| 1 | Psychiatr. Genet. 2000 Sep 10: 109-15 |
|---|---|
| PMID | 11204346 |
| Title | An association between a polymorphism of the tryptophan hydroxylase gene and aggression in schizophrenia and schizoaffective disorder. |
| Abstract | Serotonergic pathways have been implicated in impulsive and aggressive behavior. Polymorphisms in the regulatory region of the serotonin transporter (5-HTT), in intron 7 of the tryptophan hydroxylase (TPH) gene and in the MAOA gene were previously reported to be associated with mood and anxiety disorders, impulsivity and aggression. In this study, we analyzed these polymorphisms in men and women with schizophrenia or schizoaffective disorder (n = 84) who met our criteria for violence (history of two or more assaults on others) or nonviolence (no history of either assaultive or threatening behavior). In males, a modest association between TPH genotype and history of violence (chi-square test = 6.703, degrees of freedom = 2, P = 0.035) was not statistically significant after correction for multiple comparisons (corrected P = 0.21). The TPH L allele was more frequent in violent males (chi-square = 5.323, degrees of freedom = 1, P = 0.021) but this difference also failed to withstand correction (corrected P = 0.126). No significant associations were found for either the 5-HTT or MAOA polymorphisms in males or females. These results tend to support previous reports by New et al. (1996; 1998) of an association between the TPH L allele and impulsive aggression in males with personality disorder, but larger studies are needed. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 2 | Psychiatry Res 2000 Dec 97: 101-6 |
| PMID | 11166082 |
| Title | Attempted suicide and polymorphism of the serotonin transporter gene in Chinese patients with schizophrenia. |
| Abstract | Abnormalities of serotonin synthesis and metabolism may be associated with suicidality. The serotonin transporter gene (5-HTT) is one of the important genes involved in the regulation of serotonin neurotransmission. We examined the association of suicidal behavior in Chinese schizophrenic patients with a functional polymorphism of the promoter region of the 5-HTT gene (5-HTTLPR). The 5-HTTLPR genotype was determined by polymerase chain reaction for 76 suicidal and 262 non-suicidal patients with a diagnosis of schizophrenia (DSM-IV criteria). All subjects were unrelated to each other, and all were Chinese. There was no significant genotypic or allelic association of the 5-HTTLPR polymorphism with history of attempted suicide. From our results, this 5-HTTLPR polymorphism is unlikely to have a major effect on suicidal behavior in Chinese patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 3 | Psychiatry Res 2000 Dec 97: 101-6 |
| PMID | 11166082 |
| Title | Attempted suicide and polymorphism of the serotonin transporter gene in Chinese patients with schizophrenia. |
| Abstract | Abnormalities of serotonin synthesis and metabolism may be associated with suicidality. The serotonin transporter gene (5-HTT) is one of the important genes involved in the regulation of serotonin neurotransmission. We examined the association of suicidal behavior in Chinese schizophrenic patients with a functional polymorphism of the promoter region of the 5-HTT gene (5-HTTLPR). The 5-HTTLPR genotype was determined by polymerase chain reaction for 76 suicidal and 262 non-suicidal patients with a diagnosis of schizophrenia (DSM-IV criteria). All subjects were unrelated to each other, and all were Chinese. There was no significant genotypic or allelic association of the 5-HTTLPR polymorphism with history of attempted suicide. From our results, this 5-HTTLPR polymorphism is unlikely to have a major effect on suicidal behavior in Chinese patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 4 | Schizophr. Res. 2000 Sep 44: 177-81 |
| PMID | 10962219 |
| Title | Association study of a functional serotonin transporter gene polymorphism with schizophrenia, psychopathology and clozapine response. |
| Abstract | Serotonin is implicated in the pathogenesis of schizophrenia. Following serotonin release, the serotonin transporter (5-HTT) is the major determinant of serotonin inactivation. The present study tested the hypothesis that a biallelic polymorphism in the 5' regulatory region of the 5-HTT gene (5-HTTLPR) confers susceptibility to schizophrenia, association with the clinical manifestations of schizophrenia or clozapine response. 90 treatment-resistant schizophrenic patients were assessed using the Brief Psychiatric Rating Scale before and after clozapine treatment. The results demonstrated that the 5-HTTLPR variants did not play a major role in the susceptibility, clinical manifestations or clozapine response in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 5 | Schizophr. Res. 2000 Sep 44: 177-81 |
| PMID | 10962219 |
| Title | Association study of a functional serotonin transporter gene polymorphism with schizophrenia, psychopathology and clozapine response. |
| Abstract | Serotonin is implicated in the pathogenesis of schizophrenia. Following serotonin release, the serotonin transporter (5-HTT) is the major determinant of serotonin inactivation. The present study tested the hypothesis that a biallelic polymorphism in the 5' regulatory region of the 5-HTT gene (5-HTTLPR) confers susceptibility to schizophrenia, association with the clinical manifestations of schizophrenia or clozapine response. 90 treatment-resistant schizophrenic patients were assessed using the Brief Psychiatric Rating Scale before and after clozapine treatment. The results demonstrated that the 5-HTTLPR variants did not play a major role in the susceptibility, clinical manifestations or clozapine response in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 6 | 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 |
| 7 | Zh Nevrol Psikhiatr Im S S Korsakova 2001 -1 101: 40-1 |
| PMID | 11712269 |
| Title | [Serotonin transporter gene polymorphism in families with schizophrenia]. |
| Abstract | Recently association between VNTR-17 (12 copies, allel 12) and schizophrenia has been reported. Relations between allele polymorphism of serotonin transporter gene and schizophrenia in 71 Russian families with schizophrenia (n = 253) were studied. Genotyping was made by VNTR-17 and HTTLPR loci. Allele 10 was transmitted 25 times and allele 12 was transmitted 28 times. In the case of HTTLPR polymorphism allele I was transmitted 26 times and allele s was transmitted 19 times. These differences in transmission also were statistically insignificant (p = 0.69). Therefore, our findings do not support association between 5-HTT polymorphism and susceptibility to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 8 | Psychiatr. Genet. 2001 Jun 11: 89-94 |
| PMID | 11525423 |
| Title | Serotonergic pathway genes and subtypes of alcoholism: association studies. |
| Abstract | Disturbances of the serotonergic pathway have been implicated in many psychiatric disorders, including alcoholism, aggression, schizophrenia and depression. The personality dimension of harm avoidance is correlated positively with the activity of mesolimbic serotonergic neurons. The goal of this study was to determine the role of the genes in this pathway in the development of type II alcoholism. A sample of alcoholics and normal controls were screened with the variations in tryptophan hydroxylase (TPH), serotonin receptors (5-HT2A and 5-HT2C), serotonin transporter (5-HTT), and monoamine oxidase A (MAO-A) genes. The results of association studies for type II alcoholics were the most significant with 5-HTT (P = 0.011) and MAO-A (P = 0.029) genes. However, after correction for multiple comparisons, none of the results reached the significance level. These data indicate that the genes in the serotonergic pathway may be involved in the development of type II alcoholism but the gene effects are very small. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 9 | Mol. Psychiatry 2001 Mar 6: 179-85 |
| PMID | 11317220 |
| Title | Serotonin transporter polymorphisms: no association with response to antipsychotic treatment, but associations with the schizoparanoid and residual subtypes of schizophrenia. |
| Abstract | The human serotonin transporter gene (5-HTT) demonstrates two polymorphisms with possible functional impact: a 44-bp insertion/deletion polymorphism of the promoter region and a 17-bp variable number of tandem repeat polymorphism (VNTR) in intron 2 (STin2). Such genetic polymorphisms in the serotoninergic system may increase the susceptibility to schizophrenia or may serve as predictors of therapeutic response. We therefore analyzed these polymorphisms as susceptibility factors for schizophrenia by comparison of 684 schizophrenic inpatients with 587 healthy controls. We furthermore compared the therapeutic outcome of schizophrenic patients differentiated by the 5-HTT genotypes. Schizo-affective patients were more frequently homozygous for the 44-bp insertion allele (Odds ratio, OR: 1.6, 95% confidence interval, CI: 1.1--2.3, P < 0.03) than were all other schizophrenic patients and controls. The 17-bp VNTR alleles found were: STin2.7, 9, 10, and 12. Sequence analysis revealed seven different sequence motifs with an invariable arrangement. Patients with schizo-paranoid schizophrenia were more frequently homozygous for the STin2.12 allele than were controls (OR: 1.4, CI: 1.1--1.8, P < 0.007) and all other schizophrenic patients (OR: 1.6, CI: 1.2--2.3). The STin2.9 allele represented a risk factor for the residual subtype of schizophrenia (OR: 6.4, CI: 2.5--16.2, P < 0.001). On the basis of global clinical impressions, as well as measurements with the positive and negative syndrome scale we found no association of the polymorphisms with therapeutic response. In conclusion, the 44-bp polymorphism may be associated with the schizo-affective and the 17-bp VNTR with the residual and schizo-paranoid subtype of schizophrenia, findings which require further biochemical and epidemiological confirmation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 10 | Mol. Psychiatry 2001 Mar 6: 179-85 |
| PMID | 11317220 |
| Title | Serotonin transporter polymorphisms: no association with response to antipsychotic treatment, but associations with the schizoparanoid and residual subtypes of schizophrenia. |
| Abstract | The human serotonin transporter gene (5-HTT) demonstrates two polymorphisms with possible functional impact: a 44-bp insertion/deletion polymorphism of the promoter region and a 17-bp variable number of tandem repeat polymorphism (VNTR) in intron 2 (STin2). Such genetic polymorphisms in the serotoninergic system may increase the susceptibility to schizophrenia or may serve as predictors of therapeutic response. We therefore analyzed these polymorphisms as susceptibility factors for schizophrenia by comparison of 684 schizophrenic inpatients with 587 healthy controls. We furthermore compared the therapeutic outcome of schizophrenic patients differentiated by the 5-HTT genotypes. Schizo-affective patients were more frequently homozygous for the 44-bp insertion allele (Odds ratio, OR: 1.6, 95% confidence interval, CI: 1.1--2.3, P < 0.03) than were all other schizophrenic patients and controls. The 17-bp VNTR alleles found were: STin2.7, 9, 10, and 12. Sequence analysis revealed seven different sequence motifs with an invariable arrangement. Patients with schizo-paranoid schizophrenia were more frequently homozygous for the STin2.12 allele than were controls (OR: 1.4, CI: 1.1--1.8, P < 0.007) and all other schizophrenic patients (OR: 1.6, CI: 1.2--2.3). The STin2.9 allele represented a risk factor for the residual subtype of schizophrenia (OR: 6.4, CI: 2.5--16.2, P < 0.001). On the basis of global clinical impressions, as well as measurements with the positive and negative syndrome scale we found no association of the polymorphisms with therapeutic response. In conclusion, the 44-bp polymorphism may be associated with the schizo-affective and the 17-bp VNTR with the residual and schizo-paranoid subtype of schizophrenia, findings which require further biochemical and epidemiological confirmation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 11 | Nervenarzt 2002 Jul 73: 581-92; quiz 593-4 |
| PMID | 12212520 |
| Title | [Genetics of bipolar affective disorders. Current status of research for identification of susceptibility genes]. |
| Abstract | Bipolar affective disorder is a highly heritable condition, as evidenced by twin, family, and adoption studies. However, the mode of inheritance is complex and linkage findings have been difficult to replicate. Despite these limitations, consistent linkage findings have emerged for several chromosomes, notably 3p12-p14, 4p16, 10q25-q26, and 12q23-q24. Three additional areas, 13q32-q33, 18p11-q11, and 22q12-q13, have shown linkage in regions that appear to overlap with linkage findings in schizophrenia. These chromosomal regions might harbour genes that contribute to the development of bipolar affective disorder. Recent candidate gene studies include some positive results for the serotonin transporter gene (5-HTT) on 17q11-q12 and the catechol-O-methyltransferase gene (COMT) on 22q11. New methods are being developed for linkage disequilibrium mapping and candidate gene approaches. One can be optimistic that over the next few years bipolar susceptibility genes will be identified. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 12 | Psychiatr. Genet. 2002 Sep 12: 137-41 |
| PMID | 12218657 |
| Title | Major psychiatric disorders and the serotonin transporter gene (SLC6A4): family-based association studies. |
