT1A1: sulfotransferase family, cytosolic, 1A, phenol-preferring, member 1; SULT1A2: sulfotransferase family, cytosolic, 1A, phenol-preferring, member 2; SULT1A3: sulfotransferase family, cytosolic, 1A, phenol-preferring, member 3; SULT1B1: sulfotransferase family, cytosolic, 1B, member 1; SULT1C1: sulfotransferase family, cytosolic, 1C, member 1; SULT1C2: sulfotransferase family, cytosolic, 1C, member 2; SULT1C3: sulfotransferase family, cytosolic, 1C, member 3; SULT1C4: sulfotransferase family, cytosolic, 1C, member 4; SULT1E1: sulfotransferase family 1E, estrogen-preferring, member 1; SULT2A1: sulfotransferase family, cytosolic, 2A, (DHEA)-preferring, member 1; SULT2B1: sulfotransferase family, cytosolic, 2B, member 1; SULT4A1: sulfotransferase family 4A, member 1; SULT6B1: sulfotransferase family, cytosolic, 6B, member 1; TBX21: T-box 21; TBXAS1: thromboxane A synthase 1 (platelet); TDO2: tryptophan 2,3-dioxygenase; TGFB1: transforming growth factor, beta 1; TMEM163: transmembrane protein 163; TNF: tumor necrosis factor; TNFRSF1A: tumor necrosis factor receptor superfamily, member 1A; TNR: tenascin R; TPH1: tryptophan hydroxylase 1; TPH2: tryptophan hydroxylase 2; TPMT: thiopurine S-methyltransferase; TSPO: translocator protein (18kDa); TST: thiopurine S-methyltransferase; UCHL1: ubiquitin carboxyl-terminal esterase L1 Int. J. Mol. Sci. 2020, 21, 3059 16 of 82

(ubiquitin thiolesterase); UCHL3: ubiquitin carboxyl-terminal esterase L3 (ubiquitin thiolesterase); UGT1A1: UDP glucuronosyltransferase 1 family, polypeptide A1; UGT1A3: UDP glucuronosyltransferase 1 family, polypeptide A3; UGT1A4: UDP glucuronosyltransferase 1 family, polypeptide A4; UGT1A5: UDP glucuronosyltransferase 1 family, polypeptide A5; UGT1A6: UDP glucuronosyltransferase 1 family, polypeptide A6; UGT1A7: UDP glucuronosyltransferase 1 family, polypeptide A7; UGT1A8: UDP glucuronosyltransferase 1 family, polypeptide A8; UGT1A9: UDP glucuronosyltransferase 1 family, polypeptide A9; UGT1A10: UDP glucuronosyltransferase 1 family, polypeptide A10; UGT2A1: UDP glucuronosyltransferase 2 family, polypeptide A1, complex locus; UGT2A3: UDP glucuronosyltransferase 2 family, polypeptide A3; UGT2B4: UDP glucuronosyltransferase 2 family, polypeptide B4; UGT2B7: UDP glucuronosyltransferase 2 family, polypeptide B7; UGT2B10: UDP glucuronosyltransferase 2 family, polypeptide B10; UGT2B11: UDP glucuronosyltransferase 2 family, polypeptide B11; UGT2B15: UDP glucuronosyltransferase 2 family, polypeptide B15; UGT2B17: UDP glucuronosyltransferase 2 family, polypeptide B17; UGT2B28: UDP glucuronosyltransferase 2 family, polypeptide B28; UGT3A1: UDP glycosyltransferase 3 family, polypeptide A1; UGT8: UDP glycosyltransferase 8; UGTs: glucuronosyltransferase family; XDH: Xanthine dehydrogenase; XKR4: XK, Kell blood group complex subunit-related family, member 4; WARS: tryptophanyl-tRNA synthetase; WARS2: tryptophanyl tRNA synthetase 2, mitochondrial.

4.2. Galantamine Galantamine is a major substrate of CYP2D6, CYP3A4, ABCB1, and UGT1A1 and an inhibitor of ACHE and BCHE. APOE, APP, ACHE, BCHE, CHRNA4, CHRNA7, and CHRNB2 variants may also affect galantamine efficacy and safety [120,138–141]. Galantamine is mainly metabolized by CYP2D6 and CYP3A4 enzymes. Major metabolic pathways are glucuronidation, O-demethylation, N-demethylation, N-oxidation, and epimerization [142]. Galantamine is a substrate of ABCB1. CYP2D6 variants are major determinants of galantamine pharmacokinetics, with CYP2D6-PMs presenting 45% and 61% higher dose-adjusted galantamine plasma concentrations than heterozygous and homozygous CYP2D6-EMs [120,143]; however, these pharmacokinetic changes might not substantially affect pharmacodynamics [144]. The coadministration of galantamine with CYP2D6 and CYP3A4 strong inhibitors increases its [48,145]. Galantamine bioavailability and its therapeutic effects may be modified by interaction with foods and nutritional components [146]. Some recent studies show promising results with galantamine in cases of drug abuse (, cocaine, and cannabis) [147,148] and TBI [149]. In combination with CDP-Choline, memantine, and antipsychotics, galantamine might be useful in schizophrenia [150,151].

4.3. Rivastigmine Rivastigmine is a dual inhibitor of acetylcholinesterase (AChE; EC 3.1.1.7) and butyrylcholinesterase (BuChE; EC 3.1.1.8) in AD [152,153]. APOE, APP, CHAT, ACHE, BCHE, CHRNA4, CHRNB2, and MAPT variants may affect rivastigmine pharmacokinetics and pharmacodynamics. CYP enzymes are not involved in the metabolism of rivastigmine [120,138,145,154]. UGT2B7-PMs show higher rivastigmine levels with a poor response to treatment [155]. In combination treatments with memantine, carriers of CYP2D6*3, UGT2B7, and UGT1A9*5 variants show differential responses to treatment. Two SNPs on the intronic region of CHAT (rs2177370 and rs3793790) [156] and CHRNA7 variants may influence the response to AChEIs [157]. Two SNPs, one intronic marker in PRKCE-rs6720975 and an intergenic NBEA-rs17798800 marker, might also contribute to differential therapeutic response to AChEIs [158]. Females with the BChE-wt/wt show a better benefit with rivastigmine than males, and BChE-K* male carriers show a faster cognitive decline than females [159]. AD patients harboring the BChE K-variant (rs1803274), causing a reduced enzyme activity, show low clinical response to rivastigmine. The K-variant (p. A539T) and other SNPs located outside the coding sequence in 5’UTR (rs1126680) and/or intron 2 (rs55781031) of the BCHE gene are responsible for reduced enzyme activity and poor response to rivastigmine [160]. Rivastigmine may be useful in VD and Parkinson’s disease [161,162] and in combination with low-dose quetiapine can improve psychotic symptoms in LBD [163]. Int. J. Mol. Sci. 2020, 21, 3059 17 of 82

4.4. Memantine Memantine is an N-Methyl-D-Aspartate (NMDA) receptor antagonist which binds preferentially to NMDA receptor-operated cation channels [108]. Memantine inhibits the actions of glutamate via NMDA receptors and antagonizes GRIN2A, GRIN2B, GRIN3A, HTR3A, and CHRFAM7A. APOE, PSEN1, and MAPT are pathogenic genes which might influence the effects of memantine in AD, and variants in some mechanistic genes (GRIN2A, GRIN2B, GRIN3A, HTR3A, CHRFAM7A, c-Fos, Homer1b, and PSD-95) may also modify its therapeutic effects. CYP2B6 and CYP2D6 are strongly inhibited by memantine. In contrast, CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2E1, and CYP3A4 are weakly inhibited [55,120,164,165]. Studies in human liver microsomes show that memantine inhibits CYP2B6 and CYP2D6; decreases CYP2A6 and CYP2C19; and has no effect on CYP1A2, CYP2E1, CYP2C9, or CYP3A4 [166]. The coadministration of CYP2B6 substrates decreases memantine metabolism by 65%. NR1I2 rs1523130 is the only genetic covariate for memantine clearance in clinical studies. NR1I2 rs1523130 CT/TT carriers show a slower memantine elimination than carriers of the CC genotype [165]. NMDA receptors are glutamate receptors with Mg2+-mediated voltage-dependence effects in synaptic plasticity. Mutations in NMDA receptor subunits are present in NDDs. Patients with severe epileptic encephalopathy harbor the missense variant GluN2AN615K (GRIN2A C1845A), which affects NMDA receptor channel blockers, including memantine [167]. Memantine can be used alone or in combination with AChEIs in AD [168,169]. Proteomic studies in the hippocampus and the cerebral cortex of AD-related transgenic mice (3 Tg-AD) treated with × memantine revealed alterations in the expression of 233 and 342 proteins, respectively [170]. In APP23 transgenic mice with cerebral amyloid angiopathy (CAA), memantine reduces cerebrovascular Aβ and hemosiderin deposits by enhancing Aβ-cleaving IDE expression [171]. Memantine is useful for the treatment of both cognitive deterioration and BDs in AD and other forms of dementia [172,173]. AD patients treated with memantine plus citalopram show improvement in BDs [174]; in combination with antipsychotics, it may improve verbal memory, learning, verbal letter fluency, and working memory with no effect on psychotic symptoms in patients with chronic schizophrenia [175,176]; at a dose of 20 mg/day, it may be effective in patients with obsessive-compulsive disorder [177]; at 10 mg/day, it may be helpful in [178]; and, in combination with , it enhances the efficacy of naltrexone in reducing alcohol drinking and craving [179]. Memantine might also be useful in the treatment of punctate and dynamic allodynia by the blockade of the microglia Kir2.1 channel to suppress microglia activation [180], and in combination with , it may be beneficial in neuropathic pain [181].

4.5. Multifactorial Treatments Most studies in which AD patients are treated with multifactorial combinations reveal that APOE-3/3 carriers are the best responders and that APOE-4/4 carriers are the worst responders. Concerning CYP-related PGx outcomes, CYP2D6-EMs are the best responders, CYP2D6-PMs are the worst responders, and CYP2D6-IMs and UMs show an intermediate response [1–3,56,71,106,112,115,116,118] (Figures4–6) . In linkage disequilibrium with and adjacent to the APOE locus (19q13.2) is the TOMM40 gene, which encodes an outer mitochondrial membrane translocase involved in the transport of Aβ and other proteins into mitochondria. A poly T repeat in an intronic polymorphism (rs10524523) (intron 6) in the TOMM40 gene has been implicated in AD pathogenesis and PGx. The number of “T”-residues in the rs10524523 (“523”) locus differentiates 3 allele groups: “short” (S, T 19), “long” ≤ (L, 20 T 29), and “very long” (VL, T 30). rs10524523 L variants are associated with a higher risk ≤ ≤ ≥ for late-onset AD (LOAD). APOE-TOMM40 interactions affect the risk of AD and the response to drugs. The S/VL and VL/VL TOMM40 poly T genotypes interact with all APOE genotypes; however, the APOE-4/4-TOMM40-L/L association is unique, accounting for 30% of APOE-4/4 carriers. TOMM40 poly T-S/S carriers are the best responders, VL/VL and S/VL carriers are intermediate responders, and L/L carriers are the worst responders to treatment. TOMM40-L/L and S/L carriers in haplotypes with APOE-4 are the worst responders to treatment. TOMM40-S/S carriers and, to a lesser extent, Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 18 of 87 variant GluN2AN615K (GRIN2A C1845A), which affects NMDA receptor channel blockers, including memantine [167]. Memantine can be used alone or in combination with AChEIs in AD [168,169]. Proteomic studies in the hippocampus and the cerebral cortex of AD-related transgenic mice (3× Tg-AD) treated with memantine revealed alterations in the expression of 233 and 342 proteins, respectively [170]. In APP23 transgenic mice with cerebral amyloid angiopathy (CAA), memantine reduces cerebrovascular Aβ and hemosiderin deposits by enhancing Aβ-cleaving IDE expression [171]. Memantine is useful for the treatment of both cognitive deterioration and BDs in AD and other forms of dementia [172,173]. AD patients treated with memantine plus citalopram show improvement in BDs [174]; in combination with antipsychotics, it may improve verbal memory, learning, verbal letter fluency, and working memory with no effect on psychotic symptoms in patients with chronic schizophrenia [175,176]; at a dose of 20 mg/day, it may be effective in patients with obsessive-compulsive disorder [177]; at 10 mg/day, it may be helpful in migraine [178]; and, in combination with naltrexone, it enhances the of naltrexone in reducing alcohol drinking and craving [179]. Memantine might also be useful in the treatment of punctate and dynamic allodynia by the blockade of the microglia Kir2.1 channel to suppress microglia activation [180], and in combination with dextromethorphan, it may be beneficial in neuropathic pain [181]. Int. J. Mol. Sci. 2020, 21, 3059 18 of 82 4.5. Multifactorial Treatments TOMM40-SMost studies/VL and in TOMM40-VLwhich AD patients/VL carriers are treated in haplotypes with multifactorial with APOE-3 combinationsare the best reveal responders that APOE-3/3to treatment. carriers The areTOMM40-L the best/ Lrespondersgenotype isand exclusively that APOE-4/4 associated carriers with are the theAPOE-4 worst/4 responders.genotype in Concerning100% of the CYP-related cases, and this PGx haplotype outcomes, (4/ 4-LCYP2D6-EMs/L) might be are responsible the best responders, for premature CYP2D6-PMs neurodegeneration are the worstand consequent responders, early and onset CYP2D6-IMs of the disease, aand faster UMs cognitive show deterioration, an intermediate and a limited response response [1– to 3,56,71,106,112,115,116,118]conventional treatments [4, 116(Figures] (Figure 4–6).5).

Figure 4. APOE-related responder/nonresponder rate in patients with Alzhimer’s disease treated with Figurea multifactorial 4. APOE-related/combination responder/nonresponder treatment for one year. rate Responders: in patients with Final Alzhimer’s Mini-Mental disease State treated Examination with a(MMSE) multifactorial/combination score > basal MMSE score.treatment NonResponders: for one year. Final Responders: MMSE score Final< basal Mini-Mental MMSE score. State Data Source: Cacabelos et al., 2014.

Epigenetic factors are important in AD pathogenesis and response to treatment [5,26,57,61,65,71]. Sirtuin variants may alter the epigenetic machinery, contributing to AD pathogenesis. The SIRT2-C/T genotype (rs10410544) (50.92%) has been associated with AD susceptibility in the APOEε4-negative population (SIRT2-C/C, 34.72%; SIRT2-T/T 14.36%). SIRT2-APOE bigenic clusters yield 18 haplotypes that influence the PGx outcome. APOE-3/4 and APOE-4/4 genotypes accumulate in SIRT2-T/T > SIRT2-C/T > SIRT2-C/C carriers, and SIRT2-T/T and SIRT2-C/T genotypes accumulate in APOE-4/4 carriers. SIRT2-C/T carriers tend to be the best responders, SIRT2-T/T carriers are intermediate responders, and SIRT2-C/C carriers are the worst responders to a multifactorial treatment. PGx outcomes related to APOE-SIRT2 bigenic clusters show that 33CC carriers respond better than 33TT and 34CT carriers, whereas 24CC and 44CC carriers are the worst responders. SIRT2-C/T-CYP2D6-EMs are the best responders [5]. Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 19 of 87

Examination (MMSE) score > basal MMSE score. NonResponders: Final MMSE score < basal MMSE score. Data Source: Cacabelos et al., 2014.

In linkage disequilibrium with and adjacent to the APOE locus (19q13.2) is the TOMM40 gene, which encodes an outer mitochondrial membrane translocase involved in the transport of Aβ and other proteins into mitochondria. A poly T repeat in an intronic polymorphism (rs10524523) (intron 6) in the TOMM40 gene has been implicated in AD pathogenesis and PGx. The number of “T”- residues in the rs10524523 (“523”) locus differentiates 3 allele groups: “short” (S, T ≤ 19), “long” (L, 20 ≤ T ≤ 29), and “very long” (VL, T ≥ 30). rs10524523 L variants are associated with a higher risk for late-onset AD (LOAD). APOE-TOMM40 interactions affect the risk of AD and the response to drugs. The S/VL and VL/VL TOMM40 poly T genotypes interact with all APOE genotypes; however, the APOE-4/4-TOMM40-L/L association is unique, accounting for 30% of APOE-4/4 carriers. TOMM40 poly T-S/S carriers are the best responders, VL/VL and S/VL carriers are intermediate responders, and L/L carriers are the worst responders to treatment. TOMM40-L/L and S/L carriers in haplotypes with APOE-4 are the worst responders to treatment. TOMM40-S/S carriers and, to a lesser extent, TOMM40-S/VL and TOMM40-VL/VL carriers in haplotypes with APOE-3 are the best responders to treatment. The TOMM40-L/L genotype is exclusively associated with the APOE-4/4 genotype in 100% of the cases, and this haplotype (4/4-L/L) might be responsible for premature neurodegeneration and consequent early onset of the disease, a faster cognitive deterioration, and a limited response to Int. J. Mol.conventional Sci. 2020, 21 ,treatments 3059 [4,116] (Figure 5). 19 of 82

Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 20 of 87

susceptibility in the APOEε4-negative population (SIRT2-C/C, 34.72%; SIRT2-T/T 14.36%). SIRT2- APOE bigenic clusters yield 18 haplotypes that influence the PGx outcome. APOE-3/4 and APOE-4/4 genotypes accumulate in SIRT2-T/T > SIRT2-C/T > SIRT2-C/C carriers, and SIRT2-T/T and SIRT2-C/T genotypes accumulate in APOE-4/4 carriers. SIRT2-C/T carriers tend to be the best responders, SIRT2- T/T carriers are intermediate responders, and SIRT2-C/C carriers are the worst responders to a Figuremultifactorial 5. TOMM40-related treatment. PGx responder outcomes/nonresponder related to rate APOE-SIRT2 in patients with bigenic Alzhimer’s clusters disease show treatedthat 33CC with acarriers multifactorial respond/combination better than treatment 33TT and for 34CT one carriers, year. Responders: whereas 24CC Final MMSEand 44CC score carriers> basal are MMSE the worst score. responders.Figure SIRT2-C/T-CYP2D6-EMs5. TOMM40-related responder/nonresponder are the best responders rate [5]. in patients with Alzhimer’s disease treated Nonresponders: Final MMSE score < basal MMSE score. Data Source: Cacabelos et al., 2014. with a multifactorial/combination treatment for one year. Responders: Final MMSE score > basal MMSE score. Nonresponders: Final MMSE score < basal MMSE score. Data Source: Cacabelos et al., 2014.

Epigenetic factors are important in AD pathogenesis and response to treatment [5,26,57,61,65,71]. Sirtuin variants may alter the epigenetic machinery, contributing to AD pathogenesis. The SIRT2-C/T genotype (rs10410544) (50.92%) has been associated with AD

Figure 6. CYP2D6-related responder/nonresponder rate in patients with Alzhimer’s disease treated with

a multifactorialFigure 6. CYP2D6-related/combination treatment responder/nonresponder for one year. Responders: rate in patients Final with MMSE Alzhimer’s score > diseasebasal MMSEtreated score. Nonresponders:with a multifactorial/combinati Final MMSE scoreon< basaltreatment MMSE for score.one year. Data Resp Source:onders: Cacabelos Final MMSE et al., score 2019. > basal MMSE score. Nonresponders: Final MMSE score < basal MMSE score. Data Source: Cacabelos et al., 2019.

5. Pharmacogenomics of Neuropsychiatric Disorders

5.1. Psychotic Disorders Psychotic symptoms (hallucinations and delusions) are strongly related to AD-associated cognitive dysfunction, gradually progressing in parallel with disease severity [182]. In addition, symptoms of personality changes, paranoia, hallucinations, cravings, agitation, and changes in appetite may represent a prodromal noncognitive phenotype of risk for dementia [183]. Over 500 genes are potentially associated with psychosis and schizophrenia (SCZ) [25]. Several BDs in dementia incorporate SCZ genes. Major biological pathways and mechanisms associated with SCZ genes include glutaminergic receptors (GRIA1, GRIN2, GRIK4, and GRM5), serotonergic receptors (HTR2A and HTR2C), GABAergic receptors (GABRA1 and GABRB2), dopaminergic receptors (DRD1 and DRD2), calcium-related channels (CACNA1H and CACNA1B), and solute

Int. J. Mol. Sci. 2020, 21, 3059 20 of 82

5. Pharmacogenomics of Neuropsychiatric Disorders

5.1. Psychotic Disorders Psychotic symptoms (hallucinations and delusions) are strongly related to AD-associated cognitive dysfunction, gradually progressing in parallel with disease severity [182]. In addition, symptoms of personality changes, paranoia, hallucinations, cravings, agitation, and changes in appetite may represent a prodromal noncognitive phenotype of risk for dementia [183]. Over 500 genes are potentially associated with psychosis and schizophrenia (SCZ) [25]. Several BDs in dementia incorporate SCZ genes. Major biological pathways and mechanisms associated with SCZ genes include glutaminergic receptors (GRIA1, GRIN2, GRIK4, and GRM5), serotonergic receptors (HTR2A and HTR2C), GABAergic receptors (GABRA1 and GABRB2), dopaminergic receptors (DRD1 and DRD2), calcium-related channels (CACNA1H and CACNA1B), and solute carrier transporters (SLC1A1 and SLC6A2) [184]. Aberrant motor behavior is strongly associated with the APOE-4/4 genotype and the presence of both Lewy bodies and cerebral amyloid angiopathy [185]. Antipsychotics are drugs of current use (>50%) to treat BDs in dementia with limited efficacy in aggressive behaviors and psychotic symptoms. These drugs increase mortality and risk of psychomotor disorders and cerebrovascular events. Neuroleptics are prescribed for long periods of time in combination with antidepressants and anti-dementia drugs [186,187]. Antipsychotics (Table3) are associated with the PGx activity of less than 100 pharmagenes. The different pharmacological categories of antipsychotics (phenothiazines with aliphatic side-chain, piperazine-related phenothiazines, piperidine phenothiazines, butyrophenones, indole derivatives, thioxanthenes, diphenylbutylpiperidines, diazepines, oxazepines, thiazepines, oxepines, benzamides, and other neuroleptics) are substrates, inhibitors, or inducers of 32, 16, and 3 enzyme/protein gene products, respectively, and are transported by at least 14 different protein transporters. CYP enzymes participate in the metabolism of 90% of antipsychotics. These drugs are major substrates of CYP3A4 (75%), CYP2D6 (72%), CYP1A2 (46%), CYP2C19 (22%), and UGT1A4 (33%); inhibitors of CYP2D6 (50%), CYP3A4 (42%), ABCB1 (29%), CYP1A2 (25%), CYP2C19 (21%), and CYP2C9 (15%); and inducers of GSTM1, MAOB, and SLCO3A1 with low affinity (<5%). About 50% of antipsychotics are transported by ABCB1. Other transporters responsible for the influx-efflux of neuroleptics are KCNH2 (22%); KCNE1 and KCNE2 (18%); KCNQ1 (18%); and SLC6A2, SLC6A4, and SCN5A (11%). Haloperidol is associated with 31 pharmagenes, Olanzapine is associated with 28, and Thioridazine is associated with 27 [55,103]. The (SLC6A3) gene has been the focus of attention for years in the PGx of antipsychotic drugs. The study of 6 SNPs (rs2652511 (T-844C) and rs2975226 (T-71A) in the 5’-regulatory region, rs2963238 (A1491C) in intron 1, a 30-bp VNTR in intron 8, rs27072 and the 40-bp VNTR in the 3’-region) showed association of allele and genotype frequencies with response to clozapine [188]. Major ADRs with antipsychotics are extrapyramidal symptoms, tardive dyskinesia, antipsychotic-induced weight gain, and clozapine-induced agranulocytosis. Antipsychotic-induced extrapyramidal symptoms are associated with DRD2, SLC18A2, HTR2A, GRIK3, and SLC6A3 VNTR and COMT Val158Met polymorphisms [189,190]. SNPs in ADORA1, ADORA2A, and ADORA3 have been associated with psychopathological symptoms, extrapyramidal symptoms, akathisia, and tardive dyskinesia [191]. RGS2*T/*T(rs2746073), RGS2*C/*C (rs4606), and RGS2*A/*A (rs2746071) are associated with high risk for extrapyramidal symptoms in Russian patients treated with haloperidol [192]. Several SNPs in genes of the mTOR pathway (AKT1, rs1130214; FCHSD1, rs456998; Raptor, rs7211818; and DDIT4, rs1053639) have also been associated with extrapyramidal disorders in Spanish patients under antipsychotic treatment [193]. Tardive dyskinesia (TD) is an involuntary movement disorder that occurs in over 20% of patients after chronic treatment with antipsychotics. Disrupted in schizophrenia 1 (DISC1) gene variants, SNP variation in several CYPs, especially CYP2D6, and in HSPG2, CNR1, DPP6, LC18A2, MTNR1A, PIP5K2A, DRD2, DRD3, VMAT2, HSPG2, HTR2A, HTR2C, and SOD2 variants influence TD [194–196]. Int. J. Mol. Sci. 2020, 21, 3059 21 of 82

An intron-1 SNP (rs6977820) of the DPP6 (dipeptidyl peptidase-like protein-6) gene has been associated with TD in Japanese patients. DPP6 is an auxiliary subunit of Kv4 that regulates the activity of dopaminergic neurons. Decreased expression of DPP6 in the brain can be reversed by haloperidol treatment [197]. Another SNP (rs2445142) in the HSPG2 (heparan sulfate proteoglycan 2) gene has been associated with TD in both Japanese and Caucasian populations [198]. Carriers of the CNR1-rs806374 (T>C) CC genotype are more likely to develop TD and severe motor dysfunction than TT or TC among Caucasians. Cannabinoid receptor 1 (CNR1) activators inhibit movement, and this effect is prevented by and selective CNR1 antagonists [199]. A number of SNPs in the SLC18A2 gene that encodes VMAT2 (vesicular monoamine transporter 2) may affect TD, including the rs2015586 markerInt. J. Mol. (with Sci. 2020 deleterious, 21, x FOR PEER eff REVIEWects) and the rs363224 marker (with protective effects 22 in of carriers 87 of the low-expression AA genotype) [200]. Two VMAT2 inhibitors, Valbenazine and Deutetrabenazine, have Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 22 of 87 been approvedHyperprolactinemia for treating is TDa common [201–203 ADR]. in users of neuroleptic drugs. Risperidone-induced prolactin response is associated with 3 UGT1A1 SNPs (UGT1A1*80c.-364C>T, UGT1A1*93 c.- HyperprolactinemiaHyperprolactinemia is is a acommon common ADR ADR in users in users of neuroleptic of neuroleptic drugs. Risperidone-induced drugs. Risperidone-induced 3156G>A, and UGT1A1 c.-2950A>G) [204]. prolactinprolactin response response is associatedis associated with with 3 UGT1A13 UGT1A1SNPs SNPs ( UGT1A1*80c.-364C(UGT1A1*80c.-364C>T,>T, UGT1A1*93 UGT1A1*93 c.- c.-3156G>A, Antipsychotic-induced weight gain occurs in over 30–40% of patients with SCZ. All and3156G>A,UGT1A1 and c.-2950A UGT1A1> c.-2950A>GG)[204]. ) [204]. antipsychotics are associated with weight gain in antipsychotic-naïve and first-episode patients; Antipsychotic-induced weight gain occurs in over 30–40% of patients with SCZ. All however,Antipsychotic-induced weight gain is greatest weight in gain patients occurs treated in over with 30–40% the second-generation of patients with antipsychotics SCZ. All antipsychotics antipsychotics are associated with weight gain in antipsychotic-naïve and first-episode patients; areclozapine associated and with olanzapine. weight The gain propor in antipsychotic-naïvetion of patients with body and weight first-episode gain (>7% baseline) patients; is however,>20% weight however, weight gain is greatest in patients treated with the second-generation antipsychotics gainfor is ziprasidone, greatest in >30% patients for quetiapine, treated with and the45%second-generation for aripiprazole [205]. antipsychotics This ADR is caused clozapine by different and olanzapine. clozapine and olanzapine. The proportion of patients with body weight gain (>7% baseline) is >20% factors: pharmacological properties of the drug, pharmacogenetic factors, environmental factors, and Thefor proportion ziprasidone, of >30% patients for quetiapine, with body and weight 45% for aripiprazole gain (>7% [205]. baseline) This ADR is >20% is caused for ziprasidone,by different >30% for ethnicity [206]. quetiapine,factors: pharmacological and 45% for aripiprazoleproperties of the [205 drug,]. This pharmacogenetic ADR is caused factors, by environmental different factors: factors, pharmacological and propertiesethnicity of[206]. theTable drug, 3. Pharmacological pharmacogenetic profile and factors, pharmacoge environmentalnetics of selected factors, antipsychotics. and ethnicity [206].

Atypical Antipsychotics TableTable 3.3. Pharmacological profile profile and andpharmacoge pharmacogeneticsnetics of selected of selectedantipsychotics. antipsychotics. Drug Properties Pharmacogenetics Atypical Antipsychotics Name: AripiprazoleAtypical; 129722-12-9; Antipsychotics Abilify; Drug Properties Pharmacogenetics Drug Abilitat; Abilify Discmelt;Properties OPC-1459 Pharmacogenetics Name: Aripiprazole; 129722-12-9; Abilify; Pathogenic genes: DRD2, DRD3, IUPACName: Name: Aripiprazole 7-{4-[4-(2,3-dichlorophenyl); 129722-12-9; Abilify; Abilitat; Abilify Discmelt; OPC-1459 HTR1A, HTR2A, HTR2C piperazin-1-yl]butoxy}-1,2,3,4-Abilitat; Abilify Discmelt; OPC-1459 IUPAC Name: 7-{4-[4-(2,3-dichlorophenyl) MechanisticPathogenic genes:genes: DRD2 ADRA1A, DRD3,, tetrahydroquinolin-2-one Pathogenic genes: DRD2, DRD3, piperazin-1-yl]butoxy}-1,2,3,4-IUPAC Name: 7-{4-[4-(2,3-dichlorophenyl) DRD2HTR1A, , HTR2ADRD3,, HTR2CDRD4, HRHs, piperazin-1-yl]butoxy}-1,2,3,4-tetrahydroquinolin- HTR1A, HTR2A, HTR2C Moleculartetrahydroquinolin-2-one Formula: 448.38538 g/mol HTR1AMechanistic, HTR2A genes:, HTR2B, ADRA1A HTR2C,, 2-one Mechanistic genes: ADRA1A, DRD2, HTR7DRD2 , DRD3, DRD4, HRHs, Molecular Weight:Formula: C 448.3853823H27Cl2N 3g/molO2 DRD3, DRD4, HRHs, HTR1A, HTR2A, Molecular Formula: 448.38538 g/mol MetabolicHTR1A,HTR2B, HTR2A genes: HTR2C,, HTR2B, HTR7 HTR2C, Mechanism: Partial at the D2 and 5- HTR7 MolecularMolecular Weight: Weight: C23H27CCl232NH327OCl2 2N3O2 Substrate:Metabolic CYP2D6 genes: (major), HT1A receptors, and as an antagonist at the 5- CYP3A4MetabolicSubstrate: (major), genes: CYP3A5 CYP2D6 (major), CYP3A4 MechanismMechanism:: PartialPartial agonist agonist at the at theD2 and D and 5- HT2A receptor 2 Substrate:(major), CYP2D6CYP3A5 (major), 5-HT receptors, and as an antagonist at theTransporter genes: ABCB1 Effect:HT1A receptors, Antipsychotic1A and as anagent; antagonist H1-receptor at the 5- CYP3A4Transporter (major), CYP3A5 genes: ABCB1 5-HT2A receptor antagonist;HT2A receptor Serotonergic agonist Transporter genes: ABCB1 Name:Effect:E ffAsenapineect:AntipsychoticAntipsychotic maleate agent; agent;; Saphris; H1-receptorH1-receptor Org5222 antagonist; Serotonergic agonist maleate;antagonist; 85650-56-2; Serotonergic Org agonist 5222 maleate; Org- Name:Name: Asenapine Asenapine maleate maleate; Saphris;; Saphris; Org5222 Org5222 5222 maleate Pathogenic genes: ADRA2A, maleate;maleate; 85650-56-2; 85650-56-2; Org Org5222 5222 maleate; maleate; Org- IUPAC Name: (2Z)-but-2-enedioic acid; 17- DRD1, PathogenicDRD2, DRD3 genes:, ADRA2ADRD4, , DRD1, 5222 maleateOrg-5222 maleate chloro-4-methyl-13-oxa-4- HTR1APathogenic,DRD2 HTR2A , DRD3genes:, HTR2C, DRD4, ADRA2AHTR7, HTR1A , , HTR2A, IUPAC Name: (2Z)-but-2-enedioic2 6 7 12 acid; 17- azatetracyclo[12.4.0.0IUPAC Name: (2Z)-but-2-enedioic, .0 , ]octadeca- acid; MechanisticDRD1, HTR2CDRD2 ,genes:,HTR7 DRD3 ,ADRA1A DRD4,, chloro-4-methyl-13-oxa-4-17-chloro-4-methyl-13-oxa-4-azatetracyclo[12.4.0.02, 1(14),7,9,11,15,17-hexaene ADRA2AHTR1A,Mechanistic HTR2A, ADRA2B, HTR2C genes:, , ADRA2CHTR7ADRA1A , , azatetracyclo[12.4.0.06.07,12]octadeca-1(14),7,9,11,15,17-hexaene2,6.07,12]octadeca- ADRA2A ADRA2B ADRA2C DRD1 DRD1Mechanistic, DRD2 ,genes: , DRD3 ,ADRA1A , DRD4, , , Molecular1(14),7,9,11,15,17-hexaene Formula: C21H20 ClNO5 DRD2, DRD3, DRD4, HRH1, HRH2, Molecular Formula: C21H20ClNO5 HRH1ADRA2A, HRH2, ADRA2B, HTR1A, , ADRA2CHTR1B, DRD1, HTR1ADRD2,, HTR1BDRD3, HTR2A, DRD4, HTR2B, , MolecularMolecular Formula: Weight: C21H401.840220ClNO5 g/mol HTR2A,HTR2C HTR2B, HTR5A, HTR2C, HTR6, HTR5A, HTR7, Molecular Weight: 401.8402 g/mol HRH1, HRH2, HTR1A, HTR1B, HTR6, HTR7Metabolic genes: Mechanism: Its main activity is associated toHTR2A, HTR2B, HTR2C, HTR5A, MetabolicSubstrate: genes: CYP1A1 CYP1A2 MechanismMolecularcombination Weight:: Its main of401.8402 antagonistic activity g/mol is associated actions at Dto2 and , (major), HTR6 Substrate:, HTR7CYP2D6 CYP1A1(minor),, CYP3A4CYP1A2(minor), combination5-HT2A ofreceptors antagonistic actions at D2 and 5- Mechanism: Its main activity is associated to (major),MetabolicUGT1A4 CYP2D6 genes: (minor), CYP3A4 HT2A receptorsEffect: Antipsychotic agent; Dopaminergic combination of antagonistic actions at D2 and 5- (minor), Substrate:Inhibitor: UGT1A4 CYP1A1 CYP2D6, CYP1A2(weak) Effect:antagonist; Antipsychotic Serotonergic agent; antagonist;Dopaminergic HT2A receptors (major), CYP2D6 (minor), CYP3A4 antagonist;Alpha-adrenergic Serotonergic antagonist; antagonist; Alpha- Inhibitor: CYP2D6 (weak) (minor), UGT1A4 adrenergicEffect:Beta-adrenergic Antipsychotic antagoni antagonist st;agent; Beta-adrenergicDopaminergic Inhibitor: CYP2D6 (weak) antagonistantagonist; Serotonergic antagonist; Alpha- adrenergic antagonist; Beta-adrenergic Pathogenic genes: ADRA2A, Name:antagonist Clozapine ; Leponex; Fazaclo; Iprox; DRD1, DRD2, DRD3, DRD4, CLOZARIL; Clozapin Pathogenic genes: ADRA2A, Name: Clozapine; Leponex; Fazaclo; Iprox; DTNBP1, HTR2A, LPL, NRXN1, DRD1, DRD2, DRD3, DRD4, IUPACCLOZARIL; Name: Clozapin 6-chloro-10-(4-methylpiperazin- TNF 1-yl)-2,9-diazatricyclo[9.4.0.03,8]pentadeca- MechanisticDTNBP1, HTR2A genes:, LPL , NRXN1ADRAs, 1(15),3,5,7,9,11,13-heptaeneIUPAC Name: 6-chloro-10-(4-methylpiperazin- CHRMsTNF , DRD1, DRD2, DRD3, 3 8 1-yl)-2,9-diazatricyclo[9.4.0.0 , ]pentadeca- DRD4Mechanistic, HRH1 , genes:HTR1F , HTR2AADRAs, 1(15),3,5,7,9,11,13-heptaene CHRMs, DRD1, DRD2, DRD3, Molecular Formula: C18H19ClN4 HTR2C, HTR3A, HTR6, NRXN1 MetabolicDRD4, HRH1 genes:, HTR1F , HTR2A, Molecular Formula: C18H19ClN4 HTR2C, HTR3A, HTR6, NRXN1 Metabolic genes:

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Hyperprolactinemia is a common ADR in users of neuroleptic drugs. Risperidone-induced prolactin response is associated with 3 UGT1A1 SNPs (UGT1A1*80c.-364C>T, UGT1A1*93 c.- 3156G>A, and UGT1A1 c.-2950A>G) [204]. Antipsychotic-induced weight gain occurs in over 30–40% of patients with SCZ. All antipsychotics are associated with weight gain in antipsychotic-naïve and first-episode patients; however, weight gain is greatest in patients treated with the second-generation antipsychotics clozapine and olanzapine. The proportion of patients with body weight gain (>7% baseline) is >20% for ziprasidone, >30% for quetiapine, and 45% for aripiprazole [205]. This ADR is caused by different factors: pharmacological properties of the drug, pharmacogenetic factors, environmental factors, and ethnicity [206].

Table 3. Pharmacological profile and pharmacogenetics of selected antipsychotics.

Atypical Antipsychotics Drug Properties Pharmacogenetics Name: Aripiprazole; 129722-12-9; Abilify; Abilitat; Abilify Discmelt; OPC-1459 IUPAC Name: 7-{4-[4-(2,3-dichlorophenyl) Pathogenic genes: DRD2, DRD3, piperazin-1-yl]butoxy}-1,2,3,4- HTR1A, HTR2A, HTR2C tetrahydroquinolin-2-one Mechanistic genes: ADRA1A, DRD2, DRD3, DRD4, HRHs, Molecular Formula: 448.38538 g/mol HTR1A, HTR2A, HTR2B, HTR2C, HTR7 Molecular Weight: C23H27Cl2N3O2 Metabolic genes: Mechanism: at the D2 and 5- Substrate: CYP2D6 (major), HT1A receptors, and as an antagonist at the 5- CYP3A4 (major), CYP3A5

HT2A receptor Transporter genes: ABCB1 Effect: Antipsychotic agent; H1-receptor antagonist; Serotonergic agonist Name: Asenapine maleate; Saphris; Org5222 maleate; 85650-56-2; Org 5222 maleate; Org- 5222 maleate Pathogenic genes: ADRA2A, IUPAC Name: (2Z)-but-2-enedioic acid; 17- DRD1, DRD2, DRD3, DRD4, chloro-4-methyl-13-oxa-4- HTR1A, HTR2A, HTR2C, HTR7 2 6 7 12 azatetracyclo[12.4.0.0 , .0 , ]octadeca- Mechanistic genes: ADRA1A, Int. J. Mol. Sci. 2020, 21, 3059 1(14),7,9,11,15,17-hexaene ADRA2A, ADRA2B, ADRA2C, 22 of 82 DRD1, DRD2, DRD3, DRD4, Molecular Formula: C21H20ClNO5 HRH1, HRH2, HTR1A, HTR1B, HTR2A, HTR2B, HTR2C, HTR5A, Molecular Weight: 401.8402Table g/mol 3. Cont. HTR6, HTR7 Mechanism: Its mainAtypical activity Antipsychotics is associated to Metabolic genes: Int. J. Mol. Sci.Drug 2020, 21, x FOR PEER REVIEW Properties Substrate: CYP1A1Pharmacogenetics, 23CYP1A2 of 87 combination of antagonistic actions at D2 and 5- (major), CYP2D6 (minor), CYP3A4 HT2A receptorsName: Clozapine ; Leponex; Fazaclo; Iprox; Pathogenic genes: ADRA2A, DRD1, Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW Substrate: CYP1A2 23 (major), of 87 Effect:CLOZARIL; Antipsychotic Clozapin agent; Dopaminergic (minor),DRD2 UGT1A4, DRD3 , DRD4, DTNBP1, Molecular Weight: 326.82326 g/mol CYP2A6 (minor), CYP2C8 (minor), antagonist;IUPAC Serotonergic Name: antagonist; Alpha- Inhibitor:HTR2A CYP2D6, LPL, NRXN1(weak) , TNF CYP2C9 Substrate: (minor), CYP1A2 CYP2C19 (minor),(major), adrenergic6-chloro-10-(4-methylpiperazin-1-yl)-2,9- antagonist; Beta-adrenergic Mechanistic genes: ADRAs, CHRMs, Molecular Weight: 326.823263 8 g/mol CYP2A6CYP2D6 (minor),(minor), CYP2C8 CYP3A4/5 (minor), antagonistMechanism:diazatricyclo[9.4.0.0 It shows serotonergic,, ]pentadeca-1(15),3,5,7,9,11, adrenergic, DRD1, DRD2, DRD3, DRD4, HRH1, and cholinergic13-heptaene neurotransmitter systems in CYP2C9(major),HTR1F FMO3(minor),, HTR2AUGT1A1, CYP2C19, HTR2C UGT1A3 (minor),, HTR3A, , Pathogenic genes: ADRA2A, Name:Mechanism:addition Clozapine to more It shows ;selective, Leponex; serotonergic, regionally Fazaclo; adrenergic, specificIprox; CYP2D6UGT1A4HTR6 (minor),, NRXN1 CYP3A4/5 Molecular Formula: C18H19ClN4 DRD1, DRD2, DRD3, DRD4, CLOZARIL;andeffects cholinergic on Clozapinthe neurotransmittermesolimbic dopaminergic systems in (major), Inhibitor:Metabolic FMO3 , CYP1A2UGT1A1, genes: UGT1A3(weak),, DTNBP1, HTR2A, LPL, NRXN1, additionsystem.Molecular It to also more displays Weight: selective, antagonistic326.82326 regionally g /activitymol specific at UGT1A4CYP2C9Substrate: (moderate),CYP1A2 CYP2C19(major), CYP2A6 IUPAC Name: 6-chloro-10-(4-methylpiperazin- TNF CYP2C8 CYP2C9 effectsH1-receptorsMechanism: on the mesolimbicIt shows serotonergic, dopaminergic adrenergic, (moderate), Inhibitor:(minor), CYP2D6CYP1A2 (moderate), (minor),(weak), 1-yl)-2,9-diazatricyclo[9.4.0.03,8]pentadeca- Mechanistic(minor), genes:CYP2C19 (minor),ADRAs, CYP2D6 system.and It cholinergicalso displays neurotransmitter antagonistic activity systems at inCYP2C9CYP2E1 (weak),(moderate), CYP3A4 (weak)CYP2C19 1(15),3,5,7,9,11,13-heptaeneEffect: Dopaminergic antagonist; Serotonergic CHRMs,(minor), DRD1CYP3A4, DRD2/5, (major),DRD3, FMO3, H1-receptorsaddition to more selective, regionally specific(moderate),Transporter genes:CYP2D6 ABCB1 (moderate), antagonist; Histamine antagonist; Muscarinic UGT1A1, UGT1A3, UGT1A4 effects on the mesolimbic dopaminergic system.DRD4CYP2E1 It , (weak),HRH1, CYP3A4HTR1F, (weak)HTR2A , PleiotropicInhibitor: genes:CYP1A2 APOA5(weak),, CYP2C9 MolecularEffect:antagonist;also Dopaminergic displaysFormula: GABA antagonistic C 18antagonist;Hantagonist;19ClN4activity Serotonergic atGABA H1-receptors HTR2C, HTR3A, HTR6, NRXN1 TransporterAPOC3,(moderate), APOD genes:, CNR1ABCB1CYP2C19, FABP1(moderate),, antagonist;modulator; AntipsychoticHistamine antagonist; agent Muscarinic Metabolic genes: PleiotropicGNB3, GSK3BCYP2D6 , LPLgenes:(moderate),, RGS2 , TNFAPOA5CYP2E1 , (weak), antagonist; GABA antagonist; GABA APOC3,CYP3A4 APOD,(weak) CNR1, FABP1, modulator;Name:E ffect:Iloperidone AntipsychoticDopaminergic; Zomaril; agent antagonist; 133454-47-4; Serotonergic GNB3, GSK3BTransporter, LPL, RGS2 genes:, TNFABCB1 Fanapt;antagonist; Fanapta; HP Histamine 873 antagonist; Muscarinic Pleiotropic genes: APOA5, APOC3, Name:antagonist; Iloperidone GABA; Zomaril; antagonist; 133454-47-4; GABA modulator; IUPAC Name: 1-(4-{3-[4-(6-fluoro-1,2- PathogenicAPOD , genes:CNR1, FABP1ADRA2A, GNB3, , GSK3B, Fanapt;Antipsychotic Fanapta; HP agent873 benzoxazol-3-yl)piperidin-1-yl]propoxy}-3- CNTF, LPLDRD1, RGS2, ,DRD2TNF , DRD3, IUPACmethoxyphenyl)ethan-1-one Name: 1-(4-{3-[4-(6-fluoro-1,2- PathogenicDRD4, HTR2A ,genes: HTR7 , NRG3ADRA2A , Name: Iloperidone; Zomaril; 133454-47-4; benzoxazol-3-yl)piperidin-1-yl]propoxy}-3- CNTFMechanistic, DRD1 ,genes: DRD2 ,ADRA1A DRD3,, Fanapt; Fanapta; HP 873 Molecular Formula: C24H27FN2O4 DRD4ADRA2A, HTR2APathogenic, ADRA2B, HTR7 genes:,, NRG3ADRA2CADRA2A , , CNTF, methoxyphenyl)ethan-1-one IUPAC Name: MechanisticADRB1,DRD1 ADRB2 , DRD2genes:, DRD1, DRD3ADRA1A, DRD2, DRD4,, , HTR2A, Molecular1-(4-{3-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1- Formula: C24H27FN2O4 ADRA2ADRD3, HTR7DRD4, ADRA2B, NRG3, DRD5, , ADRA2CGFRA2,, Molecular Weight: 426.480583 g/mol Mechanistic genes: ADRA1A, yl]propoxy}-3-methoxyphenyl)ethan-1-one ADRB1GRIA4, , HRH1ADRB2, ,HTR1A DRD1, , HTR2ADRD2,, ADRA2A, ADRA2B, ADRA2C, ADRB1, Molecular Formula: C24H27FN2O4 DRD3HTR2C, , DRD4HTR6, , DRD5HTR7,, GFRA2NPAS3,, MolecularMechanism: Weight: It has 426.480583mixed D2/5-HT g/mol2 antagonist ADRB2, DRD1, DRD2, DRD3, DRD4, GRIA4NUDT9P1, HRH1, TNR, , XKR4HTR1A , HTR2A, activity.Molecular It exhibits Weight: high affinity426.480583 for 5-HT g/mol2A, D2, DRD5, GFRA2, GRIA4, HRH1, HTR1A, HTR2CMetabolic,HTR2A HTR6 genes:,HTR2C HTR7,HTR6 NPAS3HTR7, NPAS3 Mechanism:and DMechanism:3 receptors, It has low Itmixed to has moderate mixed D2/5-HT D affinity/25-HT antagonist forantagonist D1, , , , , , 2 2 NUDT9P1 Substrate:NUDT9P1, TNR CYP1A2, XKR4, TNR ,, XKR4CYP2E1, activity.D4, Hactivity.1, It5-HT exhibits1A It, exhibits5-HT high6, affinity high5HT7 a, ffi forandnity 5-HT ADR for2A 5-HTα, 1/Dα2C2, ,D , 2A MetabolicCYP2D62 Metabolic (major), genes: CYP3A4 genes: (major) andreceptors, D3and receptors, Dand3 receptors, lowno toaffinity moderate low to moderatefor affinity muscarinic aforffinity D1, for D1, Transporter Substrate:Substrate: CYP1A2genes:CYP1A2 , CYP2E1SLC6A2, CYP2E1,, , CYP2D6 Dreceptors.4, HD1, 4,H5-HT It1 ,has 5-HT1A, low5-HT1A ,affinity 5-HT6, 5HT6, 7 5HTfor, and histamine7, andADR ADRα1/ αH2Cα1 1/α2C CYP2D6(major), (major),CYP3A4 CYP3A4(major) (major) receptors,receptors, and andno noaffinity affinity forfor muscarinicmuscarinic receptors. SLCO3A1 receptors Transporter genes: SLC6A2 It has low affinity for histamine H receptorsTransporterPleiotropic genes: genes: ADRB2 SLC6A2, CELF4,, , receptors.Effect: Antipsychotic It has low affinity agent; for Dopaminergichistamine1 H1 SLCO3A1CERKL,SLCO3A1 DRD5 , HTR1F, NPAS3, receptorsantagonist;Effect: AntipsychoticSerotonergic agent; Dopaminergicantagonist; Pleiotropic genes: ADRB2, CELF4, PleiotropicNRG3, NUBPL genes:, PALLD ADRB2 , CELF4, Effect:Antidepressantantagonist; Antipsychotic Serotonergiceffects; agent;Anxiolytic antagonist;Dopaminergic activity; CERKL, DRD5, HTR1F, NPAS3, NRG3, CERKL, DRD5, HTR1F, NPAS3, antagonist;ReductionAntidepressant of riskSerotonergic for e ffweightects; Anxiolytic gain;antagonist; Cognitive activity; NUBPL, PALLD NRG3, NUBPL, PALLD AntidepressantFunctionReduction Improved ofeffects;risk for Anxiolytic weight gain; activity; Cognitive Function Improved Reduction of risk for weight gain; Cognitive Pathogenic genes: COMT, DRD1, Name:Name: Olanzapine Olanzapine; Zyprexa;; Zyprexa; 132539-06-1; 132539-06-1; Function Improved DRD2, PathogenicDRD3, DRD4 genes:, COMTGRM3,,DRD1 , ZyprexaZyprexa Zydis; Zydis; Olansek; Olansek; Symbyax Symbyax PathogenicHTR2A,DRD2 HTR2C genes:, DRD3, LPL COMT , DRD4, DRD1, GRM3, , HTR2A, Name:IUPAC Olanzapine Name: ; Zyprexa; 132539-06-1; HTR2C, LPL IUPAC Name: 5-methyl-8-(4-methylpiperazin- DRD2Mechanistic, DRD3 , genes:DRD4 , ABCB1,GRM3, Zyprexa Zydis; Olansek; Symbyax Mechanistic genes: ABCB1, ADRA1A, 5-methyl-8-(4-methylpiperazin-1-yl)-4-thia-2,9-HTR2AADRA1A, HTR2C, ADRB3, LPL, AHR, BDNF, 1-yl)-4-thia-2,9-diazatricyclo[8.4.0.03,7]tetradeca-1(14),3(7),5,8,10, ADRB3, AHR, BDNF, CHRM1, MechanisticCHRM1, CHRM2,genes: CHRM3,ABCB1, IUPACdiazatricyclo[8.4.0.0³,12-hexaene Name: 5-methyl-8-(4-methylpiperazin-⁷]tetradeca- CHRM2, CHRM3, CHRM4, CHRM5, 1-yl)-4-thia-2,9-1(14),3(7),5,8,10,12-hexaene ADRA1ACHRM4,COMT , CHRM5ADRB3, DRD1, , COMTAHR,, DRD2, BDNF,DRD1, DRD3,, DRD4, Molecular Formula: C H N S diazatricyclo[8.4.0.0³,⁷]tetradeca-17 20 4 CHRM1,DRD2, GABRs DRD3,CHRM2,, GRIN2B, DRD4 , HRH1CHRM3,GABRs, HTR2A, , 1(14),3(7),5,8,10,12-hexaeneMolecular Weight: 312.4325 g/mol CHRM4,GRIN2B,HTR2C CHRM5HRH1, HTR3A, ,HTR2A COMT, HTR6,, , HTR2CDRD1 LEP,, , RGS2, Molecular Formula: C17H20N4S DRD2HTR3A, ,RGS7 HTR6,DRD3,SLC6A4, LEPDRD4, RGS2 STAT3, GABRs, RGS7TMEM163,, Mechanism: It displays potent antagonism of , , Metabolic genes: serotonin 5-HT and 5-HT , dopamine D GRIN2B,SLC6A4,, STAT3HRH1,, TMEM163HTR2A, HTR2C , Molecular Formula: C2A17H20N4S 2C 1-4 Substrate: COMT CYP1A2 histamine H and α -adrenergic receptors. ItHTR3AMetabolic, HTR6, genes: LEP , RGS2, , RGS7, (major), 1 1 CYP2C9, CYP2D6 CYP3A43, Molecularshows Weight: moderate 312.4325 antagonism g/mol of 5-HT and SLC6A4, Substrate: STAT3 ,COMT TMEM163, (major),CYP1A2 3 CYP3A5, FMO1 FMO3, GSTM3, muscarinic M receptors, and weak bindingMetabolic(major), to CYP2C9, genes: CYP2D6 , (major), 1-5 TPMT, UGT1A1, UGT1A4, UGT2B10 MolecularGABA-A, Weight: BZD, 312.4325 and β-adrenergic g/mol receptors. CYP3A43, Substrate: CYP3A5, COMT FMO1, CYP1A2, FMO3, Mechanism: It displays potent antagonism of Inhibitor: ABCB1, CYP1A2 (weak), (major),GSTM3, CYP2C9,TPMT, UGT1A1, CYP2D6 UGT1A4, (major), serotonin 5-HT2A and 5-HT2C, dopamine D1-4, CYP2C9 (weak), CYP2C19 (weak), CYP3A43, CYP3A5, FMO1, FMO3, Mechanism:histamineEffect: H 1AntipsychoticIt and displays α1-adrenergic potent agent; antagonism GABAreceptors. modulator; ofIt UGT2B10CYP2D6 (weak), CYP3A4 (weak) Muscarinic antagonist; Serotonin uptake GSTM3, TPMT, UGT1A1, UGT1A4, serotoninshows moderate 5-HT2A andantagonism 5-HT2C, dopamineof 5-HT3 Dand1-4, Inhibitor:Inducer: ABCB1GSTM1,, MAOB,CYP1A2 SLCO3A1 inhibitor; Dopaminergic antagonist; SerotonergicUGT2B10 histaminemuscarinic HM1 1-5and receptors, α1-adrenergic and weak receptors. binding toIt (weak), TransporterCYP2C9 (weak), genes: CYP2C19KCNH2 , SLC6A2, antagonist; Histamine antagonist; Inhibitor:SLC6A4, ABCB1 SLCO3A1, CYP1A2 showsGABA-A, moderate BZD, and antagonism β-adrenergic of receptors. 5-HT3 and (weak), CYP2D6 (weak), CYP3A4 Antiemetic activity Pleiotropic genes: APOA5, APOC3, muscarinic M1-5 receptors, and weak binding to (weak), CYP2C9 (weak), CYP2C19 GNB3, LEP, LEPR, LPL GABA-A, BZD, and β-adrenergic receptors. (weak), CYP2D6 (weak), CYP3A4

