key: cord-015684-q10sx1dm
authors: Cacabelos, Ramón
title: Pharmacogenomic Biomarkers in Neuropsychiatry: The Path to Personalized Medicine in Mental Disorders
date: 2009
journal: The Handbook of Neuropsychiatric Biomarkers, Endophenotypes and Genes
DOI: 10.1007/978-90-481-2298-1_1
sha: 
doc_id: 15684
cord_uid: q10sx1dm

Neuropsychiatric disorders and dementia represent a major cause of disability and high cost in developed societies. Most disorders of the central nervous system (CNS) share some common features, such as a genomic background in which hundreds of genes might be involved, genome-environment interactions, complex pathogenic pathways, poor therapeutic outcomes, and chronic disability. Recent advances in genomic medicine can contribute to accelerate our understanding on the pathogenesis of CNS disorders, improve diagnostic accuracy with the introduction of novel biomarkers, and personalize therapeutics with the incorporation of pharmacogenetic and pharmacogenomic procedures to drug development and clinical practice. The pharmacological treatment of CNS disorders, in general, accounts for 10–20% of direct costs, and less than 30–40% of the patients are moderate responders to conventional drugs, some of which may cause important adverse drugs reactions (ADRs). Pharmacogenetic and pharmacogenomic factors may account for 60–90% of drug variability in drug disposition and pharmacodynamics. Approximately 60–80% of CNS drugs are metabolized via enzymes of the CYP gene superfamily; 18% of neuroleptics are major substrates of CYP1A2 enzymes, 40% of CYP2D6, and 23% of CYP3A4; 24% of antidepressants are major substrates of CYP1A2 enzymes, 5% of CYP2B6, 38% of CYP2C19, 85% of CYP2D6, and 38% of CYP3A4; 7% of benzodiazepines are major substrates of CYP2C19 enzymes, 20% of CYP2D6, and 95% of CYP3A4. About 10–20% of Caucasians are carriers of defective CYP2D6 polymorphic variants that alter the metabolism of many psychotropic agents. Other 100 genes participate in the efficacy and safety of psychotropic drugs. The incorporation of pharmacogenetic/ pharmacogenomic protocols to CNS research and clinical practice can foster therapeutics optimization by helping to develop cost-effective pharmaceuticals and improving drug efficacy and safety. To achieve this goal several measures have to be taken, including: (a) educate physicians and the public on the use of genetic/ genomic screening in the daily clinical practice; (b) standardize genetic testing for major categories of drugs; (c) validate pharmacogenetic and pharmacogenomic procedures according to drug category and pathology; (d) regulate ethical, social, and economic issues; and (e) incorporate pharmacogenetic and pharmacogenomic procedures to both drugs in development and drugs in the market to optimize therapeutics.

Central nervous system (CNS) disorders are the third problem of health in developed countries, representing 10-15% of deaths, after cardiovascular disorders (25-30%) and cancer (20-25%) . Approximately, 127 million Europeans suffer brain disorders. The total annual cost of brain disorders in Europe is about €386 billion, with €135 billion of direct medical expenditures (€78 billion, inpatients; €45 billion, outpatients; €13 billion, pharmacological treatment), €179 billion of indirect costs (lost workdays, productivity loss, permanent disability), and €72 billion of direct non-medical costs. Mental disorders represent €240 billion (62% of the total cost, excluding dementia), followed by neurological diseases (€84 billion, 22%). 1 Senile dementia is becoming a major problem of health in developed countries, and the primary cause of disability in the elderly. Alzheimer's disease (AD) is the most frequent form of dementia (50-70%), followed by vascular dementia (30-40%) , and mixed dementia (15-20%) . These prevalent forms of agerelated neurodegeneration affect more than 25 million people at present, and probably more than 75 million people will be at risk in the next 20-25 years worldwide. The prevalence of dementia increases exponentially from approximately 1% at 60-65 years of age to more than 30-35% in people older than 80 years. It is very likely that in those patients older than 75-80 years of age most cases of dementia are mixed in nature (degenerative + vascular), whereas pure AD cases are very rare after 80 years of age. The average annual cost per person with dementia ranges from €10,000 to 40,000, depending upon disease stage and country, with a lifetime cost per patient of more than €150,000. In some countries, approximately 80% of the global costs of dementia (direct + indirect costs) are assumed by the patients and/or their families. About 10-20% of the costs in dementia are attributed to pharmacological treatment, including anti-dementia drugs, psychotropics (antidepressants, neuroleptics, anxiolytics), and other drugs currently prescribed in the elderly (antiparkinsonians, anticonvulsants, vasoactive compounds, antiinfl ammatory drugs, etc). In addition, during the past 20 years more than 300 drugs have been partially or totally developed for AD, with the subsequent costs for the pharmaceutical industry, and only 5 drugs with moderate-to-poor effi cacy and questionable cost-effectiveness have been approved in developed countries. [2] [3] [4] The lack of accurate diagnostic markers for early prediction and an effective therapy of CNS disorders are the two most important problems to effi ciently diagnose and halt disease progression. The pharmacological treatment of CNS disorders, in general, accounts for 10-20% of direct costs, and less than 30-40% of the patients are moderate responders to conventional drugs, some of which may cause important adverse drugs reactions (ADRs). In the case of dementia, less than 20% of the patients can benefi t from current drugs (donepezil, rivastigmine, galantamine, memantine), with doubtful cost-effectiveness. The pathogenic mechanisms of most CNS disorders (e.g., psychosis, depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, etc) are poorly understood. This circumstance makes it diffi cult the implantation of a molecular intervention to neutralize causative factors. In fact, more than 80% of the 25,000 genes integrating the human genome are expressed in the CNS at different periods of the life span, and only a few neurotransmitters (e.g., noradrenaline, dopamine, acetylcholine, GABA, histamine, and less than ten neuropeptides) are the actual targets of conventional psychopharmacology. Common features in CNS disorders include the following: (a) polygenic/ complex disorders in which genomic and environmental factors are involved; (b) deterioration of higher activities of the CNS; (c) multifactorial dysfunctions in several brain circuits; and (d) accumulation of toxic proteins in the nervous tissue in cases of neurodegeneration. For instance, the neuropathological hallmark of Alzheimer's disease (AD) (amyloid deposition in senile plaques, neurofi brillary tangle formation, and neuronal loss) is but the phenotypic expression of a pathogenic process in which more than 200 genes and their products are potentially involved.

Drug metabolism, and the mechanisms underlying drug effi cacy and safety, are also genetically regulated complex traits in which hundreds of genes cooperatively participate. Structural and functional genomics studies demonstrate that genomic factors, probably induced by environmental factors, cerebrovascular dysfunction, and epigenetic phenomena, might be responsible for pathogenic events leading to premature neuronal dysfunction and/or death.

Pharmacogenetic and pharmacogenomic factors may account for 60-90% of drug variability in drug disposition and pharmacodynamics. About 10-20% of Caucasians are carriers of defective CYP2D6 polymorphic variants that alter the metabolism of many psychotropic agents. The incorporation of pharmacogenetic/pharmacogenomic protocols to CNS research and clinical practice can foster therapeutics optimization by helping to develop cost-effective pharmaceuticals and improving drug effi cacy and safety. [5] [6] [7] 

Extensive molecular genetics studies carried out in the past 2 decades have demonstrated that most CNS disorders are multifactorial, polygenic/complex disorders in which hundreds of genes distributed across the human genome might be involved (Tables 40.1-40. 3). 8, 9 For example, 255 genes have been associated with dementia (Table 40 .1), 205 with schizophrenia (Table  40. 2), 106 with depression (Table 40. 3), 107 with anxiety, 103 with stroke, 385 with different types of ataxia, 155 with epilepsiy, 83 with meningioma, 105 with glioblastoma, 27 with astrocytoma, 73 with Parkinson's disease, and more than 30 genes with cerebrovascular disorders. 8, 10 Many of these genetic associations could not be replicated in different settings and different populations due to many complex (methodological, technological) factors. 8, 11, 12 Furthermore, the same genomic defect can give rise to apparent diverse phenotypes, and different genomic defects can converge in an apparently common phenotype, this increasing the complexity of genomic studies (e.g., patient recruitment, pure controls, concomitant pathology, epigenetic factors, environmental factors). Several candidate genes for schizophrenia may also be associated with bipolar disorder, including G72, DISC1, NRG1, RGS4, NCAM1, DAO, GRM3, GRM4, GRIN2B, MLC1, SYNGR1, and SLC12A6. Genes associated with bipolar disorder include TRPM2 (21q22.3), GPR50 (Xq28), Citron (12q24), CHP1.5 (18p11.2), GCHI (14q22-24), MLC1 (22q13), GABRA5 (15q11-q13), BCR (22q11), CUX2, FLJ32356 (12q23-q24), and NAPG (18p11). 9 Another paradigmatic example of heterogeneity and complexity is dementia, one of the most heterogeneous disorders of the CNS. The genetic defects identifi ed in AD during the past 25 years can be classifi ed into three main categories: (a) Mendelian or mutational defects in genes directly linked to AD, including (i) 32 mutations in the amyloid beta (Aβ)(ABP) precursor protein (APP) gene (21q21); (ii) 165 mutations in the presenilin 1 (PS1) gene (14q24.3); and (iii) 12 mutations in the presenilin 2 (PS2) gene (1q31-q42) 8, 10, 13 (Table 40 .1). (b) Multiple polymorphic variants of risk characterized in more than 200 different genes distributed across the human genome can increase neuronal vulnerability to premature death 8 (Table 40 .1). Among these genes of susceptibility, the apolipoprotein E (APOE) gene (19q13.2) is the most prevalent as a risk factor for AD, especially in those subjects harbouring the APOE-4 allele, whereas carriers of the APOE-2 allele might be protected against dementia. 8 APOE-related pathogenic mechanisms are also associated with brain aging and with the neuropathological hallmarks of AD. 8 (c) Diverse mutations located in mitochondrial DNA (mtDNA) through heteroplasmic transmission can infl uence aging and oxidative stress conditions, conferring phenotypic heterogeneity. 8, 14, 15 It is also likely that defective functions of genes associated with longevity may infl uence premature neuronal survival, since neurons are potential pacemakers defi ning life span in mammals. 8 All these genetic factors may interact in still unknown genetic networks leading to a cascade of pathogenic events characterized by abnormal protein processing and misfolding with subsequent accumulation of abnormal proteins (conformational changes), ubiquitin-proteasome system dysfunction, excitotoxic reactions, oxidative and nitrosative stress, mitochondrial injury, synaptic failure, altered metal homeostasis, dysfunction of axonal and dendritic transport, and chaperone misoperation 8,16-20 ( Fig. 40.1 ). These pathogenic events may exert an additive effect, converging in fi nal pathways leading to premature neuronal death. Some of these mechanisms are common to several neurodegenerative disorders which differ depending upon the gene(s) affected and the involvement of specifi c genetic networks, together with cerebrovascular factors, epigenetic factors (DNA methylation) and environmental conditions (nutrition, toxicity, social factors, etc). 8, [16] [17] [18] [19] [20] [21] [22] The higher the number of genes involved in AD pathogenesis, the earlier the onset of the disease, the faster its clinical course, and the poorer its therapeutic outcome. 8, [16] [17] [18] [19] [20] High throughput microarray gene expression profi ling is an effective approach for the identifi cation of candidate genes and associated molecular pathways implicated in a wide variety of biological processes or disease states. The cellular complexity of the CNS (with 10 3 different cell types) and synapses (with each of the 10 11 neurons in the brain having around 10 3 -10 4 synapses with a complex multiprotein structure integrated by 10 3 different proteins) requires a very powerful technology for gene expression profi ling, which is still in the very early stages and is not devoid of technical obstacles and limitations. 23 Transcripts of 16,896 genes have been measured in different CNS regions. Each region possess its own unique transcriptome fi ngerprint that is independent of age, gender and energy intake. Less than 10% of genes are affected by age, diet or gender, with most of these changes occurring between middle and old age. Gender and energy restriction have robust infl uences on the hippocampal transcriptome of middle-aged animals. Prominent functional groups of age-and energy-sensitive genes are those encoding proteins involved in DNA damage responses, mitochondrial and proteasome functions, cell fate determination and synaptic vesicle traffi cking. The systematic transcriptome dataset provides a window into mechanisms of neuropathogenesis and CNS vulnerability. 24 With the advent of modern genomic technologies, new loci have been associated with different neuropsychiatric disorders, and novel pathogenic mechanisms have been postulated. Cryptic chromosome imbalances are increasingly acknowledged as a cause for mental retardation and learning disability. With subtelomeric screening, nine chromosomal anomalies and submicroscopic deletions of 1pter, 2qter, 4pter, 5qter and 9qter have been identifi ed in patients with mental retardation. 25 Increased DNA fragmentation was observed in non-GABAergic neurons in bipolar disorder, suggesting that non-GABAergic cell may be selectively vulnerable to oxidative stress and apoptosis in patients with bipolar disorder. 26 [17] [18] [19] [20] With laser microdissection, RNA amplifi cation, and array hybridization, expression of more than 1,000 genes was detected in CA1 and CA3 hippocampal neurons under normoxic conditions. The comparison of each region under normoxic and ischemic conditions revealed more than 5,000 ischemia-regulated genes for each individual cell type. 27 Microarray technology has helped to elucidate gene expression profi les and potential pathogenic mechanisms in many other CNS disorders including schizophrenia and bipolar disorder, [28] [29] [30] speech and language disorders, 31 Parkinson's disease, 32, 33 Huntington's disease, 34 prion disease, 35 drug addiction, 36,37 alcoholism, 38 brain trauma, 39 epilepsy, [40] [41] [42] Cockayne syndrome, 43 Rett syndrome, 44 Friedreich ataxia, 45 neuronal ceroid lipofuscinosis, 46 multiple sclerosis, 47 amyotrophic lateral esclerosis, 48 acute pneumococcal meningitis, 49 and the role of lipids in brain injury, psychiatric disorders, and neurodegenerative diseases. [50] [51] [52] Interactions between genomic factors and environmental factors have been proposed as important contributors for brain neuropathology. In schizophrenia, neurodevelopmental disturbances, neurotoxins and perinatal infections, myelin-and olygodendrocytes abnormalities and synaptic dysfunctions have been suggested as pathophysiological factors. Individual genotoxicants can induce distinct gene expression signatures. Exposure of the brain to environmental agents during critical periods of neuronal development can alter neuronal viability and differentiation, global gene expression, stress and immune response, and signal transduction. 53 The binomial genome-neurotoxicants effect can be documented in cases of drug abuse or alcohol dependence. Functional gene expression differences between inbred alcohol-preferring and nonpreferring rats suggest the presence of powerful genomic infl uences on alcohol dependence. 54 Alcohol dependence and associated cognitive impairment may result from neuroadaptations to chronic alcohol consumption involving changes in expression of multiple genes. It has been suggested that cycles of alcohol intoxication/withdrawal, which may initially activate nuclear factor-kappa B (NF-κB), when repeated over years downregulate p65 (RELA) mRNA expression and NF-κB and p50 homodimer DNA-binding. Downregulation of the dominant p50 homodimer, a potent inhibitor of gene transcription apparently results in depression of κB regulated genes. Alterations in expression of p50 homodimer/NF-κB regulated genes may contribute to neuroplastic adaptation underlying alcoholism. 55 Gene expression profi ling of the nucleus accumbens of cocaine abusers suggests a dysregulation of myelin. 56 Humans who abused cocaine, cannabis and/or phencyclidine share a decrease in transcription of calmodulin-related genes and increased transcription related to lipid/cholesterol and Golgi/ER function. 57 Another important issue in the pathogenesis and therapeutics of CNS disorders is the role of microR-NAs (miRNAs). miRNAs are small (22 nucleotide), endogenous noncoding RNA molecules that posttranscriptionally regulate expression of protein-coding genes. Computational predictions estimate that the vertebrate genomes may contain up to 1,000 miRNA genes. miRNAs are generated from long primary transcripts that are processed in multiple steps to cytoplasmic 22 nucleotide mature miRNAs. The mature miRNA is incorporated into the miRNA-induced silencing complex (miRISC), which guides it to target sequences located in 3′ UTRs where by incomplete base-pairing induce mRNA destabilization or translational repression of the target genes. An inventory of miRNA expression profi les from 13 regions of the mouse CNS has been reported. 58 This inventory of CNS miRNA profi les provides an important step toward further elucidation of miRNA function and miRNA-related gene regulatory networks in the mammalian CNS. 58

