| 1 | Eur. J. Pharmacol. 2000 Dec 410: 165-181 |
|---|---|
| PMID | 11134668 |
| Title | Pharmacogenetics and the serotonin system: initial studies and future directions. |
| Abstract | Serotonin (5-hydroxytryptamine, 5-HT) appears to play a role in the pathophysiology of a range of neuropsychiatric disorders, and serotonergic agents are of central importance in neuropharmacology. Genes encoding various components of the 5-HT system are being studied as risk factors in depression, schizophrenia, obsessive-compulsive disorder, aggression, alcoholism, and autism. Recently, pharmacogenetic research has begun to examine possible genetic influences on therapeutic response to drugs affecting the serotonin system. Genes regulating the synthesis (TPH), storage (VMAT2), membrane uptake (HTT), and metabolism (MAOA) of 5-HT, as well as a number of 5-HT receptors (HTR1A, HTR1B, HTR2A, HTR2C, and HTR5A), have been studied and this initial research is reviewed here. After a brief introduction to serotonin neurobiology and a general discussion of appropriate genetic methodology, each of the major 5-HT-related genes and their encoded proteins are reviewed in turn. For each gene, relevant polymorphisms and research on functional variants are discussed; following brief reviews of the disorder or trait association and linkage studies, pharmacogenetic studies performed to date are covered. The critical and manifold roles of the serotonin system, the great abundance of targets within the system, the wide range of serotonergic agents-available and in development-and the promising preliminary results suggest that the serotonin system offers a particularly rich area for pharmacogenetic research. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 2 | J Clin Psychiatry 2001 -1 62 Suppl 23: 45-66 |
| PMID | 11603885 |
| Title | Genetic dissection of atypical antipsychotic-induced weight gain: novel preliminary data on the pharmacogenetic puzzle. |
| Abstract | Atypical antipsychotics such as clozapine represent a significant improvement over typical antipsychotics in the treatment of schizophrenia, particularly regarding extrapyramidal symptoms. Despite their benefits, use is limited by the occurrence of adverse reactions such as sedation and weight gain. This article provides a comprehensive review and discussion of obesity-related pathways and integrates these with the known mechanisms of atypical antipsychotic action to identify candidate molecules that may be disrupted during antipsychotic treatment. Novel preliminary data are presented to genetically dissect these obesity pathways and elucidate the genetic contribution of these candidate molecules to clozapine-induced weight gain. There is considerable variability among individuals with respect to the ability of clozapine to induce weight gain. Genetic predisposition to clozapine-induced weight gain has been suggested. Therefore, genetic variation in these candidate molecules may predict patient susceptibility to clozapine-induced weight gain. This hypothesis was tested for 10 genetic polymorphisms across 9 candidate genes, including the serotonin 2C, 2A, and 1A receptor genes (HTR2C/2A/1A); the histamine H1 and H2 receptor genes (H1R/H2R); the cytochrome P450 1A2 gene (CYPIA2); the beta3 and alpha,alpha-adrenergic receptor genes (ADRB3/ADRAIA); and tumor necrosis factor alpha (TNF-alpha). Prospective weight gain data were obtained for 80 patients with schizophrenia who completed a structured clozapine trial. Trends were observed for ADRB3, ADRA1A, TNF-alpha, and HTR2C; however, replication in larger, independent samples is required. Although in its infancy, psychiatric pharmacogenetics will in the future aid clinical practice in the prediction of response and side effects, such as antipsychotic-induced weight gain, and minimize the current "trial and error" approach to prescribing. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 3 | Zhonghua Yi Xue Za Zhi 2002 Aug 82: 1097-101 |
| PMID | 12425817 |
| Title | [Association of antipsychotic agent-induced weight gain with a polymorphism of the promotor region of the 5-HT2C receptor gene]. |
| Abstract | To determine whether 5-hydroxytryptamine 2C (5-HT2C) receptor gene 759C/T polymorphism influences the weight gain following antipsychotic agents (APS) treatment in patient with schizophrenia. DNA was extracted from the peripheral blood of 117 Chinese first-episode patients of Han nationality with schizophrenia diagnosed according to CCMD-II-R criteria. PCR-RELP technique was used to analyse the frequencies of 5-HTR2C receptor gene 759C/T hemizygote (male) and genotype (female). Monotherapy with APS (chlorpromazine or rispperidone) was given for 10 weeks. The body weight was taken and body mass index (BMI) was calculated on admission and every week subsequently for each patient. The correlation of hemizygote or genotype and the BMI was analyzed. Ten weeks after treatment, there was an average increase in body weight of (3.2 +/- 3.5) kg or (5.7 +/- 6.2)% of the baseline weight with a range of -7 kg approximately 12 kg or -7.8% approximately 32%. The frequency of mutant hemizygote was 58% among the 58 male subjects; the frequency of mutant homozygote was 0%, and the frequency of mutant heterozygote was 27.0% among the 59 female subjects. The body weight gain > 7% occurred in 53% of wild type hemizygote males and 47% of wild type homozygote females; and only 18% of mutant hemizygote males and 13% of mutant heterozygote females. The proportions of 759T hemizygote males or heterozygote females in those with body weight gain > 7% and those with body weight < 7% were significantly different (chi(2) = 22.35, v1, P = 0.000 1; chi(2) = 12.36, v1, P = 0.000 1). Patients without mutant allele were five to six times more likely to develop substantial weight gain (OR = 5.11, 6.68). The 5-HT2C-receptor gene -759C/T polymorphism is associated with APS-induced weight gain. 759C-->T may be a protective factor for the development of weight gain in Chinese schizophrenic patients of Han nationality. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 4 | Zhonghua Yi Xue Za Zhi 2002 Aug 82: 1097-101 |
| PMID | 12425817 |
| Title | [Association of antipsychotic agent-induced weight gain with a polymorphism of the promotor region of the 5-HT2C receptor gene]. |
| Abstract | To determine whether 5-hydroxytryptamine 2C (5-HT2C) receptor gene 759C/T polymorphism influences the weight gain following antipsychotic agents (APS) treatment in patient with schizophrenia. DNA was extracted from the peripheral blood of 117 Chinese first-episode patients of Han nationality with schizophrenia diagnosed according to CCMD-II-R criteria. PCR-RELP technique was used to analyse the frequencies of 5-HTR2C receptor gene 759C/T hemizygote (male) and genotype (female). Monotherapy with APS (chlorpromazine or rispperidone) was given for 10 weeks. The body weight was taken and body mass index (BMI) was calculated on admission and every week subsequently for each patient. The correlation of hemizygote or genotype and the BMI was analyzed. Ten weeks after treatment, there was an average increase in body weight of (3.2 +/- 3.5) kg or (5.7 +/- 6.2)% of the baseline weight with a range of -7 kg approximately 12 kg or -7.8% approximately 32%. The frequency of mutant hemizygote was 58% among the 58 male subjects; the frequency of mutant homozygote was 0%, and the frequency of mutant heterozygote was 27.0% among the 59 female subjects. The body weight gain > 7% occurred in 53% of wild type hemizygote males and 47% of wild type homozygote females; and only 18% of mutant hemizygote males and 13% of mutant heterozygote females. The proportions of 759T hemizygote males or heterozygote females in those with body weight gain > 7% and those with body weight < 7% were significantly different (chi(2) = 22.35, v1, P = 0.000 1; chi(2) = 12.36, v1, P = 0.000 1). Patients without mutant allele were five to six times more likely to develop substantial weight gain (OR = 5.11, 6.68). The 5-HT2C-receptor gene -759C/T polymorphism is associated with APS-induced weight gain. 759C-->T may be a protective factor for the development of weight gain in Chinese schizophrenic patients of Han nationality. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 5 | Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2003 Apr 20: 98-102 |
| PMID | 12673575 |
| Title | [Pharmacogenetic assessment of antipsychotic-induced tardive dyskinesia: contribution of 5-hydroxytryptamine 2C receptor gene and of a combination of dopamine D3 variant allele (Gly) and MnSOD wild allele (Val)]. |
| Abstract | To further investigate whether the functional polymorphisms of dopamine D2 receptor (DRD2) and dopamine D3 receptor (DRD3) genes associate with the development of tardive dyskinesia (TD) in schizophrenia, and whether the interactive effects of DRD2, DRD3, 5-hydroxytryptamine 2C receptor (HTR2C) and manganese superoxide dismutase (MnSOD) genes contribute to the severity of TD. The patients with schizophrenia were assessed for TD by the Abnormal Involuntary Movement Scale (AIMS). Eventually, 42 schizophrenics with persistent TD were in the TD group, and 59 schizophrenics without TD were in the non-TD group. The polymorphism of each candidate gene was analyzed using a polymerase chain reaction-based restriction fragment length polymorphism analysis. The genotype distributions of the candidate genes in the groups were all consistent with the Hardy-Weinberg equilibrium. Allele frequencies for -759C/T and -697G/C polymorphisms in HTR2C gene showed a significant excess of -697 variant (P<0.05) in the patients with TD, compared against those in patients without TD. There were no differences in the distributions of the allelic frequencies and genotypes of Taq I. A polymorphism in DRD2 gene, of Ser/Gly polymorphism in DRD3 gene, and of Ala-9Val polymorphism in MnSOD gene between the TD group and non-TD group (P>0.05). Interestingly, as compared with the other joint allelic types, a significant excess of carrying both DRD3 variant allele (Gly) and MnSOD wild allele (Val) was found in the TD group (P<0.05). However, neither the allele and genotypes nor the clinical demographic characteristics contributed to the higher total AIMS scores in the patients of the TD group. There were no significant differences in any of the clinical demographic characteristics between the subgroups of any genotype in TD and non-TD groups. The excess of -697 variant in the promoter regulation region of the HTR2C gene may be a risk factor for the susceptibility to the occurrence of TD in Chinese male patients with schizophrenia. A combination of DRD3 variant allele (Gly) and MnSOD wild allele (Val) may increase the susceptibility to the development of TD. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 6 | Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2003 Apr 20: 98-102 |
| PMID | 12673575 |
| Title | [Pharmacogenetic assessment of antipsychotic-induced tardive dyskinesia: contribution of 5-hydroxytryptamine 2C receptor gene and of a combination of dopamine D3 variant allele (Gly) and MnSOD wild allele (Val)]. |