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Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW (weak) 24 of 87 Int. J. Mol. Sci. 2020, 21, x FOR PEEREffect: REVIEW Antipsychotic agent; GABA modulator; Inducer: GSTM1, 24 ofMAOB, 87 Muscarinic antagonist; Serotonin uptake (weak)SLCO3A1 Effect:inhibitor; Antipsychotic Dopamine agent;rgic GABA modulator;antagonist; (weak) Transporter Inducer: GSTM1,genes: KCNH2MAOB, , Int. J. Mol. Sci. 2020, 21, 3059 Effect:MuscarinicSerotonergic Antipsychotic antagonistantagonist; agent;; Histamine SerotoninGABA modulator; antagonist; uptake SLCO3A1 SLC6A2,Inducer: SLC6A4, GSTM1, SLCO3A1 MAOB, 23 of 82 Muscarinicinhibitor;Antiemetic activityantagonistDopamine ; rgicSerotonin antagonist; uptake SLCO3A1TransporterPleiotropic genes:genes: KCNH2APOA5, , inhibitor;Serotonergic antagonist;Dopamine Histaminergic antagonist;antagonist; TransporterSLC6A2,APOC3, SLC6A4,GNB3 , genes:LEP SLCO3A1, LEPR KCNH2, LPL , SerotonergicAntiemeticName: Paliperidoneactivity antagonist; Table;Histamine Paliperidone; 3. Cont. antagonist; 9- SLC6A2,Pleiotropic SLC6A4, genes: SLCO3A1 APOA5 , AntiemeticHydroxyrisperidone; activity Invega; 144598-75-4; 9- PleiotropicAPOC3, GNB3 , genes:LEP, LEPR ,APOA5 LPL , Atypical Antipsychotics Name:OH-risperidone; Paliperidone Invega; SustennaPaliperidone; 9- APOC3, GNB3, LEP, LEPR, LPL Drug Properties Pharmacogenetics Name:Hydroxyrisperidone;IUPAC PaliperidoneName: Invega;; 3-{2-[4-(6-fluoro-1,2-Paliperidone; 144598-75-4; 9-9- Pathogenic genes: ADRA2A, Hydroxyrisperidone;OH-risperidone;benzoxazol-3-yl)piperidin-1-yl]ethyl}-9-Name: Paliperidone Invega Invega; Sustenna; Paliperidone; 144598-75-4; 9- DRD2, HTR2A OH-risperidone;IUPAChydroxy-2-methyl-4H,6H,7H,8H,9H-9-Hydroxyrisperidone; Name: Invega Sustenna3-{2-[4-(6-fluoro-1,2- Invega; 144598-75-4; 9-OH-risperidone; Invega Sustenna PathogenicMechanistic genes:genes: ADRA2AADRA1A, , IUPACbenzoxazol-3-yl)piperidin-1-yl]ethyl}-9-pyrido[1,2-a]pyrimidin-4-one Name: 3-{2-[4-(6-fluoro-1,2- PathogenicDRD2ADRA1B, HTR2APathogenic, ADRA1Dgenes: genes: , ADRA2AADRA2sADRA2A, , , DRD2, benzoxazol-3-yl)piperidin-1-yl]ethyl}-9-hydroxy-2-methyl-4H,6H,7H,8H,9H-IUPAC Name: DRD2BDNF,, HTR2A HTR2ADRD2 , HRH1, HTR1A, hydroxy-2-methyl-4H,6H,7H,8H,9H-Molecular3-{2-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1- Formula:C23H27FN4O3 Mechanistic genes: ADRA1A, pyrido[1,2-a]pyrimidin-4-one MechanisticMechanistic genes: genes: ADRA1AADRA1A, , pyrido[1,2-a]pyrimidin-4-oneyl]ethyl}-9-hydroxy-2-methyl-4H,6H,7H,8H,9H- ADRA1BHTR2A, ,HTR2C ADRA1D , ADRA2s, ADRA1BMetabolicADRA1B, genes:ADRA1D, ADRA1D , ADRA2s, ADRA2s, , BDNF, Molecularpyrido[1,2-a]pyrimidin-4-one Formula:C23H27FN4O3 BDNF, DRD2, HRH1, HTR1A, Molecular Weight: 426.483883 g/mol BDNF, DRD2DRD2, ,HRH1 HRH1, HTR1A, HTR1A, HTR2A, , Molecular Formula:C23H27FN4O3 HTR2A Substrate:, HTR2C ADH, Molecular Formula: C23H27FN4O3 HTR2C HTR2AMetabolicCYP2D6, HTR2C(minor), genes: CYP3A4/5 Mechanism: Mixed central serotonergic and Metabolic genes: MolecularMolecular Weight: Weight: 426.483883426.483883 g/mol g/mol Metabolic(major), UGTs genes: Substrate:Substrate: ADH, CYP2D6ADH(minor),, Moleculardopaminergic Weight: antagonism. 426.483883 Demonstrates g/mol high Substrate: ADH, Mechanism: Mixed central serotonergic andCYP2D6 Inhibitor:CYP3A4(minor), ABCB15 , CYP3A4/5UGTsCYP2D6 Mechanism:affinity to α1 , MixedD2, H1 , centraland 5-HT serotonergic2C receptors, and and / (major), dopaminergic antagonism. Demonstrates highCYP2D6(major),(moderate),Inhibitor: (minor),UGTs CYP3A4/5 ABCB1 (moderate)CYP3A4/5, CYP2D6 Mechanism:low affinity forMixed muscarinic central and serotonergic 5-HT1A receptors and dopaminergicaffinity toantagonism.α ,D ,H , andDemonstrates 5-HT receptors, high (major), and UGTs dopaminergic antagonism.1 2 1 Demonstrates2C high Transporter Inhibitor:(moderate), genes:ABCB1CYP3A4 ABCB1, CYP2D6 /5 (moderate) affinityEffect: toAntipsychotic α1, D2, H1, and agent; 5-HT 2CNeuroprotective receptors, and low affinity for muscarinic and 5-HT1A receptors Inhibitor:Transporter ABCB1 genes:, CYP2D6ABCB1 affinity to α1, D2, H1, and 5-HT2C receptors, and (moderate), CYP3A4/5 (moderate) lowagent; affinity H1-receptor for muscarinic antagonist;and 5-HT1A receptorsAlpha- (moderate), CYP3A4/5 (moderate) low affinityEffect: forAntipsychotic muscarinic and agent; 5-HT Neuroprotective1A receptors Transporter genes: ABCB1 Effect:adrenergic Antipsychotic antagonist; agent;Serotonergic Neuroprotective antagonist; Transporter genes: ABCB1 Effect:agent; Antipsychotic H1-receptor agent; antagonist; Neuroprotective Alpha-adrenergic agent;Dopaminergicantagonist; H1-receptor antagonist Serotonergic antagonist; antagonist; Alpha- agent; H1-receptor antagonist; Alpha- adrenergicName:Dopaminergic Quetiapine antagonist; antagonist SerotonergicFumarate; antagonist;Seroquel; adrenergicDopaminergicQuetiapine antagonist; antagonisthemifumarate; Serotonergic 111974-72-2;antagonist; Name: Quetiapine Fumarate; Seroquel; DopaminergicSeroquel XR; UNII-2S3PL1B6UJantagonist Pathogenic genes: ADRA2A, Name:Quetiapine Quetiapine hemifumarate; Fumarate 111974-72-2;; Seroquel; Seroquel Name: Quetiapine Fumarate; Seroquel; DRD1, DRD2, DRD4, HTR1A, QuetiapineIUPACXR; UNII-2S3PL1B6UJ hemifumarate;Name: 2-[2-(4-{2-thia-9-111974-72-2; QuetiapineSeroquelazatricyclo[9.4.0.0³, XR; UNII-2S3PL1B6UJhemifumarate;⁸]pentadeca- 111974-72-2; PathogenicHTR2APathogenic, RGS4 genes: genes: ADRA2AADRA2A, , DRD1, IUPAC Name: PathogenicDRD2 ,genes:DRD4 , HTR1AADRA2A, HTR2A, , RGS4 SeroquelIUPAC1(15),3,5,7,9,11,13-heptaen-10-yl}piperazin-1- XR; UNII-2S3PL1B6UJName: 2-[2-(4-{2-thia-9- DRD1Mechanistic, DRD2 , genes:DRD4 , ADRA1sHTR1A, , 2-[2-(4-{2-thia-9-azatricyclo[9.4.0.03,8]pentadeca-DRD1, MechanisticDRD2, DRD4 genes:, HTR1AADRA1s, , IUPACyl)ethoxy]ethan-1-ol Name: 2-[2-(4-{2-thia-9- HTR2AADRA2s, RGS4, BDNF, CHRM1, CHRM3, azatricyclo[9.4.0.0³,1(15),3,5,7,9,11,13-heptaen-10-yl}piperazin-1-yl)⁸]pentadeca- ADRA2s, BDNF, CHRM1, CHRM3, azatricyclo[9.4.0.0³,⁸]pentadeca- HTR2AMechanisticCHRM5,, RGS4 DRD1 genes:, DRD2 ADRA1s, DRD4, , 1(15),3,5,7,9,11,13-heptaen-10-yl}piperazin-1-ethoxy]ethan-1-ol CHRM5, DRD1, DRD2, DRD4, HRH1, 1(15),3,5,7,9,11,13-heptaen-10-yl}piperazin-1-Molecular Formula: C46H54N6O8S2 MechanisticADRA2sHRH1, ,HTR1A BDNF, genes:, CHRM1,HTR1E, ADRA1s CHRM3,HTR2A, , yl)ethoxy]ethan-1-ol HTR1A, HTR1E, HTR2A, HTR2B, Molecular Formula: C46H54N6O8S2 ADRA2sHTR2B,, HTR7BDNF, CHRM1, CHRM3, yl)ethoxy]ethan-1-ol CHRM5,HTR7 DRD1, DRD2, DRD4, CHRM5, DRD1, DRD2, DRD4, MolecularMolecularMolecular Formula: Weight: Weight: 883.08636C46H883.0863654N6O g/mol8S2 g /mol HRH1Metabolic, MetabolicHTR1A genes:, HTR1E, genes: HTR2A, Molecular Formula: C46H54N6O8S2 HRH1, HTR1A, HTR1E, HTR2A, HTR2B, Substrate:Substrate: HTR7 CYP2D6CYP2D6 (minor),(minor), Mechanism:Mechanism: AntagonistAntagonist atat multiple multiple HTR2B,MetabolicCYP3A4/5 CYP3A4HTR7 genes: (major),/5 (major), CYP3A7,, CYP2C19 Molecularneurotransmitter Weight: 883.08636 receptors: g/mol serotonin 5-HT1A Molecularneurotransmitter Weight: receptors:883.08636 g/molserotonin 5-HT1A MetabolicCYP2C19Inhibitor: genes: ABCB1, SLC6A2 and 5-HT2, dopamine D1 and D2, histamine H Substrate:1, CYP2D6 (minor), and 5-HT2, dopamine D1 and D2, histamine H1, Mechanism:and adrenergic Antagonistα - and α -receptorsat multiple CYP3A4/5 Substrate: Inhibitor:Transporter ABCB1,(major),CYP2D6 genes: SLC6A2 CYP3A7(minor),ABCB1 , KCNE1, Mechanism: Antagonist1 2at multiple neurotransmitterand adrenergic α 1-receptors: and α2-receptors serotonin 5-HT1A CYP3A4/5CYP2C19TransporterKCNE2 (major),, KCNH2genes: , KCNQ1CYP3A7ABCB1, SCN5A,, , neurotransmitterEffect: Antipsychotic receptors: agent;serotonin Adrenergic 5-HT1A SLC6A2 andEffect: 5-HT 2,Antipsychotic dopamine D1 andagent; D2, histamineAdrenergic H1, CYP2C19 KCNE1 Inhibitor:, KCNE2 ABCB1,, KCNH2 SLC6A2, KCNQ1 , and 5-HTantagonist;2, dopamine Histamine D1 and antagonist; D2, histamine Serotonergic H1, andantagonist; adrenergic Histamine α1- and αantagonist;2-receptors Serotonergic Inhibitor: ABCB1, SLC6A2 antagonist; Dopaminergic antagonist; SedativeTransporterSCN5A, SLC6A2 genes: ABCB1, and adrenergic α1- and α2-receptors Effect:antagonist;activity; Antipsychotic Dopaminergic Orthostatic hypotensionagent; antagonist; Adrenergic Sedative TransporterKCNE1, KCNE2 genes:, KCNH2 , KCNQ1ABCB1,, Effect: Antipsychotic agent; Adrenergic antagonist;activity; Orthostatic Histamine hypotension antagonist; Serotonergic KCNE1SCN5A,, KCNE2SLC6A2, KCNH2, KCNQ1, antagonist;Name: Histamine Risperidone antagonist;; Risperdal; Serotonergic Risperidal; antagonist;Name: Risperidone Dopaminergic; Risperdal; antagonist; Risperidal; Sedative SCN5A,Pathogenic PathogenicSLC6A2 genes: genes: ADRA2AADRA2A, , BDNF, antagonist;106266-06-2; Dopaminergic Risperdal antagonist; Consta; Rispolept Sedative COMT, DRD1, DRD2, DRD3, DRD4, activity;106266-06-2; Orthostatic Risperdal hypotension Consta; Rispolept BDNF, COMT, DRD1, DRD2, activity;IUPAC Orthostatic Name: hypotension3-{2-[4-(6-fluoro-1,2- GRM3, HTR2A, HTR2C, HTR7, PON1, PathogenicDRD3, DRD4 genes:, GRM3 ,ADRA2A HTR2A, , Name:IUPACbenzoxazol-3-yl)piperidin-1-yl]ethyl}-2-methyl-4H, RisperidoneName: ; Risperdal;3-{2-[4-(6-fluoro-1,2- Risperidal; RGS4 Name: Risperidone; Risperdal; Risperidal; PathogenicBDNFHTR2C, , HTR7,COMT genes: PON1, DRD1 , RGS4ADRA2A, DRD2 ,, 106266-06-2;benzoxazol-3-yl)piperidin-1-yl]ethyl}-2-6H,7H,8H,9H-pyrido[1,2-a]pyrimidin-4-one Risperdal Consta; Rispolept Mechanistic genes: ADRA1A, 106266-06-2; Risperdal Consta; Rispolept BDNFDRD3Mechanistic,, COMTDRD4 ,, genes:GRM3DRD1 ,, ADRA1AHTR2ADRD2,, , IUPACmethyl-4H,6H,7H,8H,9H-pyrido[1,2- Name: 3-{2-[4-(6-fluoro-1,2- ADRA1B, ADRA2s, DRD1, DRD2, Molecular Formula: C23H27FN4O2 DRD3HTR2CADRA1B, , DRD4HTR7,, ADRA2s, PON1GRM3, DRD1, RGS4, HTR2A, DRD2 , , IUPACbenzoxazol-3-yl)piperidin-1-yl]ethyl}-2-a]pyrimidin-4-one Name: 3-{2-[4-(6-fluoro-1,2- DRD3, DRD4, FOS, HTR2A, HTR2C, Molecular Weight: 410.484483 g/mol HTR2CMechanisticDRD3, HTR3AHTR7,DRD4 PON1,genes:HTR3C, FOS, RGS4 ,,HTR6 ADRA1A HTR2A , HTR7,, , NR1I2, benzoxazol-3-yl)piperidin-1-yl]ethyl}-2-methyl-4H,6H,7H,8H,9H-pyrido[1,2- MechanisticADRA1BHTR2CSTAT3, , HTR3AADRA2s genes:, , HTR3CDRD1 ADRA1A,, DRD2HTR6,, , methyl-4H,6H,7H,8H,9H-pyrido[1,2-a]pyrimidin-4-oneMolecularMechanism: Formula: Antagonist C23H27FN at4O multiple2 ADRA1BDRD3HTR7,, NR1I2,Metabolic, DRD4ADRA2s STAT3, , genes: FOSDRD1 , , HTR2ADRD2,, a]pyrimidin-4-oneneurotransmitter receptors: serotonin 5-HT1A DRD3HTR2C, ,Substrate: DRD4HTR3A, , FOSCOMT,HTR3C, ,HTR2A CYP2D6 HTR6,, (major), Molecularand 5-HTFormula:2, dopamine C23H27FN D14Oand2 D2, histamine H1, HTR2C, CYP3A4HTR3A/5, (minor)HTR3C, HTR6, Molecularand adrenergicFormula: Cα231H- and27FNα4O2-receptors2 HTR7, NR1I2, STAT3 HTR7, NR1I2,Inhibitor: STAT3ABCB1 , CYP2D6 (weak), Effect: Antipsychotic agent; H1-receptor CYP3A4 (weak) Inducer: MAOB antagonist; Dopaminergic antagonist; Transporter genes: ABCB1, KCNH2, Alpha-adrenergic antagonist; Serotonergic SLC6A4 antagonist; Somnolence; Orthostatic hypotension Pleiotropic genes: APOA5, BDNF, RGS2 Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 25 of 87

Metabolic genes: Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 25 of 87 Molecular Weight: 410.484483 g/mol Substrate: COMT, CYP2D6 (major), CYP3A4/5 (minor) Mechanism: Antagonist at multiple Metabolic genes: Inhibitor: ABCB1, CYP2D6 neurotransmitterMolecular Weight: receptors: 410.484483 serotonin g/mol 5-HT1A Substrate: COMT, CYP2D6 (weak), CYP3A4 (weak) and 5-HT2, dopamine D1 and D2, histamine H1, (major), CYP3A4/5 (minor) Mechanism: Antagonist at multiple Inducer: MAOB and adrenergic α1- and α2-receptors Inhibitor: ABCB1, CYP2D6 neurotransmitter receptors: serotonin 5-HT1A Transporter genes: ABCB1, Effect: Antipsychotic agent; H1-receptor (weak), CYP3A4 (weak) and 5-HT2, dopamine D1 and D2, histamine H1, KCNH2, SLC6A4 antagonist; Dopaminergic antagonist; Alpha- Inducer: MAOB and adrenergic α1- and α2-receptors Pleiotropic genes: APOA5, BDNF, Int. J. Mol. Sci. 2020, 21, 3059 Transporter genes: ABCB1, 24 of 82 adrenergic antagonist; Serotonergic antagonist; RGS2 Effect: Antipsychotic agent; H1-receptor Somnolence; Orthostatic hypotension KCNH2, SLC6A4 antagonist; Dopaminergic antagonist; Alpha- Name: Ziprasidone; Geodon; 146939-27-7; Pleiotropic genes: APOA5, BDNF, adrenergic antagonist; Serotonergic antagonist; Zeldox; Ziprazidone;Table 3. Cont.Ziprasidone RGS2 Somnolence; Orthostatic hypotension hydrochloride Name: ZiprasidoneAtypical; Geodon; Antipsychotics 146939-27-7; IUPAC Name: 5-{2-[4-(1,2-benzothiazol-3- Drug Zeldox; Ziprazidone;Properties Ziprasidone Pathogenic genes:Pharmacogenetics DRD2, DRD3, yl)piperazin-1-yl]ethyl}-6-chloro-2,3-dihydro- hydrochloride DRD4, HTR1A, HTR2A, HTR2C, 1H-indol-2-oneName: Ziprasidone ; Geodon; 146939-27-7; IUPACZeldox; Name: Ziprazidone; 5-{2-[4-(1,2-benzothiazol-3- Ziprasidone hydrochlorideRGS4 Pathogenic genes: DRD2, DRD3, Molecularyl)piperazin-1-yl]ethyl}-6-chloro-2,3-dihydro- Formula: C21H21ClN4OS Mechanistic genes: ADRA1A, IUPAC Name: DRD4, HTR1A, HTR2A, HTR2C, 1H-indol-2-one DRD2, PathogenicDRD3, HRH1 genes:, HTR1ADRD2, ,DRD3 , 5-{2-[4-(1,2-benzothiazol-3-yl)piperazin-1- RGS4 yl]ethyl}-6-chloro-2,3-dihydro-1H-indol-2-oneHTR1B,DRD4 HTR1D, HTR1A, HTR2A, HTR2A, HTR2C, HTR2C , RGS4 Mechanistic genes: ADRA1A, MolecularMolecular Weight:Formula: 412.93564 C21H21ClN g/mol4OS MetabolicMechanistic genes: genes: ADRA1A, DRD2, Molecular Formula: C21H21ClN4OS DRD2, DRD3, HRH1, HTR1A, Substrate:DRD3 , HRH1AOX1, HTR1A (major),, HTR1B, Mechanism: It has high affinity for D2, D3, 5- HTR1B, HTR1D, HTR2A, HTR2C Molecular Weight: 412.93564 g/mol CYP1A2HTR1D (minor),, HTR2A CYP3A4, HTR2C (major) HTMolecular2A, 5-HT Weight:1A, 5-HT 412.935642C, 5-HT g/mol1D, and α1- MetabolicMetabolic genes: genes: Mechanism: It has high affinity for D ,D , Inhibitor: CYP2D6 (moderate), adrenergic, and moderate affinity for histamine2 3 Substrate:Substrate: AOX1AOX1 (major),(major),CYP1A2 Mechanism:5-HT2A ,It 5-HT has 1Ahigh, 5-HT affinity2C, 5-HT for1D D,2 and, D3, 5- CYP3A4 (moderate), SLC6A2, H1 receptors. It functions as antagonist at D2, 5- CYP1A2(minor), (minor),CYP3A4 CYP3A4(major) (major) α -adrenergic, and moderate affinity for SLC6A4 HT2A, 15-HT1A, 5-HT2C, 5-HT1D, and α1- Inhibitor: CYP2D6 (moderate), HT2A, histamineand 5-HT1D H receptorsreceptors. and It functionsas agonist as at antagonist 5- Inhibitor: CYP2D6 (moderate), adrenergic, and moderate1 affinity for histamine TransporterCYP3A4 genes:(moderate), KCNH2,SLC6A2, SLC6A4 HT1A receptor.at D2, 5-HT It 2Amoderately, and 5-HT inhibits1D receptors reuptake and as CYP3A4 (moderate), SLC6A2, H1 receptors. It functions as antagonist at D2, 5- SLC6A2,Transporter SLC6A4 genes: KCNH2, SLC6A2, of serotoninagonist and at 5-HTnorepinephrine1A receptor. It moderately inhibitsSLC6A4 HT2A, and 5-HT1D receptors and as agonist at 5- PleiotropicSLC6A4 genes: CHRM1, RRAS2 Effect:reuptake Antipsychotic of serotonin agent; and norepinephrine Histamine Transporter genes: KCNH2, HT1A receptor. It moderately inhibits reuptake Pleiotropic genes: CHRM1, RRAS2 antagonist;Effect: AntipsychoticDopaminergic agent; Histamineantagonist; SLC6A2, SLC6A4 of serotonin and norepinephrine Serotonergicantagonist; antagonist; Dopaminergic Muscarinic antagonist; antagonist; Pleiotropic genes: CHRM1, RRAS2 Effect: Antipsychotic agent; Histamine Serotonin–norepinephrineSerotonergic antagonist; reuptake Muscarinic inhibitor antagonist; antagonist; Dopaminergic antagonist; Serotonin–norepinephrineTypical Antipsychotics reuptake inhibitor Serotonergic antagonist; Muscarinic antagonist; ButyrophenonesTypical Antipsychotics Serotonin–norepinephrine reuptake inhibitor Drug PropertiesButyrophenones Pharmacogenetics Drug Typical AntipsychoticsProperties Pharmacogenetics Name: Bromperidol; Impromen; Butyrophenones Bromoperidol;Name: Bromperidol Tesoprel; 10457-90-6;; Impromen; Azurene Bromoperidol; Drug Tesoprel; 10457-90-6;Properties Azurene Pharmacogenetics IUPAC Name: 4-[4-(4-bromophenyl)-4- Name: Bromperidol; Impromen; hydroxypiperidin-1-yl]-1-(4-IUPAC Name: Bromoperidol; Tesoprel; 10457-90-6; Azurene fluorophenyl)butan-1-one4-[4-(4-bromophenyl)-4-hydroxypiperidin-1-yl]-1- IUPAC Name: 4-[4-(4-bromophenyl)-4- (4-fluorophenyl)butan-1-one Pathogenic genes: DRD2, HTR2A Molecularhydroxypiperidin-1-yl]-1-(4- Formula: C21H23BrFNO2 Pathogenic genes: DRD2, HTR2A Molecular Formula: C21H23BrFNO2 Mechanistic genes: DRD2, HTR2A fluorophenyl)butan-1-one Mechanistic genes: DRD2, HTR2A Metabolic genes: MolecularMolecular Weight: Weight: 420.315223420.315223 g/mol g/mol PathogenicMetabolic genes: genes:DRD2, HTR2A Molecular Formula: C21H23BrFNO2 Substrate:Substrate: CYP2D6CYP2D6 (minor),(minor), CYP3A4 Mechanism: Potent dopaminergic D2 antagonist.Mechanistic genes: DRD2, HTR2A Mechanism: Potent dopaminergic D2 CYP3A4(major), (major),UGTs UGTs Has weak α1-adrenolitic activity. It is a moderateMetabolic genes: antagonist.Molecular HasWeight: weak 420.315223 α1-adrenolitic g/mol activity. It is Inhibitor:Inhibitor: CYP2D6CYP2D6 (moderate)(moderate) serotonin 5-HT2 antagonist. Has no Substrate: CYP2D6 (minor), a moderateantihistaminic serotonin or 5-HT anticholinergic2 antagonist. e ffHasects. no It actsTransporter on Transporter genes: ABCB1 genes: ABCB1 Mechanism: Potent dopaminergic D2 CYP3A4 (major), UGTs antihistaminicthe mesocortex, or anticholinergic limbic system, effects. and It basal acts ganglia antagonist. Has weak α1-adrenolitic activity. It is Inhibitor: CYP2D6 (moderate) Int. J. Mol. Sci. 2020, 21, x FOR PEERon REVIEWthe(nigrostriate mesocortex, pathway) limbic system, and basal 26 of 87 a moderate serotonin 5-HT2 antagonist. Has no Transporter genes: ABCB1 ganglia (nigrostriate pathway) antihistaminicEffect: Antipsychotic or anticholinergic agent; effects. Dopamine It acts IUPACEffect: AntipsychoticName: 4-[4-(4-chlorophenyl)-4- agent; Dopamine Mechanistic genes: ANKK1, on theantagonist; mesocortex,α1-adrenolitic limbic system, activity and basal hydroxypiperidin-1-yl]-1-(4-antagonist; α1-adrenolitic activity BDNF, COMT, DRD1, DRD2, gangliaName: (nigrostriate Haloperidol pathway); Haldol; Eukystol; Serenace; fluorophenyl)butan-1-one DTNBP1,PathogenicPathogenic GRIN2A,genes: genes: ADRA2A,GRIN3B,ADRA2A, BDNF, Name:Effect:Aloperidin; HaloperidolAntipsychotic Aloperidol; Haldol;agent; DopamineEukystol; GRIN2C,BDNF, DRD1, GRIN2B,DRD1, DRD2, SLC6A3DRD2, DRD4, DRD4, DTNBP1, Serenace;antagonist;IUPAC Aloperidin; α1 Name:-adrenolitic Aloperidol activity MetabolicGRIN2B, genes:HTR2A Molecular Formula: C21H23ClFNO2 DTNBP1, GRIN2B, HTR2A 4-[4-(4-chlorophenyl)-4-hydroxypiperidin-1- Pathogenic Substrate:Mechanistic genes:CBR1 genes: , ADRA2A,CYP1A1ANKK1, BDNF, Name: Haloperidol; Haldol; Eukystol; COMT, DRD1, DRD2, DTNBP1, yl]-1-(4-fluorophenyl)butan-1-one (minor),BDNF, CYP1A2DRD1, (minor),DRD2, CYP2A6 DRD4,, Serenace; Aloperidin; Aloperidol GRIN2A, GRIN3B, GRIN2C, GRIN2B, Molecular Formula: C21H23ClFNO2 CYP2C8DTNBP1, (minor), GRIN2B, CYP2C9 HTR2A (minor), Molecular Weight: 375.864223 g/mol SLC6A3 Molecular Weight: 375.864223 g/mol CYP2C19Metabolic (minor), CYP2D6 genes: (major), CYP3A4Substrate:/5 (major), GSTP1CBR1, CYP1A1, UGTs (minor), Mechanism:Mechanism: HaloperidolHaloperidol is a butyrophenone is a butyrophenone Inhibitor:CYP1A2 ABCB1, CYP2A6CYP2D6 CYP2C8 antipsychotic which blocks postsynaptic (minor), , antipsychotic which blocks postsynaptic (moderate), CYP3A4CYP2C9 (moderate) CYP2C19 mesolimbic dopaminergic D and D receptors in (minor), (minor), mesolimbic dopaminergic D1 and 1D2 receptors2 CYP2D6 CYP3A4 5 brain. Depresses release of hypothalamic andTransporter(minor), genes: (major),ABCB1, / in brain. Depresses release of hypothalamic and GSTP1 UGTs hypophyseal hormones. Believed to depressABCC1, (major),KCNE1, KCNE2,, KCNH2, hypophyseal hormones. Believed to depress Inhibitor: ABCB1, CYP2D6 reticular activating system KCNJ11, KCNQ1, SLC6A3 (moderate), CYP3A4 (moderate) reticular activating system Pleiotropic genes: CHRM2, FOS, Effect:E ffect:AntipsychoticAntipsychotic agent; agent; Serotonergic Transporter genes: ABCB1, ABCC1, antagonist; Dopaminergic antagonist; Antiemetic;GSK3B, HRH1, HTR2A, HTT, antagonist; Dopaminergic antagonist; KCNE1, KCNE2, KCNH2, KCNJ11, Antidyskinesia agent; Sedative effects; IL1RN KCNQ1, SLC6A3 Antiemetic; Antidyskinesia agent; Sedative Hypotension Pleiotropic genes: CHRM2, FOS, effects; Hypotension GSK3B, HRH1, HTR2A, HTT, IL1RN Phenothiazines Drug Properties Pharmacogenetics Name: Chlorpromazine; Largactil; Thorazine; Contomin; Chloropromazine; Aminazine

IUPAC Name: [3-(2-chloro-10H-phenothiazin- Pathogenic genes: BDNF, DRD1, 10-yl)propyl]dimethylamine DRD2, DRD3, DRD4, HTR2A Mechanistic genes: ADRA1A, Molecular Formula: C17H19ClN2S ADRA1B, CHRM1, CHRM2, DRD1, DRD2, DRD3, DRD4, HRH1, Molecular Weight: 318.86416 g/mol HTR1A, HTR2A, HTR2C Metabolic genes: Mechanism: Blocks postsynaptic mesolimbic Substrate: CYP1A2 (minor), dopaminergic receptors in the brain. Has actions CYP2A6, CYP2C9, CYP2C19, at all levels of CNS, particularly at subcortical CYP2D6 (major), CYP3A4 (minor), levels; also acts on multiple organ systems. Also FMO1, UGT1A3, UGT1A4 exhibits weak ganglionic blocking, has a strong Inhibitor: CYP1A2, CYP2D6 α-adrenergic blocking effect and depresses the (strong), CYP2C19, CYP2E1 (weak), release of hypothalamic and hypophyseal CYP3A4, DAO hormones. Depresses the reticular activating Transporter genes: ABCB1, CFTR system Pleiotropic genes: ACACA, BDNF, Effect: Antipsychotic agent; Dopaminergic FABP1, LEP, NPY antagonist; Antiemetic; Anticholinergic effects; Sedative effects; Antihistaminic effects; Anti- serotonergic activity; Hypotension Name: Fluphenazine; Triflumethazine; Fluorophenazine; Fluorfenazine; Pathogenic genes: DRD1, DRD2 Fluorphenazine; Siqualine Mechanistic genes: CALM1, IUPAC Name: 2-(4-{3-[2-(trifluoromethyl)- DRD1, DRD2 10H-phenothiazin-10-yl]propyl}piperazin-1- Metabolic genes: yl)ethan-1-ol Substrate: CYP2B6, CYP2D6 (major) Molecular Formula: C22H26F3N3OS Inhibitor: ABCB1, CYP1A2 (weak), CYP2A6, CYP2C9 (weak), Molecular Weight: 437.52155 g/mol CYP2C19, CYP2D6 (strong), CYP2E1 (weak), CYP3A4 Mechanism: Blocks postsynaptic mesolimbic Transporter genes: ABCB1 dopaminergic D1 and D2 receptors in the brain.

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Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 26 of 87 IUPAC Name: 4-[4-(4-chlorophenyl)-4- Mechanistic genes: ANKK1, hydroxypiperidin-1-yl]-1-(4- BDNF, COMT, DRD1, DRD2, IUPAC Name: 4-[4-(4-chlorophenyl)-4- Mechanistic genes: ANKK1, fluorophenyl)butan-1-one DTNBP1, GRIN2A, GRIN3B, hydroxypiperidin-1-yl]-1-(4- BDNF, COMT, DRD1, DRD2, GRIN2C, GRIN2B, SLC6A3 fluorophenyl)butan-1-one DTNBP1, GRIN2A, GRIN3B, Metabolic genes: Molecular Formula: C21H23ClFNO2 GRIN2C, GRIN2B, SLC6A3 Substrate: CBR1, CYP1A1 Metabolic genes: Molecular Formula: C21H23ClFNO2 (minor), CYP1A2 (minor), CYP2A6, Substrate: CBR1, CYP1A1 CYP2C8 (minor), CYP2C9 (minor), Molecular Weight: 375.864223 g/mol (minor), CYP1A2 (minor), CYP2A6, CYP2C19 (minor), CYP2D6 (major), CYP2C8 (minor), CYP2C9 (minor), Molecular Weight: 375.864223 g/mol CYP3A4/5 (major), GSTP1, UGTs CYP2C19 (minor), CYP2D6 (major), Mechanism: Haloperidol is a butyrophenone Inhibitor: ABCB1, CYP2D6 antipsychotic which blocks postsynaptic CYP3A4/5 (major), GSTP1, UGTs Mechanism: Haloperidol is a butyrophenone (moderate), CYP3A4 (moderate) mesolimbic dopaminergic D1 and D2 receptors Inhibitor: ABCB1, CYP2D6 antipsychotic which blocks postsynaptic Transporter genes: ABCB1, in brain. Depresses release of hypothalamic and (moderate), CYP3A4 (moderate) mesolimbic dopaminergic D1 and D2 receptors ABCC1, KCNE1, KCNE2, KCNH2, hypophyseal hormones. Believed to depress Transporter genes: ABCB1, in brain. Depresses release of hypothalamic and KCNJ11, KCNQ1, SLC6A3 reticular activating system ABCC1, KCNE1, KCNE2, KCNH2, hypophyseal hormones. Believed to depress Pleiotropic genes: CHRM2, FOS, Effect: Antipsychotic agent; Serotonergic KCNJ11, KCNQ1, SLC6A3 reticular activating system GSK3B, HRH1, HTR2A, HTT, antagonist; Dopaminergic antagonist; Pleiotropic genes: CHRM2, FOS, Int. J. Mol. Sci. 2020, 21, 3059 Effect: Antipsychotic agent; Serotonergic IL1RN 25 of 82 Antiemetic; Antidyskinesia agent; Sedative GSK3B, HRH1, HTR2A, HTT, antagonist; Dopaminergic antagonist; effects; Hypotension IL1RN Antiemetic; Antidyskinesia agent; Sedative Phenothiazines effects; Hypotension Table 3. Cont. Drug Properties Pharmacogenetics Phenothiazines Drug Name: ChlorpromazinePropertiesPhenothiazines; Largactil; Thorazine; Pharmacogenetics Drug Contomin; Chloropromazine;Properties Aminazine Pharmacogenetics Name: Chlorpromazine; Largactil; Thorazine; Name: Chlorpromazine; Largactil; Thorazine; Contomin;IUPAC Name: Chloropromazine; [3-(2-chloro-10H-phenothiazin- Aminazine Contomin; Chloropromazine; Aminazine Pathogenic genes: BDNF, DRD1, 10-yl)propyl]dimethylamine DRD2, PathogenicDRD3, DRD4 genes:, HTR2ABDNF , DRD1, IUPACIUPAC Name: Name: [3-(2-chloro-10H-phenothiazin-[3-(2-chloro-10H- Pathogenic genes: BDNF, DRD1, MechanisticDRD2 , DRD3genes:, DRD4 ADRA1A,, HTR2A 10-yl)propyl]dimethylaminephenothiazin-10-yl)propyl]dimethylamine DRD2, DRD3, DRD4, HTR2A Molecular Formula: C17H19ClN2S ADRA1B,Mechanistic CHRM1, CHRM2, genes: ADRA1A, DRD1, Mechanistic genes: ADRA1A, Molecular Formula: C17H19ClN2S ADRA1B, CHRM1, CHRM2, DRD1, Molecular Formula: C17H19ClN2S DRD2, DRD3, DRD4, HRH1, ADRA1B,DRD2, CHRM1, DRD3, CHRM2, DRD4, DRD1, HRH1, HTR1A, MolecularMolecular Weight: Weight: 318.86416318.86416 g/mol g /mol HTR1A, HTR2A, HTR2C DRD2, HTR2A,DRD3, HTR2CDRD4, HRH1, Metabolic genes: Mechanism: Blocks postsynaptic mesolimbicHTR1A,Metabolic HTR2A, HTR2C genes: MolecularMechanism: Weight: Blocks 318.86416 postsynaptic g/mol mesolimbic Substrate: CYP1A2 (minor), dopaminergic receptors in the brain. Has actionsMetabolicSubstrate: genes: CYP1A2 (minor), CYP2A6, dopaminergic receptors in the brain. Has actions CYP2A6, CYP2C9, CYP2C19, Mechanism:at all levels Blocks of CNS, postsynaptic particularly mesolimbic at subcortical Substrate:CYP2C9, CYP1A2 CYP2C19, (minor), CYP2D6 (major), at all levels;levels alsoof CNS, acts onparticularly multiple organat subcortical systems. AlsoCYP2D6CYP3A4 (major), CYP3A4FMO1 (minor),UGT1A3 dopaminergic receptors in the brain. Has actions CYP2A6, CYP2C9,(minor), CYP2C19,, , levels;exhibits also acts weak on multiple ganglionic organ blocking, systems. has Also a strong FMO1,UGT1A4 UGT1A3, UGT1A4 at all levels of CNS, particularly at subcortical CYP2D6 (major), CYP3A4 (minor), exhibitsα-adrenergic weak ganglionic blocking blocking, effect and has depresses a strong the Inhibitor:Inhibitor: CYP1A2,CYP1A2, CYP2D6 CYP2D6 (strong), levels; also acts on multiple organ systems. Also FMO1, UGT1A3, UGT1A4 α-adrenergicrelease ofblocking hypothalamic effect and and depresses hypophyseal the (strong),CYP2C19, CYP2C19, CYP2E1 CYP2E1(weak), (weak),CYP3A4, exhibits weak ganglionic blocking, has a strong Inhibitor: CYP1A2, CYP2D6 releasehormones. of hypothalamic Depresses theand reticular hypophyseal CYP3A4,DAO DAO α-adrenergicactivating blocking system effect and depresses the (strong), CYP2C19, CYP2E1 (weak), hormones. Depresses the reticular activating TransporterTransporter genes: genes:ABCB1ABCB1, CFTR , CFTR release of hypothalamic and hypophyseal CYP3A4,Pleiotropic DAO genes: ACACA, BDNF, systemEff ect: Antipsychotic agent; Dopaminergic Pleiotropic genes: ACACA, BDNF, hormones. Depresses the reticular activating TransporterFABP1, genes: LEP, ABCB1 NPY , CFTR Effect:antagonist; Antipsychotic Antiemetic; agent; Anticholinergic Dopaminergic eff ects;FABP1, LEP, NPY system Pleiotropic genes: ACACA, BDNF, antagonist;Sedative Antiemetic; effects; Antihistaminic Anticholinergic effects; effects; Effect: Antipsychotic agent; Dopaminergic FABP1, LEP, NPY SedativeAnti-serotonergic effects; Antihistaminic activity; Hypotension effects; Anti- antagonist; Antiemetic; Anticholinergic effects; serotonergicName: Fluphenazineactivity; Hypotension; Triflumethazine; Sedative effects; Antihistaminic effects; Anti- Name:Fluorophenazine; Fluphenazine Fluorfenazine;; Triflumethazine; Fluorphenazine; serotonergic activity; Hypotension Fluorophenazine;Siqualine Fluorfenazine; Pathogenic genes: DRD1, DRD2 Name: Fluphenazine; Triflumethazine; Fluorphenazine;IUPAC Name: Siqualine Mechanistic genes: CALM1, Fluorophenazine; Fluorfenazine; Pathogenic genes: DRD1, DRD2 IUPAC2-(4-{3-[2-(trifluoromethyl)-10H-phenothiazin-10- Name: 2-(4-{3-[2-(trifluoromethyl)- DRD1, DRD2 Fluorphenazine; Siqualine Mechanistic genes: CALM1, 10H-phenothiazin-10-yl]propyl}piperazin-1-yl]propyl}piperazin-1-yl)ethan-1-ol MetabolicPathogenic genes: genes: DRD1, DRD2 IUPAC Name: 2-(4-{3-[2-(trifluoromethyl)- DRD1, DRD2Mechanistic genes: CALM1, DRD1, yl)ethan-1-olMolecular Formula: C H F N OS Substrate: CYP2B6, CYP2D6 10H-phenothiazin-10-yl]propyl}piperazin-1-22 26 3 3 MetabolicDRD2 genes: (major) Molecular Weight: 437.52155 g/mol Metabolic genes: Int. J. Mol. Sci. 2020, 21, x FOR PEERyl)ethan-1-olMolecular REVIEW Formula: C22H26F3N3OS Substrate: CYP2B6, 27CYP2D6 of 87 Inhibitor:Substrate: ABCB1,CYP2B6, CYP1A2 CYP2D6 (major) Mechanism: Blocks postsynaptic mesolimbic(major) 22 26 3 3 (weak),Inhibitor: CYP2A6, ABCB1,CYP2C9 CYP1A2 (weak),(weak), DepressesMoleculardopaminergic Formula:release D CofandH hypothalamicF DNreceptorsOS inand the brain. Inhibitor: ABCB1, CYP1A2 Molecular Weight: 437.521551 2 g/mol CYP2C19,CYP2A6, CYP2D6 CYP2C9 (weak),(strong),CYP2C19, hypophysealDepresses hormones. release of Believed hypothalamic to depress and (weak), CYP2A6, CYP2C9 (weak), CYP2E1CYP2D6 (weak),(strong), CYP3A4 CYP2E1 (weak), reticularMolecularhypophyseal activating Weight: hormones.system,437.52155 thus g/mol Believed affecting to basal depress CYP2C19, CYP2D6 (strong), Mechanism: Blocks postsynaptic mesolimbic TransporterCYP3A4 genes: ABCB1 reticular activating system, thus affecting basalCYP2E1 (weak), CYP3A4 metabolism, body1 temperature,2 wakefulness, Transporter genes: ABCB1 dopaminergicmetabolism, D and body D temperature, receptors in wakefulness,the brain. vasomotorMechanism: tone, Blocks and emesispostsynaptic mesolimbic Transporter genes: ABCB1 vasomotor tone, and emesis Effect:dopaminergic Antipsychotic D1 and D 2agent; receptors Dopaminergic in the brain. Effect: Antipsychotic agent; Dopaminergic antagonist; Antiemesis; Anticholinergic effects; Sedativeantagonist; effects Antiemesis; Anticholinergic effects; Sedative effects Name: Perphenazine; Trilafon; Perphenazin; Etaperazine;Name: Perfenazine;Perphenazine Fentazin; Trilafon; Perphenazin;Pathogenic genes: ADRA2A, Etaperazine; Perfenazine; Fentazin DRD1, DRD2, HTR2A, HTR2C, IUPAC Name: 2-[4-[3-(2-chlorophenothiazin- Pathogenic genes: ADRA2A, DRD1, RGS4 10-yl)propyl]piperazin-1-yl]ethanolIUPAC Name: 2-[4-[3-(2-chlorophenothiazin- DRD2, HTR2A, HTR2C, RGS4 10-yl)propyl]piperazin-1-yl]ethanol MechanisticMechanistic genes: genes: ADRA1AADRA1A, , Molecular Formula: C21H26ClN3OS ADRA2AADRA2A, DRD1,, DRD1DRD2,,DRD2 HTR2A,, HTR2A, Molecular Formula: C21H26ClN3OS HTR2C,HTR2C, RGS4 RGS4 MolecularMolecular Weight: Weight: 403.96864403.96864 g/mol g/mol MetabolicMetabolic genes: genes: Mechanism: Blocks postsynaptic mesolimbic Substrate:Substrate: CYP1A2CYP1A2 (major),(major), CYP2C8 Mechanism: Blocks postsynaptic mesolimbic dopaminergic receptors in brain. Exhibits CYP2C8(major), (major),CYP2C9 CYP2C9(major), (major),CYP2C18 dopaminergicα-adrenergic-blocking receptors in brain. effect andExhibits depresses α- CYP2C18(major), (major),CYP2C19 CYP2C19(major), CYP2D6 (minor), CYP3A4/5 (major) adrenergic-blockingrelease of hypothalamic effect and depresses and hypophyseal release (major), CYP2D6 (minor), of hypothalamic and hypophyseal hormones. Inhibitor: CYP1A2 (weak), CYP2D6 hormones. Binds to the dopamine D1 and DCYP3A4/52 (major) Binds receptorsto the dopamine and inhibits D1 and their D2 activityreceptors and (strong) Inhibitor:Transporter CYP1A2 genes: ABCB1(weak), inhibitsE fftheirect: activityAntipsychotic agent; Antiemetic; CYP2D6 (strong) Effect:Dopaminergic Antipsychotic antagonist; agent; AntiemesisAntiemetic; Transporter genes: ABCB1 Dopaminergic antagonist; Antiemesis Name: Thioridazine; Mellaril; Melleril; Pathogenic genes: ADRA2A, Thioridazin; Meleril; Sonapax DRD1, DRD2 Mechanistic genes: ADRA1s, IUPAC Name: 10-[2-(1-methylpiperidin-2- ADRA2s, DRD1, DRD2 yl)ethyl]-2-methylsulfanylphenothiazine Metabolic genes: Substrate: CYP1A2 (major), Molecular Formula: C21H26N2S2 CYP2C19 (minor), CYP2A6, CYP2D6 (major), CYP2J2 (major), CYP3A4 (major) Molecular Weight: 370.57454 g/mol Inhibitor: ABCB1, CYP1A2 (weak), CYP2A6, CYP2C9 (weak), Mechanism: Blocks postsynaptic mesolimbic CYP2C19 (weak), CYP2D6 dopaminergic receptors in brain. Exhibits strong (moderate), CYP2E1 (weak), α-adrenergic-blocking effect and depresses CYP3A4 (weak), KCNH release of hypothalamic and hypophyseal Transporter genes: ABCB1, hormones KCNE1, KCNE2, KCNH2, KCNJ11, Effect: Antipsychotic agent; Dopaminergic KCNQ1 antagonist; Alpha-adrenergic antagonist; H1- Pleiotropic genes: ADRBs, receptor antagonist; Serotonergic antagonist CHRM2, FABP1, HRH1 Name: Trifluoperazine; Trifluperazine; Trifluoroperazine; Trifluoperazina; Triflurin; Triperazine Pathogenic genes: DRD2, IL12B IUPAC Name: 10-[3-(4-methylpiperazin-1- Mechanistic genes: ABCB1, yl)propyl]-2-(trifluoromethyl)-10H- ADRA1A, ADRA1B, CALMs, phenothiazine DRD2, HRH1 Metabolic genes: Molecular Formula: C21H24F3N3S Substrate: CYP1A2 (major), UGT1A4 Molecular Weight: 407.49557 g/mol Inhibitor: CALMs, POR Transporter genes: ABCB1 Mechanism: Blocks postsynaptic mesolimbic dopaminergic receptors in brain. Exhibits α- Pleiotropic genes: IL12B adrenergic-blocking effect and depresses release of hypothalamic and hypophyseal

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Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 27 of 87 Depresses release of hypothalamic and Depresseshypophyseal release hormones. of Believedhypothalamic to depress and hypophysealreticular activating hormones. system, Believed thus affecting to depress basal reticularmetabolism, activating body system,temperature, thus affecting wakefulness, basal metabolism,vasomotor tone, body and temperature, emesis wakefulness, Effect:vasomotor Antipsychotic tone, and emesis agent; Dopaminergic Effect:antagonist; Antipsychotic Antiemesis; Anagent;ticholinergic Dopaminergic effects; antagonist;Sedative effects Antiemesis; Anticholinergic effects; Name:Sedative Perphenazine effects ; Trilafon; Perphenazin; Etaperazine; Perfenazine; Fentazin Pathogenic genes: ADRA2A, Name: Perphenazine; Trilafon; Perphenazin; DRD1, DRD2, HTR2A, HTR2C, Etaperazine;IUPAC Name: Perfenazine; 2-[4-[3-(2-chlorophenothiazin- Fentazin Pathogenic genes: ADRA2A, DRD1RGS4 , DRD2, HTR2A, HTR2C, IUPAC10-yl)propyl]piperazin-1-yl]ethanol Name: 2-[4-[3-(2-chlorophenothiazin- RGS4Mechanistic genes: ADRA1A, Molecular10-yl)propyl]piperazin-1-yl]ethanol Formula: C21H26ClN3OS ADRA2AMechanistic, DRD1 genes:, DRD2 ADRA1A, HTR2A,, HTR2C, RGS4 Molecular Formula: C21H26ClN3OS ADRA2A, DRD1, DRD2, HTR2A, Molecular Weight: 403.96864 g/mol HTR2C,Metabolic RGS4 genes: Substrate: CYP1A2 (major), Mechanism:Molecular Weight: Blocks 403.96864 postsynaptic g/mol mesolimbic Metabolic genes: CYP2C8 Substrate: (major), CYP1A2 CYP2C9 (major), Mechanism:dopaminergic Blocksreceptors postsynaptic in brain. Exhibitsmesolimbic α- CYP2C18 (major), CYP2C19 adrenergic-blocking effect and depresses release CYP2C8 (major), CYP2C9 (major), dopaminergic receptors in brain. Exhibits α- CYP2C18(major), CYP2D6(major), CYP2C19(minor), of hypothalamic and hypophyseal hormones. adrenergic-blocking effect and depresses release (major),CYP3A4/5 (major)CYP2D6 (minor), Binds to the dopamine D1 and D2 receptors and Int. J. Mol. Sci. 2020, 21, 3059 of hypothalamic and hypophyseal hormones. Inhibitor: CYP1A2 (weak), 26 of 82 inhibits their activity CYP3A4/5 (major) Binds to the dopamine D1 and D2 receptors and CYP2D6 Inhibitor: (strong) CYP1A2 (weak), inhibitsEffect: theirAntipsychotic activity agent; Antiemetic; Transporter genes: ABCB1 Dopaminergic antagonist; Antiemesis CYP2D6 (strong) Effect: Antipsychotic Tableagent; 3. Cont.Antiemetic; Transporter genes: ABCB1 Name:Dopaminergic Thioridazine antagonist;; AntiemesisMellaril; Melleril; Pathogenic genes: ADRA2A, Phenothiazines DRD1, DRD2 Name:Thioridazin; Thioridazine Meleril; Sonapax; Mellaril; Melleril; Pathogenic genes: ADRA2A, Drug Properties MechanisticDRD1, DRD2 genes:Pharmacogenetics ADRA1s, IUPACThioridazin; Name: Meleril; 10-[2-(1-methylpiperidin-2- Sonapax ADRA2sMechanistic, DRD1 ,genes: DRD2 ADRA1s, Name: Thioridazine; Mellaril; Melleril; Pathogenic genes: ADRA2A, DRD1, IUPACyl)ethyl]-2-methylsulfanylphenothiazine Name: 10-[2-(1-methylpiperidin-2- Metabolic genes: Thioridazin; Meleril; Sonapax ADRA2sDRD2, DRD1, DRD2 yl)ethyl]-2-methylsulfanylphenothiazine Substrate: CYP1A2 (major), IUPAC Name: 10-[2-(1-methylpiperidin-2- MetabolicMechanistic genes: genes: ADRA1s, Molecular Formula: C21H26N2S2 CYP2C19 (minor), CYP2A6, yl)ethyl]-2-methylsulfanylphenothiazine Substrate:ADRA2s CYP1A2, DRD1, DRD2(major), CYP2D6 (major), CYP2J2 (major), Molecular Formula: C21H26N2S2 CYP2C19Metabolic (minor), genes: CYP2A6, Molecular Formula: C21H26N2S2 CYP3A4 (major) Molecular Weight: 370.57454 g/mol CYP2D6Substrate: (major), CYP2J2CYP1A2 (major),(major), CYP2C19

Molecular Weight: 370.57454 g/mol CYP3A4Inhibitor:(minor), (major) ABCB1, CYP2A6 , CYP2D6CYP1A2(major), Molecular Weight: 370.57454 g/mol (weak), CYP2J2CYP2A6, CYP2C9CYP3A4 (weak), Mechanism:Mechanism: BlocksBlocks postsynaptic postsynaptic mesolimbic mesolimbic Inhibitor: ABCB1,(major), CYP1A2(major) CYP2C19Inhibitor: (weak)ABCB1,, CYP2D6 CYP1A2 dopaminergicdopaminergic receptors receptors in brain. in Exhibits brain. Exhibits strong strong(weak), CYP2A6, CYP2C9 (weak), (weak), Mechanism: Blocks postsynaptic mesolimbic (moderate),CYP2A6, CYP2E1 CYP2C9 (weak),(weak),CYP2C19 α-adrenergic-blockingα-adrenergic-blocking effect e ffectand and depresses depresses CYP2C19 (weak), CYP2D6 dopaminergic receptors in brain. Exhibits strong , CYP2D6 CYP2E1 release of hypothalamic and hypophyseal CYP3A4(weak) (weak), KCNH (moderate), release of hypothalamic and hypophyseal (moderate), CYP2E1CYP3A4 (weak),KCNH α-adrenergic-blockinghormones effect and depresses Transporter(weak), genes: (weak),ABCB1, hormones CYP3A4Transporter (weak), KCNH genes: ABCB1 KCNE1 release of hypothalamic and hypophyseal KCNE1, KCNE2, KCNH2, KCNJ11, , Effect: Antipsychotic agent; Dopaminergic TransporterKCNE2 , KCNH2genes: , KCNJ11ABCB1, KCNQ1, hormonesEffect: Antipsychotic agent; Dopaminergic KCNQ1 antagonist; Alpha-adrenergic antagonist; KCNE1,Pleiotropic KCNE2, KCNH2 genes:, KCNJ11ADRBs,, CHRM2, antagonist; Alpha-adrenergic antagonist; H1- Pleiotropic genes: ADRBs, Effect:H 1Antipsychotic-receptor antagonist; agent; Serotonergic Dopaminergic antagonist FABP1, HRH1 receptor antagonist; Serotonergic antagonist KCNQ1 antagonist; Alpha-adrenergic antagonist; H1- CHRM2, FABP1, HRH1 Name: Trifluoperazine; Trifluperazine; Pleiotropic genes: ADRBs, Name:receptorTrifluoroperazine; antagonist;Trifluoperazine Serotonergic Trifluoperazina;; Trifluperazine; antagonist Triflurin; CHRM2, FABP1, HRH1 Trifluoroperazine;Name:Triperazine Trifluoperazine Trifluoperazina;; Trifluperazine; Triflurin; Triperazine Trifluoroperazine;IUPAC Name: Trifluoperazina;10-[3-(4-methylpiperazin-1- Triflurin; Pathogenic genes: DRD2, IL12B IUPAC Name: 10-[3-(4-methylpiperazin-1- Triperazineyl)propyl]-2-(trifluoromethyl)-10H-phenothiazine PathogenicMechanisticPathogenic genes: genes: DRD2 genes: , IL12BDRD2ABCB1, , IL12B yl)propyl]-2-(trifluoromethyl)-10H- IUPAC Name: 10-[3-(4-methylpiperazin-1- MechanisticADRA1AMechanistic, ADRA1B,genes: genes: CALMs,ABCB1,ABCB1, ADRA1A, phenothiazineMolecular Formula: C21H24F3N3S yl)propyl]-2-(trifluoromethyl)-10H- ADRA1ADRD2, HRH1ADRA1B,, ADRA1B, CALMs, DRD2,CALMs, HRH1 Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEWMolecular Weight: 28 of 87 phenothiazine 407.49557 g/mol MetabolicMetabolic genes: genes: Molecular Formula: C21H24F3N3S DRD2, HRH1 Substrate: CYP1A2 (major), UGT1A4 Mechanism: Blocks postsynaptic mesolimbicMetabolic Substrate: genes: CYP1A2 (major), Molecularhormones. Formula:This agent C21 Halso24F3N 3functionsS as a Inhibitor: CALMs, POR dopaminergic receptors in brain. Exhibits UGT1A4 Substrate: CYP1A2 (major), Molecularcalmodulinα-adrenergic-blocking Weight: inhibitor 407.49557 e ffg/molect and depresses Inhibitor:Transporter CALMs, genes: POR ABCB1 UGT1A4Pleiotropic genes: IL12B MolecularEffect:release Antipsychotic Weight: of hypothalamic 407.49557 agent; g/mol and Dopaminergic hypophyseal Transporter genes: ABCB1 Mechanism: Blocks postsynaptic mesolimbic Inhibitor: CALMs, POR antagonist;hormones. Antiemesis; This agent Cytosolic also functions calcium as a dopaminergic receptors in brain. Exhibits α- PleiotropicTransporter genes: genes: IL12B ABCB1 elevationMechanism:calmodulin Blocks inhibitor postsynaptic mesolimbic dopaminergicadrenergic-blocking receptors effect in brain.and Exhibitsdepresses α- Pleiotropic genes: IL12B Effect: AntipsychoticThioxanthenes agent; Dopaminergic adrenergic-blockingrelease of hypothalamic effect andand hypophyseal depresses Drug antagonist; Antiemesis;Properties Cytosolic Pharmacogenetics releasecalcium of hypothalamic elevation and hypophyseal Name: Thiothixene, ThioxanthenesTiotixene; Cis- Drug Thiothixene; Navane; Thiothixine;Properties Navan Pharmacogenetics IUPACName: Name: Thiothixene (9Z)-N,N-dimethyl-9-[3-(4-, Tiotixene; Cis-Thiothixene; methylpiperazin-1-Navane; Thiothixine; Navan yl)propylidene]thioxanthene-2-sulfonamideIUPAC Name: (9Z)-N,N-dimethyl-9-[3-(4- methylpiperazin-1-yl)propylidene]thioxanthene- Molecular2-sulfonamide Formula: C23H29N3O2S2 Pathogenic genes: ADRA2A, DRD1, PathogenicDRD2, DRD3 genes:, ADRA2ADRD4, , DRD1, Molecular Formula: C H N O S 23 29 3 2 2 HTR2A DRD2, DRD3, DRD4, HTR2A MolecularMolecular Weight: Weight: 443.62526443.62526 g/mol g/mol MechanisticMechanistic genes: genes: ADRA1sADRA1s, , ADRA2s, CHRM1, CHRM2, DRD1, Mechanism: Elicits antipsychotic activity byADRA2s, CHRM1, CHRM2, DRD1, Mechanism: Elicits antipsychotic activity by DRD2, DRD3, DRD4, HRH1, HRH2, postsynaptic blockade of CNS dopamine DRD2, DRD3, DRD4, HRH1, postsynaptic blockade of CNS dopamine HTR1s, HTR2s receptors resulting in inhibition of HRH2, HTR1s, HTR2s Metabolic genes: receptorsdopamine-mediated resulting in inhibition effects. of Also dopamine- has MetabolicSubstrate: genes: CYP1A2 (major) mediatedα-adrenergic effects. blockingAlso activity.has α-adrenergic Antagonistic Substrate:Inhibitor: CYP1A2CYP2D6 (major)(moderate) blockingeffect activity. on dopaminergic Antagonistic (D ,D ,Deffect,D ),on 1 2 3 4 Inhibitor:Transporter CYP2D6 genes: (moderate)KCNE1 , KCNE2, dopaminergichistaminergic (D1, (HD2, ),D sertoninergic3, D4), histaminergic (5-HT , 5-HT ), 1 1 Transporter2 KCNH6 , genes:KCNQ1 , SCN5AKCNE1, (H1), sertoninergicadrenergic (α 1(5-HT- and 1α, 25-HT) and2), muscarinic adrenergic (M 1 and KCNE2, KCNH6, KCNQ1, SCN5A (α1- andM2 ) receptorsα2) and muscarinic (M1 and M2) receptorsEffect: Antipsychotic agent; Dopamine Effect:antagonist; Antipsychotic Antisympathomimetic agent; Dopamine properties; antagonist;Anticholinergic Antisympathomimetic effects; Antidepressant properties; eff ects, AnticholinergicAntiaggressive effects; properties; Antidepressant H1-receptor effects, antagonist; Serotonergic agonist Antiaggressive properties; H1-receptor antagonist; Serotonergic agonist Name: Zuclopenthixol; Zuclopentixol; Clopixol; Zuclopenthixolum; Acuphase; Cisordinol IUPAC Name: 2-[4-[(3Z)-3-(2- chlorothioxanthen-9-ylidene)propyl]piperazin- 1-yl]ethanol

Molecular Formula: C22H25ClN2OS Pathogenic genes: ADRA2A, DRD1, DRD2 Molecular Weight: 400.9647 g/mol Mechanistic genes: ADRA1s, ADRA2s, CHRMs, DRD1, DRD2, Mechanism: It mainly acts by antagonism of D1 HRH1, HTR2s and D2 dopamine receptors. It also has high Metabolic genes: affinity for alpha1-adrenergic and 5-HT2 Substrate: CYP2D6 (major), receptors. It has weaker CYP3A4 (major)

blocking activity, and even lower affinity for muscarinic cholinergic and alpha2-adrenergic receptors Effect: Antipsychotic agent; Dopaminergic antagonist; H1-receptor antagonist; Serotonergic antagonist; Alpha-adrenergic antagonist. Typical Antipsychotics, Miscellaneous Drug Properties Pharmacogenetics

Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 28 of 87

hormones. This agent also functions as a calmodulin inhibitor Effect: Antipsychotic agent; Dopaminergic antagonist; Antiemesis; Cytosolic calcium elevation Thioxanthenes Drug Properties Pharmacogenetics Name: Thiothixene, Tiotixene; Cis- Thiothixene; Navane; Thiothixine; Navan IUPAC Name: (9Z)-N,N-dimethyl-9-[3-(4- methylpiperazin-1- yl)propylidene]thioxanthene-2-sulfonamide