| Abstract | The serotonin transporter (5-HTT) is a suitable candidate gene to test for involvement in the pathogenesis of major psychiatric disorders. We used the method of family-based controls to test for association between disease and a variable number tandem repeat (VNTR) in intron 2 of the gene, which has received support for involvement in the pathogenesis of several psychiatric disorders. We analysed 413 proband-parent trios of Bulgarian origin: 266 had a schizophrenic proband, 103 had a bipolar proband and 44 had a schizoaffective proband. The results were analysed using the extended transmission disequilibrium test. Possible effects of different alleles on certain clinical variables were examined by correlation analysis. Three alleles were detected: STin2.9, STin2.10 and STin2.12. None of the three diagnostic samples showed preferential transmission of alleles that reached conventional levels of statistical significance. We could not confirm previous results that STin2.12 allele increases susceptibility to bipolar disorder type I. The rare STin2.9 showed a non-significant trend for preferential transmission in the sample as a whole: 18 transmitted versus 11 non-transmitted (P = 0.2). The VNTR polymorphism in the 5-HTT gene does not appear to be a major risk factor for increasing susceptibility to major psychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 13 | Neuropsychobiology 2002 -1 45: 131-3 |
| PMID | 11979062 |
| Title | Association for serotonin transporter gene variable number tandem repeat polymorphism and schizophrenic disorders. |
| Abstract | In contrast with two previous western reports, a recent study on a Chinese population found an association for allele 12 of the variable number tandem repeat (VNTR) in the second intron of the serotonin transporter (5-HTT) gene and schizophrenic disorders. We have replicated this finding for a Chinese population in Taiwan (114 schizophrenic patients and 127 controls), demonstrating a modest but significant statistical association for the 5-HTT-VNTR allele 12 and schizophrenic patients (one-sided p = 0.043). This positive finding further supports the proposition that the 5-HTT-VNTR allele 12 is a risk factor for schizophrenic disorders in Chinese populations, although the effect is weak. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 14 | World J. Biol. Psychiatry 2002 Jul 3: 133-46 |
| PMID | 12478878 |
| Title | Receptor and transporter imaging studies in schizophrenia, depression, bulimia and Tourette's disorder--implications for psychopharmacology. |
| Abstract | Considerable progress has been achieved over the past 15 years in uncovering the biological basis of major psychiatric disorders. To determine patterns of brain dysfunction and to uncover the mechanism of action of centrally active compounds we used single photon emission computerized tomography (SPECT) as well as positron emission tomography (PET) in patients diagnosed with schizophrenia, depression, bulimia and Tourette's disorder. Striatal D2 and 5-HT1A receptors were studied in schizophrenia and 5-HT transporters (5-HTT) in depression and bulimia. Patients were either drug-naïve or drug free, or we studied the influence of specifically acting compounds on receptor/transporter occupancy. We could demonstrate that atypical antipsychotics have a dose-dependent (with the exception of clozapine and quetiapine) lower striatal D2 receptor occupancy rate compared with typical neuroleptics, paralleling the more favourable extrapyramidal side effects of atypical antipsychotics. However, no association between striatal D2 receptor occupancy rates and antipsychotic efficacy has been found. The measurement of 5-HT1A receptors in drug-naïve schizophrenic patients using the in vivo PET methodology revealed an increase of cortical 5-HT1A receptor binding potential in schizophrenia. beta-CIT as a ligand for measurement of 5-HT transporter densities (5-HTT) revealed lower rates in depression compared to age- and sex-matching healthy controls, a measurement that has also been obtained for bulimia. We also documented seasonal variations in brain serotonergic function by our finding of reduced brain 5-HTT availability in winter (compared to summer) in healthy controls. Furthermore, displaceable [123I] beta-CIT binding in the area corresponding to the left striatum (representing predominantly the density of dopamine transporters) was significantly reduced in SAD patients compared to healthy controls. In depression as well as in bulimia, selective serotonin reuptake inhibitors significantly decreased the beta-CIT binding potential, however, no significant dose relationship has been obtained in depression. Genotyping depressed patients for the serotonin transporter promoter gene region (5-HTTLPR) did not provide evidence for in vivo functional regulation of 5-HTT availability by 5-HTTLPR in the thalamus-hypothalamus and mesencephalon-pons of healthy subjects. In patients suffering from Tourette's disorder (TD) we were unable to detect differences of dopamine transporter densities between psychotropic drug-naïve TD patients and controls. Furthermore, no difference could be found between currently treated (with antipsychotics) and psychotropic drug-naïve TD patients. Our data provide insight into the pathophysiology of neuropsychiatric disorders and may guide future psychopharmacological drug developments. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 15 | World J. Biol. Psychiatry 2002 Jul 3: 133-46 |
| PMID | 12478878 |
| Title | Receptor and transporter imaging studies in schizophrenia, depression, bulimia and Tourette's disorder--implications for psychopharmacology. |
| Abstract | Considerable progress has been achieved over the past 15 years in uncovering the biological basis of major psychiatric disorders. To determine patterns of brain dysfunction and to uncover the mechanism of action of centrally active compounds we used single photon emission computerized tomography (SPECT) as well as positron emission tomography (PET) in patients diagnosed with schizophrenia, depression, bulimia and Tourette's disorder. Striatal D2 and 5-HT1A receptors were studied in schizophrenia and 5-HT transporters (5-HTT) in depression and bulimia. Patients were either drug-naïve or drug free, or we studied the influence of specifically acting compounds on receptor/transporter occupancy. We could demonstrate that atypical antipsychotics have a dose-dependent (with the exception of clozapine and quetiapine) lower striatal D2 receptor occupancy rate compared with typical neuroleptics, paralleling the more favourable extrapyramidal side effects of atypical antipsychotics. However, no association between striatal D2 receptor occupancy rates and antipsychotic efficacy has been found. The measurement of 5-HT1A receptors in drug-naïve schizophrenic patients using the in vivo PET methodology revealed an increase of cortical 5-HT1A receptor binding potential in schizophrenia. beta-CIT as a ligand for measurement of 5-HT transporter densities (5-HTT) revealed lower rates in depression compared to age- and sex-matching healthy controls, a measurement that has also been obtained for bulimia. We also documented seasonal variations in brain serotonergic function by our finding of reduced brain 5-HTT availability in winter (compared to summer) in healthy controls. Furthermore, displaceable [123I] beta-CIT binding in the area corresponding to the left striatum (representing predominantly the density of dopamine transporters) was significantly reduced in SAD patients compared to healthy controls. In depression as well as in bulimia, selective serotonin reuptake inhibitors significantly decreased the beta-CIT binding potential, however, no significant dose relationship has been obtained in depression. Genotyping depressed patients for the serotonin transporter promoter gene region (5-HTTLPR) did not provide evidence for in vivo functional regulation of 5-HTT availability by 5-HTTLPR in the thalamus-hypothalamus and mesencephalon-pons of healthy subjects. In patients suffering from Tourette's disorder (TD) we were unable to detect differences of dopamine transporter densities between psychotropic drug-naïve TD patients and controls. Furthermore, no difference could be found between currently treated (with antipsychotics) and psychotropic drug-naïve TD patients. Our data provide insight into the pathophysiology of neuropsychiatric disorders and may guide future psychopharmacological drug developments. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 16 | Am. J. Med. Genet. 2002 Apr 114: 323-8 |
| PMID | 11920857 |
| Title | Correlation between serotonin uptake in human blood platelets with the 44-bp polymorphism and the 17-bp variable number of tandem repeat of the serotonin transporter. |
| Abstract | Dysfunctions of the central serotonin (5-hydroxytryptamine, 5-HT) system seem to be associated with psychiatric disorders such as schizophrenia or depression. Previous studies suggested that a 44-bp insertion/deletion polymorphism of the 5-HT transporter (5-HTT) promoter region might influence the transcriptional activity of the 5-HTT gene, and the insertion variant resulted in increased 5-HTT expression and 5-HT uptake. Moreover, a 17-bp variable number of tandem repeat (VNTR) polymorphism of the second intron may act as a transcriptional regulator with allele dependent differential enhancer-like properties. Since the 5-HTT of human platelets shares many properties with the transporter of neural tissue, platelets are widely used as a surrogate tissue source, possibly reflecting central 5-HT metabolism. Therefore, we investigated the impact of the 44-bp polymorphism and the 17-bp VNTR for 5-HT uptake in platelets of 50 male subjects. We found no significant effect of the 44-bp polymorphism and of the 17-bp VNTR on maximum rate (Vmax) of 5-HT uptake. However, individuals homozygous for the 5-HTT intron 2 allele with 12 repeats (STin2.12) of the 17-bp VNTR appeared to have lower affinity of 5-HT uptake than individuals heterozygous for the STin2.10/STin2.9 allele. This was also observed for the combined analysis of both polymorphisms. In conclusion, we found no association between the different genotypes of the 44-bp polymorphism and the 17-bp VNTR and maximum rate of 5-HT uptake into platelets. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 17 | Eur. Psychiatry 2003 Mar 18: 77-81 |
| PMID | 12711403 |
| Title | Tardive dyskinesia is not associated with the polymorphisms of 5-HT2A receptor gene, serotonin transporter gene and catechol-o-methyltransferase gene. |
| Abstract | The pathophysiology of tardive dyskinesia (TD) is not completely understood.Aim. - To assess the relationship of TD with 5-HT2A receptor gene, serotonin transporter gene (5 HTT), and catechol-o-methyltransferase (COMT) gene polymorphisms. Our study comprised 111 unrelated subjects who strictly met DSM-IV criteria for schizophrenia and 32 TD, and 79 healthy unrelated controls; all the subjects were of Turkish origin. The analyses of 5-HT2A receptor gene, 5 HTT gene, and COMT gene polymorphisms were performed using polymerase chain reaction (PCR) technique. The polymorphisms of these genes were not significantly different between the schizophrenic patients, TD and control subjects. Our findings indicated that 5-HT2A receptor gene, 5 HTT gene, and COMT gene polymorphisms were similar in schizophrenia with non-TD, schizophrenia with TD, and healthy controls. These polymorphisms, though, do not help to evaluate the susceptibility to TD. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 18 | Eur. Psychiatry 2003 Mar 18: 77-81 |
| PMID | 12711403 |
| Title | Tardive dyskinesia is not associated with the polymorphisms of 5-HT2A receptor gene, serotonin transporter gene and catechol-o-methyltransferase gene. |
| Abstract | The pathophysiology of tardive dyskinesia (TD) is not completely understood.Aim. - To assess the relationship of TD with 5-HT2A receptor gene, serotonin transporter gene (5 HTT), and catechol-o-methyltransferase (COMT) gene polymorphisms. Our study comprised 111 unrelated subjects who strictly met DSM-IV criteria for schizophrenia and 32 TD, and 79 healthy unrelated controls; all the subjects were of Turkish origin. The analyses of 5-HT2A receptor gene, 5 HTT gene, and COMT gene polymorphisms were performed using polymerase chain reaction (PCR) technique. The polymorphisms of these genes were not significantly different between the schizophrenic patients, TD and control subjects. Our findings indicated that 5-HT2A receptor gene, 5 HTT gene, and COMT gene polymorphisms were similar in schizophrenia with non-TD, schizophrenia with TD, and healthy controls. These polymorphisms, though, do not help to evaluate the susceptibility to TD. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 19 | World J. Biol. Psychiatry 2003 Jan 4: 25-9 |
| PMID | 12582974 |
| Title | Serotonin transporter gene polymorphism and schizoid personality traits in the patients with psychosis and psychiatrically well subjects. |
| Abstract | serotonin transporter (5-HTT) gene allelic variants were shown to be associated with Neuroticism and Harm Avoidance but the results were not replicated in other studies. The current investigation was undertaken in a further attempt to study the relationship between 5-HTT polymorphism and personality traits. to evaluate a spectrum of personality traits, MMPI was administered to a sample including patients with affective disorders (n=114), patients with schizophrenia spectrum illnesses (n=110) and psychiatrically well controls (n=124). All groups were genotyped for VNTR-17 and functional insertion-deletion (5-HTTLPR) polymorphisms. an association was found between 5-HTTLPR polymorphism and scores on three MMPI scales: Psychopathic deviance, Paranoia and schizophrenia in patients with affective disorders and S chizophrenia in normal subjects. Both affected and control individuals with 'ss' genotype exhibited lower scores on these scales. we demonstrated that functional deletion/insertion allelic variation associated with decreased expression of serotonin transporter ('s' allele or 'ss' genotype) may restrict expression of schizoid traits in normal subjects and patients with affective disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 20 | Biol. Psychiatry 2004 Jun 55: 1090-4 |