| Abstract | To further investigate whether the functional polymorphisms of dopamine D2 receptor (DRD2) and dopamine D3 receptor (DRD3) genes associate with the development of tardive dyskinesia (TD) in schizophrenia, and whether the interactive effects of DRD2, DRD3, 5-hydroxytryptamine 2C receptor (HTR2C) and manganese superoxide dismutase (MnSOD) genes contribute to the severity of TD. The patients with schizophrenia were assessed for TD by the Abnormal Involuntary Movement Scale (AIMS). Eventually, 42 schizophrenics with persistent TD were in the TD group, and 59 schizophrenics without TD were in the non-TD group. The polymorphism of each candidate gene was analyzed using a polymerase chain reaction-based restriction fragment length polymorphism analysis. The genotype distributions of the candidate genes in the groups were all consistent with the Hardy-Weinberg equilibrium. Allele frequencies for -759C/T and -697G/C polymorphisms in HTR2C gene showed a significant excess of -697 variant (P<0.05) in the patients with TD, compared against those in patients without TD. There were no differences in the distributions of the allelic frequencies and genotypes of Taq I. A polymorphism in DRD2 gene, of Ser/Gly polymorphism in DRD3 gene, and of Ala-9Val polymorphism in MnSOD gene between the TD group and non-TD group (P>0.05). Interestingly, as compared with the other joint allelic types, a significant excess of carrying both DRD3 variant allele (Gly) and MnSOD wild allele (Val) was found in the TD group (P<0.05). However, neither the allele and genotypes nor the clinical demographic characteristics contributed to the higher total AIMS scores in the patients of the TD group. There were no significant differences in any of the clinical demographic characteristics between the subgroups of any genotype in TD and non-TD groups. The excess of -697 variant in the promoter regulation region of the HTR2C gene may be a risk factor for the susceptibility to the occurrence of TD in Chinese male patients with schizophrenia. A combination of DRD3 variant allele (Gly) and MnSOD wild allele (Val) may increase the susceptibility to the development of TD. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 7 | Neurosci. Lett. 2003 Aug 346: 169-72 |
| PMID | 12853111 |
| Title | RNA editing of serotonin 2C receptor in human postmortem brains of major mental disorders. |
| Abstract | The importance of serotonin 2C receptor (HTR2C) in mental disorders has been implicated by studies of HTR2C-deficient mice and linkage and association studies. Recent studies have revealed that RNA editing of HTR2C is involved in mental disorders. Here we examined RNA editing efficiencies of site A and D of HTR2C in the prefrontal cortex samples of patients with bipolar disorder, schizophrenia, and major depression as well as control subjects by using primer extension combined with denaturing high performance liquid chromatography. Postmortem samples were donated by the Stanley Foundation Brain Collection. We could not find significant alterations of RNA editing efficiencies of these sites in patients. However, we found trends for increased RNA editing efficiencies of site D in depressive patients (P=0.08) and site A in suicide victims (P=0.07). These findings are in accordance with the previous findings, and suggest that altered RNA editing of HTR2C may have some significance in major depression and suicide. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 8 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2005 Apr 134B: 84-9 |
| PMID | 15717293 |
| Title | Serotonin receptor 2C (HTR2C) and schizophrenia: examination of possible medication and genetic influences on expression levels. |
| Abstract | The serotonin receptor 2C (HTR2C) gene is of interest in schizophrenia due to its involvement in regulation of dopamine activity in the prefrontal cortex. We have previously reported a decreased expression of HTR2C mRNA levels in the prefrontal cortex of schizophrenia patients. The variability in mRNA expression levels is evaluated here more closely in relation to promoter haplotypes and neuroleptic treatment received by the patients. The decrease in HTR2C mRNA was present in neuroleptic treated individuals and in patients untreated at death, indicating that the lower expression is not a short-term medication effect. Three promoter polymorphisms were used to construct haplotypes. No SNP displayed genotypic or haplotypic association with the disease. Gene expression of HTR2C was not affected by haplotype and the expression decrease in schizophrenia patients was similar in all haplotype combinations (diplotypes). We conclude that the decrease in HTR2C expression in schizophrenia may be related to the disease mechanism rather than to drug treatment. The disease related changes in HTR2C expression are not related to the promoter variants typed in our sample, but could be due to other regulatory variants or trans-acting factors. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 9 | Pharmacogenomics J. 2007 Oct 7: 318-24 |
| PMID | 17016522 |
| Title | The association between HTR2C polymorphisms and obesity in psychiatric patients using antipsychotics: a cross-sectional study. |
| Abstract | The use of antipsychotics is associated with an increased risk of obesity. This consideration makes it important to search for determinants that can predict the risk for antipsychotic-induced obesity. In this cross-sectional study, we investigated whether polymorphisms in the HTR2C gene were associated with obesity (body mass index >30 kg/m2) in patients using antipsychotics. We examined polymorphisms in the promoter region of the HTR2C gene ((HTR2C:c.1-142948(GT)n, rs3813928 (-997 G/A), rs3813929 (-759 C/T), rs518147 (-697 G/C)) and an intragenic polymorphism (rs1414334:C>G). The results of the logistic regression were expressed as adjusted odds ratios (OR). In total, we included 127 patients mainly diagnosed with schizophrenia or schizoaffective disorder (89%). The results indicate that a combined genotype carrying the variant HTR2C:c.1-142948(GT)n 13 repeat allele, the common allele rs3813929 C, the variant allele rs518147 C and the variant allele rs1414334 C is significantly related to an increased risk of obesity (OR 3.71 (95% confidence interval: 1.24-11.12)). |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 10 | Psychopharmacology (Berl.) 2007 Mar 190: 479-84 |
| PMID | 17102980 |
| Title | Serotonin and dopamine receptor gene polymorphisms and the risk of extrapyramidal side effects in perphenazine-treated schizophrenic patients. |
| Abstract | Perphenazine, a classical antipsychotic drug, has the potential to induce extrapyramidal side effects (EPS). Dopaminergic and serotonergic pathways are involved in the therapeutic and adverse effects of the drug. To evaluate the impact of polymorphisms in the dopamine D(2) and D(3) and serotonin 2A and 2C receptor genes (DRD2, DRD3, HTR2A, and HTR2C) on short-term effects of perphenazine monotherapy in schizophrenic patients. Forty-seven Estonian inpatients were evaluated before and after 4-6 weeks of treatment by Simpson-Angus rating scale, Barnes scale, and Positive and Negative Symptom Scale. Genotyping was performed for common DRD2, DRD3, HTR2A, and HTR2C gene polymorphisms, previously reported to influence receptor expression and/or function. Most of the patients (n = 37) responded to the treatment and no significant association was observed between the polymorphisms and antipsychotic response. The 102C allele of HTR2A and the -697C and 23Ser alleles of HTR2C were more frequent among patients with EPS (n = 25) compared to patients without EPS (n = 22) (p = 0.02, 0.01, and 0.02, respectively). The difference between patients with and without EPS in variant allele frequencies remained significant after multiple model analyses including age, gender, and duration of antipsychotic treatment as covariants. There was no significant association between EPS occurrence and polymorphisms in the DRD2 and DRD3 genes. An association was observed between polymorphisms in HTR2A and HTR2C genes and occurrence of acute EPS in schizophrenic patients treated with perphenazine monotherapy. Larger study populations are needed to confirm our findings. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 11 | Hum Psychopharmacol 2007 Oct 22: 463-7 |
| PMID | 17702092 |
| Title | HTR2C haplotypes and antipsychotics-induced weight gain: X-linked multimarker analysis. |
| Abstract | The 5HT2C receptor (HTR2C) has been hypothesized to represent an important modulator in feeding behavior. Evidence was based on the observation that knock-out mice for the HTR2C receptor gene develop obesity and that many antipsychotics (AP) with potent HTR2C antagonism may induce weight gain in susceptible individuals. Pharmacogenetic studies focusing either on the Cys23Ser polymorphism or on the -759C/T promoter polymorphism of the X-linked HTR2C receptor gene revealed significant findings for the -759C/T polymorphism, however, no study has performed haplotype analyses for both polymorphisms. We analyzed three functional polymorphisms (Cys23Ser, -759C/T, and (GT)12-18/(CT) 4-5) of the HTR2C in 139 schizophrenic patients mainly treated with clozapine. Weight gain was assessed over a time course of 6-14 weeks (mean 8.2 weeks). Single marker and haplotype analysis revealed no significant associations with AP-induced weight gain. The haplotype Long-C-Ser was protective against weight gain, but the number of subjects available for that analysis was small. Our pilot study did not detect any significant haplotype conferring risk for antipsychotic-induced weight gain although the statistical model took into account the X-linked heterogeneity and did correct for confounding factors (i.e., ethnicity, medications, clinical response, time of assessment). |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 12 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2007 Apr 144B: 291-9 |
| PMID | 17192951 |
| Title | HTR2C and HTR1A gene variants in German and Italian suicide attempters and completers. |
| Abstract | The serotonin 2C (HTR2C) and 1A (HTR1A) receptors have been involved in suicide-related behaviors. We studied gene variants of both receptors in suicide attempters and completers. The sample was composed of 167 German suicide attempters (affective spectrum n = 107, schizophrenia spectrum n = 35, borderline personality disorder n = 25), 92 Caucasian individuals who committed suicide, 312 German healthy subjects, 152 Italian suicide attempters (major depression n = 68 and bipolar disorder n = 84), and 131 Italian healthy volunteers. HTR2C (SNP: rs547536, rs2192372, rs6318, rs2428707, rs4272555, rs1801412) and HTR1A (SNP: rs1423691, rs878567, and rs6295) variants were analyzed in the German sample. HTR2C rs6318 and HTR1A rs6295 were analyzed in the Italian sample. Haplotype analysis in relation to suicidal behaviors did not reveal any significant association. Single markers and haplotypes were not or only marginally associated with other related features, such as violence of suicide attempt, family history for suicide attempt or State-Trait Anger Expression Inventory (STAXI) and Questionnaire for Measuring Factors of Aggression (FAF) scores. In conclusion, our study does not support the notion that HTR2C and HTR1A gene variants are major contributors to suicide-, anger-, or aggression-related behaviors in our sample. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 13 | J Clin Psychopharmacol 2007 Aug 27: 338-43 |