Molecular Formula: C23H29N3O2S2 Pathogenic genes: ADRA2A, DRD1, DRD2, DRD3, DRD4, HTR2A Molecular Weight: 443.62526 g/mol Mechanistic genes: ADRA1s, ADRA2s, CHRM1, CHRM2, DRD1, Mechanism: Elicits antipsychotic activity by DRD2, DRD3, DRD4, HRH1, postsynaptic blockade of CNS dopamine HRH2, HTR1s, HTR2s receptors resulting in inhibition of dopamine- Metabolic genes: mediated effects. Also has α-adrenergic Substrate: CYP1A2 (major) blocking activity. Antagonistic effect on Inhibitor: CYP2D6 (moderate) dopaminergic (D1, D2, D3, D4), histaminergic Transporter genes: KCNE1, (H1), sertoninergic (5-HT1, 5-HT2), adrenergic KCNE2, KCNH6, KCNQ1, SCN5A (α1- and α2) and muscarinic (M1 and M2) receptors Effect: Antipsychotic agent; Dopamine Int. J. Mol. Sci. 2020, 21, 3059 antagonist; Antisympathomimetic properties; 27 of 82 Anticholinergic effects; Antidepressant effects, Antiaggressive properties; H1-receptor antagonist; SerotonergicTable agonist 3. Cont. Name: Zuclopenthixol; Zuclopentixol; Clopixol; Zuclopenthixolum;Thioxanthenes Acuphase; Drug Cisordinol Properties Pharmacogenetics IUPACName: ZuclopenthixolName: ; Zuclopentixol;2-[4-[(3Z)-3-(2- Clopixol; chlorothioxanthen-9-ylidene)propyl]piperazin-Zuclopenthixolum; Acuphase; Cisordinol 1-yl]ethanol IUPAC Name: 2-[4-[(3Z)-3-(2-chlorothioxanthen- 9-ylidene)propyl]piperazin-1-yl]ethanol Molecular Formula: C22H25ClN2OS Pathogenic genes: ADRA2A, Molecular Formula: C H ClN OS Pathogenic genes: ADRA2A, DRD1, 22 25 2 DRD1, DRD2DRD2 MolecularMolecular Weight: Weight: 400.9647400.9647 g/mol g/mol MechanisticMechanistic genes: genes: ADRA1sADRA1s, , ADRA2sADRA2s, CHRMs, CHRMs, DRD1, ,DRD1 DRD2, DRD2, , Mechanism: It mainly acts by antagonism of D1 HRH1, HTR2s Mechanism:and D2 Itdopamine mainly acts receptors. by antagonism It alsohas of D high1 HRH1, HTR2s Metabolic genes: and Da2ffi dopaminenity for alpha1-adrenergic receptors. It also and has 5-HT high2 Metabolic genes: Substrate: CYP2D6 (major), affinityreceptors. for alpha1-adrenergic It has weaker histamine and H5-HT1 receptor2 Substrate: CYP2D6 (major), CYP3A4 (major) receptors.blocking It has activity, weaker and histamine even lower H1 receptor affinity forCYP3A4 (major)

blockingmuscarinic activity, cholinergicand even andlower affinity for alpha2-adrenergic receptors Int. J. Mol. Sci. 2020, 21, x FOR PEERmuscarinic REVIEW cholinergic and alpha2-adrenergic 29 of 87 receptorsEffect: Antipsychotic agent; Dopaminergic Effect:Name:antagonist; AntipsychoticLoxapine H1 -receptor Succinateagent; antagonist; ;Dopaminergic 27833-64-3; Serotonergic Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEWantagonist; Alpha-adrenergic antagonist. 29 of 87 antagonist;Loxapac; Loxapine H 1-receptorsuccinate salt; Cloxazepin;antagonist; SerotonergicDaxolin Typical antagoni Antipsychotics,st; Alpha-adrenergic Miscellaneous Name: Loxapine Succinate; 27833-64-3; Drug antagonist. Properties Pathogenic genes:Pharmacogenetics DRD1, DRD2, Loxapac;IUPAC Name: Loxapine butanedioic succinate acid;8-chloro-6-(4- salt; Cloxazepin; methylpiperazin-1-Name:Typical Loxapine Antipsychotics, Succinate Miscellaneous; 27833-64-3; Loxapac; HTR2A DaxolinLoxapine succinate salt; Cloxazepin; DaxolinMechanistic genes: DRD1, DRD2, Drug yl)benzo[b][1,4]benzoxazepineProperties PathogenicPharmacogenetics genes: DRD1, DRD2, IUPAC Name: butanedioic acid;8-chloro-6-(4- HTR2A Pathogenic genes: DRD1, DRD2, IUPAC Name: butanedioic acid;8-chloro-6-(4-HTR2A methylpiperazin-1-Molecular Formula: C22H24ClN3O5 MetabolicHTR2A genes: methylpiperazin-1-yl)benzo[b][1,4]benzoxazepineMechanistic genes: DRD1, DRD2, yl)benzo[b][1,4]benzoxazepine Mechanistic genes: DRD1, DRD2, Molecular Weight: 445.89606 g/mol Substrate: CYP1A2 (major), Molecular Formula: C22H24ClN3O5 HTR2A HTR2A 22 24 3 5 CYP2D6 (major), CYP3A4 (major), Molecular Formula: C H ClN O Metabolic genes: Mechanism:Molecular Blocks Weight: postsynaptic445.89606 mesolimbic g/mol D1 FMOs, UGT1A4Metabolic genes: Substrate:Substrate: CYP1A2CYP1A2 (major),(major), CYP2D6 andMolecular D2 receptors Weight: 445.89606in brain; g/mol also possesses Pleiotropic genes: HTR2A Mechanism: Blocks postsynaptic mesolimbicCYP2D6 D1 (major), (major),CYP3A4 CYP3A4(major), (major),FMOs , serotoninand 5-HT D receptors2-blocking in activity brain; also possesses Mechanism:2 Blocks postsynaptic mesolimbic D1 FMOs, UGT1A4 Effect:serotonin Antipsychotic 5-HT -blocking agent; activity Dopamine and D2 receptors in2 brain; also possesses Pleiotropic genes: HTR2A antagonist; Serotonergic antagonist Pleiotropic genes: HTR2A serotoninEffect: 5-HTAntipsychotic2-blocking activity agent; Dopamine Name:Effect:antagonist; PimozideAntipsychotic Serotonergic; Orap; Opiran;agent; antagonist Neoperidole;Dopamine Pimozidum; 2062-78-4 antagonist;Name: Serotonergic Pimozide; Orap;antagonist Opiran; Neoperidole; IUPAC Name: 3-[1-[4,4-bis(4- Mechanistic genes: ADRA1A, Name:Pimozidum; Pimozide; 2062-78-4Orap; Opiran; Neoperidole; CACNs,Mechanistic DRD1, DRD2 genes:, KCNH2ADRA1A , fluorophenyl)butyl]piperidin-4-yl]-1H-Pimozidum; 2062-78-4 benzimidazol-2-oneIUPAC Name: 3-[1-[4,4-bis(4-fluorophenyl) MetabolicCACNs genes:, DRD1 , DRD2, KCNH2 IUPACbutyl]piperidin-4-yl]-1H-benzimidazol-2-one Name: 3-[1-[4,4-bis(4- Mechanistic genes: ADRA1A, Substrate:Metabolic CYP1A2 genes: (minor), Molecularfluorophenyl)butyl]piperidin-4-yl]-1H- Formula: C28H29F2N3O CACNs,Substrate: DRD1, DRD2CYP1A2, KCNH2(minor), CYP2D6 Molecular Formula: C28H29F2N3O CYP2D6 (minor), CYP3A4 (major) benzimidazol-2-one Metabolic(minor), genes:CYP3A4 (major) Inhibitor: ABCB1, CYP2C19 MolecularMolecular Weight: Weight: 461.546166461.546166 g/mol g/mol Substrate:Inhibitor: CYP1A2ABCB1 , CYP2C19(minor), (weak), Molecular Formula: C28H29F2N3O (weak), CYP2D6 (strong), CYP2E1 Mechanism: It is a potent centrally-acting CYP2D6CYP2D6 (minor),(strong), CYP3A4CYP2E1 (major) (weak), Mechanism: It is a potent centrally-acting (weak), CYP3A4 (moderate), dopamine-receptor antagonist resulting in its Inhibitor:CYP3A4 ABCB1(moderate),, CYP2C19KCNH2 Moleculardopamine-receptor Weight: 461.546166antagonist g/molresulting in its KCNH2 characteristic neuroleptic effects. Binds and (weak), TransporterCYP2D6 (strong), genes: CYP2E1KCNE1, KCNE2, characteristic neuroleptic effects. Binds and TransporterKCNH2 KCNJ11genes: KCNKs,KCNE1 KCNQ1, Mechanism:inhibits theIt is dopamine a potent D2 receptorcentrally-acting in the CNS. (weak), It CYP3A4, (moderate),, , inhibits the dopamine D2 receptor in the CNS. It KCNE2,SCN5A KCNH2, KCNJ11, KCNKs, dopamine-receptoris antagonist ofantagonist ADRA1A resulting in its KCNH2 is antagonist of ADRA1A KCNQ1Pleiotropic, SCN5A genes: CHRM2 characteristicEffect: Antipsychotic neuroleptic agent;effects. H1-receptor Binds and Transporter genes: KCNE1, Effect: Antipsychotic agent; H1-receptor Pleiotropic genes: CHRM2 inhibitsantagonist; the dopamine Dopaminergic D2 receptor antagonist; in the CNS. It KCNE2, KCNH2, KCNJ11, KCNKs, antagonist; Dopaminergic antagonist; is antagonistAntidyskinesia of ADRA agent;1A Serotonergic antagonistKCNQ1, SCN5A Antidyskinesia agent; Serotonergic antagonist Effect: Antipsychotic agent; H1-receptor Pleiotropic genes: CHRM2 Name:antagonist; Sulpiride Dopaminergic; Sulpyrid; antagonist;Aiglonyl; Dogmatil;Antidyskinesia Dolmatil; agent; Sulpirid Serotonergic antagonist Name:IUPAC SulpirideName: ; N-[(1-ethylpyrrolidin-2-Sulpyrid; Aiglonyl; Dogmatil;yl)methyl]-2-methoxy-5-sulfamoylbenzamide Dolmatil; Sulpirid IUPAC Name: N-[(1-ethylpyrrolidin-2- Molecular Formula: C15H23N3O4S yl)methyl]-2-methoxy-5-sulfamoylbenzamide Pathogenic genes: DRD2, DRD Mechanistic genes: DRD2, DRD3, Molecular Formula:Weight: 341.42582 C15H23N3 Og/mol4S PRLH Pathogenic genes: DRD2, DRD Mechanism: It is a selective antagonist at Metabolic genes: Mechanistic genes: DRD2, DRD3, Molecularpostsynaptic Weight: D2 and 341.42582 D3-receptors. g/mol It appears to Substrate: CYP1A2, CYP2B1, PRLH lack effects on norepinephrine, acetylcholine, CYP3As Mechanism: It is a selective antagonist at Metabolic genes: serotonin, histamine, or GABA receptors. It also Inhibitor: CYP1A2, CYP2B1, postsynaptic D2 and D3-receptors. It appears to Substrate: CYP1A2, CYP2B1, stimulates secretion of prolactin CYP3As lack effects on norepinephrine, acetylcholine, CYP3As Effect: Antipsychotic agent; Dopaminergic serotonin, histamine, or GABA receptors. It also Inhibitor: CYP1A2, CYP2B1, antagonist; Antidepressant effect; Antiemesis. stimulates secretion of prolactin CYP3As Sedation (>600 mg/day); Dopamine reuptake Effect: Antipsychotic agent; Dopaminergic inhibition (<200 mg/day); Antiemesis, antagonist; Antidepressant effect; Antiemesis. Antimigraine effects; Antivertiginous activity; Sedation (>600 mg/day); Dopamine reuptake Prolactin-releasing stimulation inhibition (<200 mg/day); Antiemesis, Over 100 permutatedAntimigraine pathways mayeffects; be An involvedtivertiginous in weight activity; gain regulation in response to neuroleptics, and Genome-wideProlactin-releasing association stimulation studies (GWAS) analysis revealed that Peroxisome proliferatorOver 100 activated permutated receptor pathways gamma may(PPARG) be involved and Proprotein in weight convertase, gain regulation subtilisin/hexin-type in response to 1 neuroleptics,(PCSK1) are involvedand Genome-wide in antipsychotic-induced association studies weight (GWAS) gain [207].analysis Genetic revealed associations that Peroxisome between proliferatorpathogenic genesactivated and receptor genes involved gamma in(PPARG) lipid metabolism and Proprotein cannot convertase, be ruled outsubtilisin/hexin-type as feasible links in 1 (PCSK1)body weight are changesinvolved in in response antipsychotic-induced to psychotropic weighttreatments. gain In [207]. fact, lipoproteinGenetic associations lipase (LPL), between a key pathogenic genes and genes involved in lipid metabolism cannot be ruled out as feasible links in body weight changes in response to psychotropic treatments. In fact, lipoprotein lipase (LPL), a key

Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 29 of 87

Name: Loxapine Succinate; 27833-64-3; Loxapac; Loxapine succinate salt; Cloxazepin; Daxolin IUPAC Name: butanedioic acid;8-chloro-6-(4- Pathogenic genes: DRD1, DRD2, methylpiperazin-1- HTR2A yl)benzo[b][1,4]benzoxazepine Mechanistic genes: DRD1, DRD2, HTR2A Molecular Formula: C22H24ClN3O5 Metabolic genes: Molecular Weight: 445.89606 g/mol Substrate: CYP1A2 (major), CYP2D6 (major), CYP3A4 (major), Mechanism: Blocks postsynaptic mesolimbic D1 FMOs, UGT1A4 and D2 receptors in brain; also possesses Pleiotropic genes: HTR2A serotonin 5-HT2-blocking activity Effect: Antipsychotic agent; Dopamine antagonist; Serotonergic antagonist Name: Pimozide; Orap; Opiran; Neoperidole; Pimozidum; 2062-78-4 IUPAC Name: 3-[1-[4,4-bis(4- Mechanistic genes: ADRA1A, fluorophenyl)butyl]piperidin-4-yl]-1H- CACNs, DRD1, DRD2, KCNH2 benzimidazol-2-one Metabolic genes: Substrate: CYP1A2 (minor), Molecular Formula: C28H29F2N3O CYP2D6 (minor), CYP3A4 (major) Inhibitor: ABCB1, CYP2C19 Molecular Weight: 461.546166 g/mol (weak), CYP2D6 (strong), CYP2E1 Mechanism: It is a potent centrally-acting (weak), CYP3A4 (moderate), dopamine-receptor antagonist resulting in its KCNH2 characteristic neuroleptic effects. Binds and Transporter genes: KCNE1, Int. J. Mol. Sci. 2020, 21, 3059 inhibits the dopamine D2 receptor in the CNS. It KCNE2, KCNH2, KCNJ11, KCNKs, 28 of 82 is antagonist of ADRA1A KCNQ1, SCN5A Effect: Antipsychotic agent; H1-receptor Pleiotropic genes: CHRM2 antagonist; DopaminergicTable 3. Cont.antagonist; Antidyskinesia agent; Serotonergic antagonist Typical Antipsychotics, Miscellaneous Name: Sulpiride; Sulpyrid; Aiglonyl; Drug Properties Pharmacogenetics Dogmatil; Dolmatil; Sulpirid Name: Sulpiride; Sulpyrid; Aiglonyl; Dogmatil; IUPAC Name: N-[(1-ethylpyrrolidin-2- Dolmatil; Sulpirid yl)methyl]-2-methoxy-5-sulfamoylbenzamide IUPAC Name: N-[(1-ethylpyrrolidin- Molecular2-yl)methyl]-2-methoxy-5-sulfamoylbenzamide Formula: C15H23N3O4S Pathogenic genes: DRD2, DRD Molecular Formula: C15H23N3O4S Mechanistic genes: DRD2, DRD3, MolecularMolecular Weight: Weight: 341.42582341.42582 g/mol g/mol Pathogenic genes: DRD2, DRD PRLH Mechanistic genes: DRD2, DRD3, Mechanism:Mechanism: It is Ita is selective a selective antagonist antagonist at MetabolicPRLH genes: postsynapticpostsynaptic D2 and D D2 and3-receptors. D3-receptors. It appears It appears to toSubstrate:Metabolic CYP1A2 genes:, CYP2B1, lack effectslack e ffonects norepinephrine, on norepinephrine, acetylcholine, acetylcholine, CYP3AsSubstrate: CYP1A2, CYP2B1, CYP3As serotonin, histamine, or GABA receptors. It also serotonin, histamine, or GABA receptors. It also Inhibitor:Inhibitor: CYP1A2,CYP1A2, CYP2B1, CYP2B1, CYP3As stimulates secretion of prolactin stimulates secretion of prolactin CYP3As

EffectE: ffAntipsychoticect: Antipsychotic agent; agent; Dopaminergic Dopaminergic antagonist;antagonist; Antidepressant Antidepressant effect; e ffAntiemesis.ect; Antiemesis. Sedation (>600 mg/day); Dopamine reuptake Sedation (>600 mg/day); Dopamine reuptake inhibition (<200 mg/day); Antiemesis, inhibition (<200 mg/day); Antiemesis, Antimigraine effects; Antivertiginous activity; AntimigraineProlactin-releasing effects; An stimulationtivertiginous activity; Prolactin-releasing stimulation Over 100 permutated pathways may be involved in weight gain regulation in response to neuroleptics,Over 100 permutatedand Genome-wide pathways association may studies be involved (GWAS) inanalysis weight revealed gain regulationthat Peroxisome in response to neuroleptics,proliferator activated and Genome-wide receptor gamma association (PPARG) and studies Proprotein (GWAS) convertase, analysis subtilisin/hexin-type revealed that 1 Peroxisome proliferator(PCSK1) are activated involved receptorin antipsychotic-induced gamma (PPARG) weight and gain Proprotein [207]. Genetic convertase, associations subtilisin between /hexin-type pathogenic genes and genes involved in lipid metabolism cannot be ruled out as feasible links in 1 (PCSK1) are involved in antipsychotic-induced weight gain [207]. Genetic associations between body weight changes in response to psychotropic treatments. In fact, lipoprotein lipase (LPL), a key pathogenic genes and genes involved in lipid metabolism cannot be ruled out as feasible links in body weight changes in response to psychotropic treatments. In fact, lipoprotein lipase (LPL), a key enzyme in triglyceride hydrolysis, is expressed in brain regions which are structural substrates of higher activities of the CNS (learning, memory, behavior, cognition), and SNPs in the LPL gene locus (8p22) (rs253 C allele) have been associated with SCZ [208]. Stimulation of the serotonin (5-HT)1A receptor (HTR1A) contributes to the mechanism of action of clozapine and lurasidone. rs358532 and rs6449693, tag SNPs for rs6295, may predict response to lurasidone [209]. The CYP1A2*1F/*1F genotype has been associated with clozapine-induced generalized tonic-clonic seizures in Brazilian patients [210]. The study of 6 SNPs in the tryptophan hydroxylase (TPH) gene (rs4570625, rs11178997, rs11178998, rs7954758, rs7305115, and rs4290270) revealed association of the rs10784941 and rs4565946 markers and the rs4570625-rs4565946 haplotype with SCZ. TPH2 variants and the rs4570625-rs4565946 G-C haplotype do not affect response to antipsychotic drugs [211]. Antipsychotic-related ADRs can be substantially reduced with the incorporation of PGx procedures into clinical practice [27,43,103].

5.2. Depressive Disorders Depression is the second most common psychiatric symptom in AD, after apathy. The prevalence of depression in AD varies from 5% to >40% in different studies. Patients with severe AD show a higher prevalence of depression [212,213] and depressive symptoms are associated with a faster rate of memory decline [214]. There is evidence that early life depression can be a risk factor for later life dementia and that later life depression may represent a prodrome to dementia [215], with sex-specific differences [216], especially in cases with cerebral amyloidopathy (>50%) [217]. Furthermore, depressed patients with mild cognitive impairment (MCI) have worse cognitive performance and greater loss of gray-matter volume in the cerebellum and parahippocampal gyrus [218]. Low psychomotor speed has also been associated with an increased risk of developing dementia and depressive symptoms [219]. Cardiovascular risk factors may contribute to depression in patients with MCI [220]. Late-life depression (LLD) affects 15% of the elderly population. CYP2D6, SLC6A4 5-HTTLPR, and Int. J. Mol. Sci. 2020, 21, 3059 29 of 82 brain-derived neurotrophic factor (BDNF) variants influence the PGx of this condition, as recently reported by the Clinical Pharmacogenetics Implementation Consortium [221]. Some studies indicate that the APOE genotype may influence the incidence of BDs and treatment in dementia [111,117], while others did not find association of APOE-4 with depression, anxiety, apathy, agitation, irritability, or sleep disturbances in cognitively impaired subjects [222]. Genome-wide association studies (GWAS) identified 31 genes located in 19 risk loci for major depressive disorder (MDD). Common and rare variants of L3MBTL2 are associated with AD. mRNA expression levels of SORCS3 and OAT are differentially expressed in AD brain tissues, and 13 MDD risk genes may interact with core AD genes such as HACE1, NEGR1, and SLC6A15 [223]. The treatment of depression in dementia can be pharmacological, with antidepressants, especially selective serotonin reuptake inhibitors as a first choice, or nonpharmacological (emotion-oriented therapies, behavioral, and cognitive-behavioral modification programs; structured activity programs; sensory-stimulation therapies; multisensory approaches; music therapy; and mindfulness-based interventions) [224]. Meta-analyses of double-blind randomized controlled trials comparing antidepressants versus placebo for depression in AD revealed inefficacy in most cases with different drugs (sertraline, , , fluoxetine, and clomipramine) [225]. The mechanisms underlying depression in dementia still remain unclarified [226]. About 60% of depressive patients receive an inappropriate medication according to their pharmacogenetic background [66,227,228], and community psychiatrists and pharmacists are more accurate in their psychotropic prescriptions when they know the CYP profile of their patients [228–230]. Antidepressants are associated with the PGx activity of over 600 genes. The different pharmacological categories of antidepressants (nonselective monoamine reuptake inhibitors, selective serotonin reuptake inhibitors, nonselective monoamine oxidase (MAO) inhibitors, and other chemical modalities) are substrates, inhibitors, or inducers of 40, 22, and 9 enzyme/protein gene products, respectively, and are transported by 13 different protein transporters (Figures1–3 and Table4). Enzymes of the Cytochrome P450 (CYP) family are involved in 100% of drugs approved for the treatment of depression. Antidepressants are major substrates of CYP2D6 (86%), CYP3A4 (72%), CYP2C19 (60%), CYP1A2 (57%), CYP2C9 (34%), UGT1A4 (29%), and UGT1A3 (25%); inhibitors of CYP2D6 (69%), CYP3A4 (55%), CYP1A2 (45%), CYP2C19 (45%), CYP2C9 (34%), SLC6A4 (32%), MAOA (29%), MAOB (29%), and ABCB1 (25%); and inducers of CYP3A4 (5%), CYP1A2 (5%), CYP2B6 (5%), CYP2C9 (3%), CYP2C19 (3%), CYP2D6 (3%), and ABCB1 (3%). Major transporters of antidepressants are SLC6A4 (62%), ABCB1 (55%), and SLC6A2 (40%) (Table4). Sertraline is associated with 31 pharmagenes, Milnacipran is associated with 31, Mirtazapine is associated with 30, is associated with 28, and Imipramine is associated with 28 [55,103]. The PGx of antidepressants has become quite well known over the past 20 years, with no relevant breakthroughs in the past decade [55,66]. CYP2C19 and CYP2D6 variants affect the occurrence of ADRs in patients treated with selective serotonin reuptake inhibitors (SSRIs) (citalopram, escitalopram, sertraline, fluvoxamine, fluoxetine, and paroxetine), including anxiety, nightmares, and panic attacks associated with CYP2D6 and electrocardiogram (ECG)-prolonged QT associated with CYP2C19 [231]. Prolonged QTc interval is prevalent in patients with moderate-severe dementia, with behavioral symptoms, with global and temporal atrophy, and with leukoaraiosis [232]. A pharmacogenetic risk score has been proposed with top-scoring SNPs (rs12248560, rs878567, and rs17710780). The HTR1A rs878567 and CYP2C19 rs12248560 variants showed association with depression severity [233]. ACE variants influence mood in AD [111]. The coadministration of ACE inhibitors and statins with antidepressants may affect therapeutic outcomes [234]. Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 31 of 87 Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 31 of 87 products, respectively, and are transported by 13 different protein transporters (Figures 1–3 and products,Table 4). Enzymes respectively, of the and Cytochrome are transported P450 (CYP) by 13 family different are involved protein transportersin 100% of drugs (Figures approved 1–3 and for Tablethe treatment 4). Enzymes of depression. of the Cytochrome Antidepressants P450 (CYP) are mafamilyjor substrates are involved of CYP2D6 in 100% of(86%), drugs CYP3A4 approved (72%), for theCYP2C19 treatment (60%), of depression. CYP1A2 (57%), Antidepressants CYP2C9 (34%), are maUGT1A4jor substrates (29%), ofand CYP2D6 UGT1A3 (86%), (25%); CYP3A4 inhibitors (72%), of CYP2C19CYP2D6 (69%),(60%), CYP3A4CYP1A2 (55%),(57%), CYP2C9CYP1A2 (34%),(45%), UGT1A4CYP2C19 (29%), (45%), and CYP2C9 UGT1A3 (34%), (25%); SLC6A4 inhibitors (32%), of CYP2D6MAOA (29%),(69%), MAOBCYP3A4 (29%), (55%), and CYP1A2 ABCB1 (45%), (25%); CYP2C19 and inducers (45%), of CYP2C9 CYP3A4 (34%), (5%), SLC6A4CYP1A2 (32%), (5%), MAOACYP2B6 (29%),(5%), CYP2C9 MAOB (3%),(29%), CYP2C19 and ABCB1 (3%), (25%); CYP2D6 and (3%), inducers and ABCB1 of CYP3A4 (3%). Major(5%), transportersCYP1A2 (5%), of CYP2B6antidepressants (5%), CYP2C9 are SLC6A4 (3%), CYP2C19 (62%), ABCB1 (3%), CYP2D6 (55%), (3%),and SLC6A2and ABCB1 (40%) (3%). (Table Major 4). transporters Sertraline ofis antidepressantsassociated with 31are pharmagenes, SLC6A4 (62%), Milnacipran ABCB1 (55%),is associated and SLC6A2 with 31, (40%)Mirtazapine (Table is 4). associated Sertraline with is associated30, Fluoxetine with is 31 associated pharmagenes, with Milnacipran28, and Imipra is associatedmine is associated with 31, Mirtazapinewith 28 [55,103]. is associated The PGx with of 30,antidepressants Fluoxetine is has associated become quitewith well28, andknown Imipra overmine the past is associated 20 years, with with no 28 relevant [55,103]. breakthroughs The PGx of antidepressantsin the past decade has [55,66]. become quite well known over the past 20 years, with no relevant breakthroughs Int. J.in Mol. the Sci.past2020 decade, 21, 3059 [55,66]. 30 of 82 Table 4. Pharmacological profile and pharmacogenetics of selected antidepressants.

Table 4. PharmacologicalMonoamine profile and Oxidase pharmacoge Inhibitorsnetics (MAOIs) of selected antidepressants. Table 4. Pharmacological profile and pharmacogenetics of selected antidepressants. Drug MonoamineProperties Oxidase Inhibitors (MAOIs) Pharmacogenetics Drug Name:Monoamine MoclobemideProperties Oxidase ; InhibitorsAurorix; (MAOIs) Pharmacogenetics Drug Name:Moclamine; Moclobemide Manerix;Properties Moclobemidum;; Aurorix; Pharmacogenetics Moclamine;MoclobemidName: Manerix; Moclobemide Moclobemidum;; Aurorix; MoclobemidIUPACMoclamine; Name: Manerix; 4-chloro-N-[2- Moclobemidum; IUPAC(morpholin-4-yl)ethyl]benzamideMoclobemid Name: 4-chloro-N-[2-

(morpholin-4-yl)ethyl]benzamideMolecularIUPAC Formula: Name :C13H17ClN2O 2 4-chloro-N-[2-(morpholin-4- Pathogenic genes: MAOA Molecular Formula: C13H17ClN2O2 Mechanistic genes: MAOA Molecularyl)ethyl]benzamide Weight: 268.73928 g/mol PathogenicPathogenic genes: MAOA genes: MAOA MetabolicMechanistic genes: genes: MAOA Molecular Formula: C H ClN O Mechanistic genes: MAOA Molecular Weight: 268.7392813 g/mol17 2 2 Metabolic genes: Category: Monoamine oxidase A Metabolic Substrate genes:: CYP2C19 (major), CYP2D6 Molecular Weight: 268.73928 g/mol Substrate: CYP2C19 (major), Category:inhibitors Monoamine oxidase A (major), Substrate CYP2E1: CYP2C19 (major), CYP2D6 MechanismCategory:: InvolvesMonoamine the oxidaseselective, A Inhibitor:CYP2D6 CYP1A2(major), (weak) CYP2E1, CYP2C19 inhibitors (major), Inhibitor:CYP2E1 CYP1A2 (weak), reversibleinhibitors inhibition of MAO-A. This (weak), CYP2D6 (weak), MAOA (strong), Mechanism: Involves the selective, Inhibitor:CYP2C19 CYP1A2(weak), (weak)CYP2D6, CYP2C19(weak), inhibition leads to a decrease in the MAOB (moderate) reversibleMechanism: inhibitionInvolves of MAO-A. the selective, This (weak), CYP2D6MAOA (strong), (weak), MAOBMAOA (strong), inhibitionmetabolismreversible leads and inhibitionto a destructiondecrease of MAO-A. in theof This MAOB (moderate)(moderate)

metabolismmonoaminesinhibition inand leadsthe . todestruction a decrease inof the metabolism and destruction of monoaminesThis results inin thean neurotransmitters.increase in the monoamines in the neurotransmitters. Thismonoamines. results in an increase in the Effect:This resultsAntidepressant in an increase inagent; the monoamines.monoamines. Effect:Monoamine AntidepressantOxidase inhibition. agent; Effect: Antidepressant agent; Monoamine MonoamineName: Phenelzine Oxidase sulfate inhibition.; Estinerval; Oxidase inhibition. Name:Nardelzine; Phenelzine sulfate; Estinerval;Kalgan; Nardelzine;Phenethylhydrazin;Name: Phenelzine Phenelzine sulfate Kalgan;;sulfate Estinerval; Phenethylhydrazin;salt Nardelzine; Kalgan; Phenelzine Phenethylhydrazin; sulfate Phenelzine sulfate salt saltIUPAC Name: (2- IUPACphenylethyl)hydrazineIUPAC NameName:: (2-phenylethyl)hydrazine (2- PathogenicPathogenic genes: MAOA genes: MAOA phenylethyl)hydrazineMolecularMolecular Formula: Formula: C8 H14NC2OH4S N O S 8 14 2 4 MechanisticMechanistic genes: MAOA, genes: MAOA,MAOB PathogenicMAOB genes: MAOA MolecularMolecular Formula: Weight: C8H14234.27276N2O4S g/mol Metabolic genes: Molecular Weight: 234.27276 g/mol MechanisticMetabolic genes: genes: MAOA, MAOB Substrate: COMT, MAOA, MAOB Category: Monoamine oxidase inhibitors,MetabolicSubstrate: genes: COMT, MAOA, MAOB MolecularCategory: Weight:Monoamine 234.27276 g/moloxidase non-selective SubstrateInhibitor:Inhibitor:: COMT,CYP2C8CYP2C8 MAOA, (moderate), MAOB(moderate), inhibitors, non-selective Category:Mechanism: MonoamineIrreversible, oxidase non-selective CYP2D6, Inhibitor:CYP2D6, CYP3A4 CYP2C8 CYP3A4 (moderate), (moderate),(moderate), MAOA, Mechanism: Irreversible, non-selective inhibitors,inhibition non-selective of MAO. It causes an increaseCYP2D6,MAOB MAOA, CYP3A4 MAOB (moderate), MAOA, inhibition of MAO. It causes an increase Mechanism:in the levelsIrreversible, of serotonin, non-selective norepinephrine, MAOB in the levels of serotonin, Int. J. Mol. Sci. 2020, 21, x FOR PEERinhibition REVIEWand of dopamine MAO. It incauses the neuron an increase 32 of 87 norepinephrine, and dopamine in the in theEff ect: levelsAntidepressant of activity;serotonin, neuron norepinephrine,Name:Monoamine Rasagiline and mesylate Oxidase dopamine inhibition; 161735-79- in the Effect: Antidepressant activity; neuron1; Azilect;Name: Rasagiline Rasagiline mesilate; mesylate ;TVP- 161735-79-1; Monoamine Oxidase inhibition Effect:1012; Agilect Azilect;Antidepressant Rasagiline mesilate; activity; TVP-1012; MonoamineIUPACAgilect Name: Oxidase (1R)-N-(prop-2-yn-1-yl)- inhibition

2,3-dihydro-1H-inden-1-amineIUPAC Name: (1R)-N-(prop-2-yn-1-yl)-2, 3-dihydro-1H-inden-1-amine Pathogenic genes: PARK2 Molecular Formula: C13H17NO3S PathogenicMechanistic genes: PARK2 genes: BCL2, Molecular Formula: C13H17NO3S MechanisticBCL2L1, genes MAOB: BCL2, BCL2L1, MAOB Molecular Weight: 267.34398 g/mol Molecular Weight: 267.34398 g/mol MetabolicMetabolic genes: genes: Substrate: CYP1A2 (major), CYP2D6, Category: Monoamine oxidase B Substrate: CYP1A2 (major), Category: Monoamine oxidase B UGT1A1CYP2D6, UGT1A3, UGT1A1, UGT1A4, UGT1A3, UGT1A6, , inhibitorsinhibitors UGT1A7UGT1A4, UGT1A9, UGT1A6, UGT1A10, UGT1A7, UGT2B7, , Mechanism: Potent, irreversible, Mechanism: Potent, irreversible, selectiveUGT2B15UGT1A9 , UGT1A10, UGT2B7, selective inhibitor of brain monoamine inhibitor of brain monoamine oxidase Inhibitor:UGT2B15 MAOB oxidase(MAO) (MAO) type type B, whichB, which plays plays a major a role in Inhibitor: MAOB major rolecatabolism in catabolism of dopamine. of dopamine. Effect: Antidepressant activity; Effect: Antidepressant activity; MonoamineMonoamine Oxidase Oxidase inhibition;inhibition; NeuroprotectiveNeuroprotective agent; Antiparkinsonianagent; Antiparkinsonianagent. agent. Name: Selegiline; Selegiline hydrochloride; L-Deprenyl hydrochloride; 14611-52-0; Eldepryl; Selegiline Hcl; Zelapar IUPAC Name: methyl(1-phenylpropan- 2-yl)(prop-2-yn-1-yl)amine

Molecular Formula: C13H18ClN Pathogenic genes: MAOA, PARK2 Mechanistic genes: MAOA, MAOB Molecular Weight: 223.74172 g/mol Metabolic genes: Substrate: CYP1A2 (minor), CYP2A6 Category: Monoamine oxidase B (minor), CYP2B6 (major), CYP2C8 inhibitors (minor), CYP2C19 (major), CYP2D6 (minor), CYP2E1 (minor), CYP3A4 Mechanism: Selective, irreversible (minor), MAOA inhibition of MAO-B. It binds to MAO-B Inhibitor: CYP1A2 (weak), CYP2A6 within the nigrostriatal pathways in the (weak), CYP2C9 (weak), CYP2C19 (weak), central nervous system, thus blocking CYP2D6 (weak), CYP2E1 (weak), CYP3A4 microsomal metabolism of dopamine (weak), MAOB (strong), MAOA and enhancing the dopaminergic Transporter genes: SCNA activity in the substantia nigra. It may also increase dopaminergic activity through mechanisms other than inhibition of MAO-B. At higher doses, it can also inhibit MAO-A. Effect: Antidepressant activity; Monoamine Oxidase inhibition Neuroprotective agent; Antiparkinsonian agent. Name: Tranylcypromine sulphate; Pathogenic genes: MAOA , NTRK2 , Tylciprine; Phenylcyclopromine sulfate; SLC6A4 Dl-Tranylcypromine sulfate; EINECS Mechanistic genes: MAOA, MAOB 236-807-1; 1-Amino-2- Metabolic genes: phenylcyclopropane sulfate Substrate: CYP2A6 (major) IUPAC Name: (1R)-2- Inhibitor: CYP1A2 (moderate), CYP2A6 phenylcyclopropan-1-amine (strong), CYP2C8 (weak), CYP2C9 (weak),

Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 32 of 87

Name: Rasagiline mesylate; 161735-79- 1; Azilect; Rasagiline mesilate; TVP- 1012; Agilect IUPAC Name: (1R)-N-(prop-2-yn-1-yl)- 2,3-dihydro-1H-inden-1-amine

Molecular Formula: C13H17NO3S Pathogenic genes: PARK2 Mechanistic genes: BCL2, BCL2L1, MAOB Molecular Weight: 267.34398 g/mol Metabolic genes: Substrate: CYP1A2 (major), CYP2D6, Category: Monoamine oxidase B UGT1A1, UGT1A3, UGT1A4, UGT1A6, inhibitors UGT1A7, UGT1A9, UGT1A10, UGT2B7, Mechanism: Potent, irreversible, UGT2B15 selective inhibitor of brain monoamine Inhibitor: MAOB oxidase (MAO) type B, which plays a major role in catabolism of dopamine. Effect: Antidepressant activity; Int. J. Mol. Sci. 2020, 21, 3059 Monoamine Oxidase inhibition; 31 of 82 Neuroprotective agent; Antiparkinsonian agent. Name: Selegiline;Table 4. Cont.Selegiline hydrochloride;Monoamine Oxidase InhibitorsL-Deprenyl (MAOIs) Drug hydrochloride; 14611-52-0;Properties Eldepryl; Pharmacogenetics SelegilineName: Hcl; Selegiline Zelapar ; Selegiline IUPAChydrochloride; Name: methyl(1-phenylpropan- L-Deprenyl hydrochloride; 2-yl)(prop-2-yn-1-yl)amine14611-52-0; Eldepryl; Selegiline Hcl; Zelapar IUPAC Name: Molecular Formula: C13H18ClN Pathogenic genes: MAOA, PARK2 methyl(1-phenylpropan-2-yl) Pathogenic genes: MAOA, PARK2 (prop-2-yn-1-yl)amine Mechanistic genes: MAOA, MechanisticMAOB genes: MAOA, MAOB MolecularMolecular Weight: Formula: 223.74172C13 g/molH18ClN MetabolicMetabolic genes: genes: Molecular Weight: 223.74172 g/mol SubstrateSubstrate:: CYP1A2CYP1A2 (minor),(minor), CYP2A6 Category: Monoamine oxidase B (minor),CYP2A6 CYP2B6(minor), (major),CYP2B6 CYP2C8(major), Category: Monoamine oxidase B (minor),CYP2C8 CYP2C19(minor), (major),CYP2C19 CYP2D6(major), inhibitorsinhibitors (minor),CYP2D6 CYP2E1(minor), (minor),CYP2E1 CYP3A4(minor), Mechanism: Selective, irreversible Mechanism: Selective, irreversible (minor),CYP3A4 MAOA (minor), MAOA inhibition of MAO-B. It binds to MAO-B inhibition of MAO-B. It binds to MAO-B Inhibitor:Inhibitor: CYP1A2CYP1A2 (weak),(weak), CYP2A6 within withinthe nigrostriatal the nigrostriatal pathways pathways in the in the CYP2A6 (weak), CYP2C9 (weak), (weak), CYP2C9 (weak), CYP2C19 (weak), centralcentral nervous nervous system, system, thus thusblocking blocking CYP2C19 (weak), CYP2D6 (weak), CYP2D6 (weak), CYP2E1 (weak), CYP3A4 microsomalmicrosomal metabolism metabolism of dopamine of dopamine and CYP2E1 (weak), CYP3A4 (weak), (weak), MAOB (strong), MAOA and enhancing thethe dopaminergic dopaminergic activity in MAOB (strong), MAOA Transporter genes: SCNA activitythe in substantiathe substantia nigra. nigra. It may It alsomay increase Transporter genes: SCNA dopaminergic activity through also increase dopaminergic activity mechanisms other than inhibition of through mechanisms other than MAO-B. At higher doses, it can also inhibitioninhibit of MAO-B. MAO-A. At higher doses, it can also inhibit MAO-A. Effect: Antidepressant activity; Effect: Antidepressant activity; Monoamine Oxidase inhibition MonoamineNeuroprotective Oxidase agent; inhibition NeuroprotectiveAntiparkinsonian agent. agent; Int. J. Mol. Sci. 2020, 21, x FOR PEERAntiparkinsonian REVIEW agent. 33 of 87 Name: Tranylcypromine sulphate; Name: Tranylcypromine sulphate; Tylciprine; Phenylcyclopromine sulfate;Pathogenic genes: MAOA , NTRK2 , Tylciprine; Phenylcyclopromine sulfate; CYP2C19 (moderate), CYP2D6 MolecularDl-Tranylcypromine Formula: C18H24N sulfate;2O4S EINECSSLC6A4 (moderate),Pathogenic CYP2E1 genes: (weak),MAOA, CYP3A4 Dl-Tranylcypromine236-807-1; sulfate; EINECS Mechanistic genes: MAOA, MAOB (weak), MAOA,NTRK2, MAOB SLC6A4 236-807-1;1-Amino-2-phenylcyclopropane 1-Amino-2- sulfateMetabolic genes: Molecular Weight: 364.45916 g/mol TransporterMechanistic genes: SLC6A4 genes: MAOA, phenylcyclopropane sulfate Substrate: CYP2A6 (major) IUPAC Name: PleiotropicMAOB genes: FOS, NTRK2 Category:IUPAC(1R)-2-phenylcyclopropan-1-amine MonoamineName: oxidase(1R)-2- Inhibitor:Metabolic CYP1A2 genes: (moderate), CYP2A6 phenylcyclopropan-1-amine (strong), CYP2C8 (weak), CYP2C9 (weak), inhibitors,Molecular non-selective Formula: C18H24N2O4S Substrate: CYP2A6 (major) Mechanism: It increases endogenous Molecular Weight: 364.45916 g/mol Inhibitor: CYP1A2 (moderate), concentrations of epinephrine, Category: Monoamine oxidase inhibitors, CYP2A6 (strong), CYP2C8 (weak), norepinephrine, dopamine, serotonin non-selective CYP2C9 (weak), CYP2C19 through inhibition of MAO responsible (moderate), CYP2D6 (moderate), for Mechanism:breakdownIt increasesof endogenousthese CYP2E1 (weak), CYP3A4 (weak),

neurotransmittersconcentrations of epinephrine, MAOA, MAOB norepinephrine, dopamine, serotonin Effect: Monoamine Oxidase inhibition; Transporter genes: SLC6A4 through inhibition of MAO responsible Pleiotropic genes: FOS, NTRK2 Antidepressantfor breakdown activity; of these Anti-anxiety neurotransmitters activity Effect: Monoamine Oxidase inhibition; Tricyclics (TCA) and other Norepinephrinereuptake inhibitors Antidepressant activity; Drug Anti-anxietyProperties activity Pharmacogenetics Name: Hydrochloride; Annoyltin; Amitriptyline HCl; 549-18-8; Tryptizol; Domical Pathogenic genes: ABCB1, GNB3, HTRs, IUPAC Name: dimethyl(3- NTRK2, SLC6A4, TNF {tricyclo[9.4.0.0³,⁸]pentadeca- Mechanistic genes: ADRA1A, HTRs, 1(15),3,5,7,11,13-hexaen-2- NTRK1, NTRK2 ylidene}propyl)amine Metabolic genes: Substrate: ABCB1, CYP1A2 (minor), Molecular Formula: C20H24ClN CYP2B6 (minor), CYP2C9 (minor), CYP2C19 (minor), CYP2D6 (major), Molecular Weight: 313.86426 g/mol CYP3A4/5 (major), GSTP1, UGT1A3, UGT1A4, UGT2B10 Category: Tricyclics Inhibitor: ABCB1, ABCC2, ABCG2, CYP1A2 (moderate), CYP2C9 (moderate), Mechanism: Increases synaptic CYP2C19 (moderate), CYP2D6 (moderate), concentration of serotonin and/or CYP2E1 (weak norepinephrine in the central nervous Transporter genes: ABCB1, ABCC2, system by inhibiting their reuptake in ABCG2, KCNE2, KCNH2, KCNQ1, SCN5A, the presynaptic neuronal membrane SLC6A4 Effect: Adrenergic Uptake inhibition; Pleiotropic genes: FABP1, GNAS, GNB3, Antimigraine activity; Analgesic NTRK1, TNF (nonnarcotic) activity; Antidepressant action Name: ; Asendin; Demolox; 14028-44-5; Asendis; Moxadi IUPAC Name: 13-chloro-10-(piperazin- 1-yl)-2-oxa-9- azatricyclo[9.4.0.0³,⁸]pentadeca- Pathogenic genes: GNB3, SLC6A4 1(11),3,5,7,9,12,14-heptaene Mechanistic genes: ADRA1A, ADRA2A, CHRMs, DRD1, DRD2, GABRs, GABBRs, Molecular Formula: C17H16ClN3O HTRs Metabolic genes: Molecular Weight: 313.78144 g/mol Substrate: CYP2D6 (major) Transporter genes: SLC6A2, SLC6A4 Pleiotropic genes: DRD2, GNAS, GNB3 Category: Tricyclics Mechanism: Reduces reuptake of serotonin and norepinephrine. The metabolite, 7-OH-amoxapine, has

Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 33 of 87 Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 33 of 87

CYP2C19 (moderate), CYP2D6 CYP2C19 (moderate), CYP2D6 Molecular Formula: C18H24N2O4S (moderate), CYP2E1 (weak), CYP3A4 Molecular Formula: C18H24N2O4S (moderate), CYP2E1 (weak), CYP3A4 (weak), MAOA, MAOB (weak), MAOA, MAOB Molecular Weight: 364.45916 g/mol Transporter genes: SLC6A4 Molecular Weight: 364.45916 g/mol Transporter genes: SLC6A4 Pleiotropic genes: FOS, NTRK2 Category: Monoamine oxidase Pleiotropic genes: FOS, NTRK2 Category: Monoamine oxidase inhibitors, non-selective inhibitors, non-selective Mechanism: It increases endogenous Mechanism: It increases endogenous concentrations of epinephrine, concentrations of epinephrine, norepinephrine, dopamine, serotonin norepinephrine, dopamine, serotonin through inhibition of MAO responsible through inhibition of MAO responsible for breakdown of these for breakdown of these neurotransmitters neurotransmitters Int. J. Mol. Sci. 2020, 21, 3059 Effect: Monoamine Oxidase inhibition; 32 of 82 Effect: Monoamine Oxidase inhibition; Antidepressant activity; Anti-anxiety Antidepressant activity; Anti-anxiety activity activity Tricyclics (TCA) and otheTabler Nor 4.epinephrinereuptakeCont. inhibitors Tricyclics (TCA) and other Norepinephrinereuptake inhibitors Drug Properties Pharmacogenetics Drug Tricyclics (TCA) andProperties other Norepinephrinereuptake inhibitorsPharmacogenetics Name: Amitriptyline Hydrochloride; Drug Name: AmitriptylineProperties Hydrochloride; Pharmacogenetics Annoyltin; Amitriptyline HCl; 549-18-8; Annoyltin; Amitriptyline HCl; 549-18-8; Tryptizol;Name: Domical Amitriptyline HydrochloridePathogenic; genes: ABCB1, GNB3, HTRs, Tryptizol;Annoyltin; Domical Amitriptyline HCl; 549-18-8;PathogenicPathogenic genes: ABCB1 genes:, ABCB1GNB3,, GNB3HTRs,, IUPAC Name: dimethyl(3- NTRK2, SLC6A4, TNF Tryptizol; Domical NTRK2, HTRsSLC6A4, NTRK2, TNF , SLC6A4, TNF IUPAC Name: dimethyl(3- Mechanistic genes: ADRA1A, HTRs, {tricyclo[9.4.0.0³,⁸]pentadeca- Mechanistic genes: ADRA1A, {tricyclo[9.4.0.0³,IUPAC Name⁸]pentadeca-: dimethyl(3- Mechanistic genes: ADRA1A, HTRs, 1(15),3,5,7,11,13-hexaen-2- NTRK1, HTRsNTRK2, NTRK1 , NTRK2 1(15),3,5,7,11,13-hexaen-2-{tricyclo[9.4.0.03,8]pentadeca-1(15),3,5,NTRK1, NTRK2 ylidene}propyl)amine MetabolicMetabolic genes: genes: ylidene}propyl)amine7,11,13-hexaen-2-ylidene}propyl)amine Metabolic genes: Substrate:Substrate: ABCB1ABCB1, CYP1A2, CYP1A2 (minor), Substrate: ABCB1, CYP1A2 (minor), MolecularMolecular Formula: Formula: C20H24ClNC H ClN CYP2B6 (minor),(minor),CYP2B6 CYP2C9(minor), (minor),CYP2C9 Molecular Formula: C20H24ClN20 24 CYP2B6 (minor), CYP2C9 (minor), CYP2C19(minor), (minor),CYP2C19 CYP2D6(minor), (major), Molecular Weight: 313.86426 g/mol CYP2C19 (minor), CYP2D6 (major), Molecular Weight: 313.86426 g/mol CYP3A4/5CYP2D6 (major),(major), GSTP1,CYP3A4 UGT1A3/5 , MolecularCategory: Weight:Tricyclics 313.86426 g/mol CYP3A4/5 (major), GSTP1, UGT1A3, UGT1A4(major),, UGT2B10GSTP1, UGT1A3, UGT1A4UGT1A4, UGT2B10, UGT2B10 Mechanism: Increases synaptic Inhibitor: ABCB1, ABCC2, ABCG2, Category: Tricyclics Inhibitor:Inhibitor: ABCB1ABCB1, ABCC2, ABCC2, ABCG2, , Category:concentration Tricyclics of serotonin and/or CYP1A2 (moderate), CYP2C9 (moderate), CYP1A2ABCG2 (moderate),, CYP1A2 CYP2C9(moderate), (moderate), Mechanism:norepinephrine Increases in the centralsynaptic nervous CYP2C19 (moderate), CYP2D6 (moderate), Mechanism: Increases synaptic CYP2C19CYP2C9 (moderate),(moderate), CYP2D6CYP2C19 (moderate), concentrationsystem byof inhibiting serotonin their reuptakeand/or inCYP2E1 the (weak concentrationpresynaptic of neuronalserotonin membrane and/or CYP2E1 (moderate),(weak CYP2D6 (moderate), norepinephrine in the central nervous TransporterCYP2E1 genes:(weak) ABCB1, ABCC2, norepinephrine in the central nervous Transporter genes: ABCB1, ABCC2, system by inhibiting their reuptake in ABCG2, TransporterKCNE2, KCNH2 genes:, KCNQ1ABCB1, SCN5A, , systemE byffect: inhibitingAdrenergic their Uptake reuptake inhibition; in ABCG2, KCNE2, KCNH2, KCNQ1, SCN5A, the presynaptic neuronal membrane SLC6A4 ABCC2, ABCG2, KCNE2, KCNH2, the presynapticAntimigraine neuronal activity; membrane Analgesic SLC6A4 Effect: (nonnarcotic)Adrenergic activity;Uptake inhibition; PleiotropicKCNQ1 genes:, SCN5A FABP1, SLC6A4, GNAS, GNB3, Effect: Adrenergic Uptake inhibition; Pleiotropic genes: FABP1, GNAS, GNB3, AntimigraineAntidepressant activity; action Analgesic NTRK1, TNFPleiotropic genes: FABP1, GNAS, Antimigraine activity; Analgesic (nonnarcotic) activity; Antidepressant NTRK1, GNB3TNF , NTRK1, TNF (nonnarcotic) activity; Antidepressant action action Name: Amoxapine; Asendin; Demolox; Name:14028-44-5; Amoxapine Asendis;; Asendin; Moxadi Demolox; Name: Amoxapine; Asendin; Demolox; 14028-44-5; Asendis; Moxadi 14028-44-5;IUPAC Asendis; Name :Moxadi 13-chloro-10-(piperazin- IUPAC1-yl)-2-oxa-9-azatricyclo[9.4.0.0 Name: 13-chloro-10-(piperazin-3,8] IUPAC Name: 13-chloro-10-(piperazin- 1-yl)-2-oxa-9-pentadeca-1(11),3,5,7,9,12,14-heptaene 1-yl)-2-oxa-9- PathogenicPathogenic genes: GNB3 genes:, SLC6A4GNB3, SLC6A4 azatricyclo[9.4.0.0³,Molecular Formula:⁸]pentadeca-C H ClN O Pathogenic genes: GNB3, SLC6A4 azatricyclo[9.4.0.0³,⁸]pentadeca-17 16 3 MechanisticMechanistic genes: ADRA1A genes: ADRA1A, ADRA2A, , 1(11),3,5,7,9,12,14-heptaene MechanisticADRA2A genes:, CHRMs ADRA1A, DRD1, ADRA2A, DRD2,, 1(11),3,5,7,9,12,14-heptaeneMolecular Weight: 313.78144 g/molCHRMs, DRD1, DRD2, GABRs, GABBRs, CHRMs,GABRs DRD1,, GABBRsDRD2, GABRs, HTRs, GABBRs, Molecular Formula: C17H16ClN3O HTRs MolecularCategory: Formula:Tricyclics C17H16ClN3O HTRs Metabolic genes: Metabolic genes: Mechanism: Reduces reuptake of MetabolicSubstrate: genes: CYP2D6 (major) Molecular Weight: 313.78144 g/mol Substrate:Transporter CYP2D6 genes: (major)SLC6A2 , Molecularserotonin Weight: and 313.78144 norepinephrine. g/mol The Substrate: CYP2D6 (major) TransporterSLC6A4 genes: SLC6A2, SLC6A4 metabolite, 7-OH-amoxapine, has Transporter genes: SLC6A2, SLC6A4 PleiotropicPleiotropic genes: DRD2 genes:, GNASDRD2, GNB3, GNAS , Categorysignificant: Tricyclics dopamine receptor-blockingPleiotropic genes: DRD2, GNAS, GNB3 Categoryactivity: Tricyclics GNB3 Mechanism: Reduces reuptake of Mechanism:Effect: SerotoninReduces uptakereuptake inhibition; of serotonin and norepinephrine. The serotoninAdrenergic and norepinephrine. uptake inhibition; The Dopamine metabolite, 7-OH-amoxapine, has metabolite,antagonism; 7-OH-amoxapine, Neurotransmitter has uptake inhibition; Antidepressant action; Anti-anxiety activity

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significant dopamine receptor-blocking significant dopamine receptor-blocking activity activity Effect: Serotonin uptake inhibition; Effect: Serotonin uptake inhibition; Adrenergic uptake inhibition; Adrenergic uptake inhibition; Dopamine antagonism; Dopamine antagonism; Neurotransmitter uptake inhibition; Neurotransmitter uptake inhibition; Antidepressant action; Anti-anxiety Int. J. Mol. Sci. 2020, 21, 3059 Antidepressant action; Anti-anxiety 33 of 82 activity activity Name: Clomipramine Hydrochloride; Name: Clomipramine Hydrochloride; Anafranil; Clomipramine HCL; 17321- Anafranil; ClomipramineTable 4.HCL;Cont. 17321- 77-6; Anaphranil; 3-(3-chloro-10,11- 77-6; Anaphranil; 3-(3-chloro-10,11- Tricyclicsdihydro-5H-dibenzo[b,f]azepin-5-yl)- (TCA) and other Norepinephrinereuptake inhibitors dihydro-5H-dibenzo[b,f]azepin-5-yl)- Drug N,N-dimethylpropan-1-amineProperties Pharmacogenetics N,N-dimethylpropan-1-amine hydrochlorideName: Clomipramine Hydrochloride; hydrochloride IUPACAnafranil; Name: Clomipramine (3-{14-chloro-2- HCL; IUPAC Name: (3-{14-chloro-2- azatricyclo[9.4.0.0³,17321-77-6; Anaphranil;⁸]pentadeca- 3-(3-chloro- azatricyclo[9.4.0.0³,10,11-dihydro-5H-dibenzo[b,f]azepin-⁸]pentadeca- 1(11),3,5,7,12,14-hexaen-2- 1(11),3,5,7,12,14-hexaen-2-5-yl)-N,N-dimethylpropan-1-amine yl}propyl)dimethylamine yl}propyl)dimethylaminehydrochloride PathogenicPathogenic genes: HTR2A genes:, SLC6A4HTR2A, Pathogenic genes: HTR2A, SLC6A4 IUPAC Name: (3-{14-chloro-2- SLC6A4 Molecular Formula: C19H3 824Cl2N2 Mechanistic genes: ADRA1s, CHRMs, Molecularazatricyclo[9.4.0.0 Formula: C19H,24]pentadeca-1(11),3,5,7,Cl2N2 Mechanistic genes: ADRA1s, CHRMs, CHRNs, MechanisticHRH1, HTR2s, genes: HTR3ADRA1s , 12,14-hexaen-2-yl}propyl)dimethylamineCHRNs, HRH1, HTR2s, HTR3 MetabolicCHRMs genes:, CHRNs , HRH1, HTR2s, Metabolic genes: MolecularMolecular Weight: Formula: 351.31326C 19g/molH24Cl 2N2 Substrate:HTR3 CYP1A2 (major), CYP2A6, Molecular Weight: 351.31326 g/mol Substrate:Metabolic CYP1A2 genes: (major), CYP2A6, Molecular Weight: 351.31326 g/molCYP2B6, CYP2C19 (major), CYP2D6 CYP2B6,Substrate: CYP2C19CYP1A2 (major),(major), CYP2D6 (minor), CYP3A4 (major), CYP3A5 (major), Category: Tricyclics (minor), CYP2A6CYP3A4, (major),CYP2B6 CYP3A5, CYP2C19 (major), Category: Tricyclics UGT1A4(major), CYP2D6 (minor), CYP3A4 CategoryMechanism:: Tricyclics It is a strong, but not UGT1A4 Inhibitor:(major), CYP2C9CYP3A5 (moderate),(major), CYP2C19UGT1A4 completely selective serotonin reuptakeInhibitor: CYP2C9 (moderate), CYP2C19 Mechanism: It is a strong, but not (strong), Inhibitor:CYP2D6 CYP2C9(moderate),(moderate), GSTP1, Mechanism:inhibitor; It asis itsa activestrong, main but metabolite not (strong), CYP2D6 (moderate), GSTP1, completely selective serotonin reuptake SLC6A4 CYP2C19 (strong), CYP2D6 completelydesmethyclomipramine selective serotonin actsreuptake preferably SLC6A4 as (moderate), GSTP1, SLC6A4 inhibitor;an inhibitoras its active of noradrenaline main metabolite reuptake. Transporter genes: SLC6A4 inhibitor; as its active main metabolite TransporterTransporter genes: SLC6A4 genes: SLC6A4 desmethyclomipramineα1-receptor blockage acts and preferably Pleiotropic genes: FABP1, PTGS2 desmethyclomipramine acts preferably PleiotropicPleiotropic genes: FABP1, genes: PTGS2FABP1, PTGS2 as anβ inhibitor of noradrenaline as an -down-regulationinhibitor of noradrenaline have been noted and reuptake.most α1-receptor likely play blockage a role in itsand short β- term reuptake. α1-receptor blockage and β- down-regulationeffects. A blockadehave been of sodium-channelsnoted and down-regulation have been noted and most likelyand NDMA-receptorsplay a role in its short term most likely play a role in its short term effects. A blockade of sodium-channels effects. EAff ect:blockadeSerotonin of sodium-channels uptake inhibition; and NDMA-receptorsAntidepressant action; Anti-anxiety and NDMA-receptors Effect: activity;Serotonin Antiobsessional uptake inhibition; effects; Analgesic Effect: Serotonin uptake inhibition; Antidepressanteffects action; Anti-anxiety Antidepressant action; Anti-anxiety activity;Name: Antiobsessional Hydrochloride effects; activity; Antiobsessional effects; ; AnalgesicNorpramin; effects Desipramine Hcl; DMI Pathogenic genes: ABCB1, Analgesic effects Name: hydrochloride;Desipramine Pertofrane;Hydrochloride; Pertofran CRHR1, CRHR2, FKBP5, HTR1A, Name: Desipramine Hydrochloride; PathogenicIL1B , NR3C1genes: , NTRK2ABCB1, ,PDE5A CRHR1, , Norpramin;IUPAC Desipramine Name Hcl; DMI Pathogenic3 8 genes: ABCB1, CRHR1, Norpramin; Desipramine: (3-{2-azatricyclo[9.4.0.0 Hcl; DMI CRHR2, ] , SLC6A4FKBP5,, TBX21HTR1A, IL1B, NR3C1, hydrochloride; Pertofrane; Pertofran CRHR2, FKBP5, HTR1A, IL1B, NR3C1, hydrochloride;pentadeca-1(15),3,5,7,11,13-hexaen-2-yl} Pertofrane; Pertofran NTRK2, PDE5AMechanistic, SLC6A4 genes:, TBX21ADCY1 , IUPACpropyl)(methyl)amine Name: (3-{2- NTRK2, PDE5A, SLC6A4, TBX21 IUPAC Name: (3-{2- MechanisticADRA1A genes:, ADRBs ADCY1, CHRMs, ADRA1A, , azatricyclo[9.4.0.0³,8]pentadeca- Mechanistic genes: ADCY1, ADRA1A, azatricyclo[9.4.0.0³,Molecular Formula:8]pentadeca-C18H23ClN2 ADRBs, HTR1ACHRMs,, IFNA1HTR1A, PDE1C, IFNA1, PSMD9, PDE1C, , 1(15),3,5,7,11,13-hexaen-2- ADRBs, PRKCSHCHRMs, ,HTR1ASTAT3, IFNA1, PDE1C, 1(15),3,5,7,11,13-hexaen-2-Molecular Weight: 302.84162 g/molPSMD9, PRKCSH, STAT3 yl}propyl)(methyl)amine PSMD9, MetabolicPRKCSH, STAT3 genes: yl}propyl)(methyl)amine Metabolic genes: Category: Tricyclics Metabolic genes: Substrate:Substrate: CYP1A2CYP1A2 (minor),(minor), CYP2C9, Molecular Formula: C18H23ClN2 Substrate:CYP2C9 CYP1A2, CYP2D6 (minor),(major) CYP2C9, MolecularMechanism: Formula:Increases C18H23ClN the2 synaptic CYP2D6 (major) Inhibitor: ABCB1, CYP2A6 concentration of norepinephrine in theCYP2D6 (major) Inhibitor:(moderate), ABCB1,CYP2B6 CYP2A6(moderate), (moderate), MolecularCNS Weight: by inhibition 302.84162 of its g/mol reuptake by the Inhibitor: ABCB1, CYP2A6 (moderate), CYP2B6 CYP2C19(moderate),(moderate), CYP2C19 CYP2D6(moderate), Molecularpresynaptic Weight: neuronal302.84162 membrane. g/mol CYP2B6 (moderate), CYP2C19 (moderate), CYP2D6(moderate), (moderate),CYP2E1 CYP2E1(weak), (weak), Additional receptor effects includingCYP2D6 (moderate), CYP2E1 (weak), CYP3A4 CYP3A4(moderate),(moderate), SLC6A2, SLC6A2SLC22A3, Categorydesensitization: Tricyclics of adenyl cyclase, CYP3A4 (moderate), SLC6A2, SLC22A3 Category: Tricyclics TransporterSLC22A3 genes: ABCB1, SLC6A2, down-regulation of β-adrenergic Transporter genes: ABCB1, SLC6A2, Transporter genes: ABCB1, Mechanism:receptors, Increases and down-regulation the synaptic of SLC6A3, SLC6A4, SLC22A3 Mechanism: Increases the synaptic SLC6A3, SLC6A2SLC6A4,, SLC6A3SLC22A3, SLC6A4 , concentrationserotonin of receptorsnorepinephrine in the Pleiotropic genes: NTRK2, FOS concentration of norepinephrine in the PleiotropicSLC22A3 genes: NTRK2, FOS Effect: Enzyme inhibition; Adrenergic Pleiotropic genes: NTRK2, FOS uptake inhibition; Antidepressant action; Analgesic activity Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 35 of 87