The introduction of novel procedures into an integral genomic medicine protocol for CNS disorders is an imperative requirement in drug development and in the clinical practice to improve diagnostic accuracy and to optimize therapeutics. This kind of protocol should integrate the following components: (i) clinical history, (ii) laboratory tests, (iii) neuropsychological assessment, (iv) cardiovascular evaluation, (v) conventional X-ray technology, (vi) structural neuroimaging, (vii) functional neuroimaging, (viii) computerized brain electrophysiology, (ix) cerebrovascular evaluation, (x) structural genomics, (xi) functional genomics, (xii) pharmacogenetics, (xiii) pharmacogenomics, (ix) nutrigenetics, (x) nutrigenomics, (xi) bioinformatics for data management, and (xii) artifi cial intelligence procedures for diagnostic assignments and probabilistic therapeutic options (Table 40 .4). 2, 8, [16] [17] [18] [19] [20] [21] [22] 59, 60 All these procedures, under personalized strategies adapted to the complexity of each case, are essential to depict a clinical profi le based on specifi c biomarkers correlating with individual genomic profi les.

Functional genomics studies have demonstrated the infl uence of many genes on CNS pathogenesis and phenotype expression (Tables 40.1-40. 3). Taking AD as an example, it has been demonstrated that mutations in the APP, PS1, PS2, and MAPT genes give rise to wellcharacterized differential neuropathological and clinical phenotypes of dementia. 8 The analysis of genotypephenotype correlations has also revealed that the presence of the APOE-4 allele in AD, in conjunction with other genes, infl uences disease onset, brain atrophy, cerebrovascular perfusion, blood pressure, β-amyloid deposition, ApoE secretion, lipid metabolism, brain bioelectrical activity, cognition, apoptosis, and treatment outcome. 8, [16] [17] [18] [19] [20] [21] [22] 61 The characterization of phenotypic profi les according to age, cognitive performance (MMSE and ADAS-Cog score), serum ApoE levels, serum lipid levels including cholesterol (CHO), HDL-CHO, LDL-CHO, VLDL-CHO, and triglyceride (TG) levels, as well as serum nitric oxide (NO), β-amyloid, and histamine levels, reveals sex-related differences in 25% of the biological parameters and almost no differences (0.24%) when patients are classifi ed as APOE-4(−) and APOE-4(+) carriers, probably indicating that genderrelated factors may infl uence these parametric variables more powerfully than the presence or absence of the APOE-4 allele; in contrast, when patients are classifi ed according to their APOE genotype, dramatic differences emerge among APOE genotypes (>45%), with a clear biological disadvantage in APOE-4/4 carriers who exhibit (i) earlier age of onset, (ii) low ApoE levels, (iii) high CHO and LDL-CHO levels, and (iv) low NO, β-amyloid, and histamine levels in blood. 8, [16] [17] [18] [19] [20] [21] [22] 61 These phenotypic differences are less pronounced when AD patients are classifi ed according to their PS1 (15.6%) or ACE genotypes (23.52%), refl ecting a weak impact of PS1-and ACE-related genotypes on the phenotypic expression of biological markers in AD. PS1related genotypes appear to infl uence age of onset, blood histamine levels and cerebrovascular hemodynamics, as refl ected by signifi cant changes in systolic (Sv), diastolic (Dv), and mean velocities (Mv) in the left middle cerebral arteries (MCA). 19 ACE-related phenotypes seem to be more infl uential than PS1 genotypes in defi ning biological phenotypes, such as age of onset, cognitive performance, HDL-CHO levels, ACE and NO levels, and brain blood fl ow Mv in MCA. However, when APOE and PS1 genotypes are integrated in bigenic clusters and the resulting bigenic genotypes are differentiated according to their corresponding phenotypes, an almost logarithmic increased expression of differential phenotypes is observed (61.46% variation), indicating the existence of a synergistic effect of the bigenic (APOE + PS1) cluster on the expression of biological markers, apparently unrelated to APP/PS1 mutations, since none of the patients included in the sample were carriers of either APP or PS1 mutations. 19, 61, 62 These examples illustrate the potential additive effects of AD-related genes on the phenotypic expression of biological markers. Furthermore, the analysis of genotype-phenotype correlations with a monogenic or bigenic approach documents a modest genotype-related variation in serum amyloid-β (ABP) levels, suggesting that peripheral levels of ABP are of relative value as predictors of disease-stage or as markers of disease progression and/ or treatment-related disease-modifying effects. 19, 61, 62 The peripheral levels of ABP in serum exhibit an APOE-dependent pattern according to which both APOE-4(+) and APOE-2(+) carriers tend to show higher ABP levels than APOE-4(−) or APOE-3 carriers 19,61-63 ( Fig. 40 est concentration of serum histamine is systematically present in APOE-2(+) and APOE-4(+) carriers, and the highest levels of histamine are seen in APOE-3(+) carriers ( Fig. 40.3 ). Central and peripheral histaminergic mechanisms may regulate cerebrovascular function in AD, which is signifi cantly altered in APOE-4/4 carriers. 19, [61] [62] [63] [64] [65] [66] These observations can lead to the conclusion that the simple quantifi cation of biochemical markers in fl uids or tissues of AD patients with the aim of identifying pathogenic mechanisms and/or monitoring therapeutic effects, when they are not accompanied by differential genotyping for sample homogenization, are of very poor value. Differential patterns of APOE-, PS1-, PS2-, and trigenic (APOE + PS1 + PS2) cluster-related lymphocyte apoptosis have been detected in AD. Fas receptor expression is signifi cantly increased in AD, especially in APOE-4 carriers where lymphocyte apoptosis is more relevant. 19, 67 It has been demonstrated that brain activity slowing correlates with progressive GDS staging in dementia 8, 16, [18] [19] [20] (Fig. 40.4 ). In the general population subjects harbouring the APOE-4/4 genotype exhibit a premature slowing in brain mapping activity represented by increased slow delta and theta activities as compared with other APOE genotypes. In patients with AD, slow activity predominates in APOE-4 carriers with similar GDS stage 8,16,18-20 ( Fig. 40.4) .

AD patients harbouring the APOE-4/4 genotype also exhibit a dramatically different brain optical topography map refl ecting a genotype-specifi c differential pattern of neocortical oxygenation as well as a poorer activation of cortical neurons in response to somatosensory stimuli ( Fig. 40 .5). All these examples of genotype-phenotype correlations, as a gross approach to functional genomics, illustrate the importance of genotype-related differences in AD and their impact on phenotype expression. 8, [16] [17] [18] [19] [20] [21] [22] 62, 63 Similar protocols are applied to schizophrenia, depression, anxiety and other neuropsychiatric disorders. Most biological parameters, potentially modifi able by monogenic genotypes and/or polygenic cluster profi les, can be used in clinical trials for monitoring effi cacy outcomes. These parametric variables also show a genotypedependent profi le in different types of dementia (e.g., AD vs. vascular dementia). For instance, striking differences have been found between AD and vascular dementia in structural and functional genomics studies. 8, [16] [17] [18] [19] [20] [21] [22] 62, 63 

Our understanding of the pathophysiology of CNS disorders has advanced dramatically in the last 30 years, especially in terms of their molecular pathogenesis and genetics. Drug treatment of CNS disorders has also made remarkable strides, with the introduction of many new drugs for the treatment of schizophrenia, depression, anxiety, epilepsy, Parkinson's disease, and Alzheimer's disease, among many other quantitatively and qualita-tively important neuropsychiatric disorders. Improvement in terms of clinical outcome, however, has fallen short of expectations, with up to one third of the patients continuing to experience clinical relapse or unacceptable medication-related side effects in spite of efforts to identify optimal treatment regimes with one or more drugs. 68 Potential reasons to explain this historical setback might be that: (a) the molecular pathology of most CNS disorders is still poorly understood; (b) drug targets are inappropriate, not fi tting into the real etiology of the disease; (c) most treatments are symptomatic, but not anti-pathogenic; (d) the genetic component of most CNS disorders is poorly defi ned; and (e) the understanding of genome-drug interactions is very limited.

With the advent of recent knowledge on the human genome 69,70 and the identifi cation and characterization of many genes associated with CNS disorders, 8, 19 as well as novel data regarding CYP family genes and other genes whose enzymatic products are responsible for drug metabolism in the liver (e.g., NATs, ABCBs/ MDRs, TPMT), it has been convincingly postulated that the incorporation of pharmacogenetic and pharmacogenomic procedures ( Fig. 40 .6) in drug development might bring about substantial benefi ts in terms of therapeutics optimization in CNS disorders and in many other complex disorders, assuming that genetic factors are determinant for both neuronal dysregulation (and/or neuronal death) 8,16-22 and drug metabolism. [71] [72] [73] Fig. 40.6 Effi cacy and safety issues associated with pharmacogenetics and pharmacogenomics (Adapted from R. Cacabelos 19, 20 ) However, this fi eld is still in its infancy; and the incorporation of pharmacogenomic strategies to drug development and pharmacological screening in CNS disorders is not an easy task. The natural course of technical events to achieve effi cient goals in pharmacogenetics and pharmacogenomics include the following steps: (a) genetic testing of mutant genes and/or polymorphic variants of risk; (b) genomic screening, and understanding of transcriptomic, proteomic, and metabolomic networks; (c) functional genomics studies and genotype-phenotype correlation analysis; and (d) pharmacogenetics and pharmacogenomics developments, addressing drug safety and effi cacy, respectively. 8, [16] [17] [18] [19] [20] [21] [22] [74] [75] [76] [77] With pharmacogenetics we can understand how genomic factors associated with genes encoding enzymes responsible for drug metabolism regulate pharmacokinetics and pharmacodynamics (mostly safety issues). [78] [79] [80] With pharmacogenomics we can differentiate the specifi c disease-modifying effects of drugs (effi cacy issues) acting on pathogenic mechanisms directly linked to genes whose mutations determine the disease phenotype. [16] [17] [18] [19] [20] [21] [22] [74] [75] [76] [77] The capacity of drugs to reverse the effects of the activation of pathogenic cascades (phenotype expression) regulated by networking genes basically deals with effi cacy issues. At present, the terms pharmacogenetics and pharmacogenomics are often used interchangeably to refer to studies of the contribution of inheritance to variation in the drug response phenotype 73 ; however, from historical and didactic reasons (until a more suitable and universal defi nition can be established) it would be preferable to maintain the term of pharmacogenetics for the discipline dealing with genetic factors associated with drug metabolism and safety issues, whereas pharmacogenomics would refer to the reciprocal infl uence of drugs and genomic factors on pathogenetic cascades and disease-associated gene expression (effi cacy issues). [18] [19] [20] [21] [22] [74] [75] [76] [77] The application of these procedures to CNS disorders is a very diffi cult task, since most neuropsychiatric diseases are complex disorders in which hundreds of genes might be involved 8, [16] [17] [18] [19] [20] [21] [22] [74] [75] [76] [77] (Tables 40.1-40.3 ). In addition, it is very unlikely that a single drug be able to reverse the multifactorial mechanisms associated with neuronal dysfunction in most CNS processes with a complex phenotype affecting mood, personality, behaviour, cognition, and functioning. This heterogeneous clinical picture usually requires the utilization of different drugs administered simultaneously. This is particularly important in the elderly population. In fact, the average number of drugs taken by patients with dementia ranges from six to more than ten per day depending upon their physical and mental conditions. Nursing home residents receive, on average, seven to eight medications each month, and more than 30% of residents have monthly drug regimes of nine or more medications, including (in descending order) analgesics, antipyretics, gastrointestinal agents, electrolytic and caloric preparations, central nervous system (CNS) agents, anti-infective agents, and cardiovascular agents. 81 In population-based studies more than 35% of patients older than 85 years are moderate or chronic antidepressant users. 82 Polypharmacy, drug-drug interactions, adverse reactions, and non-compliance are substantial therapeutic problems in the pharmacological management of elderly patients, 83 adding further complications and costs to the patients and their caregivers. In 2000-2001, 23.0-36.5% of elderly individuals received at least 1 of 33 potentially inappropriate medications in ten health maintenance organizations (HMOs) of the USA. 84 Although drug effect is a complex phenotype that depends on many factors, it is estimated that genetics accounts for 20-95% of variability in drug disposition and pharmacodynamics. 79 Under these circumstances, therapeutics optimization is a major goal in neuropsychiatric disorders and in the elderly population, and novel pharmacogenetic and pharmacogenomic procedures may help in this endeavour. [16] [17] [18] [19] [20] [21] [22] [74] [75] [76] [77] 