| PMID | 17632216 |
| Title | The association between HTR2C gene polymorphisms and the metabolic syndrome in patients with schizophrenia. |
| Abstract | The use of antipsychotics is associated with metabolic side effects, which put patients with schizophrenia or related disorders at risk for cardiovascular morbidity. The high interindividual variability in antipsychotic-induced metabolic abnormalities suggests that genetic makeup is a possible determinant. In this cross-sectional study, we investigated whether genotypes of the HTR2C receptor are associated with the metabolic syndrome in patients using antipsychotics. Patients were identified from a schizophrenia disease management program. In this program, patients' blood pressure, triglycerides, high-density lipoprotein-cholesterol, and waist circumference are measured regularly during follow-up. The primary end point of our study was the prevalence of the metabolic syndrome as classified by a modified version of the National Cholesterol Education Program's Adult Treatment Panel III. Primary determinants were polymorphisms in the HTR2C receptor gene (HTR2C:c.1-142948[GT]n, rs3813928 [-997 G/A], rs3813929 [-759 C/T], rs518147 [-697 G/C], and rs1414334 [C > G]). The included patients (n = 112) mainly (>80%) used atypical antipsychotics (clozapine, olanzapine, and risperidone). Carriership of the variant alleles of the HTR2C polymorphisms rs518147, rs1414334, and HTR2C:c.1-142948(GT)n was associated with an increased risk of the metabolic syndrome (adjusted odds ratio [OR], 2.62 [95% confidence interval {CI}, 1.00-6.85]; OR, 4.09 [95% CI, 1.41-11.89]; and OR, 3.12 [95% CI, 1.13-8.16]), respectively. Our findings suggest that HTR2C genotypes are associated with antincreased risk of metabolic syndrome in patients taking antipsychotics. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 14 | Pharmacogenomics 2008 Oct 9: 1437-43 |
| PMID | 18855532 |
| Title | Variants of dopamine and serotonin candidate genes as predictors of response to risperidone treatment in first-episode schizophrenia. |
| Abstract | Abnormalities in dopaminergic and serotonergic transmission systems are thought to be involved in the pathophysiology of schizophrenia and the mechanisms underlying the therapeutic effects of antipsychotics. We conducted a pharmacogenetic study to evaluate whether variants in dopamine-related genes (DRD1-DRD5, AKT1 and GSK3beta) and serotonin receptor genes (HTR1A, HTR1B, HTR1D, HTR2A, HTR2C, HTR6 and HTR7) can be used to predict the efficacy of risperidone treatment for schizophrenia. A total of 120 first-episode neuroleptic-naive schizophrenia patients were treated with risperidone monotherapy for 8 weeks and clinical symptoms were evaluated by the Positive and Negative Syndrome Scale. Among the 30 variants that we examined, two SNPs in DRD2 (-241A>G [rs1799978] and TaqIA [rs1800497]) and two SNPs in AKT1 (AKT1-SNP1 [rs3803300] and AKT1-SNP5 [rs2494732]) were significant predictors of treatment response to risperidone. These data suggest that the SNPs in DRD2 and AKT1 may influence the treatment response to risperidone in schizophrenia patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 15 | J Clin Psychiatry 2008 Sep 69: 1416-22 |
| PMID | 19193342 |
| Title | Multiple genetic factors in olanzapine-induced weight gain in schizophrenia patients: a cohort study. |
| Abstract | One of the clinically significant adverse effects of olanzapine treatment is weight gain, which shows substantial inter-individual differences and may be influenced by genetic variation. The aim of this investigation was identification of genetic risk factors associated with olanzapine-induced weight gain. Inpatients with DSM-IV-TR schizophrenia (N = 164) were administered olanzapine for 8 to 24 (mean +/- SD = 17.9 +/- 9.4) weeks. The clinical background, body mass index (BMI), and clinical response to olanzapine were investigated. Twenty-one loci of diverse candidate genes encoding dopamine, serotonin (5-HT), histamine, and adrenergic receptors, tumor necrosis factor-alpha, ghrelin, adiponectin, and peroxisome proliferator-activated receptor gamma-2, were analyzed. The study was conducted from June 2001 to June 2003 at 4 psychiatric hospitals in Japan. BMI increased by a mean +/- SD 4.3 +/- 10.7% after treatment with olanzapine (mean +/- SD dose = 15.5 +/- 5.8 mg/day). Olanzapine-induced weight gain correlated negatively with baseline BMI and positively with clinical global improvement and the length of olanzapine treatment (p < .0001), but it did not correlate with the daily dose of olanzapine, concomitant antipsychotics, sex, age, or smoking. Four genetic variants, the 102T allele of HTR2A, the 825T allele of GNB3, the 23Cys allele of HTR2C, and the 64Arg/Arg genotype of ADRB3, were significantly associated with olanzapine-induced weight gain. Stepwise regression analysis revealed that the baseline BMI predicted 12.5% of the weight gain, and the 2 latter genetic factors added 6.8%. The patients with double and triple genetic risk factors showed 5.1% and 8.8% BMI increases, respectively, during olanzapine treatment, whereas the patients with a single or no risk factor showed approximately a 1% BMI increase. We identified genetic variants of 5-HT(2A) and 5-HT(2C) receptors, the G-protein beta-3 subunit, and the adrenergic receptor beta-3, as genetic risk factors for olanzapine-induced weight gain, and they showed additive genetic effects on weight gain. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 16 | J Psychiatr Res 2008 Sep 42: 884-93 |
| PMID | 18086475 |
| Title | Gene polymorphism influencing treatment response in psychotic patients in a naturalistic setting. |
| Abstract | Many patients with psychotic symptoms respond poorly to treatment. Factors possibly affecting treatment response include the presence of polymorphisms in genes coding for various receptor populations, drug-metabolizing enzymes or transport proteins. To investigate whether genetic polymorphisms could be indicators of treatment response to antipsychotic drugs. The genes of interest were the dopamine D2 receptor gene (DRD2), the serotonin 2A and 2C receptor genes (HTR2A and HTR2C), the P-glycoprotein gene (ABCB1 or MDR1) and the drug-metabolizing cytochrome P450 2D6 gene (CYP2D6). Data for this naturalistic, cross-sectional study of patients requiring antipsychotic drugs and attending the Psychosis Outpatient Care clinic in Jönköping, Sweden were obtained from patient interviews, blood samples and information from patient files. Blood samples were genotyped for DRD2 Taq1 A, Ins/Del and Ser311Cys, HTR2A T102C, HTR2C Cys23Ser, ABCB1 1236C>T, 2677G>T/A, 3435C>T and genetic variants of CYP2D6. The patients (n=116) were grouped according to the CANSEPT method regarding significant social and clinical needs and significant side effects. Patients on olanzapine homozygous for ABCB1 3435T, had more significant social and clinical needs than others. Patients with one or two DRD2 Taq1 A1 alleles had a greater risk of significant side effects, particularly if they were male, Caucasian, had a schizophrenic or delusional disorder or were taking strong dopamine D2-receptor antagonistic drugs. If these results are confirmed, patients carrying the DRD2 Taq1 A1 allele would benefit from using drugs without strong dopamine D2 receptor antagonistic properties. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 17 | Eur. J. Clin. Pharmacol. 2008 May 64: 477-82 |
| PMID | 18205001 |
| Title | Further evidence for the association between 5-HT2C receptor gene polymorphisms and extrapyramidal side effects in male schizophrenic patients. |
| Abstract | Antipsychotic-induced extrapyramidal side effects (EPS) are still a major problem in the treatment of schizophrenia. Serotonin 2C receptors (5-HT(2C)) have regulatory effects on dopaminergic pathways in brain regions involved with EPS. Polymorphisms in the 5-HT(2C) gene (HTR2C) have been suggested to be associated with the risk of developing EPS. Our purpose was to evaluate the impact of polymorphisms in the HTR2C gene on the occurrence of EPS in male schizophrenic patients. Ninety-nine male Caucasian chronic schizophrenic patients on long-term treatment with classical antipsychotics were genotyped for the -997 G/A, -759 C/T, -697 G/C and Cys23Ser polymorphisms of HTR2C. EPS (dystonia, parkinsonism, tardive dyskinesia) were assessed by the Simpson-Angus Scale and the Abnormal Involuntary Movement Scale. Fifty-one patients had current or previous history of EPS, whereas 48 patients had no symptoms or history of EPS. To rule out a possible association between HTR2C polymorphisms and schizophrenia, 112 healthy male volunteers were also genotyped. Allele frequencies of -997A, -759T and -697C did not differ between the groups, whereas patients with EPS had a significantly (p = 0.025) higher frequency of the 23Ser allele (0.29) than did patients without EPS (0.15) or healthy volunteers (0.13). A similar trend was observed for a haplotype including the -997G, -759C, -697C and 23Ser alleles (p = 0.04). Results confirm previously reported associations between the HTR2C 23Ser allele and EPS occurrence and suggest the novel finding of an HTR2C haplotype association with EPS in male chronic schizophrenic patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 18 | Eur. J. Clin. Pharmacol. 2008 May 64: 477-82 |
| PMID | 18205001 |
| Title | Further evidence for the association between 5-HT2C receptor gene polymorphisms and extrapyramidal side effects in male schizophrenic patients. |
| Abstract | Antipsychotic-induced extrapyramidal side effects (EPS) are still a major problem in the treatment of schizophrenia. Serotonin 2C receptors (5-HT(2C)) have regulatory effects on dopaminergic pathways in brain regions involved with EPS. Polymorphisms in the 5-HT(2C) gene (HTR2C) have been suggested to be associated with the risk of developing EPS. Our purpose was to evaluate the impact of polymorphisms in the HTR2C gene on the occurrence of EPS in male schizophrenic patients. Ninety-nine male Caucasian chronic schizophrenic patients on long-term treatment with classical antipsychotics were genotyped for the -997 G/A, -759 C/T, -697 G/C and Cys23Ser polymorphisms of HTR2C. EPS (dystonia, parkinsonism, tardive dyskinesia) were assessed by the Simpson-Angus Scale and the Abnormal Involuntary Movement Scale. Fifty-one patients had current or previous history of EPS, whereas 48 patients had no symptoms or history of EPS. To rule out a possible association between HTR2C polymorphisms and schizophrenia, 112 healthy male volunteers were also genotyped. Allele frequencies of -997A, -759T and -697C did not differ between the groups, whereas patients with EPS had a significantly (p = 0.025) higher frequency of the 23Ser allele (0.29) than did patients without EPS (0.15) or healthy volunteers (0.13). A similar trend was observed for a haplotype including the -997G, -759C, -697C and 23Ser alleles (p = 0.04). Results confirm previously reported associations between the HTR2C 23Ser allele and EPS occurrence and suggest the novel finding of an HTR2C haplotype association with EPS in male chronic schizophrenic patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 19 | J Clin Pharm Ther 2008 Feb 33: 55-60 |