CNS by inhibition of its reuptake by the presynaptic neuronal membrane. Int. J. Mol. Sci. 2020, 21, x FOR PEERAdditional REVIEW receptor effects including 35 of 87 desensitization of adenyl cyclase, down- regulationCNS by inhibition of β-adrenergic of its reuptake receptors, by the andpresynaptic down-regulation neuronal of membrane.serotonin receptorsAdditional receptor effects including Effect:desensitization Enzyme of inhibition; adenyl cyclase, Adrenergic down- uptakeregulation inhibition; of β-adrenergic Antidepressant receptors, action;and down-regulationAnalgesic activity of serotonin Int. J. Mol. Sci. 2020, 21, 3059 Name:receptors Doxepin Hydrochloride; 34 of 82 Silenor;Effect: EnzymeAdapin; inhibition;Novoxapin; Adrenergic Toruan; Curatinuptake inhibition; Antidepressant IUPACaction; AnalgesicName: activity Table dimethyl(3-{9- 4. Cont. oxatricyclo[9.4.0.0³,Name: Doxepin⁸]pentadeca- Hydrochloride; Tricyclics (TCA) and other Norepinephrinereuptake inhibitors 1(15),3,5,7,11,13-hexaen-2-Silenor; Adapin; Novoxapin; Toruan; Drug Properties Pathogenic genes:Pharmacogenetics ABCB1, SLC6A4 Curatin ylidene}propyl)amine Mechanistic genes: ADRBs, CHRMs, IUPACName: Name: Doxepin Hydrochloridedimethyl(3-{9-; Silenor; Adapin; Novoxapin;19 22 Toruan; CuratinHRH1, HRH2, HTRs Molecularoxatricyclo[9.4.0.0³, Formula:⁸ ]pentadeca-C H ClNO Metabolic genes: 1(15),3,5,7,11,13-hexaen-2-IUPAC Name: dimethyl(3-{9-oxatricyclo Pathogenic genes: ABCB1, Pathogenic Substrate: genes: CYP1A1 ABCB1 (minor),, SLC6A4 CYP1A2 Molecular[9.4.0.0 Weight:3,8]pentadeca-1(15),3,5,7,11,13- 315.83708 g/mol SLC6A4 ylidene}propyl)amine Mechanistic genes: ADRBs, CHRMs, hexaen-2-ylidene}propyl)amine (minor), MechanisticCYP2C9 genes:(minor),ADRBs CYP2C19, HRH1, HRH2, HTRs Molecular Formula: C19H22ClNO (major), CHRMsCYP2D6, HRH1 (major),, HRH2 , CYP3A4/5HTRs CategoryMolecular: Tricyclics Formula: C H ClNO 19 22 (minor),Metabolic MetabolicGSTP1 genes:, UGT1A3 genes:, UGT1A4 Molecular Weight: 315.83708 g/mol Inhibitor:Substrate:Substrate: CYP2C19CYP1A1CYP1A1 (strong),(minor),(minor), CYP2D6CYP1A2 MechanismMolecular Weight:: It increases 315.83708 the g/molsynaptic (moderate)(minor),CYP1A2 CYP2C9(minor), (minor),CYP2C9 CYP2C19(minor), concentrationCategory: ofTricyclics serotonin and Transporter(major), CYP2C19CYP2D6 genes:(major), (major),ABCB1CYP2D6 , CYP3A4/5KCNH2(major),, norepinephrineMechanism: in thIte CNS increases by inhibition the synaptic Category: Tricyclics SLC6A2(minor),, CYP3A4SLC6A4GSTP1, / UGT1A35 (minor),, UGT1A4GSTP1, of theirconcentration reuptake by of serotoninthe presynaptic and Inhibitor:UGT1A3 CYP2C19, UGT1A4 (strong), CYP2D6 neuronalMechanismnorepinephrine membrane: It increases in the the CNS synaptic by inhibition Inhibitor: CYP2C19 (strong), (moderate) Effectconcentration: ofAdrenergic their reuptakeof uptaserotonin byke the inhibition; presynaptic and CYP2D6 (moderate) Transporter genes: ABCB1, KCNH2, Histaminenorepinephrineneuronal Antagonism; membranein the CNS Antidepressant by inhibition Transporter genes: ABCB1, SLC6A2, SLC6A4 action;of their Eff Analgesicreuptakeect: Adrenergic byeffects; the uptake presynaptic Pruritus inhibition; KCNH2, SLC6A2, SLC6A4 reductionneuronalHistamine membrane Antagonism; Antidepressant Name:Effect: action; AdrenergicImipramine Analgesic upta Hydrochloride; effkeects; inhibition; Pruritus Tofranil;Histaminereduction Imipramine Antagonism; Hcl;Antidepressant 113-52-0; Chimoreptin;action;Name: Analgesic FeinalminImipramine effects; Hydrochloride; Pruritus IUPACreductionTofranil; ImipramineName: Hcl; 113-52-0;(3-{2- Pathogenic genes: ABCB1, BDNF, azatricyclo[9.4.0.0³,Name:Chimoreptin; Imipramine⁸]pentadeca- Feinalmin Hydrochloride; PathogenicHTR2A genes:, SLC6A4 ABCB1, BDNF, HTR2A, Mechanistic genes: ADRB2, 1(15),3,5,7,11,13-hexaen-2-Tofranil;IUPAC Imipramine Name: Hcl; 113-52-0; SLC6A4 DRD2, CHRMs, HTR2A, SCNs yl}propyl)dimethylamineChimoreptin;(3-{2-azatricyclo[9.4.0.0 Feinalmin 3,8]pentadeca-1(15),Mechanistic genes: ADRB2, DRD2, Metabolic genes: IUPAC3,5,7,11,13-hexaen-2-yl}propyl) Name: (3-{2- CHRMs, HTR2A, SCNs Substrate: CYP1A2 (minor), Moleculardimethylamine Formula: C19H25ClN2 MetabolicPathogenic genes: genes: ABCB1, BDNF, HTR2A, azatricyclo[9.4.0.0³,⁸]pentadeca- CYP2B6 (minor), CYP2C19 (major), SLC6A4 Substrate: CYP1A2 (minor), CYP2B6 1(15),3,5,7,11,13-hexaen-2-Molecular Formula: C19H25ClN2 CYP2D6 (major), CYP3A4 (minor), yl}propyl)dimethylamine (minor),Mechanistic CYP3A7CYP2C19 genes:, GSTP1 (major),,ADRB2UGT1A3 , CYP2D6, DRD2, MolecularMolecular Weight: Weight: 316.8682316.8682 g/mol g/mol (major),CHRMs ,CYP3A4UGT1A4 HTR2A ,(minor),, SCNsUGT2B10 CYP3A7, GSTP1, MolecularCategory: Formula:Tricyclics C19H25ClN2 UGT1A3MetabolicInhibitor:, UGT1A4 genes: , CYP1A2UGT2B10(weak), Category: Tricyclics Mechanism: It binds the Inhibitor:Substrate:CYP2C9 CYP1A2CYP1A2(moderate), (weak),(minor),CYP2C19 CYP2C9CYP2B6 (moderate),(minor),(weak), CYP2C19 CYP2C19CYP2D6 (major),(weak),(moderate), CYP2D6CYP2D6 Mechanism:Molecularsodium-dependent Weight: It binds 316.8682 the serotonin g/mol sodium- transporter and sodium-dependent norepinephrine(moderate),(major), CYP2E1CYP3A4 CYP2E1 (weak),(minor), (weak),CYP3A4 CYP3A7 CYP3A4, GSTP1, dependent serotonin transporter and (moderate), FMO1, SLC22A2, transporter preventing or reducing the(moderate),UGT1A3, UGT1A4 FMO1,, SLC22A2UGT2B10, SLC22A3 sodium-dependent norepinephrine SLC22A3 Categoryreuptake: Tricyclics of norepinephrine and serotoninTransporter Inhibitor: CYP1A2genes: ABCB1(weak),, SLC6A2CYP2C9, transporter preventing or reducing the Transporter genes: ABCB1, by nerve cells. It causes down-regulationSLC6A4(moderate),, SLC22A2 CYP2C19, SLC22A3 (weak), CYP2D6 reuptakeMechanism: of It norepinephrinebinds the sodium- and SLC6A2, SLC6A4, SLC22A2, of cerebral cortical beta-adrenergic Pleiotropic(moderate), genes: CYP2E1 ADRB2 (weak),, BDNF , CYP3A4FABP1, serotonindependentreceptors by serotoninnerve cells. transporter It causes down- and SLC22A3 FOS(moderate),, ORM1 FMO1, SLC22A2, SLC22A3 regulationsodium-dependent of cerebral norepinephrinecortical beta- Pleiotropic genes: ADRB2, BDNF, Effect: Adrenergic uptake inhibition;TransporterFABP1 genes:, FOS, ORM1ABCB1, SLC6A2, adrenergictransporter receptors preventing or reducing the Antidepressant action; Antienuretic SLC6A4, SLC22A2, SLC22A3 reuptake of norepinephrine and Effect: effAdrenergicects; Analgesic upta activity;ke inhibition; attention Pleiotropic genes: ADRB2, BDNF, FABP1, serotoninenhancer by nerve cells. It causes down- Antidepressant action; Antienuretic FOS, ORM1 regulation of cerebral cortical beta- adrenergic receptors Effect: Adrenergic uptake inhibition; Antidepressant action; Antienuretic

Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 36 of 87

effects; Analgesic activity; attention enhancer Name: Hydrochloride; Int. J. Mol. Sci. 2020, 21, x FOR PEERPamelor; REVIEW Allegron; Altilev; Nortrilen; 36 of 87 Int. J. Mol. Sci. 2020, 21, 3059 894-71-3 35 of 82 effects;IUPAC AnalgesicName: activity; methyl(3-attention enhancer{tricyclo[9.4.0.0³, ⁸]pentadeca- 1(15),3,5,7,11,13-hexaen-2-Table 4. Cont. Name:ylidene}propyl)amine Nortriptyline Hydrochloride; Pathogenic genes: ABCB1, GNB3, HTR1B, TricyclicsPamelor; (TCA) Allegron; and other Altilev; Norepinephrinereuptake Nortrilen; NR3C1 inhibitors, SLC6A4 Drug 894-71-3Molecular Formula:Properties C19H22ClN Mechanistic genes:Pharmacogenetics ADCY1, ADRA2s, IUPACName: NortriptylineName: Hydrochloride;methyl(3- ADRBs, GNB3, HRH1, HTRs {tricyclo[9.4.0.0³,⁸]pentadeca- Metabolic genes: MolecularPamelor; Weight: Allegron; 299.83768 Altilev; g/mol Nortrilen; 1(15),3,5,7,11,13-hexaen-2-894-71-3 Substrate: CYP1A2 (minor), CYP2C19 Pathogenic(minor), Pathogenic CYP2D6genes: ABCB1 genes:(major),, GNB3ABCB1 , CYP3A4HTR1B, GNB3,, ylidene}propyl)amineIUPAC Name: methyl(3-{tricyclo Category: 3Tricyclics8 NR3C1(minor),, SLC6A4 HTR1BUGTs , NR3C1, SLC6A4 [9.4.0.0 , ]pentadeca-1(15),3,5,7,11,13- Mechanistic genes: ADCY1, Molecular Formula: C19H22ClN Mechanistic Inhibitor: CYP2C8genes: (moderate),ADCY1, ADRA2s CYP2C9, hexaen-2-ylidene}propyl)amine ADRA2s, ADRBs, GNB3, HRH1, Mechanism: Inhibits the reuptake of the ADRBs(moderate),, GNB3 CYP2C19, HRH1 ,(moderate), HTRs CYP2D6 neurotransmitterMolecular Formula: serotoninC19H 22ClNat the MetabolicHTRs genes: Molecular Weight: 299.83768 g/mol (weak), MetabolicCYP2E1 genes:(weak), CYP3A4 neuronalMolecular membrane Weight: or299.83768 acts at g /molbeta- Substrate: CYP1A2 (minor), CYP2C19 (moderate)Substrate: CYP1A2 (minor), adrenergic receptors. It has additional (minor), CYP2D6 (major), CYP3A4 Category: Tricyclics TransporterCYP2C19 genes:(minor), ABCB1CYP2D6, SLC6A2, Category:receptor Tricyclicseffects including (minor),SLC6A4 (major),UGTs CYP3A4 (minor), UGTs Mechanism: Inhibits the reuptake of the desensitization of adenyl cyclase, down- Pleiotropic InhibitorInhibitor: :genes: CYP2C8 HTR1BCYP2C8 (moderate), (moderate), CYP2C9 Mechanism:neurotransmitter Inhibits serotoninthe reuptake at the of neuronalthe regulation of β-adrenergic receptors, (moderate),CYP2C9 CYP2C19(moderate), (moderate),CYP2C19 CYP2D6 membrane or acts at beta-adrenergic neurotransmitterand down-regulation serotonin of serotoninat the (weak), (moderate),CYP2E1 CYP2D6(weak),(weak), CYP3A4 receptors. It has additional receptor effects neuronalreceptors membrane or acts at beta- CYP2E1 (weak), CYP3A4 including desensitization of adenyl cyclase,(moderate) adrenergic receptors. It has additional (moderate) Effect:down-regulation Adrenergic ofuptakeβ-adrenergic inhibitor; receptors, Transporter genes: ABCB1, SLC6A2, receptor effects including Transporter genes: ABCB1, Antidepressantand down-regulation agent; of serotoninAnalgesic receptors SLC6A4 SLC6A2, SLC6A4 desensitizationactivity; Hypno-se of adenyldative cyclase,activity down- Pleiotropic genes: HTR1B regulationEffect: Adrenergicof β-adrenergic uptake inhibitor;receptors, Pleiotropic genes: HTR1B andName:Antidepressant down-regulation Protriptyline agent; Hydrochloride Analgesicof serotonin activity; Hypno-sedative activity receptors IUPAC Name: methyl(3- Effect:Name: Adrenergic Protriptyline uptake Hydrochloride inhibitor; {tricyclo[9.4.0.0³,⁸]pentadeca- Antidepressant agent; Analgesic 1(15),3,5,7,9,11,13-heptaen-2-IUPAC Name: methyl(3-{tricyclo Mechanistic genes: SLC6A2, activity;[9.4.0.0 Hypno-se3,8]pentadeca-1(15),3,5,7,9,dative activity SLC6A4 yl}propyl)amine Mechanistic genes: SLC6A2, SLC6A4 11,13-heptaen-2-yl}propyl)amine Metabolic genes: Name: Protriptyline Hydrochloride Metabolic genes: Molecular Formula: C19H22ClN Substrate: CYP1A2 (minor), Molecular Formula: C19H22ClN Substrate: CYP1A2 (minor), CYP2C19 IUPAC Name: methyl(3- CYP2C19 (minor), CYP2D6 Molecular Weight: 299.83768 g/mol (minor), (major),CYP2D6CYP3A4 (major), (minor)CYP3A4 (minor) {tricyclo[9.4.0.0³,Molecular Weight:⁸]pentadeca- 299.83768 g/mol Inhibitor:Inhibitor: CYP1A2CYP1A2 (moderate),(moderate), CYP2C9 1(15),3,5,7,9,11,13-heptaen-2-Category: Tricyclics (moderate),CYP2C9 CYP2C19(moderate), (moderate),CYP2C19 CYP2D6 yl}propyl)amineCategory: Tricyclics Mechanism: Increases synaptic Mechanistic(moderate),(moderate), CYP3A4 genes: SLC6A2 CYP2D6(moderate), SLC6A4(moderate), concentration of serotonin and/or MetabolicCYP3A4 genes:(moderate) MolecularMechanism: Formula: Increases C19H22 ClN synaptic Transporter genes: SLC6A2, SLC6A4 norepinephrine in CNS by inhibition of their Substrate:Transporter CYP1A2 genes: (minor),SLC6A2 CYP2C19, concentrationreuptake by presynapticof serotonin neuronal and/or membrane Pleiotropic genes: ADRA1A, GNAS, (minor), SLC6A4CYP2D6 (major), CYP3A4 (minor) Molecularnorepinephrine Weight: in CNS 299.83768 by inhibition g/mol of ITGB3 Effect: Adrenergic uptake inhibitor; Inhibitor:Pleiotropic CYP1A2 genes: (moderate),ADRA1A CYP2C9, their reuptake by presynaptic neuronal Antidepressant agent; Analgesic activity;(moderate),GNAS CYP2C19, ITGB3 (moderate), CYP2D6 Category:membrane Tricyclics Anti-migraine effect (moderate), CYP3A4 (moderate) Int. J. Mol. Sci. 2020, 21, x FOR PEEREffect: REVIEW Adrenergic uptake inhibitor; 37 of 87 Name: Trimipramine; Sapilent; Surmontil;Transporter genes: SLC6A2, SLC6A4 Mechanism:Antidepressant Increasesagent; Analgesicsynaptic Beta-Methylimipramine; Trimeprimina Pleiotropic genes: ADRA1A, GNAS, concentrationactivity; Anti-migraine of serotonin effect and/or Transporter genes: SLC6A2, SLC6A4, Molecular Formula: C20H26N2 3 ITGB38 norepinephrineName:IUPAC NameTrimipramine; in: (3-{2-azatricyclo[9.4.0.0CNS by inhibitionSapilent; of ,PathogenicSLC22A1] , SLC22A2 genes: ABCB1 , SLC6A4 theirpentadeca-1(15),3,5,7,11,13-hexaen-2-yl}-2- reuptake by presynaptic neuronal Surmontil; Beta-Methylimipramine; MechanisticPathogenic genes genes:: SLC6A2ABCB1, SLC6A4, , Molecularmethylpropyl) Weight: dimethylamine 294.43384 g/mol membraneTrimeprimina SLC22A1SLC6A4, SLC22A2 Effect:Molecular Adrenergic Formula: uptakeC H inhibitor;N IUPACCategory: TricyclicsName: 20 26 2 (3-{2- MetabolicMechanistic genes: genes: SLC6A2, Antidepressant agent; Analgesic azatricyclo[9.4.0.0³,Molecular Weight:8]pentadeca-294.43384 g/mol Substrate:SLC6A4 CYP2C19, SLC22A1 (major),, SLC22A2 CYP2D6 activity;1(15),3,5,7,11,13-hexaen-2-yl}-2-Mechanism: Anti-migraine Increases effect synaptic (major), MetabolicCYP3A4/5 (major) genes: Category: Tricyclics Substrate: CYP2C19 (major), Name:methylpropyl)dimethylamineconcentration Trimipramine; of serotonin Sapilent;and/or Pathogenic Inhibitor: genes: ABCB1 ABCB1 , SLC6A4 Surmontil;norepinephrineMechanism: Beta-Methylimipramine; inIncreases CNS by synaptic inhibition of MechanisticCYP2D6 genes(major),: SLC6A2CYP3A4, /SLC6A45 (major), Trimepriminatheirconcentration reuptake by of presynaptic serotonin and neuronal/or SLC22A1Inhibitor:, SLC22A2 ABCB1 Transporter genes: SLC6A2, IUPACmembranenorepinephrine Name: in CNS by inhibition(3-{2- ofMetabolic their genes: SLC6A4, SLC22A1, SLC22A2 azatricyclo[9.4.0.0³,Effect:reuptake Adrenergic by presynaptic8 ]pentadeca-uptake neuronal inhibition; membrane Substrate: CYP2C19 (major), CYP2D6 1(15),3,5,7,11,13-hexaen-2-yl}-2-AntidepressantEffect: Adrenergic action; uptake Antihistaminic inhibition; (major), CYP3A4/5 (major) methylpropyl)dimethylamineactivity;Antidepressant Sedative effect action; Antihistaminic Inhibitor: ABCB1 Selective Serotoninactivity; Sedativeand Norepinephrine effect Reuptake Inhibitors (SSNRI) Drug Properties Pharmacogenetics Name: Desvenlafaxine; O- Desmethylvenlafaxine; 93413-62-8; 4-(2- (Dimethylamino)-1-(1- hydroxycyclohexyl)ethyl)phenol; 4-[2- (Dimethylamino)-1-(1- hydroxycyclohexyl)ethyl]phenol; Pathogenic genes: ABCB1, SLC6A4 Desvenlafaxine (INN) Mechanistic genes: HTR1A, SLC6A2, IUPAC Name: 4-[2-(dimethylamino)-1- SLC6A3, SLC6A4 (1-hydroxycyclohexyl)ethyl]phenol Metabolic genes: Substrate: CYP3A4 (minor), UGTs Molecular Formula: C16H25NO2 Inhibitor: CYP2D6 (weak), SLC6A2, SLC6A4 Molecular Weight: 263.3752 g/mol Transporter genes: ABCB1, SLC6A2, Mechanism: It is a potent and selective SLC6A4 serotonin and norepinephrine reuptake inhibitor Effect: Serotonin uptake inhibition; Norepinephrine uptake inhibition; Antidepressant activity Name: Duloxetine Hydrochloride; 136434-34-9; Duloxetine HCl; Cymbalta; (S)-N-Methyl-3-(naphthalen-1-yloxy)-3- (thiophen-2-yl)propan-1-amine hydrochloride; (S)-Duloxetine HCl IUPAC Name: methyl[(3S)-3- Pathogenic genes: ABCB1, SLC6A4 (naphthalen-1-yloxy)-3-(thiophen-2- Mechanistic genes: COMT, HTR1A, SLC6A2, yl)propyl]amine SLC6A4

Molecular Formula: C18H20ClNOS Metabolic genes: Substrate: CYP1A2 (major), CYP2D6 (major) Inhibitor: ABCB1, CYP1A2 (moderate), Molecular Weight: 333.8755 g/mol CYP2B6 (moderate), CYP2C19 (moderate), CYP2D6 (moderate), CYP3A4/5 Mechanism: It is a selective serotonin- (moderate), SLC6A2, SLC6A4 and norepinephrine-reuptake inhibitor Transporter genes: ABCB1, SLC6A2, SLC6A4 and a weak inhibitor of dopamine reuptake Effect: Antidepressant activity; Anti- anxiety activity; Serotonin uptake inhibition; Norepinephrine uptake inhibition; Anti-Fibromyalgia agent;

Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 37 of 87

Transporter genes: SLC6A2, SLC6A4, Molecular Formula: C20H26N2 SLC22A1, SLC22A2 Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 37 of 87 Molecular Weight: 294.43384 g/mol Transporter genes: SLC6A2, SLC6A4, Molecular Formula: C20H26N2 Category: Tricyclics SLC22A1, SLC22A2 MolecularMechanism: Weight: Increases 294.43384 g/molsynaptic concentration of serotonin and/or Category:norepinephrine Tricyclics in CN S by inhibition of their reuptake by presynaptic neuronal Mechanism:membrane Increases synaptic

concentrationEffect: Adrenergic of serotoninuptake inhibition; and/or norepinephrineAntidepressant inacti CNon;S byAntihistaminic inhibition of theiractivity; reuptake Sedative by effectpresynaptic neuronal membrane Selective Serotonin and Norepinephrine Reuptake Inhibitors (SSNRI) Effect: Adrenergic uptake inhibition; Int. J. Mol. Sci.Drug2020, 21, 3059 Properties Pharmacogenetics 36 of 82 Antidepressant action; Antihistaminic Name: Desvenlafaxine; O- activity; Sedative effect Desmethylvenlafaxine; 93413-62-8; 4-(2- Selective Serotonin and Norepinephrine Reuptake Inhibitors (SSNRI) (Dimethylamino)-1-(1-Table 4. Cont. Drug hydroxycyclohexyl)ethyl)phenol;Properties 4-[2- Pharmacogenetics SelectiveName Serotonin: andDesvenlafaxine; Norepinephrine ReuptakeO- Inhibitors (SSNRI) Drug (Dimethylamino)-1-(1-Properties Pharmacogenetics Desmethylvenlafaxine;hydroxycyclohexyl)ethyl]phenol; 93413-62-8; 4-(2- Name: Desvenlafaxine; Pathogenic genes: ABCB1, SLC6A4 (Dimethylamino)-1-(1-Desvenlafaxine (INN) hydroxycyclohexyl)ethyl)phenol;O-Desmethylvenlafaxine; 93413-62-8; 4-[2- Mechanistic genes: HTR1A, SLC6A2, IUPAC Name: 4-[2-(dimethylamino)-1- (Dimethylamino)-1-(1-4-(2-(Dimethylamino)-1-(1-hydroxycyclohexyl)SLC6A3, SLC6A4 (1-hydroxycyclohexyl)ethyl]phenolethyl)phenol; 4-[2-(Dimethylamino)-1-(1- Metabolic genes: hydroxycyclohexyl)ethyl]phenol; Pathogenic genes: ABCB1, hydroxycyclohexyl)ethyl]phenol; Pathogenic Substrate genes:: CYP3A4 ABCB1 (minor),, SLC6A4 UGTs DesvenlafaxineMolecular Formula: (INN) C 16H25NO2 SLC6A4 Desvenlafaxine (INN) Mechanistic Inhibitor: CYP2D6genes: HTR1A(weak),, SLC6A2,, IUPAC Name: 4-[2-(dimethylamino)-1- SLC6A3,Mechanistic SLC6A4 genes: HTR1A, IUPAC Name: 4-[2-(dimethylamino)-1- SLC6A4SLC6A2 , SLC6A3, SLC6A4 (1-hydroxycyclohexyl)ethyl]phenolMolecular Weight: 263.3752 g/mol Metabolic genes: (1-hydroxycyclohexyl)ethyl]phenol TransporterMetabolic genes genes:: ABCB1, SLC6A2, Substrate: CYP3A4 (minor), UGTs MolecularMechanismMolecular Formula:: It Formula: is a potent C16HC 25 andNOH 2 NO selective SLC6A4 Substrate: CYP3A4 (minor), UGTs 16 25 2 Inhibitor: CYP2D6 (weak), SLC6A2, serotonin and norepinephrine reuptake Inhibitor: CYP2D6 (weak), Molecular Weight: 263.3752 g/mol SLC6A4 SLC6A2, SLC6A4 Molecularinhibitor Weight: 263.3752 g/mol Mechanism: It is a potent and selective TransporterTransporter genes: genes: ABCB1ABCB1, SLC6A2, , Effect: Serotonin uptake inhibition; Mechanismserotonin: andIt is norepinephrinea potent and selective reuptake SLC6A4 SLC6A2, SLC6A4 Norepinephrineinhibitor uptake inhibition; serotoninAntidepressant and norepinephrine activity reuptake inhibitorEffect: Serotonin uptake inhibition; Name: Duloxetine Hydrochloride; Norepinephrine uptake inhibition; Effect:136434-34-9; Serotonin Duloxetine uptake HCl; inhibition;Cymbalta; Antidepressant activity Norepinephrine(S)-N-Methyl-3-(naphthalen-1-yloxy)-3- uptake inhibition; Antidepressant(thiophen-2-yl)propan-1-amineName: Duloxetine activity Hydrochloride ; 136434-34-9; Duloxetine HCl; Cymbalta; Name:hydrochloride; Duloxetine (S)-Duloxetine Hydrochloride HCl ; 136434-34-9;(S)-N-Methyl-3-(naphthalen-1-yloxy)-3- Duloxetine HCl; Cymbalta; Pathogenic genes: ABCB1, IUPAC Name: methyl[(3S)-3- SLC6A4 (S)-N-Methyl-3-(naphthalen-1-yloxy)-3-(thiophen-2-yl)propan-1-amine Pathogenic genes: ABCB1, SLC6A4 (naphthalen-1-yloxy)-3-(thiophen-2-hydrochloride; (S)-Duloxetine HCl Mechanistic genes: COMT, (thiophen-2-yl)propan-1-amine Mechanistic genes: COMT, HTR1A, SLC6A2, yl)propyl]amine HTR1A, SLC6A2, SLC6A4 IUPAC Name: methyl[(3S)-3-(naphthalen- hydrochloride; (S)-Duloxetine HCl SLC6A4 Metabolic genes: 1-yloxy)-3-(thiophen-2-yl)propyl]amine IUPACMolecular Formula:Name: C18Hmethyl[(3S)-3-20ClNOS MetabolicSubstrate: genes: CYP1A2 (major), Pathogenic genes: ABCB1, SLC6A4 (naphthalen-1-yloxy)-3-(thiophen-2-Molecular Formula: C H ClNOS SubstrateCYP2D6: CYP1A2(major) (major), CYP2D6 (major) 18 20 Mechanistic genes: COMT, HTR1A, SLC6A2, yl)propyl]amine Inhibitor:Inhibitor: ABCB1,ABCB1, CYP1A2 CYP1A2 (moderate), Molecular Weight: 333.8755 g/mol Molecular Weight: 333.8755 g/mol SLC6A4CYP2B6 (moderate), (moderate), CYP2B6CYP2C19(moderate), (moderate), MolecularMechanism: Formula:It is aC selective18H20ClNOS serotonin- andMetabolicCYP2D6CYP2C19 genes:(moderate), (moderate), CYP2D6CYP3A4/5 Mechanism: It is a selective serotonin- Int. J. Mol. Sci. 2020, 21, x FOR PEERnorepinephrine-reuptake REVIEW inhibitor and a (moderate), Substrate(moderate),: CYP1A2SLC6A2 (major),,CYP3A4 SLC6A4 CYP2D6/5 (moderate), 38 (major) of 87 andweak norepinephrine-reuptake inhibitor of dopamine reuptakeinhibitor Transporter Inhibitor:SLC6A2 genes ABCB1,,:SLC6A4 ABCB1 CYP1A2, SLC6A2 (moderate),, SLC6A4 Molecular Weight: 333.8755 g/mol AnalgesicandE ffaect: weak Antidepressantactivity; inhibitor Urinary activity;of continencedopamine Anti-anxiety CYP2B6 Transporter(moderate), genes:CYP2C19ABCB1 (moderate),, improvementreuptakeactivity; Serotonin uptake inhibition; CYP2D6SLC6A2 (moderate),, SLC6A4 CYP3A4/5 Mechanism: It is a selective serotonin- Effect:Norepinephrine Antidepressant uptake activity; inhibition; Anti- (moderate), SLC6A2, SLC6A4 and norepinephrine-reuptake inhibitor Name:anxietyAnti-Fibromyalgia activity;Levomilnacipran Serotonin agent; Analgesic; uptakeUNII- activity; Transporter genes: ABCB1, SLC6A2, SLC6A4 andUGM0326TXX;inhibition;Urinary a weak continenceNorepi inhibitorUGM0326TXX;nephrine improvement of dopamine Fetzima;uptake reuptake(1S,2R)-2-(aminomethyl)-N,N-diethyl- inhibition;Name: Levomilnacipran Anti-Fibromyalgia; agent; Effect: Antidepressant activity; Anti- 1-phenylcyclopropane-1-carboxamide;UNII-UGM0326TXX; UGM0326TXX; Fetzima; anxietyF2695 activity; Serotonin uptake (1S,2R)-2-(aminomethyl)-N,N-diethyl-1- inhibition;IUPACphenylcyclopropane-1-carboxamide; NorepiName:nephrine (1S,2R)-2-uptake F2695 Pathogenic genes: SLC6A4 inhibition;(aminomethyl)-N,N-diethyl-1- Anti-Fibromyalgia agent; IUPAC Name: (1S,2R)-2-(aminomethyl)-N,N-PathogenicMechanistic genes: SLC6A4 genes: HCRTR1, phenylcyclopropane-1-carboxamidediethyl-1-phenylcyclopropane-1-carboxamide MechanisticHCRTR2, genes: HDC, HCRTR1, HRH1, SLC6A2,HCRTR2, SLC6A4 HDC, HRH1, SLC6A2, SLC6A4 MolecularMolecular Formula: Formula: C15CH1522NH222ON 2O Metabolic genes: Metabolic genes: Molecular Weight: 246.34798 g/mol Substrate: ABCB1 (minor), Substrate: ABCB1 (minor), CYP2C19 Molecular Weight: 246.34798 g/mol CYP2C19 (minor), CYP2C8 Mechanism: Potentiation of serotonin and(minor),(minor), CYP2C8CYP2D6 (minor),(minor), CYP2D6CYP2J2 norephinephrine in the central nervous Mechanism: Potentiation of serotonin (minor),(minor), CYP2J2 (minor),CYP3A4 CYP3A4(major) (major) system through inhibition of reuptake atTransporterTransporter genes: SLC6A2 genes: SLC6A2, SLC6A4, and norephinephrine in the central serotonin and norepinephrine transporters SLC6A4 nervous system through inhibition of Effect: Serotonin uptake inhibition; reuptake at serotonin and Norepinephrine uptake inhibition; norepinephrineAntidepressant transporters activity Effect: Serotonin uptake inhibition; Norepinephrine uptake inhibition; Antidepressant activity Name: Milnacipran Hydrochloride; Toledomin; Midalcipran; Ixel; Savella; Milnacipranum IUPAC Name: (1R,2S)-2- (aminomethyl)-N,N-diethyl-1- Pathogenic genes: BDNF phenylcyclopropane-1-carboxamide Mechanistic genes: ADRA2A, BDNF, SLC6A2, SLC6A4 Molecular Formula: C15H22N2O Metabolic genes: Substrate: COMT, CYP1A2 (minor), Molecular Weight: 246.34798 g/mol CYP2A6 (minor), CYP2B6 (minor), CYP2C8, CYP2C9 (minor), CYP2C19 Mechanism: It is a potent inhibitor of (minor), CYP2D6 (minor), CYP2E1 neuronal norepinephrine and serotonin (minor), CYP3A4/5 (minor), UGTs reuptake. It inhibits norepinephrine Inhibitor: CYP3A4/5 (moderate) uptake with approximately 3-fold Inducer: CYP1A2, CYP2B6, CYP2C8, higher in vitro than serotonin CYP2C9, CYP2C19, CYP3A4/5 without directly affecting the uptake of Transporter genes: SLC6A2, SLC6A4 dopamine or other neurotransmitters Effect: Analgesic action; Anti- fibromyalgia action; Serotonin uptake inhibition; Adrenergic uptake inhibition; Antidepressant activity Name: Venlafaxine Hydrochloride; Pathogenic genes: ABCB1, BDNF, CREB1, 99300-78-4; VENLAFAXINE HCl; FKBP5, HTR1A, HTR2A, NR3C1, SLC6A3, Effexor XR; Dobupal; Trevilor SLC6A4, TPH2 IUPAC Name: 1-[2-(dimethylamino)-1- Mechanistic genes: BDNF, FKBP5 (4-methoxyphenyl)ethyl]cyclohexan-1- Metabolic genes: ol Substrate: ABCB1, CYP2C9 (minor), CYP2C19 (minor), CYP2D6 (major), Molecular Formula: C17H28ClNO2 CYP3A4 (major) Inhibitor: ABCB1, CYP1A2 (weak), Molecular Weight: 313.86272 g/mol CYP2B6 (weak), CYP2D6 (weak), CYP3A4

Mechanism: Active metabolite, O- (weak), SLC6A2, SLC6A3, SLC6A4 desmethylvenlafaxine (ODV), are Transporter genes: ABCB1, ABCC1,

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Int. J. Mol. Sci. 2020, 21, x FOR PEERAnalgesic REVIEW activity; Urinary continence 38 of 87 improvement Analgesic activity; Urinary continence Name:improvement Levomilnacipran ; UNII- UGM0326TXX; UGM0326TXX; Fetzima; (1S,2R)-2-(aminomethyl)-N,N-diethyl-Name: Levomilnacipran; UNII- 1-phenylcyclopropane-1-carboxamide;UGM0326TXX; UGM0326TXX; Fetzima; F2695(1S,2R)-2-(aminomethyl)-N,N-diethyl- IUPAC1-phenylcyclopropane-1-carboxamide; Name: (1S,2R)-2- F2695 (aminomethyl)-N,N-diethyl-1- Pathogenic genes: SLC6A4 IUPAC Name: (1S,2R)-2- phenylcyclopropane-1-carboxamide Mechanistic genes: HCRTR1, HCRTR2, (aminomethyl)-N,N-diethyl-1- HDC,Pathogenic HRH1, genes: SLC6A2, SLC6A4 SLC6A4 Molecularphenylcyclopropane-1-carboxamide Formula: C15H22N2O MetabolicMechanistic genes: genes: HCRTR1, HCRTR2, HDC, HRH1, SLC6A2, SLC6A4 Molecular Formula: C15H22N2O Substrate: ABCB1 (minor), CYP2C19 Molecular Weight: 246.34798 g/mol (minor),Metabolic genes:CYP2C8 (minor), CYP2D6 Substrate: ABCB1 (minor), CYP2C19 Mechanism: Potentiation of serotonin (minor), CYP2J2 (minor), CYP3A4 (major) Molecular Weight: 246.34798 g/mol (minor), CYP2C8 (minor), CYP2D6 and norephinephrine in the central Transporter genes: SLC6A2, SLC6A4 (minor), CYP2J2 (minor), CYP3A4 (major) nervousMechanism: system Potentiation through inhibitionof serotonin of Transporter genes: SLC6A2, SLC6A4 reuptakeand norephinephrine at serotonin in the centraland Int. J. Mol. Sci. 2020, 21, 3059 norepinephrinenervous system transporters through inhibition of 37 of 82 Effect:reuptake Serotonin at uptakeserotonin inhibition; and Norepinephrinenorepinephrine transportersuptake inhibition; AntidepressantEffect: Serotonin activity Tableuptake 4. Cont.inhibition; Norepinephrine uptake inhibition; SelectiveName: Serotonin Milnacipran and Norepinephrine Hydrochloride Reuptake; Inhibitors (SSNRI) Drug Toledomin;Antidepressant Midalcipran; activityProperties Ixel; Savella; Pharmacogenetics Name: Milnacipran Hydrochloride; MilnacipranumName: Milnacipran Hydrochloride; Toledomin; Midalcipran; Ixel; Savella; IUPACToledomin; Midalcipran;Name: Ixel;(1R,2S)-2- Savella; (aminomethyl)-N,N-diethyl-1-MilnacipranumMilnacipranum PathogenicPathogenic genes: genes:BDNF BDNF phenylcyclopropane-1-carboxamideIUPAC Name: (1R,2S)-2- IUPAC Name: Mechanistic genes: ADRA2A, BDNF, (aminomethyl)-N,N-diethyl-1- Mechanistic genes: ADRA2A, (1R,2S)-2-(aminomethyl)-N,N- SLC6A2PathogenicBDNF, SLC6A4 genes:, SLC6A2 BDNF, SLC6A4 Molecularphenylcyclopropane-1-carboxamide Formula: C15H22N2O diethyl-1-phenylcyclopropane-1-carboxamideMetabolicMechanisticMetabolic genes: genes: genes: ADRA2A, BDNF, SLC6A2Substrate:, SLC6A4 COMT, CYP1A2 (minor), MolecularMolecular Formula: Formula: C15HC1522NH222ON 2O Substrate: COMT, CYP1A2 (minor), Molecular Weight: 246.34798 g/mol CYP2A6MetabolicCYP2A6 genes:(minor),(minor), CYP2B6CYP2B6 (minor),(minor), Molecular Weight: 246.34798 g/mol CYP2C8, CYP2C9 (minor), CYP2C19 CYP2C8 Substrate, CYP2C9: COMT , (minor),CYP1A2 CYP2C19(minor), Mechanism:Molecular Weight: It is a 246.34798potent inhibitor g/mol of (minor), CYP2D6 (minor), CYP2E1 Mechanism: It is a potent inhibitor of (minor),CYP2A6 CYP2D6(minor), (minor),CYP2B6 CYP2E1(minor), neuronalneuronal norepinephrine norepinephrine and and serotonin serotonin (minor), CYP3A4/5 (minor), UGTs (minor),CYP2C8 ,CYP3A4/5 CYP2C9 (minor), (minor), UGTs CYP2C19 reuptake.Mechanism:reuptake. It ItItinhibi inhibitsis a tspotent norepinephrinenorepinephrine inhibitor of uptake Inhibitor: CYP3A4/5 (moderate) (minor), Inhibitor: CYP2D6 CYP3A4/5 (minor),(moderate) CYP2E1 uptakeneuronalwith approximately withnorepinephrine approximately 3-fold and higher serotonin 3-fold potency Inducer: CYP1A2, CYP2B6, CYP2C8, (minor), Inducer:CYP2C9 CYP3A4/5 CYP1A2, CYP2C19 (minor),, CYP2B6, CYP3A4 UGTs, CYP2C8 /5 , higherreuptake.in vitro potency thanIt inhibi serotoninin vitrots norepinephrinethan without serotonin directly CYP2C9 Inhibitor:Transporter, CYP2C19 CYP3A4/5,genes: CYP3A4/5 (moderate)SLC6A2 , withoutuptakeaffecting directlywith the uptake approximatelyaffecting of dopaminethe uptake 3-fold or of other Transporter Inducer:SLC6A4 CYP1A2genes: SLC6A2, CYP2B6, SLC6A4, CYP2C8 , dopaminehigherneurotransmitters potency or other in neurotransmittersvitro than serotonin CYP2C9, CYP2C19, CYP3A4/5 withoutEffect: directlyAnalgesic affecting action; the Anti-fibromyalgia uptake of Effect: Analgesic action; Anti- Transporter genes: SLC6A2, SLC6A4 fibromyalgiadopamineaction; Serotoninor otheraction; neurotransmitters uptake Serotonin inhibition; uptake inhibition;Effect:Adrenergic Analgesic uptakeAdrenergic inhibition;action; uptakeAnti- Antidepressant activity inhibition;fibromyalgia Antidepressant action; Serotonin activity uptake inhibition;Name: VenlafaxineAdrenergic Hydrochloride uptake; Name: Venlafaxine Hydrochloride; Pathogenic genes: ABCB1, BDNF, CREB1, inhibition;99300-78-4; Antidepressant VENLAFAXINE activity HCl; Effexor 99300-78-4; VENLAFAXINE HCl; FKBP5,Pathogenic HTR1A, HTR2A, genes: NR3C1,ABCB1, SLC6A3, BDNF, Name:XR; Dobupal;Venlafaxine Trevilor Hydrochloride; Effexor XR; Dobupal; Trevilor SLC6A4,PathogenicCREB1, TPH2 genesFKBP5, : ABCB1, HTR1A, BDNF, HTR2A, CREB1, 99300-78-4; VENLAFAXINE HCl; IUPACIUPAC Name: Name 1-[2-(dimethylamino)-1-: 1-[2-(dimethylamino)-1- MechanisticFKBP5,NR3C1, HTR1A, genes SLC6A3, HTR2A,: BDNF, SLC6A4, NR3C1, FKBP5 TPH2SLC6A3, Effexor(4-methoxyphenyl)ethyl]cyclohexan-1-ol XR; Dobupal; Trevilor (4-methoxyphenyl)ethyl]cyclohexan-1- MetabolicSLC6A4,Mechanistic TPH2 genes: genes: BDNF, FKBP5 IUPAC Name: 1-[2-(dimethylamino)-1- Metabolic genes: ol Molecular Formula: C17H28ClNO2 Mechanistic Substrate: genesABCB1,: BDNF, CYP2C9 FKBP5 (minor) , Int. J. Mol. Sci. 2020, 21, x FOR PEER(4-methoxyphenyl)ethyl]cyclohexan-1- REVIEW Substrate: ABCB1, CYP2C9 39(minor) of 87 , Molecular Weight: 313.86272 g/mol CYP2C19Metabolic genes:(minor) , CYP2D6 (major), Molecularol Formula: C17H28ClNO2 CYP2C19 (minor), CYP2D6 (major), CYP3A4 Substrate (major): ABCB1, CYP2C9 (minor), potent inhibitors of neuronal serotonin ABCG2,CYP3A4 SLC6A2,(major) SLC6A3, SLC6A4 Mechanism: Active metabolite, CYP2C19 (minor), CYP2D6 (major), 17 28 2 InhibitorInhibitor: ABCB1,ABCB1, CYP1A2 CYP1A2 (weak),, andMolecularO-desmethylvenlafaxine norepinephrine Weight:Formula: 313.86272 reuptakeC H ClNO (ODV), g/moland weak are potent Pleiotropic genes: : DRD2, HTR2A, (weak)TPH2 CYP2B6CYP3A4CYP2B6 (weak)(major)(weak), CYP2D6, CYP2D6 (weak)(weak), CYP3A4, inhibitorsinhibitors of do ofpamine neuronal reuptake serotonin and (weak)InhibitorCYP3A4, SLC6A2,: ABCB1,(weak) SLC6A3, , SLC6A2,CYP1A2 SLC6A4 SLC6A3, (weak), Effect:Mechanism:Molecularnorepinephrine Serotonin Weight: Active reuptake313.86272uptake metabolite, and inhibition;g/mol weak O- inhibitors of dopamine reuptake TransporterCYP2B6SLC6A4 (weak) genes, CYP2D6: ABCB1, (weak) , CYP3A4ABCC1, Norepinephrinedesmethylvenlafaxine up take(ODV), inhibition; are Mechanism: Active metabolite, O- (weak)Transporter, SLC6A2, SLC6A3, genes: SLC6A4ABCB1, ABCC1, AntidepressantEffect: Serotonin acti uptakevity; Anti-anxiety inhibition; ABCG2, SLC6A2, SLC6A3, SLC6A4 desmethylvenlafaxine (ODV), are Transporter genes: ABCB1, ABCC1, activity,Norepinephrine Analgesic effects uptake inhibition; Pleiotropic genes: DRD2, HTR2A, Selective SelectiveAntidepressant Serotonin activity;Reuptake Anti-anxiety Inhibitors (SSRI)ReuptakeTPH2 Inhibitors (SSRI) activity, Analgesic effects Drug Properties Pharmacogenetics Selective Serotonin Reuptake Inhibitors (SSRI) Name: Citalopram Hydrobromide; Drug Properties Pharmacogenetics Nitalapram; Cipram; Celexa; Celapram; CiprapineName: Citalopram Hydrobromide; Nitalapram; Cipram; Celexa; Celapram; Pathogenic genes: ABCB1, BDNF, IUPAC Name: 1-[3- Pathogenic genes: ABCB1, BDNF, CREB1, CREB1, CRHR1, CRHR2, FKBP5, Ciprapine CRHR1, CRHR2, FKBP5, GRIA3, GRIK2, (dimethylamino)propyl]-1-(4- GRIA3, GRIK2, GRIK4, GSK3B, IUPAC Name: fluorophenyl)-1,3-dihydro-2- GRIK4HTR1A, GSK3B, ,HTR1B HTR1A, HTR2A, HTR1B, MAOA, HTR2A, , 1-[3-(dimethylamino)propyl] benzofuran-5-carbonitrile MAOASLC6A4, SLC6A4, TPH1, TPH1, TPH2, TPH2 -1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran- MechanisticMechanistic genes: genes:ADRs, CHRMsADRs, CHRMs, DRDs,, 5-carbonitrile Molecular Formula: C20H21FN2O FKBP5DRDs, GABRs, FKBP5, GRIK4, GABRs, HRHs, GRIK4, HTR1A, HRHs, , Molecular Formula: C20H21FN2O HTR1BHTR1A, HTR1D, HTR1B, HTR2A, HTR1D, SLC6A4, HTR2A, TPH1, SLC6A4, TPH1 MolecularMolecular Weight: Weight: 324.391943324.391943 g/mol g/mol Metabolic genes: SubstrateMetabolic: ABCC1 genes:, COMT, CYP2C19 (major), Mechanism: Selectively inhibits serotonin Mechanism: Selectively inhibits CYP2D6Substrate: (minor), CYP3A4ABCC1 (major),, COMT CYP3A5, reuptake in the presynaptic neurons and CYP2C19 (major), CYP2D6 (minor), serotonin reuptake in the presynaptic Inhibitor: ABCB1, CYP1A2 (weak), CYP2B6 has minimal effects on norepinephrine or CYP3A4 (major), CYP3A5 neurons and has minimal effects on (weak), CYP2C19 (weak), CYP2D6 (weak), dopamine Inhibitor: ABCB1, CYP1A2 (weak), norepinephrine or dopamine MAOACYP2B6, MAOB (weak), CYP2C19 (weak), Effect:Effect: SerotoninSerotonin uptake inhibition;inhibition; TransporterCYP2D6 genes(weak),: ABCB1MAOA, SLC6A4, MAOB SerotonergicSerotonergic neurotransmissionneurotransmission enhancer; PleiotropicTransporter genes: BDNF genes: ABCB1, SLC6A4 enhancer;Antidepressive Antidepressive activity, Agitation activity, reduction, Pleiotropic genes: BDNF AgitationAnti-Anxiety reduction, activity Anti-Anxiety activity Name: Escitalopram oxalate; Lexapro; Cipralex; 219861-08-2; UNII- 5U85DBW7LO; Esertia IUPAC Name: (1S)-1-[3- Pathogenic genes: ABCB1, CREB1, (dimethylamino)propyl]-1-(4- FKBP5, GRIA3, GRIK2, GRIK4, NR3C1, fluorophenyl)-1,3-dihydro-2- SLC6A4 benzofuran-5-carbonitrile Mechanistic genes: ADRAs, ADRBs, DDC, DRDs, CHRMs, GABRs, HRHs, Molecular Formula: C22H23FN2O5 HTRs, IL6 Metabolic genes: Molecular Weight: 414.426823 g/mol Substrate: ABCB1, CYP2C9 (minor), CYP2C19 (major), CYP2D6 (major), Mechanism: Inhibits the reuptake of CYP3A4 (major) serotonin with little to no effect on Inhibitor: ABCB1, CYP1A2 (weak), norepinephrine or dopamine reuptake. CYP2C9 (weak), CYP2C19 (weak),

It has very low affinity for 5-HT1-7, α - CYP2D6 (moderate), CYP2E1 (weak), and β-adrenergic, D1-5, H1-3, M1-5, and CYP3A4 (weak), SLC6A4 receptors Transporter genes: ABCB1, SLC6A4 Effect: Serotonin uptake inhibition; Pleiotropic genes: IL6 Serotonergic neurotransmission enhancer; Antidepressive activity; Anti- anxiety activity Name: Fluoxetine Hydrochloride; Pathogenic genes: ABCB1, BDNF, CREB1, Prozac; Fluoxetine Hcl; 59333-67-4; FKBP5, GSK3B, HTR1A, HTR2A, MAOA, Sarafem; Fluctin NR3C1, NTRK2, SLC6A4, TBX21, TPH1, IUPAC Name: methyl({3-phenyl-3-[4- TPH2 (trifluoromethyl)phenoxy]propyl})amin Mechanistic genes: BDNF, CHRMs, CREB1, e DRD3, GSK3B, HTRs, MAOA, SLC6A4, TPH2

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potent inhibitors of neuronal serotonin ABCG2, SLC6A2, SLC6A3, SLC6A4 and norepinephrine reuptake and weak Pleiotropic genes: DRD2, HTR2A, TPH2 inhibitors of dopamine reuptake Effect: Serotonin uptake inhibition; Norepinephrine uptake inhibition; Antidepressant activity; Anti-anxiety activity, Analgesic effects Selective Selective Serotonin Reuptake Inhibitors (SSRI)Reuptake Inhibitors (SSRI) Drug Properties Pharmacogenetics Name: Citalopram Hydrobromide; Nitalapram; Cipram; Celexa; Celapram; Ciprapine IUPAC Name: 1-[3- Pathogenic genes: ABCB1, BDNF, CREB1, (dimethylamino)propyl]-1-(4- CRHR1, CRHR2, FKBP5, GRIA3, GRIK2, fluorophenyl)-1,3-dihydro-2- GRIK4, GSK3B, HTR1A, HTR1B, HTR2A, benzofuran-5-carbonitrile MAOA, SLC6A4, TPH1, TPH2 Mechanistic genes: ADRs, CHRMs, DRDs, Molecular Formula: C20H21FN2O FKBP5, GABRs, GRIK4, HRHs, HTR1A, HTR1B, HTR1D, HTR2A, SLC6A4, TPH1 Molecular Weight: 324.391943 g/mol Metabolic genes: Substrate: ABCC1, COMT, CYP2C19 (major), Mechanism: Selectively inhibits CYP2D6 (minor), CYP3A4 (major), CYP3A5 serotonin reuptake in the presynaptic Inhibitor: ABCB1, CYP1A2 (weak), CYP2B6 neurons and has minimal effects on (weak), CYP2C19 (weak), CYP2D6 (weak), norepinephrine or dopamine MAOA, MAOB Effect: Serotonin uptake inhibition; Transporter genes: ABCB1, SLC6A4 Int. J. Mol. Sci. 2020, 21, 3059 38 of 82 Serotonergic neurotransmission Pleiotropic genes: BDNF enhancer; Antidepressive activity, Agitation reduction, Anti-Anxiety Table 4. Cont. activity Name:Selective Escitalopram Serotonin oxalate; Reuptake Lexapro; Inhibitors (SSRI) Drug Cipralex; 219861-08-2;Properties UNII- Pharmacogenetics 5U85DBW7LO;Name: Escitalopram Esertia oxalate; Lexapro; IUPACCipralex; 219861-08-2;Name: (1S)-1-[3- Pathogenic genes: ABCB1, CREB1, (dimethylamino)propyl]-1-(4- FKBP5, GRIA3, GRIK2, GRIK4, NR3C1, UNII-5U85DBW7LO; Esertia Pathogenic genes: ABCB1, CREB1, SLC6A4 fluorophenyl)-1,3-dihydro-2-IUPAC Name: FKBP5, GRIA3, GRIK2, GRIK4, NR3C1, benzofuran-5-carbonitrile(1S)-1-[3-(dimethylamino)propyl]-1-(4- MechanisticSLC6A4 genes: ADRAs, ADRBs, fluorophenyl)-1,3-dihydro-2-benzofuran-DDCMechanistic, DRDs, CHRMs genes:, ADRAsGABRs,, ADRBsHRHs,, Molecular5-carbonitrile Formula: C22H23FN2O5 HTRsDDC, IL6, DRDs, CHRMs, GABRs, HRHs, MetabolicHTRs, genes:IL6 Molecular Formula: C H FN O 22 23 2 5 Metabolic genes: Molecular Weight: 414.426823 g/mol Substrate: ABCB1, CYP2C9 (minor), Molecular Weight: 414.426823 g/mol CYP2C19Substrate: (major),ABCB1 CYP2D6, CYP2C9 (minor),(major), CYP2C19 (major), CYP2D6 (major), Mechanism:Mechanism: InhibitsInhibits the the reuptake reuptake ofof CYP3A4 (major) CYP3A4 (major) serotoninserotonin with with little little to to nono effeffectect on on Inhibitor: ABCB1, CYP1A2 (weak), Inhibitor: ABCB1, CYP1A2 (weak), norepinephrinenorepinephrine or ordopamine dopamine reuptake. reuptake. It CYP2C9CYP2C9 (weak),(weak), CYP2C19CYP2C19(weak), (weak), has very low affinity for 5-HT , α - and It has very low affinity for 5-HT1-71-7, α - CYP2D6CYP2D6 (moderate),(moderate), CYP2E1CYP2E1 (weak), β-adrenergic, D ,H ,M , and and β-adrenergic, 1-5D1-5, 1-3H1-3, 1-5M1-5, and CYP3A4CYP3A4 (weak),(weak), SLC6A4SLC6A4 benzodiazepine receptors benzodiazepine receptors TransporterTransporter genes: genes: ABCB1ABCB1, SLC6A4, SLC6A4 Effect:Effect: SerotoninSerotonin uptake inhibition;inhibition; PleiotropicPleiotropic genes: genes: IL6 IL6 SerotonergicSerotonergic neurotransmissionneurotransmission enhancer; enhancer;Antidepressive Antidepressi activity;ve activity; Anti-anxiety Anti- activity anxiety activity Name:Name: FluoxetineFluoxetine HydrochlorideHydrochloride; ; Pathogenic genes: ABCB1, BDNF, CREB1, Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW Pathogenic genes: ABCB1, BDNF 40 of , 87 Prozac;Prozac; Fluoxetine Fluoxetine Hcl;Hcl; 59333-67-4;59333-67-4; FKBP5, GSK3B, HTR1A, HTR2A, MAOA, Sarafem; Fluctin CREB1, FKBP5, GSK3B, HTR1A, Sarafem; Fluctin NR3C1, NTRK2, SLC6A4, TBX21, TPH1, MetabolicHTR2A genes:, MAOA , NR3C1, NTRK2, IUPACIUPAC Name: Name :methyl({3-phenyl-3-[4- methyl({3-phenyl-3- TPH2 Molecular Formula: C17H19ClF3NO SubstrateSLC6A4: CYP1A2, TBX21 (major),, TPH1 ,CYP2B6TPH2 (major), Int. J. Mol. Sci. 2020, 21, x FOR PEER[4-(trifluoromethyl)phenoxy]propyl})amine REVIEW 40 of 87 (trifluoromethyl)phenoxy]propyl})amin MechanisticCYP2C8Mechanistic (major), genes CYP2C9: genes: BDNF ,BDNF (major),CHRMs, CHRMs ,CYP2C19 CREB1, , e Molecular Formula: C17H19ClF3NO DRD3(major),CREB1, GSK3B CYP2D6, ,DRD3 HTRs (major),,, MAOAGSK3B ,CYP2E1 ,SLC6A4HTRs ,, MAOA(minor),TPH2 , MetabolicSLC6A4 genes:, TPH2 MolecularMolecular Weight: Weight: 345.78707345.78707 g/mol g/mol CYP3A4/5 (major), POR Molecular Formula: C17H19ClF3NO SubstrateMetabolic: CYP1A2 genes: (major), CYP2B6 (major), Inhibitor: ABCB1, CYP1A2 (moderate), Mechanism: Potentiates serotonergic CYP2C8Substrate: (major),CYP1A2 CYP2C9 (major),(major), CYP2B6CYP2C19 Mechanism: Potentiates serotonergic CYP2B6 (weak), CYP2C8 (moderate), CYP2C9 activity in CNS resulting from its (major),(major), CYP2D6CYP2C8 (major),(major), CYP2E1CYP2C9 (minor), activity in CNS resulting from its (weak), CYP2C19 (moderate), CYP2D6 (strong), Molecularinhibition Weight: of CNS 345.78707 neuronal g/mol reuptake of CYP3A4/5(major), (major),CYP2C19 POR (major), CYP2D6 inhibitionserotonin of CNS neuronal reuptake of CYP3A4 (moderate), MAOA, SLC6A4 Inhibitor:(major), CYP2E1ABCB1, (minor),CYP1A2 CYP3A4(moderate),/5 serotonin Transporter(major), PORgenes: ABCB1, KCNH2, Mechanism: Potentiates serotonergic CYP2B6 (weak), CYP2C8 (moderate), CYP2C9 Effect: Serotonin uptake inhibition; SLC6A4Inhibitor: ABCB1, CYP1A2 activity in CNS resulting from its (weak), CYP2C19 (moderate), CYP2D6 (strong), Serotonin agent; Antidepressive Pleiotropic(moderate), genes:CYP2B6 DRD3,(weak), FABP1,CYP2C8 HTR2A, inhibition of CNS neuronal reuptake of CYP3A4(moderate), (moderate),CYP2C9 MAOA(weak),, SLC6A4CYP2C19 activity;Effect: Anti-obsessiSerotonin uptakeve activity; inhibition; Anti- IFNA1, NTRK2, PDE5A, TPH1 serotonin Transporter(moderate), genes:CYP2D6 ABCB1(strong),, KCNH2,CYP3A4 anxietySerotonin activity; agent; Anorexigenic Antidepressive effects activity; Effect: Serotonin uptake inhibition; SLC6A4(moderate), MAOA, SLC6A4 Name:Anti-obsessive Fluvoxamine activity; Maleate Anti-anxiety; Luvox; Pathogenic genes: BDNF, HTR2A, Serotonin agent; Antidepressive PleiotropicTransporter genes: genes: DRD3ABCB1, FABP1, KCNH2,, HTR2A, 61718-82-9;activity; AnorexigenicFevarin; Faverin; effects Floxyfral SIGMAR1, TPH1 activity; Anti-obsessive activity; Anti- IFNA1SLC6A4, NTRK2, PDE5A, TPH1 IUPAC Name: (2-aminoethoxy)({5- anxiety activity; Anorexigenic effects MechanisticPleiotropic genes genes:: DRD3BDNF, FABP1, HTRs, , methoxy-1-[4- SLC6A4HTR2A, SIGMAR1, IFNA1, NTRK2, PDE5A, TPH1 Name: Fluvoxamine Maleate; Luvox; Pathogenic genes: BDNF, HTR2A, (trifluoromethyl)phenyl]pentylidene})aName: Fluvoxamine Maleate; Luvox; Metabolic genes: 61718-82-9; Fevarin; Faverin; Floxyfral SIGMAR1Pathogenic, TPH1 genes: BDNF, HTR2A, mine61718-82-9; Fevarin; Faverin; Floxyfral Substrate: CYP1A2 (major), CYP2C19 IUPAC Name: (2-aminoethoxy)({5- MechanisticSIGMAR1 , TPH1genes: BDNF, HTRs, (major),Mechanistic CYP2D6 (major), genes: BDNF CYP3A4HTRs (major) Molecularmethoxy-1-[4-IUPAC NameFormula:: (2-aminoethoxy)({5- C19H25F3N2O6 SLC6A4, SIGMAR1 , , Inhibitor:SLC6A4 , SIGMAR1ABCB1, CYP1A2 (strong), (trifluoromethyl)phenyl]pentylidene})amethoxy-1-[4-(trifluoromethyl)phenyl] Metabolic genes: pentylidene})amine CYP2B6Metabolic (weak), genes: CYP2C9 (moderate), Molecularmine Weight: 434.40681 g/mol Substrate: CYP1A2 (major), CYP2C19 CYP2C19Substrate: (moderate),CYP1A2 (major), CYP2C19CYP2D6 Molecular Formula: C19H25F3N2O6 (major), CYP2D6 (major), CYP3A4 (major) Mechanism:Molecular Formula: Inhibits C19 HCNS25F3N 2Oneuron6 (moderate),(major), CYP2D6CYP3A4(major), (weak),CYP3A4 MAOA, Molecular Weight: 434.40681 g/mol Inhibitor: ABCB1, CYP1A2 (strong), serotonin uptake SLC6A4(major) CYP2B6Inhibitor: (weak),ABCB1 CYP2C9, CYP1A2 (moderate),(strong), Effect:MolecularMechanism: Antidepressive Weight:Inhibits 434.40681 CNSactivity; neurong/mol Anti- Transporter genes: ABCB1, KCNH2, CYP2C19CYP2B6 (weak),(moderate),CYP2C9 (moderate),CYP2D6 anxietyserotonin activity; uptake Serotonin uptake SCL6A4 Mechanism: Inhibits CNS neuron (moderate),CYP2C19 CYP3A4(moderate), (weak),CYP2D6 MAOA, inhibition Pleiotropic genes: CREB1, TPH1 serotonin uptake SLC6A4(moderate), CYP3A4 (weak), MAOA, Effect: Antidepressive activity; SLC6A4 Name:Effect: ParoxetineAntidepressive; Paxil; activity; Aropax; Anti-Paxil Transporter genes: ABCB1, KCNH2, Anti-anxiety activity; Serotonin uptake PathogenicTransporter genes: genes: ABCB1ABCB1, KCNH2CREB1, CR; Seroxat; Pexeva SCL6A4 , , anxietyinhibition activity; Serotonin uptake HTR1BSCL6A4, HTR2A, HTR3B, MAOA, SLC6A3, Pleiotropic genes: CREB1, TPH1 IUPACinhibition Name: (3S,4R)-3-[(2H-1,3- SLC6A4Pleiotropic, TNF, TPH1 genes:, TPH2CREB1 , TPH1 benzodioxol-5-yloxy)methyl]-4-(4-Name: Paroxetine; Paxil; Aropax; Paxil Mechanistic genes: CREB1, HTR2A, Pathogenic genes: ABCB1, CREB1, fluorophenyl)piperidineCR; Seroxat; Pexeva HTR3A, SLC6A4, STAT3, TNF HTR1B, HTR2A, HTR3B, MAOA, SLC6A3, Metabolic genes: MolecularIUPAC Formula:Name: C(3S,4R)-3-[(2H-1,3-19H20FNO3 SLC6A4, TNF, TPH1, TPH2 Substrate: ABCB1, COMT, CYP1A2 benzodioxol-5-yloxy)methyl]-4-(4- Mechanistic genes: CREB1, HTR2A, (minor), CYP2C19 (minor), CYP2D6 fluorophenyl)piperidine HTR3A, SLC6A4, STAT3, TNF Molecular Weight: 329.365403 g/mol (major), CYP3A4 (major), MAOA, MAOB Metabolic genes: Molecular Formula: C19H20FNO3 Inhibitor: ABCB1, CYP1A2 (weak), Substrate: ABCB1, COMT, CYP1A2 Mechanism: It is an SSRI. Presumably CYP2B6 (moderate), CYP2C9 (weak), (minor), CYP2C19 (minor), CYP2D6 acts by inhibiting serotonin reuptake CYP2C19 (weak), CYP2D6 (strong), Molecular Weight: 329.365403 g/mol (major), CYP3A4 (major), MAOA, MAOB from brain synapse stimulating its CYP3A4 (weak), SLC6A3, SLC6A4 activity in the brain Inhibitor: ABCB1, CYP1A2 (weak), Mechanism: It is an SSRI. Presumably Transporter genes: ABCB1, SLC6A3, Effect: Serotonin uptake inhibition; CYP2B6 (moderate), CYP2C9 (weak), acts by inhibiting serotonin reuptake SLC6A4 Serotonergic neurotransmission CYP2C19 (weak), CYP2D6 (strong), from brain synapse stimulating its Pleiotropic genes: HTR1D, HTR3C, HTR6, enhancer; Antidepressant activity; Anti- CYP3A4 (weak), SLC6A3, SLC6A4 activity in the brain HTT, TPH1, TPH2 anxiety activity; Anti-obsessive activity. Transporter genes: ABCB1, SLC6A3, Effect: Serotonin uptake inhibition; Name: Sertraline Hydrochloride; SLC6A4 Serotonergic neurotransmission Pathogenic genes: ABCB1, CREB1, GNB3, 79559-97-0; Sertraline HCl; Zoloft; Pleiotropic genes: HTR1D, HTR3C, HTR6, enhancer; Antidepressant activity; Anti- HTR1B, MAOA, SIGMAR1, SLC6A4, TNF, Lustral; Gladem HTT, TPH1, TPH2 anxiety activity; Anti-obsessive activity. TPH1, TPH2 IUPAC Name: (1S,4S)-4-(3,4- Mechanistic genes: HTR1B, HTR1D, Name: Sertraline Hydrochloride; Pathogenic genes: ABCB1, CREB1, GNB3, dichlorophenyl)-N-methyl-1,2,3,4- SIGMAR1, SLC6A2, SLC6A3, SLC6A4, TNF 79559-97-0; Sertraline HCl; Zoloft; HTR1B, MAOA, SIGMAR1, SLC6A4, TNF, tetrahydronaphthalen-1-amine Metabolic genes: Lustral; Gladem TPH1, TPH2 IUPAC Name: (1S,4S)-4-(3,4- Substrate: CYP2A6, CYP2B6 (minor), Molecular Formula: C17H18Cl3N Mechanistic genes: HTR1B, HTR1D, CYP2C9 (minor), CYP2C19 (major), dichlorophenyl)-N-methyl-1,2,3,4- SIGMAR1, SLC6A2, SLC6A3, SLC6A4, TNF tetrahydronaphthalen-1-amine Metabolic genes: Substrate: CYP2A6, CYP2B6 (minor), Molecular Formula: C17H18Cl3N CYP2C9 (minor), CYP2C19 (major),

Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 40 of 87

Metabolic genes: Molecular Formula: C17H19ClF3NO Substrate: CYP1A2 (major), CYP2B6 (major), CYP2C8 (major), CYP2C9 (major), CYP2C19 Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 40 of 87 (major), CYP2D6 (major), CYP2E1 (minor), Molecular Weight: 345.78707 g/mol CYP3A4/5 (major), POR Metabolic genes: Inhibitor: ABCB1, CYP1A2 (moderate), Molecular Formula: C17H19ClF3NO Substrate: CYP1A2 (major), CYP2B6 (major), Mechanism: Potentiates serotonergic CYP2B6 (weak), CYP2C8 (moderate), CYP2C9 CYP2C8 (major), CYP2C9 (major), CYP2C19 activity in CNS resulting from its (weak), CYP2C19 (moderate), CYP2D6 (strong), (major), CYP2D6 (major), CYP2E1 (minor), inhibition of CNS neuronal reuptake of CYP3A4 (moderate), MAOA, SLC6A4 Molecular Weight: 345.78707 g/mol CYP3A4/5 (major), POR serotonin Transporter genes: ABCB1, KCNH2, Inhibitor: ABCB1, CYP1A2 (moderate), Effect: Serotonin uptake inhibition; SLC6A4 Mechanism: Potentiates serotonergic CYP2B6 (weak), CYP2C8 (moderate), CYP2C9 Serotonin agent; Antidepressive Pleiotropic genes: DRD3, FABP1, HTR2A, activity in CNS resulting from its (weak), CYP2C19 (moderate), CYP2D6 (strong), activity; Anti-obsessive activity; Anti- IFNA1, NTRK2, PDE5A, TPH1 inhibition of CNS neuronal reuptake of CYP3A4 (moderate), MAOA, SLC6A4 anxiety activity; Anorexigenic effects serotonin Transporter genes: ABCB1, KCNH2, Name: Fluvoxamine Maleate; Luvox; Effect: Serotonin uptake inhibition; SLC6A4Pathogenic genes: BDNF, HTR2A, 61718-82-9; Fevarin; Faverin; Floxyfral Serotonin agent; Antidepressive PleiotropicSIGMAR1, genes:TPH1 DRD3, FABP1, HTR2A, IUPAC Name: (2-aminoethoxy)({5- activity; Anti-obsessive activity; Anti- IFNA1Mechanistic, NTRK2 , PDE5Agenes: , TPH1BDNF , HTRs, anxietymethoxy-1-[4- activity; Anorexigenic effects SLC6A4, SIGMAR1 (trifluoromethyl)phenyl]pentylidene})a Metabolic genes: Name: Fluvoxamine Maleate; Luvox; Pathogenic genes: BDNF, HTR2A, mine Substrate: CYP1A2 (major), CYP2C19 61718-82-9; Fevarin; Faverin; Floxyfral SIGMAR1, TPH1 (major), CYP2D6 (major), CYP3A4 (major) IUPACMolecular Name: Formula: (2-aminoethoxy)({5- C19H25F3N2O6 Mechanistic genes: BDNF, HTRs, Inhibitor: ABCB1, CYP1A2 (strong), methoxy-1-[4- SLC6A4, SIGMAR1 CYP2B6 (weak), CYP2C9 (moderate), (trifluoromethyl)phenyl]pentylidene})aMolecular Weight: 434.40681 g/mol Metabolic genes: CYP2C19 (moderate), CYP2D6 mine Substrate: CYP1A2 (major), CYP2C19 Int. J. Mol. Sci. 2020, 21, 3059 (moderate), CYP3A4 (weak), MAOA39, of 82 Mechanism: Inhibits CNS neuron (major), CYP2D6 (major), CYP3A4 (major) Molecular Formula: C19H25F3N2O6 SLC6A4 serotonin uptake Inhibitor: ABCB1, CYP1A2 (strong), Transporter genes: ABCB1, KCNH2, Effect: Antidepressive activity; Anti- CYP2B6 (weak), CYP2C9 (moderate), Molecular Weight: 434.40681Table 4. g/molCont. SCL6A4 anxiety activity; Serotonin uptake CYP2C19 (moderate), CYP2D6 inhibition Pleiotropic genes: CREB1, TPH1 Mechanism:Selective Inhibits Serotonin CNS Reuptake neuron Inhibitors (moderate), (SSRI) CYP3A4 (weak), MAOA, Drug Name: ParoxetineProperties; Paxil; Aropax; Paxil SLC6A4 Pharmacogenetics serotonin uptake Pathogenic genes: ABCB1, CREB1, Effect:CR; Seroxat; Antidepressive Pexeva activity; Anti- Transporter genes: ABCB1, KCNH2, Name: Paroxetine; Paxil; Aropax; Paxil CR;HTR1BPathogenic, HTR2A, HTR3B genes:, MAOAABCB1,, SLC6A3CREB1,, Seroxat; Pexeva SCL6A4 anxietyIUPAC activity;Name: Serotonin(3S,4R)-3-[(2H-1,3- uptake SLC6A4HTR1B, TNF, TPH1HTR2A, TPH2, HTR3B , MAOA, Pleiotropic genes: CREB1, TPH1 inhibitionIUPACbenzodioxol-5-yloxy)methyl]-4-(4- Name : (3S,4R)-3-[(2H-1,3- MechanisticSLC6A3 ,genes:SLC6A4 ,CREB1TNF, TPH1, HTR2A, TPH2, Name:benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)piperidine Paroxetine; Paxil; Aropax; Paxil HTR3AMechanistic, SLC6A4, STAT3 genes:, TNFCREB1 , HTR2A, Pathogenic genes: ABCB1, CREB1, CR;fluorophenyl)piperidine Seroxat; Pexeva MetabolicHTR3A genes:, SLC6A4, STAT3, TNF Molecular Formula: C19H20FNO3 HTR1BMetabolic, HTR2A, HTR3B genes:, MAOA, SLC6A3, Molecular Formula: C H FNO Substrate: ABCB1, COMT, CYP1A2 IUPAC Name: (3S,4R)-3-[(2H-1,3-19 20 3 SLC6A4Substrate:, TNF, TPH1ABCB1, TPH2, COMT , CYP1A2 (minor), CYP2C19 (minor), CYP2D6 benzodioxol-5-yloxy)methyl]-4-(4-Molecular Weight: 329.365403 g/mol Mechanistic(minor), genes:CYP2C19 CREB1(minor),, HTR2ACYP2D6, fluorophenyl)piperidineMolecular Weight: 329.365403 g/mol (major), CYP3A4CYP3A4 (major), MAOAMAOA, MAOB Mechanism: It is an SSRI. Presumably actsHTR3A by (major),, SLC6A4, STAT3(major),, TNF , Inhibitor:MAOB ABCB1, CYP1A2 (weak), inhibitingMechanism: serotonin It is an reuptake SSRI. Presumably from brain Metabolic genes: Molecular Formula: C19H20FNO3 CYP2B6Inhibitor: (moderate),ABCB1 CYP2C9CYP1A2 (weak), synapse stimulating its activity in the brain Substrate: ABCB1, COMT, , CYP1A2(weak), acts by inhibiting serotonin reuptake CYP2C19CYP2B6 (weak),(moderate), CYP2D6CYP2C9 (strong),(weak), (minor), CYP2C19 (minor), CYP2D6 from brain synapse stimulating its CYP3A4CYP2C19 (weak),(weak), SLC6A3CYP2D6, SLC6A4(strong), MolecularEffect: Serotonin Weight: uptake 329.365403 inhibition; g/mol (major), CYP3A4 (major), MAOA, MAOB activity in the brain TransporterCYP3A4 genes:(weak), SLC6A3ABCB1, , SLC6A4SLC6A3, SerotonergicEffect: Serotonin neurotransmission uptake inhibition; enhancer; Inhibitor:Transporter ABCB1 genes:, CYP1A2ABCB1 ,(weak),SLC6A3 , Mechanism: It is an SSRI. Presumably SLC6A4 AntidepressantSerotonergic activity;neurotransmission Anti-anxiety activity; CYP2B6SLC6A4 (moderate), CYP2C9 (weak), actsAnti-obsessive by inhibiting activity. serotonin reuptake Pleiotropic genes: HTR1D, HTR3C, HTR6, enhancer; Antidepressant activity; Anti- CYP2C19Pleiotropic (weak), genes: CYP2D6HTR1D (strong),, HTR3C , from brain synapse stimulating its HTT, TPH1, TPH2 anxiety activity; Anti-obsessive activity. CYP3A4HTR6 (weak),, HTT SLC6A3, TPH1,, SLC6A4TPH2 activity in the brain Name:Name: SertralineSertraline Hydrochloride; Hydrochloride;79559-97-0; Transporter genes: ABCB1, SLC6A3, Effect: Serotonin uptake inhibition; PathogenicPathogenic genes: genes:ABCB1ABCB1, CREB1, CREB1, GNB3,, Sertraline79559-97-0; HCl; Sertraline Zoloft; Lustral; HCl; Gladem Zoloft; SLC6A4GNB3 , HTR1B, MAOA, SIGMAR1, Serotonergic neurotransmission HTR1B, MAOA, SIGMAR1, SLC6A4, TNF, IUPACLustral; Name Gladem: (1S,4S)-4-(3,4- PleiotropicSLC6A4 genes:, TNF HTR1D, TPH1, HTR3C, TPH2 , HTR6, enhancer; Antidepressant activity; Anti- TPH1, TPH2 Int. J. Mol. Sci. 2020, 21, x FOR PEERdichlorophenyl)-N-methyl-1,2,3,4- REVIEW HTT, TPH1Mechanistic, TPH2 genes: HTR1B 41, HTR1D of 87 , anxietyIUPAC activity; Name: Anti-obsessive (1S,4S)-4-(3,4- activity. Mechanistic genes: HTR1B, HTR1D, tetrahydronaphthalen-1-amine SIGMAR1, SLC6A2, SLC6A3, SLC6A4, dichlorophenyl)-N-methyl-1,2,3,4- SIGMAR1, SLC6A2, SLC6A3, SLC6A4, TNF Name: Sertraline Hydrochloride; PathogenicCYP2D6TNF genes:(minor), ABCB1 CYP3A4, CREB1 ,(minor), GNB3, Moleculartetrahydronaphthalen-1-amine Formula: C17H18Cl3 N Metabolic genes: 79559-97-0;Molecular Weight:Sertraline 342.69052 HCl; g/molZoloft; HTR1BMAOA,Metabolic ,MAOA MAOB,, SIGMAR1UGT1A1 genes: , ,UGT2B7 SLC6A4 , TNF, Lustral;Molecular Gladem Weight: 342.69052 g/mol Substrate:Substrate: CYP2A6CYP2A6, CYP2B6, CYP2B6 (minor),(minor), Molecular Formula: C17H18Cl3N TPH1 Inhibitor:, TPH2 ABCB1, ACHE, CYP1A1, IUPACMechanism : Name:It has selective(1S,4S)-4-(3,4- inhibitory CYP2C9CYP2C9 (minor),(minor), CYP2C19CYP2C19 (major),(major), Mechanism: It has selective inhibitory effectsMechanisticCYP1A2 (weak), genes: CYP2B6 HTR1B ,(moderate), HTR1D, CYP2D6 (minor), CYP3A4 (minor), dichlorophenyl)-N-methyl-1,2,3,4-oneffects presynaptic on serotoninpresynaptic reuptake serotonin and only CYP2C8 (weak), CYP2C9 (weak), CYP2C19 SIGMAR1MAOA, SLC6A2MAOB, SLC6A3UGT1A1, SLC6A4UGT2B7, TNF tetrahydronaphthalen-1-amineveryreuptake weak and effects only on very norepinephrine weak effects and on , , , Metabolic(moderate),Inhibitor: genes: CYP2D6 ABCB1 (moderate),, ACHE, CYP1A1 CYP3A4, dopaminenorepinephrine neuronal and uptake dopamine neuronal (moderate), Substrate:CYP1A2 SLC6A4CYP2A6(weak), , CYP2B6CYP2B6 (moderate),(minor), Molecularuptake Formula: C17H18Cl3N CYP2C9TransporterCYP2C8 (minor), genes:(weak), CYP2C19CYP2C9ABCB1 , (weak),(major),SLC6A2 ,

Effect: Serotonin uptake inhibition; SLC6A3CYP2C19, SLC6A4(moderate), CYP2D6 ESerotonergicffect: Serotonin uptakeneurotransmission inhibition; Pleiotropic(moderate), genes:CYP3A4 FABP1(moderate),, FOS, GNB3, enhancer; Antidepressant activity; Anti- SLC6A4 Serotonergic neurotransmission enhancer; TPH1, TPH2 Antidepressantanxiety activity; activity; Anti-obsessive Anti-anxiety activity activity; Transporter genes: ABCB1, SLC6A2, Anti-obsessiveSeroto activitySerotonin Modulators SLC6A3, SLC6A4 Drug Properties PleiotropicPharmacogenetics genes: FABP1 , FOS, GNB3, TPH1, TPH2 Name: Nefazodone Hydrochloride; Serotonin Modulators Serzone; Nefazodone Hcl; Dutonin; Drug Properties Pharmacogenetics 82752-99-6; Menfazon Name:IUPAC Nefazodone Name: Hydrochloride 1-{3-[4-(3-; Serzone; Nefazodone Hcl; Dutonin; 82752-99-6; chlorophenyl)piperazin-1-yl]propyl}-3- Menfazon ethyl-4-(2-phenoxyethyl)-4,5-dihydro- IUPAC Name: 1-{3-[4-(3-chlorophenyl) 1H-1,2,4-triazol-5-one PathogenicPathogenic genes genes:: ABCB1ABCB1, , HTR1AHTR1A,, piperazin-1-yl]propyl}-3-ethyl-4-(2-phenoxyethyl) HTR2A -4,5-dihydro-1H-1,2,4-triazol- 5-one HTR2A Molecular Formula: C25H33Cl2N5O2 MechanisticMechanistic genes genes:: ADRA1AADRA1A, HTR1s, HTR1s, , Molecular Formula: C25H33Cl2N5O2 HTR2sHTR2s Metabolic genes: Molecular Weight: 506.46782 g/mol Metabolic genes: Molecular Weight: 506.46782 g/mol Substrate: CYP2D6 (major), CYP3A4 Substrate: CYP2D6 (major), CYP3A4 Mechanism: Blocks potently and selectively (major), CYP3A5 (major) (major), CYP3A5 (major) postsynapticMechanism:5-HT Blocks2A receptors potently and moderatelyand Inhibitor: ABCB1, ABCC2, CYP1A2 inhibitsselectively serotonin postsynaptic and noradrenaline 5-HT reuptake.2A Inhibitor(weak),: CYP2B6ABCB1, (weak),ABCC2CYP2C8, CYP1A2(weak), Alsoreceptors blocks αand1 receptors. moderately Antagonist inhibits of (weak),CYP2D6 CYP2B6(weak), (weak),CYP3A4 CYP2C8(strong), (weak), adrenoceptorsserotonin and alpha noradrenaline 1 and reuptake. CYP2D6SLC6A2 (weak), CYP3A4 (strong), SLC6A2 5-hydroxytryptamine receptors 2 Also blocks α1 receptors. Antagonist of TransporterTransporter genes genes:: ABCB1ABCB1, , ABCC2,, ABCB11, SLC6A2 Eadrenoceptorsffect: Serotonin uptakealpha inhibition;1 and 5- ABCB11, SLC6A2 Noradrenalinehydroxytryptamine uptake receptors inhibition; 2 Alpha-adrenergicEffect: Serotonin antagonism; uptake inhibition; Antidepressant activity; Muscle relaxation, Sedation Noradrenaline uptake inhibition; Alpha-adrenergic antagonism; Antidepressant activity; Muscle relaxation, Sedation Name: Trazodone Hydrochloride; Desyrel; 25332-39-2; Trazodone Hcl; Molipaxin; Trittico IUPAC Name: 2-{3-[4-(3- Pathogenic genes: ABCB1, GNB3, HTR1A, chlorophenyl)piperazin-1-yl]propyl}- HTR2A, SLC6A4 2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3- Mechanistic genes: ADRA1s, ADRA2s, one HRH1, HTR2A, HTR2C Metabolic genes: Molecular Formula: C19H23Cl2N5O Substrate: CYP1A2 (minor), CYP2D6 (minor), CYP3A4 (major), GSTs, SOD2 Inhibitor: CYP2D6 (moderate), CYP3A4 Molecular Weight: 408.32482 g/mol (weak), SLC6A4 Inducer: ABCB1

Mechanism: Inhibits reuptake of Transporter genes: ABCB1, SLC6A4 serotonin, causes adrenoreceptor Pleiotropic genes: GNAS, GNB3, HTR2A subsensitivity, and induces significant changes in 5-HT presynaptic receptor adrenoreceptors. Also significantly

Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 41 of 87

CYP2D6 (minor), CYP3A4 (minor), Molecular Weight: 342.69052 g/mol MAOA, MAOB, UGT1A1, UGT2B7 Inhibitor: ABCB1, ACHE, CYP1A1, Mechanism: It has selective inhibitory CYP1A2 (weak), CYP2B6 (moderate), effects on presynaptic serotonin CYP2C8 (weak), CYP2C9 (weak), CYP2C19 reuptake and only very weak effects on (moderate), CYP2D6 (moderate), CYP3A4 norepinephrine and dopamine neuronal (moderate), SLC6A4 uptake Transporter genes: ABCB1, SLC6A2, Effect: Serotonin uptake inhibition; SLC6A3, SLC6A4 Serotonergic neurotransmission Pleiotropic genes: FABP1, FOS, GNB3, enhancer; Antidepressant activity; Anti- TPH1, TPH2 anxiety activity; Anti-obsessive activity SerotoSerotonin Modulators Drug Properties Pharmacogenetics Name: Nefazodone Hydrochloride; Serzone; Nefazodone Hcl; Dutonin; 82752-99-6; Menfazon IUPAC Name: 1-{3-[4-(3- chlorophenyl)piperazin-1-yl]propyl}-3- ethyl-4-(2-phenoxyethyl)-4,5-dihydro- 1H-1,2,4-triazol-5-one Pathogenic genes: ABCB1, HTR1A, HTR2A Molecular Formula: C25H33Cl2N5O2 Mechanistic genes: ADRA1A, HTR1s, HTR2s Molecular Weight: 506.46782 g/mol Metabolic genes: Substrate: CYP2D6 (major), CYP3A4 Mechanism: Blocks potently and (major), CYP3A5 (major) selectively postsynaptic 5-HT2A Inhibitor: ABCB1, ABCC2, CYP1A2 receptors and moderately inhibits (weak), CYP2B6 (weak), CYP2C8 (weak), CYP2D6 (weak), CYP3A4 (strong), SLC6A2 serotonin and noradrenaline reuptake. Also blocks α1 receptors. Antagonist of Transporter genes: ABCB1, ABCC2, adrenoceptors alpha 1 and 5- ABCB11, SLC6A2 hydroxytryptamine receptors 2 Int. J. Mol. Sci. 2020, 21, 3059 Effect: Serotonin uptake inhibition; 40 of 82 Noradrenaline uptake inhibition; Alpha-adrenergic antagonism; Antidepressant activity;Table 4. Cont.Muscle relaxation, SedationSerotonin Modulators Drug Name: TrazodoneProperties Hydrochloride; Pharmacogenetics Desyrel; 25332-39-2; Trazodone Hcl; Name: Trazodone Hydrochloride; Desyrel; Molipaxin;25332-39-2; Trittico Trazodone Hcl; Molipaxin; Trittico IUPAC Name: 2-{3-[4-(3- IUPAC Name: 2-{3-[4-(3-chlorophenyl) PathogenicPathogenic genes: ABCB1 genes:, GNB3ABCB1, HTR1A, GNB3, chlorophenyl)piperazin-1-yl]propyl}- Int. J. Mol. Sci. 2020, 21, x FOR PEERpiperazin-1-yl]propyl}-2H,3H-[1,2,4]triazolo REVIEW HTR2A, HTR1ASLC6A4, HTR2A , SLC6A4 42 of 87 2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-[4,3-a]pyridin-3-one MechanisticMechanistic genes: genes:ADRA1sADRA1s, ADRA2s, , one HRH1, HTR2AADRA2s, HTR2C, HRH1 , HTR2A, HTR2C Int. J. Mol. Sci. 2020, 21, x FOR PEERblocksMolecular REVIEW histamine Formula: (H1) andC H α1-adrenergicCl N O 42 of 87 19 23 2 5 MetabolicMetabolic genes: genes: receptors Substrate: CYP1A2 (minor), CYP2D6 MolecularMolecular Formula: Weight: 408.32482C19H23Cl2N g5/Omol Substrate: CYP1A2 (minor), CYP2D6 blocks histamine (H1) and α1-adrenergic (minor), CYP3A4 (major), GSTs, SOD2 Mechanism: Inhibits reuptake of serotonin,(minor), CYP3A4 (major), GSTs, SOD2 Effect:receptors Serotonin uptake inhibitor; Anti- Inhibitor: CYP2D6 (moderate), causes adrenoreceptor subsensitivity, and Inhibitor: CYP2D6 (moderate), CYP3A4 anxiety activity; Antidepressant agent; CYP3A4 (weak), SLC6A4 induces significant changes in 5-HT presynaptic(weak), SLC6A4Inducer: ABCB1 HypnoticMolecular effects Weight: 408.32482 g/mol Effect:receptor Serotonin adrenoreceptors. uptake inhibitor; Also significantly Anti- Inducer:Transporter ABCB1 genes: ABCB1, SLC6A4

anxietyblocks histamineactivity;Miscellaneous Antidepressant (H1) and Antidepressantsα1-adrenergic agent; GNAS GNB3 Mechanism: Inhibits reuptake of TransporterPleiotropic genes: ABCB1 genes:, SLC6A4, , Drug Hypnoticreceptors effectsProperties HTR2APharmacogenetics serotonin, causes adrenoreceptor Pleiotropic genes: GNAS, GNB3, HTR2A Name:Effect: SerotoninAgomelatine; uptake inhibitor;138112-76-2; Anti-anxiety subsensitivity,Miscellaneous and induces Antidepressants significant Valdoxan;activity; Antidepressant Thymanax; Melitor; agent; HypnoticN-(2-(7- effects Drug changes in 5-HTProperties presynaptic receptor Pharmacogenetics Methoxynaphthalen-1-Miscellaneous Antidepressants Name:adrenoreceptors. ; Also 138112-76-2;significantly Drug Valdoxan;yl)ethyl)acetamide Thymanax; Properties Melitor; N-(2-(7- Pharmacogenetics Methoxynaphthalen-1-IUPACName: Agomelatine;Name:138112-76-2; N-[2-(7- Valdoxan;

yl)ethyl)acetamidemethoxynaphthalen-1-Thymanax; Melitor; N-(2-(7- IUPACyl)ethyl]acetamideMethoxynaphthalen-1-yl)ethyl)acetamide Name: N-[2-(7- methoxynaphthalen-1-IUPAC Name: N-[2-(7- Molecular Formula: C15H17NO2 Mechanistic genes: HTR2C, MTNR1A, methoxynaphthalen-1-yl)ethyl]acetamide yl)ethyl]acetamide MTNR1B MolecularMolecular Weight: Formula: 243.30098C15H17 NOg/mol2 Metabolic genes: Molecular Formula: C15H17NO2 MechanisticMechanistic genes: genes:HTR2C,HTR2C, MTNR1A, Molecular Weight: 243.30098 g/mol Substrate: CYP1A1 (major), CYP1A2 Category: Melatonergic agonist and 5- MTNR1BMTNR1A, MTNR1B (major), CYP2C9 (minor), CYP2C19 HT2CMolecularCategory: antagonists Weight:Melatonergic 243.30098 agonist g/mol and 5-HT2CMetabolicMetabolic genes: genes: (minor) Substrate: CYP1A1 (major), CYP1A2 Mechanismantagonists: It behaves as an agonist at Substrate: CYP1A1 (major), CYP1A2 Category: Melatonergic agonist and 5- (major), CYP2C9 (minor), CYP2C19 (major), CYP2C9 (minor), CYP2C19 HT2CmelatoninMechanism: antagonists receptorsIt behaves and as as an an antagonist agonist at (minor) melatonin receptors and as an antagonist at(minor) Mechanismat serotonin :(5-HT)(2C) It behaves receptorsas an agonist at serotonin (5-HT)(2C) receptors melatoninEffect: receptorsNorepinephrine-dopamine and as an antagonist atdisinhibitor;E serotoninffect: Norepinephrine-dopamine (5-HT)(2C) Antidepressant receptors activity; disinhibitor; Anti-anxietyEffect:Antidepressant Norepinephrine-dopamineactivity activity;; Sleep Anti-anxiety induction; activity; Sleep induction; Circadian rhythms Circadiandisinhibitor; rhythms Antide resynchronization;pressant activity; resynchronization; Psychological excitement Anti-anxietyPsychological activityexcitement; Sleep reduction induction; reduction Name:Circadian Bupropionrhythms resynchronization;Hydrochloride; 31677-93-7;PsychologicalName: excitementWellbutrin; Hydrochloride; reduction Zyban; 31677-93-7; Wellbutrin; Zyban; Bupropion Hcl Name:Bupropion Bupropion Hcl Hydrochloride; PathogenicPathogenic genes: SLC6A3 genes:, SLC6A3SLC6A4, SLC6A4 31677-93-7;IUPACIUPAC Name: Name :2-(tert-butylamino)-1-(3-Wellbutrin; 2-(tert-butylamino)- Zyban; Mechanistic genes: ADRA1A chlorophenyl)propan-1-one1-(3-chlorophenyl)propan-1-one Mechanistic genes: ADRA1A, CHRNB2, , Bupropion Hcl CHRNB2, DRD2 DRD2Pathogenic genes: SLC6A3, SLC6A4 MolecularIUPACMolecular Name: Formula: Formula: 2-(tert-butylamino)-1-(3- CC13HH19Cl2ClNONO 13 19 2 MetabolicMetabolic genes: genes: chlorophenyl)propan-1-one MechanisticSubstrate: genes:COMT ADRA1A, CYP1A2, CHRNB2(minor),, Molecular Weight: 276.20206 g/mol Substrate: COMT, CYP1A2 (minor), Molecular Weight: 276.20206 g/mol DRD2 CYP2A6 (minor), CYP2B6 (major) Molecular Formula: C13H19Cl2NO Category: Dopamine-Reuptake Inhibitor MetabolicCYP2A6CYP2C9 (minor), genes: (minor),CYP2B6 CYP2C19(major) CYP2C9(minor), Category: Dopamine-Reuptake (minor), Substrate: CYP2D6CYP2C19 COMT(minor), , (minor),CYP1A2CYP2E1 CYP2D6(minor),(minor), InhibitorMolecularMechanism: Weight:It is a 276.20206 relatively g/mol weak inhibitor of the neuronal uptake of norepinephrine and(minor),CYP2A6CYP3A4 CYP2E1(minor), (minor)(minor),CYP2B6 CYP3A4(major) CYP2C9 (minor) Mechanism: It is a relatively weak Category:dopamine Dopamine-Reuptake (minor), Inhibitor: Inhibitor:CYP2C19 CYP2D6CYP2D6 (strong)(minor),(strong) CYP2D6 inhibitorInhibitor of the neuronal uptake of TransporterTransporter genes: genes:SLC6A2SLC6A2, SLC6A3, SLC6A3, , Effect: Dopamine uptake inhibition; (minor), CYP2E1 (minor), CYP3A4 (minor) norepinephrine and dopamine SLC6A4 SLC6A4 Mechanism:Anti-addiction It /Substanceis a relatively abuse treatmentweak Inhibitor: CYP2D6 (strong) Effect: Dopamine uptake inhibition; Pleiotropic genes: DRD2 inhibitoragent; Smoking of the cessationneuronal enhancer; uptake of TransporterPleiotropic genes: genes: DRD2 SLC6A2 , SLC6A3, Anti-addiction/Substance abuse norepinephrineAntidepressant and activity dopamine SLC6A4 treatment agent; Smoking cessation Effect: Dopamine uptake inhibition; Pleiotropic genes: DRD2 Anti-addiction/Substanceenhancer; Antidepressant activity abuse Name:treatment Mirtazapine; agent; Smoking Zispin; Remergil;cessation Pathogenic genes: ABCB1, FKBP5, Remeron;enhancer; 6-Azamianserin;Antidepressant activity Remergon HTR1A, HTR2A, MAOA, SLC6A3, Name:IUPAC Mirtazapine;Name: Zispin;5-methyl-2,5,19- Remergil; SLC6A4Pathogenic, TPH2 genes: ABCB1, FKBP5, Remeron;triazatetracyclo[13.4.0.0², 6-Azamianserin; Remergon HTR1AMechanistic, HTR2A genes:, ADRA1sMAOA,, ADRA2ASLC6A3, 8 IUPAC.0 ,¹³]nonadeca-1(15),8,10,12,16,18- Name: 5-methyl-2,5,19- CHRMs,SLC6A4, FKBP5TPH2 , HRH1, HTR2s, HTR3s triazatetracyclo[13.4.0.0²,hexaene MetabolicMechanistic genes: genes: ADRA1s, ADRA2A, .08,¹³]nonadeca-1(15),8,10,12,16,18- CHRMs, Substrate FKBP5: CYP1A2, HRH1 , HTR2s,(major), HTR3s CYP2C9 Molecular Formula: C17H19N3 (minor), CYP2D6 (major), CYP3A4 (major), hexaene Metabolic genes: Substrate: CYP1A2 (major), CYP2C9 Molecular Formula: C17H19N3 (minor), CYP2D6 (major), CYP3A4 (major),

Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 42 of 87

blocks histamine (H1) and α1-adrenergic receptors

Effect: Serotonin uptake inhibitor; Anti- anxiety activity; Antidepressant agent; Hypnotic effects Miscellaneous Antidepressants Drug Properties Pharmacogenetics Name: Agomelatine; 138112-76-2; Valdoxan; Thymanax; Melitor; N-(2-(7- Methoxynaphthalen-1- yl)ethyl)acetamide IUPAC Name: N-[2-(7- methoxynaphthalen-1- yl)ethyl]acetamide

Molecular Formula: C15H17NO2 Mechanistic genes: HTR2C, MTNR1A, MTNR1B Molecular Weight: 243.30098 g/mol Metabolic genes: Substrate: CYP1A1 (major), CYP1A2 Category: Melatonergic agonist and 5- (major), CYP2C9 (minor), CYP2C19 HT2C antagonists (minor) Mechanism: It behaves as an agonist at melatonin receptors and as an antagonist at serotonin (5-HT)(2C) receptors Effect: Norepinephrine-dopamine disinhibitor; Antidepressant activity; Anti-anxiety activity; Sleep induction; Circadian rhythms resynchronization; Psychological excitement reduction Name: Bupropion Hydrochloride; 31677-93-7; Wellbutrin; Zyban; Bupropion Hcl IUPAC Name: 2-(tert-butylamino)-1-(3- Pathogenic genes: SLC6A3, SLC6A4 chlorophenyl)propan-1-one Mechanistic genes: ADRA1A, CHRNB2, DRD2 Molecular Formula: C13H19Cl2NO Metabolic genes: Int. J. Mol. Sci. 2020, 21, 3059 41 of 82 Molecular Weight: 276.20206 g/mol Substrate: COMT, CYP1A2 (minor), CYP2A6 (minor), CYP2B6 (major) CYP2C9 Category: Dopamine-Reuptake (minor), CYP2C19 (minor), CYP2D6 Inhibitor Table 4. Cont. (minor), CYP2E1 (minor), CYP3A4 (minor) Mechanism: It is a relatively weak Miscellaneous Antidepressants Inhibitor: CYP2D6 (strong) Int. J. Mol. Sci. 2020, 21, x FOR PEERinhibitor REVIEW of the neuronal uptake of Transporter genes: SLC6A2, 43SLC6A3 of 87 , Drug Properties Pharmacogenetics norepinephrine and dopamine SLC6A4 Name: Mirtazapine; Zispin; Remergil; Effect: Dopamine uptake inhibition; PleiotropicUGT1A1,Pathogenic UGT1A3genes: DRD2, genes:UGT1A4 ABCB1, UGT1A6, FKBP5, , Remeron; 6-Azamianserin; Remergon Anti-addiction/SubstanceMolecular Weight: 265.35286 g/molabuse UGT1A7,HTR1A UGT1A9, HTR2A, UGT1A10, MAOA, ,UGT2B7SLC6A3, , treatmentIUPAC Nameagent;: Smoking cessation UGT2B15SLC6A4 , TPH2 2 enhancer;Category:5-methyl-2,5,19-triazatetracyclo[13.4.0.0 Antidepressantα2-Adrenergic Antagonistactivity , InhibitorMechanistic: CYP1A2 genes: (weak),ADRA1s CYP3A4, 8 13 ADRA2A, CHRMs, FKBP5, HRH1, .0 , ]nonadeca-1(15),8,10,12,16,18-hexaene(weak), CYP2D6 (weak), MAOA, MAOB Name: Mirtazapine; Zispin; Remergil; PathogenicHTR2s, genes: HTR3s ABCB1, FKBP5, Mechanism:Molecular Formula:It has centralC H presynapticN Remeron; 6-Azamianserin;17 Remergon19 3 HTR1A Inducer, : HTR2ACYP1A2,, CYP2D6,MAOA, CYP3A4SLC6A3 , α2-adrenergic antagonist effects, which Metabolic genes: Molecular Weight: 265.35286 g/mol Transporter genes: ABCB1, SLC6A3, IUPACresult in Name:increased 5-methyl-2,5,19- release of SLC6A4, TPH2Substrate: CYP1A2 (major), CYP2C9 SLC6A4 (minor), CYP2D6 (major), CYP3A4 triazatetracyclo[13.4.0.0²,norepinephrineCategory: α2-Adrenergic and serotonin. Antagonist Also a Mechanistic genes: ADRA1s, ADRA2A, .08,¹³]nonadeca-1(15),8,10,12,16,18- CHRMs,Pleiotropic FKBP5(major), genes:, HRH1UGT1A1 TPH2, HTR2s, , UGT1A3 HTR3s, UGT1A4 , potentMechanism: antagonistIt has of central5-HT2 presynapticand 5-HT3 hexaene MetabolicUGT1A6 genes: , UGT1A7, UGT1A9, serotoninα2-adrenergic receptors, antagonist H1 e ffects,histamine which result in UGT1A10, UGT2B7, UGT2B15 Substrate: CYP1A2 (major), CYP2C9 receptorsincreased and release a moderate of norepinephrine peripheral α and1- Inhibitor: CYP1A2 (weak), CYP3A4 Molecular Formula: C17H19N3 (minor), CYP2D6 (major), CYP3A4 (major), adrenergicserotonin. and Also muscarinic a potent antagonistantagonist of 5-HT2 (weak), CYP2D6 (weak), MAOA, Effect:and 5-HT Histamine3 serotonin H1 receptors, antagonism; H1 histamine MAOB Adrenergicreceptors and a moderatealpha-antagonism; peripheral Inducer: CYP1A2, CYP2D6, CYP3A4 α Antidepressant1-adrenergic andactivity; muscarinic Anxiolytic antagonist Transporter genes: ABCB1, SLC6A3, effectsEffect: Histamine H1 antagonism; Adrenergic SLC6A4 Pleiotropic genes: TPH2 Name:alpha-antagonism; Reboxetine AntidepressantMesylate; Vestra activity; mesylate;Anxiolytic effectsDavedax mesylate; ReboxetineName: Reboxetine mesilate; Edronax; Mesylate; 98769-84-Vestra mesylate; 7 Davedax mesylate; Reboxetine mesilate; Edronax; 98769-84-7 Pathogenic genes: ABCB1, SLC6A3, IUPAC Name: (2S)-2-[(S)-2- Pathogenic genes: ABCB1, SLC6A3, ethoxyphenoxy(phenyl)methyl]morphoIUPAC Name: (2S)-2-[(S)-2-ethoxyphenoxySLC6A4 SLC6A4 line(phenyl)methyl]morpholine MechanisticMechanistic genes: genes:ADRsADRs, CHRMs, CHRMs, , CHRNs, HRHsCHRNs, DRDs, HRHs, GH1, DRDs, HTRs, GH1, POMC, HTRs, , MolecularMolecular Formula: Formula: C20CH2027HNO27NO6S 6S PRL POMC, PRL Molecular Weight: 409.49648 g/mol MetabolicMetabolic genes: genes: Molecular Weight: 409.49648 g/mol Category: Norepinephrine inhibitor Substrate:Substrate: CYP3A4CYP3A4 (major)(major) Inhibitor:Inhibitor: ABCB1ABCB1, CYP2D6, CYP2D6 (weak),(weak), Category:Mechanism: NorepinephrineIt is a highly inhibitor selective and potent CYP3A4 CYP3A4(weak) (weak) inhibitor of noradrenaline reuptake. Only has Transporter genes: ABCB1, SLC6A2, Mechanism: It is a highly selective and Transporter genes: ABCB1, SLC6A2, weak effect on 5-HT reuptake SLC6A3, SLC6A4 potent inhibitor of noradrenaline SLC6A3, SLC6A4 Effect: Adrenergic uptake inhibitor; Pleiotropic genes: ADRB2, POMC reuptake. Only has weak effect on 5-HT Pleiotropic genes: ADRB2, POMC Antidepressant activity; Anti-anxiety activity; reuptake Attention enhancer Effect: Adrenergic uptake inhibitor; Antidepressant activity; Anti-anxiety The influence of PGxactivity; factors Attention on theenhancer pharmacogenetics and pharmacodynamics of many antidepressantsCYP2C19 and has CYP2D6 been reasonably variants affect well the documented occurrence of [55 ADRs,66,235 in– patients237]; however, treated with important selective aspects suchserotonin as body reuptake weight inhibitors gain, suicidality, (SSRIs) (citalopram, cyclothymic escitalopram, reactions, sertraline, cardiovascular fluvoxamine, risks, fluoxetine, and potential and paroxetine), including anxiety, nightmares, and panic attacks associated with CYP2D6 and neurotoxicity still remain obscure [55]. electrocardiogram (ECG)-prolonged QT associated with CYP2C19 [231]. Prolonged QTc interval is Lithium is the gold standard for the treatment of bipolar disorder (BPD) and BPD-like symptoms prevalent in patients with moderate-severe dementia, with behavioral symptoms, with global and in atemporal reduced atrophy, number and of cases with withleukoaraiosis dementia. [232]. The A response pharmacogenetic to lithium risk is score very variablehas been andproposed depends on thewith PGx top-scoring background SNPs of each(rs12248560, patient rs878567, [238]. Lithium and rs17710780). PGx is very The complex. HTR1A rs878567 Caution and and CYP2C19 personalized dosers12248560 adjustment variants is highly showed recommended association with in depression patients with severity the following[233]. ACE genotypes:variants influenceBCR (Asn796Ser),mood BDNFin AD(C /[111].G (rs988748) The coadministration and G/A (Val66Met)), of ACE inhibitorsCACNG2 and(rs2284017, statins with rs2284018, antidepressants and rs5750285), may affectGSK3B (T-50Ctherapeutic and GSK3-beta*C), outcomes [234].INPP1 (C973A and rs1882891), mtDNA (carriers of the 0398A polymorphism show aThe better influence response of toPGx lithium), factors NTRK2on the pharmacogenetics(rs1387923 and rs1565445),and pharmacodynamics and variants of in many other genes (ABCG2,antidepressants CCND1, has CREB1, been DRD1,reasonably ESR1, well FMR1, documented GRIK2, [55,66,235–237]; IMPA1, IMPA2, however, NR3C1, important PTGES, aspects SLC6A4, and VEGFAsuch)[ as55 body,56,238 weight]. gain, suicidality, cyclothymic reactions, cardiovascular risks, and potential neurotoxicity still remain obscure [55]. 5.3. AnxietyLithium Disorders is the gold standard for the treatment of bipolar disorder (BPD) and BPD-like symptoms inAnxiety-like a reduced number disorders of cases are with present dementia. in 30–40% The response of cases to with lithium dementia is very duringvariable theand disease depends process. on the PGx background of each patient [238]. Lithium PGx is very complex. Caution and personalized Anxiety is a risk factor for dementia [239,240], and anxiety-like behaviors are persistent in patients with dose adjustment is highly recommended in patients with the following genotypes: BCR (Asn796Ser), BDNF (C/G (rs988748) and G/A (Val66Met)), CACNG2 (rs2284017, rs2284018, and rs5750285), GSK3B

Int. J. Mol. Sci. 2020, 21, 3059 42 of 82 dementia. Early-onset AD patients exhibit greater prevalence of all BDs, especially anxiety, irritability, and sleep disorders [241]. The neurobiology of anxiety in dementia is unknown. Subjective cognitive decline (SCD) (self-reported cognitive deficits), without measurable cognitive impairment, has been associated with brain structural alterations and APOE-4. SCD cases show decreased total cortical volumes and cortical surface area, which are especially prominent in APOE-4 carriers. Anxiety symptoms are negatively associated with the right cortical surface area in APOE-4 noncarriers with SCD [242]. Depression, anxiety, and cerebrovascular risk contribute to SCD [243]. Benzodiazepines are currently prescribed for ameliorating this symptomatology; however, benzodiazepines contribute to cognitive and psychomotor dysfunction [244].

5.4. Sleep Disorders Chronic sleep disorders might represent a risk factor for dementia, and alterations in circadian rhythms and consequent sleep disorders are common in AD and age-related disorders [245–248]. The neurobiology of circadian rhythms in AD is not well documented. Different neurotransmitters influence circadian changes and sleep disorders (insomnia, parasomnias, sleep-wake disorders, hypersomnolence, sleep-related movement disorders, and sleep-related breathing disorders), including melatonin, histamine, GABA, hypocretin, dopamine, noradrenaline, serotonin, and adenosine. Genomic alterations in these systems (e.g., pathogenic genes) may affect the efficacy and safety of anxiolytics and hypnotics used in the treatment of some of these disorders [55]. Over 100 genes have been associated with sleep disorders in AD [249]. In the triple transgenic AD mouse model (3 Tg-AD), there is an abnormal expression of Per genes in the suprachiasmatic × nucleus (SCN) [250]. The glymphatic system might be an effective mechanism of brain Aβ-amyloid clearance particularly effective during sleep. Aquaporin-4 may play a role in glymphatic function, since ablation of Aquaporin-4 results in impairment of Aβ clearance mechanism and increased brain Aβ-amyloid deposition. The AQP4 variant rs72878776 is associated with poorer overall sleep quality, and other SNPs might moderate the effect of sleep latency (rs491148, rs9951307, rs7135406, rs3875089, and rs151246) and duration (rs72878776, rs491148, and rs2339214) on brain Aβ-amyloid burden [251]. Homer1a and mGluR1/5 are implicated in sleep function to weaken synapses during sleep and to restore synapse homeostasis [252]. Evening secretion of melatonin is delayed and mildly impaired in patients with AD [253]. Rapid eye movement (REM) sleep influences memory consolidation. Noradrenaline participates in the regulation of REM sleep to maintain neuronal integrity and brain house-keeping functions [254]. Sleep dysfunction and Aβ deposition show synergistic effects to impair brain function. Brain Aβ deposition is associated with subjective measures of sleep quality and cognition. Nocturnal awakenings are associated with Aβ deposition in the precuneus and poor cognitive performance [255]. Extracellular levels of Aβ and tau show a fluctuating pattern during the normal sleep-wake cycle. Increased wakefulness and disturbed sleep lead to increased Aβ production and decreased Aβ clearance; additionally, chronic wakefulness increases Aβ aggregation and deposition, and Aβ accumulation results in disturbed sleep. Sleep deprivation increases brain and CSF tau levels and the spread of tau protein aggregates in neural tissues, correlating with decreased nonrapid eye movement (NREM) sleep slow wave activity [256,257]. Sleep disorders may precede cognitive impairment. Sleep disturbances alter periodic sleep architecture and electroencephalogram (EEG) patterns in prodromal stages [258]. Age-related cognitive impairment is associated with reduced delta, theta, and sigma power as well as spindle maximal amplitude during NREM sleep. Early sleep biomarkers of potential cognitive decline are poor sleep consolidation, lower amplitude, and faster frequency of spindles [259]. Decreased nonrapid eye movement (NREM) sleep slow wave activity associates with Aβ deposition and tauopathy. Aβ decreases nonrapid eye movement sleep and increases wakefulness. Aβ upregulates the expression levels of tau, pTau, orexin A, and [260]. antagonists (e.g., Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 45 of 87

Sleep disorders may precede cognitive impairment. Sleep disturbances alter periodic sleep architecture and electroencephalogram (EEG) patterns in prodromal stages [258]. Age-related cognitive impairment is associated with reduced delta, theta, and sigma power as well as spindle maximal amplitude during NREM sleep. Early sleep biomarkers of potential cognitive decline are Int.poor J. Mol. sleep Sci. 2020consolidation,, 21, 3059 lower amplitude, and faster frequency of spindles [259]. Decreased 43 of 82 nonrapid eye movement (NREM) sleep slow wave activity associates with Aβ deposition and tauopathy. Aβ decreases nonrapid eye movement sleep and increases wakefulness. Aβ upregulates Suvorexant)the expression have levels been ofproposed tau, pTau, as orexin potential A, an candidatesd adenosine for A1 the receptor treatment [260]. of Orexin sleep disordersreceptor and BDs inantagonists AD [261]. (e.g., Suvorexant) have been proposed as potential candidates for the treatment of sleep disorders and BDs in AD [261]. Anxiolytics, hypnotics, and sedatives are associated with the PGx activity of 445 genes. DifferentAnxiolytics, categories hypnotics, of anxiolytics and sedatives (benzodiazepines, are associated with the diphenylmethane PGx activity of 445derivatives, genes. Different carbamates, categories of anxiolytics (benzodiazepines, diphenylmethane derivatives, carbamates, dibenzo- dibenzo-bicyclo-octadiene derivatives, and azaspirodecanodiones), hypnotics, and sedatives bicyclo-octadiene derivatives, and azaspirodecanodiones), hypnotics, and sedatives (, (barbiturates,aldehydes, benzodiazepines, aldehydes, benzodiazepines,piperidinediones, melatonin piperidinediones, receptor , melatonin and other receptor chemicals, agonists, and otheralone chemicals,or in combination) alone are or substrates, in combination) inhibitors, are or inducers substrates, of 47, inhibitors, 18, and 30 enzyme/protein or inducers ofgene 47, 18, and 30products, enzyme respectively,/protein gene and products, are transported respectively, by at least and 30 areprotein transported transporters by (Figures at least 2–3 30 proteinand Table transporters (Figures5). CYP2 enzymesand3 and participate Table5). in CYP the enzymesmetabolism participate of over 92% in theof drugs metabolism of these ofpharmacological over 92% of drugs of thesecategories. pharmacological About 70% of categories. drugs currently About used 70% for of the drugs treatment currently of anxiety, used panic for the attacks, treatment sleep of anxiety, panicdisorders, attacks, agitation, sleep disorders,and behavioral agitation, anomalies and behavioralare major substrates anomalies of are CYP3A4, major substratesfollowed by of CYP3A4, CYP2C19 (41%); CYP3A5 (38%); CYP2D6 (36%); CYP2C9 (30%); CYP1A2 (27%); CYP2B6 (19%); followed by CYP2C19 (41%); CYP3A5 (38%); CYP2D6 (36%); CYP2C9 (30%); CYP1A2 (27%); CYP2B6 UGT1A4 (14%); UGT2B15 (11%); and UGT1A1, UGT1A3, UGT1A6, UGT1A10, and UGT2B7 (8%); (19%);only 10% UGT1A4 are inhibitors (14%); UGT2B15of CYP3A4 (11%);and CYP2C9; and UGT1A1, 8% are inducers UGT1A3, of CYP3A4, UGT1A6, and UGT1A10, about 5% are and UGT2B7 (8%);inducers only of 10% CYP1A2, are inhibitors CYP2A6, CYP7A1, of CYP3A4 and andABCC2. CYP2C9; Over 50% 8% of are these inducers drugs are of CYP3A4,transported and by about 5% areproteins inducers of the of CLCN CYP1A2, family, CYP2A6, 16% are transported CYP7A1, and by ABCB1, ABCC2. 9% Overare transported 50% of these by NQ1I2, drugs and are 5% transported byare proteins transported of the by CLCNABCC2, family, KCNE1, 16% KCNH2, are transported and SLCO1B1. by ABCB1, 9% are is transportedassociated with by 80 NQ1I2, and 5%pharmagenes, are transported Midazolam by ABCC2, is associated KCNE1, with KCNH2, 24, Temazepam and SLCO1B1. is associated Phenobarbital with 20, is associated is with 80associated pharmagenes, with 23, Midazolam and Alprazolam is associated is associated with with 24, 14 [55,103]. Temazepam is associated with 20, Diazepam is associated with 23, and Alprazolam is associated with 14 [55,103]. Table 5. Pharmacological profile and pharmacogenetics of selected anxiolytics, sedatives, and hypnotics. Table5. Pharmacological profile and pharmacogenetics of selected anxiolytics, sedatives, and hypnotics. Barbiturates Drug PropertiesBarbiturates Pharmacogenetics Drug Properties Pharmacogenetics Name: Amobarbital; Amylobarbitone; Name: Amobarbital; Amylobarbitone; Barbamyl;Barbamyl; Pentymal; Pentymal; Amytal; Amytal; Barbamil Barbamil

IUPACIUPAC Name Name:: 5-ethyl-5-(3-methylbutyl)- 5-ethyl-5-(3-methylbutyl)-1,3- 1,3-diazinane-2,4,6-trionediazinane-2,4,6-trione Molecular Formula: C11H18N2O3

MolecularMolecular Weight: Formula:226.27222 C11H18N g2O/mol3 Pathogenic genes: GABRs Pathogenic genes: GABRs Mechanism: Interferes with transmission of Mechanistic genes: CHRNAs, Mechanistic genes: CHRNAs, CLCNs, impulses resulting in an imbalance in central CLCNs, GABRAs, GABRBs, GABRAs, GABRBs, GRIA2, NDUFs inhibitoryMolecular and Weight: facilitatory 226.27222 mechanisms. g/mol Binds to GRIA2, NDUFs Metabolic genes: alpha or beta subunits of GABA-A receptor. MetabolicSubstrate: genesUGT2B7,: UGT2B15 DecreasesMechanism: input Interferes resistance, with depresses transmission burst and of Inducer:Substrate:CYP2A6 UGT2B7, UGT2B15 tonicimpulses firing, resulting especially in inan ventrobasal imbalance andin central TransporterInducer: CYP2A6 genes: CLCNs intralaminar neurons. Increases burst duration inhibitory and facilitatory mechanisms. Binds Transporter genes: CLCNs Int. J. Mol. Sci. 2020, 21, x FOR PEERandto REVIEW alpha mean or conductance beta subunits at of individual GABA-A chloride receptor. 46 of 87 channelsDecreases and input the amplitude resistance, and depresses decay time burst of inhibitory postsynaptic currents. Blocks the andcurrents. tonic firing,Blocks especially the AMPA in ventrobasal receptor and AMPA receptor and appears to bind neuronal intralaminarappears to neuronbind s. neuronalIncreases nicotinicburst nicotinic acetylcholine receptors. durationacetylcholine and meanreceptors. conductance at individual Effect: Hypnotic activity; Sedation; GABA chlorideEffect: Hypnoticchannels activity;and the Sedation;amplitude GABA and modulator decaymodulator time of inhibitory postsynaptic Name: Mephobarbital; Mebaral; Mephobarbitone;Name: Mephobarbital; Enphenemal; Mebaral; Prominal; MethylphenobarbitoneMephobarbitone; Enphenemal; Prominal; Pathogenic genes: GABRA1, Methylphenobarbitone GABRB3, GABRG2, GABRD IUPAC Name: Pathogenic genes: GABRA1, GABRB3, Mechanistic genes: GABRAs, 5-ethyl-1-methyl-5-phenyl-1,3-diazinane-IUPAC Name: 5-ethyl-1-methyl-5-phenyl- GABRG2, GABRD GABRBs, GABRD, GABRE, 2,4,6-trione1,3-diazinane-2,4,6-trione Mechanistic genes: GABRAs, GABRBs, GABRGs,GABRD, GABRE,GABRP, GABRGs, GABRQ, GABRP, MolecularMolecular Formula: Formula:C C1313HH1414N22O3 GABRRsGABRQ, GABRRs Metabolic genes: MolecularMolecular Weight: Weight:246.26186 246.26186 g /g/molmol Metabolic genes: Substrate: CYP2B6 (minor), CYP2C9 Mechanism: Increases seizure threshold in motor Substrate: CYP2B6 (minor), Mechanism: Increases seizure threshold in CYP2C9(minor), CYP2C19(minor), (major),CYP2C19CYP2D6 cortex. Depresses monosynaptic and Inhibitor: CYP2C19 (weak) motor cortex. Depresses monosynaptic and (major), CYP2D6 polysynaptic transmission in CNS. Inducer: CYP2A6 polysynaptic transmission in CNS. Inhibitor: CYP2C19 (weak) EEffectffect: Hypnotic: Hypnotic activity; activity; Sedation; Sedation; Anti-anxiety; Anti- GABA Modulator, Anticonvulsant Inducer: CYP2A6 anxiety; GABA Modulator, Anticonvulsant Name: Pentobarbital; Pentobarbitone; Nembutal; Mebubarbital; Mebumal; Ethamina Pathogenic genes: BDNF, IL6, IUPAC Name: 5-ethyl-5-pentan-2-yl-1,3- TNF diazinane-2,4,6-trione Mechanistic genes: GABRA6, GABRB3, GRIA1, GRIA2, NPY Molecular Formula: C11H18N2O3 Metabolic genes: Substrate: CYP1A2, CYP2B6, Molecular Weight: 226.27222 g/mol CYP2D6, PTGS1, PTGS2 Mechanism: Prolongs the post-synaptic Inducer: CYP2A6, CYP3A4 inhibitory effect of GABA in the thalamus. Transporter genes: KCNE1, Inhibits the excitatory AMPA-type glutamate KCNH2, NR1I2, NR1I3, Pleiotropic genes: APP, BDNF, receptors, resulting in a profound suppression of glutamatergic BLK, CNR1, CRHR1, FOS, neurotransmission ICAM1, IL1B, IL6, KRAS, NPPA, Effect: Hypnotic activity; Sedation; GABA NPY, TNF, TNFRSF1A Modulator; Anticonvulsant; Anesthesia (Adjuvant) Pathogenic genes: CASR, GABRA6, LEP, PSEN1, PTGS2, Name: Phenobarbital; Luminal; TGFB1, TNF Phenobarbitone; Phenobarbitol; Gardenal; Mechanistic genes: CACNs, Phenemal CLCNs, GABRAs, GRIAs, GSTA1, NR1I3 Metabolic genes: Substrate: ABCC2, ACSL4, CBR3, CES1, CES2, COMT, IUPAC Name: 5-ethyl-5-phenyl-1,3- CYP1A2 (minor), CYP2C9 diazinane-2,4,6-trione (minor), CYP2C19 (major), CYP2E1 (minor), CYP4B1, CYP7A1, EPHX1, GSTM1, GSTP1, GSTT1, NNMT, NQO1, TBXAS1, TPMT Inhibitor: ABCB1, ABCC2, Molecular Formula: C12H12N2O3 ABCC4, ABCG2, CYP2C19 (strong), CYP2J2 (strong), CYP27A1 (strong), SLC10A1,

Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 46 of 87

Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 46 of 87 currents. Blocks the AMPA receptor and appears to bind neuronal nicotinic currents. Blocks the AMPA receptor and acetylcholine receptors. appears to bind neuronal nicotinic Effect:acetylcholine Hypnotic receptors. activity; Sedation; GABA modulator Effect: Hypnotic activity; Sedation; GABA Name:modulator Mephobarbital; Mebaral; Mephobarbitone; Enphenemal; Prominal; Pathogenic genes: GABRA1, Name: Mephobarbital; Mebaral; GABRB3, GABRG2, GABRD Methylphenobarbitone Pathogenic genes: GABRA1, Mephobarbitone; Enphenemal; Prominal; Mechanistic genes: GABRAs, IUPAC Name: 5-ethyl-1-methyl-5-phenyl- GABRB3, GABRG2, GABRD Methylphenobarbitone GABRBs, GABRD, GABRE, 1,3-diazinane-2,4,6-trione Mechanistic genes: GABRAs, IUPAC Name: 5-ethyl-1-methyl-5-phenyl- GABRGs, GABRP, GABRQ, GABRBs, GABRD, GABRE, Molecular1,3-diazinane-2,4,6-trione Formula: C13H14 N2O3 GABRRs GABRGs, GABRP, GABRQ, Metabolic genes: MolecularMolecular Weight:Formula: 246.26186 C13H14N 2g/molO3 GABRRs Substrate: CYP2B6 (minor), Metabolic genes: Int. J. Mol. Sci. 2020, 21, 3059 Mechanism:Molecular Weight: Increases 246.26186 seizure g/mol threshold in CYP2C9 (minor), CYP2C19 44 of 82 motor cortex. Depresses monosynaptic and Substrate: CYP2B6 (minor), Mechanism: Increases seizure threshold in (major), CYP2D6 polysynaptic transmission in CNS. CYP2C9 (minor), CYP2C19 motor cortex. Depresses monosynaptic and Inhibitor: CYP2C19 (weak) Effect: Hypnotic activity; Sedation; Anti- (major), CYP2D6 polysynaptic transmissionTable in CNS. 5. Cont. Inducer: CYP2A6 anxiety; GABA Modulator, Anticonvulsant Inhibitor: CYP2C19 (weak) Effect: Hypnotic activity; Sedation; Anti- Name: PentobarbitalBarbiturates; Pentobarbitone; Inducer: CYP2A6 anxiety; GABA Modulator, Anticonvulsant Drug Nembutal; Mebubarbital;Properties Mebumal; Pharmacogenetics Name: Pentobarbital; Pentobarbitone; Ethamina Name:Nembutal; Pentobarbital Mebubarbital;; Pentobarbitone; Mebumal; Pathogenic genes: BDNF, IL6, Nembutal;IUPAC Name: Mebubarbital; 5-ethyl-5-pentan-2-yl-1,3- Mebumal; Ethamina TNF Ethamina Pathogenic genes: BDNF, IL6, diazinane-2,4,6-trione MechanisticPathogenic genes: BDNF,GABRA6, IL6, TNF IUPACIUPAC Name Name:: 5-ethyl-5-pentan-2-yl-1,3- TNF 5-ethyl-5-pentan-2-yl-1,3-diazinane-2,4,6-trione GABRB3,Mechanistic GRIA1, genes: GRIA2,GABRA6, NPY GABRB3, Moleculardiazinane-2,4,6-trione Formula: C 11H18N2O3 Mechanistic genes: GABRA6, MetabolicGRIA1, GRIA2,genes: NPY Molecular Formula: C11H18N2O3 GABRB3,Metabolic GRIA1, genes: GRIA2, NPY Molecular Formula: C11H18N2O3 Substrate: CYP1A2, CYP2B6, Molecular Weight: 226.27222 g/mol MetabolicSubstrate: genes:CYP1A2, CYP2B6, CYP2D6, Molecular Weight: 226.27222 g/mol CYP2D6, PTGS1, PTGS2 PTGS1,Substrate: PTGS2 CYP1A2,Inducer: CYP2B6,CYP2A6, CYP3A4 Mechanism:MechanismMolecular Weight::Prolongs Prolongs 226.27222 the post-synapticthe g/molpost-synaptic Inducer: CYP2A6, CYP3A4 CYP2D6,Transporter PTGS1, genes: PTGS2KCNE1, KCNH2, inhibitoryinhibitory e ffeffectect of of GABA GABA in thein the thalamus. thalamus. TransporterNR1I2, NR1I3, genes: KCNE1, Mechanism: Prolongs the post-synaptic Inducer: CYP2A6, CYP3A4 InhibitsInhibits the the excitatory excitatory AMPA-type AMPA-type glutamate glutamate KCNH2,Pleiotropic NR1I2, genes: NR1I3,APP, BDNF, BLK, receptors,inhibitory resulting effect of in GABA a profound in the suppression thalamus. of Transporter genes: KCNE1, receptors, resulting in a profound PleiotropicCNR1, CRHR1, genes: FOS, APP, ICAM1, BDNF, IL1B, IL6, glutamatergicInhibits the excitatory neurotransmission AMPA-type glutamate KCNH2, NR1I2, NR1I3, suppression of glutamatergic BLK,KRAS, CNR1, NPPA, NPY,CRHR1, TNF, TNFRSF1AFOS, receptors, resulting in a profound Pleiotropic genes: APP, BDNF, Eneurotransmissionffect: Hypnotic activity; Sedation; GABA ICAM1, IL1B, IL6, KRAS, NPPA, suppression of glutamatergic BLK, CNR1, CRHR1, FOS, Modulator;Effect: Hypnotic Anticonvulsant; activity; AnesthesiaSedation; GABA NPY, TNF, TNFRSF1A (Adjuvant)neurotransmission ICAM1, IL1B, IL6, KRAS, NPPA, Modulator; Anticonvulsant; Anesthesia Effect: Hypnotic activity; Sedation; GABA NPY, TNF, TNFRSF1A Name:(Adjuvant) Phenobarbital ; Luminal; Phenobarbitone; Pathogenic genes: CASR, GABRA6, LEP, Phenobarbitol;Modulator; Gardenal;Anticonvulsant; Phenemal Anesthesia PathogenicPSEN1, PTGS2, genes: TGFB1, TNFCASR, (Adjuvant) IUPAC Name: GABRA6,Mechanistic LEP, genes:PSEN1,CACNs, PTGS2, CLCNs, Name: Phenobarbital; Luminal; Pathogenic genes: CASR, 5-ethyl-5-phenyl-1,3-diazinane-2,4,6-trione TGFB1,GABRAs, TNF GRIAs, GSTA1, NR1I3 Phenobarbitone; Phenobarbitol; Gardenal; GABRA6,Metabolic LEP, genes: PSEN1, PTGS2, MolecularName: Formula:PhenobarbitalC H N; O Luminal; Mechanistic genes: CACNs, Phenemal 12 12 2 3 TGFB1,Substrate: TNF ABCC2, ACSL4, CBR3, CES1, Phenobarbitone; Phenobarbitol; Gardenal; CLCNs, GABRAs, GRIAs, GSTA1, Molecular Weight: 232.23528 g/mol MechanisticCES2, COMT, genes: CYP1A2 (minor),CACNs, CYP2C9 NR1I3 Phenemal CYP2C19 CYP2E1 Mechanism: It is a barbituric acid derivative that CLCNs,(minor), GABRAs, GRIAs,(major), GSTA1, Metabolic genes:CYP4B1, CYP7A1, EPHX1, acts as a nonselective central nervous system NR1I3(minor), Substrate:GSTM1, GSTP1, ABCC2, GSTT1, ACSL4, NNMT, NQO1, depressant. It potentiates action on GABA-A Metabolic genes: CBR3,TBXAS1, CES1, TPMT CES2, COMT, receptors,IUPAC andName: modulates 5-ethyl-5-phenyl-1,3- chloride currents Substrate: ABCC2, ACSL4, CYP1A2Inhibitor: (minor),ABCB1, ABCC2,CYP2C9 ABCC4, throughdiazinane-2,4,6-trione receptor channels. It also inhibits CBR3, CES1, CES2, COMT, IUPAC Name: 5-ethyl-5-phenyl-1,3- (minor),ABCG2, CYP2C19CYP2C19(strong), (major),CYP2J2 glutamate induced depolarizations CYP1A2 (minor), CYP2C9 diazinane-2,4,6-trione CYP2E1(strong), CYP27A1(minor), (strong),CYP4B1,SLC10A1, (minor), CYP2C19 (major), CYP7A1,SULT1A1 EPHX1, GSTM1, CYP2E1Inducer: ABCB1,(minor), ABCC1, CYP4B1, ABCC2, ABCC3, GSTP1, GSTT1, NNMT, NQO1, CYP7A1,ABCC4, CYP1A1,EPHX1, CYP1A2, GSTM1, CYP2A6, TBXAS1, TPMT GSTP1,CYP2B6, GSTT1, CYP2C8, NNMT, CYP2C9, NQO1, CYP2C18, Inhibitor: ABCB1, ABCC2, Molecular Formula: C12H12N2O3 TBXAS1,CYP2C19, TPMT CYP2D6, CYP2E1, CYP3A4, ABCC4, ABCG2, CYP2C19 CYP4A11,Inhibitor: CYP4F3,ABCB1, CYP7A1, ABCC2, CYP8B1, Molecular Formula: C12H12N2O3 (strong),CYP24A1, CYP2J2 SCN1A, SLC22A1,(strong), SLCO1B1, ABCC4, ABCG2, CYP2C19 CYP27A1SULT1C2, (strong), SULT2A1, TPMT,SLC10A1, UGT1A1, (strong), CYP2J2 (strong), Effect: Hypnotic activity; Sedation; GABA UGT1A4, UGT1A7, UGT1A9, UGT2B7 Modulator; Anticonvulsant; Carcinogen; Central CYP27A1Transporter (strong), genes: ABCB1,SLC10A1, ABCB11,