| PMID | 15158428 |
| Title | Serotonin transporter promoter and intron 2 polymorphisms: relationship between allelic variants and gene expression. |
| Abstract | Two polymorphic regions of serotonin transporter (5-HTT) gene: a 44 base pair (bp) insertion/deletion in the promoter region (5-HTTLPR) and a 17 bp variable number of tandem repeats in second intron (VNTR-2), seem to modulate the gene's transcription in allele-dependent manner. We have earlier demonstrated association with 5-HTT gene in families multiply affected by schizophrenia. Here, we investigated separate and combined effects of VNTR-2 and 5-HTTLPR on the rate of peripheral 5-HTT transcription in a sample of offspring from those families. Relative 5-HTT mRNA levels were determined in 53 permanent lymphoblast cell lines by semiquantitative real-time polymerase chain reaction using beta-actin as reference. Since the low-expressing alleles (short [S], 10) appeared to act dominantly, genotypes were grouped as "high-expressing" (long [L]/L, 12/12) versus "low-expressing" (S, 10). At both loci, nonsignificant differences in 5-HTT mRNA levels ( approximately 30%) were observed between "high"- and "low-expressing" genotypes. In order to search for the potential combined effect of 5-HTTLPR and VNTR-2, levels of 5-HTT mRNA were compared among three groups of samples having "low-expressing" genotype at none, one, or both loci. Increase in number of "low-expressing" genotypes significantly reduced relative 5-HTT gene expression (p <.02). Our results indicate weak individual influence, but possible combined effect, of 5-HTTLPR and VNTR-2 polymorphisms on 5-HTT gene expression. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 21 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2004 Apr 126B: 1-7 |
| PMID | 15048639 |
| Title | Serotonin transporter polymorphism and depressive-related symptoms in schizophrenia. |
| Abstract | A role for the serotonin transporter (5-HTT) gene polymorphism in mental illnesses and anxiety-traits has been implicated. The contribution of genetic factors in personality traits and the manifestation of specific symptoms in psychiatric illnesses have yet to be elucidated. Anxious-depressive symptoms are a significant component in a pattern of schizophrenic symptoms. This study focused on the relation between 5-HTT polymorphism and clinical presentations of schizophrenia, specifically those related to the affective spectrum. Using clinical and psychological analyses, we tested the genetic association between the 5-HTTLPR polymorphism (5-HTT gene-linked polymorphic region) and anxiety- and depressive-related symptoms emerged in schizophrenia. In 260 patients with an ICD-10 diagnosis of schizophrenia (broad definition), we studied the 5-HTTLPR genotype (insertion-deletion polymorphism), the Positive and Negative Syndrome Scale (PANSS), and self-rated inventories (EPI, MMPI, STAI) scores. Patients with the "ss" genotype (deletion variant) scored significantly higher on "Guilt feelings" and "Depression" items, as compared with those of the "ll" genotype (insertion variant) (P = 0.016, 0.039, respectively). The frequency of the "ss" genotype was reduced in patients with no depression or guilt feelings, or in those patients exhibiting questionable symptoms. In contrast, the "ss" genotype carriers prevailed among the patients with mild, moderate, or severe ratings of the symptoms. The scores on all anxiety- and depression-related traits, self-rated by the patients, did not significantly differ by genotype. Our finding may contribute to understanding of molecular genetic features underlying an appearance of psychopathological symptoms emerged in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 22 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2004 Apr 126B: 1-7 |
| PMID | 15048639 |
| Title | Serotonin transporter polymorphism and depressive-related symptoms in schizophrenia. |
| Abstract | A role for the serotonin transporter (5-HTT) gene polymorphism in mental illnesses and anxiety-traits has been implicated. The contribution of genetic factors in personality traits and the manifestation of specific symptoms in psychiatric illnesses have yet to be elucidated. Anxious-depressive symptoms are a significant component in a pattern of schizophrenic symptoms. This study focused on the relation between 5-HTT polymorphism and clinical presentations of schizophrenia, specifically those related to the affective spectrum. Using clinical and psychological analyses, we tested the genetic association between the 5-HTTLPR polymorphism (5-HTT gene-linked polymorphic region) and anxiety- and depressive-related symptoms emerged in schizophrenia. In 260 patients with an ICD-10 diagnosis of schizophrenia (broad definition), we studied the 5-HTTLPR genotype (insertion-deletion polymorphism), the Positive and Negative Syndrome Scale (PANSS), and self-rated inventories (EPI, MMPI, STAI) scores. Patients with the "ss" genotype (deletion variant) scored significantly higher on "Guilt feelings" and "Depression" items, as compared with those of the "ll" genotype (insertion variant) (P = 0.016, 0.039, respectively). The frequency of the "ss" genotype was reduced in patients with no depression or guilt feelings, or in those patients exhibiting questionable symptoms. In contrast, the "ss" genotype carriers prevailed among the patients with mild, moderate, or severe ratings of the symptoms. The scores on all anxiety- and depression-related traits, self-rated by the patients, did not significantly differ by genotype. Our finding may contribute to understanding of molecular genetic features underlying an appearance of psychopathological symptoms emerged in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 23 | Int. J. Neuropsychopharmacol. 2005 Mar 8: 87-92 |
| PMID | 15638952 |
| Title | Family-based association study of the 5-HT transporter gene and schizophrenia. |
| Abstract | The gene coding for the 5-HT transporter (5-HTT) is considered as a candidate gene for schizophrenia, because this transporter plays a key role in serotonin neurotransmission. Previous genetic studies focusing on this gene yielded conflicting results, presumably because of stratification biases linked to the case-control association study approach, and the potential genetic and phenotypic heterogeneity of schizophrenia. We investigated the 5-HTTLPR and 17-bp VNTR (variable number of tandem repeats) polymorphisms of this gene in 103 trios using the transmission disequilibrium test. No preferential transmission of either allele of the 17-bp VNTR was observed, but an excess of transmission of the L allele of the 5-HTTLPR polymorphism was detected (p = 0.03). As the haplotype analyses did not improve the strength of the association, our data provide convergent evidence for a significant role of the 5-HTTLPR promoter polymorphism of the 5-HTT gene in the vulnerability to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 24 | Eur Neuropsychopharmacol 2006 May 16: 268-71 |
| PMID | 16274962 |
| Title | Association study between the novel functional polymorphism of the serotonin transporter gene and suicidal behaviour in schizophrenia. |
| Abstract | A serotonin transporter gene linked polymorphic region (5-HTTLPR) has been investigated in several genetic association studies, including studies of schizophrenia and suicidality. The current study was designed to examine whether the new long (A/G) variant polymorphism of the 5-HTT gene may be associated with suicide attempts of 290 Caucasian schizophrenic patients. Among these patients, 92 had a history of suicide attempt. No association with history of suicide attempt was found in the multiallelic 5-HTTLPR (p = 0.305), however we found significant association with the intron 2 VNTR polymorphism (p = 0.018). When we performed a haplotype analysis, we found association between suicide attempt and haplotype distribution (p = 0.031). These findings suggest that the intron 2 VNTR polymorphism in serotonin transporter gene may influence suicidal behaviour in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 25 | Eur Neuropsychopharmacol 2006 May 16: 268-71 |
| PMID | 16274962 |
| Title | Association study between the novel functional polymorphism of the serotonin transporter gene and suicidal behaviour in schizophrenia. |
| Abstract | A serotonin transporter gene linked polymorphic region (5-HTTLPR) has been investigated in several genetic association studies, including studies of schizophrenia and suicidality. The current study was designed to examine whether the new long (A/G) variant polymorphism of the 5-HTT gene may be associated with suicide attempts of 290 Caucasian schizophrenic patients. Among these patients, 92 had a history of suicide attempt. No association with history of suicide attempt was found in the multiallelic 5-HTTLPR (p = 0.305), however we found significant association with the intron 2 VNTR polymorphism (p = 0.018). When we performed a haplotype analysis, we found association between suicide attempt and haplotype distribution (p = 0.031). These findings suggest that the intron 2 VNTR polymorphism in serotonin transporter gene may influence suicidal behaviour in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 26 | Eur Neuropsychopharmacol 2006 Dec 16: 572-9 |
| PMID | 16713194 |
| Title | Serotonin transporter characteristics in lymphocytes and platelets of male aggressive schizophrenia patients compared to non-aggressive schizophrenia patients. |
| Abstract | A large body of literature indicates that disturbances of central serotonin (5-HT) function play an important role in aggressive behavior. Results from open-label and placebo-controlled trials as well as the reported inverse relationship between 5-HT function and aggression in human subjects, suggest that reduced 5-HT activity is associated with aggressive behavior. The activity of the 5-HT transporter (5-HTT), as determined by [(3)H]5-HT uptake to blood lymphocytes, was measured in 20 currently aggressive and 20 non-aggressive male schizophrenia patients. In addition, the pharmacodynamic characteristics of platelet 5-HTT were assessed by [(3)H]citalopram binding. There were no significant differences in the density (B(max)) of platelet [(3)H]citalopram binding sites between the two groups. Similarly, the dissociation constant (K(d)) values were indistinguishable. The maximum uptake velocity (V(max)) of [(3)H]5-HT to fresh lymphocytes and the K(m) values of the 5-HT to the transporter were significantly higher in currently aggressive compared to the non-aggressive schizophrenia patients. The association of high V(max) values with current aggressive behavior provides further support to the involvement of the 5-HTT in aggressive behavior as well as to the efficacy of 5-HTT blockers in the control of aggression. The role of the various components of the serotonergic system in the pathophysiology and treatment of aggressive behavior in schizophrenia needs to be further evaluated. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 27 | Neuroscience 2006 -1 139: 1397-403 |
| PMID | 16600514 |
| Title | Fatty acids differentially affect serotonin receptor and transporter binding in the rat brain. |
| Abstract | The aim of this study was to examine the influence of different fat diets on serotonin receptor and transporter binding. Male Sprague-Dawley rats were fed a diet of either high saturated fat, omega-6 polyunsaturated fatty acid, omega-3 polyunsaturated fatty acid or low fat (control) for eight weeks. Using Beta-Imager quantification techniques, [(3)H]ketanserin, [(3)H]mesulergine and [(3)H]paroxetine binding to serotonin (5-HT)(2A), 5-HT(2C) receptors and 5-HT transporters (5-HTT) was measured throughout the brain in all four groups. All three high fatty acid diets influenced serotonin receptor binding, however the most pronounced effects were that compared with the low fat control group, i) 5-HT(2A) receptor binding was increased in the caudate putamen, but reduced in the mammillary nucleus in high saturated fat and high omega-6 polyunsaturated fatty acid diet groups; ii) 5-HT(2C) receptor binding was reduced in the mamillary nucleus of saturated fat group and reduced in prefrontal cortex of the omega-6 polyunsaturated fatty acid and omega-3 polyunsaturated fatty acid groups; and iii) 5-HTT binding was reduced in the hippocampus in the omega-6 polyunsaturated fatty acid group. Overall, the omega-6 polyunsaturated fatty acid diet exerted the most influence on serotonin receptor and transporter binding. These results may be of importance in relation to neuropsychiatric diseases such as schizophrenia, where associations between altered fatty acid levels and the serotonergic system have been made. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 28 | Eur Neuropsychopharmacol 2006 Aug 16: 429-36 |
| PMID | 16431091 |
| Title | Characterization of the serotonin transporter in lymphocytes and platelets of schizophrenia patients treated with atypical or typical antipsychotics compared to healthy individuals. |