| PMID | 18211617 |
| Title | Lack of association between the -759C/T polymorphism of the 5-HT2C receptor gene and olanzapine-induced weight gain among Korean schizophrenic patients. |
| Abstract | Weight gain can be an adverse effect of antipsychotics that significantly affects long-term health and treatment compliance. Many reports have suggested that the 5-HT2C receptor gene (HTR2C) is related to appetite and eating behaviours associated with body weight change. We hypothesized that there was a relationship between the HTR2C -759C/T polymorphism and olanzapine-induced weight gain. Seventy-nine Korean schizophrenic patients were examined. Their weight was measured before starting olanzapine and after long-term treatment for at least 3 months. We controlled the use of drugs other than olanzapine except benzodiazepines and anticholinergics. Genotyping for the HTR2C -759C/T polymorphism was performed on all participants. We found that long-term treatment with olanzapine resulted in mean gains in weight and BMI of 5.2 kg and 1.93 kg/m(2), respectively. However, body weight changes from baseline to the study endpoint were not significantly associated with genotypes. The frequency of the T allele did not differ significantly between subjects with weight gains below and above a clinically significant cutoff, defined as 7% relative to baseline (chi(2) = 0.213, P = 0.445), indicating that the T allele had no protective effect against olanzapine-induced weight gain. The findings from this study do not support the presence of a relationship between the -759C/T polymorphism of the HTR2C gene and weight gain in Korean schizophrenic patients receiving olanzapine treatment. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 20 | Pharmacogenomics J. 2009 Aug 9: 234-41 |
| PMID | 19434072 |
| Title | Olanzapine-induced weight gain is associated with the -759C/T and -697G/C polymorphisms of the HTR2C gene. |
| Abstract | Weight gain, a serious problem associated with some antipsychotic drugs, notably olanzapine and clozapine, was suggested to be associated with -759C/T polymorphism of the 5-HT2C receptor gene. This study aimed to examine a potential association of two functional polymorphisms of the promoter region of this gene: -759C/T (rs3813929) and -697G/C (rs518147), with weight gain after 6 weeks of olanzapine monotherapy. It included 107 patients with schizophrenia; among them 36 are first-episode drug-naive patients. Analysis was carried out by PCR-restriction fragment length polymorphism. A protective effect of -759T and -697C alleles was found: significantly less patients with -697C (3/51) and no patient with -759T (0/28) alleles experienced body mass index increase >or=10% (P=0.0006 and 0.002, respectively). The same was true for drug-naive patients possessing any of the variant alleles. There was a significant association of haplotypes with a >or=10% body mass index increase (P=0.001). On the basis of the additional statistical analysis, the more important role of -697C allele was suggested. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 21 | J Clin Psychopharmacol 2009 Feb 29: 65-8 |
| PMID | 19142110 |
| Title | Association between HTR2C and HTR2A polymorphisms and metabolic abnormalities in patients treated with olanzapine or clozapine. |
| Abstract | Serotonin 2C and 2A receptor (5-HT2C and 5-HT2A) antagonisms are hypothesized to play a role in the metabolic adverse effects induced by olanzapine and clozapine. Associations between polymorphisms in 5-HT2C and 5-HT2A receptor coding genes, HTR2C and HTR2A, with antipsychotic-induced weight gain have been reported. The impact of HTR2C and HTR2A polymorphisms on body mass index (BMI), glucose-insulin homeostasis, and blood lipid levels was evaluated in 46 patients with schizophrenia or schizoaffective disorder and treated with olanzapine (n = 28) or clozapine (n = 18) for at least 6 months. Olanzapine-treated patients with HTR2C haplotype C (-759C, -697C, and 23Ser) had higher BMI (P = 0.029) and C peptide levels (P = 0.029) compared with patients with haplotype B (-759T, -697C, and 23Cys). The frequency of patients homozygous for the HTR2C haplotype A (-759C, -697G, and 23Cys) was significantly higher among clozapine-treated patients with obesity (BMI >/= 30 kg/m) compared with nonobese patients (P = 0.015; odds ratio, 28; 95% confidence interval, 2-380). Patients carrying the HTR2A haplotype 2 (-1438A, 102T, and 452His) had significantly higher C peptide levels compared with haplotype 3 (-1438A, 102T, and 452Tyr) carriers in the olanzapine group (P = 0.034) and in the overall study population (P = 0.019). None of the haplotypes were associated with serum levels of insulin, triglycerides, and cholesterol or with homeostasis model assessment index for insulin resistance. In conclusion, both HTR2C and HTR2A gene polymorphisms seem to be associated with the occurrence of metabolic abnormalities in patients treated with olanzapine or clozapine. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 22 | J Clin Psychopharmacol 2009 Feb 29: 16-20 |
| PMID | 19142101 |
| Title | HTR2C gene polymorphisms and the metabolic syndrome in patients with schizophrenia: a replication study. |
| Abstract | In a previous study, we found an association between 5-hydroxytryptamine (serotonin) receptor 2C (HTR2C) polymorphisms and the occurrence of the metabolic syndrome in patients using antipsychotics. In the current study, we set out to replicate our findings in another sample of patients and to explore in a pooled analysis of both samples the influence of the effect of individual antipsychotics. Data for this cross-sectional study came from 2 different samples, the original sample (n = 112) and the replication sample (n = 164). Primary end point was the prevalence of the metabolic syndrome as classified by a modified version of the National Cholesterol Education Program's Adult Treatment Panel III. Primary determinants were polymorphisms in the promoter region of the HTR2C gene [HTR2C:c.1-142948(GT)n, rs3813929 (-759 C/T), and rs518147 (-697 G/C)] and an intragenic polymorphism (rs1414334:C>G). The variants of HTR2C:c.1-142948(GT)n (odds ratio [OR], 1.69; 95% confidence interval [CI], 0.75-3.81) and rs1414334 (OR, 2.35; 95% CI, 0.96-5.77) were not significantly associated with the metabolic syndrome in the replication sample but did show significance in the pooled analysis (OR, 2.09; 95% CI, 1.12-3.91; and OR, 2.35; 95% CI, 1.19-4.62, respectively). The variant rs1414334 C allele was specifically associated with the metabolic syndrome in patients using clozapine (OR, 9.20; 95% CI, 1.95-43.45) or risperidone (OR, 5.35; 95% CI, 1.26-22.83). This study extends previous findings to a larger sample of patients and implicates specific antipsychotic drugs. The increased risk for the metabolic syndrome is particularly strong in carriers of the rs1414334 C allele using clozapine or risperidone. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 23 | Pharmacogenomics 2010 Nov 11: 1561-71 |
| PMID | 21121776 |
| Title | Polymorphisms of the HTR2C gene and antipsychotic-induced weight gain: an update and meta-analysis. |
| Abstract | This study aims to test for possible associations between the gene coding for the 5-HT2C receptor and antipsychotic-induced weight gain. Four HTR2C polymorphisms (rs498207, C-759T, G-697C and Ser23Cys) were investigated in our sample of 205 chronic schizophrenia patients. Significant over-representation of the C-G-Cys23 haplotype in patients with weight gain (OR: 1.93; 95% CI: 1.04-3.56; p = 0.0015) was found. Similarly, haplotype analyses of percentage weight change were also significant (p = 0.029) for the C-G-Cys23 haplotype associated with the highest average percent weight gain. Observations in the polymorphisms are consistent with previous studies. An updated meta-analysis of nine previous studies plus our current sample suggest that the -759C allele is associated with antipsychotic-induced weight gain. Additional studies, including the resequencing of the region surrounding the HTR2C promoter, and functional studies of the promoter polymorphisms, may elucidate the mechanism underlying this genetic association. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 24 | Psychiatry Res 2010 Feb 175: 271-3 |
| PMID | 20045196 |
| Title | Absence of weight gain association with the HTR2C -759C/T polymorphism in patients with schizophrenia treated with iloperidone. |
| Abstract | Weight gain is a common side effect of antipsychotics, contributing to poor treatment adherence, and previously linked to the -759C/T polymorphism near the serotonin receptor 2C gene. The effect of this polymorphism was analyzed in schizophrenia patients treated with iloperidone for up to 7 months. No association was detected with the modest weight changes observed in these patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 25 | Psychiatry Clin. Neurosci. 2010 Feb 64: 57-61 |
| PMID | 20015120 |
| Title | Mutation screening and assessment of the effect of genetic variations on expression and RNA editing of serotonin receptor 2C in the human brain. |
| Abstract | Serotonin receptor 2C (HTR2C) has been postulated as being involved in the etiology or pathophysiology of mental disorders such as bipolar disorder, major depression and schizophrenia. We previously revealed the altered mRNA expression and RNA editing of HTR2C in the postmortem brains of patients with mental disorders. Here we examined the relationship between genetic variations and expression level or RNA editing level of HTR2C in the human brain. We performed mutation screening of the HTR2C gene by sequencing all exons, exon-intron boundaries, and promoter region in the same cohort used for expression and RNA editing studies (n = 58). Using the detected genetic variations, we examined the relationship between genetic variations and expression or RNA editing level. We did not find novel mutations or single nucleotide polymorphisms that were specific to patients. Genotype and haplotype-based analyses revealed that genetic variations of HTR2C did not account for observed altered expression or RNA editing level of HTR2C in the brain. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 26 | Pharmacogenomics J. 2010 Feb 10: 20-9 |
| PMID | 19636338 |
| Title | Pharmacogenetics and olanzapine treatment: CYP1A2*1F and serotonergic polymorphisms influence therapeutic outcome. |