The pharmacogenomic outcome depends upon many different determinant factors including (i) genomic profi le (family history, ethnic background, disease-related genotype, pharmacogenetic genotype, pharmacogenomic genotype, nutrigenetic genotype, nutrigenomic genotype), (ii) disease phenotype (age at onset, disease severity, clinical symptoms), (iii) concomitant pathology, (iv) genotype-phenotype correlations, (v) nutritional conditions, (vi) age and gender, (vii) pharmacological profi le of the drugs, (viii) drug-drug interactions, (ix) gene expression profi le, (x) transcriptomic cascade, (xi) proteomic profi le, and (xii) metabolomic networking ( Fig. 40.7) . The dissection and further integration of all these factors is of paramount importance for the assessment of the pharmacogenomic outcome in terms of safety and effi cacy (Figs. 40.8 and 40.9). 

More than 80% of psychotropic drugs (Table 40 .5) are metabolized by enzymes known to be genetically variable, including: (a) esterases: butyrylcholinesterase, paraoxonase/arylesterase; (b) transferases: N-acetyltransferase, sulfotransferase, thiol methyltransferase, thiopurine methyltransferase, catechol-O-methyltransferase, glutathione-S-transferases, UDP-glucuronosyltransferases, glucosyltransferase, histamine methyltransferase; (c) Reductases: NADPH: quinine oxidoreductase, glucose-6-phosphate dehydrogenase; (d) oxidases: alcohol dehydrogenase, aldehydehydrogenase, monoamine oxidase B, catalase, superoxide dismutase, trimethylamine N-oxidase, dihydropyrimidine dehydrogenase; and (e) cytochrome P450 enzymes, such as CYP1A1, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A5 (Table 40 .6) and many others. 19, 20 Polymorphic variants in these genes can induce alterations in drug metabolism modifying the effi cacy and safety of the prescribed drugs. 85 Drug metabolism includes phase I reactions (i.e., oxidation, reduction, hydrolysis) and phase II conjugation reactions (i.e., acetylation, glucuronidation, sulfation, methylation). 80 The principal enzymes with polymorphic variants involved in phase I reactions are the following: CYP3A4/5/7, CYP2E1, CYP2D6, CYP2C19, CYP2C9, CYP2C8, CYP2B6, CYP2A6, CYP1B1, CYP1A1/2, epoxide hydrolase, esterases, NQO1 (NADPH-quinone oxidoreductase), DPD (dihydropyrimidine dehydrogenase), ADH (alcohol dehydrogenase), and ALDH (aldehyde dehydrogenase). Major enzymes involved in phase II reactions include the following: UGTs (uridine 5′-triphosphate glucuronosyl transferases), TPMT (thiopurine methyltransferase), COMT (catechol-O-methyltransferase), HMT (histamine methyl-transferase), STs (sulfotransferases), GST-A (glutathion S-transferase A), GST-P, GST-T, GST-M, NAT2 (N-acetyl transferase), NAT1, and others. 86 Polymorphisms in genes associated with phase II metabolism enzymes, such as GSTM1, GSTT1, NAT2 and TPMT are well understood, and information is also emerging on other GST polymorphisms and on polymorphisms in the UDP-glucuronosyltransferases and sulfotransferases.

The typical paradigm for the pharmacogenetics of phase I drug metabolism is represented by the cytochrome P-450 enzymes, a superfamily of microsomal Nonsteroidal anti-infl ammatory drug drug-metabolizing enzymes. P450 enzymes comprise a superfamily of heme-thiolate proteins widely distributed in bacteria, fungi, plants and animals. The P450 enzymes are encoded in genes of the CYP superfamily (Table 40 .6) and act as terminal oxidases in multicomponent electron transfer chains which are called P450containing monooxigenase systems. Some of the enzymatic products of the CYP gene superfamily can share substrates, inhibitors and inducers whereas others are quite specifi c for their substrates and interacting drugs. [18] [19] [20] [71] [72] [73] [78] [79] [80] There are more than 200 P450 genes identifi ed in different species. Saito et al 87 provided a catalogue of 680 variants among eight CYP450 genes, nine esterase genes, and two other genes in the Japanese population.

The microsomal, membrane-associated, P450 isoforms CYP3A4, CYP2D6, CYP2C9, CYP2C19, CYP2E1, and CYP1A2 are responsible for the oxidative metabolism of more than 90% of marketed drugs. About 60-80% of the psychotropic agents currently used for the treatment of neuropsychiatric disorders are metabolized via enzymes of the CYP family, especially CYP1A2, CYP2B6, CYP2C8/9, CYP2C19, CYP2D6 and CYP3A4 (Table 40 .5). CYP3A4 metabolizes more drug molecules than all other isoforms together. Most of these polymorphisms exhibit geographic and ethnic differences. [88] [89] [90] [91] [92] [93] [94] These differences infl uence drug metabolism in different ethnic groups in which drug dosage should be adjusted according to their enzymatic capacity, differentiating normal or extensive metabolizers (EMs), poor metabolizers (PMs) and ultrarapid metabolizers (UMs). Most drugs act as substrates, inhibitors or inducers of CYP enzymes. Enzyme induction enables some xenobiotics to accelerate their own biotransformation (auto-induction) or the biotransformation and elimination of other drugs. A number of P450 enzymes in human liver are inducible. Induction of the majority of P450 enzymes occurs by increase in the rate of gene transcription and involves ligand-activated transcription factors, aryl hydrocarbon receptor, constitutive androstane receptor (CAR), and pregnane X receptor (PXR). 93, 95 In general, binding of the appropriate ligand to the receptor initiates the induction process that cascades through a dimerization of the receptors, their translocation to the nucleus and binding to specifi c regions in the promoters of CYPs. 95 CYPs are also expressed in the CNS, and a complete characterization of constitutive and induced CYPs in brain is essential for understanding the role of these enzymes in neurobiological functions and in age-related and xenobiotic-induced neurotoxicity. 96 Assuming that the human genome contains about 20,000-30,000 genes, at the present time only 0.31% of commercial drugs have been assigned to corresponding genes whose gene products might be involved in pharmacokinetic and pharmacodynamic activities of a given drug; and only 4% of the human genes have been assigned to a particular drug metabolic pathway. Supposing a theoretical number of 100,000 chemicals in current use worldwide, and assuming that practically all human genes can interact with drugs taken by human beings, each gene in the human genome should be involved in the metabolism and/or biopharmacological effect of 30-40 drugs; however, assuming that most xenobiotic substances in contact with our organism can infl uence genomic function, it might be possible that for 1,000,000 xenobiotics in daily contact with humans, an average of 350-500 xenobiotics have to be assigned to each one of the genes potentially involved in drug metabolism and/or xenobiotics processing. To fulfi l this task a single gene has to possess the capacity of metabolizing many different xenobiotic substances and at the same time many different genes have to cooperate in orchestrated networks to metabolize a particular drug or xenobiotic under sequential biotransformation steps (Figs. 40.7 and 40.8). Numerous chemicals increase the metabolic capability of organisms by their ability to activate genes encoding various xenochemical-metabolizing enzymes, such as CYPs, transferases and transporters. Many natural and artifi cial substances induce the hepatic CYP subfamilies in humans, and these inductions might lead to clinically important drug-drug interactions. Some of the key cellular receptors that mediate such inductions have been recently identifi ed, including nuclear receptors, such as the constitutive androstane receptor (CAR, NR1I3), the retinoid X receptor (RXR, NR2B1), the pregnane X receptor (PXR, NR1I3), and the vitamin D receptor (VDR, NR1I1) and steroid receptors such as the glucocorticoid receptor (GR, NR3C1). 97 There is a wide promiscuity of these receptors in the induction of CYPs in response to xenobiotics. Indeed, this adaptive system acts as an effective network where receptors share partners, ligands, DNA response elements and target genes, infl uencing their mutual relative expression. 97,98

The most important enzymes of the P450 cytochrome family in drug metabolism by decreasing order are CYP3A4, CYP2D6, CYP2C9, CYP2C19, and CYP2A6. [85] [86] [87] 94, 99, 100 The predominant allelic variants in the CYP2A6 gene are CYP2A6 * 2 (Leu160His) and CYP2A6del. The CYP2A6 * 2 mutation inactivates the enzyme and is present in 1-3% of Caucasians. The CYP2A6del mutation results in no enzyme activity and is present in 1% of Caucasians and 15% of Asians. [18] [19] [20] 86 The most frequent mutations in the CYP2C9 gene are CYP2C9 * 2 (Arg144Cys), with reduced affi nity for P450 in 8-13% of Caucasians, and CYP2C9 * 3 (Ile359Leu), with alterations in the specifi city for the substrate in 6-9% of Caucasians and 2-3% of Asians. [18] [19] [20] 86 The most prevalent polymorphic variants in the CYP2C19 gene are CYP2C19 * 2, with an aberrant splicing site resulting in enzyme inactivation in 13% of Caucasians, 23-32% of Asians, 13% of Africans, and 14-15% of Ethiopians and Saoudians, and CYP2C19 * 3, a premature stop codon resulting in an inactive enzyme present in 6-10% of Asians, and almost absent in Caucasians. [18] [19] [20] 86, 101 The most important mutations in the CYP2D6 gene are the following: CYP2D6 * 2xN, CYP2D6 * 4, CYP2D6 * 5, CYP2D6 * 10 and CYP2D6 * 17. [18] [19] [20] 96, 102 The CYP2D6 * 2xN mutation gives rise to a gene duplication or multiplication resulting in an increased enzyme activity which appears in 1-5% of the Caucasian population, 0-2% of Asians, 2% of Africans, and 10-16% of Ethiopians. The defective splicing caused by the CYP2D6 * 4 mutation inactivates the enzyme and is present in 12-21% of Caucasians. The deletion in CYP2D6 * 5 abolishes enzyme activity and shows a frequency of 2-7% in Caucasians, 1% in Asians, 2% in Africans, and 1-3% in Ethiopians. The polymorphism CYP2D6 * 10 causes Pro34Ser and Ser486Thr mutations with unstable enzyme activity in 1-2% of Caucasians, 6% of Asians, 4% of Africans, and 1-3% of Ethiopians. The CYP2D6 * 17 variant causes Thr107Ile and Arg296Cys substitutions which produce a reduced affi nity for substrates in 51% of Asians, 6% of Africans, and 3-9% of Ethiopians, and is practically absent in Caucasians. [18] [19] [20] 86, 96, 102 