| Abstract | A rapidly growing body of data suggests that abnormalities in serotonergic function might be involved in the pathophysiology of schizophrenia and that serotonergic mechanisms play a role in the therapeutic effects of antipsychotics. The activity of the serotonin transporter (5-HTT), as determined by [(3)H]5-HT uptake to blood lymphocytes, was measured in 38 medicated schizophrenia patients (15 of them treated with typical antipsychotics and 23 treated with atypical antipsychotics) and 15 healthy control subjects. In addition, the pharmacodynamic characteristics of platelet 5-HTT were assessed by [(3)H]citalopram binding. There were no significant differences in the density (B(max)) of platelet [(3)H]citalopram binding sites between the three groups. Similarly, the dissociation constant (K(d)) values were indistinguishable. There were no significant differences in the maximal uptake velocity (V(max)) of [(3)H]5-HT to fresh lymphocytes between the three groups. The affinity (K(m)) values of 5-HT to the 5-HTT were significantly higher in schizophrenia patients treated with typical antipsychotics compared with control subjects. The K(m) values in schizophrenia patients treated with atypical antipsychotics were significantly lower compared with those observed in the group of schizophrenia patients treated with typical antipsychotics; however, they were comparable to values in the control group. The high values of K(m) associated with typical antipsychotic treatment may be relevant to the high risk of developing extrapyramidal side effects (EPS). The role of the various components of the serotonergic system in the etiopathology of schizophrenia and the mechanisms by which antipsychotics achieve their therapeutic effects need to be further evaluated. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 29 | Neurosci. Lett. 2007 Feb 414: 1-4 |
| PMID | 17287080 |
| Title | Response of risperidone treatment may be associated with polymorphisms of HTT gene in Chinese schizophrenia patients. |
| Abstract | Serotonin transporter (5-HTT) is a key component of the serotonergic neurotransmitter system. Few studies have focused on polymorphisms of the serotonin transporter and antipsychotic response and, in particular, there have so far been no published studies on the association between the serotonin transporter and response to risperidone. This study examined the relationship between two polymorphisms of the serotonin transporter and the efficacy of risperidone treatment in 129 patients with schizophrenia. Our results revealed that patients with l allele of HTTRLP showed a greater improvement than those without l allele on the overall brief psychiatric rating scale (BPRS) (P=0.025). But no such relationship was found for the HTTVNTR. In haplotype analysis, the frequency of L-12 haplotype showed a significant difference between the responder group and the non-responder group (P=0.005). Our study has, for the first time, produced evidence that the potential for therapy in patients with schizophrenia is related to the HTTRLP polymorphism in the HTT gene and haplotype L-12 may help to predict risperidone treatment efficiency. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 30 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2007 Mar 31: 416-20 |
| PMID | 17174018 |
| Title | Association between obsessive-compulsive disorder and a variable number of tandem repeats polymorphism in intron 2 of the serotonin transporter gene. |
| Abstract | Pharmacological studies indicate a dysregulation of the serotonergic system in obsessive-compulsive disorder (OCD). A variable number tandem repeats (VNTR) polymorphism with three alleles (Stin2.9, Stin2.10, Stin2.12) has been described in intron 2 of the serotonin transporter (5-HTT) gene. This polymorphism has been associated with unipolar depression, bipolar disorder, schizophrenia, and anxiety disorders including OCD. The association between OCD and the polymorphism is examined in 97 OCD patients, 578 psychiatric controls and 406 healthy controls, all Spanish Caucasians. Genotype frequencies for the polymorphism were significantly different in OCD patients, psychiatric patients and controls. There was a significant excess of 12/12 and 12/10 genotypes in OCD patients compared to psychiatric patients and controls. Our results indicate a possible association between the Stin2.12 allele of the VNTR polymorphism and OCD. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 31 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2007 Apr 31: 741-5 |
| PMID | 17291660 |
| Title | Association study of serotonin 2A receptor (5-HT2A) and serotonin transporter (5-HTT) gene polymorphisms with schizophrenia. |
| Abstract | To investigate (i) the association between four serotonergic polymorphisms (A-1438G and T102C of the 5-HT2A receptor gene, and 5-HTT VNTR and 5-HTTLPR of the 5-HT transporter gene) and schizophrenia and (ii) the potential interaction of those polymorphisms in the development of schizophrenia. 227 outpatients with schizophrenia (DSM-IV criteria) and 420 unrelated healthy controls from Asturias (Northern Spain) were genotyped using standard methods. Both groups showed Hardy-Weinberg equilibrium for the analyzed genetic variability. A-1438G and T102C polymorphisms are in complete linkage disequilibrium in our population. There was an apparent difference in the distribution of genotypes for the A-1438G (or T102C) polymorphisms (p=0.018, not significant after a Bonferroni correction). The 5-HT2A -1438A (or 102T) allele was significantly more frequent in patients than controls (0.53 and 0.45, respectively; corrected p=0.028, OR=1.39 (95% CI=1.11-1.75)). Genotype and allele distributions for 5-HTT polymorphisms were similar in both groups. However, assessment of the combined influence of 5-HT2A A-1438G and 5-HTTLPR polymorphisms demonstrated a significant effect (chi(2) (3)=11.51, p=0.009), whereby the combination of -1438A and 5-HTTLPR S alleles was associated with schizophrenia. Our findings support a possible synergistic effect of genetic factors influencing serotonergic neurotransmission on susceptibility to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 32 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2008 Apr 147: 301-7 |
| PMID | 17886257 |
| Title | Haplotype analysis confirms association of the serotonin transporter (5-HTT) gene with schizophrenia but not with major depression. |
| Abstract | Serotonin (5-HT) has been implicated in the pathophysiology of several psychiatric disorders including major depressive disorder (MDD) and schizophrenia (SCZ). The serotonin transporter (5-HTT) is a major regulator of 5-HT function. 5-HTT gene polymorphic variants have been associated with both MDD and SCZ. A case-control design was used for candidate gene-disease association in 194 MDD patients, 155 schizophrenic psychosis patients, and 246 healthy controls, all North European Caucasians. Four polymorphisms were analyzed in terms of genotype, allele, and haplotype-based associations. Linkage disequilibrium (LD) analysis was also carried out. Bonferroni correction was used for multiple testing. Haplotype-based analyses showed significant associations between 5-HTT and SCZ but not MDD. No single locus associations were observed. In agreement with published meta-analysis our results indicate that 5-HTT associates with SCZ but not with MDD. It appears that risk for SCZ maps within a specific 5-HTT haplotype block. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 33 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2008 Apr 147: 301-7 |
| PMID | 17886257 |
| Title | Haplotype analysis confirms association of the serotonin transporter (5-HTT) gene with schizophrenia but not with major depression. |
| Abstract | Serotonin (5-HT) has been implicated in the pathophysiology of several psychiatric disorders including major depressive disorder (MDD) and schizophrenia (SCZ). The serotonin transporter (5-HTT) is a major regulator of 5-HT function. 5-HTT gene polymorphic variants have been associated with both MDD and SCZ. A case-control design was used for candidate gene-disease association in 194 MDD patients, 155 schizophrenic psychosis patients, and 246 healthy controls, all North European Caucasians. Four polymorphisms were analyzed in terms of genotype, allele, and haplotype-based associations. Linkage disequilibrium (LD) analysis was also carried out. Bonferroni correction was used for multiple testing. Haplotype-based analyses showed significant associations between 5-HTT and SCZ but not MDD. No single locus associations were observed. In agreement with published meta-analysis our results indicate that 5-HTT associates with SCZ but not with MDD. It appears that risk for SCZ maps within a specific 5-HTT haplotype block. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 34 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2008 Aug 32: 1562-6 |
| PMID | 18573584 |
| Title | Acute antipyschotic efficacy and side effects in schizophrenia: association with serotonin transporter promoter genotypes. |
| Abstract | The serotonin transporter (5-HTT) plays an important role in serotonergic neurotransmission. In the present study, we investigated the effects of the 44 bp insertion/deletion polymorphism in the promoter region of 5-HTT gene (5-HTTLPR) on symptomatology of psychosis and clinical response to antipsychotic drugs. In total 56 patients acutely treated with haloperidol or risperidone either for the first episode of schizophrenia, schizophreniform or schizoaffective disorders, or for the relapse of these psychotic disorders after tapering their maintenance treatment, were genotyped for the 5-HTTLPR L and S alleles and for the new A/G functional variant within the L alelle (La/g). Psychopathological symptoms were assessed with the Brief Psychiatric Rating Scale (BPRS) and with Clinical Global Impression (CGI) twice: at 8-12 days after the first dose of antipsychotic and after 4 weeks. Extrapyramidal side effects were assessed with the Simpson-Angus Extrapyramidal Side Effects Scale (EPS), the Barnes Akathisia Scale (BARS) and the Abnormal Involuntary Movement Scale (AIMS). Age, body mass index (BMI), illness duration, drug type and dosage were considered as covariates when analysing association with genetic variants as they were associated with baseline or final BPRS and CGI scores and/or extrapyramidal side effects. 5-HTTLPR was not associated with baseline and final BPRS and CGI scores or with the CGI% reduction. However, the 5-HTTLPR S allele was associated with a lower improvement in BPRS scores (P=0.022) and this effect was even stronger after pooling subjects with S or Lg containing alleles (P=0.006). We did not observe any effect of 5-HTTLPR on acute antipsychotics side effects. Present result supports a contribution of serotonin system to neuroleptics efficacy for the treatment of schizophrenia. The analysis of the La/g functional variant may significantly improve the predictive power of 5-HTTLPR genotyping and represent a step further towards the development of the personalized antipsychotic treatment. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 35 | BMC Psychiatry 2008 -1 8: 28 |
| PMID | 18430257 |
| Title | ADHD and Disruptive Behavior scores - associations with MAO-A and 5-HTT genes and with platelet MAO-B activity in adolescents. |
| Abstract | Pharmacological and genetic studies suggest the importance of the dopaminergic, serotonergic, and noradrenergic systems in the pathogenesis of Attention Deficit Hyperactivity Disorder (ADHD) and Disruptive Behavior Disorder (DBD). We have, in a population-based sample, studied associations between dimensions of the ADHD/DBD phenotype and Monoamine Oxidase B (MAO-B) activity in platelets and polymorphisms in two serotonergic genes: the Monoamine Oxidase A Variable Number of Tandem Repeats (MAO-A VNTR) and the 5-Hydroxytryptamine Transporter gene-Linked Polymorphic Region (5-HTT LPR). A population-based sample of twins, with an average age of 16 years, was assessed for ADHD/DBD with a clinical interview; Kiddie Schedule for Affective Disorders and schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL). Blood was drawn from 247 subjects and analyzed for platelet MAO-B activity and polymorphisms in the MAO-A and 5-HTT genes. We found an association in girls between low platelet MAO-B activity and symptoms of Oppositional Defiant Disorder (ODD). In girls, there was also an association between the heterozygote long/short 5-HTT LPR genotype and symptoms of conduct disorder. Furthermore the heterozygote 5-HTT LPR genotype in boys was found to be associated with symptoms of Conduct Disorder (CD). In boys, hemizygosity for the short MAO-A VNTR allele was associated with disruptive behavior. Our study suggests that the serotonin system, in addition to the dopamine system, should be further investigated when studying genetic influences on the development of Disruptive Behavior Disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 36 | Zh Nevrol Psikhiatr Im S S Korsakova 2009 -1 109: 50-4 |
| PMID | 20037522 |
| Title | [The role of genotype-environment interactions in the development of symptoms of anxiety and depression related to the disease burden for family]. |
| Abstract | The association of 5-HTTLPR and Val66Met BDNF genotypes with symptoms of anxiety and depression related to stress caused by severe chronic psychiatric disease of a family member has been studied. Genotyping has been conducted in the group of 214 unaffected parents of patients with schizophrenia and 100 healthy age-matched controls. The diplotype Met*ss was associated with higher scores of depressive symptoms as assessed by MMPI in the group of parents but not in the control group. The most marked differences were seen in the subgroup of parents whose children had the greatest severity of symptoms. The results suggest that the interaction of 5-HTT and BDNF genes may moderate the association between objective and subjective burden of disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 37 | Psychol Med 2009 Nov 39: 1783-97 |
| PMID | 19573260 |
| Title | The effect of COMT, BDNF, 5-HTT, NRG1 and DTNBP1 genes on hippocampal and lateral ventricular volume in psychosis. |