| Abstract | Psychiatric pharmacotherapy with olanzapine is commonplace. We investigated the influence of CYP1A2*1F (-163A, rs762551) and serotonergic polymorphisms on olanzapine serum concentrations and clinical outcome in a naturalistic clinical setting. Included were 124 Caucasian psychiatric inpatients treated with olanzapine for at least 4 weeks with steady-state serum concentrations available for 73 patients. The CYP1A2*1F polymorphism was reported to affect the inducibility of CYP1A2. In our study population, CYP1A2*1F/*1F genotype alone resulted in a 22% reduction of dose-/body weight-normalized olanzapine serum concentrations compared to homo- and heterozygote carriers of CYP1A2*1A (both groups without inducers). This effect was independent of the well-known effect of inducing agents (here tobacco smoke and carbamazepine which led to on average 28% lower concentrations in CYP1A2*1A carriers and 26% lower concentrations in CYP1A2*1F/*1F carriers). Consistently, patients with the CYP1A2*1F/*1F genotype taking inducers had 22% lower concentrations compared to CYP1A2*1A carriers taking inducers. The influence of genotype alone remained significant after Bonferroni's post hoc test. Higher olanzapine concentrations were significantly correlated with better improvement of paranoid and depressive symptoms in patients with schizophrenic disorders (Spearman's r=0.5, P=0.026 and P=0.006, respectively). No relationship between serum concentrations and the side effects (DOTES) score was detected. However, patients with the 5-HTR2A intron 2 (rs7997012) AA genotype suffered from more pronounced side effects compared to carriers of the GA or GG genotype (P=0.018 and P=0.002). Short-term weight gain under olanzapine therapy was significantly lower for 5-HTR2C -759 T-allele carriers (P=0.011). Our data suggest that the CYP1A2*1F/*1F genotype exhibits a significant influence on olanzapine concentrations independent of other inducing factors. Thus, CYP1A2*1F genotyping may be useful for clinical treatment decisions given the fact that olanzapine serum concentrations correlated with treatment response. Side effects and weight gain, however, seem to be more influenced by serotonergic polymorphisms. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 27 | Pharmacogenomics 2010 May 11: 685-92 |
| PMID | 20415561 |
| Title | HTR2C promoter polymorphisms are associated with risperidone efficacy in Chinese female patients. |
| Abstract | A number of studies demonstrate that the polymorphisms in the 5 region of HTR2C play a pivotal role in antipsychotic drug efficacy. Since risperidone is an antagonist of HTR2C, polymorphic variations in HTR2C may explain variability in response to risperidone treatment. We analyzed HTR2C polymorphisms for association with efficacy of risperidone monotherapy. We genotyped five SNPs distributed throughout the HTR2C gene and examined them for association using the Brief Psychiatric Rating Scale score in 130 Chinese schizophrenic patients following an 8-week period of risperidone monotherapy. All the patients were receiving the atypical antipsychotic drug treatment for the first time and had a 4-week medication-free period before research began. We found rs518147, rs1023574 and rs9698290 were significantly associated with risperidone treatment in female patients (F = 4.75, degrees of freedom = 2 and p = 0.011; F = 4.329, degrees of freedom = 2 and p = 0.016; F = 4.188, degrees of freedom = 2 and p = 0.019, respectively) and they were also found to be in one linkage disequilibrium block. Our results indicate that variants in the HTR2C promoter region are likely to affect the risperidone therapeutic effect in female mainland patients. It may be helpful to investigate a combination of other clinical factors to predict atypical antipsychotic efficacy. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 28 | Pharmacogenomics 2010 Jun 11: 773-80 |
| PMID | 20504252 |
| Title | Association of HTR2C, but not LEP or INSIG2, genes with antipsychotic-induced weight gain in a German sample. |
| Abstract | Drug-induced bodyweight gain (BWG) is a serious concern in pharmacotherapy with second-generation antipsychotics. The interindividual variability is likely to be modulated by genetic factors. In the past, pharmacogenetic studies yielded conflicting results, and none of the identified genetic alterations exerts sufficient predictive value for this severe side effect of psychopharmacotherapy. We aimed to contribute to the replication and extension of prior association findings and investigated the genes encoding serotonin 2C receptor (HTR2C), insulin-induced gene 2 (INSIG2) and leptin (LEP). We investigated the association of HTR2C, LEP and INSIG2 SNPs with antipsychotic-induced BWG in 128 German schizophrenic patients. Genotyping was performed for nine SNPs (HTR2C: rs498207, rs3813928, rs6318 and rs3813929; INSIG2: rs17587100, rs10490624, rs17047764 and rs7566605; LEP: rs7799039). Association analysis included logistic regression analysis and Pearson s chi(2) tests. We report a significant association of three HTR2C SNPs (rs498207, rs3813928 and rs3813929) and of the respective haplotype with antipsychotic-induced BWG. Regarding the X-chromosomal SNP rs498207, individuals with AA/A genotype gained more weight than those with GG/G genotype. The association observed with the SNP rs498207 was also significant after correcting for multiple testing (p = 0.0196). No association was found for INSIG2 and LEP SNPs. The results contribute to the accumulating evidence for an association of the X-chromosomal HTR2C gene with antipsychotic-induced BWG. The proposed underlying mechanisms include decreased HTR2C gene expression with reduced 5-HT-modulated activation of hypothalamic proopiomelanocortin-neurons, and inverse 5-HT(2C) agonism in the presence of D(2) receptor antagonism. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 29 | Schizophr. Res. 2011 Feb 125: 179-86 |
| PMID | 21185157 |
| Title | Association between HTR2C polymorphisms and metabolic syndrome in patients with schizophrenia treated with atypical antipsychotics. |
| Abstract | Previous research indicates that common single-nucleotide polymorphisms (SNPs) in the serotonin 5-HT2C receptor gene (HTR2C) are associated with metabolic syndrome (MetS) related to antipsychotic treatment. This study analyzes a large sample of patients with schizophrenia treated with atypical antipsychotics to determine whether variation in the HTR2C is associated with MetS. Six tag SNPs, capturing all common genetic variations in the HTR2C gene in the Han population, were genotyped in 456 Chinese schizophrenic inpatients treated with atypical antipsychotics (clozapine: 171, olanzapine: 91, and risperidone: 194). Single-marker based analysis shows that of the six HTR2C SNPs, the rs498177 SNP showed a significant association with MetS in female patients, and the C allele was associated with an increased risk of MetS (for genotype TT/TC/CC: MetS vs. non-MetS=50%/27%/23% vs. 69%/28%/3%, and for allele T/C: MetS vs. non-MetS=63%/37% vs. 83%/17%, p=0.0007). Haplotype analysis shows that the A-C type of rs521018-rs498177 in the HTR2C gene significantly decreased the risk of MetS (corrected p=0.0108) in female patients. The results of this study support the role of HTR2C genetic variants in susceptibility to MetS in patients treated with atypical antipsychotics. However, this association is gender-dependent. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 30 | Schizophr. Res. 2011 Feb 125: 179-86 |
| PMID | 21185157 |
| Title | Association between HTR2C polymorphisms and metabolic syndrome in patients with schizophrenia treated with atypical antipsychotics. |
| Abstract | Previous research indicates that common single-nucleotide polymorphisms (SNPs) in the serotonin 5-HT2C receptor gene (HTR2C) are associated with metabolic syndrome (MetS) related to antipsychotic treatment. This study analyzes a large sample of patients with schizophrenia treated with atypical antipsychotics to determine whether variation in the HTR2C is associated with MetS. Six tag SNPs, capturing all common genetic variations in the HTR2C gene in the Han population, were genotyped in 456 Chinese schizophrenic inpatients treated with atypical antipsychotics (clozapine: 171, olanzapine: 91, and risperidone: 194). Single-marker based analysis shows that of the six HTR2C SNPs, the rs498177 SNP showed a significant association with MetS in female patients, and the C allele was associated with an increased risk of MetS (for genotype TT/TC/CC: MetS vs. non-MetS=50%/27%/23% vs. 69%/28%/3%, and for allele T/C: MetS vs. non-MetS=63%/37% vs. 83%/17%, p=0.0007). Haplotype analysis shows that the A-C type of rs521018-rs498177 in the HTR2C gene significantly decreased the risk of MetS (corrected p=0.0108) in female patients. The results of this study support the role of HTR2C genetic variants in susceptibility to MetS in patients treated with atypical antipsychotics. However, this association is gender-dependent. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 31 | CNS Drugs 2011 Dec 25: 1035-59 |
| PMID | 22133326 |
| Title | Atypical antipsychotic-induced weight gain: insights into mechanisms of action. |
| Abstract | Prescriptions for second-generation antipsychotics (SGAs) have surpassed those for first-generation agents in the treatment of schizophrenia and bipolar disorder. While SGAs have the benefit of a much reduced risk of causing movement disorders, they have been associated with weight gain and metabolic effects. These adverse reactions are not uncommon, and threaten to have a significant impact on the patient's health over the long-term treatment that the patient requires. Currently, the aetiology of these effects is not known. This article reviews the data exploring the weight gain phenomenon. The literature was reviewed from searches of PubMed and the references of major articles in the field. The SGAs present a heterogeneous risk for weight gain. In addition, different individuals receiving the same drug can exhibit substantially different weight changes. This pattern suggests that a group of factors are associated with the weight gain phenomenon rather than a single mechanism. Coupled with the genetic profile that the patient brings to the treatment, the risk for SGA-induced weight gain will be different for different drugs and different individuals. Targets for exploration of the weight gain phenomenon include receptor interactions involving serotonin, histamine, dopamine, adrenergic, cannabinoid and muscarinic receptors. The association of SGA-induced weight gain and the role of orexigenic and anorexigenic peptides are reviewed. Also, a brief discussion of genetic factors associated with SGA-induced weight gain is presented, including that of the serotonin 5-HT(2C) receptor gene (HTR2C) and the cannabinoid 1 receptor gene (CNR1). The most promising data associated with SGA-induced weight gain include investigations of the histamine H(1), 5-HT(2A), 5-HT(2C), muscarinic M(3) and adrenergic receptors. In addition, work in the genetic area promises to result in a better understanding of the variation in risk associated with different individuals. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 32 | Transl Psychiatry 2011 -1 1: e64 |
| PMID | 22832356 |
| Title | Disease- and age-related changes in histone acetylation at gene promoters in psychiatric disorders. |