The CYP2D6 enzyme, encoded by a gene that maps on 22q13.1-13.2, catalyses the oxidative metabolism of more than 100 clinically important and commonly prescribed drugs such as cholinesterase inhibitors, antidepressants, neuroleptics, opioids, some β-blockers, class I antiarrhythmics, analgesics and many other drug categories, acting as substrates, inhibitors or inducers with which most psychotropics may potentially interact (Table 40 .5), this leading to the outcome of ADRs. [18] [19] [20] 86, 96, 103 The CYP2D6 locus is highly polymorphic, with more than 100 different CYP2D6 alleles identifi ed in the general population showing defi cient (poor metabolizers, PM), normal (extensive metabolizers, EM) or increased enzymatic activity (ultra-rapid metabolizers, UM). 100,104 Most individuals (>80%) are EMs; however, remarkable interethnic differences exist in the frequency of the PM and UM phenotypes among different societies all over the world. [18] [19] [20] 89, [91] [92] [93] [94] 102 On the average, approximately 6.28% of the world population belongs to the PM category. Europeans (7.86%), Polynesians (7.27%), and Africans (6.73%) exhibit the highest rate of PMs, whereas Orientals (0.94%) show the lowest rate. The frequency of PMs among Middle Eastern populations, Asians, and Americans is in the range of 2-3%. [16] [17] [18] [19] [20] 94 CYP2D6 gene duplications are relatively infrequent among Northern Europeans, but in East Africa the frequency of alleles with duplication of CYP2D6 is as high as 29%. 73 The most frequent CYP2D6 alleles in the European population are the following: CYP2D6 * 1 (wild-type) (normal), CYP2D6 * 2 (2850C > T)(normal), CYP2D6 * 3 (2549A > del)(inactive), CYP2D6 * 4 (1846G > A)(inactive), CYP2D6 * 5 (gene deletion)(inactive), CYP2D6 * 6 (1707T > del)(inactive), CYP2D6 * 7 (2935A > C)(inac-tive), CYP2D6 * 8 (1758G > T)(inactive), CYP2D6 * 9 (2613-2615 delAGA)(partially active), CYP2D6 * 10 (100C > T)(partially active), CYP2D6 * 11 (883G > C) (inactive), CYP2D6 * 12 (124G > A)(inactive), CYP2D6 * 17 (1023C > T)(partially active), and CYP2D6 gene duplications (with increased or decreased enzymatic activity depending upon the alleles involved). [16] [17] [18] [19] [20] [104] [105] [106] In the Spanish population, where the mixture of ancestral cultures has occurred for centuries, the distribution of the CYP2D6 genotypes differentiates 4 major categories of CYP2D6-related metabolizer types: (i) Extensive Metabolizers (EM)( * 1/ * 1, * 1/ * 10); (ii) Intermediate Metabolizers (IM)( * 1/ * 3, * 1/ * 4, * 1/ * 5, * 1/ * 6, * 1/ * 7, * 10/ * 10, * 4/ * 10, * 6/ * 10, * 7/ * 10); (iii) Poor Metabolizers (PM)( * 4/ * 4, * 5/ * 5); and (iv) Ultra-rapid Metabolizers (UM)( * 1xN/ * 1, * 1xN/ * 4, Dupl). In this sample we have found 51.61% EMs, 32.26% IMs, 9.03% PMs, and 7.10% UMs. 20, [74] [75] [76] [77] The distribution of all major genotypes is the following: * 1/ * 1, 47.10%; * 1/ * 10, 4.52%; * 1/ * 3, 1.95%; * 1/ * 4, 17.42%; * 1/ * 5, 3.87%; * 1/ * 6, 2.58%; * 1/ * 7, 0.65%; * 10/ * 10, 1.30%; * 4/ * 10, 3.23%; * 6/ * 10, 0.65%; * 7/ * 10, 0.65%; * 4/ * 4, 8.37%; * 5/ * 5, 0.65%; * 1xN/ * 1, 4.52%; * 1xN/ * 4, 1.95%; and Dupl, 0.65%. 20, [74] [75] [76] [77] In some instances, there is association of CYP2D6 variants of risk with genes potentially involved in the pathogenesis of specifi c CNS disorders. When comparing AD cases with controls, we observed that EMs are more prevalent in AD ( * 1/ * 1, 49.42%; * 1/ * 10, 8.04%)(total AD-EMs: 57.47%) than in controls ( * 1/ * 1, 44.12%; * 1/ * 10, 0%)(total C-EMs: 44.12%). In contrast, IMs are more frequent in controls (41.18%) than in AD (25.29%), especially the * 1/ * 4 (C: 23.53%; AD: 12.64%) and * 4/ * 10 genotypes (C: 5.88%; AD: 1.15%). The frequency of PMs was similar in AD (9.20%) and controls (8.82%), and UMs were more frequent among AD cases (8.04%) than in controls (5.88%). 20, 74, 75, 77 

We have also investigated the association of CYP2D6 genotypes with AD-related genes, such as APP, MAPT, APOE, PS1, PS2, A2M, ACE, AGT, FOS, and PRNP variants. 20, 74, 75, 77 No APP or MAPT mutations have been found in AD cases. Homozygous APOE-2/2 (12.56%) and APOE-4/4 (12.50%) accumulate in UMs, and APOE-4/4 cases were also more frequent in PMs (6.66%) than in EMs (3.95%) or IMs (0%). PS1-1/1 genotypes were more frequent in EMs (45%), whereas PS-1/2 genotypes were over-represented in IMs (63.16%) and UMs (60%). The presence of the PS1-2/2 genotype was especially high in PMs (38.46%) and UMs (20%). A mutation in the PS2 gene exon 5 (PS2E5+) was markedly present in UMs (66.67%). About 100% of UMs were A2M-V100I-A/A, and the A2M-V100I-G/G genotype was absent in PMs and UMs. The A2M-I/I genotype was absent in UMs, and 100% of UMs were A2M-I/D and ACE-D/D. Homozygous mutations in the FOS gene (B/B) were only present in UMs, as well. AGT-T235T cases were absent in PMs, and the AGT-M174M genotype appeared in 100% of PMs. Likewise, the PRNP-M129M variant was present in 100% of PMs and UMs. 20, 74, 75, 77 These association studies clearly show that in PMs and UMs there is an accumulation of AD-related polymorphic variants of risk which might be responsible for the defective therapeutic responses currently seen in these AD clusters. 20, [74] [75] [76] [77] 

It appears that different CYP2D6 variants, expressing EMs, IMs, PMs, and UMs, infl uence to some extent several biochemical parameters, liver function, and vascular hemodynamic parameters which might affect drug effi cacy and safety. Blood glucose levels are found elevated in EMs ( * 1/ * 1 vs. * 4/ * 10, p < 0.05) and in some IMs ( * 4/ * 10 vs. * 1xN/ * 4, p < 0.05), whereas other IMs ( * 1/ * 5 vs. * 4/ * 4, p < 0.05) tend to show lower levels of glucose compared with PMs ( * 4/ * 4) or UMs ( * 1xN/ * 4) (Table 40 .7). The highest levels of total-cholesterol are detected in the EMs with the CYP2D6 * 1/ * 10 genotype (vs. * 1/ * 1, * 1/ * 4 and * 1xN/ * 1, p < 0.05). The same pattern has been observed with regard to LDLcholesterol levels, which are signifi cantly higher in the EM-* 1/ * 10. In general, both total cholesterol levels and LDL-cholesterol levels are higher in EMs (with a signifi cant difference between * 1/ * 1 and * 1/ * 10), intermediate levels are seen in IMs, and much lower levels in PMs and UMs; and the opposite occurs with HDLcholesterol levels, which on average appear much lower in EMs than in IMs, PMs, and UMs, with the highest levels detected in * 1/ * 3 and * 1xN/ * 4 (Table 40 .8). The levels of triglycerides are very variable among different CYP2D6 polymorphisms, with the highest levels present in IMs ( * 4/ * 10 vs. * 4/ * 5 and * 1xN/ * 1, p < 0.02). These data clearly indicate that lipid metabolism can be infl uenced by CYP2D6 variants or that specifi c phenotypes determined by multiple lipid-related genomic clusters are necessary to confer the character of EMs and IMs. Other possibility might be that some lipid metabolism genotypes interact with CYP2D6-related enzyme products leading to defi ne the pheno-genotype of PMs and UMs. No signifi cant changes in blood pressure values have been found among CYP2D6 genotypes; however, important differences became apparent in brain cerebrovascular hemodynamics (Table 40 .9). In general terms, the best (2) 0.88 ± 0.07 (6) 0.56 ± 0.02 ( LDL-cholesterol levels, than in IMs ( * 4/ * 10, p < 0.05); and diastolic velocities (Dv) also tend to be much lower in * 1/ * 10 and especially in PMs ( * 4/ * 4) and UMs ( * 1xN/ * 4), whereas the best Dv is measured in * 1/ * 5 IMs. More striking are the results of both the pulsatility index (PI = (Sv-Dv)/Mv) and resistance index (RI = (Sv-Dv)/Sv), which are worse in IMs and PMs than in EMs and UMs (Table 40 .9). These data taken together seem to indicate that CYP2D6-related AD PMs exhibit a poorer cerebrovascular function which might affect drug penetration in the brain with the consequent therapeutic implications. [16] [17] [18] [19] [20] [74] [75] [76] [77] 

Some conventional anti-dementia drugs (tacrine, donepezil, galantamine) are metabolized via CYP-related enzymes, especially CYP2D6, CYP3A4, and CYP1A2, and polymorphic variants of the CYP2D6 gene can affect the liver metabolism, safety and effi cacy of some cholinesterase inhibitors. 107, 108 In order to elucidate whether or not CYP2D6-related variants may infl uence transaminase activity, we have studied the association of GOT, GPT, and GGT activity with the most prevalent CYP2D6 genotypes in AD (Table 40 .10). Globally, UMs and PMs tend to show the highest GOT activity and IMs the lowest. Signifi cant differences appear among different IM-related genotypes. The * 10/ * 10 genotype exhibited the lowest GOT activity with marked differences as compared to UMs (p < 0.05 vs. * 1xN/ * 1; p < 0.05 vs. * 1xN/ * 4). GPT activity was signifi cantly higher in PMs ( * 4/ * 4) than in EMs ( * 1/ * 10, p < 0.05) or IMs ( * 1/ * 4, * 1/ * 5, p < 0.05). The lowest GPT activity was found in EMs and IMs. Striking differences have been found in GGT activity between PMs ( * 4/ * 4), which showed the highest levels, and EMs ( * 1/ * 1, p < 0.05; * 1/ * 10, p < 0.05), IMs ( * 1/ * 5, p < 0.05), or UMs ( * 1xN/ * 1, p < 0.01) ) ( Table  40 .10). Interesting enough, the * 10/ * 10 genotype, with the lowest values of GOT and GPT, exhibited the second highest levels of GGT after * 4/ * 4, probably indicating that CYP2D6-related enzymes differentially regulate drug metabolism and transaminase activity in the liver. These results are also clear in demonstrating the direct effect of CYP2D6 variants on transaminase activity 20,77,109 (Table 40 .10). (2) 16.28 ± 7.40 (11) 18.14 ± 6.79 (17) Intermediate metabolizers * 1/ * 3 22.33 ± 1.52 (3, 4) 24.66 ± 10. 59 22.00 ± 8.71 * 1/ * 4 21.76 ± 3.57 (5, 6) 21.88 ± 8.40 32.23 ± 25.53 * 1/ * 5 18.33 ± 2.33 (7, 8) 16.16 ± 5.60 (12, 13) 18.50 ± 6.47 ( 

No clinical trials have been performed to date to elucidate the infl uence of CYP2D6 variants on the therapeutic outcome in AD in response to cholinesterase inhibitors or other anti-dementia drugs. To overcome this lack of pharmacogenetic information, we have performed the fi rst prospective study in AD patients who received a combination therapy with (a) an endogenous nucleotide and choline donor, CDP-choline (500 mg/day), (b) a nootropic substance, piracetam (1,600 mg/day), (c) a vasoactive compound, 1,6 dimethyl 8β-(5bromonicotinoyl-oxymethyl)-10α-methoxyergoline (nicergoline) ( (Fig. 40.10 ). Among EMs, AD patients harbouring the * 1/ * 10 genotype responded better than patients with the * 1/ * 1 genotype. The best responders among IMs were the * 1/ * 3, * 1/ * 6 and * 1/ * 5 genotypes, whereas the * 1/ * 4, * 10/ * 10, and * 4/ * 10 genotypes were poor responders. Among PMs and UMs, the poorest responders were carriers of the * 4/ * 4 and * 1xN/ * 1 genotypes, respectively. 20, 77, 109 From all these data we can conclude the following: (i) The most frequent CYP2D6 variants in the Spanish population are the * 1/ * 1 (47.10%), * 1/ * 4 (17.42%), * 4/ * 4 (8.37%), * 1/ * 10 (4.52%) and * 1xN/ * 1 (4.52%), accounting for more than 80% of the population; (ii) the frequency of EMs, IMs, PMs, and UMs is about 51.61%, 32.26%, 9.03%, and 7.10%, respectively; (iii) EMs are more prevalent in AD (57.47%) than in controls (44.12%); IMs are more frequent in controls (41.18%) Fig. 40 .10 CYP2D6-related therapeutic response to a multifactorial treatment in Alzheimer's disease over a 1-year period (Adapted from R. Cacabelos 77, 109 ).Patients received a combina-tion therapy for 1 year, and cognitive function (MMSE score) was assessed at baseline (B) and after 1, 3, 6, 9, and 12 months of treatment. than in AD (25.29%), especially the * 1/ * 4 (C: 23.53%; AD: 12.64%) and * 4/ * 10 genotypes (C: 5.88%; AD: 1.15%); the frequency of PMs is similar in AD (9.20%) and controls (8.82%); and UMs are more frequent among AD cases (8.04%) than in controls (5.88%); (iv) there is an accumulation of AD-related genes of risk in PMs and UMs; (v) PMs and UMs tend to show higher transaminase activities than EMs and IMs; (vi) EMs and IMs are the best responders, and PMs and UMs are the worst responders to a combination therapy with cholinesterase inhibitors, neuroprotectants, and vasoactive substances; and (vii) the pharmacogenetic response in AD appears to be dependent upon the networking activity of genes involved in drug metabolism and genes involved in AD pathogenesis. [16] [17] [18] [19] [20] [74] [75] [76] [77] 109, 110 Taking into consideration the available data, it might be inferred that at least 15% of the AD population may exhibit an abnormal metabolism of cholinesterase inhibitors and/or other drugs which undergo oxidation via CYP2D6-related enzymes. Approximately 50% of this population cluster would show an ultrarapid metabolism, requiring higher doses of cholinesterase inhibitors to reach a therapeutic threshold, whereas the other 50% of the cluster would exhibit a poor metabolism, displaying potential adverse events at low doses. If we take into account that approximately 60-70% of therapeutic outcomes depend upon pharmacogenomic criteria (e.g., pathogenic mechanisms associated with AD-related genes), it can be postulated that pharmacogenetic and pharmacogenomic factors are responsible for 75-85% of the therapeutic response (effi cacy) in AD patients treated with conventional drugs. [16] [17] [18] [19] [20] [74] [75] [76] [77] 109, 110 Of particular interest are the potential interactions of cholinesterase inhibitors with other drugs of current use in patients with AD, such as antidepressants, neuroleptics, antiarrhythmics, analgesics, and antiemetics which are metabolized by the cytochrome P450 CYP2D6 enzyme. 111 Although most studies predict the safety of donepezil 112 and galantamine, 107 as the two principal cholinesterase inhibitors metabolized by CYP2D6-related enzymes, 113, 114 no pharmacogenetic studies have been performed so far on an individual basis to personalize the treatment, and most studies reporting safety issues are the result of pooling together pharmacological and clinical information obtained with routine procedures. 103, [115] [116] [117] In certain cases, genetic polymorphism in the expression of CYP2D6 is not expected to affect the pharmacodynamics of some cholinesterase inhibitors because major meta-bolic pathways are glucuronidation, O-demethylation, N-demethylation, N-oxidation, and epimerization. However, excretion rates are substantially different in EMs and PMs. For instance, in EMs, urinary metabolites resulting from O-demethylation of galantamine represent 33.2% of the dose compared with 5.2% in PMs, which show correspondingly higher urinary excretion of unchanged galantamine and its N-oxide. 118 Therefore, still there are many unanswered questions regarding the metabolism of cholinesterase inhibitors and their interaction with other drugs (potentially leading to ADRs) which require pharmacogenetic elucidation. It is also worth to mention that dose titration (a common practice in AD patients treated with cholinesterase inhibitors; e.g., tacrine, donepezil) is an unwise strategy, since approximately 30-60% of drug failure or lack of therapeutic effi cacy (and/or ADR manifestation) is not a matter of drug dosage but a problem of poor metabolizing capacity in PMs. Additionally, inappropriate drug use is one of the risk factors for adverse drug reactions (ADRs) in the elderly. The prevalence of use of potentially inappropriate medications in patients older than 65 years of age admitted to a general medical or geriatric ward ranges from 16% to 20%, 119 and these numbers may double in ambulatory patients. Overall, the most prevalent inappropriate drugs currently prescribed to the elderly are amiodarone, long-acting benzodiazepines and anticholinergic antispasmodics; however, the list of drugs with potential risk also include antidepressant, antihistaminics, NSAIDs, amphetamines, laxatives, clonidine, indomethacin, and several neuroleptics, 119 most of which are processed via CYP2D6 and CYP3A5 enzymes. 120 Therefore, pre-treatment CYP screening might be of great help to rationalize and optimize therapeutics in the elderly, by avoiding medications of risk in PMs and UMs.