| Abstract | Morphometric endophenotypes which have been proposed for psychotic disorders include lateral ventricular enlargement and hippocampal volume reductions. Genetic epidemiological studies support an overlap between schizophrenia and bipolar disorder, and COMT, BDNF, 5-HTT, NRG1 and DTNBP1 genes have been implicated in the aetiology of both these disorders. This study examined associations between these candidate genes and morphometric endophenotypes for psychosis. A total of 383 subjects (128 patients with psychosis, 194 of their unaffected relatives and 61 healthy controls) from the Maudsley Family Psychosis Study underwent structural magnetic resonance imaging and genotyping. The effect of candidate genes on brain morphometry was examined using linear regression models adjusting for clinical group, age, sex and correlations between members of the same family. The results showed no evidence of association between variation in COMT genotype and lateral ventricular, and left or right hippocampal volumes. Neither was there any effect of the BDNF, 5-HTTLPR, NRG1 and DTNBP1 genotypes on these regional brain volumes. Abnormal hippocampal and lateral ventricular volumes are among the most replicated endophenotypes for psychosis; however, the influences of COMT, BDNF, 5-HTT, NRG1 and DTNBP1 genes on these key brain regions must be very subtle if at all present. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 38 | Neurosci. Lett. 2009 Apr 453: 210-3 |
| PMID | 19429037 |
| Title | Haplotype analysis confirms association of the serotonin transporter (5-HTT) gene with schizophrenia in the Han Chinese population. |
| Abstract | Serotonin transmission has long been suspected as being involved in the pathogenesis of schizophrenia. 5-HTT is a promising candidate gene for schizophrenia due to its critical role in regulating serotonin transmission and role in the mechanism of the atypical antipsychotic drugs. A common polymorphism STin2 VNTR in the 5-HTT gene has been extensively investigated in the genetic association studies, but the results are conflicting. Meanwhile, the SNPs of the 5-HTT gene have been much less explored. We therefore conducted a case-control study of the association between STin2 VNTR and three tagging SNPs in 5-HTT and schizophrenia in the Han Chinese population based on a cohort of 329 schizophrenic patients and 288 control subjects. No association was found in the single locus, but haplotype-based analyses revealed significant association between two haplotypes with schizophrenia even after Bonferroni correction (P=0.00000538 and 0.011). |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 39 | Neurosci. Lett. 2009 Apr 453: 210-3 |
| PMID | 19429037 |
| Title | Haplotype analysis confirms association of the serotonin transporter (5-HTT) gene with schizophrenia in the Han Chinese population. |
| Abstract | Serotonin transmission has long been suspected as being involved in the pathogenesis of schizophrenia. 5-HTT is a promising candidate gene for schizophrenia due to its critical role in regulating serotonin transmission and role in the mechanism of the atypical antipsychotic drugs. A common polymorphism STin2 VNTR in the 5-HTT gene has been extensively investigated in the genetic association studies, but the results are conflicting. Meanwhile, the SNPs of the 5-HTT gene have been much less explored. We therefore conducted a case-control study of the association between STin2 VNTR and three tagging SNPs in 5-HTT and schizophrenia in the Han Chinese population based on a cohort of 329 schizophrenic patients and 288 control subjects. No association was found in the single locus, but haplotype-based analyses revealed significant association between two haplotypes with schizophrenia even after Bonferroni correction (P=0.00000538 and 0.011). |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 40 | Exp Clin Psychopharmacol 2009 Jun 17: 173-80 |
| PMID | 19586232 |
| Title | Serotonin transporter genotype and depressive symptoms moderate effects of nicotine on spatial working memory. |
| Abstract | Smokers may use nicotine to self-medicate for situation-specific or person-specific cognitive or affective deficits. Although evidence suggests that nicotine replacement therapy (NRT), relative to placebo, enhances spatial working memory (SWM) in smoking-abstinent smokers with schizophrenia, the extent to which NRT may be helpful in attenuating abstinence-related SWM in other groups with deficits in SWM is unknown. Depressive symptoms are associated with both tobacco smoking and deficits in SWM. Previous studies have found that smoking abstinence increases depressive affect and depression-related hemispheric asymmetries in brain activation. Although the serotonin neurotransmitter system is closely associated with depression and the effects of nicotine, the authors are not aware of any studies that have evaluated the possible role of individual differences in serotonin transporter (5-HTT) genotype and depressive symptoms as moderators of the effects of NRT on SWM. Thus, the current study assessed the effects of NRT (nicotine patch) on SWM in relation to: (1) depressive traits and (2) 5-HTT genotype. Smoking-deprived habitual smokers (N = 64) completed the dot recall test of SWM during counterbalanced and double-blind nicotine and placebo testing sessions. There was a marginal overall effect of NRT on SWM. More importantly, NRT enhanced SWM in 5-HTT short allele carriers, relative to those with two long alleles, and this enhancement in short-allele carriers was greater for individuals with higher levels of depressive symptoms. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 41 | J. Neurosci. Res. 2009 Dec 87: 3649-57 |
| PMID | 19533737 |
| Title | Serotonin transporter, 5-HT1A receptor, and behavior in DBA/2J mice in comparison with four inbred mouse strains. |
| Abstract | Prepulse inhibition (PPI), the reduction in acoustic startle produced when it is preceded by a weak prepulse stimulus, is impaired in schizophrenic patients. The DBA/2J mouse strain displayed deficient PPI and is therefore suggested as an experimental animal model for the loss of sensorimotor gating in schizophrenia. Brain serotonin (5-HT) has been implicated in the pathophysiology of several psychiatric disorders, including major depressive disorder and schizophrenia. In the present study, behavior, 5-HT transporter (5-HTT) mRNA level, 5-HT(1A) receptor mRNA level, and 5-HT(1A) receptor density in the brain regions were studied in DBA/2J mice in comparison with four inbred mouse strains (CBA/Lac, C57BL/6, BALB/c, and ICR). A decrease in 5-HTT mRNA level in the midbrain and a reduced density of 5-HT(1A) receptors in the frontal cortex without significant changes in 5-HT(1A) receptor mRNA level in DBA/2J mice were found. It was shown that, along with decreased PPI, DBA/2J mice demonstrated considerably reduced immobility in the tail suspension test and in the forced swim test. No significant interstrain differences in intermale aggression, or in light-dark box and elevated plus-maze tests, were found. The results suggested the involvement of decreased 5-HTT gene expression and 5-HT(1A) receptor density in genetically defined PPI deficiency and showed a lack of any association between PPI deficiency and predisposition to aggressive, anxiety, and depressive-like behaviors. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 42 | J. Neurosci. Res. 2009 Dec 87: 3649-57 |
| PMID | 19533737 |
| Title | Serotonin transporter, 5-HT1A receptor, and behavior in DBA/2J mice in comparison with four inbred mouse strains. |
| Abstract | Prepulse inhibition (PPI), the reduction in acoustic startle produced when it is preceded by a weak prepulse stimulus, is impaired in schizophrenic patients. The DBA/2J mouse strain displayed deficient PPI and is therefore suggested as an experimental animal model for the loss of sensorimotor gating in schizophrenia. Brain serotonin (5-HT) has been implicated in the pathophysiology of several psychiatric disorders, including major depressive disorder and schizophrenia. In the present study, behavior, 5-HT transporter (5-HTT) mRNA level, 5-HT(1A) receptor mRNA level, and 5-HT(1A) receptor density in the brain regions were studied in DBA/2J mice in comparison with four inbred mouse strains (CBA/Lac, C57BL/6, BALB/c, and ICR). A decrease in 5-HTT mRNA level in the midbrain and a reduced density of 5-HT(1A) receptors in the frontal cortex without significant changes in 5-HT(1A) receptor mRNA level in DBA/2J mice were found. It was shown that, along with decreased PPI, DBA/2J mice demonstrated considerably reduced immobility in the tail suspension test and in the forced swim test. No significant interstrain differences in intermale aggression, or in light-dark box and elevated plus-maze tests, were found. The results suggested the involvement of decreased 5-HTT gene expression and 5-HT(1A) receptor density in genetically defined PPI deficiency and showed a lack of any association between PPI deficiency and predisposition to aggressive, anxiety, and depressive-like behaviors. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 43 | Curr. Med. Chem. 2010 -1 17: 2482-91 |
| PMID | 20491647 |
| Title | Huntington's disease: the value of transcranial meganetic stimulation. |
| Abstract | Huntington's disease (HD) is a genetic neurodegenerative process whose etiology is based on a localized disturbance in the short arm of chromosome 4 that encodes the huntingtin protein (HTT). The elongation of triple CAG for glutamine characterizes this change. Mutated HTT (mHTT) causes the appearance of intracellular aggregates inducing alterations in mitochondrial metabolism in the form of reactive oxygen species (ROS) and ATP depletion. The oxidative imbalance caused by mHTT leads the neurons to a state of oxidative stress resulting in damage to macromolecules and cellular death. Since the discovery of certain mechanisms underlying the pathogenesis of HD, several therapeutic procedures have been shown to delay or slow the evolution of the condition and have demonstrated the biochemical and molecular mechanism involved. The studies have reported that transcranial magnetic stimulation (TMS) may improve motor and other symptoms associated with neurodegenerative and neuropsychiatric processes such as major depression, schizophrenia, epilepsy, neuropathic pain, amyotrophic lateral sclerosis, progressive muscle atrophy, multiple sclerosis, stroke, Alzheimer's disease, Parkinson's disease or HD. This study focuses on the effect of TMS on oxidative stress and neurogenesis in studies and its possible usefulness in HD. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 44 | Psychiatry Res 2010 Feb 175: 189-94 |
| PMID | 20031235 |
| Title | Serotonin transporter polymorphisms and early response to antipsychotic treatment in first episode of psychosis. |
| Abstract | There is substantial evidence suggesting that individual variability in antipsychotic treatment response could be genetically determined. Variations in several serotonin transporter (5-HTT) gene polymorphisms have been associated with antipsychotic response among chronic patients with schizophrenia, although their implication in early response among first-episode patients remains unclear. Two polymorphisms in the 5-HTT gene (a 44 bp insertion/deletion in the promoter region and the functional polymorphism rs25531) were genotyped in a sample of 147 drug-naïve patients experiencing a first episode of a non-affective psychosis. Early (6 weeks) response to antipsychotic treatment with haloperidol, olanzapine or risperidone was assessed with the Brief Psychiatric Rating Scale, the Scale for the Assessment of Positive Symptoms, and the Scale for the Assessment of Negative Symptoms. No clear association was found between the rs25531 variant and treatment response. However, significant associations were observed between 5-HTT-LPR variants and early negative symptom response among first-episode patients with psychosis. Our results suggest a minor contribution to antipsychotic drug response of genetic alterations in the 5-HTT gene. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 45 | J Psychiatr Res 2010 Dec 44: 1158-62 |
| PMID | 20452607 |
| Title | Influence of serotonin transporter gene polymorphisms on clozapine response in Brazilian schizophrenics. |
| Abstract | schizophrenia is a severe mental illness affecting around 1% of adults with a high degree of morbidity and mortality. Affected individuals are at increased risk for unemployment, handicap, obesity, diabetes mellitus, hearth attack and suicide. Antipsychotic drugs are the best treatment for this disease, but about 20% of patients display drug resistance, or refractoriness, and may receive a special neuroleptic named Clozapine. Despite its superiority from other neuroleptics, only 30-60% of drug-resistant patients are responsive to clozapine. Clozapine's action results from interactions between dopaminergic and serotonergic neurotransmitter systems and since clozapine appears to exert its effect strongly through the serotonergic systems, alterations in serotonin synaptic levels may influence antipsychotic response. The serotonin transporter (5-HTT) is responsible for pre-synaptic re-uptake of serotonin, making this transporter a logical candidate gene for prediction of clozapine response and to increase understanding about mechanisms of refractoriness. Therefore, we investigated the influence of two polymorphisms in the 5-HTT gene (HTTLPR/rs25531 and VNTR Stin2) in clozapine response in a sample of 116 schizophrenic individuals of European descent from South-Brazil. Significant differences between responders and non-responders to clozapine were observed for the HTTLPR/rs25531 polymorphism. Nonresponders to clozapine showed a higher frequency of S'-allele (P = 0.01) and also were more likely to be S'/S' homozygous or S'/L' heterozygous than those who did respond (P = 0.04). After controlling for confounding variables, logistic regression analyses confirmed this association (OR = 3.15; 95% CI: 1.13-8.80). The observed association suggests that increased availability of extracellular serotonin concentrations at all synapses may reduce clozapine effect. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 46 | J Psychiatr Res 2010 Dec 44: 1158-62 |