Nervous System Depressant; Excitatory Amino ABCC1, ABCC2, ABCC3, ABCC4, ABCC6, Acid Antagonist; Respiratory depression ABCG2, SCN1A, SLC22A1, SLCO1B1, (dose-dependent) SLCO1B3, SLCO2B1, SLC10A1 Pleiotropic genes: ACHE, ADIPOQ, AHR, APOA1, APOE, CAT, CBS, CCND1, CDA, CXCR2, DDC, DPP4, FGB, FKBP5, GH1, GNAS, GRK5, HLA-B, HNF4A, IGF1, IL1B, IL6, LEP, LEPR, LIPC, MET, MTNR1A, NR1I2, NR3C1, PPARGC1A, PRKAB1, PSEN2, RB1, RXRA, TGFB1, TNF Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 47 of 87

Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW SULT1A1 47 of 87 Inducer: ABCB1, ABCC1, ABCC2, ABCC3, ABCC4, Molecular Weight: 232.23528 g/mol SULT1A1 CYP1A1, Inducer: CYP1A2,ABCB1, CYP2A6,ABCC1, ABCC2,CYP2B6, CYP2C8,ABCC3, CYP2C9,ABCC4, CYP2C18, CYP2C19, CYP2D6, Molecular Weight: 232.23528 g/mol CYP1A1, CYP1A2, CYP2A6, CYP2E1, CYP3A4, CYP4A11, Mechanism: It is a barbituric acid derivative CYP2B6, CYP2C8, CYP2C9, CYP4F3, CYP7A1, CYP8B1, that acts as a nonselective central nervous CYP2C18, CYP2C19, CYP2D6, CYP24A1, SCN1A, SLC22A1, system depressant. It potentiates action on CYP2E1, CYP3A4, CYP4A11, Mechanism: It is a barbituric acid derivative SLCO1B1, SULT1C2, SULT2A1, GABA-A receptors, and modulates chloride CYP4F3, CYP7A1, CYP8B1, that acts as a nonselective central nervous TPMT,CYP24A1, UGT1A1,SCN1A, SLC22A1,UGT1A4, systemcurrents depressant. through receptor It potentiates channels. action It also on UGT1A7,SLCO1B1, UGT1A9, SULT1C UGT2B72, SULT2A1, GABA-Ainhibits glutamate receptors, induced and modulates depolarizations chloride TPMT,Transporter UGT1A1, genes: UGT1A4,ABCB1, currents through receptor channels. It also ABCB11, ABCC1, ABCC2, ABCC3, UGT1A7, UGT1A9, UGT2B7 inhibits glutamate induced depolarizations TransporterABCC4, ABCC6, genes: ABCG2, SCN1A,ABCB1, ABCB11,SLC22A1, ABCC1, SLCO1B1, ABCC2, SLCO1B3, ABCC3, SLCO2B1, SLC10A1 ABCC4, ABCC6, ABCG2, SCN1A, Effect: Hypnotic activity; Sedation; GABA SLC22A1,Pleiotropic SLCO1B1,genes: SLCO1B3,ACHE, Modulator; Anticonvulsant; Carcinogen; SLCO2B1,ADIPOQ, SLC10A1AHR, APOA1, APOE, Central Nervous System Depressant; Effect: Hypnotic activity; Sedation; GABA PleiotropicCAT, CBS, CCND1, genes: CDA, CXCR2,ACHE, Excitatory Amino Acid Antagonist; Modulator; Anticonvulsant; Carcinogen; ADIPOQ,DDC, DPP4, AHR, FGB, APOA1, FKBP5, APOE, GH1, Respiratory depression ( dose-dependent) GNAS, GRK5, HLA-B, HNF4A, Central Nervous System Depressant; CAT, CBS, CCND1, CDA, CXCR2, Excitatory Amino Acid Antagonist; DDC,IGF1, IL1B,DPP4, IL6, FGB, LEP, FKBP5, LEPR, LIPC,GH1, Int. J. Mol. Sci. 2020, 21, 3059 Respiratory depression ( dose-dependent) GNAS,MET, MTNR1A, GRK5, HLA-B, NR1I2, HNF4A,NR3C1, 45 of 82 PPARGC1A, PRKAB1, PSEN2, IGF1, IL1B, IL6, LEP, LEPR, LIPC, MET,RB1, RXRA, MTNR1A, TGFB1, NR1I2, TNF NR3C1, BenzodiazepinesTable 5. Cont. PPARGC1A, PRKAB1, PSEN2, Drug Properties RB1, RXRA,Pharmacogenetics TGFB1, TNF Benzodiazepines Name: Alprazolam; Xanax; Trankimazin; Drug BenzodiazepinesProperties Pharmacogenetics Drug Tafil; Cassadan; TranquinalProperties Pharmacogenetics NameIUPAC: Alprazolam; Name: 8-chloro-1-methyl-6-phenyl-Xanax; Trankimazin; Tafil; Cassadan;Name: Alprazolam; Tranquinal Xanax; Trankimazin; 4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepineTafil; Cassadan; Tranquinal IUPAC Name: 8-chloro-1-methyl-6-phenyl- IUPAC Name: 8-chloro-1-methyl-6-phenyl- Pathogenic genes: GABRs 4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepineMolecular Formula: C17H13ClN4 4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine MechanisticPathogenic genesgenes: GABRs: CLCNs, Molecular Formula: C17H13ClN4 GABRsMechanistic genes: CLCNs, GABRs Molecular Weight: 308.76492 g/mol Pathogenic genes: GABRs Molecular Formula: C17H13ClN4 Metabolic genes Molecular Weight: 308.76492 g/mol MechanisticMetabolic genes genes: : : CLCNs, Mechanism: Binds to the GABA Substrate:Substrate: CYP1A1CYP1A1 (minor), (minor), CYP1A2 Mechanism: Binds to the GABA benzodiazepine GABRs benzodiazepineMolecular Weight: 308.76492receptor g/mol complex, CYP1A2(minor), CYP2B6,(minor), CYP2C9,CYP2B6, CYP2C19 receptor complex, particularly in the limbic Metabolic(minor), CYP2D6genes: (minor), CYP3A4/5 particularly in the limbic system and reticular CYP2C9, CYP2C19 (minor), systemMechanism: and reticular Binds formation. to Thethe inhibitoryGABA (major)Substrate: CYP1A1 (minor), formation. The inhibitory effect of GABA on CYP2D6 (minor), CYP3A4/5 effbenzodiazepineect of GABA on neuronalreceptor excitability complex, increases CYP1A2Transporter (minor), genes: CLCNsCYP2B6, (major) theparticularlyneuronal neuronal excitability membranein the limbic increases permeability system theand toneuronalreticular chloride CYP2C9, CYP2C19 (minor), ions resulting in hyperpolarization and Transporter genes: CLCNs formation.membrane Thepermeability inhibitory effectto chloride of GABA ions on CYP2D6 (minor), CYP3A4/5 stabilizationresulting in hyperpolarization and (major) neuronal excitability increases the neuronal Emembranestabilizationffect: Anti-Anxiety permeability Agent; Hypnoticto chloride activity; ions Transporter genes: CLCNs Sedation;resultingEffect: GABA Anti-Anxietyin Modulatorhyperpolarization Agent; Hypnotic and Name:stabilizationactivity; Bromazepam Sedation ; GABA; Compedium; Modulator Creosedin; Lectopam;EffectName:: Bromazepam Lexaurin;Anti-Anxiety Lexilium; Compedium; Agent; Hypnotic Pathogenic genes: GABRs IUPACactivity;Creosedin; Name Sedation Lectopam;: 7-bromo-5-pyridin-; GABA Lexaurin; Modulator Lexilium Mechanistic genes: CLCNs, 2-yl-1,3-dihydro-1,4-benzodiazepin-2-oneIUPACName: Bromazepam Name: 7-bromo-5-pyridin-2-yl-1,3-; Compedium; GABRs Moleculardihydro-1,4-benzodiazepin-2-oneCreosedin; Formula: Lectopam;C Lexaurin;H BrN OLexilium Pathogenic genes: GABRs Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 14 10 3 Metabolic genes: 48 of 87 IUPAC Name: 7-bromo-5-pyridin-2-yl-1,3- MechanisticPathogenic genes:genes:GABRs CLCNs, MolecularMolecular Weight: Formula:316.1527 C14H10BrN g/mol3O Substrate: CYP1A2, CYP2C19, GABRsMechanistic genes: CLCNs, GABRs dihydro-1,4-benzodiazepin-2-oneGABA neuron in the Central Nervous System Mechanism: Binds to stereospecific MetabolicCYP3A4Metabolic (major), genes: genes: CYP3A5 (limbic system, reticular formation). Enhances Inhibitor: CYP2E1 (weak) benzodiazepineMolecular Formula:Weight: receptors 316.1527 C14H on10BrN the g/mol3 postsynapticO Substrate: CYP1A2, CYP2C19,CYP2C19, CYP3A4 the inhibitory GABA-effect on neuronal GABA neuron in the Central Nervous System TransporterCYP3A4(major), (major),CYP3A5 genes: CYP3A5 ABCB1, (limbicMechanism:excitability system, by reticularincreasingBinds formation). cellularto stereospecific permeability Enhances CLCNs Inhibitor: CYP2E1 (weak)(weak) thebenzodiazepineMolecularto inhibitorychloride Weight: GABA-e receptors 316.1527ions,ffect on g/molthe neuronalresulting postsynaptic in Transporter genes: ABCB1, CLCNs Transporter genes: ABCB1, excitabilityhyperpolarization by increasing (a less cellular excitable permeability state) and to Mechanism: Binds to stereospecific CLCNs chloridestabilization ions, resultingof cellular in membrane hyperpolarization (a lessbenzodiazepine excitable state) receptors and stabilization on the postsynaptic of cellular Effect: Anti-Anxiety Agent; GABA membrane Modulator; Skeletal muscle relaxant Effect: Anti-Anxiety Agent; GABA Modulator; Name: Chlordiazepoxide; Chlozepid; Skeletal muscle relaxant Elenium; Chlorodiazepoxide; Name:Methaminodiazepoxide; Chlordiazepoxide; Chlordiazepoxid Chlozepid; Elenium; Chlorodiazepoxide;IUPAC Name: Methaminodiazepoxide;7-chloro-4-hydroxy-N- Chlordiazepoxid methyl-5-phenyl-3H-1,4-benzodiazepin-2- IUPAC Name: 7-chloro-4-hydroxy-N- imine Pathogenic genes: BDNF, methyl-5-phenyl-3H-1,4-benzodiazepin-2-imine CLCNs, GABRs MolecularMolecular Formula: Formula:C C16HH14ClNClN3O 16 14 3 MechanisticPathogenic genes:genes:BDNF, CLCNs, CLCNs, GABRs Molecular Weight: 299.75486 g/mol GABRsMechanistic genes: CLCNs, GABRs Molecular Weight: 299.75486 g/mol Mechanism: Binds to the GABA receptor type A MetabolicMetabolic genes: genes: Substrate: CYP2D6, CYP3A4 (major) andMechanism: increasesthe Binds inhibitory to the GABA effect receptor of GABA type on Substrate: CYP2D6, CYP3A4 neuronal excitability by enhancing neuronal (major)Transporter genes: ABCB1, CLCNs A and increases the inhibitory effect of GABA Pleiotropic genes: BDNF membraneon neuronal permeability excitability to chloride by ions,enhancing thus Transporter genes: ABCB1, resulting in hyperpolarization and stabilization CLCNs neuronal membrane permeability to chloride Effions,ect: thusSedation; resulting Anti-Anxiety in hyperpolarization Agent; GABA and Pleiotropic genes: BDNF Modulator,stabilization Skeletal muscle relaxant, Anticonvulsant; Amnesic properties, Anesthesia Effect: Sedation; Anti-Anxiety Agent; GABA (Adjuvant) Modulator, Skeletal muscle relaxant, Anticonvulsant; Amnesic properties, Anesthesia (Adjuvant) Name: Clobazam; Urbanyl; Chlorepin; Clorepin; Frisium; Clobazamum IUPAC Name: 7-chloro-1-methyl-5-phenyl- 1,5-benzodiazepine-2,4-dione

Molecular Formula: C16H13ClN2O2 Pathogenic genes: GABRA1, GABRB3, GABRG2, GABRD Molecular Weight: 300.73962 g/mol Mechanistic genes: CLCNs, GABRs Mechanism: Binds to stereospecific receptors Metabolic genes: on the postsynaptic GABA neuron at several Substrate: CYP2B6 (minor), sites within the CNS (limbic system, reticular CYP2C18 (minor), CYP2C19 (major), formation). Enhances the inhibitory effect of CYP3A4 (major), CYP3A5 (major) Transporter genes: CLCNs GABA on neuronal excitability by increasing neuronal membrane permeability to chloride ions, which results in hyperpolarization (a less excitable state) and stabilization Effect: Anti-Anxiety Agent; GABA Modulator; Anticonvulsant Name: Clonazepam; Rivotril; Antelepsin; Iktorivil; Chlonazepam; Cloazepam Pathogenic genes: GABRA1 IUPAC Name: 5-(2-chlorophenyl)-7-nitro- Mechanistic genes: GABRAs 1,3-dihydro-1,4-benzodiazepin-2-one Metabolic genes:

Molecular Formula: C15H10ClN3O3 Substrate: CYP3A4/5 (major), NAT2 Molecular Weight: 315.7112 g/mol

Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 48 of 87

GABA neuron in the Central Nervous System Int. J. Mol. Sci. 2020, 21, x FOR PEER(limbic REVIEW system, reticular formation). Enhances 48 of 87 the inhibitory GABA-effect on neuronal GABAexcitability neuron by inincreasing the Central cellular Nervous permeability System (limbicto system,chloride reticular ions, formation). resulting Enhances in thehyperpolarization inhibitory GABA-effect (a less excitable on state)neuronal and excitabilitystabilization by of increasing cellular membrane cellular permeability toEffect :chloride Anti-Anxiety ions, Agent; GABAresulting in hyperpolarizationModulator; Skeletal (a muscleless excitable relaxant state) and stabilizationName: Chlordiazepoxide of cellular membrane; Chlozepid; EffectElenium;: Anti-Anxiety Agent;Chlorodiazepoxide; GABA Modulator;Methaminodiazepoxide; Skeletal muscle Chlordiazepoxid relaxant Name:IUPAC ChlordiazepoxideName: 7-chloro-4-hydroxy-N-; Chlozepid; Elenium;methyl-5-phenyl-3H-1,4-benzodiazepin-2- Chlorodiazepoxide; Methaminodiazepoxide;imine Chlordiazepoxid Pathogenic genes: BDNF, IUPAC Name: 7-chloro-4-hydroxy-N- CLCNs, GABRs Molecular Formula: C16H14ClN3O methyl-5-phenyl-3H-1,4-benzodiazepin-2- Mechanistic genes: CLCNs, imine PathogenicGABRs genes: BDNF, Molecular Weight: 299.75486 g/mol CLCNs,Metabolic GABRs genes: Molecular Formula: C16H14ClN3O Mechanism: Binds to the GABA receptor type Mechanistic Substrate: CYP2D6,genes: CYP3A4CLCNs, A and increases the inhibitory effect of GABA GABRs(major) Molecular Weight: 299.75486 g/mol on neuronal excitability by enhancing MetabolicTransporter genes: genes: ABCB1, CLCNs Mechanism:neuronal membrane Binds to thepermeability GABA receptor to chloride type Substrate: CYP2D6, CYP3A4 Pleiotropic genes: BDNF Aions, and thus increases resulting the inhibitory in hyperpolarization effect of GABA and (major) Int. J. Mol. Sci. 2020, 21, 3059 46 of 82 onstabilization neuronal excitability by enhancing Transporter genes: ABCB1, CLCNs neuronalEffect: Sedation; membrane Anti-Anxiety permeability Agent; to chloride GABA ions,Modulator, thus resulting Skeletal in hyperpolarization muscle relaxant, and Pleiotropic genes: BDNF Table 5. Cont. stabilizationAnticonvulsant; Amnesic properties, EffectAnesthesia: Sedation; (Adjuvant) Anti-AnxietyBenzodiazepines Agent; GABA Drug Modulator,Name: Clobazam SkeletalProperties; Urbanyl; muscle Chlorepin; relaxant, Pharmacogenetics Name:Anticonvulsant;Clorepin; Clobazam Frisium; ; Urbanyl; ClobazamumAmnesic Chlorepin; properties, Clorepin; Frisium;AnesthesiaIUPAC ClobazamumName: (Adjuvant) 7-chloro-1-methyl-5-phenyl- Name:1,5-benzodiazepine-2,4-dione Clobazam; Urbanyl; Chlorepin; IUPAC Name: 7-chloro-1-methyl-5-phenyl- Clorepin; Frisium; Clobazamum 1,5-benzodiazepine-2,4-dioneMolecular Formula: C16H13ClN2O2 IUPAC Name: 7-chloro-1-methyl-5-phenyl- Pathogenic genes: GABRA1, Molecular Formula: C H ClN O Pathogenic genes: GABRA1, GABRB3, 1,5-benzodiazepine-2,4-dione16 13 2 2 GABRB3GABRG2, GABRG2, GABRD, GABRD Molecular Weight: 300.73962 g/mol Molecular Weight: 300.73962 g/mol MechanisticMechanistic genes: genes: CLCNsCLCNs, GABRs, GABRs Molecular Formula: C16H13ClN2O2 Mechanism:Mechanism:Binds Binds to to stereospecific stereospecific receptors receptors on PathogenicMetabolicMetabolic genes: genes:genes: GABRA1, theon postsynaptic the postsynaptic GABA GABA neuron neuron at several at several sites GABRB3 Substrate:, GABRG2 CYP2B6CYP2B6, GABRD(minor), (minor),CYP2C18 Molecular Weight: 300.73962 g/mol (minor), CYP2C19 (major), CYP3A4 withinsites within the CNS the (limbic CNS (limbic system, system, reticular reticular MechanisticCYP2C18 (minor), genes: CYP2C19CLCNs, GABRs (major), (major), CYP3A5 (major) formation).Mechanism:formation). Enhances EnhancesBinds to the stereospecificthe inhibitory inhibitory e receptorsff ecteffect of of MetabolicCYP3A4 (major), genes: CYP3A5 (major) GABA on neuronal excitability by increasing Transporter genes: CLCNs onGABA the postsynapticon neuronal GABAexcitability neuron by atincreasing several Transporter Substrate: genes:CYP2B6 CLCNs (minor), neuronal membrane permeability to chloride neuronal membrane permeability to chloride CYP2C18 (minor), CYP2C19 (major), ions,sites whichwithin results the CNS in hyperpolarization(limbic system, reticular (a less ions, which results in hyperpolarization (a less CYP3A4 (major), CYP3A5 (major) excitableformation). state) Enhances and stabilization the inhibitory effect of GABAexcitable on state) neuronal and stabilizationexcitability by increasing Transporter genes: CLCNs Effect: Anti-Anxiety Agent; GABA Modulator; neuronalEffect: Anti-Anxiety membrane permeabilityAgent; GABA to chloride Anticonvulsant ions,Modulator; which results Anticonvulsant in hyperpolarization (a less Name:excitableName: Clonazepam Clonazepam state) and ;stabilization Rivotril;; Rivotril; Antelepsin; Antelepsin; Int. J. Mol. Sci. 2020, 21, x FOR PEERIktorivil; REVIEW Chlonazepam; Cloazepam 49 of 87 EffectIktorivil;: Anti-Anxiety Chlonazepam; Agent; Cloazepam GABA IUPAC Name: 5-(2-chlorophenyl)-7-nitro- Pathogenic genes: GABRA1 Modulator;Mechanism:IUPAC Name: Anticonvulsant Enhance 5-(2-chlorophenyl)-7-nitro- the activity of γ- 1,3-dihydro-1,4-benzodiazepin-2-one Mechanistic genes: GABRAs Name:aminobutyric1,3-dihydro-1,4-benzodiazepin-2-one Clonazepam acid ;(GABA). Rivotril; Antelepsin;Suppresses the Metabolic genes: MolecularIktorivil;spike-and-wave Chlonazepam; Formula: dischargeC15H Cloazepam10 inClN absence3O3 seizures Molecular Formula: C15H10ClN3O3 Pathogenic Substrate: genes: CYP3A4/5 GABRA1 (major), MolecularIUPACby depressing Name: Weight: nerve5-(2-chlorophenyl)-7-nitro-315.7112 transmission g/mol in the motor NAT2Pathogenic genes: GABRA1 cortex. Depresses all levels of the CNS, Mechanistic genes: GABRAs Mechanism:1,3-dihydro-1,4-benzodiazepin-2-oneEnhance the activity of Mechanistic genes: GABRAsMetabolic Molecular Weight: 315.7112 g/mol Metabolic genes: γ-aminobutyricincluding the limbic acid (GABA). and reticular Suppresses formation, the genes: Molecular Formula: C15H10ClN3O3 Substrate: CYP3A4/5 (major), spike-and-waveby binding to the discharge benzodiazepine in absence site seizures on the by Substrate: CYP3A4/5 (major), NAT2 NAT2 depressingGABA receptor nerve transmission complex and in themodulating motor cortex.MolecularGABA Depresses Weight: all 315.7112 levels of theg/mol CNS, including

theEffect: limbic Anticonvulsant; and reticular formation, GABA Modulator; by binding to theAntipanic benzodiazepine effect site on the GABA receptor complex and modulating GABA Name: Clorazepate Dipotassium; EffTranxilium;ect: Anticonvulsant; Tranxene; GABAAbbott-35616; Modulator; 4306 AntipanicCB; Dipotassium effect clorazepate Name:IUPAC Clorazepate Name: dipotassium;7-chloro-2-oxo-5- Dipotassium; Tranxilium; Tranxene;phenyl-1,3-dihydro-1,4-benzodiazepine-3- Abbott-35616; 4306 CB; Dipotassium clorazepatecarboxylate;hydroxide IUPAC Name: dipotassium;7-chloro-2- oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-Molecular Formula: C16H11ClK2N2O4 carboxylate;hydroxide Pathogenic genes: GABRs Pathogenic genes: GABRs Molecular Formula: C H ClK N O Mechanistic genes: CLCNs, 16 11 2 2 4 Mechanistic genes: CLCNs, GABRs Molecular Weight: 408.91914 g/mol GABRs Molecular Weight: 408.91914 g/mol Metabolic genes: Metabolic genes: Mechanism: Depresses all levels of the CNS, Substrate: CYP3A4 (major), CYP3A5 Mechanism: Depresses all levels of the CNS, Substrate: CYP3A4 (major), including the limbic and reticular formation, by (major) including the limbic and reticular formation, CYP3A5 (major) binding to the benzodiazepine site on the Transporter genes: CLCNs Transporter genes: CLCNs γ-aminobutyricby binding to the acid benzodiazepine (GABA) receptor site complex on the andγ-aminobutyric modulating GABA, acidresulting (GABA) in anreceptor increased neuronalcomplex membrane and modulating permeability GABA, to resulting chloride ionsin whichan producesincreased a hyperpolarizationneuronal membrane and stabilizationpermeability to chloride ions which produces Effa ect:hyperpolarizationSkeletal muscle and relaxant. stabilization Anti-Anxiety Agent;Effect GABA: Skeletal Modulator; muscle relaxant. Anticonvulsant Anti- Anxiety Agent; GABA Modulator; Anticonvulsant Name: Diazepam; Valium; Ansiolisina; Diazemuls; Apaurin; Faustan IUPAC Name: 7-chloro-1-methyl-5-phenyl- 3H-1,4-benzodiazepin-2-one Pathogenic genes: BDNF, CNR1, GABRD Molecular Formula: C16H13ClN2O Mechanistic genes: ACHE, BCHE, BDNF, CACNA1C, Molecular Weight: 284.74022 g/mol CHRMs, GABRs, TSPO Metabolic genes: Mechanism: Binds to stereospecific Substrate: CYP1A2 (minor), benzodiazepine receptors on the postsynaptic CYP2B6 (minor), CYP2C9 GABA neuron at several sites within the CNS. (minor), CYP2C19 (minor), Enhancement of the inhibitory effect of GABA CYP3A4/5 (major), UGTs on neuronal excitability results by increased Inhibitor: CYP2C19 (weak), neuronal membrane permeability to chloride CYP3A4 (weak), UGT2B7 ions, thus resulting in hyperpolarization and Transporter genes: ABCB1 stabilization. It antagonizes with translocator Pleiotropic genes: FOS, IL6, protein SPG7 Effect: Sedation; Anti-Anxiety Agent; GABA Modulator, Skeletal muscle relaxant, Anticonvulsant; Amnesic properties, Anesthesia; Antiemetics

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Mechanism: Enhance the activity of γ- aminobutyric acid (GABA). Suppresses the spike-and-wave discharge in absence seizures by depressing nerve transmission in the motor cortex. Depresses all levels of the CNS, including the limbic and reticular formation, by binding to the benzodiazepine site on the GABA receptor complex and modulating GABA Effect: Anticonvulsant; GABA Modulator; Antipanic effect Name: Clorazepate Dipotassium; Tranxilium; Tranxene; Abbott-35616; 4306 CB; Dipotassium clorazepate IUPAC Name: dipotassium;7-chloro-2-oxo-5- phenyl-1,3-dihydro-1,4-benzodiazepine-3- carboxylate;hydroxide

Molecular Formula: C16H11ClK2N2O4 Pathogenic genes: GABRs Mechanistic genes: CLCNs, Molecular Weight: 408.91914 g/mol GABRs Metabolic genes: Mechanism: Depresses all levels of the CNS, Substrate: CYP3A4 (major), including the limbic and reticular formation, CYP3A5 (major) by binding to the benzodiazepine site on the Transporter genes: CLCNs γ-aminobutyric acid (GABA) receptor complex and modulating GABA, resulting in an increased neuronal membrane permeability to chloride ions which produces Int. J. Mol. Sci. 2020 21 , , 3059 a hyperpolarization and stabilization 47 of 82 Effect: Skeletal muscle relaxant. Anti- Anxiety Agent; GABA Modulator; Anticonvulsant Table 5. Cont. Name: Diazepam; Valium;Benzodiazepines Ansiolisina; Drug Diazemuls; Apaurin;Properties Faustan Pharmacogenetics Name:IUPAC Diazepam Name: ;7-chloro-1-methyl-5-phenyl- Valium; Ansiolisina; Diazemuls; Apaurin; Faustan 3H-1,4-benzodiazepin-2-one Pathogenic genes: BDNF, CNR1, IUPAC Name: 7-chloro-1-methyl-5-phenyl- GABRD 3H-1,4-benzodiazepin-2-one16 13 2 Molecular Formula: C H ClN O Mechanistic genes: ACHE, Pathogenic genes: BDNF, CNR1, GABRD Molecular Formula: C H ClN O 16 13 2 BCHE,Mechanistic BDNF, genes: CACNA1C,ACHE, BCHE, BDNF, MolecularMolecular Weight: Weight:284.74022 284.74022 g /g/molmol CHRMs,CACNA1C, GABRs, CHRMs, TSPO GABRs, TSPO MetabolicMetabolic genes: genes: Mechanism: Binds to stereospecific Mechanism: Binds to stereospecific Substrate: CYP1A2CYP1A2(minor), (minor),CYP2B6 benzodiazepine receptors on the postsynaptic benzodiazepine receptors on the postsynaptic (minor), CYP2C9 (minor), CYP2C19 GABA neuron at several sites within the CNS. CYP2B6 (minor), CYP2C9 (minor), CYP3A4/5 (major), UGTs EnhancementGABA neuron of at the several inhibitory sites ewithinffect of the GABA CNS. on (minor), CYP2C19 (minor), Inhibitor: CYP2C19 (weak), CYP3A4 neuronalEnhancement excitability of the resultsinhibitory by increasedeffect of GABA CYP3A4/5 (major), UGTs (weak), UGT2B7 neuronalon neuronal membrane excitability permeability results by to chlorideincreased Inhibitor: CYP2C19 (weak), Transporter genes: ABCB1 Int. J. Mol. Sci. 2020, 21, x FOR PEERions,neuronal REVIEW thus resultingmembrane in hyperpolarizationpermeability to chloride and CYP3A4 (weak), UGT2B7 50 of 87 Pleiotropic genes: FOS, IL6, SPG7 stabilization.ions, thus resulting It antagonizes in hyperpolarization with and Transporter genes: ABCB1 translocatorstabilization.Name: Estazolam protein It antagonizes; Eurodin; with Nuctalon; translocator Pleiotropic genes: FOS, IL6, Int. J. Mol. Sci. 2020, 21, x FOR PEEREproteinffProSom; ect:REVIEWSedation; Esilgan; Anti-Anxiety Julodin Agent; GABA SPG7 50 of 87 Modulator,Effect: Sedation; Skeletal Anti-Anxiety muscle relaxant, Agent; GABA Anticonvulsant;IUPAC Name: Amnesic 8-chloro-6-phenyl-4H- properties, Anesthesia; Modulator,Name: Estazolam Skeletal; Eurodin; muscle relaxant, Nuctalon; Antiemetics[1,2,4]triazolo[4,3-a][1,4]benzodiazepine Anticonvulsant;ProSom; Esilgan; Amnesic Julodin properties, Name:Anesthesia; Estazolam Antiemetics; Eurodin; Nuctalon; ProSom; Molecular Formula: C16H11ClN4 Esilgan;IUPAC Julodin Name: 8-chloro-6-phenyl-4H- Pathogenic genes: GABRB3 [1,2,4]triazolo[4,3-a][1,4]benzodiazepine Mechanistic genes: CLCNs, IUPAC Name: 8-chloro-6-phenyl-4H-[1,2,4] triazolo[4,3-a][1,4]benzodiazepineMolecular Weight: 294.73834 g/mol GABRAs, GABRBs, GABRD, Molecular Formula: C16H11ClN4 PathogenicGABRE, genes:GABRGs, GABRB3 GABRP, Molecular Formula: C H ClN Mechanism: Binds16 11to 4 stereospecific GABRQ, GABRRs, TSPO MechanisticPathogenic genes:genes:GABRB3 CLCNs, Molecularbenzodiazepine Weight: receptors294.73834 on g the/mol postsynaptic Molecular Weight: 294.73834 g/mol GABRAs,MetabolicMechanistic genes:GABRBs, genes: CLCNs,GABRD, GABRAs, Mechanism:GABA neuronBinds at several to stereospecific sites within the CNS, GABRE, GABRBs,Substrate GABRD,GABRGs,: CYP1A2, GABRE, CYP2A6,GABRP, GABRGs, benzodiazepineMechanism:including the receptors Bindslimbic ontosystem, the postsynapticstereospecific reticular GABRQ,CYP2C9,GABRP, GABRRs, GABRQ,CYP2C19, TSPO GABRRs, CYP2D6, TSPO GABAbenzodiazepineformation. neuron Enhancement at severalreceptors sites onof within the the postsynaptic theinhibitory CNS, MetabolicCYP2E1,Metabolic genes: genes:CYP3A4 (major), includingGABAeffect neuronof the GABA limbic at several system,on neuronal sites reticular within excitability formation.the CNS, CYP3A5 Substrate:Substrate (major: CYP1A2,CYP1A2,) CYP2A6, CYP2A6, CYP2C9, Enhancementincludingresults by the ofincreased the limbic inhibitory neuronal system, effect ofmembranereticular GABA on CYP2C9,TransporterCYP2C19, CYP2C19, CYP2D6,genes: CLCNs CYP2E1,CYP2D6, CYP3A4 neuronal excitability results by increased (major), CYP3A5 (major) formation.permeability Enhancement to chloride ions.of the This inhibitory shift in CYP2E1, CYP3A4 (major), neuronal membrane permeability to chloride Transporter genes: CLCNs effectchloride of ionsGABA results on inneuronal hyperpolarization excitability (a CYP3A5 (major) ions.less Thisexcitable shift instate) chloride and stabilization ions results in hyperpolarizationresults by increased (a less excitableneuronal state)membrane and Transporter genes: CLCNs Effect: Anti-Anxiety Agent; GABA stabilizationpermeability to chloride ions. This shift in chlorideModulator; ions Hypnotic results inactivity; hyperpolarization Sedation; (a Effect: Anti-Anxiety Agent; GABA Modulator; lessSkeletal excitable muscle state) relaxant; and stabilization Anticonvulsant Hypnotic activity; Sedation; Skeletal muscle relaxant;EffectName:: Anti-Anxiety AnticonvulsantFlurazepam; Dalmane;Agent; GABA Dalmadorm; Modulator;Flurazepamum; Hypnotic Felmane; activity; Noctosom Sedation; Name: Flurazepam; Dalmane; Dalmadorm; SkeletalIUPAC muscle relaxant;Name: Anticonvulsant7-chloro-1-[2- Flurazepamum; Felmane; Noctosom Name:(diethylamino)ethyl]-5-(2-fluorophenyl)-3H- Flurazepam; Dalmane; Dalmadorm; IUPACFlurazepamum;1,4-benzodiazepin-2-one Name: Felmane; Noctosom 7-chloro-1-[2-(diethylamino)ethyl]-5-(2- Pathogenic genes: GABRB3 IUPAC Name: 7-chloro-1-[2- fluorophenyl)-3H-1,4-benzodiazepin-2-oneMolecular Formula: C21H23ClFN3O MechanisticPathogenic genes:genes: GABRB3CACNA1C, (diethylamino)ethyl]-5-(2-fluorophenyl)-3H- Mechanistic genes: CACNA1C, CLCNs, Molecular Formula: C21H23ClFN3O CLCNs, GABRs 1,4-benzodiazepin-2-one GABRs Molecular Weight: 387.878223 g/mol PathogenicMetabolic genes: genes: GABRB3 Molecular Weight: 387.878223 g/mol Metabolic genes: Molecular Formula: C21H23ClFN3O Mechanistic Substrate: genes:CYP3A4 CACNA1C, (major), Mechanism:Mechanism:Binds Binds to stereospecific to stereospecific Substrate: CYP3A4 (major), CYP3A5 CLCNs,CYP3A5 GABRs (major) , MAO benzodiazepine receptors on the postsynaptic (major), MAO benzodiazepine receptors on the postsynaptic Inhibitor: ABCB1, CYP2E1 GABAMolecular neuron Weight: at several 387.878223 sites within g/mol the CNS, MetabolicInhibitor: genes:ABCB1, CYP2E1 (weak) GABA neuron at several sites within the CNS, (weak) including the limbic system, reticular formation. TransporterSubstrate: genes:CYP3A4ABCB1, (major) CACNA1C,, Mechanism:including the Bindslimbic tosystem, stereospecific reticular Enhancement of inhibitory effect of GABA on CYP3A5TransporterCLCNs (major) genes:, MAO ABCB1, formation. Enhancement of inhibitory effect neuronalbenzodiazepine excitability receptors results on by the increased postsynaptic CACNA1C, Inhibitor: CLCNs ABCB1, CYP2E1 of GABA on neuronal excitability results by neuronalGABA neuron membrane at several permeability sites within to chloride the CNS, ions (weak) includingincreased neuronalthe limbic membrane system, permeability reticular Effect: Anti-Anxiety Agent; GABA Modulator; Transporter genes: ABCB1, formation.to chloride Enhancementions of inhibitory effect Sedation CACNA1C, CLCNs ofEffect GABA: Anti-Anxiety on neuronal Agent; excitability GABA results by increasedModulator; neuronal Sedation membrane permeability toName: chloride Lorazepam ions ; Ativan; Temesta; O- EffectChloroxazepam;: Anti-Anxiety O-Chlorooxazepam; Agent; GABA Modulator;Almazine Sedation Pathogenic genes: GABRs Name:IUPAC Lorazepam Name: 7-chloro-5-(2-chlorophenyl)-3-; Ativan; Temesta; O- Mechanistic genes: CLCNs, Chloroxazepam;hydroxy-1,3-dihydro-1,4-benzodiazepin-2- O-Chlorooxazepam; GABRs, TSPO Almazineone PathogenicMetabolic genes: genes: GABRs IUPAC Name: 7-chloro-5-(2-chlorophenyl)-3- Mechanistic Substrate: CYP3A4genes: (minor)CLCNs,, hydroxy-1,3-dihydro-1,4-benzodiazepin-2-Molecular Formula: C15H10Cl2N2O2 GABRs,UGT1A1, TSPO UGT1A3, UGT1A4, one MetabolicUGT1A6, genes:UGT1A7, UGT1A9, UGT1A10, Substrate: UGT2B4,CYP3A4 UGT2B7,(minor), Molecular Weight: 321.1581 g/mol Molecular Formula: C15H10Cl2N2O2 UGT2B15 UGT1A1, UGT1A3, UGT1A4, UGT1A6,Transporter UGT1A7, genes: CLCNs UGT1A9, Mechanism: Binds to stereospecific UGT1A10, UGT2B4, UGT2B7, Molecularbenzodiazepine Weight: receptors 321.1581 ong/mol postsynaptic UGT2B15 GABA neuron at several sites within CNS, Transporter genes: CLCNs Mechanism: Binds to stereospecific benzodiazepine receptors on postsynaptic GABA neuron at several sites within CNS,

Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 50 of 87

Name: Estazolam; Eurodin; Nuctalon; ProSom; Esilgan; Julodin IUPAC Name: 8-chloro-6-phenyl-4H- [1,2,4]triazolo[4,3-a][1,4]benzodiazepine

Molecular Formula: C16H11ClN4 Pathogenic genes: GABRB3 Mechanistic genes: CLCNs, Molecular Weight: 294.73834 g/mol GABRAs, GABRBs, GABRD, GABRE, GABRGs, GABRP, Mechanism: Binds to stereospecific GABRQ, GABRRs, TSPO benzodiazepine receptors on the postsynaptic Metabolic genes: GABA neuron at several sites within the CNS, Substrate: CYP1A2, CYP2A6, including the limbic system, reticular CYP2C9, CYP2C19, CYP2D6, formation. Enhancement of the inhibitory CYP2E1, CYP3A4 (major), effect of GABA on neuronal excitability CYP3A5 (major) results by increased neuronal membrane Transporter genes: CLCNs permeability to chloride ions. This shift in chloride ions results in hyperpolarization (a less excitable state) and stabilization Effect: Anti-Anxiety Agent; GABA Modulator; Hypnotic activity; Sedation; Skeletal muscle relaxant; Anticonvulsant Name: Flurazepam; Dalmane; Dalmadorm; Flurazepamum; Felmane; Noctosom IUPAC Name: 7-chloro-1-[2- (diethylamino)ethyl]-5-(2-fluorophenyl)-3H- 1,4-benzodiazepin-2-one Pathogenic genes: GABRB3 Molecular Formula: C21H23ClFN3O Mechanistic genes: CACNA1C, CLCNs, GABRs Molecular Weight: 387.878223 g/mol Metabolic genes: Substrate: CYP3A4 (major), Mechanism: Binds to stereospecific CYP3A5 (major), MAO Int. J. Mol. Sci. 2020, 21, 3059 48 of 82 benzodiazepine receptors on the postsynaptic Inhibitor: ABCB1, CYP2E1 GABA neuron at several sites within the CNS, (weak) including the limbic system, reticular Transporter genes: ABCB1,

formation. EnhancementTable of inhibitory 5. Cont. effect CACNA1C, CLCNs of GABA on neuronal excitability results by increased neuronal membraneBenzodiazepines permeability Drug Properties Pharmacogenetics to chloride ions Name:Effect :Lorazepam Anti-Anxiety; Ativan; Agent; Temesta; GABA O-Chloroxazepam; O-Chlorooxazepam; Int. J. Mol. Sci. 2020, 21, x FOR PEERModulator; REVIEW Sedation 51 of 87 Almazine Name: Lorazepam; Ativan; Temesta; O- IUPAC Name: 7-chloro-5-(2-chlorophenyl)- Chloroxazepam;including limbic O-Chlorooxazepam;system, reticular formation. 3-hydroxy-1,3-dihydro-1,4-benzodiazepin-2-one AlmazineEnhancement of inhibitory effect of GABA on Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW Pathogenic genes: GABRs 51 of 87 MolecularIUPACneuronal Name: Formula:excitability 7-chloro-5-(2-chlorophenyl)-3-C15 Hresults10Cl2 Nby2O 2 increased MechanisticPathogenic genes:genes:GABRs CLCNs, Molecularhydroxy-1,3-dihydro-1,4-benzodiazepin-2-neuronal Weight:membrane321.1581 permeability g/mol to chloride including limbic system, reticular formation. Mechanistic genes: CLCNs, GABRs, ions. This shift in chloride ions results in GABRs, TSPO Mechanism:oneEnhancement Binds of inhibitory to stereospecific effect of GABA on TSPO hyperpolarization (a less excitable state) and Metabolic genes: benzodiazepineneuronal excitability receptors results on postsynaptic by increased GABA Metabolic genes: stabilization. Binds to GABAA receptors Substrate: CYP3A4 (minor), neuronMolecularneuronal at several membrane Formula: sites C withinpermeability15H10Cl CNS,2N2O including2to chloride Substrate: CYP3A4 (minor), UGT1A1, enhancing the effects of GABA by increasing UGT1A1, UGT1A3, UGT1A4, limbicions. system,This shift reticular in chloride formation. ions Enhancement results in UGT1A3, UGT1A4, UGT1A6, UGT1A7, GABA affinity for its receptor UGT1A6,UGT1A9, UGT1A10,UGT1A7, UGT2B4,UGT1A9, UGT2B7, ofhyperpolarization inhibitory effect of (a GABA less excitable on neuronal state) and excitabilityEffect: Anti-Anxiety results byincreased Agent; GABA neuronal UGT1A10,UGT2B15 UGT2B4, UGT2B7, Molecularstabilization. Weight: Binds 321.1581 to GABAA g/mol receptors membraneModulator; permeability Sedation; Skeletal to chloride muscle ions. This UGT2B15Transporter genes: CLCNs enhancing the effects of GABA by increasing shiftrelaxant; in chloride Anticonvulsant. ions results Antiemetic; in hyperpolarization Transporter genes: CLCNs Mechanism:GABA affinity forBinds its receptor to stereospecific (aHypnotic less excitable activity; state) Preanesthetic and stabilization. agent Binds to GABAAbenzodiazepineEffect: receptorsAnti-Anxiety enhancingreceptors Agent; the onGABA effpostsynapticects of GABA byGABAName:Modulator; increasing Midazolamneuron Sedation; GABA at several;a Versed;ffi Skeletalnity sites for Dormicum; muscle its within receptor CNS, Midazolamum; 59467-70-8; Midazolamum Effrelaxant;ect: Anti-Anxiety Anticonvulsant. Agent; Antiemetic; GABA Modulator; Sedation;IUPACHypnotic Name: Skeletal activity; 8-chloro-6-(2-fluorophenyl)-1- muscle Preanesthetic relaxant; agent Anticonvulsant.methyl-4H-imidazo[1,5-Name: Midazolam Antiemetic;; Versed; Hypnotic Dormicum; activity; Mechanistic genes: CLCNs, Preanesthetica][1,4]benzodiazepineMidazolamum; agent 59467-70-8; Midazolamum GABRs Name:IUPAC Midazolam Name: 8-chloro-6-(2-fluorophenyl)-1-; Versed; Dormicum; Metabolic genes: Molecular Formula: C18H13ClFN3 Midazolamum; 59467-70-8; Midazolamum Substrate: CYP1A2, CYP2A6, methyl-4H-imidazo[1,5- Mechanistic genes: CLCNs, CYP2B6 (minor), CYP2C19 IUPACa][1,4]benzodiazepine Name: 8-chloro-6-(2-fluorophenyl)- GABRs 1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepineMolecular Weight: 325.767323 g/mol (minor), CYP2D6, CYP2E1, MetabolicMechanistic genes: genes: CLCNs, GABRs Molecular Formula: C18H13ClFN3 CYP3A4 (major), CYP3A5 MolecularMechanism: Formula: BindsC18 H13toClFN stereospecific3 MetabolicSubstrate: genes:CYP1A2, CYP2A6, (major)Substrate:, CYP3A7,CYP1A2, CYP2A6,UGT1A4, CYP2B6 Molecularbenzodiazepine Weight: receptors325.767323 on g/ molpostsynaptic CYP2B6 (minor), CYP2C19 UGT2B7,(minor) ,UGT2B10 CYP2C19 (minor), CYP2D6, GABAMolecular neuron. Weight: Enhancement 325.767323 g/molof inhibitory (minor), CYP2D6, CYP2E1, Mechanism: Binds to stereospecific CYP2E1,Inhibitor: CYP3A4 CYP2C8(major) (weak), CYP3A5, effect of GABA on neuronal excitability results CYP3A4 (major), CYP3A5 benzodiazepineMechanism: receptorsBinds onto postsynaptic stereospecific GABA CYP2C9(major) , CYP3A7,(weak), UGT1A4, CYP3A4 UGT2B7, neuron.by Enhancementincreased ofneuronal inhibitory emembraneffect of (major), CYP3A7, UGT1A4, benzodiazepine receptors on postsynaptic (strong)UGT2B10 GABApermeability on neuronal to chloride excitability ions. results This byshift in UGT2B7, UGT2B10 GABA neuron. Enhancement of inhibitory Inducer:Inhibitor: CYP3A4CYP2C8 (weak), CYP2C9 increasedchloride neuronalions results membrane in hyperpolarization permeability to(a (weak),Inhibitor:CYP3A4 CYP2C8(strong) (weak) Inducer:, effect of GABA on neuronal excitability results Transporter genes: ABCB1, chlorideless excitable ions. This state) shift and in stabilization chloride ions results in CYP2C9CYP3A4 (weak), CYP3A4 by increased neuronal membrane CLCNs, NR1I2 hyperpolarizationEffect: Sedation; (aHypnotic less excitable activity; state) Anti- and (strong)Transporter genes: ABCB1, CLCNs, stabilizationpermeability to chloride ions. This shift in Anxiety Agent; GABA Modulator, Skeletal NR1I2Inducer: CYP3A4 chloride ions results in hyperpolarization (a Effmuscleect: Sedation; relaxant; Hypnotic Amnestic activity; properties; Anti-Anxiety Transporter genes: ABCB1, less excitable state) and stabilization Agent;Anesthesia; GABA Preanesthetia Modulator, Skeletal muscle CLCNs, NR1I2 relaxant;Effect: Sedation; Amnestic Hypnotic properties; activity; Anesthesia; Anti- Name: Nitrazepam; Benzalin; Mogadon; PreanesthetiaAnxiety Agent; GABA Modulator, Skeletal Remnos; Nitrados; Imeson muscle relaxant; Amnestic properties; Name:IUPAC Nitrazepam Name: 7-nitro-5-phenyl-1,3-dihydro-; Benzalin; Mogadon; Remnos;Anesthesia; Nitrados; Preanesthetia Imeson 1,4-benzodiazepin-2-one Name: Nitrazepam; Benzalin; Mogadon; IUPAC Name: Remnos; Nitrados; Imeson 7-nitro-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-oneMolecular Formula: C15H11N3O3 IUPAC Name: 7-nitro-5-phenyl-1,3-dihydro- Pathogenic genes: GABRA1, Molecular Formula: C15H11N3O3 Pathogenic genes: GABRA1, GABRB3, Molecular1,4-benzodiazepin-2-one Weight: 281.26614 g/mol GABRB3, GABRG2, GABRD GABRG2, GABRD Molecular Weight: 281.26614 g/mol Mechanistic genes: CLCNs, Mechanism:Molecular Formula: Binds C 15H11toN 3O3stereospecific Mechanistic genes: CLCNs, GABRs, GLRs Mechanism: Binds to stereospecific GABRs, GLRs benzodiazepine receptors on postsynaptic PathogenicMetabolic genes:genes: GABRA1, benzodiazepine receptors on postsynaptic GABA MetabolicSubstrate: genes:CYP3A4 (major) GABAMolecular neuron Weight: at CNS 281.26614 (limbic system, g/mol reticular GABRB3, GABRG2, GABRD neuron at CNS (limbic system, reticular TransporterSubstrate: CYP3A4 genes: CLCNs(major) formation). Enhances inhibitory effect of Mechanistic genes: CLCNs, formation).Mechanism: Enhances Binds inhibitory to effstereospecificect of GABA Transporter genes: CLCNs onGABA neuronal on neuronal excitability excitability by increasing by increasing neuronal GABRs, GLRs benzodiazepine receptors on postsynaptic membraneneuronal membrane permeability permeability to chloride ionsto chloride Metabolic genes: GABA neuron at CNS (limbic system, reticular ions Substrate: CYP3A4 (major) Effformation).ect: Sedation; Enhances Hypnotic inhibitory activity; effect of Effect: Sedation; Hypnotic activity; Transporter genes: CLCNs Anticonvulsant;GABA on neuronal Anti-Anxiety excitability Agent; by increasing GABA ModulatorAnticonvulsant; Anti-Anxiety Agent; GABA neuronal membrane permeability to chloride Modulator ions Name:Effect: OxazepamSedation; Hypnotic; Adumbran; activity; Tazepam; Pathogenic genes: GABRs Serax;Anticonvulsant; Anxiolit; Praxiten Anti-Anxiety Agent; GABA Mechanistic genes: CLCNs, Modulator

Name: Oxazepam; Adumbran; Tazepam; Pathogenic genes: GABRs Serax; Anxiolit; Praxiten Mechanistic genes: CLCNs,

Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 52 of 87 Int. J. Mol. Sci. 2020, 21, 3059 49 of 82

Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW GABRs 52 of 87 IUPAC Name: 7-chloro-3-hydroxy-5-phenyl- Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW Metabolic genes: 52 of 87 1,3-dihydro-1,4-benzodiazepin-2-one Table 5. Cont. GABRs Substrate: CYP2D6, UGT2B7, IUPAC Name: 7-chloro-3-hydroxy-5-phenyl- MetabolicGABRsUGT2B15 genes: 1,3-dihydro-1,4-benzodiazepin-2-oneIUPAC Name: 7-chloro-3-hydroxy-5-phenyl-Benzodiazepines Molecular Formula: C15H11ClN2O2 Metabolic Substrate:Inhibitor: genes: UGT2B7CYP2D6, UGT2B7, Drug 1,3-dihydro-1,4-benzodiazepin-2-oneProperties Pharmacogenetics UGT2B15 Substrate:Inducer: CYP1A2 CYP2D6, UGT2B7, Name: Oxazepam; Adumbran; Tazepam; Serax; Molecular Formula: C15H11ClN2O2 UGT2B15Transporter Inhibitor: UGT2B7genes: CLCNs Anxiolit;Molecular Praxiten Weight: 286.71304 g/mol Molecular Formula: C15H11ClN2O2 Inducer:Inhibitor: CYP1A2 UGT2B7 IUPAC Name: 7-chloro-3-hydroxy-5-phenyl- Transporter Inducer: CYP1A2 genes: CLCNs 1,3-dihydro-1,4-benzodiazepin-2-oneMolecularMechanism: Weight: Effects 286.71304 appear tog/mol be mediated Transporter genes: CLCNs Molecularthrough inhibitory Weight: 286.71304neurotransmitter g/mol GABA; Molecular Formula: C15H11ClN2O2 Mechanism:site and mechanism Effects ofappear action to within be mediated the CNS MolecularthroughMechanism:appear toinhibitory Weight: involve Effects286.71304 macromolecularne appearurotransmitter gto/mol be mediated complexGABA; Mechanism:sitethrough(GABA andA mechanism-receptor-chlorideinhibitoryEffectsappear neof urotransmitteraction to bewithin mediatedionophore the GABA; CNS Pathogenic genes: GABRs throughappearsitecomplex) and inhibitoryto mechanism whichinvolve neurotransmitterincludes macromolecular of action GABA withinA GABA; receptors, complexthe CNS site Mechanistic genes: CLCNs, GABRs Metabolic genes: and(GABAappearhigh-affinity mechanism Ato-receptor-chloride involve benzodiazepine of action macromolecular within receptors, the CNSionophore complex appear and to involve macromolecular complex Substrate: CYP2D6, UGT2B7, UGT2B15 complex)(GABAchlorideA -receptor-chloridechannels. which includes Enhancement GABA ofA ionophorereceptors,inhibitory (GABAA-receptor-chloride ionophore complex) Inhibitor: UGT2B7 Inducer: CYP1A2 high-affinitycomplex)effect of whichGABA benzodiazepine includes on neuronal GABA receptors, Aexcitability receptors, and which includes GABA receptors, high-affinity Transporter genes: CLCNs chloridehigh-affinityresults bychannels. increasedbenzodiazepine EnhaA ncementneuronal receptors, of membraneinhibitory and benzodiazepine receptors, and chloride channels. Enhancementeffectchloridepermeability of channels. GABA of to inhibitory chloride Enhaon neuronalncement eions.ffect of Thisof GABAexcitability inhibitory shift on in neuronalresultseffectchloride of excitabilityby ions GABAincreased results on results neuronalin byhyperpolarization increased excitabilitymembrane neuronalpermeabilityresults(less excitable membraneby increasedto state) chloride permeability and neuronal stabilization ions. This to membrane chloride shift in ions.chloridepermeabilityEffect This: Sedation; shiftions intoresults chloride chlorideGABA in Modulator; ions ions.hyperpolarization results This Anti- inshift in hyperpolarization(lesschlorideAnxiety excitable Agent;ions state) resultsAnti-Alcohol (less andexcitable in stabilization hyperpolarization withdrawal state) and stabilizationEffect(lessagent excitable : Sedation; state) GABA and Modulator; stabilization Anti- EffAnxietyEffectNameect: Sedation;:: Sedation;Quazepam Agent; GABAAnti-Alcohol GABA; Doral; Modulator; Modulator; Dormalin; withdrawal Anti-Anxiety Anti- Agent;agentAnxietyProsedar; Anti-Alcohol Agent; Oniria; Anti-Alcohol Quazium withdrawal withdrawal agent Name:NameagentIUPAC Quazepam: Quazepam Name: 7-chloro-5-(2-fluorophenyl)-1-; Doral;; Doral; Dormalin; Dormalin; Prosedar; Oniria;Prosedar;Name(2,2,2-trifluoroethyl)-3H-1,4-benzodiazepine- Quazium: Quazepam Oniria; Quazium; Doral; Dormalin; IUPACIUPACProsedar;2-thione Name Name: Oniria;: 7-chloro-5-(2-fluorophenyl)-1-(2,2, 7-chloro-5-(2-fluorophenyl)-1- Quazium 2-trifluoroethyl)-3H-1,4-benzodiazepine-2-thione(2,2,2-trifluoroethyl)-3H-1,4-benzodiazepine-IUPAC Name: 7-chloro-5-(2-fluorophenyl)-1- 2-thione(2,2,2-trifluoroethyl)-3H-1,4-benzodiazepine-Molecular Formula: C17H11ClF4N2S Pathogenic genes: GABRB3 Molecular Formula: C17H11ClF4N2S 2-thione MechanisticPathogenic genes:genes:GABRB3 CLCNs, MolecularMolecularMolecular Weight: Formula:Weight:386.794253 386.794253 C17H11ClF g4 /Ng/molmol2S PathogenicGABRsMechanistic genes: genes: GABRB3CLCNs, GABRs Mechanism:Molecular Formula:Binds to stereospecificC17H11ClF4N2S MechanisticPathogenicMetabolicMetabolic genes: genes: genes:genes: GABRB3 CLCNs, Mechanism: Binds to stereospecific benzodiazepineMolecular Weight: receptors 386.794253 on postsynaptic g/mol GABA GABRsMechanistic Substrate: CYP2C9CYP2C9genes:(minor) (minor)CLCNs,, CYP2C19, neuronMolecularbenzodiazepine at several Weight: sitesreceptors 386.794253 within CNSon g/mol (limbicpostsynaptic system, MetabolicGABRsCYP2C19(minor) , CYP3A4genes:(minor) (major), CYP3A4, FMO1, FMO3 reticularMechanism:GABA formation).neuron atBinds Enhancesseveral to sites inhibitorystereospecific within e ffCNSect of Metabolic(major) Substrate:Transporter, FMO1, genes: CYP2C9 genes: FMO3 CLCNs (minor), GABAbenzodiazepineMechanism:(limbic on system, neuronal reticularBindsreceptors excitability formation).to on by stereospecificpostsynaptic increasing Enhances CYP2C19 Transporter Substrate: (minor)genes:CYP2C9 CLCNs, CYP3A4(minor) ,

neuronalGABAbenzodiazepineinhibitory neuron membrane effect at receptors permeabilityseveralof GABA siteson toonpostsynapticwithin chloride neuronal CNS ions, (major)CYP2C19, FMO1, (minor) FMO3, CYP3A4 resulting(limbicGABAexcitability system,neuron in hyperpolarization by increasing reticularat several formation). neuronal sites and within stabilization membrane Enhances CNS Transporter(major), FMO1, genes: FMO3 CLCNs

Effinhibitory(limbicpermeabilityect: Hypnotic system, effect to reticular activity; chlorideof GABA Sedation;formation). ions, on resultingGABA Enhancesneuronal in Transporter genes: CLCNs