There are substantial differences between individuals in the effects of psychotropic drugs in the treatment of neuropsychiatric disorders. Pharmacogenetic studies of psychotropic drug response have focused on determining the relationship between variation in specifi c candidate genes and the positive and adverse effects of drug treatment. 121 More than 200 different genes are potentially involved in the metabolism of psychotropic drugs infl uencing pharmacokinetics and pharmacodynamics. Of all genes affecting drug metabolism, effi cacy and safety, the CYP gene family is the most relevant since more than 60% of CNS drugs are metabolized by cytochrome P450 enzymes. [122] [123] [124] Approximately, 18% of neuroleptics are major substrates of CYP1A2 enzymes, 40% of CYP2D6, and 23% of CYP3A4; 24% of antidepressants are major substrates of CYP1A2 enzymes, 5% of CYP2B6, 38% of CYP2C19, 85% of CYP2D6, and 38% of CYP3A4; 7% of benzodiazepines are major substrates of CYP2C19 enzymes, 20% of CYP2D6, and 95% of CYP3A4 (Table 40 .5). Approximately, 80% of patients with resistant depression, 60% of patients non-responsive to neuroleptics, and 50-70% of patients with paradoxical responses to benzodiazepines are carriers of mutant variants of the CYP2D6, CYP2C9 and CYP3A4 genes, falling within the categories of poor or ultra-rapid metabolizers.

Other genes infl uencing psychotropic drug activity include the following: ABCB1 ( [128] [129] [130] [131] [132] [133] [134] [135] [136] [137] [138] (Table 40.5) .

Historically, the vast majority of pharmacogenetic studies of CNS disorders have been addressed to evaluate the impact of cytochrome P450 enzymes on drug metabolism. [125] [126] [127] Furthermore, conventional targets for psychotropic drugs were the neurotransmitters dopamine, serotonin, noradrenaline, GABA, ion channels, acetylcholine and their respective biosynthetic and catalyzing enzymes, receptors and transporters 121 ; however, in the past few years many different genes have been associated with both pathogenesis and pharmacogenomics of neuropsychiatric disorders. Some of these genes and their products constitute potential targets for future treatments. New developments in genomics, including whole genome genotyping approaches and comprehensive information on genomic variation across populations, coupled with large-scale clinical trials in which DNA collection is routine, now provide the impetus for a next generation of pharmacogenetic studies and identifi cation of novel candidate drugs. [139] [140] [141] Cyclic nucleotide phosphodiesterases (PDEs) are a family of enzymes that degrade cAMP and cGMP. Intracellular cyclic nucleotide levels increase in response to neurotransmitters and are down-regulated through hydrolysis catalyzed by PDEs, which are therefore candidate therapeutic targets. cAMP is a second messenger involved in learning, memory, and mood, and cGMP modulates brain processes that are controlled by the nitric oxide (NO)/cGMP pathway. The analysis of SNPs in 21 genes of this superfamily revealed that polymorphisms in PDE9A and PDE11A are associated with major depressive disorder. In addition, remission on antidepressants was associated with polymorphisms in PDE1A and PDE11A. According to these results, it has been postulated that PDE11A (haplotype GAACC) has a role in the pathogenesis of major depression. 142 Another example is the purinergic receptor gene P2RX(7), located in a major linkage hotspot for schizophrenia and bipolar disorder (12q21-33), which has been associated with bipolar disorder, but nine functionally characterized variants of P2RX(7) did not show association with schizophrenia. 143 The possible role of a tag SNP (the 1359G/A polymorphism) of the gene encoding the cannabinoid receptor type 1 (CNR1) has been investigated in schizophrenics treated with atypical antipsychotics. No difference in 1359G/A polymorphism was observed between patients and control subjects, and no relation-ships were noted between this polymorphism and any clinical parameter considered as potential intermediate factor; however, the G allele was signifi cantly higher among non-responders vs. responsive patients, suggesting that the G allele of the CNR1 gene could be a pharmacogenetic rather than a vulnerability factor for schizophrenics. 144 Synaptic dysfunction is a potential pathogenic factor in schizophrenia. Cholesterol is an essential component of myelin and has proved important for synapse formation and lipid raft function. It has been demonstrated that the antipsychotic drugs clozapine and haloperidol stimulate lipogenic gene expression in glioma cells in culture through activation of the sterol regulatory element-binding protein (SREBP) transcription factors. Recently, the action of chlorpromazine, haloperidol, clozapine, olanzapine, risperidone and ziprasidone on SREBP and SREBP-controlled gene expression (acetyl-CoA acetyltransferase 2, acetoacetyl-CoA thiolase, ACAT2; 3-hydroxy-3-methylglutaryl-CoA reductase, HMGCR; 3-hydroxy-3-methylglutaryl-CoA synthase 1, HMGCS1; FDPS; sterol-C5-desaturase like, SC5DL; 7-dehydrocholesterol reductase, DHCR7; low density lipoprotein receptor, LDLR; fatty acid synthase; farsenyl diphosphate synthase, FASN; stearoyl-CoA desaturase, delta-9-desaturase, SCD1) has been investigated in different CNS human cell lines, demonstrating that antipsychotic-induced activation of lipogenesis is most prominent in glial cells and that this mechanism could be relevant for the therapeutic efficacy of some antipsychotic drugs. 145 RGS2 (regulator of G-protein signaling 2) modulates dopamine receptor signal transduction. Functional variants of this gene (RGS2-rs 4606 C/G) may infl uence susceptibility to extrapyramidal symptoms induced by antipsychotic drugs. This SNP is located in the 3′-regulatory region of the gene, and is known to infl uence RGS2 mRNA levels and protein expression. 146 Furthermore, RGS4 (regulator of G protein signaling 4) genotypes predict both the severity at baseline symptoms and relative responsiveness to antipsychotic medication. 147 Tardive dyskinesia is characterized by involuntary movements predominantly in the orofacial region and develops in approximately 20% of patients during long-term treatment with typical antipsychotics. Polymorphic variants of CYP1A2, CYP2D6, and DRD3 genes have been associated with tardive dyskinesia in schizophrenics. 148, 149 In contrast, the haplotype T-4b-Glu of the endothelial nitric oxide synthase (NOS3) gene (-786T > C in the promoter region, 27-bp variable number of tandem repeats in intron 4, Glu298Asp in exon 7) might represent a protective haplotype against tardive dyskinesia after long-term antipsychotic treatment. 150 The T102C variant in the serotonin 2A receptor (HTR2A) and the Ser9Gly variant in the dopamine D3 receptor (DRD3) were associated with a risperidone response to exacerbated schizophrenia. The patients with T/T in the HTR2A gene show less clinical improvement than do those with T/C or C/C. The C allele is more frequent in responders. When combinations of both polymorphisms are considered, patients who have T/T in the HTR2A gene and encode Ser/Ser or Ser/Gly from DRD3 gene have a higher propensity to non-responsiveness compared to other subjects, suggesting that the HTR2A T102C variant could be a potential indicator of clinical improvement after risperidone treatment. 151 There is a signifi cant relationship between a promoter region polymorphism in the serotonin transporter gene and antidepressant response, as well as for associations between candidate neurotransmitter receptor genes and second generation antipsychotic drug response. 121 Polymorphic variants of several serotonin receptor subtypes seem to be involved in the efficacy and symptomatic response of schizophrenic patients to atypical antipsychotics. For instance, the −1019 C/G polymorphism of the HTR1A receptor gene is associated with negative symptom response to risperidone in schizophrenics. 152 Interaction between COMT and NOTCH4 genotypes may also predict the treatment response to typical neuroleptics in patients with schizophrenia. 153 The effi cacy of iloperidone in patients with schizophrenia has been associated with the homozygous condition for the rs1800169 G/G genotype of the ciliary neurotrophic factor (CNTF) gene. 154 Dopamine receptor interacting proteins (DRIPs) are pivotally involved in regulating dopamine receptor signal transduction. Two SNPs in the dopamine receptor interacting protein gene, NEF3, which encodes the DRIP, neurofi lament-medium (NF-M), were associated with early response (rs1457266, rs1379357). A 5 SNP haplotype spanning NEF3 was over-represented in early responders. Since NEF3 is primarily associated with dopamine D1 receptor function, it is likely that both genes cooperate in eliciting genotype-specifi c antipsychotic response. 155 The improvement in the Positive and Negative Syndrome Scale (PANSS) positive subscore was found signifi cantly greater in patients homozygous for the A1287 allele of the SLC6A2 (Solute Carrier Family 6 (Noradrenaline Transporter), Member 2) gene, and smaller in patients homozygous for the C-182 allele of the SLC6A2 gene, suggesting that these polymorphisms of the noradrenaline transporter gene are specifi cally involved in the variation of positive symptoms in schizophrenia. 156 Weight gain is a problem commonly found in patients treated with neuroleptics, tricyclic antidepressants, and some antiepileptics (e.g., valproic acid). The adipocyte-derived hormone, leptin, has been associated with body weight and energy homeostasis, and abnormal regulation of leptin could play a role in weight gain induced by antipsychotics. The leptin gene promoter variant G2548A was associated with clozapine-induced weight in Chinese patients with chronic schizophrenia. 157 Likewise, studies in Caucasians suggest that genetic vulnerability in the leptin gene (−1548G/A) and leptin receptor (Q223R) may predispose some individuals to excessive weight gain from increased exposure to olanzapine. 158, 159 The development of selective type 5 metabotropic glutamate receptor (mGlu5) antagonists, such as 2-methyl-6-(phenylethynyl)-pyridine (MPEP) and 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (MTEP), has demonstrated the potential involvement of these receptors in several CNS disorders including depression, anxiety, epilepsy, Parkinson's disease, drug addiction, and alcoholism. Treatment with MPEP and MTEP can induce gene expression related to ATP synthesis, hydrolase activity, and signaling pathways associated with mitogen-activated protein kinase (MAPK) in the frontal cortex, this constituting another potential therapeutic target in some neuropsychiatric disorders. 160 A new marker (rs1954787) in the GRIK4 gene, which codes for the kainic acid-type glutamate receptor KA1, has been associated with response to the antidepressant citalopram, suggesting that the glutamate system plays a role in modulating response to selective serotonin reuptake inhibitors (SSRIs). 161 Glycogen synthase kinase-3β (GSK3B) activity is increased in the brain of patients with major depressive disorders. Inhibition of GSK3B is thought to be a key feature in the therapeutic mechanism of antidepressants. Four polymorphisms of the GSK3B gene [rs334555 (−50 T > C); rs13321783 (IVS7 + 9227 A > G); rs2319398 (IVS + 11660 G > T); rs6808874 (IVS + 4251 T > A)] have been genotyped in Chinese patients with major depression. GSK3B TAGT carriers showed poorer response to antidepressants. 162 Lithium has been used for over 40 years as an effective prophylactic agent in bipolar disorder. Response to lithium treatment seems to be, at least in part, genetically determined. It has been suggested that lithium exerts an effect on signal transduction pathways, such as the cyclic adenosine monophosphate (cAMP) pathway. Association studies in patients with bipolar disorders revealed that CREB1-1H SNP (G/A change at 2q32.3-q34) and CREB1-7H (T/C change) may be associated with bipolar disorder and lithium response. 163 DNA oligonucleotide microarrays have been used to evaluate gene expression in the substantia nigra of patients with Parkinson's disease (PD). Sporadic PD is characterized by progressive death of dopaminergic neurons within the substantia nigra, where cell death is not uniform. The lateral tier of the substantia nigra (SNL) degenerates earlier and more severely than the more medial nigral component (SNM). Genes expressed more highly in the PD SNL included the cell death gene, p53 effector related to PMP22, the TNFR gene, TNFR superfamily, member 21, and the mitochondrial complex I gene, NADH dehydrogenase (ubiquinone) 1-beta subcomplex, 3, 12 kDa (NDUFβ3). Genes that were more highly expressed in PD SNM included the dopamine cell signaling gene, cyclic adenosine monophosphate-regulated phosphoprotein, 21 kDa, the activated macrophage gene, stabilin 1, and two glutathione peroxidase (GPX) genes, GPX1 and GPX3. This gene expression profi le reveals that there is increased expression of genes encoding pro-infl ammatory cytokines and subunits of the mitochondrial electron transport chain in glial cells, and that there is a decreased expression of several glutathione-related genes in the GNL, suggesting a molecular basis for pathoclisis. 164 These fi ndings may contribute to open new therapeutic avenues in PD, where glial cells might represent potential targets to halt disease progression.