| PMID | 20452607 |
| Title | Influence of serotonin transporter gene polymorphisms on clozapine response in Brazilian schizophrenics. |
| Abstract | schizophrenia is a severe mental illness affecting around 1% of adults with a high degree of morbidity and mortality. Affected individuals are at increased risk for unemployment, handicap, obesity, diabetes mellitus, hearth attack and suicide. Antipsychotic drugs are the best treatment for this disease, but about 20% of patients display drug resistance, or refractoriness, and may receive a special neuroleptic named Clozapine. Despite its superiority from other neuroleptics, only 30-60% of drug-resistant patients are responsive to clozapine. Clozapine's action results from interactions between dopaminergic and serotonergic neurotransmitter systems and since clozapine appears to exert its effect strongly through the serotonergic systems, alterations in serotonin synaptic levels may influence antipsychotic response. The serotonin transporter (5-HTT) is responsible for pre-synaptic re-uptake of serotonin, making this transporter a logical candidate gene for prediction of clozapine response and to increase understanding about mechanisms of refractoriness. Therefore, we investigated the influence of two polymorphisms in the 5-HTT gene (HTTLPR/rs25531 and VNTR Stin2) in clozapine response in a sample of 116 schizophrenic individuals of European descent from South-Brazil. Significant differences between responders and non-responders to clozapine were observed for the HTTLPR/rs25531 polymorphism. Nonresponders to clozapine showed a higher frequency of S'-allele (P = 0.01) and also were more likely to be S'/S' homozygous or S'/L' heterozygous than those who did respond (P = 0.04). After controlling for confounding variables, logistic regression analyses confirmed this association (OR = 3.15; 95% CI: 1.13-8.80). The observed association suggests that increased availability of extracellular serotonin concentrations at all synapses may reduce clozapine effect. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 47 | J Psychiatr Res 2010 Dec 44: 1158-62 |
| PMID | 20452607 |
| Title | Influence of serotonin transporter gene polymorphisms on clozapine response in Brazilian schizophrenics. |
| Abstract | schizophrenia is a severe mental illness affecting around 1% of adults with a high degree of morbidity and mortality. Affected individuals are at increased risk for unemployment, handicap, obesity, diabetes mellitus, hearth attack and suicide. Antipsychotic drugs are the best treatment for this disease, but about 20% of patients display drug resistance, or refractoriness, and may receive a special neuroleptic named Clozapine. Despite its superiority from other neuroleptics, only 30-60% of drug-resistant patients are responsive to clozapine. Clozapine's action results from interactions between dopaminergic and serotonergic neurotransmitter systems and since clozapine appears to exert its effect strongly through the serotonergic systems, alterations in serotonin synaptic levels may influence antipsychotic response. The serotonin transporter (5-HTT) is responsible for pre-synaptic re-uptake of serotonin, making this transporter a logical candidate gene for prediction of clozapine response and to increase understanding about mechanisms of refractoriness. Therefore, we investigated the influence of two polymorphisms in the 5-HTT gene (HTTLPR/rs25531 and VNTR Stin2) in clozapine response in a sample of 116 schizophrenic individuals of European descent from South-Brazil. Significant differences between responders and non-responders to clozapine were observed for the HTTLPR/rs25531 polymorphism. Nonresponders to clozapine showed a higher frequency of S'-allele (P = 0.01) and also were more likely to be S'/S' homozygous or S'/L' heterozygous than those who did respond (P = 0.04). After controlling for confounding variables, logistic regression analyses confirmed this association (OR = 3.15; 95% CI: 1.13-8.80). The observed association suggests that increased availability of extracellular serotonin concentrations at all synapses may reduce clozapine effect. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 48 | Schizophr. Res. 2010 Aug 121: 160-71 |
| PMID | 20451351 |
| Title | Overexpression of serotonin receptor and transporter mRNA in blood leukocytes of antipsychotic-free and antipsychotic-naïve schizophrenic patients: gender differences. |
| Abstract | Abnormal serotonin (5-HT) activity has been implicated in schizophrenia. However, the role of 5-HT receptors and transporter (5-HTT) in male and female schizophrenia remains largely unknown. Recent studies suggest that 5-HT system expressed in the peripheral leukocyte could be a marker of the illness. 46 acute schizophrenic patients (male=35, female=11) that were antipsychotic-naïve or antipsychotic-free for at least three months (average=27.3 months) and 44 age- and sex-matched healthy subjects (male=24, female=20) were included for blood leukocytes expression of 5-HT(1A), 5-HT(2A) and 5-HT(7) receptor and 5-HTT mRNA, using real-time PCR technique. ANOVA analysis showed a significant increase of 5HT(2A) mRNA and 5-HTT mRNA (each >2-fold, P<0.01) and a trend increase of 5HT(1A) mRNA (P<0.15) and 5-HT(7) mRNA (P<0.09) level in blood leukocytes of pooled schizophrenic patients than in the healthy subjects. The elevation was mainly found in the male patients. Within-sex analysis showed that the male antipsychotic-free schizophrenic patients exhibited greater 5-HT(1A) and 5-HT(7) mRNA expression (P<0.05, each ) whereas female antipsychotic-free patients showed decreased 5-HT(1A) mRNA expression (P<0.05) when compared with the male and female healthy subjects, respectively. The correlations between 5-HT mRNA and clinical symptoms (PANSS scales) were calculated. The present findings showed an abnormal expression of leukocyte 5-HT system in antipsychotic-free and antipsychotic-naïve schizophrenia especially in the male patients. Because of the greater accumulative dose of antipsychotics in the relatively smaller number of the female patients of the study, further study is needed to confirm the present findings. If replicated, blood serotonergic markers could add to the diagnosis and individualized pharmacotherapy of schizophrenic patients, especially the male patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 49 | Schizophr. Res. 2010 Aug 121: 160-71 |
| PMID | 20451351 |
| Title | Overexpression of serotonin receptor and transporter mRNA in blood leukocytes of antipsychotic-free and antipsychotic-naïve schizophrenic patients: gender differences. |
| Abstract | Abnormal serotonin (5-HT) activity has been implicated in schizophrenia. However, the role of 5-HT receptors and transporter (5-HTT) in male and female schizophrenia remains largely unknown. Recent studies suggest that 5-HT system expressed in the peripheral leukocyte could be a marker of the illness. 46 acute schizophrenic patients (male=35, female=11) that were antipsychotic-naïve or antipsychotic-free for at least three months (average=27.3 months) and 44 age- and sex-matched healthy subjects (male=24, female=20) were included for blood leukocytes expression of 5-HT(1A), 5-HT(2A) and 5-HT(7) receptor and 5-HTT mRNA, using real-time PCR technique. ANOVA analysis showed a significant increase of 5HT(2A) mRNA and 5-HTT mRNA (each >2-fold, P<0.01) and a trend increase of 5HT(1A) mRNA (P<0.15) and 5-HT(7) mRNA (P<0.09) level in blood leukocytes of pooled schizophrenic patients than in the healthy subjects. The elevation was mainly found in the male patients. Within-sex analysis showed that the male antipsychotic-free schizophrenic patients exhibited greater 5-HT(1A) and 5-HT(7) mRNA expression (P<0.05, each ) whereas female antipsychotic-free patients showed decreased 5-HT(1A) mRNA expression (P<0.05) when compared with the male and female healthy subjects, respectively. The correlations between 5-HT mRNA and clinical symptoms (PANSS scales) were calculated. The present findings showed an abnormal expression of leukocyte 5-HT system in antipsychotic-free and antipsychotic-naïve schizophrenia especially in the male patients. Because of the greater accumulative dose of antipsychotics in the relatively smaller number of the female patients of the study, further study is needed to confirm the present findings. If replicated, blood serotonergic markers could add to the diagnosis and individualized pharmacotherapy of schizophrenic patients, especially the male patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 50 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2010 Feb 34: 81-5 |
| PMID | 19818823 |
| Title | HTTLPR functional polymorphism in schizophrenia: executive functions vs. sustained attention dissociation. |
| Abstract | Recently attention has been addressed to the role of 5-HT in cognition and several experimental studies revealed that manipulations of the central 5-HT system can produce quite specific changes in cognitive functioning. These results may suggest new treatment strategies to improve cognition in psychiatric conditions characterized by neuropsychological impairments, such as schizophrenia. It is possible to investigate the involvement of 5-HT in cognition by examining the impact of genetic variation in key regulators of serotoninergic neurotransmission. Among these, the serotonin transporter (5-HTT) presents a functional polymorphism in the transcriptional control region of the gene (5-HTTLPR) affecting transcriptional efficiency. In the present study, we aimed to analyze the effect of 5-HTTLPR polymorphism on specific cognitive functions, known to be affected by 5-HT manipulation and altered in schizophrenia. 223 schizophrenia patients were tested with Wisconsin Card Sorting Test (WCST), for the evaluation of cognitive flexibility, Continuous Performance Test (CPT), for the evaluation of attention, and genotyped for the 5-HTTLPR. We found a significant association between HTT polymorphism and executive functions and inversely with sustained attention. The presence of the high-activity long (L) allele in homozygosis was a predictor of better executive performances and poorer performances of attention. Our findings suggest that factors affecting serotonin availability may play a specific role in cognitive processes, probably through complex modulation of the different performance components. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 51 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2010 Jan 153B: 291-7 |
| PMID | 19330775 |
| Title | Risk variants in the S100B gene predict elevated S100B serum concentrations in healthy individuals. |
| Abstract | Several lines of evidence suggest an important role of the S100B protein and its coding gene in different neuropathological and psychiatric disorders like dementia, bipolar affective disorders and schizophrenia. To clarify whether a direct link exists between gene and gene product, that is, whether S100B variants directly modulate S100B serum concentration, 196 healthy individuals were assessed for S100B serum concentrations and genotyped for five potentially functional S100B SNPs. Functional variants of the serotonergic genes 5-HT1A and 5-HTT possibly modulating S100B serum levels were also studied. Further, publicly available human postmortem gene expression data were re-analyzed to elucidate the impact of S100B, 5-HT1A and 5-HTT SNPs on frontal cortex S100B mRNA expression. Several S100B SNPs, particularly rs9722, and the S100B haplotype T-G-G-A (including rs2186358-rs11542311-rs2300403-rs9722) were associated with elevated S100B serum concentrations (Bonferroni corrected P < 0.05). Of these, rs11542311 was also associated with S100B mRNA expression directly (Bonferroni corrected P = 0.05) and within haplotype G-A-T-C (rs11542311-rs2839356-rs9984765-rs881827; P = 0.004), again with the G-allele increasing S100B expression. Our results suggest an important role of S100B SNPs on S100B serum concentrations and S100B mRNA expression. It hereby links recent evidence for both, the impact of S100B gene variation on various neurological or psychiatric disorders like dementia, bipolar affective disorders and schizophrenia and the strong relation between S100B serum levels and these disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 52 | Addict Biol 2010 Jul 15: 250-65 |
| PMID | 20456288 |
| Title | Cognitive effects of nicotine: genetic moderators. |
| Abstract | Cigarette smoking is the main preventable cause of death in developed countries, and the development of more effective treatments is necessary. Cumulating evidence suggests that cognitive enhancement may contribute to the addictive actions of nicotine. Several studies have demonstrated that nicotine enhances cognitive performance in both smokers and non-smokers. Genetic studies support the role of both dopamine (DA) and nicotinic acetylcholine receptors (nAChRs) associated with nicotine-induced cognitive enhancement. Based on knockout mice studies, beta2 nAChRs are thought to be essential in mediating the cognitive effects of nicotine. alpha7nAChRs are associated with attentional and sensory filtering response, especially in schizophrenic individuals. Genetic variation in D2 type DA receptors and the catechol-O-methyltransferase enzyme appears to moderate cognitive deficits induced by smoking abstinence. Serotonin transporter (5-HTT) gene variation also moderates nicotine-induced improvement in spatial working memory. Less is known about the contribution of genetic variation in DA transporter and D4 type DA receptor genetic variation on the cognitive effects of nicotine. Future research will provide a clearer understanding of the mechanism underlying the cognitive-enhancing actions of nicotine. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 53 | Eur Arch Psychiatry Clin Neurosci 2012 Dec 262: 667-76 |