Modulator;excitabilityinhibitoryhyperpolarization Anti-Anxiety byeffect increasing andof stabilizationGABA Agent neuronal on membrane neuronal permeabilityexcitability by toincreasing chloride neuronal ions, resulting membrane in Name:Effect Temazepam: Hypnotic activity;; Euhypnos; Sedation; Restoril; GABA Hydroxydiazepam;hyperpolarizationpermeabilityModulator; Anti-Anxiety to chloride and Methyloxazepam; stabilization Agentions, resulting Crisonar in EffecthyperpolarizationName:: HypnoticTemazepam activity; and; Euhypnos; stabilization Sedation; Restoril; GABA IUPAC Name: 7-chloro-3-hydroxy-1- Pathogenic genes: GABRB3 Modulator;EffectHydroxydiazepam;: Hypnotic Anti-Anxiety activity; Methyloxazepam; AgentSedation; GABA methyl-5-phenyl-3H-1,4-benzodiazepin-2-one Mechanistic genes: CLCNs, Name:Modulator;Crisonar Temazepam Anti-Anxiety; Euhypnos; Agent Restoril; Molecular Formula: C H ClN O PathogenicGABRs,Pathogenic TSPO genes: genes: GABRB3GABRB3 Hydroxydiazepam;Name: Temazepam ;Methyloxazepam; Euhypnos;16 13 2 Restoril;2 IUPAC Name: 7-chloro-3-hydroxy-1-methyl- MechanisticPathogenicMetabolicMechanistic genes: genes: genes:genes: GABRB3 CLCNs,CLCNs, GABRs, MolecularCrisonarHydroxydiazepam; Weight: 300.73962 Methyloxazepam; g/mol 5-phenyl-3H-1,4-benzodiazepin-2-one GABRs,MechanisticSubstrate:TSPO TSPO CYP2B6genes: (major)CLCNs,, Mechanism:Crisonar A short half-life benzodiazepine. Metabolic genes: IUPAC Name: 7-chloro-3-hydroxy-1-methyl- MetabolicGABRs,CYP2C9 TSPO genes:(major) , CYP2C19 Binds to stereospecific benzodiazepine receptors Substrate: CYP2B6 (major), CYP2C9 5-phenyl-3H-1,4-benzodiazepin-2-oneIUPACMolecular Name: Formula: 7-chloro-3-hydroxy-1-methyl- C16H13ClN2O2 Substrate:Metabolic(major), genes:CYP3A4CYP2B6 (major)(major),, on postsynaptic GABA neuron at several sites (major), CYP2C19 (major), CYP3A4 5-phenyl-3H-1,4-benzodiazepin-2-one within CNS, including limbic system. Enhances CYP2C9Substrate:UGT1A1,(major) , UGT1A1, (major)UGT1A3,CYP2B6, UGT1A3, CYP2C19UGT1A4,(major) UGT1A4,, inhibitoryMolecular eff Formula:ect of GABA C16H on13 neuronalClN2O2 excitability (major)CYP2C9UGT1A6,UGT1A6,, UGT1A9, (major)CYP3A4, UGT1A10,UGT1A10,CYP2C19(major), UGT2B7, Molecular Weight: 300.73962 g/mol resultsMolecular by increased Formula: neuronal C16H13ClN membrane2O2 UGT1A1,(major)UGT2B7,UGT2B15, UGT2B15UGT1A3,CYP3A4 UGT1A4,(major), permeability to chloride ions. This shift in UGT1A6,UGT1A1,Inhibitor: UGT1A9,UGT1A3,UGT1A3, UGT2B7UGT1A10,UGT1A4,

chlorideMolecular ions Weight: results in300.73962 hyperpolarization g/mol (a less UGT2B7,UGT1A6,Transporter UGT2B15UGT1A9, genes: CLCNsUGT1A10,

excitableMolecular state) Weight: and stabilization. 300.73962 g/mol It antagonizes UGT2B7, UGT2B15 with translocator protein

Effect: Hypnotic activity; Sedation; GABA Modulator; Anti-Anxiety Agent; Antidepressant activity; Anticonvulsant Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 53 of 87

Mechanism: A short half-life benzodiazepine. Inhibitor: UGT1A3, UGT2B7 Binds to stereospecific benzodiazepine Transporter genes: CLCNs Int. J. Mol. Sci. 2020, 21, x FOR PEERreceptors REVIEW on postsynaptic GABA neuron at 53 of 87 several sites within CNS, including limbic system.Mechanism: Enhances A short inhibitory half-life benzodiazepine.effect of GABA Inhibitor: UGT1A3, UGT2B7 onBinds neuronal to excitabilitystereospecific results benzodiazepine by increased Transporter genes: CLCNs neuronalreceptors membraneon postsynaptic permeability GABA toneuron chloride at ions.several This sites shift within in chloride CNS, including ions results limbic in hyperpolarizationsystem. Enhances (ainhibitory less excitable effect state)of GABA and stabilization.on neuronal Itexcitability antagonizes results with bytranslocator increased proteinneuronal membrane permeability to chloride Effections. :This Hypnotic shift activity;in chloride Sedation; ions GABAresults in Modulator;hyperpolarization Anti-Anxiety (a less Agent;excitable state) and Antidepressantstabilization. It activity;antagonizes Anticonvulsant with translocator protein Int. J. Mol. Sci. 2020, 21, 3059 Name: Triazolam; Halcion; Songar; 50 of 82 Clorazolam;Effect: Hypnotic Novidorm; activity; Trilam Sedation; GABA Modulator; Anti-Anxiety Agent; IUPAC Name: 8-chloro-6-(2-chlorophenyl)-1- Antidepressant activity; Anticonvulsant methyl-4H-[1,2,4]triazolo[4,3-Table 5. Cont. a][1,4]benzodiazepineName: Triazolam; Halcion; Songar; Clorazolam; Novidorm;Benzodiazepines Trilam Drug Properties Pharmacogenetics MolecularIUPAC Name: Formula: 8-chloro-6-(2-chlorophenyl)-1- C17H12Cl2N4 Pathogenic genes: GABRB3 Name:methyl-4H-[1,2,4]triazolo[4,3- Triazolam; Halcion; Songar; Clorazolam; Mechanistic genes: CLCNs, Novidorm;a][1,4]benzodiazepine Trilam Molecular Weight: 343.20998 g/mol GABRs, TSPO IUPAC Name: 8-chloro-6-(2-chlorophenyl)- Metabolic genes: 1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepineMechanism:Molecular Formula: Binds C 17Hto12Cl 2Nstereospecific4 Pathogenic Substrate:Pathogenic genes: CYP3A4 genes: GABRB3 GABRB3(major) , Molecularbenzodiazepine Formula: receptorsC H ClonN postsynaptic 17 12 2 4 CYP3A5MechanisticMechanistic (major) genes: genes: CLCNs, GABRs, GABAMolecular neuron Weight: at several 343.20998 sites g/mol within CNS, Molecular Weight: 343.20998 g/mol GABRs, Inhibitor:TSPO TSPO CYP2C8 (weak), including limbic system, reticular formation. CYP2C9MetabolicMetabolic (weak) genes: genes: Mechanism:EnhancementMechanism:Binds of inhibitoryBinds to stereospecific to effect stereospecific of benzodiazepine GABA on Transporter Substrate:Substrate: genes: CYP3A4CYP3A4 CLCNs (major) , CYP3A5 receptorsneuronalbenzodiazepine on excitability postsynaptic receptors results GABA on neuronbypostsynaptic increased at several CYP3A5(major) (major) sitesneuronalGABA within neuron membrane CNS, includingat several permeability limbicsites within system, to chloride CNS, reticular formation. Enhancement of inhibitory effect of GABA Inhibitor:Inhibitor: CYP2C8CYP2C8 (weak)(weak),, CYP2C9 ions.including This limbicshift insystem, chloride reticular ions formation.results in on neuronal excitability results by increased neuronalCYP2C9(weak) (weak) hyperpolarizationEnhancement of inhibitory (less excitable effect of state) GABA and on Transporter genes: CLCNs membrane permeability to chloride ions. This shiftTransporter in genes: CLCNs chloridestabilization.neuronal ions excitability results in hyperpolarization results by increased (less excitableEffectneuronal: Sedation; state) membrane and GABA stabilization. permeability Modulator; to chloride ions. This shift in chloride ions results in EffAnesthesiaect: Sedation; (Adjuvant) GABA Modulator; Anesthesia hyperpolarization (less excitable state) and (Adjuvant)Anxiolyt Miscellaneous, Miscellaneous stabilization. Drug PropertiesMiscellaneous Pharmacogenetics Drug Effect: Sedation; GABAProperties Modulator; Pharmacogenetics Name:Anesthesia Buspirone (Adjuvant); Ansial; Buspirona; Name:Buspironum; Buspirone Bespar;; Ansial; Anxiron Buspirona; Buspironum; Bespar;Anxiolyt Anxiron Miscellaneous, Miscellaneous IUPAC Name: 8-[4-(4-pyrimidin-2- Drug Properties Pharmacogenetics IUPACylpiperazin-1-yl)butyl]-8- Name: 8-[4-(4-pyrimidin-2-ylpiperazin- 1-yl)butyl]-8-azaspiro[4.5]decane-7,9-dione azaspiro[4.5]decane-7,9-dioneName: Buspirone; Ansial; Buspirona; Mechanistic genes: DRD2, Int. J. Mol. Sci. 2020, 21, x FOR PEERMolecularBuspironum; REVIEW Formula: Bespar;C21 AnxironH31N5O 2 HTR1A,Mechanistic HTR2A, HTR3s genes: 54DRD2, of 87 HTR1A, Molecular Formula: C21H31N5O2 Metabolic genes: MolecularIUPAC Weight:Name:385.50314 8-[4-(4-pyrimidin-2- g/mol HTR2A, HTR3s benzodiazepine-GABAylpiperazin-1-yl)butyl]-8- receptors. Binds to Substrate:Metabolic CYP2D6 genes: (minor), Mechanism: Decreases the spontaneous firing of MechanisticSubstrate: genes:CYP2D6 (minor)DRD2,, CYP3A4 dopamineazaspiro[4.5]decane-7,9-dione D2 receptors CYP3A4 (major), CYP3A5 serotonin-containingMolecular Weight: neurons385.50314 in g/mol the CNS by (minor)HTR1A,(major), HTR2A,CYP3A5 HTR3s(minor) Inducer: selectively binding to and acting as agonist at CYP3A4 EffectMolecular: Serotonin Formula: receptor C21H31N 5agonist;O2 Anti- Metabolic Inducer: CYP3A4genes: presynapticMechanism: CNS Decreases serotonin 5-HTthe spontaneousreceptors. Anxiety Agent 1A Substrate:Pleiotropic CYP2D6 genes: DRD2,(minor) HTR2A, Possessesfiring of partialserotonin-containing agonist activity neurons (mixed in the Pleiotropic genes: DRD2, HTR2ACYP3A4 (major), CYP3A5 agonistName:CNSMolecular by/antagonist) Chloral selectively Weight: Hydrate at 385.50314binding postsynaptic; Noctec; to g/mol and Tosyl; 5-HT acting2A 302-receptors. as (minor) Does17-0;agonist not 2,2,2-Trichloroethane-1,1-diol; bindat presynaptic to benzodiazepine-GABA CNS serotonin 5-HT receptors.1A BindsTrichloroacetaldehydereceptors.Mechanism: to dopamine Possesses Decreases D2 receptorspartial hydrate the agonist spontaneous activity Inducer: CYP3A4 Pleiotropic genes: DRD2, Eff(mixedfiringect: Serotonin of agonist/antagonist) serotonin-containing receptor agonist; at postsynaptic neurons Anti-Anxiety in the 5- HTR2A AgentIUPACHTCNS2A by Name:receptors. selectively 2,2,2-trichloroethane-1,1-diol bindingDoes tonot and bind acting toas agonist at presynaptic CNS serotonin 5-HT1A Name: ; Noctec; Tosyl; 302-17-0; 2,2,2-Trichloroethane-1,1-diol;receptors. Possesses partial agonist activity

TrichloroacetaldehydeMolecular(mixed agonist/antagonist) Formula: C hydrate2H3Cl 3atO 2postsynaptic 5- HT2A receptors. Does not bind to IUPAC Name: 2,2,2-trichloroethane-1,1-diol

MolecularMolecular Formula: Weight: 165.40302C2H3Cl3O g/mol2

Molecular Weight: 165.40302 g/mol Mechanism: It is converted to the active Mechanism: It is converted to the active compoundPathogenicPathogenic genes: genes: GABRAsGABRAs compound trichloroethanol by hepatic trichloroethanol by hepatic alcohol dehydrogenase.MechanisticMechanistic genes: genes: GABRAs;GABRAs; GLRs; alcohol dehydrogenase. The agent interacts The agent interacts with various GLRs;HTR3s HTR3s neurotransmitter-operatedwith various neurotransmitter-operated ion channels, thereby ion PleiotropicPleiotropic genes: genes: FOS, IL1B,FOS, IL6 IL1B, IL6 enhancingchannels, gamma-aminobutyricthereby enhancing acid (GABA)-Agamma- receptoraminobutyric mediated acid chloride (GABA)-A currents andreceptor inhibiting aminomediated acid receptor-activatedchloride currents ion and currents. inhibiting Enhances theamino agonistic acid ereceptor-activatedffects of glycine receptors, ion currents. inhibits AMPA-inducedEnhances the calciumagonisti influxc effects in cortical of glycine neurons, and facilitates 5-HT 3 receptor-mediated currents in receptors, inhibits AMPA-induced calcium ganglionic neurons. Overall, this results in a influx in cortical neurons, and facilitates 5-HT depressive effect on the central nervous system 3 receptor-mediated currents in ganglionic Eneurons.ffect: Hypnotic Overall, activity; this results Sedation; in a Anticonvulsant;depressive Anesthesia; Analgesic activity; GABA Modulator effect on the central nervous system Effect: Hypnotic activity; Sedation; Anticonvulsant; Anesthesia; Analgesic activity; GABA Modulator Name: Dexmedetomidine Hydrochloride; Dexmedetomidina; Dexmedetomidinum; MPV 1440; Precedex; CHEBI:4466 IUPAC Name: 5-[(1S)-1-(2,3- Mechanistic genes: ADRA2A, dimethylphenyl)ethyl]-1H-imidazole ADRA2B, ADRA2C Metabolic genes: Molecular Formula: C13H16N2 Substrate: CYP2A6 (major), UGT1A4, UGT2B10 Molecular Weight: 200.27954 g/mol Inhibitor: CYP1A2 (weak), Mechanism: Binds to the presynaptic alpha-2 CYP2C9 (weak), CYP2D6 adrenoceptors and inhibits the release of (strong), CYP3A4 (weak) norepinephrine, therefore, terminate the Inducer: ABCC2, CYP7A1, propagation of pain signals. Activation of the CYP27A1 postsynaptic alpha-2 adrenoceptors inhibits Transporter genes: ABCC2 the sympathetic activity Effect: α2-Adrenergic Agonist; Anesthesia; Sedation; Analgesia Name: Promethazine Hydrochloride; Mechanistic genes: ADRA1A, Phenergan; Promethazine Hcl; 58-33-3; CHRM2, DRD2, HRH1 Fenergan; Atosil Metabolic genes: IUPAC Name: N,N-dimethyl-1- Substrate: CYP2B6 (major), phenothiazin-10-ylpropan-2- CYP2D6 (major) amine;hydrochloride Inhibitor: CYP2C9 (weak),

Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 54 of 87

benzodiazepine-GABA receptors. Binds to dopamine D2 receptors

Effect: Serotonin receptor agonist; Anti- Anxiety Agent Name: Chloral Hydrate; Noctec; Tosyl; 302- 17-0; 2,2,2-Trichloroethane-1,1-diol; Trichloroacetaldehyde hydrate

IUPAC Name: 2,2,2-trichloroethane-1,1-diol

Molecular Formula: C2H3Cl3O2

Molecular Weight: 165.40302 g/mol

Mechanism: It is converted to the active Pathogenic genes: GABRAs compound trichloroethanol by hepatic Mechanistic genes: GABRAs; alcohol dehydrogenase. The agent interacts GLRs; HTR3s with various neurotransmitter-operated ion Pleiotropic genes: FOS, IL1B, IL6 channels, thereby enhancing gamma- aminobutyric acid (GABA)-A receptor mediated chloride currents and inhibiting amino acid receptor-activated ion currents. Enhances the agonistic effects of glycine receptors, inhibits AMPA-induced calcium influx in cortical neurons, and facilitates 5-HT Int. J. Mol. Sci. 2020, 21, 3059 3 receptor-mediated currents in ganglionic 51 of 82 neurons. Overall, this results in a depressive effect on the central nervous system Effect: Hypnotic activity;Table Sedation; 5. Cont. Anticonvulsant; Anesthesia; Analgesic Miscellaneous activity; GABA Modulator Drug Properties Pharmacogenetics Name: Dexmedetomidine Hydrochloride; Name: Dexmedetomidine Hydrochloride; Dexmedetomidina; Dexmedetomidinum; Dexmedetomidina; Dexmedetomidinum; MPV 1440; MPV 1440; Precedex; CHEBI:4466 Precedex; CHEBI:4466 IUPAC Name: 5-[(1S)-1-(2,3- Mechanistic genes: ADRA2A, IUPACdimethylphenyl)ethyl]-1H-imidazole Name: ADRA2B,Mechanistic ADRA2C genes: ADRA2A, 5-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole MetabolicADRA2B, genes: ADRA2C Molecular Formula: C13H16N2 Metabolic genes: Molecular Formula: C13H16N2 Substrate: CYP2A6 (major), Substrate: CYP2A6 (major), UGT1A4, UGT1A4, UGT2B10 MolecularMolecular Weight: Weight:200.27954 200.27954 g /g/molmol UGT2B10 Inhibitor: CYP1A2 (weak), Mechanism: Binds to the presynaptic alpha-2 Inhibitor: CYP1A2 (weak), CYP2C9 Int. J. Mol. Sci. 2020, 21, x FOR PEERMechanism: REVIEW Binds to the presynaptic alpha-2 CYP2C9 (weak), CYP2D6 55 of 87 adrenoceptors and inhibits the release of (weak), CYP2D6 (strong), CYP3A4 norepinephrine,adrenoceptors therefore,and inhibits terminate the therelease propagation of (strong)(weak), CYP3A4 (weak) ofnorepinephrine, pain signals. Activation therefore, of theterminate postsynaptic the CYP2D6 Inducer:Inducer: (weak) ABCC2ABCC2 , , CYP7A1CYP7A1, ,CYP27A1 Molecular Formula: C17H21ClN2S Int. J. Mol. Sci. 2020, 21, x FOR PEERalpha-2propagation REVIEW adrenoceptors of pain signals. inhibits Activation the sympathetic of the CYP27A1TransporterTransporter genes: genes: ABCB1 55ABCC2 of 87 activitypostsynaptic alpha-2 adrenoceptors inhibits Transporter genes: ABCC2 Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 55 of 87 CYP2D6 (weak) EffMoleculartheect: sympatheticα2-Adrenergic Weight: activity 320.88004 Agonist; Anesthesia;g/mol Sedation; MolecularEffect: α2-Adrenergic Formula: C 17Agonist;H21ClN 2Anesthesia;S Transporter genes: ABCB1 Analgesia CYP2D6 (weak) Mechanism:Sedation; Analgesia Blocks postsynaptic mesolimbic Name:Molecular Promethazine Formula: Hydrochloride;C17H21ClN2S Phenergan;Transporter genes: ABCB1 PromethazineMoleculardopaminergicName: Promethazine Weight: Hcl; receptors 58-33-3; 320.88004 Hydrochloride; Fenergan;in g/molbrain. AtosilExhibits Mechanistic genes: ADRA1A, strongPhenergan; α-adrenergic-blocking Promethazine Hcl; 58-33-3;effect and CHRM2, DRD2, HRH1 IUPAC Name: N,N-dimethyl-1-phenothiazin- Mechanism:MoleculardepressesFenergan; AtosilWeight:release Blocks 320.88004 postsynapticof hypothalamic g/mol mesolimbic and Metabolic genes: 10-ylpropan-2-amine;hydrochloride dopaminergichypophysealIUPAC Name:hormones.receptors in CompetesN,N-dimethyl-1-brain. Exhibits with Substrate: CYP2B6 (major), Mechanism: Blocks postsynaptic mesolimbic Mechanistic genes: ADRA1A, Molecularstronghistaminephenothiazin-10-ylpropan-2- α Formula:-adrenergic-blockingfor H1-receptor.C17H21 ClNReduces 2S effect stimuli and to CYP2D6 (major) dopaminergic receptors in brain. Exhibits CHRM2, DRD2, HRH1 Moleculardepressesbrainstemamine;hydrochloride Weight: reticularrelease320.88004 of system. hypothalamic g /molThe relief and of Inhibitor:Metabolic CYP2C9 genes: (weak), strong α-adrenergic-blocking effect and hypophysealnausea is related hormones. to central Competes anticholinergic with Substrate: CYP2B6 (major), CYP2D6 Mechanism:depresses Blocksrelease postsynapticof hypothalamic mesolimbic and histamineactions for H1-receptor. Reduces stimuli to (major) dopaminergichypophyseal receptorshormones. in brain. Competes Exhibits strongwith αbrainstem-adrenergic-blockingEffect: Sedation; reticular Anti-Allergic esystem.ffect and Agent;The depresses relief releaseof of Inhibitor: CYP2C9 (weak), CYP2D6 histamine for H1-receptor. Reduces stimuli to hypothalamicnauseaAntiemetic; is related Antipruritic; and hypophyseal to central Histamine anticholinergic hormones. H1 (weak) brainstem reticular system. The relief of CompetesactionsAntagonist with histamine for H1-receptor. Reduces Transporter genes: ABCB1 nausea is related to central anticholinergic stimuliEffectName:: to Sedation; brainstem Anti-Allergic; reticularRozerem; system. 196597-26-9;Agent; The relief of actions nauseaAntiemetic;TAK-375; is related Rozerem Antipruritic; to central Histamine anticholinergic H1 actions Effect: Sedation; Anti-Allergic Agent; EffAntagonistIUPACect: Sedation; Name: Anti-AllergicN-[2-[(8S)-2,6,7,8-tetrahydro- Agent; Antiemetic; Antiemetic; Antipruritic; Histamine H1 Antipruritic;Name:1H-cyclopenta[e][1]benzofuran-8- Ramelteon Histamine; Rozerem; H1 Antagonist 196597-26-9; Antagonist Pathogenic genes: MTNR1A, Name:TAK-375;yl]ethyl]propanamide Ramelteon Rozerem; Rozerem; 196597-26-9; TAK-375; Name: Ramelteon; Rozerem; 196597-26-9; MTNR1B RozeremIUPAC Name: N-[2-[(8S)-2,6,7,8-tetrahydro- TAK-375;Molecular Rozerem Formula: C16H21NO2 Mechanistic genes: MTNR1A, 1H-cyclopenta[e][1]benzofuran-8- PathogenicMTNR1B genes: MTNR1A, IUPACIUPAC Name Name:: N-[2-[(8S)-2,6,7,8-tetrahydro-1H- N-[2-[(8S)-2,6,7,8-tetrahydro- cyclopenta[e][1]benzofuran-8-yl]ethyl]propanamideyl]ethyl]propanamideMolecular Weight: 259.34344 g/mol MTNR1BMetabolicPathogenic genes: genes: MTNR1A, 1H-cyclopenta[e][1]benzofuran-8- PathogenicMTNR1B genes: MTNR1A, MolecularMechanism: Formula: Potent, C 16selectiveH21NO2 agonist of MechanisticSubstrate: CYP1A2genes: MTNR1A,(major), Molecularyl]ethyl]propanamide Formula: C16 H21NO2 MTNR1BMechanistic genes: MTNR1A, MTNR1BCYP2C19 (minor), CYP3A4 melatonin receptors MT1 and MT2 (with little MTNR1B MolecularMolecular Weight: Formula:Weight:259.34344 259.34344 C16H21NO g /g/molmol2 Mechanistic genes: MTNR1A, affinity for MT3) within suprachiasmic Metabolic(minor) genes: MTNR1BMetabolic genes: Mechanism:Mechanism:nucleus of hypothalamusPotent, Potent, selective selective agonist agonist of melatonin of Substrate: CYP1A2 (major), Molecular Weight: 259.34344 g/mol MetabolicSubstrate: genes:CYP1A2 (major), CYP2C19 receptors MT1 and MT2 (with little affinity for MT3) melatonin receptors MT1 and MT2 (with little CYP2C19(minor) (minor), CYP3A4, (minor)CYP3A4 Effect: Melatonin receptor agonist; Hyptonic Substrate: CYP1A2 (major), withinMechanism: suprachiasmic Potent, nucleus selective of agonist of (minor) affinityactivity; circadianfor MT 3rhythm) within regulation suprachiasmic melatonin receptors MT1 and MT2 (with little CYP2C19 (minor), CYP3A4 EffnucleusName:ect: Melatonin of hypothalamus receptor; Sonata;agonist; 151319-34-5; Hyptonic CL- activity; affinity for MT3) within suprachiasmic (minor) circadianEffect284846;: Melatonin Zerene; rhythm CL regulation receptor 284846 agonist; Hyptonic nucleus of hypothalamus Name:activity;IUPAC Zaleplon circadianName:; Sonata; rhythmN-[3-(3-cyanopyrazolo[1,5- 151319-34-5; regulation CL-284846; Effect: Melatonin receptor agonist; Hyptonic Zerene;Name:a]pyrimidin-7-yl)pheny CLZaleplon 284846; Sonata;l]-N-ethylacetamide 151319-34-5; CL- activity; circadian rhythm regulation IUPAC284846;Molecular Name Zerene; Formula:: N-[3-(3-cyanopyrazolo[1,5-a] CL 284846 C17H15 N5O Name: Zaleplon; Sonata; 151319-34-5; CL- pyrimidin-7-yl)phenyl]-N-ethylacetamideIUPAC Name: N-[3-(3-cyanopyrazolo[1,5- 284846;Molecular Zerene; Formula: CL 284846 C17H15 N5O a]pyrimidin-7-yl)phenyl]-N-ethylacetamide MechanisticMechanistic genes: genes: GABRA1GABRA1 Molecular Formula: C17H15N5O IUPAC Name: N-[3-(3-cyanopyrazolo[1,5- Metabolic genes: Molecular Formula:Weight: 305.3339 C17H15N g/mol5O Metabolic genes: Moleculara]pyrimidin-7-yl)pheny Weight: 305.3339l]-N-ethylacetamide g/mol Substrate:Substrate: AOX1,AOX1, CYP3A4CYP3A4(major), Molecular Formula: C17H15N5O Mechanism:MolecularMechanism: Formula:Interacts Interacts C with17 Hwith15 benzodiazepineN 5Obenzodiazepine GABA Mechanistic(major),CYP2D6, CYP2D6, genes: POR POR GABRA1 receptorGABA complex.receptor complex. Nonclinical Nonclinical studies have studies shown Pleiotropic genes: HRH1 Molecular Formula: C17H15N5O MetabolicPleiotropic genes: genes : HRH1 Molecular Weight: 305.3339 g/mol Mechanistic genes: GABRA1 thathave it bindsshown selectively that it binds to selectively brain ω1 receptor to brain situatedω1 Substrate: AOX1, CYP3A4 α Metabolic genes: onMolecularMechanism:receptor-subunit situated Weight: of Interacts GABA-A on 305.3339 α with-subunit receptor g/molbenzodiazepine complexof GABA-A (major), CYP2D6, POR Substrate: AOX1, CYP3A4 EffGABAreceptorect: Hypnotic receptor complex activity;complex. Sedation; Nonclinical Skeletal studies muscle Pleiotropic genes: HRH1 Mechanism: Interacts with benzodiazepine (major), CYP2D6, POR relaxant;haveEffect: shown Hypnotic Anti-anxiety that it activity; binds agent; selectively Sedation; Anticonvulsant; to Skeletal brain ω GABA1 GABA receptor complex. Nonclinical studies Modulatorreceptormuscle relaxant; situated Anti-anxiety on α-subunit agent; of GABA-A Pleiotropic genes: HRH1 have shown that it binds selectively to brain ω1 receptorAnticonvulsant; complex GABA Modulator receptor situated on α-subunit of GABA-A Effect:Name: HypnoticZolpidem activity; Tartrate Sedation;; 99294-93-6; Skeletal receptor complex muscleschembl40721; relaxant; MLS001401453; Anti-anxiety agent; Bio-0153; Mechanistic genes: CLCNs, Effect: Hypnotic activity; Sedation; Skeletal Anticonvulsant;chembl1723343 GABA Modulator GABRA1, TSPO muscle relaxant; Anti-anxiety agent; Name:IUPAC Name: Tartrate2,3-dihydroxybutanedioic; 99294-93-6; Metabolic genes: Anticonvulsant; GABA Modulator schembl40721;acid;N,N-dimethyl- MLS001401453;2-[6-methyl-2-(4- Bio-0153; Mechanistic Substrate: CYP1A2genes: (minor)CLCNs,, Name: Zolpidem Tartrate; 99294-93-6; chembl1723343 GABRA1,CYP2C9 TSPO(minor) , CYP2C19 methylphenyl)imidazo[1,2-a]pyridin-3- Mechanistic genes: CLCNs, schembl40721; MLS001401453; Bio-0153; Metabolic(minor), genes:CYP2D6 (minor), IUPACyl]acetamide Name: 2,3-dihydroxybutanedioic GABRA1, TSPO chembl1723343 CYP3A4 Substrate: (major) CYP1A2 (minor), acid;N,N-dimethyl-2-[6-methyl-2-(4- Metabolic genes: IUPACMolecular Name: Formula: 2,3-dihydroxybutanedioic C23H27N3O7 CYP2C9 Inhibitor: (minor) CYP3A4, (strong)CYP2C19 methylphenyl)imidazo[1,2-a]pyridin-3- Substrate: CYP1A2 (minor), acid;N,N-dimethyl-2-[6-methyl-2-(4- (minor), CYP2D6 (minor), yl]acetamide CYP2C9 (minor), CYP2C19 methylphenyl)imidazo[1,2-a]pyridin-3- CYP3A4 (major) (minor), CYP2D6 (minor), yl]acetamideMolecular Formula: C23H27N3O7 Inhibitor: CYP3A4 (strong) CYP3A4 (major) Molecular Formula: C23H27N3O7 Inhibitor: CYP3A4 (strong)

Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 55 of 87

CYP2D6 (weak) Molecular Formula: C17H21ClN2S Transporter genes: ABCB1

Molecular Weight: 320.88004 g/mol

Mechanism: Blocks postsynaptic mesolimbic dopaminergic receptors in brain. Exhibits strong α-adrenergic-blocking effect and depresses release of hypothalamic and hypophyseal hormones. Competes with histamine for H1-receptor. Reduces stimuli to brainstem reticular system. The relief of nausea is related to central anticholinergic actions Effect: Sedation; Anti-Allergic Agent; Antiemetic; Antipruritic; Histamine H1 Antagonist Name: Ramelteon; Rozerem; 196597-26-9; TAK-375; Rozerem IUPAC Name: N-[2-[(8S)-2,6,7,8-tetrahydro- 1H-cyclopenta[e][1]benzofuran-8- Pathogenic genes: MTNR1A, yl]ethyl]propanamide MTNR1B

Molecular Formula: C16H21NO2 Mechanistic genes: MTNR1A, MTNR1B Molecular Weight: 259.34344 g/mol Metabolic genes: Mechanism: Potent, selective agonist of Substrate: CYP1A2 (major), melatonin receptors MT1 and MT2 (with little CYP2C19 (minor), CYP3A4 (minor) affinity for MT3) within suprachiasmic nucleus of hypothalamus Effect: Melatonin receptor agonist; Hyptonic activity; circadian rhythm regulation Name: Zaleplon; Sonata; 151319-34-5; CL- 284846; Zerene; CL 284846 IUPAC Name: N-[3-(3-cyanopyrazolo[1,5- a]pyrimidin-7-yl)phenyl]-N-ethylacetamide Molecular Formula: C17H15N5O

Molecular Formula: C17H15N5O Mechanistic genes: GABRA1 Int. J. Mol. Sci. 2020, 21, 3059 Metabolic genes: 52 of 82 Molecular Weight: 305.3339 g/mol Substrate: AOX1, CYP3A4 Mechanism: Interacts with benzodiazepine (major), CYP2D6, POR GABA receptor complex.Table Nonclinical 5. Cont. studies Pleiotropic genes: HRH1 have shown that it binds selectively to brain ω1 receptor situated on αMiscellaneous-subunit of GABA-A Drug receptor complex Properties Pharmacogenetics Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 56 of 87 Name:Effect: Zolpidem Hypnotic Tartrateactivity;; Sedation; 99294-93-6; Skeletal schembl40721;muscle relaxant; MLS001401453; Anti-anxiety Bio-0153;agent; Transporter genes: CLCNs, chembl1723343Anticonvulsant; GABA Modulator Molecular Weight: 457.47638 g/mol NR1I2 IUPACName: NameZolpidem: 2,3-dihydroxybutanedioic Tartrate; 99294-93-6; acid;N,N-dimethyl-2-[6-methyl-2-(4-methylphenyl)schembl40721;Mechanism: Enhances MLS001401453; activity Bio-0153; of inhibitory MechanisticMechanistic genes: genes: CLCNs,CLCNs, GABRA1, imidazo[1,2-a]pyridin-3-yl]acetamidechembl1723343neurotransmitter, GABA, via selective GABRA1,TSPO TSPO agonism at benzodiazepine-1 (BZ1) receptor. MetabolicMetabolic genes: genes: MolecularIUPAC Formula:Name: 2,3-dihydroxybutanedioicC23H27N3O7 acid;N,N-dimethyl-Result is increased2-[6-methyl-2-(4- chloride conductance, Substrate:Substrate: CYP1A2CYP1A2 (minor)(minor), , CYP2C9 Molecular Weight: 457.47638 g/mol (minor), CYP2C19 (minor), CYP2D6 methylphenyl)imidazo[1,2-a]pyridin-3-neuronal hyperpolarization, inhibition of CYP2C9 (minor), CYP2C19 (minor), CYP3A4 (major) Mechanism:action potential,Enhances and activitydecrease of inhibitoryin neuronal (minor), CYP2D6 (minor), yl]acetamide Inhibitor: CYP3A4 (strong) neurotransmitter,excitability GABA, via selective agonism atCYP3A4 (major) benzodiazepine-1 (BZ1) receptor. Result is increased Transporter genes: CLCNs, NR1I2 MolecularEffect: Central Formula: nervous C23 Hsystem27N3O 7depression; Inhibitor: CYP3A4 (strong) chloride conductance, neuronal hyperpolarization, GABA-A receptor agonist; Hypnotic activity; inhibition of action potential, and decrease in neuronalSedation excitability Name: ; Imovane; Zimovane; Effect: Central nervous system depression; GABA-A receptorAmoban; agonist; (+-)-Zopiclone; Hypnotic 43200-80-2 activity; Sedation IUPAC Name: [6-(5-chloropyridin-2-yl)-5- Name: Zopiclone; Imovane; Zimovane; Amoban; oxo-7H-pyrrolo[3,4-b]pyrazin-7-yl] 4- (+-)-Zopiclone; 43200-80-2 methylpiperazine-1-carboxylate IUPAC Name: [6-(5-chloropyridin-2-yl)-5- oxo-7H-pyrrolo[3,4-b]pyrazin-7-yl]Molecular Formula: C17H17ClN6O3 4-methylpiperazine-1-carboxylate Mechanistic genes: CLCNs, GABRAsMechanistic genes: CLCNs, GABRAs MolecularMolecular Formula: Weight: C388.80828H ClN g/molO 17 17 6 3 MetabolicMetabolic genes: genes: MolecularMechanism: Weight: Reduces388.80828 sleep latency, g/mol increases Substrate:Substrate: CYP2C8CYP2C8 (major), CYP2C9 Mechanism:duration of Reducessleep, and sleep decreases latency, increasesnumber of CYP2C9(major), (major),CYP2C19 (minor),CYP2C19CYP2D6 , CYP3A4 (major) durationnocturnal of sleep,awakenings. and decreases Binds number to of nocturnalthe (minor), CYP2D6, CYP3A4 Transporter genes: CLCNs awakenings.benzodiazepine Binds toreceptor the benzodiazepine complex receptorand (major) complexmodulates and modulatesthe GABABZ the GABABZreceptor receptorchloride Transporter genes: CLCNs chloride channel macromolecular complex. Acts on channel macromolecular complex. Acts on α1, α1, α2, α3 and α5 GABAA containing receptors as a α2, α3 and α5 GABAA containing receptors as full agonist causing an enhancement of the inhibitory actionsa full ofagonist GABA. causing an enhancement of the inhibitory actions of GABA. Effect: Hypnotic activity; Sedation Effect: Hypnotic activity; Sedation 5.5. Epilepsy 5.5. Epilepsy Epilepsy is a prevalent disorder in dementia with prevalence and incidence rates 2–6-fold higher than inEpilepsy age-matched is a prevalent healthy disorder subjects. in dementia Subclinical with epileptiform prevalence and activity incidence can rates lead 2–6-fold to accelerated higher cognitive than in age-matched healthy subjects. Subclinical epileptiform activity can lead to accelerated decline. Aβ deposition may influence the propagation of synchronized abnormal discharges via cognitive decline. Aβ deposition may influence the propagation of synchronized abnormal excitatorydischarges pathways via excitatory [262 pathways]. [262]. There is a complex epileptogenesis-associated dysregulation of proteins involved in amyloid There is a complex epileptogenesis-associated dysregulation of proteins involved in amyloid β β processing and regulation in the hippocampus (HC) and parahippocampal cortex during processing and regulation in the hippocampus (HC) and parahippocampal cortex during epileptogenesis,epileptogenesis, inin which which therethere is is also also involvement involvement ofof tau tau and and proteins proteins of of the the mitochondrial mitochondrial complexes I,complexes III, IV, and I, VIII, [263 IV,]. and Seizures V [263]. are Seizures more prevalent are more inprevalent early-onset in early-onset AD with AD rapid with progression rapid [264], correlatingprogression with [264], high correlating CSF totalwith tauhigh protein CSF total levels tau protein [265]. le Avels disintegrin [265]. A disintegrin and metalloproteinase and domain-containingmetalloproteinase domain-containing protein 10 (ADAM10), protein 10 which (ADAM10), is an α -secretasewhich is an in α APP-secretase processing, in APP has been associatedprocessing, with has epilepsybeen associated as a stage-dependent with epilepsy as modulatora stage-dependent of epileptogenesis modulator of [epileptogenesis266]. [266].Potential pathogenic genes for epilepsy include ion channel genes (e.g., SCN1A, KCNQ2, SCN2A, and SCN8APotential), which pathogenic account genes for for nearlyepilepsy half include of epilepsy ion channel genes, genes together (e.g., SCN1A, with KCNQ2, a number SCN2A, of additional genes,and SCN8A such), as whichCDKL5, account STXBP1, for nearly PCDH19, half of epilepsy PRRT2, genes, LGI1, together ALDH7A1, with a number MECP2, of EPM2A,additional ARX, and genes, such as CDKL5, STXBP1, PCDH19, PRRT2, LGI1, ALDH7A1, MECP2, EPM2A, ARX, and SLC2A1 [267]. There is also an association of MTHFR rs1801133 and ABCC2 rs717620 with susceptibility SLC2A1 [267]. There is also an association of MTHFR rs1801133 and ABCC2 rs717620 with tosusceptibility generalized to tonic-clonic generalized tonic-clonic epilepsy, whileepilepsy,ABCB1 while rs717620ABCB1 rs717620is associated is associated with with poor poor response to antiepilepticsresponse to antiepileptics [268]. The influence [268]. The of influence some of of these some genesof these in genes PGx hasin PGx been has investigated been investigated under different therapeuticunder different paradigms therapeutic [55 ].paradigms [55].

Int. J. Mol. Sci. 2020, 21, 3059 53 of 82

Treatment of seizures in AD with low-dose antiepileptic drugs (AEDs) is usually well tolerated and efficacious, and selected AEDs might also help in slowing-down disease progression [269,270]. Anticonvulsants may suppress seizures in up to two-thirds of all patients, with no apparent effects on long-term prognosis [271]. Antiepileptics are associated with the PGx activity of approximately 150 genes (Table6). The GABRG2 gene encodes one of the subunits of the GABA-A receptor, the most abundant receptor of fast synaptic inhibition in the brain. GABRAG2 variants (rs211037, rs210987, rs440218, rs2422106, rs211014, and rs401750) and several PRRT2 mutations (c.649delC (p.R217Efs*12), c.649_650insC (p.R217Pfs*8), c.412C>G (p.Pro138Ala), c.439G>C (p.Asp147His), and c.623C>A (p.Ser208Tyr)) are associated with febrile seizures [272]. There is a clear association of rs211037 with epilepsy in Asian patients and of rs211037-rs210987 and rs2422106-rs211014-rs401750 haplotypes with susceptibility to symptomatic epilepsy in Chinese [273]. Different categories of anticonvulsants (barbiturates, hydantoin derivatives, oxazolidines, succinimides, benzodiazepines, carboxamides, fatty acid derivatives, and miscellaneous antiepileptics) are substrates, inhibitors, or inducers of 40, 15, and 24 enzyme/protein gene products, respectively, and are transported by at least 16 protein transporters (Table6). CYP enzymes participate in the metabolism of over 69% of drugs of these pharmacological categories. Over 65% of drugs currently used for the treatment of epilepsy and related disorders are major substrates of CYP3A4, followed by CYP3A5, CYP2E1, and UGT1A1 (32%); CYP2C8 and CYP2B6 (26%); CYP1A2, CYP2C9, CYP2C19, UGT1A3, UGT1A9, and UGT2B7 (22%); CYP1A1, CYP1A6, CYP2D6, CYP3A7, UGT1A4, and UGT1A6 (16%); and CYP2C18, CYP4B1, UGT1A10, and UGT2B15 (11%). These drugs tend to be strong inhibitors of CYP2C9 (>25%) and, to a lesser extent, of CYP1A6 and SULT1A1 (10%), and they are also potent inducers of CYP3A4 (37%). ABCB1 is the major transporter of 42% of antiepileptics, followed by ABCC2 (16%), SLC6A1 (11%), and SLCO2A1 and SLCO1B1 (10%). Phenobarbital, Valproic acid, and are the three best-characterized drugs for their pharmacogenomic profile, with over 100 genes involved in their biotransformation and metabolism [55,103,274,275]. UGT2B7 G211T and C161T polymorphisms affect the pharmacokinetics and pharmacodynamics of valproic acid (VPA) [276]. Carriers of the variant UGT1A6 19T>G, 541A>G, and 552A>C allele require higher VPA dosages than noncarriers, and carriers of the variant GRIN2B -200T>G allele are more likely to require lower VPA dosages than noncarriers [277]. VPA-related liver damage has been associated with the formation of a hepatotoxic 4-ene metabolite mediated by CYP2C9 and CYP2A6 enzymes [278]. ABAT rs1731017, SCN2A rs2304016, and ALDH5A1 rs1054899 are associated with VPA response in Chinese patients [279]. Female CYP2C19-PMs are more susceptible to VPA-induced weight gain in the Japanese population [280], and SNPs in the leptin receptor (LEPR) (rs1137101) and ankyrin repeat kinase domain containing 1 (ANKK1) (rs1800497) show associations with VPA-induced weight gain in the Chinese population [281]. Oral clearance (CL/F) of VPA in patients with the LEPR-A668G and G668G (rs1137101) variants is lower than in patients with the LEPR-A668A genotype [282]. Meropenem decreases VPA plasma levels when coadministered together. This interaction is triggered by inhibition of acylpeptide hydrolase (APEH) activity with meropenem. The study of VPA-d6 β-D-glucuronide (VPA-G) concentration in APEH rs3816877 and rs1131095 carriers revealed that patients with the APEH rs3816877 C/C genotype show higher levels than C/T carriers in the Chinese population [283]. Valproate-related neuroprotection in experimentally triggered epileptic seizures has been associated with PKC-dependent GABAAR γ2 phosphorylation at serine 327 residue [284]. SOD2 Val16Ala polymorphism may affect γ-glutamyltransferase (GGT) elevation in epileptic patients treated with VPA [285]. High initial serum concentrations of lamotrigine increase the risk of cutaneous ADRs. Genetic variants of uridine diphosphate glucuronosyltransferase (UGT) 1A4 influence lamotrigine elimination. UGT1A4*2 (P24T) and *3 (L48V) variants are associated with skin reactions but probably not in Caucasians [286]. UGT2B7-161C>T variants influence lamotrigine pharmacokinetics; specifically, the UGT2B7-161TT genotype changes lamotrigine clearance and may be useful in titrating the optimal Int. J. Mol. Sci. 2020, 21, 3059 54 of 82 lamotrigine dose [287]. OCT1 rs628031 and ABCG2 rs2231142 affect lamotrigine metabolism, and SNPs in ABCG2 rs2231142, rs3114020, HNF4α rs2071197, and ABCB1 rs1128503 are associated with lamotrigine CDR (concentration/dose normalized by body weight) in Chinese patients [288,289]. Treatment with carbamazepine, oxcarbazepine, or is associated with delayed-hypersensitivity reactions (e.g., eosinophilia, Stevens–Johnson syndrome, and toxic epidermal necrolysis) [290]. The FDA-approved label for oxcarbazepine indicates a pharmacogenomic association with hypersensitivity reactions and the HLA antigen allele HLA-B*15:02. Oxcarbazepine has structural similarities with carbamazepine, and HLA-B*15:02 is a risk factor for both carbamazepine- and oxcarbazepine-induced severe cutaneous ADRs, especially in the Asian population [290,291]. HLA-B*15:02 is highly associated with carbamazepine-related Stevens–Johnson syndrome/toxic epidermal necrolysis cases as well as phenytoin-related cutaneous ADRs and, to a lesser extent, lamotrigine ADRs; in contrast, HLA-B*40:01 and HLA-B*58:01 carriers show a lower frequency of carbamazepine-related skin complications [292]. HLA-A*31:01 has also been reported to be a genetic marker for carbamazepine-induced ADRs in both Japanese and European populations [293,294]. SCN1A rs3812718 A/G and rs2290732 A/G polymorphisms influence carbamazepine , and rs2298771 A/G is associated with carbamazepine efficacy [295]. ABCB1 rs1045642 and UGT2B7 rs7439366 affect oxcarbazepine pharmacokinetics and pharmacodynamics in Han Chinese epileptic patients [296]. PXR*1B, HNF4a rs2071197, CYP1A2*1F,ABCC2 1249G>A, and PRRT2 c.649dupC influence the pharmacokinetics and pharmacodynamics of carbamazepine [297]. ABCB1 c.3435C>T, CYP3A4*1G, CYP3A5*3, POR*28, and EPHX1 c.416A>G and c.128G>C variants influence carbamazepine metabolism in Chinese patients [298]. rs776746 and rs15524 in CYP3A5 affect carbamazepine metabolism, and rs2032582 and rs10234411 in ABCB1 contribute to interindividual variation in carbamazepine and in carbamazepine-10,11-epoxide transport in epileptic patients treated with carbamazepine in combination with phenytoin or phenobarbital [298]. SCN1A IVS5-91G>A, UGT2B7 c.802T>C, ABCC2 c.1249G>A, and EPHX1 c.337T>C carriers require higher maintenance doses of oxcarbamazepine [299,300]. Carriers of the variant SCN1A IVS5-91G>A and EPHX1 c.337T>C allele require higher carbamazepine dosages than noncarriers, and genetic variants in the SCN1A, EPHX1, and UGT2B7 genes interactively affect the concentration–dose ratio of carbamazepine [301]. SCN1A, CYP2C9, CYP2C19, and ABCB1 variants affect phenytoin metabolism. CYP2C9 and CYP2C19 polymorphisms are associated with lower phenytoin maintenance dosage in Asian patients. CYP2C19*2/*2, CYP2C19*3/*3, CYP2C19*2/*3, and heterozygous CYP2C9*3 variants require lower phenytoin maintenance dosage [301,302]. Phenytoin may cause cutaneous ADRs with variable severity (maculopapular exanthema, eosinophilia, Stevens–Johnson syndrome, and toxic epidermal necrolysis). At least 16 SNPs in CYP2C genes at 10q23.33 may contribute to this adverse effect. CYP2C9*3 carriers show a clear propensity to phenytoin-related severe cutaneous ADRs [303]. There is an association between a rare variant in the complement factor H-related 4 (CFHR4) gene and phenytoin-induced maculopapular exanthema in Europeans [304]. CACNA1G, CACNA1H, CACNA1I, and ABCB1 variants are associated with differential short-term seizure outcome in childhood absence epilepsy. In patients treated with ethosuximide, CACNA1H rs61734410/P640L and CACNA1I rs3747178 are more prevalent among not-seizure-free patients, and in patients treated with lamotrigine, ABCB1 rs2032582/S893A is more frequent in not-seizure-free patients, whereas CACNA1H rs2753326 and rs2753325 are more common in seizure-free patients [305]. Resistant epilepsy is an important problem in over 20% of patients treated with antiepileptics [306]. Pharmaco-resistance is directly linked to dysfunctions in the pharmacoepigenetic machinery [61]. The C3435T variant of the ABCB1 gene has been proposed as a crucial factor for drug resistance in epilepsy. ABCB1-C3435C carriers show a risk of pharmacoresistance in some studies, but this association has been questioned after further analyses [307]. The ABCB1 G2677T T (rs1128503) and C3435T T (rs1045642) alleles and the TT, CTT, and TTT haplotypes are associated with drug-resistant epilepsy in specific populations [308]. ABCC2 rs717620 -24 CT+TT genotypes and ABCC2 rs3740066 (3972C>T) CT+TT genotypes are overrepresented in epileptic patients resistant to antiepileptic drugs in the Chinese Int. J. Mol. Sci. 2020, 21, 3059 55 of 82 population, whereas ABCC2 rs2273697 (1249G>A) and ABCB1 rs1045642 (3435C>T) polymorphisms were not found to be associated with drug-resistant epilepsy in this population. The frequency of the haplotype TGT (ABCC2 -24C>T/ABCC2 1249G>A/ABCC2 3972C>T) in resistant patients is double that of responsive patients [309]. The TAGAA haplotype in CACNA1A accumulates in drug-resistant patients in the Chinese population [310]. Glucose type-1 transporter (GLUT1) deficiency syndrome, caused by mutations in the SLC2A1 gene, exhibits pharmacoresistance to antiepileptics. Screening of SLC2A1 pathogenic variants can predict drug response and optimization of antiepileptic drugs for the treatment of this health condition [311]. The SCN1A IVS5-91G>A AA and ABCC2 c.1249G>A GA genotypes have been shown to be associated with carbamazepine/oxcarbamazepine-resistant epilepsy in the Chinese Han population. The frequency of SCN1A-AA and ABCC2-AC haplotypes is higher in drug-resistant patients than in responsive patients [312]. Association of ABCC2 rs2273697 and rs3740066 polymorphisms and drug-resistant epilepsy has been reported in Asia Pacific epilepsy cohorts [313]. PCDH19 mutations may cause pharmacoresistant epilepsy and intellectual disability in Dravet-like syndromes. A retrospective study of antiepileptic therapy in females with PCDH19 mutations showed that the most effective drugs in these cases are clobazam and , with responder rates of 68% and 67%, respectively [314]. Clobazam binds to stereospecific receptors on the postsynaptic GABA neuron at several sites within the CNS (limbic system and reticular formation) and enhances the inhibitory effect of GABA on neuronal excitability by increasing neuronal membrane permeability to chloride ions, which results in hyperpolarization and stabilization. Clobazam is extensively metabolized by CYP enzymes. Its major metabolite is N-desmethylclobazam (norclobazam), which also display antiepileptic activity. Clobazam is a major substrate of CYP2C19 and CYP3A4 and a minor substrate of CYP2B6 and CYP2C18. CYP2C19-PMs show higher plasma levels of clobazam and increased risk of ADRs. Caution and personalized dose adjustment is recommended in patients with the following genotypes: CYP2C19 (CYP2C19*2, CYP2C19*3, CYP2C19*4, CYP2C19*5, CYP2C19*6, CYP2C19*7, CYP2C19*8, CYP2C19*17), CYP3A4 (CYP3A4*1, CYP3A4*1B, CYP3A4*2, CYP3A4*3, CYP3A4*4, CYP3A4*5, CYP3A4*6, CYP3A4*8, CYP3A4*11, CYP3A4*12, CYP3A4*13, CYP3A4*15, CYP3A4*17, CYP3A4*18, CYP3A4*19), and CYP3A5 (CYP3A5*3)[55,56] (Table6). In Japanese patients with Dravet syndrome, it seems that CYP2C19 variants may influence a positive response to the antiepileptic effects of [315]. Genotype combinations of GABRA1 rs6883877, GABRA2 rs511310, and GABRA3 rs4828696 may affect responses to antiepileptic drugs [316]. G-aminobutyric-acid (GABA) is the principal inhibitory neurotransmitter in the CNS. Imbalances in GABAergic neurotransmission are involved in the pathophysiology of epilepsy and AD. GABA transporters (GATs) regulate the influx-efflux of GABA with sodium and chloride at the synaptic cleft. GATs belong to the solute carrier 6 (SLC6) transporter family: GAT1-3 (SLC6A1, SLC6A13, and SLC6A11) and betaine/GABA transporter 1 (BGT1 and SLC6A12). BGT1 is a potential target for the treatment of epilepsy. The GAT1/BGT1 selective inhibitor EF1502 and the BGT1 selective inhibitor RPC-425 display anticonvulsant effects [317]. Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 59 of 87

epilepsy in specific populations [308]. ABCC2 rs717620 -24 CT+TT genotypes and ABCC2 rs3740066 (3972C>T) CT+TT genotypes are overrepresented in epileptic patients resistant to antiepileptic drugs in the Chinese population, whereas ABCC2 rs2273697 (1249G>A) and ABCB1 rs1045642 (3435C>T) polymorphisms were not found to be associated with drug-resistant epilepsy in this population. The frequency of the haplotype TGT (ABCC2 -24C>T/ABCC2 1249G>A/ABCC2 3972C>T) in resistant patients is double that of responsive patients [309]. The TAGAA haplotype in CACNA1A accumulates in drug-resistant patients in the Chinese population [310]. Glucose type-1 transporter (GLUT1) deficiency syndrome, caused by mutations in the SLC2A1 gene, exhibits pharmacoresistance to antiepileptics. Screening of SLC2A1 pathogenic variants can predict drug response and optimization of antiepileptic drugs for the treatment of this health condition [311]. The SCN1A IVS5-91G>A AA and ABCC2 c.1249G>A GA genotypes have been shown to be associated with carbamazepine/oxcarbamazepine-resistant epilepsy in the Chinese Han population. The frequency of SCN1A-AA and ABCC2-AC haplotypes is higher in drug-resistant patients than in responsive patients [312]. Association of ABCC2 rs2273697 and rs3740066 polymorphisms and drug-resistant epilepsy has been reported in Asia Pacific epilepsy cohorts [313]. PCDH19 mutations may cause pharmacoresistant epilepsy and intellectual disability in Dravet-like syndromes. A retrospective study of antiepileptic therapy in females with PCDH19 mutations showed that the most effective drugs in these cases are clobazam and bromide, with responder rates of 68% and 67%, respectively [314]. Clobazam binds to stereospecific receptors on the postsynaptic GABA neuron at several sites within the CNS (limbic system and reticular formation) and enhances the inhibitory effect of GABA on neuronal excitability by increasing neuronal membrane permeability to chloride ions, which results in hyperpolarization and stabilization. Clobazam is extensively metabolized by CYP enzymes. Its major metabolite is N-desmethylclobazam (norclobazam), which also display antiepileptic activity. Clobazam is a major substrate of CYP2C19 and CYP3A4 and a minor substrate of CYP2B6 and CYP2C18. CYP2C19-PMs show higher plasma levels of clobazam and increased risk of ADRs. Caution and personalized dose adjustment is recommended in patients with the following genotypes: CYP2C19 (CYP2C19*2, CYP2C19*3, CYP2C19*4, CYP2C19*5, CYP2C19*6, CYP2C19*7, CYP2C19*8, CYP2C19*17), CYP3A4 (CYP3A4*1, CYP3A4*1B, CYP3A4*2, CYP3A4*3, CYP3A4*4, CYP3A4*5, CYP3A4*6, CYP3A4*8, CYP3A4*11, CYP3A4*12, CYP3A4*13, CYP3A4*15, CYP3A4*17, Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 60 of 87 CYP3A4*18,Int. J. Mol. CYP3A4*19 Sci. 2020, 21,), 3059 and CYP3A5 (CYP3A5*3) [55,56] (Table 6). 56 of 82 In Japanese patients with Dravet syndrome, it seems that CYP2C19CYP2E1, variants may CYP3A4,influence a positive response to the antiepileptic effects of stiripentol [315]. GenotypeCYP3A5, combinations CYP3A7,of GABRA1 Molecular Formula: C15H12N2O rs6883877, GABRA2Table 6. rs511310Pharmacological, and GABRA3 properties rs4828696 and pharmacogenetics may affect responsesGSTM1, of selected to GSTT1,antiepileptic antiepileptic UGT2B7 drugs drugs. [316]. -aminobutyric-acid (GABA) is the principalAntiepileptics inhibitory neurotransmitter Inhibitor: CYP1A2 in the CNS. Imbalances in GABAergicDrug neurotransmission are involvedProperties in the pathophysiology Inducer: of epilepsyPharmacogeneticsABCB1, and ABCB4, ABCC2, ABCG2, AD. GABA transporters (GATs)Molecular regulate Weight:Name: the Carbamazepineinflux-efflux 236.27 g/mol of GABA with sodium and chloride at the synaptic cleft. GATs belong to the solute carrier 6 (SLC6) transporter CYP1A1,family: GAT1-3CYP1A2, (SLC6A1, IUPAC Name: SLC6A13, and SLC6A11) and betaine/GABA transporter 1 (BGT1 and SLC6A12).CYP2A6, BGT1 isCYP2B6; a potential Mechanism:5H-Dibenz[b,f]azepine-5-carboxamide The anticonvulsant activity of CYP2C8; CYP2C9; target for the treatment of epilepsy. The GAT1/BGT1 selective inhibitor EF1502 and the BGT1 carbamazepine,Molecular like Formula:phenytoin,C15 Hprincipally12N2O CYP2C19; CYP2D6, selective inhibitor RPC-425 display anticonvulsant effects [317]. involves limitationMolecular of Weight:seizure 236.27propagation g/mol by CYP3A4, GSTA1, reduction of post-tetanic potentiation of SULT1A1, UGT1A4 Mechanism: The anticonvulsant activity of Mechanistic genes: EPHX1, Table 6. Pharmacologicalsynaptic properties transmission. and pharmacoge Carbamazepinenetics hasof selected only Transporterantiepileptic drugs.genes: carbamazepine, like phenytoin, principally HSPA1L, MTHFR, SCN1A slight analgesic properties. Carbamazepine ABCB1, ABCB4, ABCC2 involvesAntiepileptics limitation of seizure propagation by Metabolic genes: appears to provide relief of pain in trigeminal Drug reductionProperties of post-tetanic potentiation ofPleiotropicPharmacogeneticsSubstrate: genes: HLA-CYP1A2, CYP2A6, neuralgia bysynaptic reducing transmission. synaptic transmission Carbamazepine A, has HLA-B,CYP2B6, IL6 CYP2C8, CYP2C19, within the onlytrigeminal slight analgesicnucleus. properties.The drug has MechanisticCYP2E1, CYP3A4,genes: CYP3A5, alsoName: demonstrated CarbamazepineCarbamazepine sedative, appears anticholinergic, to provide reliefEPHX1, of CYP3A7, HSPA1L, GSTM1, GSTT1, UGT2B7 antidepressant,pain in trigeminalmuscle neuralgia relaxant, by reducing MTHFR,Inhibitor: SCN1A CYP1A2 Inducer: antiarrhythmic,synaptic transmissionantidiuretic, within theand trigeminal MetabolicABCB1, genes ABCB4, ABCC2, ABCG2, neuromuscularnucleus. Thetransmission-inhibitory drug has also demonstrated Substrate:CYP1A1, CYP1A2, CYP2A6, IUPAC Name: 5H-Dibenz[b,f]azepine-5- actions. Maysedative, depress anticholinergic, activity in the antidepressant, nucleus CYP2A6,CYP2B6; CYP2C8;CYP2B6, CYP2C9; carboxamidemuscle relaxant, antiarrhythmic, antidiuretic, CYP2C19; CYP2D6, CYP3A4, ventralis of the thalamus or decrease synaptic CYP2C8, CYP2C19, and neuromuscular transmission-inhibitory GSTA1, SULT1A1, UGT1A4 transmission or decrease summation of actions. May depress activity in the nucleus Transporter genes: ABCB1, temporal stimulation leading to neural ventralis of the thalamus or decrease synaptic ABCB4, ABCC2 discharge bytransmission limiting in orflux decrease of sodium summation ions of Pleiotropic genes: HLA-A, across celltemporal membrane stimulation or other leading unknown to neural HLA-B, IL6 mechanism.discharge May decrease by limiting the turnover influx of of sodium γ- ions aminobutyricacross acid cell (GABA). membrane Stimulates or other unknown the release of ADHmechanism. and potentiates May decrease its action the turnover in of γ- promoting aminobutyricreabsorption acidof water. (GABA). Chemically Stimulates the release of ADH and potentiates its action in related to tricyclic antidepressants. promoting reabsorption of water. Chemically related to tricyclic antidepressants. Effect: Anticonvulsants, Miscellaneous. Antimanic AgentsEffect: Anticonvulsants, Miscellaneous. Antimanic Agents Name: Clonazepam Name: ClonazepamIUPAC Name : 2H-1,4-Benzodiazepin-2-one, 5-(2-chlorophenyl)-1,3-dihydro-7-nitro-; IUPAC Name:5-(o-Chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4- 2H-1,4-Benzodiazepin-2-one, 5- (2-chlorophenyl)-1,3-dihydro-7-nitro-;benzodiazepin-2-one 5-(o- Chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4- Molecular Formula: C15H10ClN3O3 benzodiazepin-2-one Molecular Weight: 315.71 g/mol

Molecular Formula:Mechanism: C15HExact10ClN mechanism3O3 of Mechanistic genes: ALB, anticonvulsant, sedative, and antipanic effects Mechanistic genes: ALB, GABA-A GABA-A is unknown; however, mechanism appears to Metabolic genes: Molecular Weight:be related 315.71 to the g/mol drug’s ability to enhanceMetabolic the Substrate: genes: CYP2E1, CYP3A4, activity of γ-aminobutyric acid (GABA).Substrate:NAT2 CYP2E1, Mechanism:Suppresses Exact the spike-and-wavemechanism dischargeof CYP3A4, in NAT2 anticonvulsant,absence sedative, seizures and by antipanic depressing effects nerve is unknown;transmission however, mechanism in the motor appears cortex. Depressesto all levels of the CNS, including the limbic and be related to the drug’s ability to enhance the reticular formation, by binding to the activity of γ-aminobutyric acid (GABA). benzodiazepine site on the GABA receptor Suppresses complexthe spike-and-wave and modulating discharge GABA in absence seizures by depressing nerve Effect: Anxiolytics, Sedatives, and Hypnotics; transmission in the motor cortex. Depresses all Benzodiazepines. Anticonvulsants; levels of the CNS, including the limbic and Benzodiazepines