Pharmacological inhibition of cyclic-dependent kinase 5 (CDK5) protects neurons under distinct stressful conditions. In AD and amyotrophic lateral sclerosis deregulation of CDK5 causes hyperphosphorylation of tau and neurofi lament proteins, respectively, leading to neuronal cell death. By two-dimensional gel electrophoresis and matrix assisted laser desorption/ionisation-time of fl ight (MALDI-TOF)-mass spectrometry, several phosphoproteins that are modulated by CDK5 inhibitors have been identifi ed. These phosphoproteins include syndapin I which is involved in vesicle recycling, and dynein light intermediate chain 2 which represents a regulatory subunit of the dynein protein complex, confi rming the role of CDK5 in synaptic signaling and axonal transport. Other phosphoproteins detected are cofi lin and collapsing response mediator protein, involved in neuronal survival and/or neurite outgrowth. Selective CDK5 inhibitors can also block mitochondrial translocation of pro-apoptotic cofi lin. Phosphoproteome and transcriptome analysis of neurons indicate that CDK5 inhibitors promote both neuronal survival and neurite outgrowth. 165 These compounds might represent novel therapeutic alternatives in neurodegenerative disorders.

Despite the promising results obtained with structural and functional genomic procedures to identify associations with disease pathogenesis and potential drug targets in CNS disorders, it must be kept in mind that allelic mRNA expression is affected by genetic and epigenetic events, both with the potential to modulate neurotransmitter tone in the CNS. 166 Epigenetics is the study of how the environment can affect the genome of the individual during its development as well as the development of its descendants, all without changing the DNA sequence, but inducing modifi cations in gene expression through DNA methylation-demethylation or through modifi cation of histones by processes of methylation, deacetylation, and phosphorylation. 167 Cumulative experiences throughout life history interact with genetic predispositions to shape the individual's behaviour. 167 Epigenetic phenomena can not be neglected in the pathogenesis and pharmacogenomics of CNS disorders. Studies in cancer research have demonstrated the antineoplastic effects of the DNA methylation inhibitor hydralazine and the histone deacetylase inhibitor valproic acid, of current use in epilepsy. 168 Novel effects of some pleiotropic drugs with activity on the CNS have to be explored to understand in full their mechanisms of action and adjust their dosages for new indications. Both hyper-and hypo-DNA methylation changes of the regulatory regions play critical roles in defi ning the altered functionality of genes (MB-COMT, MAOA, DAT1, TH, DRD1, DRD2, RELN, BDNF) in major psychiatric disorders, such as schizophrenia and bipolar disorder. 169 This complexity requires a multifactorial approach to overcome the hurdles that CNS drug development faces at the present time. 170 

Polymorphic variants in the APOE gene (19q13.2) are associated with risk (APOE-4 allele) or protection (APOE-2 allele) for AD. 8, [18] [19] [20] For many years, alterations in ApoE and defects in the APOE gene have been associated with dysfunctions in lipid metabolism, cardiovascular disease, and atherosclerosis. During the past 25 years an enormous amount of studies clearly documented the role of APOE-4 as a risk factor for AD, an the accumulation of the APOE-4 allele has been reported as a risk factor for other forms of dementia and CNS disorders. 8, [18] [19] [20] APOE-4 may infl uence AD pathology interacting with APP metabolism and ABP accumulation, enhancing hyperphosphorylation of tau protein and NFT formation, reducing choline acetyltransferase activity, increasing oxidative processes, modifying infl ammation-related neuroimmunotrophic activity and glial activation, altering lipid metabolism, lipid transport and membrane biosynthesis in sprouting and synaptic remodelling, and inducing neuronal apoptosis. 8, [18] [19] [20] 

Different APOE genotypes confer specifi c phenotypic profi les to AD patients. Some of these profi les may add risk or benefi t when the patients are treated with conventional drugs, and in many instances the clinical phenotype demands the administration of additional drugs which increase the complexity of therapeutic protocols. From studies designed to defi ne APOE-related AD phenotypes, 8, [16] [17] [18] [19] [20] [21] [22] 62, 63, [74] [75] [76] [77] 109, 110 several confi rmed conclusions can be drawn: (i) the ageat-onset is 5-10 years earlier in approximately 80% of AD cases harbouring the APOE-4/4 genotype; (ii) the serum levels of ApoE are the lowest in APOE-4/4, intermediate in APOE-3/3 and APOE-3/4, and highest in APOE-2/3 and APOE-2/4; (iii) serum cholesterol levels are higher in APOE-4/4 than in the other genotypes; (iv) HDL-cholesterol levels tend to be lower in APOE-3 homozygotes than in APOE-4 allele carriers; (v) LDL-cholesterol levels are systematically higher in APOE-4/4 than in any other genotype; (vi) triglyceride levels are signifi cantly lower in APOE-4/4; (vii) nitric oxide levels are slightly lower in APOE-4/4; (viii) serum ABP levels do not differ between APOE-4/4 and the other most frequent genotypes (APOE-3/3, APOE-3/4); (ix) blood histamine levels are dramatically reduced in APOE-4/4 as compared with the other genotypes; (x) brain atrophy is markedly increased in APOE-4/4 > APOE-3/4 > APOE-3/3; (xi) brain mapping activity shows a signifi cant increase in slow wave activity in APOE-4/4 from early stages of the disease (Fig. 40.4) ; (xii) brain hemodynamics, as refl ected by reduced brain blood fl ow velocity and increase pulsatility and resistance indices, is signifi cantly worst in APOE-4/4 (and in APOE-4 carriers, in general, as compared with APOE-3 carriers); (xiii) lymphocyte apoptosis is markedly enhanced in APOE-4 carriers; (xiv) cognitive deterioration is faster in APOE-4/4 patients than in carriers of any other APOE genotype; (xv) occasionally, in approximately 3-8% of the AD cases, the presence of some dementia-related metabolic dysfunctions (e.g., iron, folic acid, vitamin B12 defi ciencies) accumulate in APOE-4 carriers more than in APOE-3 carriers; (xvi) some behavioral disturbances (bizarre behaviors, psychotic symptoms), alterations in circadian rhythm patterns (e.g., sleep disorders), and mood disorders (anxiety, depression) are slightly more frequent in APOE-4 carriers; (xvii) aortic and systemic atherosclerosis is also more frequent in APOE-4 carriers; (xviii) liver metabolism and transaminase activity also differ in APOE-4/4 with respect to other genotypes; (xix) blood pressure (hypertension) and other cardiovascular risk factors also accumulate in APOE-4; and (xx) APOE-4/4 are the poorest responders to conventional drugs ( Fig.  40.11 ). These 20 major phenotypic features clearly illustrate the biological disadvantage of APOE-4 homozygotes and the potential consequences that these patients may experience when they receive pharmacological treatment. 2, 4, 8, [16] [17] [18] [19] [20] [21] [22] 62, 63, [74] [75] [76] [77] 109, 110 Fig. 40.11 APOE-related cognitive performance in patients with Alzheimer's disease treated with a combination therapy for 1 year (Adapted from R. Cacabelos 77, 109 ). Patients received a combination therapy for 1 year, and cognitive function (MMSE score) was assessed at baseline (B) and after 1, 3, 6, 9, and 12 months of treatment.

Several studies indicate that the presence of the APOE-4 allele differentially affects the quality and size of drug responsiveness in AD patients treated with cholinergic enhancers, neuroprotective compounds or combination therapies; however, controversial results are frequently found due to methodological problems, study design, and patients recruitment in clinical trials. From these studies we can conclude the following: (i) Multifactorial treatments combining neuroprotectants, endogenous nucleotides, nootropic agents, vasoactive substances, cholinesterase inhibitors, and NMDA antagonists associated with metabolic supplementation on an individual basis adapted to the phenotype of the patient may be useful to improve cognition and slow-down disease progression in AD. (ii) In our personal experience the best results have been obtained combining (a) CDP-choline with piracetam and metabolic supplementation, (b) CDP-choline with piracetam and anapsos, (c) CDP-choline with piracetam and cholinesterase inhibitors (donepezil, rivastigmine), (d) CDP-choline with memantine, and (e) CDPcholine, piracetam and nicergoline. (iii) Some of these combination therapies have proven to be effective, improving cognition during the fi rst 9 months of treatment, and not showing apparent side-effects. (iv) The therapeutic response in AD seems to be genotypespecifi c under different pharmacogenomic conditions. (v) In monogenic-related studies, patients with the APOE-2/3 and APOE-3/4 genotypes are the best responders, and APOE-4/4 carriers are the worst responders ( Fig. 40.11 ). (vi) PS1-and PS2-related genotypes do not appear to infl uence the therapeutic response in AD as independent genomic entities; however, APP, PS1, and PS2 mutations may drastically modify the therapeutic response to conventional drugs. (vii) In trigenic-related studies the best responders are those patients carrying the 331222-, 341122-, 341222-, and 441112-genomic clusters. (viii) A genetic defect in the exon 5 of the PS2 gene seems to exert a negative effect on cognition conferring PS2+ carriers in trigenic clusters the condition of poor responders to combination therapy. (ix) The worst responders in all genomic clusters are patients with the 441122+ genotype. (x) The APOE-4/4 genotype seems to accelerate neurodegeneration anticipating the onset of the disease by 5-10 years; and, in general, APOE-4/4 carriers show a faster disease progression and a poorer therapeutic response to all available treatments than any other polymorphic variant. (xi) Pharmacogenomic studies using trigenic, tetragenic or polygenic clusters as a harmonization procedure to reduce genomic heterogeneity are very useful to widen the therapeutic scope of limited pharmacological resources. [4] [5] [6] [16] [17] [18] [19] [20] [21] [22] 62, 63, [74] [75] [76] [77] 109, 110 

APOE infl uences liver function and CYP2D6-related enzymes probably via regulation of hepatic lipid metabolism. 20, 42, [74] [75] [76] [77] It has been observed that APOE may infl uence liver function and drug metabolism by modifying hepatic steatosis and transaminase activity. There is a clear correlation between APOE-related TG levels and GOT, GPT, and GGT activities in AD. 20, [74] [75] [76] [77] 171 Both plasma TG levels and transaminase activity are signifi cantly lower in AD patients harbouring the APOE-4/4 genotype, probably indicating (a) that low TG levels protect against liver steatosis, and (b) that the presence of the APOE-4 allele infl uences TG levels, liver steatosis, and transaminase activity. Consequently, it is very likely that APOE infl uences drug metabolism in the liver through different mechanisms, including interactions with enzymes such as transaminases and/ or cytochrome P450-related enzymes encoded in genes of the CYP Superfamily. 20, [74] [75] [76] [77] 109, 171 When APOE and CYP2D6 genotypes are integrated in bigenic clusters and the APOE + CYP2D6-related therapeutic response to a combination therapy is analyzed in AD patients after 1 year of treatment, it becomes clear that the presence of the APOE-4/4 genotype is able to convert pure CYP2D6 * 1/ * 1 EMs into full PMs (Fig. 40.12) , indicating the existence of a powerful infl uence of the APOE-4 homozygous genotype on the drug metabolizing capacity of pure CYP2D6-EMs. 20, 74, 75, 109 