| PMID | 22454241 |
| Title | Genetic polymorphisms of 5-HTT and DAT but not COMT differentially affect verbal and visuospatial working memory functioning. |
| Abstract | Working memory deficits are found in different psychiatric populations and are most pronounced in schizophrenia. There is preliminary evidence from pharmacological studies that the verbal and visuospatial subcomponents of working memory are subject to differential neurotransmitter modulation. Here, we investigated the impact of well-known polymorphisms of the dopamine transporter gene (SLC6A3, DAT) and the catechol-O-methyl-transferase gene (COMT) as well as the serotonin transporter gene (SLC6A4, 5-HTT) on these specific working memory subcomponents in a mixed sample of patients and healthy individuals. Twenty healthy subjects and 80 patients diagnosed with schizophrenia, bipolar I disorder, or obsessive-compulsive disorder underwent genotyping for the DAT variable number of tandem repeats (VNTR), the COMT val/met-, and the 5-HTT promoter length polymorphism (5-HTTLPR) and neuropsychological testing using a battery of well-characterized, brain circuit-specific working memory tasks. DAT genotype revealed a significant and selective effect on visuospatial working memory, while there was no effect on verbal working memory functioning. 5-HTT genotype, by contrast, exerted a significant and selective effect on verbal working memory task performance. COMT genotype did not show any influence on either working memory domain. The results of the present study provide evidence for a differential impact of genetic polymorphisms of the dopaminergic and serotonergic systems on verbal and visuospatial working memory functioning. Together with prior evidence suggesting the existence of subgroups of schizophrenia patients exhibiting isolated deficits in only one working memory domain, this finding further supports the idea of endophenotypically and pathophysiologically distinct subgroups of schizophrenia with implications for personalized therapeutic approaches. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 54 | Fa Yi Xue Za Zhi 2012 Dec 28: 418-21 |
| PMID | 23484320 |
| Title | [Relationship between genetic polymorphisms of 3 SNP loci in 5-HTT gene and paranoid schizophrenia]. |
| Abstract | To investigate the population genetic data of 3 SNP loci (rs25533, rs34388196 and rs1042173) of 5-hydroxytryptamine transporter (5-HTT) gene and the association with paranoid schizophrenia. Three SNP loci of 5-HTT gene were examined in 132 paranoid schizophrenia patients and 150 unrelated healthy individuals of Northern Chinese Han population by PCR-RFLP technique. The Hardy-Weinberg equilibrium test was performed using the chi-square test and the data of haplotype frequency and population genetics parameters were statistically analyzed. Among these three SNP loci, four haplotypes were obtained. There were no statistically significant differences between the patient group and the control group (P > 0.05). The DP values of the 3 SNP loci were 0.276, 0.502 and 0.502. The PIC of them were 0.151, 0.281 and 0.281. The PE of them were 0.014, 0.072 and 0.072. The three SNP loci and four haplotypes of 5-HTT gene have no association with paranoid schizophrenia, while the polymorphism still have high potential application in forensic practice. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 55 | Neuroimage 2012 Oct 63: 447-59 |
| PMID | 22789740 |
| Title | Normative database of the serotonergic system in healthy subjects using multi-tracer PET. |
| Abstract | The highly diverse serotonergic system with at least 16 different receptor subtypes is implicated in the pathophysiology of most neuropsychiatric disorders including affective and anxiety disorders, obsessive compulsive disorder, post-traumatic stress disorder, eating disorders, sleep disturbance, attention deficit/hyperactivity disorder, drug addiction, suicidal behavior, schizophrenia, Alzheimer, etc. Alterations of the interplay between various pre- and postsynaptic receptor subtypes might be involved in the pathogenesis of these disorders. However, there is a lack of comprehensive in vivo values using standardized procedures. In the current PET study we quantified 3 receptor subtypes, including the major inhibitory (5-HT(1A) and 5-HT(1B)) and excitatory (5-HT(2A)) receptors, and the transporter (5-HTT) in the brain of healthy human subjects to provide a database of standard values. PET scans were performed on 95 healthy subjects (age=28.0 ± 6.9 years; 59% males) using the selective radioligands [carbonyl-(11)C]WAY-100635, [(11)C]P943, [(18)F]altanserin and [(11)C]DASB, respectively. A standard template in MNI stereotactic space served for region of interest delineation. This template follows two anatomical parcellation schemes: 1) Brodmann areas including 41 regions and 2) AAL (automated anatomical labeling) including 52 regions. Standard values (mean, SD, and range) for each receptor and region are presented. Mean cortical and subcortical binding potential (BP) values were in good agreement with previously published human in vivo and post-mortem data. By means of linear equations, PET binding potentials were translated to post-mortem binding (provided in pmol/g), yielding 5.89 pmol/g (5-HT(1A)), 23.5 pmol/g (5-HT(1B)), 31.44 pmol/g (5-HT(2A)), and 11.33 pmol/g (5-HTT) being equivalent to the BP of 1, respectively. Furthermore, we computed individual voxel-wise maps with BP values and generated average tracer-specific whole-brain binding maps. This knowledge might improve our interpretation of the alterations taking place in the serotonergic system during neuropsychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 56 | Behav Brain Funct 2012 -1 8: 24 |
| PMID | 22594806 |
| Title | Association between a genetic variant in the serotonin transporter gene (SLC6A4) and suicidal behavior in patients with schizophrenia. |
| Abstract | The serotonin (5-hydroxytryptamin; 5-HT) system has a central role in the circuitry of cognition and emotions. Multiple lines of evidence suggest that genetic variation in the serotonin transporter gene (SLC6A4; 5-HTT) is associated with schizophrenia and suicidal behavior. In this study, we wanted to elucidate whether SLC6A4 variations is involved in attempted suicide among patients with schizophrenia in a Scandinavian case-control sample. Patients diagnosed with schizophrenia from three Scandinavian samples were assessed for presence or absence of suicide attempts, based on record reviews and interview data. Seven SLC6A4 single nucleotide polymorphisms (SNPs) were genotyped in 837 schizophrenia patients and 1,473 control individuals. Association analyses and statistical evaluations were performed with the program UNPHASED (version 3.0.9). We observed an allele association between the SNP rs16965628, located in intron one of SLC6A4, and attempted suicide (adjusted p-value 0.01), among patients with schizophrenia. No association was found to a diagnosis of schizophrenia, when patients were compared to healthy control individuals. The gene SLC6A4 appears to be involved in suicidal ideation among patients with schizophrenia. Independent replication is needed before more firm conclusions can be drawn. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 57 | J Psychiatr Res 2012 Jun 46: 767-73 |
| PMID | 22520017 |
| Title | Suicide ideators and attempters with schizophrenia--the role of 5-HTTLPR, rs25531, and 5-HTT VNTR Intron 2 variants. |
| Abstract | To examine the role of 5-HTTLPR, rs25531 and 5-HTT VNTR Intron 2 variants in subjects with psychotic disorders manifesting suicide ideation and behaviour. The study included 519 subsequently hospitalized subjects who were genotyped for 5-HTTLPR, rs25531 and 5-HTT VNTR In2 variants. Clinical assessments included structured psychiatric interview, sociodemographic characteristics, suicide ideation and behaviour (SIBQ), severity of psychopathology (PANSS) and depression (CDSS). Three subgroups were identified: suicide attempters (N = 161), suicide ideators (N = 174) and subjects who never reported suicide ideation or behaviour (comparative group, N = 184). 1) Suicide attempters scored highest on the CDSS, while no differences between the three clinical subgroups were detected in the PANSS scores; 2) Suicide attempters were more frequently the carriers of L(A) allele, while subjects in the comparative group were more frequently the carriers of low expression 5-HTTLPR/5-HTT rs25531 haplotype SL(G); 3) No difference was found between the three clinical groups in the 5-HTT VNTR In2 variants; 4) Subjects with 5-HTTLPR/5-HTT rs25531 intermediate expression haplotype (L(A)L(G,)SL(A)) scored higher on the PANSS general psychopathology subscale; 5) There was no association between suicide attempt or ideation and 5-HTTLPR/In2 or 5-HTTLPR/rs25531/In2 haplotype distribution. The suicide ideators, attempters and controls did not differ significantly in 5-HTTLPR or 5-HTT VNTR In 2 variants, but 5-HTTLPR/5-HTT rs25531 haplotype might be a useful genetic marker in distinguishing these three clinical groups. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 58 | Prog. Neurobiol. 2012 May 97: 220-38 |
| PMID | 22155432 |
| Title | Putting proteins in their place: palmitoylation in Huntington disease and other neuropsychiatric diseases. |
| Abstract | Post-translational modification of proteins by the lipid palmitate is critical for protein localization and function. Palmitoylation is regulated by the opposing enzymes palmitoyl acyltransferases (PATs) and acyl protein thioesterases, which add and remove palmitate from proteins, respectively. Palmitoylation is particularly important for a number of processes including neuronal development and synaptic activity in the central nervous system. Dysregulated palmitoylation contributes to neuropsychiatric disease. In total six PATs (HIP14, HIP14L, ZDHHC8, ZDHHC9, ZDHHC12, and ZDHHC15) and one thioesterase (PPT1) have been implicated in Huntington disease (HD), Alzheimer disease, schizophrenia, mental retardation, and infantile and adult onset forms of neuronal ceroid lipofuscinosis. Currently there is no genetic link between PATs and Alzheimer disease pathogenesis but palmitoylation of amyloid precursor protein-processing enzyme, ?-secretase, influences ?-amyloid generation. Several lines of evidence point to a role for palmitoylation by HIP14 in the pathogenesis of HD; HIP14 is dysfunctional in the presence of the HD mutation and Hip14-deficient mice develop features of HD. Wildtype huntingtin (the protein mutated in HD) enhances the PAT activity of HIP14 and mutant HTT interacts less with HIP14. Therefore, it may be that loss of the positive modulation of HIP14 activity due to reduced interaction with huntingtin is important in the disease mechanism. Preliminary evidence suggests a closely related PAT to HIP14, HIP14L, may also play a role in the pathogenesis of HD. In order to design rational therapeutic approaches to restore palmitoylation in neuropsychiatric disease, it will be critical to better understand the relationships between PATs and thioesterases with their regulators and substrates. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 59 | Schizophr Bull 2012 Jan 38: 15-22 |
| PMID | 21908796 |
| Title | Serotonin transporter gene polymorphism, childhood trauma, and cognition in patients with psychotic disorders. |
| Abstract | The functional polymorphism in the promoter region of the SLC6A4/5-HTT serotonin transporter gene (5-HTTLPR) has been linked to altered stress response. Carriers of the short (s-) allele have increased negative psychological reactions and stress hormone release compared with carriers of the long (l-) allele, interacting with severe life events including childhood trauma. High stress levels are associated with cognitive impairments in a variety of clinical and experimental studies. Patients with psychotic disorders are characterized both by more childhood traumatic events and abnormal stress responses and by significant but highly variable cognitive dysfunction. We hypothesize that 5-HTTLPR variations and long-term effects of childhood trauma interact and contribute to some of the variation in cognitive dysfunction seen in patients with psychotic disorders. Patients with psychotic disorders (schizophrenia and affective spectrums) were recruited from a catchment area-based treatment organization. History of childhood abuse was obtained by the Childhood Trauma Questionnaire. Cognitive function was assessed through a comprehensive, standardized neuropsychological test battery. 5-HTTLPR genotypes were analyzed using standard polymerase chain reaction. We observed a significant interaction between 5-HTTLPR variants and childhood trauma across cognitive domains; here, homozygotic s-carriers exposed to high levels of childhood trauma (physical neglect and abuse) had significantly poorer cognitive functioning than all other groups. Our results need replication but underline the importance of investigating childhood trauma and its interaction with genetic markers when studying cognitive dysfunction in patients with psychotic disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 60 | Neuropsychiatr Dis Treat 2013 -1 9: 1573-82 |
| PMID | 24143106 |
| Title | Evidence for single nucleotide polymorphisms and their association with bipolar disorder. |
