Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Alzheimer's disease (AD) is a major problem of health in developed societies together with cardiovascular disorders and cancer. The lack of accurate diagnostic markers for early prediction and an effective therapy are the two most important problems to efficiently halt disease progression. The pharmacological treatment in AD accounts for 10-20% of direct costs, and less than 20% of AD patients are moderate responders to conventional drugs (donepezil, rivastigmine, galantamine, memantine), with doubtful cost-effectiveness. The neuropathological hallmark of AD (amyloid deposition in senile plaques, neurofibrillary tangle formation, and neuronal loss) are buth 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 efficacy 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 AD pathogenic events leading to premature neuronal death. The AD population exhibits a higher genetic variation rate than the control population, with absolute and relative genetic variations of 40-60% and 0.85-1.89%, respectively. AD patients also differ in their genomic architecture from patients with other forms of dementia. Functional genomics studies in AD reveal that age of onset, brain atrophy, cerebrovascular hemodynamics, brain bioelectrical activity, cognitive decline, apoptosis, immune function, lipid metabolism dyshomeostasis, and amyloid deposition are associated with AD-related genes. Pioneering pharmacogenomics studies also demonstrate that the therapeutic response in AD is genotype-specific, with APOE-4/4 carriers as the worst responders to conventional treatments. About 10-20% of Caucasians are carriers of defective CYP2D6 polymorphic variants that alter the metabolism and effects of AD drugs and many psychotropic agents currently administered to patients with dementia. There is a moderate accumulation of AD-related genetic variants of risk in CYP2D6 poor metabolizers and ultra-rapid metabolizers, which are the worst responders to conventional drugs. With diverse multifactorial therapies, combining different types of drugs and metabolic factors, it is partially possible to slow-down cognitive deterioration, improving non-cognitive symptoms, such as anxiety and depression, which currently aggravate cognition and increase the difficulties in disease management; however, the association of the APOE-4 allele with specific genetic variants of other genes (e.g., CYP2D6, ACE) negatively modulate the therapeutic response to multifactorial treatments affecting cognition, mood and behaviour. Pharmacogenetic and pharmacogenomic factors may account for 60-90% of drug variability in drug disposition and pharmacodynamics. The incorporation of pharmacogenetic/pharmacogenomic protocols to AD research and clinical practice can foster therapeutics optimization by helping to develop cost-effective pharmaceuticals and improving drug efficacy and safety.
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PMID:Molecular pathology and pharmacogenomics in Alzheimer's disease: polygenic-related effects of multifactorial treatments on cognition, anxiety and depression. 1795 77

Paroxetine is characterized by large interindividual pharmacokinetic variability and heterogeneous response patterns. The present study investigates plasma concentration and therapeutic response to paroxetine for the influence of age, sex, and CYP2D6 and ABCB1 polymorphisms, the latter gene encoding for the permeability glycoprotein. Genotyping for CYP2D6 (alleles *3, *4, *5, *6, and *xN) and ABCB1 polymorphisms (61A>G, 2677G>T, and 3435C>T) was performed in 71 depressed patients who started 20 mg paroxetine per day and had plasma concentration measured after 2 weeks at a fixed dose. A dose increase to 30 mg per day was possible starting at week 2. For 63 patients, severity of depression (Montgomery-Asberg Depression Rating Scale) was assessed at weeks 0, 2, and 4 and every 2 weeks thereafter until discontinuation. Persistent response was defined as 50% improvement from baseline score sustained from the first occurrence to study end point. Paroxetine concentration significantly differed between female and male patients (median, 28 versus 16 ng/mL; P = 0.001). Differences were not significant between CYP2D6 heterozygous and homozygous extensive metabolizers (median, 27 versus 22 ng/mL; P = 0.074) and between ABCB1 genotypes (P > 0.10). When considered in a multivariate model, CYP2D6 heterozygous extensive metabolizer phenotype (P = 0.062) and female gender (P = 0.001) predicted 1.3-fold and 1.6-fold higher paroxetine concentration, respectively, but fraction of explained variability was modest (21%). Frequency of persistent response at study end point did not significantly differ according to CYP2D6 heterozygous extensive metabolizer versus homozygous extensive metabolizer phenotype and ABCB1 polymorphisms in univariate analyses. After adjusting for age, sex, paroxetine concentration at week 2, and daily dose at study end point, ABCB1 genotype contributed to improving the model significantly for 61A>G (P = 0.043), but not 2677G>T (P = 0.068) and 3435C>T (P = 0.11). None of two poor metabolizers and four ultrarapid metabolizers showed persistent response to paroxetine. The hypothesis that permeability glycoprotein activity might be a relevant predictor of therapeutic response deserves to be further investigated while controlling for pharmacokinetic variability.
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PMID:CYP2D6 and ABCB1 genetic variability: influence on paroxetine plasma level and therapeutic response. 1864 53

