DRD2 Polymorphisms Research Articles

P.1.003 - Pharmacodynamics and pharmacokinetics related gene polymorphisms affect adverse drug reactions of haloperidol

The antipsychotic action of haloperidol is due to the blockade of D2 receptors in the mesolimbic dopamine pathway, while the adverse drug reactions are associated with striatal D2 receptors blockade. Contradictory data concerning the effects of genetic polymorphisms of genes encoding these receptors and associated structures (catechol-O-Methyltransferase, glycine transporter and gene encoding the density of D2 receptors on the neuronal membrane) [1,2], and also genes encoding the elements of haloperidol biotransformation system on haloperidol metabolism rate as well as plasma drug concentration ratio is described in patients with different genotypes [3,4]. To evaluate the correlation between DRD2, SLC6A3 (DAT) and COMT genetic polymorphisms and to investigate their effect on the development of adverse drug reactions in patients with alcohol use disorder who received haloperidol. The second objective of this study was to investigate the effects of CYP2D6 and CYP3A5 genetic polymorphisms on haloperidol equilibrium concentration in patients with alcohol use disorder. The study included 114 male patients (average age 38.12±9.08; median age 39; LQ 34; UQ 48). Bio-Rad CFX Manager™ software (USA) and "SNP-Screen" sets of "Syntol" (Russia) were used to determine polymorphisms rs4680, rs1800497, rs1124493, rs2242592, rs2298826, and rs2863170. In every “SNP-Screen” set, two allele-specific hybridizations were used, which allowed to determine two alleles of studied polymorphism separately on two fluorescence channels. Genotyping was performed using the allele-specific real-time PCR. CYP2D6 and CYP3A were phenotyped with high-performance liquid chromatography-mass spectrometry using concentration of endogenous substrate of the enzyme and its urinary metabolites (6-hydroxy-1,2,3,4-tetrahydro-beta-carboline(6-HO-THBC) to pinoline ratio [5] for CYP2D6 and 6-beta-hydroxycortisol to cortisol ratio for CYP3A). The equilibrium plasma concentration was determined using LC-MS-MS. Statistical analysis of the results was performed with non-parametric methods using the ”Statsoft Statistica v. 10.0“ (Dell Statistica, Tulsa, OK, USA). The normality of samples distribution was evaluated using W-Shapiro-Wilk test and taken into account when choosing a method. The differences were considered as statistically significant at р<0.05 (power in excess of 80 %). To compare two independent groups Mann-Whitney U test was used. Results of this study detected a statistically significant difference in the adverse drug reactions intensity in patients receiving haloperidol with genotypes 9/10 and 10/10 of polymorphic marker SLC6A3 rs28363170. In patients receiving haloperidol in tablets the increases in the UKU score of 10.99 ± 2.12 (10/10) vs 13.14 ± 2.08 (9/10) (p<0.001) and in the SAS score of 5.17 ± 1.49 (10/10) vs 6.88 ± 1.37 (9/10) (p=0.006) were revealed. The results of this study showed that equilibrium concentration level / dose index depends on CYP2D6 genetic polymorphism (0.19 [0.07; 0.43] vs 0.48 [0.38; 0.55], p=0.012). Polymorphism of the SCL6A3 gene can affect the safety of haloperidol, and that should be taken into account during the choice of drug and its dosage regimen. Also our study demonstrates that CYP2D6 genetic polymorphism (1846G>A) can affect haloperidol concentration levels in patients with alcohol use disorder.

Association study of BDNF and DRD3 genes with alcohol use disorder in Schizophrenia

Alcohol use disorder (AUD) is a leading risk factor of disease burden in the world. It is also commonly comorbid with over 20% of schizophrenia patients. The brain-derived neurotrophic factor (BDNF) and dopamine D3 receptor (DRD3) have been implicated in alcohol drinking behaviour. Previous genetic studies of the BDNF and DRD3 genes produced mixed findings; however, only one study investigated two BDNF genetic markers with alcohol dependence in schizophrenia patients. We investigated 15 single-nucleotide polymorphisms (SNPs) in DRD3 and four SNPs in BDNF for possible association with alcohol abuse or dependence in schizophrenia patients of European ancestry (N = 195). The patients were assessed for the occurrence of alcohol abuse or alcohol dependence using the Structured Clinical Interview for DSM-IV Axis I Disorders, Patient Edition (SCID-I/P). We found the BDNF Val66Met to be associated with alcohol dependence (p = 0.004). We also found haplotypes across BDNF to be nominally associated with alcohol dependence. Analyses of DRD3 markers and haplotypes yielded mostly negative findings. Our findings support a role of the BDNF gene in alcohol dependence in schizophrenia patients. Larger samples are required to confirm our findings, particularly those of BDNF haplotypes.