| Abstract | Increasing evidence suggests that epigenetic factors have critical roles in gene regulation in neuropsychiatric disorders and in aging, both of which are typically associated with a wide range of gene expression abnormalities. Here, we have used chromatin immunoprecipitation-qPCR to measure levels of acetylated histone H3 at lysines 9/14 (ac-H3K9K14), two epigenetic marks associated with transcriptionally active chromatin, at the promoter regions of eight schizophrenia-related genes in n=82 postmortem prefrontal cortical samples from normal subjects and those with schizophrenia and bipolar disorder. We find that promoter-associated ac-H3K9K14 levels are correlated with gene expression levels, as measured by real-time qPCR for several genes, including, glutamic acid decarboxylase 1 (GAD1), 5-hydroxytryptamine receptor 2C (HTR2C), translocase of outer mitochondrial membrane 70 homolog A (TOMM70A) and protein phosphatase 1E (PPM1E). Ac-H3K9K14 levels of several of the genes tested were significantly negatively associated with age in normal subjects and those with bipolar disorder, but not in subjects with schizophrenia, whereby low levels of histone acetylation were observed in early age and throughout aging. Consistent with this observation, significant hypoacetylation of H3K9K14 was detected in young subjects with schizophrenia when compared with age-matched controls. Our results demonstrate that gene expression changes associated with psychiatric disease and aging result from epigenetic mechanisms involving histone acetylation. We further find that treatment with a histone deacetylase (HDAC) inhibitor alters the expression of several candidate genes for schizophrenia in mouse brain. These findings may have therapeutic implications for the clinical use of HDAC inhibitors in psychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 33 | Psychiatry Investig 2011 Sep 8: 262-8 |
| PMID | 21994515 |
| Title | Genetic Polymorphisms in the HTR2C and Peroxisome Proliferator-Activated Receptors Are Not Associated with Metabolic Syndrome in Patients with Schizophrenia Taking Clozapine. |
| Abstract | Genetic variation in the serotonin-2C receptor encoded by the HTR2C gene is one of the genetic determinants of antipsychotic-induced weight gain. Peroxisome proliferator-activated receptors are nuclear receptors regulating the expression of genes involved in lipid and glucose metabolism. In this cross-sectional study, we investigated whether HTR2C-759C/T, HTR2C-697G/C, PPAR? V227A, and PPAR? 161C/T genotypes were associated with metabolic syndrome (MetS) in patients with schizophrenia taking clozapine. One hundred forty-six Korean patients using clozapine for more than one year were genotyped for the HTR2C-759C/T, HTR2C-697G/C, PPAR? V227A, and PPAR? 161C/T polymorphisms, and their weight, waist circumference, blood pressure, triglycerides, high-density lipoprotein-cholesterol, total cholesterol, and glucose were measured. We used the criteria for MetS proposed by the National Cholesterol Education Program-adapted Adult Treatment Panel III. The prevalence of MetS was 47.3% and was similar among men (49%) and women (42.9%). We found no significant differences between patients with and without MetS in terms of genotypes or allele frequencies. Logistic regression analyses also revealed no association between MetS and each genotype. We did not find significant associations between four polymorphisms (HTR2C-759C/T, HTR2C-697G/C, PPAR? V227A, and PPAR? 161C/T) and MetS in patients with schizophrenia taking clozapine. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 34 | Mol. Psychiatry 2012 Mar 17: 242-66 |
| PMID | 21894153 |
| Title | Pharmacogenetics of antipsychotic-induced weight gain: review and clinical implications. |
| Abstract | Second-generation antipsychotics (SGAs), such as risperidone, clozapine and olanzapine, are the most common drug treatments for schizophrenia. SGAs presented an advantage over first-generation antipsychotics (FGAs), particularly regarding avoidance of extrapyramidal symptoms. However, most SGAs, and to a lesser degree FGAs, are linked to substantial weight gain. This substantial weight gain is a leading factor in patient non-compliance and poses significant risk of diabetes, lipid abnormalities (that is, metabolic syndrome) and cardiovascular events including sudden death. The purpose of this article is to review the advances made in the field of pharmacogenetics of antipsychotic-induced weight gain (AIWG). We included all published association studies in AIWG from December 2006 to date using the Medline and ISI web of knowledge databases. There has been considerable progress reaffirming previous findings and discovery of novel genetic factors. The HTR2C and leptin genes are among the most promising, and new evidence suggests that the DRD2, TNF, SNAP-25 and MC4R genes are also prominent risk factors. Further promising findings have been reported in novel susceptibility genes, such as CNR1, MDR1, ADRA1A and INSIG2. More research is required before genetically informed, personalized medicine can be applied to antipsychotic treatment; nevertheless, inroads have been made towards assessing genetic liability and plausible clinical application. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 35 | PLoS ONE 2012 -1 7: e36561 |
| PMID | 22615781 |
| Title | Candidate gene-based association study of antipsychotic-induced movement disorders in long-stay psychiatric patients: a prospective study. |
| Abstract | Four types of antipsychotic-induced movement disorders: tardive dyskinesia (TD), parkinsonism, akathisia and tardive dystonia, subtypes of TD (orofacial and limb truncal dyskinesia), subtypes of parkinsonism (rest tremor, rigidity, and bradykinesia), as well as a principal-factor of the movement disorders and their subtypes, were examined for association with variation in 10 candidate genes (PPP1R1B, BDNF, DRD3, DRD2, HTR2A, HTR2C, COMT, MnSOD, CYP1A2, and RGS2). Naturalistic study of 168 white long-stay patients with chronic mental illness requiring long-term antipsychotic treatment, examined by the same rater at least two times over a 4-year period, with a mean follow-up time of 1.1 years, with validated scales for TD, parkinsonism, akathisia, and tardive dystonia. The authors genotyped 31 SNPs, associated with movement disorders or schizophrenia in previous studies. Genotype and allele frequency comparisons were performed with multiple regression methods for continuous movement disorders. VARIOUS SNPS REACHED NOMINAL SIGNIFICANCE: TD and orofacial dyskinesia with rs6265 and rs988748, limb truncal dyskinesia with rs6314, rest tremor with rs6275, rigidity with rs6265 and rs4680, bradykinesia with rs4795390, akathisia with rs4680, tardive dystonia with rs1799732, rs4880 and rs1152746. After controlling for multiple testing, no significant results remained. The findings suggest that selected SNPs are not associated with a susceptibility to movement disorders. However, as the sample size was small and previous studies show inconsistent results, definite conclusions cannot be made. Replication is needed in larger study samples, preferably in longitudinal studies which take the fluctuating course of movement disorders and gene-environment interactions into account. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 36 | Pharmacogenomics J. 2012 Feb 12: 62-7 |
| PMID | 20680028 |
| Title | Association between HTR2C gene polymorphisms and the metabolic syndrome in patients using antipsychotics: a replication study. |
| Abstract | In two previous studies we found an association between HTR2C polymorphisms and the prevalence of the metabolic syndrome in patients using antipsychotics. In this study, we set out to replicate our findings in a third separate sample of patients. Data for this cross-sectional study came from the ongoing Pharmacotherapy Monitoring and Outcome survey study, investigating the association between schizophrenia and metabolic or cardiovascular risk factors. Primary end point was the prevalence of the metabolic syndrome. Primary determinants were two polymorphisms in the HTR2C gene: rs3813929 (-759 C/T) and rs1414334:C>G. Carriership of the variant rs1414334 C-allele was significantly associated with an increase prevalence of the metabolic syndrome (odds ratio (OR) 3.73; 95% confidence interval (CI) 1.29-10.79, P=0.015). No association was found between the HTR2C -759 C/T polymorphism and the metabolic syndrome. This study confirms previous findings that the variant C-allele of the rs1414334 polymorphism is associated with the metabolic syndrome. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 37 | PLoS ONE 2012 -1 7: e50970 |
| PMID | 23226551 |
| Title | Antipsychotic-induced movement disorders in long-stay psychiatric patients and 45 tag SNPs in 7 candidate genes: a prospective study. |
| Abstract | Four types of antipsychotic-induced movement disorders: tardive dyskinesia (TD), parkinsonism, akathisia and tardive dystonia, subtypes of TD (orofacial and limb truncal dyskinesia), subtypes of parkinsonism (rest tremor, rigidity, and bradykinesia), as well as a principal-factor of the movement disorders and their subtypes, were examined for association with variation in 7 candidate genes (GRIN2B, GRIN2A, HSPG2, DRD3, DRD4, HTR2C, and NQO1). Naturalistic study of 168 white long-stay patients with chronic mental illness requiring long-term antipsychotic treatment, examined by the same rater at least two times over a 4-year period, with a mean follow-up time of 1.1 years, with validated scales for TD, parkinsonism, akathisia, and tardive dystonia. The authors genotyped 45 tag SNPs in 7 candidate genes, associated with movement disorders or schizophrenia in previous studies. Genotype and allele frequency comparisons were performed with multiple regression methods for continuous movement disorders. Various tag SNPs reached nominal significance; TD with rs1345423, rs7192557, rs1650420, as well as rs11644461; orofacial dyskinesia with rs7192557, rs1650420, as well as rs4911871; limb truncal dyskinesia with rs1345423, rs7192557, rs1650420, as well as rs11866328; bradykinesia with rs2192970; akathisia with rs324035; and the principal-factor with rs10772715. After controlling for multiple testing, no significant results remained. The findings suggest that selected tag SNPs are not associated with a susceptibility to movement disorders. However, as the sample size was small and previous studies show inconsistent results, definite conclusions cannot be made. Replication is needed in larger study samples, preferably in longitudinal studies which take the fluctuating course of movement disorders and gene-environment interactions into account. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 38 | J Clin Psychiatry 2012 Aug 73: 1077-86 |
| PMID | 22967772 |
| Title | Pharmacogenomic associations with weight gain in olanzapine treatment of patients without schizophrenia. |
| Abstract | Pharmacogenomic analyses of weight gain during treatment with second-generation antipsychotics have resulted in a number of associations with variants in ankyrin repeat and kinase domain containing 1 (ANKK1)/dopamine D2 receptor (DRD2) and serotonin 2C receptor (HTR2C) genes. These studies primarily assessed subjects with schizophrenia who had prior antipsychotic exposure that may have influenced the amount of weight gained from subsequent therapies. We assessed the relationships between single-nucleotide polymorphisms (SNPs) in these genes with weight gain during treatment with olanzapine in a predominantly antipsychotic-naive population. The association between 5 ANKK1, 54 DRD2, and 11 HTR2C SNPs and weight change during 8 weeks of olanzapine treatment was assessed in 4 pooled studies of 205 white patients with diagnoses other than schizophrenia who were generally likely to have had limited previous antipsychotic exposure. The A allele of DRD2 rs2440390(A/G) was associated with greater weight gain in the entire study sample (P = .0473). Three HTR2C SNPs in strong linkage disequilibrium, rs6318, rs2497538, and rs1414334, were associated with greater weight gain in women but not in men (P = .0032, .0012, and .0031, respectively). A significant association with weight gain for 2 HTR2C SNPs previously reported associated with weight gain, -759C/T (rs3813929) and -697G/C (rs518147), was not found. Associations between weight gain and HTR2C and DRD2 variants in whites newly exposed to olanzapine may present opportunities for the individualization of medication selection and development based on differences in adverse events observed across genotype groups. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 39 | PLoS ONE 2012 -1 7: e43227 |