This review describes symptoms and pathophysiology of Parkinson's diseases (PD) and restless legs syndrome (RLS), and discusses the relationship between clinical outcome of DA agonists and their receptor-binding and pharmacokinetics. Oral DA agonists are divided into 2 classes; the ergots and the non-ergots. Both classes are in general equally effective against PD motor symptoms. Ergots (apart from bromocriptine) stimulate the DA D(1) subreceptor and increase dyskinesia. Furthermore, valvular heart disease (VHD) and pulmonary and retroperitoneal fibrosis appear to represent a class effect of 8beta-aminoergolines as cabergoline and pergolide The side effects profile therefore seems more beneficial for non-ergots than ergots. The main improvement of motor functions by DA agonists is related to D(2) agonism. However, in monotheraphy, the selective D(2)-receptor DA agonist sumanirole seemed less effective than ropinirole which is selective for D(2)-like DA-receptors (D(2), D(3) and D(4)). Given as adjunctive to L-dopa both drugs had equal efficacy on motor-symptoms, indicating that D(2)-receptor activity must be accompanied with stimulation of other DA receptors for optimizing the efficacy on motor symptoms. Striatal D(3) receptor loss may be more important than D(2) receptor loss for reduced response to dopaminergic treatment. D(3) stimulation may also be beneficial for the non-motor symptom depression/mood in PD and for neuron-protection. This makes D(3)-receptors a potential therapeutic target in PD. 5-HT(1A)-receptor agonism and alpha(2) adrenergic antagonism may contribute to prevention of dyskinesia. However, 5-HT-receptor activity is also associated with side effects. 5-HT(2B) agonism (and possibly 5-HT(1B) agonism) is associated with fibrotic reactions, and valvular heart disease (VHD). By interfering with the CYP450 system DA agonists may contribute to drug-drug interactions. Lack of CYP2D6 activity is also suggested as important for etiology and CNS-symptoms of PD. Based on current knowledge D2-like receptor activities (preferences for the D(3) receptor) seem most beneficial. 5-HT(1A)-receptor agonism (prevention of dyskinesia), 5-HT(2B) antagonism or no 5-HT(2B)-receptor activity also seems beneficial. Development of DA agonists containing these properties, without interfering with CYP2D6 may be beneficial.
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PMID:Receptor-binding and pharmacokinetic properties of dopaminergic agonists. 1869 Nov 32

We observed opioid-related respiratory depression in a patient receiving tramadol via patient-controlled analgesia. Predisposing factors were the patient's genetic background and renal impairment. Complete recovery occurred after naloxone administration, thus confirming opioid intoxication. Analysis of the patient's genotype revealed a CYP2D6 gene duplication resulting in ultra-rapid metabolism of tramadol to its active metabolite (+)O-desmethyltramadol. Concomitant renal impairment resulting in decreased metabolite clearance enhanced opioid toxicity. This genetic CYP2D6 variant is particularly common in specific ethnic populations and should be a future diagnostic target whenever administration of tramadol or codeine is anticipated, as both drugs are subject to a comparable CYP2D6-dependent metabolism.
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PMID:Respiratory depression with tramadol in a patient with renal impairment and CYP2D6 gene duplication. 1871 7