| Abstract | Bipolar disorder (BD) is a complex disorder with a number of susceptibility genes and environmental risk factors involved in its pathogenesis. In recent years, huge progress has been made in molecular techniques for genetic studies, which have enabled identification of numerous genomic regions and genetic variants implicated in BD across populations. Despite the abundance of genetic findings, the results have often been inconsistent and not replicated for many candidate genes/single nucleotide polymorphisms (SNPs). Therefore, the aim of the review presented here is to summarize the most important data reported so far in candidate gene and genome-wide association studies. Taking into account the abundance of association data, this review focuses on the most extensively studied genes and polymorphisms reported so far for BD to present the most promising genomic regions/SNPs involved in BD. The review of association data reveals evidence for several genes (SLC6A4/5-HTT [serotonin transporter gene], BDNF [brain-derived neurotrophic factor], DAOA [D-amino acid oxidase activator], DTNBP1 [dysbindin], NRG1 [neuregulin 1], DISC1 [disrupted in schizophrenia 1]) to be crucial candidates in BD, whereas numerous genome-wide association studies conducted in BD indicate polymorphisms in two genes (CACNA1C [calcium channel, voltage-dependent, L type, alpha 1C subunit], ANK3 [ankyrin 3]) replicated for association with BD in most of these studies. Nevertheless, further studies focusing on interactions between multiple candidate genes/SNPs, as well as systems biology and pathway analyses are necessary to integrate and improve the way we analyze the currently available association data. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 61 | Schizophr Bull 2013 Jul 39: 766-75 |
| PMID | 23512949 |
| Title | Clinical and molecular genetics of psychotic depression. |
| Abstract | This review provides a comprehensive overview of clinical and molecular genetic as well as pharmacogenetic studies regarding the clinical phenotype of "psychotic depression." Results are discussed with regard to the long-standing debate on categorical vs dimensional disease models of affective and psychotic disorders on a continuum from unipolar depression over bipolar disorder and schizoaffective disorder to schizophrenia. Clinical genetic studies suggest a familial aggregation and a considerable heritability (39%) of psychotic depression partly shared with schizoaffective disorder, schizophrenia, and affective disorders. Molecular genetic studies point to potential risk loci of psychotic depression shared with schizoaffective disorder (1q42, 22q11, 19p13), depression, bipolar disorder, and schizophrenia (6p, 8p22, 10p13-12, 10p14, 13q13-14, 13q32, 18p, 22q11-13) and several vulnerability genes possibly contributing to an increased risk of psychotic symptoms in depression (eg, BDNF, DBH, DTNBP1, DRD2, DRD4, GSK-3beta, MAO-A). Pharmacogenetic studies implicate 5-HTT, TPH1, and DTNBP1 gene variation in the mediation of antidepressant treatment response in psychotic depression. Genetic factors are suggested to contribute to the disease risk of psychotic depression in partial overlap with disorders along the affective-psychotic spectrum. Thus, genetic research focusing on psychotic depression might inspire a more dimensional, neurobiologically and symptom-oriented taxonomy of affective and psychotic disorders challenging the dichotomous Kraepelinian view. Additionally, pharmacogenetic studies might aid in the development of a more personalized treatment of psychotic depression with an individually tailored antidepressive/antipsychotic pharmacotherapy according to genotype. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 62 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2013 Dec 47: 62-8 |
| PMID | 23994047 |
| Title | Effects of olanzapine and betahistine co-treatment on serotonin transporter, 5-HT2A and dopamine D2 receptor binding density. |
| Abstract | Olanzapine is widely used in treating multiple domains of schizophrenia symptoms but induces serious metabolic side-effects. Recent evidence has showed that co-treatment of betahistine (a histaminergic H1 receptor agonist and H3 receptor antagonist) is effective for preventing olanzapine-induced weight gain/obesity, however it is not clear whether this co-treatment affects on the primary therapeutic receptor binding sites of olanzapine such as serotonergic 5-HT2A receptors (5-HT2AR) and dopaminergic D2 receptors (D2R). Therefore, this study investigated the effects of this co-treatment on 5-HT2AR, 5-HT transporter (5-HTT) and D2R bindings in various brain regions involved in antipsychotic efficacy. Female Sprague Dawley rats were administered orally (t.i.d.) with either olanzapine (1mg/kg), betahistine (2.7 mg/kg), olanzapine plus betahistine (O+B), or vehicle (control) for 2 weeks. Quantitative autoradiography was used to detect the density of [(3)H]ketanserin, [(3)H]paroxetine and [(3)H]raclopride binding site to 5-HT2AR, 5-HTT and D2R. Compared to the controls, olanzapine significantly decreased [(3)H]ketanserin bindings to 5-HT2AR in the prefrontal cortex, cingulate cortex, and nucleus accumbens. Similar changes in 5-HT2AR bindings in these nuclei were also observed in the O+B co-treatment group. Olanzapine also significantly decreased [(3)H]paroxetine binding to 5-HTT in the ventral tegmental area and substantia nigra, however, both olanzapine only and O+B co-treatment did not affect [(3)H]raclopride binding to D2R. The results confirmed the important role of 5-HT2AR in the efficacy of olanzapine, which is not influenced by the O+B co-treatment. Therefore, betahistine co-treatment would be an effective combination therapy to reduce olanzapine-induced weight gain side-effects without affecting olanzapine's actions on 5-HT2AR transmissions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 63 | Schizophr. Res. 2014 Feb 152: 373-80 |
| PMID | 24411530 |
| Title | DNA hypermethylation of serotonin transporter gene promoter in drug naïve patients with schizophrenia. |
| Abstract | Dysfunctional serotonin signaling has been linked to the pathogenesis of autism, obsessive compulsive disorder, mood disorders and schizophrenia. While the hypo-activity of serotonin signaling is involved in the pathogenesis of depression, anxiety and obsessive compulsive disorder; LSD, an agonist of serotonin type 2 receptor (5-HTR2A) induces psychosis. Therefore, anxiety and depressive disorders are treated by SSRIs which inhibit serotonin transporter (5-HTT) while psychotic disorders are controlled by drugs that block serotonin and/or dopamine receptors. Since genetic polymorphisms and epigenetic dysregulation of 5-HTT are involved in the pathogenesis of mental diseases, we analyzed DNA methylation of 5-HTT promoter in post-mortem brains and saliva samples of patients with schizophrenia (SCZ) and bipolar disorder (BD) to evaluate its potential application as a diagnostic and/or therapeutic biomarker in SCZ and BD. Whole genome DNA methylation profiling was performed for a total of 24 samples (including two saliva samples) using the Illumina 27K (for 12 samples) and 450K DNA methylation array platform (for another 12 samples), followed by bisulfite sequencing to identify candidate CpGs for further analysis. Quantitative methylation specific PCR (qMSP) was used to assess the degree of CpG methylation of 5-HTT promoter in 105 post-mortem brains (35 controls, 35 SCZ and 35 BD) and 100 saliva samples (30 controls, 30 SCZ, 20 BD and 20 first degree relatives of SCZ or BD). The U133 2.0 Plus Human Transcriptome array for a total of 30 post-mortem brain samples (each group 10) followed by quantitative real-time PCR was used to study 5-HTT expression in 105 post-mortem brain samples. The qMSP analysis for 5-HTT promoter region showed DNA hypermethylation in post-mortem brain samples of SCZ patients (~30%), particularly in drug free patients (~60%, p=0.04). Similarly, there was a trend for DNA hypermethylation in antipsychotic free BD patients (~50%, p=0.066). qMSP analysis of DNA extracted from the saliva samples also exhibited hypermethylation of 5-HTT promoter in patients with SCZ (~30%, p=0.039), which was more significant in drug naïve SCZ patients (>50%, p=0.0025). However, the difference was not significant between the controls and unaffected first degree relatives of patients with SCZ (p=0.37) and versus patients using antipsychotic drugs (p=0.2). The whole genome transcriptome analysis of post-mortem brain samples showed reduced expression of 5-HTT in SCZ compared to the control subjects (~50%, p=0.008), confirmed by quantitative real-time PCR analysis (~40%, p=0.035) which was more significant in drug free SCZ patients (~70%, p=0.022). A correlation between reduction in 5-HTT expression and DNA hypermethylation of the 5-HTT promoter in drug naïve SCZ patients suggests that an epigenetically defined hypo-activity of 5-HTT may be linked to SCZ pathogenesis. Furthermore, this epigenetic mark in DNA extracted from saliva can be considered as one of the key determinants in a panel of diagnostic and/or therapeutic biomarkers for SCZ. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 64 | Neuroscience 2015 Dec 310: 723-30 |
| PMID | 26475744 |
| Title | The CCDC55 couples cannabinoid receptor CNR1 to a putative DISC1 schizophrenia pathway. |
| Abstract | Our previous study suggested that the coiled coil domain-containing 55 gene (CCDC55), also named as NSRP1 (nuclear speckle splicing regulatory protein 1 (NSRP1)), was encompassed in a haplotype block spanning over the serotonin transporter (5-HTT) gene in patients with schizophrenia (SCZ). However, the neurobiological function of CCDC55 gene remains unknown. This study aims to uncover the potential role of CCDC55 in SCZ-associated molecular pathways. Using molecular cloning, sequencing and immune blotting to identify basic properties, yeast two-hybrid screening and glutathione S-transferase (GST) pull-down assay to test protein-protein interaction, and confocal laser scanning microscopy (CSLM) to show intracellular interaction of proteins. (i) CCDC55 is expressed as a nuclear protein in human neuronal cells; (ii) Protein-protein interaction analyses showed CCDC55 physically interacted with Ran binding protein 9 (RanBP9) and disrupted in schizophrenia 1 (DISC1); (iii) CCDC55 and RanBP9 co-localized in the nucleus of human neuronal cells; (iv) CCDC55 also interacted with the cannabinoid receptor 1 (CNR1), and with the brain cannabinoid receptor-interacting protein 1a (CNRIP1a); (v) CNR1 activation in differentiated human neuronal cells resulted in an altered RanBP9 localization. CCDC55 may be involved in a functional bridging between the CNR1 activation and the DISC1/RanBP9-associated pathways. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 65 | CNS Neurol Disord Drug Targets 2015 -1 14: 820-7 |
| PMID | 26166439 |
| Title | Genetic Polymorphisms Might Predict Suicide Attempts in Mental Disorder Patients: A Systematic Review And Meta-Analysis. |
| Abstract | The aim of the present study was to analyze if the genetic polymorphisms might predict suicide attempts in mental disorder patients. The literature review and meta-analysis were conducted using the PubMed/Medline, Web of science and Scopus database using the terms: "5-HTT or SLC6A4 or 5-SERT and suicide, suicidal ideation or suicidal behavior or suicidal attempt". Thirty articles were analyzed. We found 17 articles that showed association and 13 articles that showed no association between LPR serotonin transporter polymorphism and suicide. A higher study of suicide identified the serotonin transporter polymorphism in patients with schizophrenia, mental disorder, major depression and bipolar disorder. There is an association between the serotonin-transporter-linked polymorphic region and suicidal behavior. The mental disorders with greater relationship with the suicide were the bipolar disorder, major depression and schizophrenia. The L allele had higher risk for suicide. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 66 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2015 Jan 56: 75-80 |
| PMID | 25149912 |
| Title | Chronic betahistine co-treatment reverses olanzapine's effects on dopamine D? but not 5-HT2A/2C bindings in rat brains. |
| Abstract | Olanzapine is widely prescribed for treating schizophrenia and other mental disorders, although it leads to severe body weight gain/obesity. Chronic co-treatment with betahistine has been found to significantly decrease olanzapine-induced weight gain; however, it is not clear whether this co-treatment affects the therapeutic effects of olanzapine. This study investigated the effects of chronic treatment of olanzapine and/or betahistine on the binding density of the serotonergic 5-HT2A (5-HT2AR) and 5-HT2C (5-HT2CR) receptors, 5-HT transporter (5-HTT), and dopaminergic D? receptors (D?R) in the brain regions involved in antipsychotic efficacy, including the prefrontal cortex (PFC), cingulate cortex (Cg), nucleus accumbens (NAc), and caudate putamen (CPu). Rats were treated with olanzapine (1 mg/kg, t.i.d.) or vehicle for 3.5 weeks, and then olanzapine treatment was withdrawn for 19 days. From week 6, the two groups were divided into 4 groups (n=6) for 5 weeks' treatment: (1) olanzapine-only (1 mg/kg, t.i.d.), (2) betahistine-only (9.6 mg/kg, t.i.d.), (3) olanzapine and betahistine co-treatment (O+B), and (4) vehicle. Compared to the control, the olanzapine-only treatment significantly decreased the bindings of 5-HT2AR, 5-HT2CR, and 5-HTT in the PFC, Cg, and NAc. Similar changes were observed in the rats receiving the O+B co-treatment. The olanzapine-only treatment significantly increased the D?R binding in the Cg, NAc, and CPu, while the betahistine-only treatment reduced D?R binding. The co-treatment of betahistine reversed the D?R bindings in the NAc and CPu that were increased by olanzapine. Therefore, chronic O+B co-treatment has similar effects on serotonin transmission as the olanzapine-only treatment, but reverses the D?R that is up-regulated by chronic olanzapine treatment. The co-treatment maintains the therapeutic effects of olanzapine but decreases/prevents the excess weight gain. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |