Pharmacogenomics of Central Nervous System (CNS) Drugs

Abstract

Preclinical Research Central nervous system (CNS) disorders represent a major problem of health in developed countries, with important consequences in disability and health economics. Recent findings in CNS genomics and pharmacogenomics suggest that the introduction of pharmacogenomic procedures in clinical practice may help to optimize therapeutics (efficacy and safety issues). The genes involved in the pharmacogenomics of CNS drugs fall into five categories: (i) genes associated with CNS pathogenesis; (ii) genes associated with the mechanism of action of drugs; (iii) genes associated with drug metabolism; (iv) genes associated with drug transporters; and (v) pleiotropic genes involved in multifaceted cascades and metabolic reactions. Pharmacogenomics accounts for 30–90% variability in pharmacokinetics and pharmacodynamics. Only 20–30% of the Caucasian population processes normally approximately 60% of the current drugs that are metabolized via CYP2D6, CYP2C9, and CYP2C19. Clinical pharmacogenomics may contribute to personalizing pharmacological treatment, predicting patient/drug‐dose selection, minimizing drug interactions, increasing drug efficacy, and reducing unnecessary costs.

APOE-TOMM40 in the Pharmacogenomics of Dementia

“…From studies designed to define APOE-related AD phenotypes, several conclusions can be drawn: (i) the age-at-onset is 5-10 years earlier in approximately 80% of AD cases harboring the APOE-4/4 genotype; brain atrophy and AD neuropathology is markedly increased in APOE-4/4>APOE-3/4>APOE-3/3; (xi) brain mapping activity shows a significant increase in slow wave activity in APOE-4/4 from early stages of the disease; (xii) brain hemodynamics, as reflected by reduced brain blood flow velocity and increased pulsatility and resistance indices, is significantly worse in APOE-4/4 (and in APOE-4 carriers in general, as compared with APOE-3 carriers); brain hypoperfusion and neocortical oxygenation is also more deficient in APOE-4 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) in approximately 3-8% of the AD cases, the presence of some dementia-related metabolic dysfunctions accumulates more in APOE-4 carriers than in APOE-3 carriers; (xvi) some behavioral disturbances, alterations in circadian rhythm patterns, and mood disorders 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) hypertension and other cardiovascular risk factors also accumulate in APOE-4; and (xx) APOE-4/4 carriers are the poorest responders to conventional drugs. 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 for AD and/or concomitant pathologies [1][2][3][4][5][18][19][20][21][22][23][24][25][26][27][28][29][30][77][78][79]. In our study, it is clear that APOE-4 carriers are the worst responders to conventional treatments Figures 3 and 4.…”

“…The genes involved in the pharmacogenomic response to drugs in Alzheimer's disease (AD) fall into five major categories: (i) genes associated with AD pathogenesis and neurodegeneration (APP, PSEN1, PSEN2, MAPT, PRNP, APOE and others); (ii) genes associated with the mechanism of action of drugs (enzymes, receptors, transmitters, messengers); (iii) genes associated with drug metabolism (phase I (CYPs) and phase II reactions (UGTs, NATs); (iv) genes associated with drug transporters (ABCs, SLCs); and (v) pleiotropic genes involved in multifaceted cascades and metabolic reactions (APOs, ILs, MTHFR, ACE, AGT, NOS, etc) [1][2][3][4]. The genetic and epigenetic defects identified so far in AD include Mendelian mutations, susceptibility single-nucleotide polymorphisms (SNPs), mitochondrial DNA (mtDNA) mutations, and epigenetic changes.…”

Epigenetics of Brain Disorders: The Paradigm of Alzheimer ’s Disease

“…Among these susceptibility genes, the apolipoprotein E (APOE) gene (19q13.2)(AD2) is the most prevalent as a risk factor for AD, especially in those subjects harboring the APOE-4 allele, whereas carriers of the APOE-2 allele might be protected against dementia [1,3] APOE-related pathogenic mechanisms are also associated with brain aging and with the neuro pathological hallmarks of AD [1][2][3]34,35,[40][41][42][43][48][49][50]. mtDNA damage may also contribute to increase brain vulnerability and neuro degeneration [51,52].…”

The Pathogenic Component of the APOE-TOMM40 Region in Alzheimer’s disease: Its Implications in Metabolomics and Pharmacogenomics

“…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 for AD and/or concomitant pathologies [8][9][10][11][12][13][14][15][16][17][18][19].…”