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Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 61 of 87 Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEWreticular formation, by binding to the 61 of 87 benzodiazepine site on the GABA receptor reticular formation, by binding to the reticularcomplex andformation, modulating by GABAbinding to the Effect:benzodiazepine Anxiolytics, Sedatives, site on andthe Hypnotics;GABA receptor Int. J. Mol. Sci. 2020, 21, 3059benzodiazepine site on the GABA receptor 57 of 82 complex and modulating GABA complexBenzodiazepines. and modulating GABAAnticonvulsants; Effect: Anxiolytics, Sedatives, and Hypnotics; Effect:Benzodiazepines Anxiolytics, Sedatives, and Hypnotics; Benzodiazepines. Anticonvulsants; Benzodiazepines. Anticonvulsants; Name:Benzodiazepines Eslicarbazepine Table 6. Cont. Benzodiazepines IUPACName: Name: Eslicarbazepine [S-(-)-10-acetoxy-10,11-dihydro-Antiepileptics Drug Name:5H-dibenz[b,f]azepine-5-carboxamide]; Eslicarbazepine Properties BIA 2- Pharmacogenetics IUPAC Name: [S-(-)-10-acetoxy-10,11-dihydro- IUPAC093 Name:Name: [S-(-)-10-acetoxy-10,11-dihydro- Eslicarbazepine 5H-dibenz[b,f]azepine-5-carboxamide]; BIA Metabolic2- genes: 5H-dibenz[b,f]azepine-5-carboxamide];IUPAC Name17 16 2 3 BIA 2- Molecular093 Formula: C H: N O Substrate: ABCB1, 093 [S-(-)-10-acetoxy-10,11-dihydro-5H-dibenz Metabolic genes: MetabolicUGT1A1, genes: UGT1A4, MolecularMolecular Weight:[b,f]azepine-5-carboxamide]; Formula: 296.32 Cg/mol17H16 N2O3 BIA 2-093UGT1A9, Substrate: UGT2B7 ABCB1, Molecular Formula: C17H16N2O3 Substrate:Metabolic ABCB1, genes: Molecular Formula: C H N O Inhibitor:UGT1A1, CYP2C19 UGT1A4, Mechanism: The precise mechanisms17 16of action2 3 UGT1A1, Substrate:UGT1A4,ABCB1, UGT1A1, Molecular Weight: 296.32 g/mol Inducer:UGT1A9, UGT2B7CYP3A4, Molecularof eslicarbazepine Weight:Molecular 296.32 acetate Weight: g/mol are296.32 unknown. g/mol UGT1A9, UGT2B7UGT1A4, UGT1A9, UGT2B7 UGT1A4, Inhibitor: UGT1A9, CYP2C19 However,Mechanism: in vitro Theelectrophysiological precise mechanisms studies of action Inhibitor: Inhibitor: CYP2C19CYP2C19 Mechanism: Mechanism:The precise mechanismsThe precise mechanismsof action UGT2B4, of Inducer: UGT2B7,CYP3A4, indicateof thateslicarbazepineaction both ofeslicarbazepine eslicarbazepine acetate acetate acetateare unknown. and are unknown. Inducer: Inducer:CYP3A4,CYP3A4, UGT1A4, of eslicarbazepine acetate are unknown. UGT2B17UGT1A4, UGT1A9, UGT2B4,UGT1A9, UGT2B7, its metabolitesHowever,However, stabilize in vitroin the vitroelectrophysiological inactivatedelectrophysiological state ofstudies UGT1A4, studies UGT1A9, However, in vitro electrophysiological studies PleiotropicUGT2B4,UGT2B17 genes: HLA-BUGT2B7, voltage-gatedindicateindicate thatsodium both that eslicarbazepine bothchannels, eslicarbazepine preventing acetate acetate UGT2B4,and and UGT2B7, indicate that both eslicarbazepine acetate and UGT2B17Pleiotropic genes: HLA-B its metabolitesits metabolites stabilize stabilize the inactivated the inactivated stateUGT2B17 of state itstheir metabolites return to stabilize the activated the inactivated state and state thereby of Pleiotropic genes: HLA-B sustainingvoltage-gated repetitiveof voltage-gated sodiumneuronal sodium channels,firing channels, preventing preventingPleiotropic genes: HLA-B voltage-gatedtheir sodium return channels, to the activated preventing state and thereby Effect:their Anticonvulsants,return to the activated Miscellaneous. state and thereby their return tosustaining the activated repetitive state neuronaland thereby firing sustaining repetitive neuronal firing sustainingAntiepileptics, repetitive Carboxamide neuronal Derivativesfiring Effect:E ffect:Anticonvulsants,Anticonvulsants, Miscellaneous.Miscellaneous. Effect:Name: EthosuximideAnticonvulsants, Miscellaneous. Antiepileptics,Antiepileptics, Carboxamide Carboxamide Derivatives Derivatives Antiepileptics, Carboxamide Derivatives IUPAC Name:Name: 2,5-Pyrrolidinedione, Ethosuximide 3-ethyl-3- Name: Ethosuximide Name:methyl-, Ethosuximide (±)-;IUPAC (±)-2-Ethyl-2-methylsuccinimide Name : 2,5-Pyrrolidinedione, IUPAC3-ethyl-3-methyl-, Name: 2,5-Pyrrolidinedione, ( )-; 3-ethyl-3- IUPACMolecular Name: Formula: 2,5-Pyrrolidinedione, C7H11NO2 ± 3-ethyl-3- methyl-,( )-2-Ethyl-2-methylsuccinimide(±)-; (±)-2-Ethyl-2-methylsuccinimide methyl-, (±)-; (±)-2-Ethyl-2-methylsuccinimide± MolecularMolecular Weight:Molecular Formula: 141.17 Formula: Cg/mol7H11NO C7H2 11NO2 Molecular Formula: C7H11NO2 Mechanistic genes: Mechanism:Molecular A Weight:succinimide-derivative141.17 g/mol CACNA1GMechanistic genes: CACNA1G Molecular Weight: 141.17 g/mol Molecularanticonvulsant. Weight:Mechanism: 141.17Exact Ag/mol succinimide-derivativemechanism of MetabolicMechanisticMetabolic genes: genes:genes: MechanisticSubstrate: genes:CYP2E1, CYP3A4, anticonvulsantMechanism:anticonvulsant. action A unknown. Exactsuccinimide-derivative mechanism Increases of Substrate: CACNA1G CYP2E1, Mechanism: A succinimide-derivative CACNA1G CYP3A5 seizureanticonvulsant. thresholdanticonvulsant in cortexExact action and basal unknown.mechanism ganglia Increases of Metabolic genes: anticonvulsant. Exact mechanism of MetabolicCYP3A4, CYP3A5genes: and anticonvulsantreducesseizure synaptic threshold action response inunknown. cortex to and low- basalIncreases ganglia Substrate: CYP2E1, anticonvulsantand action reduces unknown. synaptic response Increases to Substrate: CYP2E1, frequencyseizure repetitive threshold st inimulation. cortex and Suppresses basal ganglia CYP3A4, CYP3A5 seizure thresholdlow-frequency in cortex repetitiveand basal stimulation. ganglia CYP3A4, CYP3A5 paroxysmaland reduces spike and synaptic wave activity response of the EEGto low- and reducesSuppresses synaptic paroxysmalresponse spiketo low- and wave frequency repetitive stimulation. Suppresses frequencyassociated repetitive activitywith oflapsesst theimulation. EEGof associatedconsciousness Suppresses with lapses of paroxysmal spike and wave activity of the EEG paroxysmalcommon in spike consciousnessabsence and seizures wave commonactivity of in the absence EEG seizures associated with lapses of consciousness associatedEffect: Anticonvulsants; withEffect: lapsesAnticonvulsants; Succinimides of consciousness Succinimides common in absence seizures common in absence seizures Name: Felbamate Name:Effect: Felbamate Anticonvulsants; Succinimides Effect: Anticonvulsants;IUPAC Name Succinimides: 2-Phenyl-1,3-propanediol dicarbamate IUPACName: Name: Felbamate 2-Phenyl-1,3-propanediol Mechanistic genes: Name: Felbamate dicarbamateMolecular Formula: C11H14N2O4 GABR, GRIN1, GRIN2B IUPAC Name: 2-Phenyl-1,3-propanediol Mechanistic genes: IUPAC Name:Molecular 2-Phenyl-1,3-propanediol Weight: 238.24 g/mol MetabolicMechanistic genes: genes: GABR, Molecular Formula: C11H14N2O4 Mechanistic genes: dicarbamate Substrate:GABR,GRIN1, GRIN1,CYP2E1, GRIN2B GRIN2B dicarbamate Mechanism: Felbamate, a dicarbamate,GABR, is an GRIN1, GRIN2B CYP3A4,Metabolic CYP3A5Metabolic genes: genes: Molecularanticonvulsant Formula: C agent.11H14N Exact2O4 mechanismMetabolic of genes: MolecularMolecular Formula: Weight: C238.2411H14N g/mol2O4 Inhibitor: Substrate:Substrate: CYP2C19 CYP2E1, CYP2E1, CYP3A4, action unknown, but it is suggested that Substrate: it CYP2E1, Inducer:CYP3A4,CYP3A5 CYP3A4 CYP3A5 Mechanism:increases Felbamate, seizure a dicarbamate, threshold and is reducesan CYP3A4, CYP3A5 Molecular Weight: 238.24 g/mol Transporter Inhibitor:Inhibitor: CYP2C19genes:CYP2C19 Molecularanticonvulsant Weight:seizure agent. 238.24 spread. Exact g/molIn vitro mechanismstudies indicate of Inhibitor: that CYP2C19 ABCB1 Inducer:Inducer: CYP3A4CYP3A4 action Mechanism: unknown,felbamate butFelbamate, hasit weakis suggested a inhibitorydicarbamate, that eff ectsit is on anInducer: CYP3A4 Mechanism: Felbamate, a dicarbamate, is an TransporterTransporter genes:genes:ABCB1 increasesanticonvulsant seizurebinding threshold atagent. GABA and receptorsExact reduces mechanism andseizure Transporter of genes: anticonvulsantbenzodiazepine agent. Exact receptors. mechanism The of ABCB1 spread.action In vitro unknown, studies indicatebut it is that suggested felbamate that ABCB1 it action unknown,monocarbamate, but it is suggested p-hydroxy, that and it 2-hydroxy increases seizure threshold and reduces seizure increases seizuremetabolites threshold of and felbamate reduces appear seizure to contribute spread. In vitro studies indicate that felbamate spread. In vitrolittle, studies if any, indicate to the anticonvulsant that felbamate action of the drug

Effect: Anticonvulsants Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 62 of 87

has weak inhibitory effects on binding at GABA Int. J. Mol. Sci. 2020, 21, x FOR PEERreceptors REVIEW and benzodiazepine receptors. The 62 of 87 monocarbamate, p-hydroxy, and 2-hydroxy metaboliteshas weak inhibitoryof felbamate effects appear on binding to contribute at GABA little,receptors if any, toand the benzodiazepine anticonvulsant actionreceptors. of the The monocarbamate, p-hydroxy, and 2-hydroxy Int. J. Mol. Sci. 2020, 21, x FOR PEERdrug REVIEW 62 of 87 metabolites of felbamate appear to contribute Effect:little, Anticonvulsants if any, to the anticonvulsant action of the has weak inhibitory effects on binding at GABA drug Int. J. Mol. Sci. 2020, 21, 3059Name:receptors Gabapentin and benzodiazepine receptors. The 58 of 82 monocarbamate, p-hydroxy, and 2-hydroxy IUPACEffect: Name: Anticonvulsants 2-[1-(aminomethyl) cyclohexyl] metabolites of felbamate appear to contribute acetic acid Mechanistic genes: little,Name: if any,Gabapentin to the anticonvulsant Table 6. Cont.action of the GABRR1, GABRR2, Molecular Formula: C9H17NO2. drugIUPAC Name: 2-[1-(aminomethyl) cyclohexyl] KCNH2, SCN2A Molecularacetic acid Weight: 171.24 g/molAntiepileptics MetabolicMechanistic genes: genes: Drug Effect: Anticonvulsants Properties GABRR1, PharmacogeneticsGABRR2, Mechanism:Molecular GabapentinFormula: C9 His17 anNO anticonvulsant2. Inhibitor: CYP2A6 KCNH2, SCN2A agentName: structurally GabapentinName: relatedGabapentin to the inhibitory CNS Transporter genes: Molecular Weight: 171.24 g/mol Metabolic genes: neurotransmitterIUPAC GABA Name : 2-[1-(aminomethyl) ABCB1, SLC22A4 IUPACMechanism: Name: Gabapentin 2-[1-(aminomethyl) is an anticonvulsant cyclohexyl] Inhibitor: CYP2A6 Effect: Anticonvulsants,cyclohexyl] acetic Analgesics acid and Mechanistic genes: aceticagent acid structurally related to the inhibitory CNS Transporter genes: Antipyretics GABRR1,Mechanistic GABRR2, genes: GABRR1, MolecularneurotransmitterMolecular Formula: GABA Formula:C9H 17NO2.C 9H17NO2. ABCB1, SLC22A4 MechanisticKCNH2,GABRR2, SCN2A genes: KCNH2, SCN2A Effect: MolecularAnticonvulsants, Weight: 171.24Analgesics g/mol and Metabolic genes: Name:Molecular Lamotrigine Weight: 171.24 g/mol ADORA1,Metabolic genes:ADORA2A, Antipyretics Inhibitor: CYP2A6 Mechanism:Mechanism: GabapentinGabapentin is an anticonvulsant is an anticonvulsant ADRA1A, Inhibitor: CYP2A6ADRA2A, Transporter genes: ABCB1, agent structurally related to the inhibitoryMechanistic genes: IUPACagent structurallyName: 1,2,4-Triazine-3,5-diamine, related to the inhibitory CNS6- ADRB1,Transporter SLC22A4 CACNA1E,genes: Name: LamotrigineCNS neurotransmitter GABA ADORA1, ADORA2A, (2,3-dichlorophenyl)-;neurotransmitter GABA (2) 3,5-Diamino-6-(2,3- CHRM1,ABCB1, SLC22A4CHRM2, ADRA1A, ADRA2A, dichlorophenyl)-as-triazineEffect: Anticonvulsants,Effect: Anticonvulsants, Analgesics Analgesics and and CHRM3, CHRM4, AntipyreticsIUPAC AntipyreticsName: 1,2,4-Triazine-3,5-diamine, 6-CHRM5,ADRB1, DRD1, CACNA1E,DRD2, CHRM1, CHRM2, (2,3-dichlorophenyl)-;Name: Lamotrigine (2) 3,5-Diamino-6-(2,3-GABRA1,Mechanistic Mechanistic GABRA2,genes: genes: ADORA1, Molecular Formula: C9H7Cl2N5 CHRM3, CHRM4, Name:dichlorophenyl)-as-triazine Lamotrigine GABRA3,ADORA1, ADORA2A, ADORA2A,GABRA5, ADRA1A, ADRA2A, IUPAC Name: 1,2,4-Triazine-3,5-diamine,CHRM5, DRD1, DRD2, GABRA6,ADRA1A, ADRB1, GABRB1,ADRA2A, CACNA1E, CHRM1, 6-(2,3-dichlorophenyl)-; (2) GABRA1,CHRM2, CHRM3,GABRA2, CHRM4, Molecular Formula: C9H7Cl2N5 GABRB2,ADRB1, CACNA1E,GABRB3, MolecularIUPAC Name:Weight:3,5-Diamino-6-(2,3-dichlorophenyl)-as-triazine 1,2,4-Triazine-3,5-diamine, 256.09 g/mol 6- GABRA3, GABRA5, GABRG1,CHRM1, CHRM5, GABRG2, DRD1,CHRM2, DRD2, GABRA1, (2,3-dichlorophenyl)-; (2) 3,5-Diamino-6-(2,3- GABRA6, GABRB1, Molecular Formula: C9H7Cl2N5 GABRG3,CHRM3, GABRA2, GABRD,CHRM4, GABRA3, GABRA5, dichlorophenyl)-as-triazine GABRB2,GABRA6, GABRB3, GABRB1, GABRB2, Mechanism:Molecular Possibly Weight:involves256.09 inhibition g/mol of GABRE,CHRM5, DRD1,GABRP, DRD2, Molecular Weight: 256.09 g/mol GABRB3, GABRG1, GABRG2, voltage-sensitive sodium channels, which GABRR1,GABRG1, GABRR2,GABRG2, Mechanism: Possibly involves inhibitionGABRA1, of GABRG3, GABRA2, GABRD, GABRE, stabilizesMolecular Formula:neuronal C 9H7membranesCl2N5 and GABRG3, GABRD, voltage-sensitive sodium channels, whichGABRR3,GABRA3, GABRP,GABRQ, GABRR1,GABRA5, HRH1, GABRR2, consequentlyMechanism: modulates Possibly releaseinvolves of inhibitionexcitatory of GABRE, GABRP, stabilizes neuronal membranes and HTR2A,GABRA6, HTR3A,GABRR3, OPRK1,GABRB1, GABRQ, HRH1, HTR2A, voltage-sensitive sodium channels, which GABRR1, GABRR2, amino acid consequentlyneurotransmitters modulates (e.g. releaseglutamate, of excitatory SCN2AGABRB2, HTR3A, OPRK1,GABRB3, SCN2A stabilizes neuronal membranes and GABRR3, GABRQ, HRH1, aspartate)Molecular whichamino Weight: play acid 256.09 a neurotransmitters role g/mol in generation (e.g. and glutamate, MetabolicGABRG1,Metabolic genes: GABRG2, genes: consequently modulates release of excitatory HTR2A, HTR3A, OPRK1, spread of epilepticaspartate) seizures which play a role in generation GABRG3,Substrate: and Substrate: DHFR,GABRD,DHFR, UGT1A1, amino acid neurotransmitters (e.g. glutamate, SCN2A Mechanism:spread Possibly of epileptic involves seizures inhibition of UGT1A1,GABRE, UGT1A3, UGT1A3, UGT1A4,GABRP, UGT2A7 aspartate) which play a role in generation and Metabolic genes: voltage-sensitive sodium channels, which UGT1A4,GABRR1, TransporterUGT2A7 GABRR2, genes: ABCB1, spread of epileptic seizures Substrate:SLC22A2 DHFR, Effect:stabilizes Anticonvulsants, Effect:neuronalAnticonvulsants, Miscellaneousmembranes Miscellaneous and TransporterGABRR3, GABRQ, genes: HRH1, UGT1A1,Pleiotropic UGT1A3, genes: HLA-B consequently modulates release of excitatory ABCB1,HTR2A, SLC22A2 HTR3A, OPRK1, UGT1A4, UGT2A7 amino acidName: neurotransmitters Levetiracetam (e.g. glutamate, PleiotropicSCN2A genes: HLA-B aspartate)Effect: Anticonvulsants, which play a role Miscellaneous in generation and Transporter genes: Name: LevetiracetamIUPAC Name : 1-Pyrrolidineacetamide, Metabolic genes: spread of epileptic seizures ABCB1, SLC22A2 α-ethyl-2-oxo-, (α S)-; (2)(-)-(S) - Substrate: DHFR, IUPAC Name: 1-Pyrrolidineacetamide, α- Pleiotropic genes: HLA-B α-Ethyl-2-oxo-1-pyrrolidineacetamide UGT1A1, UGT1A3, ethyl-2-oxo-,Name: Levetiracetam (α S)-; (2)(-)-(S) - α-Ethyl-2-oxo-1- UGT1A4, UGT2A7 Molecular Formula: C H N O pyrrolidineacetamideEffect: Anticonvulsants, Miscellaneous8 14 2 2 MetabolicTransporter genes: genes: IUPAC Name: 1-Pyrrolidineacetamide, α- Metabolic genes: Molecular Formula:Molecular C8 Weight:H14N2O2170.21 g/mol ABCB1,Substrate: SLC22A2 CYP2D6 ethyl-2-oxo-, (α S)-; (2)(-)-(S) - α-Ethyl-2-oxo-1- Substrate: CYP2D6 pyrrolidineacetamideMechanism: The precise mechanism byTransporterPleiotropicTransporter genes:genes: HLA-B genes: ABCB1 Molecular Weight: 170.21 g/mol ABCB1Metabolic genes: Name: Levetiracetamwhich levetiracetam exerts its antiepileptic Mechanism:Moleculare ff TheFormula:ect isprecise unknown C 8mechanismH14N and2O2 does by not which appear to Substrate: CYP2D6 IUPAC Name:derive from1-Pyrrolidineacetamide, any interaction with knownα- Transporter genes: levetiracetamMolecular Weight:exerts its 170.21 antiepileptic g/mol effect is unknownethyl-2-oxo-, andmechanisms (doesα S)-; not (2)(-)-(S) involvedappear - toα-Ethyl-2-oxo-1- in derive inhibitory from and ABCB1 excitatory neurotransmission anypyrrolidineacetamideMechanism: interaction The with precise known mechanism mechanisms by which Metabolic genes: levetiracetam exerts its antiepileptic effect is MolecularE Formula:ffect: Anticonvulsants C8H14N2O2 Substrate: CYP2D6 unknown and does not appear to derive from Transporter genes: Molecularany interaction Weight: with170.21 knowng/mol mechanisms ABCB1 Mechanism: The precise mechanism by which levetiracetam exerts its antiepileptic effect is

unknown and does not appear to derive from any interaction with known mechanisms

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involved in inhibitory and excitatory neurotransmission Effect: Anticonvulsants Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 63 of 87

involvedName: Oxcarbazepine in inhibitory and excitatory neurotransmission Int. J. Mol. Sci. 2020, 21, 3059 IUPAC Name: 5H-Dibenz[b,f]azepine-5- 59 of 82 Effect: Anticonvulsants carboxamide, 10,11-dihydro-10-oxo-; 10,11- Dihydro-10-oxo-5H-dibenz[b,f]azepine-5- Name:carboxamide Oxcarbazepine Table 6. Cont.

Antiepileptics IUPACMolecular Name: Formula: 5H-Dibenz[b,f]azepine-5-C15H12N2O2 Drug carboxamide, 10,11-dihydro-10-oxo-;Properties 10,11- Pharmacogenetics Dihydro-10-oxo-5H-dibenz[b,f]azepine-5-Name: Oxcarbazepine Mechanistic genes: SCN2A carboxamideMolecularIUPAC Weight: Name 252.27: g/mol Metabolic genes: 5H-Dibenz[b,f]azepine-5-carboxamide, Substrate: CYP3A4, MolecularMechanism:10,11-dihydro-10-oxo-; Formula: Pharmacological C15H12N2O 10,11-Dihydro-10-oxo-2 activity results UGT1A1, UGT1A3, from both5H-dibenz[b,f]azepine-5-carboxamide oxcarbazepine and its monohydroxy MechanisticUGT1A4, UGT1A6,genes: metaboliteMolecular (MHD). Formula: OxcarbazepineC H N andO MHD 15 12 2 2 SCN2AUGT1A7, UGT1A9, Molecularblock voltage-sensitive Weight: 252.27 g/molsodium channels, Molecular Weight: 252.27 g/mol MetabolicUGT1A10,Mechanistic genes: UGT2B7, genes: SCN2A stabilizing hyperexcited neuronal membranes, Mechanism: Pharmacological activity results UGT2B15 Substrate:Metabolic CYP3A4, genes: Mechanism:inhibiting repetitive Pharmacological firing, activityand decreasing results from both oxcarbazepine and its monohydroxyUGT1A1,Inhibitor: Substrate: CYP2C19UGT1A3,CYP3A4, UGT1A1, frompropagation both oxcarbazepine of synaptic and itsimpulses. monohydroxy These metabolite (MHD). Oxcarbazepine and MHDUGT1A4, UGT1A3,UGT1A6, UGT1A4, UGT1A6, metaboliteactions are (MHD). believed Oxcarbazepine to prevent andspread MHD of block voltage-sensitive sodium channels, UGT1A7,Inducer: UGT1A7, UGT1A9, UGT1A9,ABCB1, UGT1A10, blockseizures. voltage-sensitive Oxcarbazepine sodiumand MHDchannels, also stabilizing hyperexcited neuronal membranes,UGT1A10,CYP3A4,UGT2B7, CYP3A5UGT2B7, UGT2B15 stabilizingincrease potassium hyperexcited conductance neuronal andmembranes, modulate Inhibitor: CYP2C19 inhibiting repetitive firing, and decreasingUGT2B15 inhibiting repetitive firing, and decreasing Inducer: ABCB1, CYP3A4, activitypropagation of high-voltage of synaptic activated impulses. calcium These actionsInhibitor: CYP2C19 propagation of synaptic impulses. These CYP3A5 channels.are Protects believed against to prevent electrically spread of induced seizures. actions Oxcarbazepineare believed andto prevent MHD also spread increase of tonic extension seizures and, to a lesser degree, Inducer: ABCB1, seizures.chemically-inducedpotassium Oxcarbazepine conductance clonic and andseizures. MHD modulate alsoMay activity of high-voltage activated calcium channels. ProtectsCYP3A4, CYP3A5 increaseabolish potassiumor reduce conductance frequency andof chronicallymodulate against electrically induced tonic extension activityrecurring of focal high-voltage seizures activated calcium seizures and, to a lesser degree, channels. Protects against electrically induced chemically-induced clonic seizures. May abolish tonicEffect: extension orAnticonvulsants reduce seizures frequency and, of to chronically a lesser degree, recurring focal chemically-inducedseizures clonic seizures. May abolish or reduce frequency of chronically Effect: Anticonvulsants Mechanistic genes: recurring focal seizures Name: Phenobarbital COMT, GABRA1, Name: Phenobarbital CHRNA4, CHRNA7, Effect:IUPAC AnticonvulsantsIUPAC NameName:: 2,4,6(1H,3H,5H)- GRIA2, MechanisticGRIK2, GRIN1, genes: COMT, Pyrimidinetrione,2,4,6(1H,3H,5H)-Pyrimidinetrione, 5-ethyl-5-phenyl-; (2) 5-ethyl-5- 5- GRIN2A,GABRA1, GRIN2B, CHRNA4, CHRNA7, phenyl-; (2) 5-Ethyl-5-phenylbarbituric acid GRIA2, GRIK2, GRIN1, GRIN2A, Ethyl-5-phenylbarbituric acid MechanisticGRIN2C, GRIN2D,genes: GRIN2B, GRIN2C, GRIN2D, Name: PhenobarbitalMolecular Formula: C H N O COMT, GABRA1, 12 12 2 3 GRIN3A,GRIN3A, GRIN3B, GRIN3B, NR1I2 NR1I2 MolecularMolecular Formula: Weight: C12H12232.24N2O3 g/mol CHRNA4,MetabolicMetabolic genes:CHRNA7, genes: IUPAC Name: 2,4,6(1H,3H,5H)- GRIA2, Substrate: GRIK2,Substrate: CYP1A1,GRIN1,CYP1A1, CYP1A2, Mechanism: Long-acting with Pyrimidinetrione, 5-ethyl-5-phenyl-; (2) 5- GRIN2A,CYP1A2, CYP1B1, GRIN2B,CYP1B1, CYP2A6, CYP2B6, sedative, hypnotic, and anticonvulsant properties. Ethyl-5-phenylbarbituric acid GRIN2C, CYP2C8,GRIN2D, CYP2C9, CYP2C18, MolecularBarbiturates Weight: depress232.24 g/mol sensory cortex, decreaseCYP2A6, CYP2B6, GRIN3A, CYP2C19,GRIN3B, NR1I2 CYP2E1, CYP3A4, Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEWmotor activity, alter cerebellar function, andCYP2C8, CYP2C9, 64 of 87 CYP3A5, CYP3A7, CYP4A11, MolecularMechanism:produce Formula: Long-acting drowsiness, C12H12N sedation,2Obarbiturate3 and hypnosis.with MetabolicCYP2C18, In genes:CYP2C19, CYP4B1, EPHX1, UGT1A1 sedative,high doses,hypnotic, barbiturates and exhibitanticonvulsant anticonvulsant CYP2E1, Substrate: CYP1A1,CYP3A4, Effect: Anticonvulsants; Barbiturates. ABCB1, Inhibitor:ABCB11, ABCC1,CYP2C19, CYP2J2, activity. They also produce dose-dependentCYP1A2,CYP3A5, CYP1B1,CYP3A7, properties.Anxiolytics, Barbiturates Sedatives, depress and sensory Hypnotics; cortex, ABCC2, CYP27A1,ABCC3, SLC10A1, SULT1A1 Molecularrespiratory Weight: depression232.24 g/mol CYP2A6, CYP2B6, decreaseBarbiturates motor activity, alter cerebellar CYP4A11,SLCO2A1Transporter CYP4B1, genes: ABCB1, CYP2C8, CYP2C9, function,Eff ect:andAnticonvulsants; produce drowsiness, Barbiturates. sedation, EPHX1, ABCB11,UGT1A1 ABCC1, ABCC2, ABCC3, Mechanism:andName: hypnosis.Anxiolytics, Phenytoin Long-acting In Sedatives,high doses,barbiturate and Hypnotics;barbiturates with CYP2C18, Mechanistic Inhibitor:SLCO2A1 CYP2C19,CYP2C19,genes:

sedative,exhibitBarbiturates anticonvulsanthypnotic, andactivity. anticonvulsant They also CYP2E1,CYP2J2,NR1I2, SCN1A,CYP27A1,CYP3A4, SCN1B, CYP3A5, CYP3A7, properties.IUPACproduceName: Name: Barbiturates dose-dependentPhenytoin 5,5-Diphenylhydantoin depress sensoryrespiratory cortex, SLC10A1,SCN3A, SCN5A SULT1A1 decreasedepression motor activity, alter cerebellar CYP4A11,TransporterMetabolic genes: CYP4B1, genes: IUPAC Name: 5,5-Diphenylhydantoin Mechanistic genes: NR1I2, function, and produce drowsiness, sedation, EPHX1,Substrate: UGT1A1 CYP2B6, Molecular Formula: C15H12N2O2 SCN1A, SCN1B, SCN3A, SCN5A and hypnosis.Molecular In Formula:high doses,C15H 12barbituratesN2O2 Inhibitor: CYP2C19, CYP2C8,Metabolic CYP2C9, genes: CYP2J2, CYP27A1, exhibit Molecularanticonvulsant Weight: activity.252.27 g/Theymol also CYP2C18,Substrate: CYP2C19,CYP2B6, CYP2C8, produceMolecular Weight:dose-dependent 252.27 g/mol respiratory SLC10A1, SULT1A1 Mechanism: Stabilizes neuronal membranesCYP2D6, and CYP2C9, CYP3A4, CYP2C18, CYP2C19, depression TransporterCYP3A5,CYP2D6, CYP3A7, CYP3A4,genes: CYP3A5, Mechanism:decreases Stabilizes seizure activityneuronal by membranes increasing e fflux or CYP11B1,CYP3A7, CYP11B1,EPHX1, EPHX1, and decreasesdecreasing seizure influx activity of sodium by ions increasing across cell membranes in motor cortex during generationUGT1A1, of UGT1A1, UGT1A6, UGT1A6, UGT1A9 efflux or decreasing influx of sodium ions nerve impulses. Prolongs effective refractoryUGT1A9Inhibitor: SCN2A, SULT1A1 across cell membranes in motor cortex during Transporter genes: ALB, ABCB1, period and suppresses ventricular pacemaker Inhibitor: SCN2A, generation of nerve impulses. Prolongs ABCC2, SLCO1B1, SLCO1C1 automaticity, shortens action potential in heartSULT1A1 effective refractory period and suppresses Pleiotropic genes: HLA-B Effect: Class Ib Antiarrhythmics. Transporter genes: ALB, ventricular pacemaker automaticity, shortens Anticonvulsants; Hydantoins ABCB1, ABCC2, action potential in heart SLCO1B1, SLCO1C1 Effect: Class Ib Antiarrhythmics. Pleiotropic genes: HLA-B Anticonvulsants; Hydantoins Name: Primidone IUPAC Name: 4,6(1H,5H)-Pyrimidinedione, 5- ethyldihydro-5-phenyl-; 5-Ethyldihydro-5- phenyl-4,6(1H,5H)-pyrimidinedione Mechanistic genes: Molecular Formula: C12H14N2O2 GABRAs Molecular Weight: 218.25 g/mol Metabolic genes: Inducer: CYP1A2, Mechanism: Decreases neuron excitability, CYP2B6, CYP2C8, raises seizure threshold similar to CYP2C9, CYP3A4 phenobarbital. Primidone has two active metabolites, phenobarbital and phenylethylmalonamide Effect: Anticonvulsants; Barbiturates

Name: Rufinamide

IUPAC Name: 1-[(2,6-difluorophenyl)methyl]- 1H-1,2,3-triazole-4 carboxamide

Molecular Formula: C10H8F2N4O

Mechanistic genes: Molecular Weight: 238.2 g/mol MAPK10, SCN1A Metabolic genes: Mechanism: The precise mechanism(s) by Substrate: CES which rufinamide exerts its antiepileptic effect Inhibitor: CYP2E1 are unknown. The results of in vitro studies Inducer: CYP3A4 suggest that the principal mechanism of action of rufinamide is modulation of the activity of sodium channels and, in particular, prolongation of the inactive state of the channel. Rufinamide (≥ 1 μM) significantly slowed sodium channel recovery from inactivation after a prolonged prepulse in cultured cortical neurons, and limited

Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 64 of 87

Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEWEffect: Anticonvulsants; Barbiturates. ABCB1, ABCB11, ABCC1, 64 of 87 Anxiolytics, Sedatives, and Hypnotics; ABCC2, ABCC3, Effect:Barbiturates Anticonvulsants; Barbiturates. ABCB1,SLCO2A1 ABCB11, ABCC1, Anxiolytics, Sedatives, and Hypnotics; ABCC2, ABCC3, Name: Phenytoin Mechanistic genes: Barbiturates SLCO2A1 NR1I2, SCN1A, SCN1B, Name:IUPAC Phenytoin Name: 5,5-Diphenylhydantoin MechanisticSCN3A, SCN5A genes: NR1I2,Metabolic SCN1A, genes: SCN1B, Substrate: CYP2B6, IUPACMolecular Name: Formula: 5,5-Diphenylhydantoin C15H12N2O2 SCN3A, SCN5A MetabolicCYP2C8, genes: CYP2C9, Substrate:CYP2C18, CYP2B6,CYP2C19, MolecularMolecular Formula: Weight: C 252.2715H12N 2g/molO2 CYP2C8,CYP2D6, CYP2C9,CYP3A4, CYP3A5, CYP3A7, Mechanism: Stabilizes neuronal membranes CYP2C18, CYP2C19, CYP11B1, EPHX1, Molecularand decreases Weight: seizure 252.27 g/molactivity by increasing CYP2D6, CYP3A4, CYP3A5,UGT1A1, CYP3A7,UGT1A6, Mechanism:efflux or decreasingStabilizes neuronalinflux of membranessodium ions CYP11B1,UGT1A9 EPHX1, andacross decreases cell membranes seizure activity in motor by cortexincreasing during UGT1A1, Inhibitor: UGT1A6,SCN2A, effluxgeneration or decreasing of nerve influx impulses. of sodium Prolongs ions UGT1A9SULT1A1 acrosseffective cell membranesrefractory inperiod motor andcortex suppresses during Inhibitor:Transporter genes:SCN2A, ALB, generationventricular of pacemaker nerve impulses.automaticity, Prolongs shortens SULT1A1ABCB1, ABCC2, Int. J. Mol. Sci. 2020, 21, 3059effectiveaction potentialrefractory in heartperiod and suppresses 60 of 82 TransporterSLCO1B1, SLCO1C1genes: ALB, ventricularEffect: pacemakerClass automaticity,Ib Antiarrhythmics. shortens ABCB1,Pleiotropic genes:ABCC2, HLA-B actionAnticonvulsants; potential in heart Hydantoins Table 6. Cont. SLCO1B1, SLCO1C1 Effect:Name: PrimidoneClass Ib Antiarrhythmics. Pleiotropic genes: HLA-B Anticonvulsants; Hydantoins IUPAC Name: 4,6(1H,5H)-Pyrimidinedione,Antiepileptics 5- Drug Name:ethyldihydro-5-phenyl-; Primidone Properties5-Ethyldihydro-5- Pharmacogenetics phenyl-4,6(1H,5H)-pyrimidinedioneName: Primidone IUPAC Name: 4,6(1H,5H)-Pyrimidinedione, 5- Mechanistic genes: ethyldihydro-5-phenyl-;MolecularIUPAC Formula: Name: 4,6(1H,5H)-Pyrimidinedione,C 12H145-Ethyldihydro-5-N2O2 GABRAs phenyl-4,6(1H,5H)-pyrimidinedione5-ethyldihydro-5-phenyl-; 5-Ethyldihydro-5- Molecular Weight: 218.25 g/mol Metabolic genes: phenyl-4,6(1H,5H)-pyrimidinedione Mechanistic genes: Molecular Formula: C12H14N2O2 Inducer: CYP1A2, Mechanism: Decreases neuron excitability, GABRAs Mechanistic genes: GABRAs Molecular Formula: C12H14N2O2 CYP2B6, CYP2C8, Molecularraises Weight:seizure 218.25threshold g/mol similar to MetabolicMetabolic genes: genes: Molecular Weight: 218.25 g/mol Inducer:CYP2C9,Inducer: CYP3A4CYP1A2,CYP1A2, CYP2B6, Mechanism:phenobarbital. Decreases Primid oneneuron has excitability,two active CYP2B6, CYP2C8,CYP2C8, CYP2C9, CYP3A4 raisesmetabolites, Mechanism:seizure thresholdDecreasesphenobarbital neuronsimilar excitability, toand raises seizure threshold similar to phenobarbital.CYP2C9, CYP3A4 phenobarbital.phenylethylmalonamide Primidone has two active Primidone has two active metabolites, metabolites,Effect: Anticonvulsants; phenobarbital Barbiturates and phenobarbital and phenylethylmalonamide phenylethylmalonamide Effect: Anticonvulsants; Barbiturates Effect:Name: Anticonvulsants; Rufinamide Barbiturates Name: Rufinamide IUPAC Name: 1-[(2,6-difluorophenyl)methyl]- Name: RufinamideIUPAC Name : 1H-1,2,3-triazole-41-[(2,6-difluorophenyl)methyl]-1H-1,2,3-triazole-4 carboxamide IUPAC carboxamideName: 1-[(2,6-difluorophenyl)methyl]- Molecular Formula: C10H8F2N4O 1H-1,2,3-triazole-4 carboxamide Molecular Formula: C10H8F2N4O Molecular Weight: 238.2 g/mol MechanisticMechanistic genes: genes: MAPK10, Molecular Formula: C10H8F2N4O Molecular Weight: 238.2 g/mol MAPK10, SCN1A Mechanism: The precise mechanism(s) by which SCN1A MetabolicMetabolic genes: genes: Mechanism:rufinamide The exerts precise its antiepileptic mechanism(s) effect by are Mechanistic genes: Molecular Weight: 238.2 g/mol Substrate:Substrate: CES CES Int. J. Mol. Sci. 2020, 21, x FOR PEERwhich REVIEWunknown. rufinamide The exerts results its ofantiepileptic in vitro studies effect suggest MAPK10, SCN1A 65 of 87 Inhibitor:Inhibitor: CYP2E1CYP2E1 are unknown.that the principal The results mechanism of in vitro of action studies of Metabolic genes: Mechanism: The precise mechanism(s) by Inducer:Inducer: CYP3A4CYP3A4 suggestsustainedrufinamide that therepetitive principal is modulation mechanismfiring of theof activity of actionsodium- of Substrate: CES which rufinamidesodium channels exerts and,its antiepileptic in particular, effect prolongation of dependentrufinamide action is modulation potentials of the activity of Inhibitor: CYP2E1 are unknown.of the inactive The results state ofof thein channel.vitro studies Rufinamide Inducer: CYP3A4 suggestsodium (that 1 µthechannelsM) principal significantly and,mechanism slowed in sodiumofparticular, action channel ≥ of prolongationrufinamideEffect:recovery Anticonvulsants; is frommodulationof the inactivation inactive Triazoleof the after stateactivity Derivative a prolongedof ofthe sodiumchannel. prepulse channelsRufinamide in cultured and, (≥ cortical1 inμM) neurons,particular,significantly and limited slowedsustained sodium repetitive channel firing recovery of sodium-dependent from prolongationName: Tiagabine of the inactive state of the channel.inactivationaction Rufinamide potentialsafter a( ≥ prolonged1 μM) significantly prepulse in cultured cortical neurons, and limited slowedIUPAC Effsodiumect: Name:Anticonvulsants; channel3-Piperidinecarboxylic recovery Triazole Derivativefrom acid, 1- inactivation[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-,Name: after Tiagabine a prolonged prepulse in culturedhydrochloride, cortical (R)-;neurons, (-)-(R)-1-[4,4-Bis(3-methyl- and limited IUPAC Name: 3-Piperidinecarboxylic acid, 2-thienyl)-3-butenyl]nipecotic acid, 1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-, hydrochloride.hydrochloride, (R)-; (-)-(R)-1-[4,4-Bis(3-methyl-2- thienyl)-3-butenyl]nipecotic acid, hydrochloride. Molecular Formula: C20H25NO2S2 HCl Molecular Formula: C20H25NO2S2 HCl

Molecular Weight: 412.01 g/mol Mechanistic genes: ABAT Molecular Weight: 412.01 g/mol Mechanistic genes: ABAT Mechanism: Exact mechanism not definitively MetabolicMetabolic genes: genes: known; however, in vitro experiments Mechanism: Exact mechanism not definitively Substrate:Substrate: CYP3A4CYP3A4 demonstrate that it enhances activity of known; however, in vitro experiments TransporterTransporter genes:genes:SLC6A1 gamma-aminobutyric acid (GABA). It is thought demonstrate that it enhances activity of SLC6A1 that binding to GABA uptake carrier inhibits gamma-aminobutyric acid (GABA). It is uptake of GABA into presynaptic neurons, thoughtallowing that availability binding to of GABA increased uptake amount carrier of inhibitsGABA uptake to postsynaptic of GABA neurons. into Basedpresynaptic on in vitro neurons,studies, allowing tiagabine doesavailability not inhibit of uptakeincreased of amountdopamine, of GABA norepinephrine, to postsynaptic serotonin, neurons. glutamate, Basedor choline on in vitro studies, tiagabine does not inhibitEffect: uptakeAnticonvulsants of dopamine, norepinephrine, serotonin, glutamate, or choline

Effect: Anticonvulsants

Name: Topimarate IUPAC Name: β-D-Fructopyranose, 2,3:4,5-bis- O-(1-methylethylidene)-, sulfamate; 2,3:4,5-di- Mechanistic genes: O-isopropylidene-β-D-fructopyranose ACSL4, AGXT, CA1-5, sulfamate GABRA1, IGF1, KCNH2,

Molecular Formula: C12H21NO8S NR1I2, SCN1A, SCN2A Metabolic genes: Molecular Weight: 339.36 g/mol Substrate: CYP3A4 Mechanism: Blocks neuronal voltage- Inhibitor: CYP2C19 dependent sodium channels, enhances Inducer: ABCB1, CYP3A4 GABA(A) activity, antagonizes AMPA/kainate Transporter genes: glutamate receptors, and weakly inhibits ABCB1 carbonic anhydrase Effect: Anticonvulsants

Mechanistic genes: Name: Valproic acid ABAT, ACADSB, ALDH5A1, HDAC2, HDAC9, OGDH, PPARA, IUPAC Name: Pentanoic acid, 2-propyl-; (2) PPARD, PPARG Propylvaleric acid Metabolic genes: Substrate: CYP1A1, CYP1A2, CYP2A6, Molecular Formula: C8H16O2 CYP2B6, CYP2C8, CYP2C9, CYP2C18,

Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 65 of 87

Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEWsustained repetitive firing of sodium- 65 of 87 dependent action potentials sustained repetitive firing of sodium- dependentEffect: Anticonvulsants;action potentials Triazole Derivative

Effect: Anticonvulsants; Triazole Derivative Name: Tiagabine

Name:IUPAC Tiagabine Name: 3-Piperidinecarboxylic acid, 1- [4,4-bis(3-methyl-2-thienyl)-3-butenyl]-, IUPAChydrochloride, Name: 3-Piperidinecarboxylic (R)-; (-)-(R)-1-[4,4-Bis(3-methyl- acid, 1- [4,4-bis(3-methyl-2-thienyl)-3-butenyl]-,2-thienyl)-3-butenyl]nipecotic acid, hydrochloride,hydrochloride. (R)-; (-)-(R)-1-[4,4-Bis(3-methyl- 2-thienyl)-3-butenyl]nipecotic acid, hydrochloride.Molecular Formula: C20H25NO2S2 HCl

Molecular Formula: C20H25NO2S2 HCl Molecular Weight: 412.01 g/mol Mechanistic genes: ABAT Metabolic genes: MolecularMechanism: Weight: Exact 412.01 mechanism g/mol not definitivelyMechanistic Substrate: genes: CYP3A4 ABAT known; however, in vitro experimentsMetabolic Transporter genes: genes: Mechanism:demonstrate Exact that mechanism it enhances not definitively activity ofSubstrate: SLC6A1 CYP3A4 known;gamma-aminobutyric however, in vitroacid (GABA).experiments It isTransporter genes: demonstratethought that that binding it e nhancesto GABA activityuptake carrierof SLC6A1 gamma-aminobutyricinhibits uptake of acidGA BA(GABA). into presynaptic It is thoughtneurons, that bindingallowing to availabilityGABA uptake of carrierincreased inhibitsamount uptake of GABAof GA toBA po intostsynaptic presynaptic neurons. neurons,Based allowingon in vitro availability studies, tiagabine of increased does not Int. J. Mol. Sci. 2020, 21, 3059 61 of 82 amountinhibit of uptakeGABA ofto dopa postsynapticmine, norepinephrine, neurons. Basedserotonin, on in vitro glutamate, studies, or tiagabinecholine does not inhibit uptake of dopamine, norepinephrine, Table 6. Cont. serotonin,Effect: glutamate,Anticonvulsants or choline Antiepileptics Drug Effect:Name: Anticonvulsants Topimarate Properties Pharmacogenetics IUPACName: Name: Topimarate β-D-Fructopyranose, 2,3:4,5-bis- Name: Topimarate O-(1-methylethylidene)-,IUPAC Name: β-D-Fructopyranose, sulfamate; 2,3:4,5-di- Mechanistic genes: IUPACO-isopropylidene-2,3:4,5-bis-O-(1-methylethylidene)-, Name: β-D-Fructopyranose,β-D-fructopyranose 2,3:4,5-bis- sulfamate; ACSL4,Mechanistic AGXT, genes:CA1-5,ACSL4, O-(1-methylethylidene)-,sulfamate2,3:4,5-di-O-isopropylidene- sulfamate;β-D-fructopyranose 2,3:4,5-di- MechanisticGABRA1,AGXT, CA1-5,IGF1,genes: KCNH2, GABRA1, IGF1, O-isopropylidene-sulfamate β-D-fructopyranose Molecular Formula: C12H21NO8S ACSL4,NR1I2,KCNH2, AGXT, SCN1A, NR1I2, CA1-5,SCN2A SCN1A, SCN2A sulfamate Metabolic genes: Molecular Formula: C12H21NO8S GABRA1,Metabolic IGF1, genes: KCNH2, Molecular Weight: 339.36 g/mol NR1I2,Substrate: Substrate:SCN1A, CYP3A4 SCN2ACYP3A4 MolecularMolecular Formula: Weight: C12H339.3621NO8S g /mol MetabolicInhibitor:Inhibitor: genes: CYP2C19 CYP2C19 Mechanism: Blocks neuronal voltage- Inducer: ABCB1, CYP3A4 MolecularMechanism: Weight:Blocks 339.36 neuronal g/mol voltage-dependentSubstrate:Inducer: CYP3A4 ABCB1, CYP3A4 dependent sodium channels, enhances Transporter genes: ABCB1 sodium channels, enhances GABA(A) activity,Inhibitor:Transporter CYP2C19 genes: Mechanism:GABA(A)antagonizes activity,Blocks AMPA anta/kainateneuronalgonizes glutamate AMPA/kainatevoltage- receptors, Inducer:ABCB1 ABCB1, CYP3A4 dependentglutamateand weakly sodiumreceptors, inhibits channels, carbonicand weakly anhydraseenhances inhibits GABA(A)carbonic activity, anhydrase anta gonizes AMPA/kainate Transporter genes: Effect: Anticonvulsants ABCB1 glutamateEffect: Anticonvulsantsreceptors, and weakly inhibits carbonicName: anhydrase Valproic acid Mechanistic genes: ABAT, ACADSB, ALDH5A1, HDAC2, IUPAC Name: Pentanoic acid, 2-propyl-; (2) Mechanistic genes: Effect: Anticonvulsants HDAC9, OGDH, PPARA, PPARD, Name:Propylvaleric Valproic acid acid ABAT,PPARG ACADSB, MechanisticALDH5A1, genes:HDAC2, Molecular Formula: C8H16O2 Metabolic genes: Name: Valproic acid ABAT,HDAC9, Substrate: OGDH,ACADSB,CYP1A1, PPARA, CYP1A2, Molecular Weight: 144.21 g/mol IUPAC Name: Pentanoic acid, 2-propyl-; (2)ALDH5A1, PPARD,CYP2A6, PPARG CYP2B6,HDAC2, CYP2C8, PropylvalericMechanism: acidCauses increased availability ofHDAC9,MetabolicCYP2C9, OGDH, genes: CYP2C18, PPARA, CYP2C19, IUPACgamma-aminobutyric Name: Pentanoic acid, acid (GABA),2-propyl-; to brain(2) PPARD,Substrate:CYP2E1, PPARG CYP3A4,CYP1A1, CYP3A5, neurons or may enhance action of GABA or CYP4B1, CYP4F2, PTGS1, Propylvaleric acid MetabolicCYP1A2, genes: CYP2A6, mimic its action at postsynaptic receptor sites UGT1A1, UGT1A3, UGT1A4, Molecular Formula: C8H16O2 Substrate:CYP2B6, CYP1A1,CYP2C8, UGT1A6, UGT1A8, UGT1A9, CYP1A2,CYP2C9, CYP2A6,CYP2C18, UGT1A10, UGT2B7, UGT2B15 CYP2B6, CYP2C8, Molecular Formula: C8H16O2 Inhibitor: CYP2A6, CYP2C9,

CYP2C9,CYP2C19, CYP2C18, CYP2D6, CYP3A4, Effect: Anticonvulsants, Miscellaneous. HDAC9, UGT1A9, UGT2B7, Antimanic Agents; Histone Deacetylase Inhibitor UGT2B15 Transporter genes: ALB, SLC16A1, SLC22A5, SLC22A6, SLC22A7, SLC22A8, SLCO2B1

6. Conclusions Symptomatic interventions for patients with dementia involve anti-dementia drugs to improve cognition, psychotropic drugs for the treatment of behavioral disorders (BDs), and different categories of drugs for concomitant disorders. Demented patients may take >6–10 drugs/day with the consequent risk for drug–drug interactions (DDIs) and adverse drug reactions (ADRs > 80%) which accelerate cognitive decline. PGx intervention may prevent ADRs and DDIs. The pharmacoepigenetic machinery is integrated by pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes redundantly and promiscuously regulated by epigenetic mechanisms (DNA methylation, chromatin remodeling/histone changes, and miRNAs). CYP2D6, CYP2C9, CYP2C19, and CYP3A4/5 geno-phenotypes are involved in the metabolism of over 90% of drugs currently used in patients with dementia, and only 20% of the population is an extensive metabolizer for this tetragenic cluster. ADRs associated with anti-dementia drugs, antipsychotics, antidepressants, anxiolytics, hypnotics, sedatives, and antiepileptic drugs can be minimized by means of pharmacogenetic screening prior to treatment. These drugs are substrates, inhibitors, or inducers of 58, 37, and 42 enzyme/protein gene products, respectively, and are transported by 40 different protein transporters. APOE is the reference gene in most pharmacogenetic studies. In multifactorial treatments, APOE-3 carriers are the best responders and APOE-4 carriers are the worst responders; likewise, CYP2D6-EMs are the best responders and CYP2D6-PMs are the worst responders. ACHE-BCHE variants also affect the pharmacogenetic outcome as well as some genes encoding components of the epigenetic machinery. Antipsychotics show limited efficacy in aggressive behaviors and psychotic symptoms and may increase mortality and risk of psychomotor disorders and cerebrovascular events. Major ADRs with Int. J. Mol. Sci. 2020, 21, 3059 62 of 82 antipsychotics are extrapyramidal symptoms, tardive dyskinesia, weight gain, hyperprolactinemia, and agranulocytosis. Antipsychotics are associated with the activity of 100 pharmagenes; antidepressants ≈ are associated with 600; and anxiolytics, hypnotics, and sedatives are associated with 445. CYP enzymes are involved in 100% of drugs approved for the treatment of depression, and about 60% of depressive patients are receiving an inappropriate medication according to their pharmacogenetic background. Carbamazepine, oxcarbazepine, or phenytoin may cause delayed-hypersensitivity reactions associated with the HLA antigen allele HLA-B*15:02. The incorporation of pharmacogenomic strategies for a personalized treatment in dementia is an effective option to optimize limited therapeutic resources and to reduce unwanted side-effects.

7. Further Considerations Drug efficacy and safety are fundamental issues in dementia due to the complexity of the disorder and comorbidities which require polypharmacy [43]. Over 50% of patients over 60 years of age suffering chronic CNS disorders currently take 6–12 drugs/day with a high risk of drug toxicity, ADRs, and DDIs [43,56]. Over 20% of patients with depression develop dementia in a period of approximately 10 years. The chronic use of anticholinergic antidepressants might contribute to this pathogenic transformation [318]. It is also well-known that over 60% of patients chronically treated with antipsychotics develop extrapyramidal symptoms which may induce severe motor disability [319]. Over 80% of nursing home residents are daily consumers of psychotropic drugs [320,321] which are prescribed in excessive doses, for excessive duration, and without adequate monitoring and/or indications for their use [322]. Prescribing errors ( 50%) are common in patients treated with ≈ anti-dementia drugs [42], and potentially inappropriate prescribing (PIP) occurs in almost 80% of patients with dementia [323]. With appropriate PGx intervention, the frequency and intensity of PIP and ADRs may be reduced in approximately 50% of the cases. AD patients show diverse age-related comorbidities which require polypharmacy. The implementation of PGx procedures may help to minimize drug–drug interactions. For instance, CYP2C19 variants influence the effects of proton-pump inhibitors and the onset of infections [324]. ACE variants affect the pharmacokinetics and pharmacodynamics of ACE inhibitors which may interact with psychotropic drugs, contributing to cerebrovascular dysfunction [229]. Another important issue is the use of anticoagulants in patients with dementia [103]. Different antithrombotic drugs (Acenocoumarol, Acetylsalicylic acid, Argatroban, Bivalirudin, Cilostazol, Clopidogrel, Dabigatran, Rivaroxaban, Dipyridamole, Lepirudin, Prasugel, Ticagrelor, Ticlopidine, and Warfarin) can be used in patients with atrial fibrillation, thrombophlebitis, and thromboembolic or ischemic stroke. Warfarin is one of the most common anticoagulants due to its low cost; however, its narrow therapeutic window makes it a candidate to a few ADRs in patients with dementia. Warfarin prolongs prothrombin time (PT) and activated partial thromboplastin time (APTT), and phytonadione (vitamin K1) reverses its anticoagulant effect. Warfarin is a substrate of CALU, CYP1A2, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP3A4/5, CYP4F2, EPHX1, and GGCX; an inhibitor of CYP2C9, CYP2C19, and VKORC1; and an inducer of CYP2C9; and is transported by ABCB1. CYP2C9 and VKORC1 variants are determinant in warfarin efficacy and safety [55]. VKORC1 variants and CYP2C9*3 are clearly associated with warfarin maintenance dosages. CYP2C9 and VKORC1 genotypes help to identify normal responders (60%), sensitive responders (35%), and highly sensitive responders (3%) to warfarin and characterized patients who can benefit from edoxaban compared with warfarin [325]. VKORC1-AG and GG carriers need higher doses than patients with AA genotypes, and CYP2C9*1/*3 carriers need doses lower than patients with the CYP2C9*1/*1 wild genotype [326]. In the Chinese region of Xinjiang, patients with atrial fibrillation carrying the CT and TT genotypes in the GGCX gene rs259251 loci need higher warfarin doses than GGCX-CC carriers [327]. ADRB1 Ser49Gly and Arg389Gly variants are associated with cardiovascular and β-blocker response outcomes. In patients with previous history of stroke, the ADRB1 Gly49 polymorphism is associated with cardiovascular and cerebrovascular ADRs among β-blocker users [328]. Int. J. Mol. Sci. 2020, 21, 3059 63 of 82

In patients with minor ischemic stroke, platelet receptor gene ( and P2Y1) and glycoprotein gene (GPIIIa) polymorphisms influence antiplatelet drug responsiveness and clinical outcomes [329], and there are genetic differences (rs12143842) in the response of stroke patients to antihypertensive drugs (chlorthalidone, amlodipine, or lisinopril), especially regarding HNRNPA1P4 and NOS1AP variants in African Americans and PRICKLE1 and NINJ2 variants in non-Hispanic Whites [330]. Rivaroxaban is currently used in thromboprophylaxis. ABCB1 rs1045642, ABCB1 rs4148738, CYP3A4 rs35599367, and CYP3A5 rs776746 variants may influence rivaroxaban pharmacokinetics and prothrombin time dynamics [331]. The platelet-aggregation inhibitor Clopidogrel may also cause frequent complications. This antithrombotic agent is a substrate of CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4/5; and an inhibitor of CYP2B6, CYP2C9, and CYP2C19; and is transported by ABCB1. CYP2C19*2 (G681A and rs4244285), CYP2C19*3 (G363A and rs4986893), CYP2C19*17 (C806T and rs12248560), and ABCB1 (C3435T and rs1045642) carriers with ischemic stroke are particularly sensitive to clopidogrel ADRs [55]. Clopidogrel resistance is frequent in patients with chronic kidney disease. Kidney dysfunction alters the association between CYP2C19 variants and clopidogrel effects in patients with stroke or transient ischemic attack. Carriers of CYP2C19 loss-of-function alleles (CYP2C19*2 and *3) have higher odds of new stroke than noncarriers [332,333] and increased risk of thromboembolic complications following neurointerventional procedures [334]. The AKR1D1*36 (rs1872930) allele is associated with the risk of major adverse cardiovascular and cerebrovascular events in clopidogrel-treated patients [335]. About 16–50% of patients treated with clopidogrel show platelet reactivity and an increased risk of ischemic events. Some methylated CpG sites have been associated with increased stroke recurrence. Lower cg03548645 (TRAF3) DNA methylation correlates with increased platelet aggregation in patients with stroke [336]. Studies on the PGx of anticoagulants for stroke prevention in patients with atrial fibrillation are not conclusive and deserve further investigation to optimize this currently used pharmacological intervention with still unclear results [337]. Orthopedic surgery is relatively frequent in patients with NDDs who experience perioperative neurocognitive disorders (delirium and postoperative cognitive dysfunction) which increase mortality [338]. PGx assessment is highly recommended for selection of appropriate anesthetics and postsurgical treatments in order to reduce postoperatory BDs and accelerated cognitive deterioration [55]. (OUD) is infrequent in AD; however, in AD cases treated with opioids, it is important to take into account that patients with at least one copy of the CYP3A4*1B allele exhibit an accelerated rate of metabolism compared to the wild-type allele CYP3A4*1 [339] and that CYP2D6-UMs show a better response to than EMs, IMs, and PMs [55]. Several essential elements and metals (zinc, aluminum, copper, and cadmium), environmental toxicants, air pollutants (e.g., nanoparticles, particulate matter, ozone, and traffic-related air pollution), inappropriate , and drugs of abuse (, cannabis, cocaine, and ) may contribute to neurotoxicity and may interfere with conventional treatments in dementia. Over 30% of patients with prodromal dementia are current users of anticholinergic drugs [340]. Chronic exposure to these products alters behavior and deteriorates cognition and psychomotor function in a dose-dependent fashion [341–343]. The pharmacogenetic genotyping of detoxification systems may help to predict risks in susceptible subjects [55]. It is also most important to elucidate the mechanisms underlying the drug-resistance phenomenon, which occurs in over 40% of cases with NPDs and in over 70% of cases with neoplastic processes [61,71]. Globally, over 20% of patients are resistant to conventional drugs [344,345] and it is estimated that pharmacogenetic and pharmacoepigenetic factors are important contributors to drug resistance [61,346–348]. Important issues to take into account in the coming years for the appropriate management of dementia are the identification of presymptomatic biomarkers and the discovery of effective drugs. Int. J. Mol. Sci. 2020, 21, 3059 64 of 82

Predictive markers associated with pathogenic genes for the presymptomatic diagnosis of dementia should incorporate both genomic and epigenetic signatures. Concerning the development of novel anti-pathogenic drugs, actual facts show that most CNS drugs are repressive rather than neuroprotective based on the regulation of a restrictive number of neurotransmitters; however, brain function depends upon the interplay of thousands of neuronal-glial factors pending full characterization. The discovery of novel anti-pathogenic drugs with neuroprotective properties is urgently needed to efficiently treat the different forms of brain dysfunction in dementia. The development of new drugs and clinically validated methods of identifying patients for a specific treatment should rely on PGx strategies.

Funding: This paper was funded by IABRA (International Agency for Brain Research and Aging), Corunna, Spain. Acknowledgments: I would like to thank my coworkers at EuroEspes Biomedical Research Center, International Center of Neuroscience and Genomic Medicine, Corunna, for technical support in our studies on pharmacogenomics and epigenetics of dementia. Conflicts of Interest: The author is President of the International Center of Neuroscience and Genomic Medicine, EuroEspes Biotechnology, and IABRA (International Agency for Brain Research and Aging) and is also President of the World Association of Genomic Medicine and Editor-in-Chief of the World Guide for Drug Use and Pharmacogenomics. The author has no other relevant affiliations or financial involvement with any organization or entity with financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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