| PMID | 22912834 |
| Title | Quantitative analysis of focused a-to-I RNA editing sites by ultra-high-throughput sequencing in psychiatric disorders. |
| Abstract | A-to-I RNA editing is a post-transcriptional modification of single nucleotides in RNA by adenosine deamination, which thereby diversifies the gene products encoded in the genome. Thousands of potential RNA editing sites have been identified by recent studies (e.g. see Li et al, Science 2009); however, only a handful of these sites have been independently confirmed. Here, we systematically and quantitatively examined 109 putative coding region A-to-I RNA editing sites in three sets of normal human brain samples by ultra-high-throughput sequencing (uHTS). Forty of 109 putative sites, including 25 previously confirmed sites, were validated as truly edited in our brain samples, suggesting an overestimation of A-to-I RNA editing in these putative sites by Li et al (2009). To evaluate RNA editing in human disease, we analyzed 29 of the confirmed sites in subjects with major depressive disorder and schizophrenia using uHTS. In striking contrast to many prior studies, we did not find significant alterations in the frequency of RNA editing at any of the editing sites in samples from these patients, including within the 5HT(2C) serotonin receptor (HTR2C). Our results indicate that uHTS is a fast, quantitative and high-throughput method to assess RNA editing in human physiology and disease and that many prior studies of RNA editing may overestimate both the extent and disease-related variability of RNA editing at the sites we examined in the human brain. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 40 | Front Genet 2013 -1 4: 58 |
| PMID | 23637704 |
| Title | Potential Impact of miR-137 and Its Targets in Schizophrenia. |
| Abstract | The significant impact of microRNAs (miRNAs) on disease pathology is becoming increasingly evident. These small non-coding RNAs have the ability to post-transcriptionally silence the expression of thousands of genes. Therefore, dysregulation of even a single miRNA could confer a large polygenic effect. schizophrenia is a genetically complex illness thought to involve multiple genes each contributing a small risk. Large genome-wide association studies identified miR-137, a miRNA shown to be involved in neuronal maturation, as one of the top risk genes. To assess the potential mechanism of impact of miR-137 in this disorder and identify its targets, we used a combination of literature searches, ingenuity pathway analysis (IPA), and freely accessible bioinformatics resources. Using TargetScan and the schizophrenia gene resource (SZGR) database, we found that in addition to CSMD1, C10orf26, CACNA1C, TCF4, and ZNF804A, five schizophrenia risk genes whose transcripts are also validated miR-137 targets, there are other schizophrenia-associated genes that may be targets of miR-137, including ERBB4, GABRA1, GRIN2A, GRM5, GSK3B, NRG2, and HTR2C. IPA analyses of all the potential targets identified several nervous system (NS) functions as the top canonical pathways including synaptic long-term potentiation, a process implicated in learning and memory mechanisms and recently shown to be altered in patients with schizophrenia. Among the subset of targets involved in NS development and function, the top scoring pathways were ephrin receptor signaling and axonal guidance, processes that are critical for proper circuitry formation and were shown to be disrupted in schizophrenia. These results suggest that miR-137 may indeed play a substantial role in the genetic etiology of schizophrenia by regulating networks involved in neural development and brain function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 41 | Int Rev Psychiatry 2013 Oct 25: 509-33 |
| PMID | 24151799 |
| Title | Clinical validity of cytochrome P450 metabolism and serotonin gene variants in psychiatric pharmacotherapy. |
| Abstract | Adverse events, response failures and medication non-compliance are common in patients receiving medications for the treatment of mental illnesses. A systematic literature review assessed whether pharmacokinetic (PK) or pharmacodynamic (PD) responses to 26 commonly prescribed antipsychotic and antidepressant medications, including efficacy or side effects, are associated with nucleotide polymorphisms in eight commonly studied genes in psychiatric pharmacotherapy: CYP2D6, CYP2C19, CYP2C9, CYP1A2, CYP3A4, HTR2C, HTR2A, and SLC6A4. Of the 294 publications included in this review, 168 (57%) showed significant associations between gene variants and PK or PD outcomes. Other studies that showed no association often had insufficient control for confounding variables, such as co-medication use, or analysis of medications not substrates of the target gene. The strongest gene-outcome associations were for the PK profiles of CYP2C19 and CYP2D6 (93% and 90%, respectively), for the PD associations between HTR2C and weight gain (57%), and for SLC6A4 and clinical response (54%), with stronger SLC6A4 response associations for specific drug classes (60-83%). The preponderance of evidence supports the validity of analyzing nucleotide polymorphisms in CYP and pharmacodynamic genes to predict the metabolism, safety, or therapeutic efficacy of psychotropic medications commonly used for the treatment of depression, schizophrenia, and bipolar illness. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 42 | Curr Opin Psychiatry 2013 Mar 26: 144-50 |
| PMID | 23370274 |
| Title | The pharmacogenetics of antipsychotic-induced adverse events. |
| Abstract | Antipsychotic drugs are effective in alleviating a variety of symptoms and are medication of first choice in schizophrenia. However, a substantial interindividual variability in side effects often requires a lengthy 'trial-and-error' approach until the right medication is found for the right patient. Genetic factors have long been hypothesized to be involved and identification of related gene variants could be used to predict and tailor drug treatment. This review highlighting the most recent genetic findings was conducted on the two most common and most well-studied side effects: antipsychotic-induced weight gain and tardive dyskinesia. Regarding weight gain, most promising and most consistent findings were obtained in the serotonergic system (HTR2C) and with hypothalamic leptin-melanocortin genes, in particular with one variant close to the melanocortin-4-receptor (MC4R) gene. With respect to tardive dyskinesia, most interesting findings were generally obtained in genes related to the dopaminergic system (dopamine receptors D2 and D3), and more recently with glutamatergic system genes. Overall, genetic studies have been successful in identifying strong findings, in particular for antipsychotic-induced weight gain and to some extent for tardive dyskinesia. Apart from the need for replication studies in larger and well-characterized samples, the next challenge will be to create predictive algorithms that can be used for clinical practice. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 43 | Int. J. Neuropsychopharmacol. 2014 Mar 17: 485-90 |
| PMID | 24229535 |
| Title | Methylenetetrahydrofolate reductase (MTHFR) 677C/T polymorphism is associated with antipsychotic-induced weight gain in first-episode schizophrenia. |
| Abstract | Genetic variants of the methylenetetrahydrofolate reductase (MTHFR) gene involved in homocysteine metabolism may be important predictors of antipsychotic drug-induced weight gain (AIWG). We tested whether two functional MTHFR polymorphisms are related to AIWG. Weight gain was studied in two cohorts of first-episode, initially drug-naive schizophrenia patients; Chinese Han (n = 182) and Spanish Caucasians (n = 72) receiving antipsychotics for 10 wk and 3 months respectively. Blood DNA was genotyped for 677C/T and 1298A/C MTHFR polymorphisms. Patients with the 677 CC genotype had a significantly greater increase in BMI compared to T-allele carriers in both Chinese (p = 0.012) and Spanish (p = 0.017) samples. The 677C/T MTHFR polymorphism showed an additive effect, but no significant interaction, with the -759C/T HTR2C polymorphism previously associated with AIWG. These results suggest that the 677C/T MTHFR polymorphism might, along with the -759C/T HTR2C polymorphism and other genetic factors, provide a useful marker for the important and limiting side effect of AIWG. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 44 | Psychiatr. Genet. 2014 Dec 24: 249-56 |
| PMID | 25304226 |
| Title | Polymorphisms of the leptin and HTR2C genes and clozapine-induced weight change and baseline BMI in patients with chronic schizophrenia. |
| Abstract | We investigated the associations of the LEP-2548A/G and HTR2C-759C/T polymorphisms with long-term clozapine-induced weight changes and baseline BMI in chronic patients with schizophrenia. A total of 113 patients receiving clozapine for at least 1 year were enrolled. Body weight was measured cross-sectionally and data on body weight just before starting clozapine were retrospectively extracted from medical records. Clozapine-induced change in BMI was correlated inversely with the baseline BMI (P<0.001, ?=-0.347). The LEP-2548A/G polymorphism was associated significantly with the change in BMI (F=4.380, P=0.015) during clozapine use; those with the AA genotype had the highest BMI gain (1.4±3.1?kg/m), followed by those with the AG (-0.2±3.3?kg/m) and GG (-1.6±3.4?kg/m) genotypes. We also found a significant association between the leptin genotype and BMI at baseline (F=3.499, P=0.034); those with the AA genotype had the lowest baseline BMI (23.4±4.3?kg/m), followed by those with the AG (24.1±4.4?kg/m) and GG (28.8±7.3?kg/m) genotypes. In the case of the HTR2C-759C/T polymorphism, we found a trend in which T alleles were more prevalent in male patients with up to 7% increase in BMI than in those with a greater than 7% increase in BMI [12/54 (22.7%) vs. 1/27 (3.7%); Fisher's exact test: P=0.051]. This study shows an inverse correlation between the baseline BMI and change in BMI during long-term clozapine use in patients with schizophrenia, and the LEP-2548A/G polymorphism was associated significantly with both these measures. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 45 | Int J Psychiatry Clin Pract 2014 Oct 18: 229-42 |
| PMID | 25152019 |
| Title | HTR2C polymorphisms, olanzapine-induced weight gain and antipsychotic-induced metabolic syndrome in schizophrenia patients: a meta-analysis. |