Gene-gene interaction between DRD4 and COMT modulates clinical response to clozapine in treatment-resistant schizophrenia.

Clozapine is the drug of choice for treatment-resistant schizophrenia. However, its use is associated with variable clinical responses and serious adverse effects. Polymorphisms in genes encoding proteins involved in synaptic neurotransmission may account for such variability. Here, we studied independent and epistatic genetic associations of polymorphisms in DRD4 (120-bp duplication) and COMT (Val158Met) with clinical response to clozapine in people with treatment-resistant schizophrenia. We studied 93 participants who were on stable doses of clozapine for at least 12 weeks. A total score of less than or equal to 35 on the Brief Psychiatric Rating Scale was defined as a clinical response. The genetic associations were tested using logistic regression analyses. Neither polymorphism studied was found to be independently associated with response to clozapine. However, a statistically significant gene-gene interaction was observed between the polymorphisms. Participants with the COMT Val/Met or Met/Met genotype, who also had one or two DRD4 120-bp alleles (120/240 and 120/120), showed significantly better clinical response to clozapine. Our results highlight the importance of investigating gene-gene interactions, while studying the pharmacogenetics of clozapine.

A meta-analysis of data associating DRD4 gene polymorphisms with schizophrenia.

To explore the association between DRD4 polymorphisms and schizophrenia risk, a meta-analysis was carried out with 41 case–control articles. Specifically, we included 28 articles (5,735 cases and 5,278 controls) that pertained to the 48 bp variable number tandem repeat (VNTR) polymorphism, nine articles (1,517 cases and 1,746 controls) that corresponded to the 12 bp tandem repeat (TR), six articles (1,912 cases and 1,836 controls) that addressed the 120 bp TR, 10 articles (2,927 cases and 2,938 controls) that entailed the −521 C>T polymorphism, six articles (1,735 cases and 1,724 controls) that pertained to the −616 C>G polymorphism, and four articles (1,191 cases and 1,215 controls) that involved the −376 C>T polymorphism. Pooled analysis, subgroup analysis, and sensitivity analysis were performed, and the data were visualized by means of forest and funnel plots. Results of pooled analysis indicated that the −521 CC variant (Pz=0.009, odds ratio [OR] =1.218, 95% confidence interval [CI] =1.050–1.413) and genotype L/L (ie, long allele) of the 120 bp TR were risk factors of schizophrenia (Pz=0.004, OR =1.275, 95% CI =1.081–1.504). The 48 bp VNTR, the 12 bp TR, the −616 C>G polymorphism, and the −376 C>T polymorphism were not associated with schizophrenia. Additional research is warranted to explore the association between polymorphisms of DRD4 and schizophrenia risk.

ПОЛИМОРФИЗМ –141С INS/DEL ГЕНА D 2 -ДОФАМИНЕРГИЧЕСКОГО РЕЦЕПТОРА КАК МАРКЕР РАННЕГО РАЗВИТИЯ ЭССЕНЦИАЛЬНОЙ АРТЕРИАЛЬНОЙ ГИПЕРТЕНЗИИ У ПОДРОСТКОВ