A large number of women receive codeine for obstetric pain while breastfeeding. Following a case of fatal opioid poisoning in a breastfed neonate whose codeine prescribed mother was a CYP2D6 ultrarapid metabolizer (UM), we examined characteristics of mothers and infants with or without signs of central nervous system (CNS) depression following codeine exposure while breastfeeding in a case-control study. Mothers of symptomatic infants (n = 17) consumed a mean 59% higher codeine dose than mothers of asymptomatic infants (n = 55) (1.62 (0.79) mg/kg/day vs. 1.02 (0.54) mg/kg/day; P = 0.004). There was 71% concordance between maternal and neonatal CNS depression. Two mothers whose infants exhibited severe neonatal toxicity were CYP2D6 UMs and of the UGT2B7*2/*2 genotype. There may be a dose-response relationship between maternal codeine use and neonatal toxicity, and strong concordance between maternal-infant CNS depressive symptoms. Breastfed infants of mothers who are CYP2D6 UMs combined with the UGT2B7*2/*2 are at increased risk of potentially life-threatening CNS depression.
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PMID:Pharmacogenetics of neonatal opioid toxicity following maternal use of codeine during breastfeeding: a case-control study. 1909 67

Fluoxetine [+/--N-methyl-3-phenyl-3-[(alpha, alpha, (-trifluoro-p-tolyl)oxy]-propylamine)] a selective serotonin reuptake inhibitor, is widely used in treating depression and other serotonin-dependent disease conditions. Racemic, (R)- and (S)-fluoxetine are potent reversible inhibitors of CYP2D6, and the racemate has been shown to be a mechanism-based inhibitor of CYP3A4. Racemic fluoxetine also demonstrates time- and concentration-dependent inhibition of CYP2C19 catalytic activity in vitro. In this study, we compared fluoxetine, its (R)- and (S)-enantiomers, ticlopidine, and S-benzylnirvanol as potential time-dependent inhibitors of human liver microsomal CYP2C19. In a reversible inhibition protocol (30 min preincubation with liver microsomes without NADPH), we found (R)-, (S)- and racemic fluoxetine to be moderate inhibitors with IC(50) values of 21, 93, and 27 microM, respectively. However, when the preincubation was supplemented with NADPH, IC(50) values shifted to 4.0, 3.4, and 3.0 microM, respectively resulting in IC(50) shifts of 5.2-, 28-, and 9.3-fold. Ticlopidine showed a 1.8-fold shift in IC(50) value, and S-benzylnirvanol shifted right (0.41-fold shift). Follow-up K(I) and k(inact) determinations with fluoxetine confirmed time-dependent inhibition [K(I) values of 6.5, 47, and 14 microM; k(inact) values of 0.023, 0.085, 0.030 min(-1) for (R)-, (S)-, and racemate, respectively]. Although the (S)-isomer exhibits a much lower affinity for CYP2C19 inactivation relative to the (R)-enantiomer, it exhibits a more rapid rate of inactivation. Racemic norfluoxetine exhibited an 11-fold shift (18-1.5 microM) in IC(50) value, suggesting that conversion of fluoxetine to this metabolite represents a metabolic pathway leading to time-dependent inhibition. These data provide an improved understanding of the drug-interaction potential of fluoxetine.
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PMID:Differential time- and NADPH-dependent inhibition of CYP2C19 by enantiomers of fluoxetine. 1914 69