Behavioral disturbances and mood disorders are intrinsic components of dementia associated with memory disorders. 60, [172] [173] [174] The appearance of anxiety, depression, psychotic symptoms, verbal and physical aggressiveness, agitation, wandering and sleep disorders complicate the clinical picture of dementia and add important problems to the therapeutics of AD and the daily management of patients as well. Under these conditions, psychotropic drugs (antidepressants, anxyolitics, hypnotics, and neuroleptics) are required, and most of these substances contribute to deteriorate cognition and psychomotor functions. APOE-related polymorphic variants have been associated with mood disorders 175, 176 and panic disorder. 177 Gender, age, dementia severity, APOE-4, and general medical health appear to infl uence the occurrence of individual neuropsychiatric symptoms in dementia, and medical comorbidity increases the risk of agitation, irritability, disinhibition, and aberrant motor behavior. 178 A positive association between APOE-4 and neuropsychiatric symptoms 179 and depressive symptoms in AD has been reported, 180 especially in women. 181 In other studies, no association of APOE-4 with behavioral dyscontrol (euphoria, disinhibition, aberrant motor behavior, and sleep and appetite disturbances), psychosis (delusions and hallucinations), mood (depression, anxiety, and apathy), and agitation (aggression and irritability) could be found. 182 Some authors did not fi nd association of APOE-4 with major depression in AD 183, 184 or in patients with major depression in a community of older adults, 185 but an apparent protective effect of APOE-2 on depressive symptoms was detected. 186 Others, in contrast, found that APOE-4 was associated with an earlier age-of-onset, but not cognitive functioning, in late-life depression. 187 Apoe−/− mice without human ApoE or with APOE-4, but not APOE-3, show increased measures of anxiety. 188 Differences in anxiety-related behavior have been observed between APOE-defi cient C57BL/6 and wild type C57BL/6 mice, suggesting that APOE variants may affect emotional state. 189 Histamine H3 autoreceptor antagonists increase anxiety measures in wildtype, but not ApoE−/−, mice, and ApoE defi cient mice show higher sensitivity to the anxiety-reducing effects of the H1 receptor antagonist mepyramine than wildtype mice, suggesting a role of H3-autoreceptormediated signaling in anxiety-like symptoms in this AD-related animal model. 190 In humans, APOE-4 carriers with deep white matter hyperintensities in MRI show association with depressive symptoms and vascular depression. 191 . Reduced caudate nucleus volumes and genetic determinants of homocysteine metabolism accumulate in patients with psychomotor slowing and cognitive defi cits, 192 and older depressed subjects have persisting cognitive impairments associated with hippocampal volume reduction. 193, 194 Depressive symptoms are also associated with stroke and atherogenic lipid profi le. 195 Some multifactorial treatments addressing neuroprotection have shown to be effective in reducing anxiety progressively from the fi rst month to the 12 month of treatment. 109 The anxiety rate was declining from a baseline HRS-A score of 10.90 ± 5.69 to 9.07 ± 4.03 (p < 0.0000000001) at 1 month, 9.01 ± 4.38 (p < 0.000006) at 3 months, 8.90 ± 4.47 (p < 0.005) at 6 months, 7.98 ± 3.72 (p < 0.00002) at 9 months, and 8.56 ± 4.72 (p < 0.01) at 12 months of treatment (r = −0.82, a coef.: 10.57, b coef.: −0.43). 109 Similar striking results were found in depression, suggesting that improvement in mood conditions can contribute to stabilize cognitive function or that neuroprotection (with the consequent stabilization or improvement in mental performance) can enhance emotional equilibrium. 20, 74, 75, 109 At baseline, all APOE variants showed similar anxiety and depression rates, except the APOE-4/4 carriers who differed from the rest in a signifi cantly lower rates of anxiety and depression (Figs. 40.13 and 40.14). Remarkable changes in anxiety were found among different APOE genotypes (Fig. 40.13) . Practically, all APOE variants responded with a signifi cant diminution of anxiogenic symptoms, except patients with the APOE-4/4 genotype who only showed a slight improvement. The best responders were APOE-2/4 > APOE-2/3 > APOE-3/3 > APOE-3/4 carriers (Fig. 40.13) . The modest anxiolytic effect seen in APOE-4/4 patients might be due to the very low anxiety rate observed at baseline. Concerning depression, all APOE genotypes improved their depressive symptoms with treatment except those with the APOE-4/4 genotype which worsen along the treatment period, especially after 9 months (Fig.  40 .14). The best responders were patients with APOE-2/4 > APOE-2/3 > APOE-3/3 > APOE-3/4, and the worst responders were patients harbouring the APOE-4/4 genotype 20,74,75,109 (Fig. 40.14) . 

The optimization of CNS therapeutics requires the establishment of new postulates regarding (a) the costs of medicines, (b) the assessment of protocols for multifactorial treatment in chronic disorders, (c) the implementation of novel therapeutics addressing causative factors, and (d) the setting-up of pharmacogenetic/ pharmacogenomic strategies for drug development. 20, [74] [75] [76] [77] 109 The cost of medicines is a very important issue in many countries because of (i) the growing of the aging population (>5% disability), (ii) neuropsychiatric and demented patients (>5% of the population) belong to an unproductive sector with low income, and (iii) the high cost of health care systems and new health technologies in developed countries. Despite the effort of the pharmaceutical industry to demonstrate the benefi ts and cost-effectiveness of available drugs, the general impression in the medical community and in some governments is that some psychotropics and most anti-dementia drugs present in the market are not costeffective. 20, [74] [75] [76] [77] 109 Conventional drugs for neuropsychi-atric disorders are relatively simple compounds with unreasonable prices. Some new products are not superior to conventional antidepressants, neuroleptics, and anxiolytics. There is an urgent need to assess the costs of new trials with pharmacogenetics and pharmacogenomics strategies, and to implement pharmacogenetic procedures to predict drug-related adverse events. 20, 74, 75, 109 Cost-effectiveness analysis has been the most commonly applied framework for evaluating pharmacogenetics. Pharmacogenetic testing is potentially relevant to large populations that incur in high costs. For instance, the most commonly drugs metabolized by CYP2D6 account for 189 million prescriptions and US$12.8 billion annually in expenditures in the US, which represent 5-10% of total utilization and expenditures for outpatient prescription drugs. 196 Pharmacogenomics offer great potential to improve patients' health in a cost-effective manner; however, pharmacogenetics/pharmacogenomics will not be applied to all drugs available in the market, and careful evaluations should be done on a case-by-case basis prior to investing resources in R&D of pharmacogenomic-based therapeutics and making reimbursement decisions. 197 In performing pharmacogenomic studies in CNS disorders, it is necessary to rethink the therapeutic expectations of novel drugs, redesign the protocols for drug clinical trials, and incorporate biological markers as assessable parameters of effi cacy and prevention. In addition to the characterization of genomic profi les, phenotypic profi ling of responders and non-responders to conventional drugs is also important (and currently neglected). Brain imaging techniques, computerized electrophysiology, and optical topography in combination with genotyping of polygenic clusters can help in the differentiation of responders and non-responders. The early identifi cation of predictive risks requires genomic screening and molecular diagnosis, and individualized preventive programs will only be achieved when pharmacogenomic/pharmacogenetic protocols are incorporated to the clinical armamentarium with powerful bioinformatics support. 18-20,74,75.109 An important issue in AD therapeutics is that antidementia drugs should be effective in covering the clinical spectrum of dementia symptoms represented by memory defi cits, behavioural changes, and functional decline. It is diffi cult (or impossible) that a single drug be able to fulfi l this criteria. A potential solution to this problem is the implementation of cost-effective, multifactorial (combination) treatments integrating several drugs, taking into consideration that traditional neuroleptics and novel antipsychotics (and many other psychotropics) deteriorate both cognitive and psychomotor functions in the elderly and may also increase the risk of stroke. 198 Few studies with combination treatments have been reported and most of them are poorly designed. We have also to realize that the vast majority of dementia cases in people older than 75-80% are of a mixed type, in which the cerebrovascular component associated with neurodegeneration can not be therapeutically neglected. In most cases of dementia, the multifactorial (combination) therapy appears to be the most effective strategy. [18] [19] [20] [74] [75] [76] [77] 109 The combination of several drugs (neuroprotectants, vasoactive substances, AChEIs, metabolic supplementation) increases the direct costs (e.g., medication) by 5-10%, but in turn, annual global costs are reduced by approximately 18-20% and the average survival rate increases about 30% (from 8 to 12 years post-diagnosis).

There are major concerns regarding the validity of clinical trials in patients with severe dementia. Despite the questionable experience with memantine, 199 simi-lar strategies have been used to demonstrate the utility of donepezil in severe AD. 200 This kind of studies bears some important pitfalls, including (a) short duration (<1 year), (b) institutionalized patients, (c) patients receiving many different types of drugs, (d) non-evaluated drug-drug interactions, (e) side-effects (e.g., hallucinations, gastrointestinal disorders) that may require the administration of additional medication, (f) lack of biological parameters demonstrating actual benefi ts, and (e) no cost-effectiveness assessment, among many other possibilities of technical criticism. [18] [19] [20] 109, 201 Some of these methodological (and costly) problems might be overcome with the introduction of pharmacogenetic/ pharmacogenomic strategies to identify good responders who might obtain some benefi t by taking expensive medications.

Major impact factors associated with drug effi cacy and safety include the following: (i) the mechanisms of action of drugs, (ii) drug-specifi c adverse reactions, (iii) drug-drug interactions, (iv) nutritional factors, (v) vascular factors, (vi) social factors, and (vii) genomic factors (nutrigenetics, nutrigenomics, pharmacogenetics, pharmacogenomics). Among genomic factors, nutrigenetics/nutrigenomics and pharmacogenetics/pharmacogenomics account for more than 80% of effi cacy-safety outcomes in current therapeutics. [18] [19] [20] 74, 75, 77, 109 Some authors consider that priority areas for pharmacogenetic research are to predict serious adverse reactions (ADRs) and to establish variation in effi cacy. 202 Both requirements are necessary in CNS disorders to cope with effi cacy and safety issues associated with either current CNS drugs and new drugs. 121, 138 Since drug response is a complex trait, genome-wide approaches (oligonucleotide microarrays, proteomic profi ling) may provide new insights into drug metabolism and drug response. Genome-wide family-based association studies, using single SNPs or haplotypes, can identify associations with genome-wide signifi cance. 203, 204 To achieve a mature discipline of pharmacogenetics and pharmacogenomics in CNS disorders and dementia it would be convenient to accelerate the following processes: (a) educate physicians and the public on the use of genetic/genomic screening in the daily clinical practice; (b) standardize genetic testing for major categories of drugs; (c) validate pharmacogenetic and pharmacogenomic procedures according to drug category and pathology; (d) regulate ethical, social, and economic issues; and (e) incorporate pharmacogenetic and pharmacogenomic procedures to both drugs in development and drugs in the market to optimize therapeutics. [18] [19] [20] [21] [22] [74] [75] [76] [77] 109, 205 

Costs of disorders of the brain in Europe. Executive summary

A conceptual introduction to geriatric neuroscience

The clinical and costeffectiveness of donepezil, rivastigmine, galantamine and memantine for Alzheimer's disease

Pharmacological treatment of Alzheimer disease: from phychotropic drugs and cholinesterase inhibitors to pharmacogenomics

Pharmacogenomics in Alzheimer's disease

Pharmacogenomics for the treatment of dementia

Pharmacogenetics and drug development: the path to safer and more effective drugs

Molecular genetics of Alzheimer's disease and aging

Molecular genetics of bipolar disorder and depression

Confounding in genetic association studies and its solutions

Molecular genetics of schizophrenia: a critical review

Lifespan and mitochondrial control of neurodegeneration

High aggregate burden of somatic mtDNA point mutations in aging and Alzheimer's disease brain

The application of functional genomics to Alzheimer's disease

Pharmacogenomics and therapeutic prospects in Alzheimer's disease

Pharmacogenomics, nutrigenomics and therapeutic optimization in Alzheimer's disease

Pharmacogenomics, nutrigenomics and future therapeutics in Alzheimer's disease

Pharmacogenomics in Alzheimer's disease

Cerebrovascular risk factors in Alzheimer's disease: brain hemodynamics and pharmacogenomic implications

Phenotypic profi les and functional genomics in dementia with a vascular component

High throughput protein expression screening in the nervous system -needs and limitations

Gene expression atlas of the mouse central nervous system: impact and interactions of age, energy intake and gender

Subtelomeric study of 132 patients with mental retardation reveals 9 chromosomal anomalies and contributes to the delineation of submicroscopic deletions of 1pter, 2qter, 4pter, 5qter and 9qter

DNA fragmentation is increased in non-GABAergic neurons in bipolar disorder but not in schizophrenia

The functional genome of CA1 and CA3 neurons under native conditions and in response to ischemia

Fibroblast and lymphoblast gene expression profi les in schizophrenia : are non-neural cells informative ?