Background. The relevance of the search for genetic markers of essential hypertension (EH), is beyond doubt. The importance of research of dopaminergic system genes consists primarily of pleiotropic effects of dopamine on different systems and functions of the body. The aim of this study was to identify the association of polymorphism -141C 1/D D2-dopaminergic receptor (DRD2) with parameters of psycho-vegetative status and cardiovascular system indicators in adolescents with EH. Methods. We carried out an investigation of 14-17-year old (15.92 ± 1.12) Caucasian male patients with EH (n = 110) in clinic of Scientific Centre for Family Health and Human Reproduction Problems. Psychological testing, clinoorthostatic test, ambulatory blood pressure monitoring (ABPM), and genotyping have been carried. Results. 11-genotype is associated with higher «hypomania» personality traits (scale 9 of Mini-SMIL was 4.2 (4-5) in carriers of the 11-genotype and 4.0 (3-4) in 1D and DD-genotype carriers, p = 0.024), asthenosympathicotonic variant of autonomic support and pressure load (ejection fraction in carriers of the 11-genotype was 71.47 ± 5.98 % and 68.44 ± 6.01 % in 1D and DD-genotype carriers, p = 0.044, time of systolic blood pressure hypertension in carriers of the 11-genotype - 35.50 (20.5-51.5) and 18.30 (6.5-32) - in 1D and DD-genotype carriers, p = 0.010, the time of diastolic blood pressure hypertension in 11-genotype carriers was 13 (7.85-26.5) and 2 (0.9-11) - in 1D and DD-genotype carriers, p = 0,002). Conclusion. -141C I/D DRD2 polymorphism is associated with disorders of important indicators of psycho-vegetative status and cardiovascular system, including circadian organization of blood pressure, which allows considering it as a marker of early development of EH in adolescents.

Effects of genes to psychological factors in sports

With the human genome project, in addition to determining the number, structure and physical maps of our genes which were previously supposed to be between 20-25 thousands, genetic regions affecting athletic performance have also been identified.It has been determined that endurance, athletic ability and musculoskeletal as well as central nervous system (CNS) are effective in succeeding in todayÂ’s sporting events and play an important role in performance. Parameters affecting psychological performance such as stress, anxiety, aggression are effective in determining sportive achievements. Determining the genetic predisposition of the athletes in stressful environments or in sports where stress is prominent allows them to be guided by psychologists at an early age and contributes to sporting success. Related to the behavioral characteristics of the athletes, genes leading to resistance to stress, personality traits and aggressive behaviours like 5-HTT, DRD4, DRD5, ADRD1, COMT, BDNF, NRG1, GLUT4 and SLC2A4 and polymorphisms within these genes have been investigated in our review.

Dopaminergic polymorphisms associated with medication responsiveness of gait in Parkinson's disease

BackgroundGait dysfunction is a common symptom of Parkinson's disease that can cause significant disability and put patients at risk for falls. These symptoms show variable responsiveness to dopaminergic therapy. ObjectiveTo determine whether dopaminergic (rs1076560 DRD2 G > T and rs4680 catechole-o-methyltranspherase (COMT) Val158Met) or brain derived neurotrophic factor (rs6265 BDNF Val66Met) genetic polymorphisms are associated with gait function and medication responsiveness in Parkinson's disease. MethodGait function was evaluated on two days for patients (ON and OFF medication in a counterbalanced fashion) and a single session for controls. Investigators were blinded to genotype during data collection. Associations between genotype and medication responsiveness were analyzed using mixed model ANOVAs. A priori hypotheses were tested using GAITRite® electronic mat spatiotemporal gait parameters including step length, step width, velocity, portion of double and single support per gait cycle, and variability of these measures ON and OFF medication. ResultsWe found that the DRD2 polymorphism, but neither COMT nor BDNF, was consistently associated with gait function and medication responsiveness in the patients. Specifically, Parkinson's disease patients with reduced striatal D2 expression (DRD2 T allele carriers) had worse gait dysfunction and showed greater dopamine responsiveness of gait function compared to patients who were homozygous for the G allele. There was no effect of any of the genetic polymorphisms on gait for controls. Conclusions and relevanceThe findings suggest that genetic subgrouping, in particular for DRD2, may be used to identify Parkinson's disease patient subgroups that are more dopamine responsive for gait function.

An association study of Taq1A ANKK1 and C957T and \u2212\xa0141C DRD2 polymorphisms in adults with internet gaming disorder: a pilot study