Citalopram is marketed as a racemate (50:50) mixture of the S(+)-enantiomer and R(-)-enantiomer and the active S(+)-enantiomer (escitalopram) that possess inhibitory effects. Citalopram was introduced in Sweden in 1992 and is the most frequently used antidepressant to date in Sweden. In 2002, escitalopram was introduced onto the Swedish market for treatment of depression and anxiety disorders. The main objective of this study was to investigate S(+)-citalopram [i.e., the racemic drug (citalopram) or the enantiomer (escitalopram)] present in forensic autopsy cases positive for the presence of citalopram in routine screening using a non-enantioselective bioanalytical method. Fifty out of the 270 samples found positive by gas chromatography-nitrogen-phosphorus detection were further analyzed using enantioselective high-performance liquid chromatography. The 50 cases were genotyped for CYP2D6 and CYP2C19, as these isoenzymes are implicated in the metabolism of citalopram and escitalopram. In samples positive for racemic citalopram using the screening method for forensic autopsy cases, up to 20% would have been misinterpreted in the absence of an enantioselective method. An enantioselective method is thus necessary for correct interpretation of autopsy cases, after the enantiomer has been introduced onto the market. The percentage of poor metabolizers was 6% for CYP2D6 and 8% for CYP2C19.
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PMID:Enantioselective analysis of citalopram and escitalopram in postmortem blood together with genotyping for CYP2D6 and CYP2C19. 1923 31

Depression is one of the leading causes of disability and is efficiently treated by antidepressant pharmacotherapy. Pharmacological treatment is still hampered by a delayed time of onset of clinical improvement and a series of side effects. In elderly, it is complicated by an increased risk of adverse drug events, associated with age-related physiological changes, individual variability in drug metabolism mainly related to polymedication, concurrent diseases and diet. Then every physician would like to predict these impairments and to prescribe a "tailored" treatment based on individual characteristics. One of the tools for this tailored medication is the use of pharmacogenetics, leading to an evaluation of the human genome implications in the treatment response (efficacy, time of onset and adverse events). Some candidate-genes have already been identified, showing encouraging results, but only a few studies focus on depressed old subjects. The existing studies have analyzed the polymorphism of the metabolizing enzyme gene CYP2D6 and the serotonin transporter genes implications. The results are promising but more researches are necessary to include pharmacogenetic studies in the clinical practice.
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PMID:[Pharmacogenetics of depression in elderly patients]. 1925 71

Cytochrome P450 genes are involved in the metabolism of antidepressants and could influence treatment response. The aim of this study was to investigate the role of allelic variations of the cytochrome P450 CYP1A2, CYP2C9, CYP2C19 and CYP2D6 genes in antidepressant treatment response and remission rates. Two hundred and seventy-eight patients affected by major depression, responders (N = 81) and nonresponders (N=197) to at least one adequate antidepressant treatment, were recruited with a multicentre design for resistant depression and genotyped for all relevant variations. None of the considered metabolic profiles (e.g. poor, intermediate, extensive and ultrarapid metabolizers) was found to be associated with either response or remission rates. In conclusion, the investigated cytochrome genes do not seem to play a major role in antidepressant response in the present sample of depressive patients. Nevertheless, methodological and sample size limitations of this study do not allow definitive conclusions.
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PMID:Cytochrome P450 CYP1A2, CYP2C9, CYP2C19 and CYP2D6 genes are not associated with response and remission in a sample of depressive patients. 1959 58

Pharmacogenomics investigates inherited differences in drug responses including beneficial and adverse reactions. While a considerable amount of evidence for genetic influences on drug responses has been accumulated within the last decade, predominantly in small studies, its value in routine therapy is still a matter of debate. The aim of this review is to discuss well established examples where pharmacogenomic techniques can improve routine treatment. Examples include genotyping of CYP2D6 in the context of antidepressant therapy, analysis of TPMT variants for the prediction of mercaptopurine-induced bone marrow depression, VKORC1 and CYP2C9 analyses for a better control of anticoagulant administration and the SLCO1B1 variant in the context of statin-induced myopathies.
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PMID:[Pharmacogenomics in routine medical care]. 2010 57


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