Runs of homozygosity reveal highly penetrant recessive loci in schizophrenia

The use of microarrays to characterize neuropsychiatric disorders: post-mortem studies of substance abuse and schizophrenia

High-throughput analysis of promoter occupancy reveals direct neuronal targets of FOXP2, a gene mutated in speech and language disorders

Microarray analysis of oxidative stress regulated genes in mesencephalic dopaminergic neuronal cells: relevance to oxidative damage in Parkinson's disease

Towards a pathway defi nition of Parkinson's disease: a complex disorder with links to cancer, diabetes and infl ammation

Analysis of potential transcriptomic biomarkers for Huntington's disease in peripheral blood

Comprehensive transcriptional profi ling of prion infection in mouse models reveals networks of responsive genes

Transcriptional profi ling in the human prefrontal cortex : evidence for two activational states with cocaine abuse

Gene expression profi ling in the brains of human cocaine abusers

Ethanol and brain damage

Genomic responses in rat cerebral cortex after traumatic injury

Transcriptional profi ling in human epilepsy: expression array and single cell real-time qRT-PCR analysis reveal distinct cellular gene regulation

Molecular profi ling of temporal lobe epilepsy: comparison of data from human tissue and animal models

The antiepileptic drug levetiracetam selectively modifi es kindling-induced alterations in gene expression in the temporal lobe of rats

Increased apoptosis, p53 up-regulation, and cerebellar neuronal degeneration in repair-defi cient Cockayne syndrome mice

Inhibitors of differentiation (ID1, ID2, ID3 and ID4) genes are neuronal targets of MeCP2 that are elevated in Rett síndrome

HDAC inhibitors correct frataxin defi ciency in a Friedreich ataxia mouse model

Gene expression profi ling in a Mouse model of infantile neuronal lipofuscinosis reveals upregulation of immediate early genes and mediators of the infl ammatory response

Multiple sclerosis as a generalized CNS disease -comparative microarray analysis of normal appearing white matter and lesions in secondary progressive MS

Pathways and genes differentially expressed in the motor cortex of patients with sporadic amyotrophic lateral sclerosis

Gene expression in cortex and hippocampus during acute pneumococcal meningitis

Role of lipids in brain injury and diseases

Expression profi le analysis of neurodegenerative disease: advances in specifi city and resolution

Methodological considerations regarding single-cell gene expression profi ling for brain injury

Genotoxicants target distinct molecular networks in neonatal neurons

Functional gene expression differences between inbred alcohol-preferring and -non-prerats in fi ve brain regions

Neuroadaptations in human chronic alcoholics: tion of the NF-κB system

Gene expression profi le of the nucleus accumbens of human cocaine abusers : evidence for dysregulation of myelin

Transcriptional changes common to human cocaine, cannabis and phencyclidine abuse

MicroRNA expression in the adult mouse central nervous system

A pharmacogenomic approach to Alzheimer's disease

Clinical Psychiatry. Jobe TH

Genomics and phenotypic profi les in dementia: implications for pharmacological treatment

A functional genomics approach to the analysis of biological markers in Alzheimer disease

Genomic characterization of Alzheimer's disease and genotype-related phenotypic analysis of biological markers in dementia

The histamine-cytokine network in Alzheimer disease: etiopathogenic and pharmacogenomic implications

Histamine function in brain disorders

Histamine in Alzheimer's disease pathogenesis: biochemistry and functional genomics

Characterization of cytokine production, screening of lymphocyte subset patterns and in vitro apoptosis in healthy and Alzheimer's disease individuals

International Human Genome Sequencing Consortium. Finishing the euchromatic sequence of the human genome

Implications of the human genome for understanding human biology and medicine

Pharmacogenetics and pharmacogenomics. In: Emery and Rimoin's Principles and Practice of Medical Genetics. 4th Edn

Pharmacogenomics: the inherited basis for interindividual differences in drug response

Pharmacogenetics and pharmacogenomics: development, science, and translation

Pharmacogenomics and therapeutic prospect in dementia

Pharmacogenetic basis for therapeutic optimization in Alzheimer's disease

Infl uence of pharmacogenetic factors on Alzheimer's disease therapeutics

Pharmacogenetic aspects of therapy with cholinesterase inhibitors: the role of CYP2D6 in Alzheimer's disease pharmacogenetics

From pharmacogenetics and ecogenetics to pharmacogenomics

Inheritance and drug response

Pharmacogenomics-Drug disposition, drug targets, and side effects

National estimates of medication use in nursing homes

Medicare Current Benefi ciary Survey and the 1996 Medical Expenditure Survey

Antidepressant drugs prescribing among elderly subjects: a population-based study

Potentially inappropriate medication use among elderly home care patients in Europe

Potentially inappropriate medication use by elderly persons in U.S. Health Maintenance Organizations

The Metabolic & Molecular Bases of Inherited Disease

Catalog of 680 variants among eight cytochrome P450 (CYP) genes: nine esterase genes, and two other genes in the Japanese population

DNA sequence variations in a 3.7-kb noncoding sequence 5-prime of the CYP1A2 gene: implications for human population history and natural selection

PM frequencies of major CYPs in Asians and Caucasians

Polymorphisms of drug-metabolizing enzymes CYP2C9, CYP2C19, CYP2D6, CYP1A1, NAT2 and of P-glycoprotein in a Russian population

CYP2C9 allelic variants: ethnic distribution and functional signifi cance

Identifi cation and functional characterization of a new CYP2C9 variant (CYP2C9 * 5 1 ) expressed among African Americans

Molecular basis of ethnic differences in drug disposition and response

Isolation, sequence and genotyping of the drug metabolizer CYP2D6 gene in the Colombian population

Effects of prototypical microsomal enzyme inducers on cytochrome P450 expression in cultured human hepatocytes

Cytochrome P450 in the brain: a review

The expression of CYP2B6, CYP2C9 and CYP2A4 genes: a tangle of networks of nuclear and steroid receptors

Regulation of cytochrome P450 (CYP) genes by nuclear receptors

The CYP2C19 enzyme polymorphism

Cytochrome P450 2D6 variants in a Caucasian population: allele frequencies and phenotypic consequences

Clinically signifi cant drug interactions with cholinesterase inhibitors: a guide for neurologists

Assessment of the predictive power of genotypes for the in-vivo catalytic function of CYP2D6 in a German population

Ten percent of North Spanish individuals carry duplicated or triplicated CYP2D6 genes associated with ultrarapid metabolism of debrisoquine

Clinical pharmacokinetics of galantamine

Impact of the CYP2D6 polymorphism on steady-state plasma concentrations and clinical outcome of donepezil in Alzheimer's disease patients

Molecular pathology and pharmacogenomics in Alzheimer's disease: polygenic-related effects of multifactorial treatments on cognition, anxiety, and depression

Pharmacogenomic studies with a combination therapy in Alzheimer's disease

Interethnic differences in genetic polymorphisms of CYP2D6 in the U.S. population: clinical implications

Donepezil use in Alzheimer disease

Effects of cholinergic markers in rat brain and blood after short and prolonged administration of donepezil

The O-demethylation of the antidementia drug galantamine is catalyzed by cytochrome P450 2D6

Cholinesterase inhibitors in the treatment of Alzheimer's disease: a comparison of tolerability and pharmacology

Galantamine pharmacokinetics, safety, and tolerability profi les are similar in healthy Caucasian and Japanese subjects

Pharmacokinetics and drug interactions of cholinesterase inhibitors administered in Alzheimer's disease

The metabolism and excretion of galantamine in rats, dogs, and humans

Prevalence of potentially inappropriate medication use in elderly patients. Comparison between general medicine and geriatric wards

PharGKB update: II. CYP3A5, cytochrome P450, family 3, subfamily A, polypeptide 5

Genomics and the future of pharmacotherapy in psychiatry

CYP2D6 polymorphism: implications for antipsychotic drug response, schizophrenia and personality traits

Cytochrome P450 polymorphisms and response to antipsychotic therapy

Infl uence of cytochrome P450 polymorphisms on drug therapies: pharmacogenetic, pharmacoepigenetic and clinical aspects

Pharmaco-Genomics Handbook. 2nd Edn. Lexi-Comp

Drug Information Handbook with International Trade Names Index. 17th Edn. Lexi-Comp

Drug Information Handbook for Psychiatry. 6th Edn. Lexi-Comp

Pharmacogenomics in schizophrenia: the quest for individualized therapy

The role of 5-HT2C receptor polymorphisms in the pharmacogenetics of antipsychotic drug treatment

Dopamine D4 receptor gene exon III polymorphism and interindividual variation in response to clozapine

Association between multidrug resistance 1 (MDR1) gene polymorphism and therapeutic response to bromperidol in schizophrenic patients: a preliminary study

Genetic susceptibility to tardive dyskinesia among schizophrenia subjects: IV. Role of dopaminergic pathway gene polymorphisms

DRD2 promoter region variation as a predictor of sustained response to antipsychotic medication in fi rst-episode schizophrenic patients

The relationship between P-glycoprotein (PGP) polymorphisms and response to olanzapine treatment in schizophrenia

Polymorphisms of the ABCB1 gene are associated with the therapeutic response to risperidone in Chinese schizophrenia patients

Systematic investigation of genetic variability in 111 human genes -implications for studying variable drug response

Pharmacogenetics of psychotropic drug response

Individualizing antipsychotic drug therapy in schizophrenia: the promise of pharmacogenetics

Pharmacogenetics and schizophrenia

Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research

Phosphodiesterase genes are associated with susceptibility to major depression and antidepressant treatment response

Variation in the purinergic P2RX(7) receptor gene and schizophrenia

The CNR1 gene as a pharmacogenetic factor for antipsychotics rather than a susceptibility gene for schizophrenia

Druginduced activation of SREP-controlled lipogenic gene expression in CNS-related cell lines: marked differences between various antipsychotic drugs

Further evidence for association of the RGS2 gene with antipsychoticinduced parkinsonism: protective role of a functional polymorphism in the 3′-untranslated region

Ethnic stratifi cation of the association of RGS4 variants with antipsychotic treatment response in schizophrenia

Pharmacogenetic assessment of antipsychotic-induced movement disorders: contribution of the dopamine D3 receptor and cytochrome P450 1A2 genes

Association between CYP2D6 genotype and tardive dyskinesia in Korean schizophrenics

Haplotype analysis of endothelial nitric oxide synthase (NOS3) genetic variants and tardive dyskinesia in patients with schizophrenia

Could HTR2A T102C and DRD3 Ser9Gly predict clinical improvement in patients with acutely exacerbated schizophrenia? Results from treatment responses to risperidone in a naturalistic setting

The -1019 C/G polymorphism of the 5-HT1A receptor gene is associated with negative symptom response to risperidone treatment in schizophrenia patients

Interaction between NOTCH4 and catechol-O-methyltransferase genotypes in schizophrenia patients with poor response to typical neuroleptics

Effect of a ciliary neurotrophic factor polymorphism on schizophrenia symptom improvement in an iloperidone clinical trial

Association of the dopamine receptor interacting protein gene, NEF3, with early response to antipsychotic medication

Pharmacogenetic study of atypical antipsychotic drug response : involvement of the norepinephrine transporter gene

Association of clozapineinduced weight gain with a polymorphism in the leptin promoter region in patients with chronic schizophrenia in a Chinese population

Leptin and leptin receptor gene polymorphisms and increases in body mass index (BMI) from olanzapine treatment in persons with schizophrenia

Polymorphisms of the 5-HT2C receptor and leptin genes are associated with antipsychotic drug-induced weight gain in Caucasian subjects with a fi rst-episode psicosis

Transcriptional profi ling of the rat frontal cortex following administration of the mGlu5 antagonists MPEP and MTEP

Association of GRIK4 with outcome of antidepressant treatment in the STAR * D cohort

Glycogen synthase kinase-3beta gene is associated with antidepressant treatment response in Chinese major depressive disorder

Lithium response and genetic variation in the CREB family of genes

The medial and lateral substantia nigra in Parkinson's disease: mRNA profi les associated with higher brain tissue vulnerability

Phosphoproteome and transcriptome analysis of the neuronal response to a CDK5 inhibitor

Allelic mRNA expression of X-linked monoamine oxidase A (MAOA) in human brain : dissection of epigenetic and genetic factors

Epigenetics and its implications for behavioural neuroendocrinology

Antineoplastic effects of the DNA methylation inhibitor hydralazine and the histone deacetylase inhibitor valproic acid in cancer cell lines

Epigenetic alterations of the dopaminergic system in major psychiatric disorders

Central Nervous system drug development: an integrative biomarker approach toward individualized medicine

Pleiotropic effects of APOE in dementia: infl uence on functional genomics and pharmacogenetics. In: Advances in Alzheimer's and Parkinson's disease. Insights, Progress, and Perspectives

APOE-Related dementia symptoms: frequency and progression

APOE-Related frequency of cognitive and noncognitive symptoms in dementia

Behavioral changes associated with different apolipoprotein E genotypes in dementia

Polymorphisms in the angiotensin-converting enzyme gene are associated with unipolar depression, ACE activity and hypercortisolism

Apolipoprotein E gene polymorphism in early and late onset bipolar patients

Angiotensinrelated genes in patients with panic disorder

Risk factors for neuropsychiatric symptoms in dementia : the Cache County Study

Apolipoprotein E genotype infl uences presence and severity of delusions and aggressive behavior in Alzheimer disease

Alzheimer genes and proteins, and measures of cognition and depression in older men

Depression in Alzheimer's disease might be associated with apolipoprotein E epsilon 4 allele frequency in women but not in men

Four components describe behavioral symptoms in 1,120 individuals with late-onset Alzheimer's disease

Association analysis of apolipoprotein E genotype and risk of depressive symptoms in Alzheimer's disease

Behavioural pathology in Alzheimer's disease with special reference to apolipoprotein E genotype

Apolipoprotein E genotype and major depression in a community of older adults. The Cache County Study

Protective effect of the Apoε2 allele in major depressive disorder in Taiwanese

APOE is associated with age-of-onset, but not cognitive functioning, in late-life depression

ApoE isoforms and measures of anxiety in probable AD patients and Apoe-/-mice

Differences in anxietyrelated behaviour between apolipoprotein E-defi cient C57BL/6 and wild type C57BL/6 mice

Role of H3-receptor-mediated signaling in anxiety and cognition in wild-type and Apoe-/-mice

Relationship of deep white matter hyperintensities and apolipoprotein E genotype to depressive symptoms in older adults without clinical depression

Caudate nucleus volumes and genetic determinants of homocysteine metabolism in the prediction of psychomotor speed in older persons with depression

A longitudinal study of hippocampal volume, cortisol levels, and cognition in older depressed subjects

Reduced hippocapal volumes and memory loss in patients with early-and late-onset depression

Vascular/risk and late-life depression in a Korean community population

Measuring the value of pharmacogenomics

Assessing the cost-effectiveness of pharmacogenomics

Pharmacological treatment of neuropsychiatric symptoms of dementia. A review of the evidence

Memantine in moderate-to-severe Alzheimer's disease

Donepezil in patients with severe Alzheimer's disease: double-blind, parallel-group, placebo-controlled study

Donepezil for severe Alzheimer's disease

Priorities and standards in pharmacogenetic research

Genomic screening and replication using the same data set in familybased association testing

Pharm acogenomics and individualized drug therapy

Ethical considerations in the use of DNA for the diagnosis of disease