BackgroundThough Internet gaming disorder (IGD) is considered to share similar genetic vulnerability with substance addictions, little has been explored about the role of the genetic variants on IGD. This pilot study was designed to investigate the association of the Taq1A polymorphism of the ankyrin repeat and kinase domain containing 1 (ANKK1) gene and C957T and − 141C of the dopamine D2 receptor (DRD2) with IGD and their role on the personality and temperament traits in IGD among adult population.MethodsSixty-three subjects with IGD and 87 control subjects who regularly played Internet games were recruited. Self-administered questionnaires on self-control, dysfunctional impulsivity, and temperament and character domains were done. The Taq1A ANKK1 and the C957T and − 141C ins/del from the DRD2 genes were genotyped using the specific TaqMan PCR assay.ResultsThe distributions of allele and genotype frequencies were not significantly different between the IGD and control groups in both genders. In male, excessive gaming and use of gaming to escape from a negative feeling were associated with the del− genotype of the − 141C. Among IGD, the del+ genotype was associated with higher novelty seeking. Logistic regression showed no predictive value of these polymorphisms for IGD when using age and gender as covariates.ConclusionsThough no direct association of the Taq1A ANKK1 and C957T DRD2 variants with IGD were observed, the − 141C polymorphism may play a role in IGD via mediating symptoms or temperament traits.

Associations of IGF2 and DRD2 polymorphisms with laying traits in Muscovy duck.

Insulin-like growth factor 2 (IGF2) and dopamine receptor 2 (DRD2) play important roles in ovarian follicular development. In this study, we analyzed tissue-specific expression of the Muscovy duck IGF2 and DRD2 genes and cloned those genes transcripts. Polymorphisms in these genes were tightly linked with egg production traits and both genes were highly expressed in the ovary. Moreover, we identified five single nucleotide polymorphisms (SNPs) for IGF1 and 28 for DRD2. Mutations A-1864G and C-1704G of IGF2 were positively correlated with increased egg laying at 59 weeks (E59W) (P < 0.05). The C+7T and C+364G mutations of DRD2 were highly and significantly associated with first-egg age (FEA) and egg numbers at 300 days (E300D) (P < 0.01). Moreover, C+3301G and C+3545G of DRD2 were highly significantly associated with FEA, E59W and E300D (P < 0.01). Other mutations were positively associated with FEA or E300D or E59W (P < 0.05). These data suggest specific roles for IGF1 and DRD2 polymorphisms in egg production in Muscovy ducks.

Two dopaminergic genes, DRD4 and SLC6A3, are associated with body mass index in a Colombian sample of young adults

Obesity is becoming an epidemic in Latin American countries. Genetic analyses of endophenotypes for obesity, such as body mass index (BMI), are quite useful for research. In this study, we analysed two functional polymorphisms in the dopamine receptor 4 (DRD4) and dopamine transporter (SLC6A3) genes. A sample of 232 Colombian young subjects were recruited and evaluated for BMI. Two functional polymorphisms in the DRD4 and SLC6A3 and genes were genotyped by PCR and electrophoresis. A significant association was found between BMI and the polymorphisms in DRD4 and SLC6A3 genes. DRD4 4/4 genotype was associated with a lower mean BMI and SLC6A3 10/10 genotype was associated with a higher mean BMI. Our work provides additional novel findings about the association of dopaminergic genes with BMI in healthy young adults. In addition, our study is one the first analyses of candidate genes for BMI in Latin American samples.

Pharmacodynamic genetic polymorphisms affect adverse drug reactions of haloperidol in patients with alcohol-use disorder.

BackgroundAntipsychotic action of haloperidol is due to blockade of D2 receptors in the mesolimbic dopamine pathway, while the adverse drug reactions are associated with striatal D2 receptor blockade. Contradictory data concerning the effects of genetic polymorphisms of genes encoding these receptors and associated structures (catechol-O-methyltransferase [COMT], glycine transporter and gene encoding the density of D2 receptors on the neuronal membrane) are described.ObjectiveThe objectives of this study were to evaluate the correlation between DRD2, SLC6A3 (DAT) and COMT genetic polymorphisms and to investigate their effect on the development of adverse drug reactions in patients with alcohol-use disorder who received haloperidol.Patients and methodsThe study included 64 male patients (average age 41.38 ± 10.14 years, median age 40 years, lower quintile [LQ] 35 years, upper quintile [UQ] 49 years). Bio-Rad CFX Manager™ software and “SNP-Screen” sets of “Syntol” (Russia) were used to determine polymorphisms rs4680, rs1800497, rs1124493, rs2242592, rs2298826 and rs2863170. In every “SNP-Screen” set, two allele-specific hybridizations were used, which allowed to determine two alleles of studied polymorphism separately on two fluorescence channels.ResultsResults of this study detected a statistically significant difference in the adverse drug reaction intensity in patients receiving haloperidol with genotypes 9/10 and 10/10 of polymorphic marker SLC6A3 rs28363170. In patients receiving haloperidol in tablets, the increases in the UKU Side-Effect Rating Scale (UKU) score of 9.96 ± 2.24 (10/10) versus 13 ± 2.37 (9/10; p < 0.001) and in the Simpson-Angus Scale (SAS) score of 5.04 ± 1.59 (10/10) versus 6.41 ± 1.33 (9/10; p = 0.006) were revealed.ConclusionPolymorphism of the SCL6A3 gene can affect the safety of haloperidol, and this should be taken into account during the choice of drug and its dosage regimen.