| Abstract | To conduct meta-analyses of all published association studies on the HTR2C -759C/T (rs3813829) polymorphism and olanzapine-induced weight gain in schizophrenia patients and on the HTR2C -759C/T, -697G/C (rs518147) and rs1414334:C> G polymorphisms and olanzapine/clozapine/risperidone-induced metabolic syndrome in schizophrenia patients. Eligible studies were identified by searching PubMed and Web of Science databases. Meta-analyses were performed using Cochrane Review Manager (RevMan, version 5.2) to calculate the pooled odds ratio (OR) and its corresponding 95% confidence interval (CI). Our meta-analyses revealed both a significant positive association between the rs1414334 C allele and olanzapine/clozapine/risperidone-induced metabolic syndrome and a marginally significant positive association between the -697C allele and the induced metabolic syndrome in schizophrenia patients, but no significant association between the -759C/T polymorphism and the induced metabolic syndrome in schizophrenia patients. Our analysis further revealed a pronounced trend toward a significant negative association between the -759T allele and high olanzapine-induced weight gain and a trend toward a significant positive association between the -759C allele and high olanzapine-induced weight gain in Caucasian schizophrenia patients. Our results support that HTR2C polymorphisms play a role in antipsychotic-induced metabolic disturbance. More association studies are needed to further elucidate association of different HTR2C polymorphisms and antipsychotic-induced metabolic disturbance. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 46 | Genetika 2015 Feb 51: 242-7 |
| PMID | 25966590 |
| Title | [Association between serotonin receptor 2C gene Cys23Ser polymorphism and social behavior in schizophrenia patients and healthy individuals]. |
| Abstract | The purpose of this work was to search for associations between the serotonin receptor 2C gene (HTR2C) and the peculiarities of social behavior and social cognition in schizophrenia. To do this, patients with schizophrenia spectrum disorders and healthy control subjects were genotyped for the Cys23Ser HTR2C marker and underwent psychological examination, including assessment of Machiavellianism, recognition of emotions in facial expression, and theory of mind. In addition, we estimated the trait anxiety level as a potential factor affecting the relationship between the gene HTR2C and social behavior. We found a significant association between the Ser allele and a reduction of estimates on the Mach-LV Machiavellianism scale in the total sample of patients (n = 182) and control subjects (n = 189), which did not reach the confidence level in either of the groups. A tendency towards a HTR2C gene influence on the trait anxiety level was also revealed. The association between HTR2C and Machiavellianism was retained if the anxiety level was taken into account. The results suggest a pleiotropic effect of HTR2Con anxiety and Machiavellianism. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 47 | Pharmacogenomics J. 2015 Aug -1: -1 |
| PMID | 26282453 |
| Title | Association studies of genomic variants with treatment response to risperidone, clozapine, quetiapine and chlorpromazine in the Chinese Han population. |
| Abstract | schizophrenia is a widespread mental disease with a prevalence of about 1% in the world population. Continuous long-term treatment is required to maintain social functioning and prevent symptom relapse of schizophrenia patients. However, there are considerable individual differences in response to the antipsychotic drugs. There is a pressing need to identify more drug-response-related markers. But most pharmacogenomics of schizophrenia have typically focused on a few candidate genes in small sample size. In this study, 995 subjects were selected for discovering the drug-response-related markers. A total of 77 single-nucleotide polymorphisms of 25 genes have been investigated for four commonly used antipsychotic drugs in China: risperidone, clozapine, quetiapine, and chlorpromazine. Significant associations with treatment response for several genes, such as CYP2D6, CYP2C19, COMT, ABCB1, DRD3 and HTR2C have been verified in our study. Also, we found several new candidate genes (TNIK, RELN, NOTCH4 and SLC6A2) and combinations (haplotype rs1544325-rs5993883-rs6269-rs4818 in COMT) that are associated with treatment response to the four drugs. Also, multivariate interactions analysis demonstrated the combination of rs6269 in COMT and rs3813929 in HTR2C may work as a predictor to improve the clinical antipsychotic response. So our study is of great significance to improve current knowledge on the pharmacogenomics of schizophrenia, thus promoting the implementation of personalized medicine in schizophrenia.The Pharmacogenomics Journal advance online publication, 18 August 2015; doi:10.1038/tpj.2015.61. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 48 | Eur. Psychiatry 2015 Feb 30: 296-302 |
| PMID | 25284335 |
| Title | Association study of the HTR2C, leptin and adiponectin genes and serum marker analyses in clozapine treated long-term patients with schizophrenia. |
| Abstract | Clozapine treatment is associated with weight gain and cardio-metabolic consequences among patients with schizophrenia. Polymorphisms of leptin, serotonin receptor HTR2C and adiponectin genes have been associated with antipsychotic-induced weight gain and metabolic comorbidity. However, the results of the studies so far are inconclusive. The aim of the present study was first to test for a possible role of serum leptin and adiponectin levels as a marker of weight gain in association with inflammatory cytokines/adipokines (IL-6, IL-1Ra, hs-CRP and adipsin), and second to study associations between SNPs LEP rs7799039 (-2548 A/G), ADIPOQ rs1501299 and HTR2C rs1414334 and weight gain and levels of leptin and adiponectin, in 190 patients with schizophrenia on clozapine treatment, with retrospectively assessed weight change and cross-sectionally measured cytokine levels. A strong association was found between serum levels of leptin and weight gain and cytokines/adipokines related to metabolic comorbidity, especially among female patients (in women leptin vs. weight gain, IL-6 and IL-1Ra, P<0.001; in men leptin vs. weight gain, P=0.026, leptin vs. IL-1Ra, P<0.001). In male patients low adiponectin level was a more specific marker of clozapine-induced weight gain (P=0.037). The results of the present study do not support a major role of SNPs LEP rs7799039, ADIPOQ rs1501299 and HTR2C rs1414334 in the regulation of weight gain or association of serum levels of leptin and adiponectin and corresponding studied SNPs in patients with schizophrenia on clozapine treatment. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 49 | Schizophr Bull 2016 May -1: -1 |
| PMID | 27217270 |
| Title | Pharmacogenetic Associations of Antipsychotic Drug-Related Weight Gain: A Systematic Review and Meta-analysis. |
| Abstract | Although weight gain is a serious but variable adverse effect of antipsychotics that has genetic underpinnings, a comprehensive meta-analysis of pharmacogenetics of antipsychotic-related weight gain is missing. In this review, random effects meta-analyses were conducted for dominant and recessive models on associations of specific single nucleotide polymorphisms (SNP) with prospectively assessed antipsychotic-related weight or body mass index (BMI) changes (primary outcome), or categorical increases in weight or BMI (?7%; secondary outcome). Published studies, identified via systematic database search (last search: December 31, 2014), plus 3 additional cohorts, including 222 antipsychotic-naïve youth, and 81 and 141 first-episode schizophrenia adults, each with patient-level data at 3 or 4 months treatment, were meta-analyzed. Altogether, 72 articles reporting on 46 non-duplicated samples (n = 6700, mean follow-up = 25.1wk) with 38 SNPs from 20 genes/genomic regions were meta-analyzed (for each meta-analysis, studies = 2-20, n = 81-2082). Eleven SNPs from 8 genes were significantly associated with weight or BMI change, and 4 SNPs from 2 genes were significantly associated with categorical weight or BMI increase. Combined, 13 SNPs from 9 genes (Adrenoceptor Alpha-2A [ADRA2A], Adrenoceptor Beta 3 [ADRB3], Brain-Derived Neurotrophic Factor [BDNF], Dopamine Receptor D2 [DRD2], Guanine Nucleotide Binding Protein [GNB3], 5-Hydroxytryptamine (Serotonin) Receptor 2C [HTR2C], Insulin-induced gene 2 [INSIG2], Melanocortin-4 Receptor [MC4R], and Synaptosomal-associated protein, 25kDa [SNAP25]) were significantly associated with antipsychotic-related weight gain (P-values < .05-.001). SNPs in ADRA2A, DRD2, HTR2C, and MC4R had the largest effect sizes (Hedges' g's = 0.30-0.80, ORs = 1.47-1.96). Less prior antipsychotic exposure (pediatric or first episode patients) and short follow-up (1-2 mo) were associated with larger effect sizes. Individual antipsychotics did not significantly moderate effect sizes. In conclusion, antipsychotic-related weight gain is polygenic and associated with specific genetic variants, especially in genes coding for antipsychotic pharmacodynamic targets. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 50 | Schizophr. Res. 2016 Jan 170: 1-17 |
| PMID | 26621002 |
| Title | A systematic review of genetic variants associated with metabolic syndrome in patients with schizophrenia. |
| Abstract | Metabolic syndrome (MetS) is a cluster of factors that increases the risk of cardiovascular disease (CVD), one of the leading causes of mortality in patients with schizophrenia. Incidence rates of MetS are significantly higher in patients with schizophrenia compared to the general population. Several factors contribute to this high comorbidity. This systematic review focuses on genetic factors and interrogates data from association studies of genes implicated in the development of MetS in patients with schizophrenia. We aimed to identify variants that potentially contribute to the high comorbidity between these disorders. PubMed, Web of Science and Scopus databases were accessed and a systematic review of published studies was conducted. Several genes showed strong evidence for an association with MetS in patients with schizophrenia, including the fat mass and obesity associated gene (FTO), leptin and leptin receptor genes (LEP, LEPR), methylenetetrahydrofolate reductase (MTHFR) gene and the serotonin receptor 2C gene (HTR2C). Genetic association studies in complex disorders are convoluted by the multifactorial nature of these disorders, further complicating investigations of comorbidity. Recommendations for future studies include assessment of larger samples, inclusion of healthy controls, longitudinal rather than cross-sectional study designs, detailed capturing of data on confounding variables for both disorders and verification of significant findings in other populations. In future, big genomic datasets may allow for the calculation of polygenic risk scores in risk prediction of MetS in patients with schizophrenia. This could ultimately facilitate early, precise, and patient-specific pharmacological and non-pharmacological interventions to minimise CVD associated morbidity and mortality. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |