ABCB1 C3435T polymorphism is associated with susceptibility to major depression, but not with a clinical response to citalopram in a Turkish population.

BACKGROUND: The ATP-binding cassette sub-family B member 1 (ABCB1) gene, which encodes the p-glycoprotein at the blood-brain barrier, is investigated for patients' susceptibility to major depressive disorder (MDD) and their therapeutic response to antidepressants. However, there is an inconsistency between the studies of different ethnic groups. The current study aimed to determine the potential correlations of the ABCB1 gene C3435T polymorphism with the susceptibility to MDD and the therapeutic response to citalopram in a Turkish population. METHODS: Fifty-four patients with MDD who received citalopram and 70 controls from the Turkish population were genotyped for ABCB1 C3435T polymorphism. To assess the therapeutic response to citalopram, all patients were rated baseline, first, second, fourth and sixth weeks according to the 17-item Hamilton Rating Scale for Depression (HAMD-17). RESULTS: There was a significant correlation between the patient and control groups for ABCB1 C3435T polymorphism. Distribution of CC genotype and C allele frequency were higher in the patients than in the control group (p = 0.006, p = 0.020, respectively). However, no correlation between ABCB1 C3435T polymorphism and a therapeutic response to citalopram was observed. CONCLUSION: Our results suggested that C3435T polymorphism in the ABCB1 gene may be an indicator of the susceptibility to major depression, without a likely treatment response to citalopram in a Turkish population. These findings should be replicated in studies on larger patient groups with different ethnicities.

Radioligand binding to brain dopamine and serotonin receptors and transporters in Parkinson's disease: relation to gene polymorphisms.

The influence of variations in genes coding for dopamine and serotonin transporters and receptors on the expression of these structures in the brains of patients with Parkinson's disease (PD) is not known. In order to investigate the significance of dopamine and serotonin transporter and receptor gene polymorphisms on the expression of dopamine and serotonin transporters and the dopamine D(2) and serotonin 5HT(2A) receptors in brain tissue in PD, we conducted a study on brain autopsy material from 16 patients diagnosed with clinical PD and 11 controls. The polymorphisms studied were DAT1 VTNR, DRD2 Taq1A, 5HTTLPR, and 5HTR2A 102 T>C, 516 C>T, His425Tyr, and Thr25Asn. Compared to control subjects, patients with PD had a significantly lowered radioligand binding to the dopamine transporter (DAT) in nucleus caudatus (p = .001) and putamen (p = .008), and to the serotonin transporter in gyrus cingulatus (p = .010) and nucleus caudatus (p = .032). We did not observe any significant associations between genetic polymorphisms and the extent of radioligand binding or between the polymorphisms and a diagnosis of PD. In conclusion, the density of brain dopamine and serotonin transporters in patients with PD was reduced. However, there were no associations between the investigated genotypes and the expression of the corresponding receptors and transporters.

Allele and genotype frequencies of serotonin and dopamine transporter and receptor polymorphisms in a Norwegian population.

Polymorphisms in genes coding for dopaminergic and serotonergic receptors and transporters have been associated with the clinical effects and adverse drug reactions of antipsychotic and antidepressant drugs. The objective of this study was to investigate the frequency and combinations of common polymorphisms in the dopamine transporter (DAT1), dopamine D(2) receptor (DRD2), dopamine D(3) receptor (DRD3), serotonin transporter (5HTT), and serotonin 2A receptor (5HTR2A) genes in a Norwegian population. To determine the background frequency in the population, 250 blood samples were consecutively collected from healthy Norwegian blood donors (125 men and 125 women; mean age: 48±11 years). Samples were tested for DAT1 VNTR, DRD2 Taq1A, DRD3 Ser9Gly, 5HTTLPR, and four polymorphisms (102 T>C, His452Tyr, 516 C>T, and Thr25Asn) in the 5HTR2A, using polymerase chain reaction and real-time polymerase chain reaction. We observed the frequency of the nine-repeat allele of DAT1 VNTR polymorphism as 20% (95% confidence interval [CI]: 0.18-0.23), the A1 allele of DRD2 Taq1A polymorphism as 21% (95% CI: 0.19-0.23), the A1 allele of DRD3 Ser9Gly polymorphism as 68% (95% CI: 0.66-0.70), the short allele of 5HTTLPR as 38% (95% CI: 0.36-0.40), and the T allele of 5HTR2A 102 T>C polymorphism as 41% (95% CI: 0.39-0.41), and the frequencies of 5HTR2A His452Tyr and 5HTR2A Thr25Asn were 93% and 95%, respectively. The tested polymorphisms showed differences compared with other European populations. Further studies are necessary to better understand the effect of these alleles and their combinations on personality, mental disorders, drug response, and adverse reactions of psychotropic drugs.

Antipsychotic-induced extrapyramidal symptoms in patients with schizophrenia: associations with dopamine and serotonin receptor and transporter polymorphisms.

BACKGROUND: Little is known about the influence of polymorphisms of the dopamine and serotonin system on the risk for extrapyramidal symptoms (EPS) during treatment with antipsychotic drugs. METHODS: Of 119 subjects with schizophrenia treated with antipsychotics, 63 had current or previous EPS (acute dystonia, parkinsonism, tardive dyskinesia), and 56 had no such symptoms. All subjects were genotyped for a total of eight dopamine and serotonin receptor and transporter polymorphisms: the Taq1A polymorphism of the dopamine D(2) receptor (DRD2) gene, the Msc1 polymorphism of the dopamine D(3) receptor (DRD3) gene, the variable number of tandem repeat (VNTR) polymorphism of the dopamine transporter (DAT1) gene, four polymorphisms (102T/C, His452Tyr, 516 C/T, and Thr25Asn) of the serotonin 5-HT(2A) receptor (5HTR2A) gene, and the 5HTTLPR polymorphism of the serotonin transporter (5HTT) gene. RESULTS: The frequency of the A1 allele of the DRD2 Taq1A polymorphism was significantly higher in the EPS group than in the control group [16% vs. 7%, P = 0.040; odds ratio (OR) 2.4; 95% confidence interval (CI) 1.1-5.7]. Also, the 9 repeat allele of the DAT1 VNTR polymorphism was significantly more common in the EPS group (42% vs. 28%, P = 0.030; OR 1.9; 95% CI 1.1-3.3). Being a carrier of both DRD2 Taq1A A1 and DAT1 VNTR 9 repeat alleles was also significantly associated with the occurrence of EPS (19% vs. 6%, P = 0.040; OR 4.0; 95% CI 1.05-15.2) No significant differences in allele frequencies were found for the other polymorphisms. CONCLUSION: Presence of the Taq1A A1 allele of the DRD2 and the 9 repeat allele of the DAT1 VNTR polymorphisms might be risk factors for EPS caused by antipsychotic drugs.

Risk factors for extrapyramidal symptoms during treatment with selective serotonin reuptake inhibitors, including cytochrome P-450 enzyme, and serotonin and dopamine transporter and receptor polymorphisms.

INTRODUCTION: Extrapyramidal symptoms (EPS) are rare adverse drug reactions to selective serotonin reuptake inhibitors (SSRIs). This study aimed to investigate the potential risk factors for EPS associated with SSRIs including polymorphisms of cytochrome P-450 isoenzymes, and serotonin and dopamine transporters and receptors. METHODS: All spontaneous adverse drug reaction reports received by the Swedish Medical Products Agency until December 1999 that were coded with EPS and judged to be at least possibly related to SSRI treatment were included in the study. Reporting physicians received a form for collection of relevant information including current and previous use of SSRIs and antipsychotics, alcohol or substance abuse, central nervous system damage, a history of epilepsy or EPS, and a family history of Parkinson disease. A blood sample was also requested for genotyping of selected cytochrome P-450, and serotonin and dopamine transporter and receptor mutations. RESULTS: A total of 64 cases of EPS were reported. Twenty-eight forms (46%) were returned, and 20 blood samples were obtained. Identified potential risk factors included age of 65 years or older and the presence of the A1 allele of the D2 dopamine receptor gene (DRD2) Taq1A polymorphism (relative risk, 2.4; 95% confidence interval, 1.2-4.5 vs literature controls). No relationship was apparent for sex, drug dose, or other genetic polymorphisms. At least 1 additional potential risk factor for EPS, such as a history of central nervous system damage, alcohol or substance abuse, epilepsy, Parkinson disease, previous or current exposure to antipsychotic drugs, concomitant treatment with other antidopaminergic or serotonergic agents, or a history of EPS, was found in 93% of the cases. CONCLUSION: The risk of EPS with SSRIs seems to increase with advanced age and with the presence of the A1 allele of DRD2 Taq1A polymorphism. Because of the small sample size of our study and the use of historical controls rather than patients who did not experience EPS during SSRIs treatment, the DRD2 finding is preliminary and needs to be replicated in other studies before firm conclusions can be drawn. At least 1 additional potential risk factor was found in almost all cases.

Genotyping as a tool to predict adverse drug reactions.

During the last decades, the rapid development in molecular biology has contributed to the understanding of genetic factors underlying many adverse drug reactions. Until recently, most research in this area has focused on genes coding for drug-metabolizing enzymes. Inactivating mutations have been found in genes coding for enzymes belonging to the cytochrome P-450 system, which is the major system for drug metabolism in humans, but also in genes coding for other enzymes. Subjects with a lack of functional activity in these enzymes should be treated with very low doses of drugs metabolized by the same enzyme in order to avoid excessive drug levels and thereby toxic effects. In the last years, increasing attention has been directed towards genes coding for drug targets. Hitherto, most studies have been carried out on single genes known to be or assumed to be functionally related to a given adverse drug reaction. Another approach, which may become more common in the future, is testing for complex single nucleotide polymorphism patterns that may be associated with adverse drug reactions, although the functional relationship between them may be completely unknown. Due to the influence of non-genetic factors in the development of adverse drug reactions, the association between a specific genotype and an adverse drug reaction will always be lower than 100%. Therefore, there is a need for prospective large-scale studies in order to elucidate the extent of environmental influences on the adverse drug reactions for which a genetic basis has been suggested. Despite these obstacles, pharmacogenetic testing will hopefully in the future identify at least some clear-cut situations where a drug should be avoided in certain individuals in order to reduce the risk of adverse drug reactions.

Genotyping of drug targets: a method to predict adverse drug reactions?

In the last decades, advances in molecular biology have led to modern pharmacogenetics, which started as a science that focused on investigating drug metabolising enzymes and genetic determinants of pharmacokinetic variability. As more evidence has become available on the structure of drug targets and the genes coding for them, increasing attention has been directed towards pharmacodynamic explanations of variability in therapeutic response as well as in the risk for adverse drug reactions. Traditionally, genetic drug safety research has focused on variations in single genes whose functions are known to be related to given adverse drug reactions. A few such examples, malignant hyperthermia, the long QT syndrome, venous thromboembolic disease, tardive dyskinesia, and drug addiction, are presented in this article. In the future, results from the Human Genome Project together with tools such as DNA microarray technology, high-output screening systems and advanced bioinformatics, will permit a more thorough elucidation than is currently possible of the genetic components of adverse drug reactions. By screening for a large number of single nucleotide polymorphisms (SNPs), SNP patterns associated with adverse drug reactions can be discovered even though the functions of the SNPs as such are completely unknown. On the basis of these findings, it can be expected that pharmacogenetic research will identify situations where a drug should be avoided in certain individuals in order to reduce the risk for adverse drug reactions. If so, it will be feasible to use molecular diagnostics to select drugs that are safe for the individual patient.

Change from the CYP2D6 extensive metabolizer to the poor metabolizer phenotype during treatment With bupropion.

Some data indicate that bupropion inhibits the cytochrome P-450 enzyme CYP2D6, but very little published data is available on the extent of this inhibition. The objective of the present study was to quantify this inhibition in a subject treated with bupropion for smoking cessation. Genotypically, the patient was a CYP2D6 homozygous extensive metabolizer (EM). His CYP2D6 phenotype was assessed using the test drug dextromethorphan before, during, and after treatment with bupropion. During treatment with bupropion, he clearly changed from the EM to the poor metabolizer (PM) phenotype. Although the results from a single patient should be interpreted with great caution, the extent of the interaction indicates that bupropion might be a CYP2D6 inhibitor as potent as the most powerful CYP2D6 inhibitors known, such as quinidine and paroxetine.