Polymorphisms in dopaminergic system genes; association with criminal behavior and self-reported aggression in violent prison inmates from Pakistan.

Genetic factors contribute to antisocial and criminal behavior. Dopamine transporter DAT-1 (SLC6A3) and DRD2 gene for the dopamine-2 receptor are dopaminergic system genes that regulate dopamine reuptake and signaling, and may be part of the pathogenesis of psychiatric disorders including antisocial behaviors and traits. No previous studies have analyzed DAT-1 and DRD2 polymorphisms in convicted murderers, particularly from Indian subcontinent. In this study we investigated the association of 40 bp VNTR polymorphism of DAT-1 and Taq1 variant of DRD2 gene (rs1800479) with criminal behavior and self-reported aggression in 729 subjects, including 370 men in Pakistani prisons convicted of first degree murder(s) and 359 control men without any history of violence or criminal tendency. The 9R allele of DAT-1 VNTR polymorphism was more prevalent in convicted murderers compared with control samples, for either one or two risk alleles (OR = 1.49 and 3.99 respectively, P = 0.003). This potential association of DAT-1 9R allele polymorphism with murderer phenotype was confirmed assuming different genetic models of inheritance. However, no genetic association was found for DRD2 Taq1 polymorphism. In addition, a combined haplotype (9R-A2) of DAT-1 and DRD2 genes was associated with this murderer phenotype. Further, 9R allele of DAT-1 was also associated with response to verbal abuse and parental marital complications, but not with other measures pertinent to self-reported aggression. These results suggest that 9R allele, which may influence levels of intra-synaptic dopamine in the brain, may contribute to criminal tendency in this sample of violent murderers of Pakistani origin. Future studies are needed to replicate this finding in other populations of murderers and see if this finding extends to other forms of violence and lesser degrees of aggression.

Genotypes are related to neurocognitive performance but not concussion history in collegiate student-athletes

BackgroundSingle-nucleotide polymorphisms (SNPs) of neurologically relevant genes play a role in concussions from increasing susceptibility or hampering cognitive performance.ObjectiveThe purpose of this study was to investigate the effects of polymorphisms of APOE, APOE promoter, COMT and DRD2 on baseline neurocognitive function and concussion history in collegiate student-athletes.DesignCross-sectional.SettingCollegiate campus in North Carolina.Participants262 (194 males, 68 females) collegiate student-athletes.Assessment of risk factorsBuccal mucosa swabs were collected from participants. SNP genotyping was run on all samples to determine APOE, APOE promoter, COMT, and DRD2 genotypes. Participants were split into three groups based on their genotypes for each gene.Outcome measuresParticipants completed the Immediate Post-Concussion Assessment and Cognitive Testing neurocognitive assessment which generated composite scores on Verbal Memory, Visual Memory, Visuomotor Speed, and Reaction Time as well as Impulse ControlResultsNone of the genotype variables influenced number of concussions (p&gt;0.05). MANOVA analysis determined no differences for APOE promoter and DRD2 genotypes (p&gt;0.05). There were statistical differences for APOE for Visuomotor composite (APOE-e3 (m=41.2, %95 CI [40.8, 42.1]) vs e4 (m=39.1, %95 CI [37.8, 40.5], p=0.017) and Reaction Time (APOE-e4 (m=0.62, %95 CI [0.60, 0.64]) was different than both e2 (m=0.57, %95 CI [0.54, 0.60] and e3(m=0.58, %95 CI [0.56, 0.59], p&lt;0.005). There were also differences for COMT for Impulse Control (Val/Val (m=6.2 %95 CI [5.4, 7.1]) was different Val/Met (m=4.7, %95 CI [4.1, 5.2] and Met/Met (m=4.7, %95 CI [3.8, 5.6], p&lt;0.02).ConclusionsAPOE and COMT single nucleotide polymorphisms lead to significant differences in neurocognitive performance at baseline but not concussion history.Competing interestsNone.

Relationship of the functional polymorphism of dopamine D4 receptor gene with behavioral problems in school-age twins

Objective To investigate the correlation and characteristic of the functional polymorphism of the dopamine D4 receptor gene on the behavioral problems in school-age twins. Method The behavioral problems were assessed among a total of 147 twin pairs aged 6-12 years with the Achenbach Child Behavior Checklist (CBCL). The DRD4 gene polymorphism was applied for different types with polymerase chain reaction. The generalized estimating equations model was used to analyze the effect of DRD4 gene polymorphism and the interaction of DRD4 gene polymorphism with children age, gender, monozygotic/dizygotic on twins’ behavioral problems. Results (1) School-age children’s anxiety/depression, withdrawn, thought problems, attention problems, social problems, delinquent problems, aggressive behavior and total variance mainly were correlated with DRD4 gene polymorphism (P<0.05), and physical discomfort might be related with DRD4 gene polymorphism (P=0.067). Except social problems, the detection rate of behavioral problems of the twins with 4/6 genotype (Gene type carrying 5 or more repeated sequences) of DRD4 gene (6.25%-21.25%)was higher than those with other genotypes (0-14.74%). (2) Withdrawal was related to children age (χ2=4.348, P<0.05), and twins aged 6-10 might lead to withdrawal. (3) The interaction of DRD4 gene polymorphism and children age had a significant effect on withdrawal (χ2=4.348, P<0.05) and physical discomfort(χ2 =5.189, P<0.05), and the elder age (11-12 years) children had a certainly protective effect on the withdrawal and physical discomfort with 4/6 genotype in twins.The detection rates were 3.54% and 2.65% in the younger-age (6-10 years) twins, while all 0 in the elder-age (11-12 years) for the withdrawal and the physical discomfort respectively. Conclusions The DRD4 gene polymorphism may be correlated with behavioral problems in school-age twins. The interaction of DRD4 polymorphism and children age had a significantly effect on withdrawal and physical discomfort. Key words: DRD4 gene; School-age children; Twins; Behavioral problems

Pharmacogenomics and efficacy of risperidone long-term treatment in Thai autistic children and adolescence

Risperidone, atypical antipsychotics, was approved for irritability in autistic disorder. However, some patients had minimal improvement or no response to this treatment. The purpose of this study was to evaluate the association of pharmacogenomics factors and clinical outcomes in autistic children and adolescence who treated with risperidone for long periods. Sixty-seven autistic subjects diagnosed with DSM-IV criteria and treated with risperidone more than 1 year were evaluated clinical symptom by CGI, aggressive, over activity, and repetitive score. Polymorphisms of ABCB1, CYP2D6, DRD2, DRD3, and HTR2A were analyzed. Almost patients showed stable symptom on aggressive (91.04%), over activity (73.13%), repetitive (68.25%) behavior, and all clinical symptoms (82.09%). Only 4.48% of patients showed minimally worse on CGI-I score. Patients in non-stable of all symptom group had DRD2 Taq1A non-wildtype (TT and CT) frequencies higher than clinical stable group (P = 0.046), whereas other genes polymorphism showed no significant association. Interestingly, there was no patient with HTR2A-1438G &gt; A wildtype in all non-stable symptoms. However, there was no significant association due to small sample sizes. Drug levels (RIS, 9OH-RIS, and active moiety) did not show the association with any clinical outcome. Increased appetite was the common ADRs, which associated with high body weight, whereas there was not significantly associated with genetic variations and non-genetic information. In conclusion, risperidone showed efficacy to control autism, especially aggressive symptom in long-term treatment. However, dopamine 2 gene variation affect to non-stable in risperidone treated patients. This study supports pharmacogenomics testing for personalized therapeutics of risperidone in autistic disorder.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Pharmacodynamic targets of psychotic patients treated with a long-acting therapy

IntroductionGiven the poor compliance of schizofrenic patients to antipsychotic therapies, are been developed drugs in long-acting formulation that for their pharmacokinetic ensures prolonged therapeutic activities. Currently, we consider that their efficacy depends on hereditary tracts, influencing both pharmacodynamic and pharmacokinetic parameters.ObjectiveInvestigate relationships between clinical efficacy and genetic polymorphims of long-acting drugs’ pharmacodynamic targets.MethodsSeventy-eight psychotic patients, treated with atypical long-acting antipsychotics (olanzapine pamoate, paliperidone palmitate, risperidon and aripiprazole), were examined. We carried out a blood sampling to evaluate dopaminergic DRD2 and glutamatergic GRM3 genetic receptors polymorphisms. PANSS and BPRS scales were used to assess clinical condition.ResultsRegarding the GRM3 genes, the study of rs2228595 and rs6465084 polymorphisms showed a prevalence of wild type genotypic frequency of 81.2% and 56.2%, respectively. The prevalence of the patients with mutated heterozygote genotype (rs6465084 polymorphisms) resulted high (40.6%). Considering rs1989796 e rs274622 polymorphisms, the sample showed a prevalence of mutated heterozygote genotype in the 53.1% e 45.3%, respectively, with a percentage of 43.7% of patients with a mutation in homozygosis. Considering the rs146812 polymorphism, the 53.1% of patients resulted with a wild type genotype. Finally, findings showed a prevalence of 56.2% for the mutated heterozygote genotype in the DRD2 rs6277 polymorphism. The genotypic categorization analysis demonstrated a significative association between the GRM3 rs274622 polymorphism and higher BPRS scores.ConclusionsThe relationship between rs274622 polymorphism and worse clinical conditions could indicate a major resistance to long-acting antipsychotics in patients with genotypic frequency CT (mutated heterozygosis) for this polymorphism.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Risperidone-Induced Adverse Drug Reactions and Role of DRD2 (-141 C Ins/Del) and 5HTR2C (-759 C>T) Genetic Polymorphisms in Patients with Schizophrenia.

Objective:To determine the adverse drug reaction (ADR) profile of risperidone and their association with dopamine (DRD2 − 141 C Ins/Del/rs1799732) and serotonin receptor (5HTR2C −759 C>T/rs3813929) gene polymorphisms in patients with schizophrenia.Materials and Methods:The study was conducted among 289 patients who were diagnosed with schizophrenia and were on treatment with risperidone (4–8 mg/day)-based therapy for a minimum of 4 weeks. Genotyping was carried by real-time quantitative polymerase chain reaction. All the patients were observed for the occurrences of ADRs during the study. Changes in prolactin levels and body weight were analyzed for a subgroup of 102 and 97 patients, respectively.Results:Risperidone-induced extrapyramidal symptoms (EPSs) were seen in 36.7% of patients. Among them, tremors were the most common symptom 31.8%. Risperidone-induced hyperprolactinemia and weight gain were seen in 87.2% and 53.6% in subgroup patients. Adverse effects such as sedation, gastrointestinal effects, and amenorrhea were seen in 9.7% (28/289), 5.1% (15/289), and 6.1% (7/114), respectively. Occurrence of DRD2 − 141 Ins/Del and Del/Del polymorphisms were significantly associated with increased prolactin levels in response to risperidone (odds ratio [OR] = 10.45; 95% confidence interval = 1.29–84.89, P = 0.004). No such association was observed with 5HTR2C (−759 C>T) polymorphism. Weight gain and EPS were not associated with the above genetic polymorphisms.Conclusion:Hyperprolactinemia, weight gain, and EPSs (>36.7%) were common adverse effects of risperidone. DRD2 – 141C Ins/Del and Del/Del polymorphisms were significantly associated with increased prolactin levels (OR = 10.45) in response to risperidone.

No association between SLC6A2, SLC6A3, DRD2 polymorphisms and schizophrenia in the Han Chinese population

This study was intended to ascertain whether SNPs in dopaminergic and serotoninergic pathway genes SLC6A2, SLC6A3 and DRD2 are associated with schizophrenia in Han Chinese people. We conducted a case-control study by genotyping 7 SNPs of the three genes in 1034 schizophrenia patients and 1034 controls. No significant difference in the allelic or genotypic frequency was detected between cases and controls despite one positive haplotype (rs1362621-rs2242446-rs5564). Stratified analysis of gender and gene-gene interaction analysis showed no positive results. In summary, our study denies the major role of these SNPs within the three genes for schizophrenia in Han Chinese.

M55 - Pharmacogenetic Study of Antipsychotic Response To Treatment In Mexican Patients with Schizophrenia: Analysis of Response And Resistance

Background The efficacy of antipsychotics treatment in schizophrenia patients has long been established; however, clinical response to these drugs is not the same in all patients. Genetic variability has been proposed as the main reason for the different outcomes.The dopaminergic pathways, the principal mechanism of action of the antipsychotics, have been the main focus of pharmacogenetic studies in schizophrenia. Some functional single nucleotide polymorphisms (SNPs) have been associated with dopamine disposition or dopamine receptor expression, modifying the response to treatment. The aim of the study was to analyze the association between two response phenotypes (patients with response and resistant) and COMT (Val58Met), DRD2 (A-241G, C/G exon 8, C939T, Taq1A) and DRD3 (Ser9Gly) gene polymorphisms. Methods Treatment response was retrospectively/prospectively assessed. First, we gathered all reliable antipsychotics assays from medical files and through interviews with attending physicians. If these data were not conclusive, a mandatory follow-up period was added with regularly scheduled ratings (using the Positive and Negative Symptom Scale PANSS and the Functional Assessment Scale for Comprehensive Treatment of Schizophrenia FACT-Sz).Treatment response was defined on a ≥ 30% decrease on the total PANSS score (with an antipsychotic different from clozapine). The sample was classified in two main phenotypes: 95 patients on response to treatment group and 81 on resistant-to-treatment group. The genotyping of the COMT (Val58Met), DRD2 (A-241G, C/G exon 8, C939T, Taq1A), and DRD3 (Ser9Gly) gene polymorphisms was performed with allelic discrimination, using TaqMan assays. Differences in genotypes and allele frequencies between the phenotypes of patients were calculated using the X2 test. Also, we performed a logistic regression analysis to predict the likelihood of the resistance-to-treatment phenotype. Results Analysis of Val158Met/COMT showed differences between the response and the resistance groups. The GG genotype (Val/Val) was more frequent in the response group than the resistance group (47% vs. 33%, X2=6.26, 2 df , p=0.04) . We also found allele differences between groups (X2=6.65, 1 df, p Discussion The COMT/Val158Met SNP (Val/Val) was associated with the response to treatment phenotype. This finding is consistent with the antipsychotics proposed mechanism of action. The antipsychotic efficay on lowering the hyperdopaminergic state would be greater in those patients with the high-activity COMT genotype. The DRD2 SNPs analysis, the main target of several studies, did not show any significant association with the phenotypes. The COMT and DRD3 gene analyses could be associated with the resistant-to-treatment patients, so they elicit the possibility as plausible mediators of the resistance to treatment for schizophrenia.One of the limitations of this study is the size of the sample. Further analyses should be performed for the validation of these SNPs as mediators for the response or resistance to antipsychotics.

A role of interactions between N-methyl-D-aspartate and dopamine receptors in facial emotion recognition impairment in schizophrenia

To search for genetic mechanisms of facial emotion recognition (FER) impairment, one of the features of schizophrenia that affects social adaptation of patients. Based on the view implicating the interplay between dopaminergic and glutamatergic systems into the pathogenesis of schizophrenia, authors explored the interaction effects of the C366G polymorphism in the GRIN2B gene encoding NMDA receptor subunit NR2B with ANKK1/DRD2 Taq1A and 48-VNTR DRD4 polymorphisms on FER. GRIN2B -DRD2 interaction effects were studied in a sample of 237 patients and 235 healthy controls, GRIN2B - DRD4 in 268 patients and 208 controls. Both effects were significant in combined samples of patients and controls (GRIN2B X DRD2, F=4.12, p=0.043; GRIN2B X DRD4, F=6.43, p=0.012). Further analysis confirmed the interaction effect of GRIN2B and DRD2 polymorphisms on FER in patients with schizophrenia. In patients with a less efficient allele of the DRD2 in the absence of the minor allele of the GRIN2B C366G polymorphism, the results were close to normal values while patients with minor alleles of both polymorphisms showed the worst results. This finding is in line with the conceptions on a possible role of NMDA-receptor hypofunction and D2-mediated regulation of NMDA-receptor activity in FER impairments in schizophrenia.