| 1 | Int. J. Neuropsychopharmacol. 2010 Jul 13: 793-8 |
|---|---|
| PMID | 20196918 |
| Title | Schizophrenia severity and clozapine treatment outcome association with oxytocinergic genes. |
| Abstract | Antipsychotic drugs are the best means available for symptomatically treating individuals suffering from schizophrenia; however, there is a significant variability in clinical response to these psychotropic medications. Previous findings connect oxytocin (OXT) with schizophrenia and antipsychotic action. Therefore, we evaluated if OXT and OXT receptor (OXTR) genes might play a role in the symptom severity and clozapine treatment response in schizophrenia subjects. The rs2740204 variant in the OXT gene was significantly associated with treatment response (after 1000 permutations p=0.042) and nominally associated with negative symptoms in our sample. Furthermore, variants in the OXTR were nominally associated with severity of overall symptoms accessed using the Brief Psychiatric Rating Scale (rs237885, rs237887) as well as on the improvement of the positive symptoms (rs11706648, rs4686301, rs237899). Additional association studies in independent samples will be able evaluate whether OXT and OXTR genes are truly playing a role in the clozapine treatment outcome. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 2 | J Affect Disord 2010 Dec 127: 31-7 |
| PMID | 20488544 |
| Title | The association between oxytocin receptor gene (OXTR) polymorphisms and affective temperaments, as measured by TEMPS-A. |
| Abstract | Oxytocin is associated with social interaction, trust, and affectivity. Affective temperaments are traits based on Kraepelin's typological definition of the "fundamental states" of manic-depressive illness. These states can be measured by the Temperament Evaluation of Memphis, Pisa, Paris and San Diego-Autoquestionnaire version (TEMPS-A). The objective of this study is to assess the association between oxytocin receptor gene (OXTR) polymorphisms and affective temperaments. Participants consisted of 493 genetically unrelated, non-clinical Japanese subjects (307 males and 186 females). The Mini-International Neuropsychiatric Interview (MINI) was used to screen and exclude those who had a lifetime diagnosis of schizophrenia or other psychotic disorders. Fifteen OXTR tag single nucleotide polymorphisms (SNPs) were genotyped using TaqManŽ or direct sequencing. The Haploview 4.1. software determined the haplotype block structure. Haplotype-based quantitative trait association analysis with Bonferroni correction using PLINK 1.06 software was used to assess the association between haplotypes and the following affective temperaments: depressive, cyclothymic, hyperthymic, irritable, and anxious. Two haplotype blocks were identified on the OXTR. The depressive temperament was significantly associated with the most frequent haplotype GGGTGTC (rs11131149/rs2243370/rs2243369/rs13316193/rs2254298/rs2268493/rs2268491) (corrected P<0.05). This study consisted of participants from a corporation and the effect sizes were small. The findings suggest that an OXTR haplotype is associated with a discrete depressive temperament. Clarification of the biological basis of this temperamental trait may help to elucidate the pathophysiology of depressive disorder. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 3 | Psychiatry Clin. Neurosci. 2012 Dec 66: 622 |
| PMID | 23252931 |
| Title | Oxytocin receptor (OXTR) gene and risk of schizophrenia: case-control and family-based analyses and meta-analysis in a Japanese population. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic |
| 4 | PLoS ONE 2012 -1 7: e51882 |
| PMID | 23284802 |
| Title | Association between oxytocin receptor gene polymorphisms and self-rated 'empathic concern' in schizophrenia. |
| Abstract | The nonapeptide oxytocin (OXT) and its receptor (OXTR) have been implicated in social cognition, empathy, emotion and stress regulation in humans. Previous studies reported associations between OXT and OXTR genetic polymorphisms and risk for disorders characterized by impaired socio-emotional functioning, such as schizophrenia and autism. Here we investigate the influence of two single nucleotide polymorphisms (SNPs) within the OXTR gene on a measure of socio-emotional functioning in schizophrenic patients. OXTR SNPs that were previously investigated in other studies were genotyped in 145 patients diagnosed with schizophrenia according to DSM-IV and 145 healthy controls matched for age and gender. The Interpersonal Reactivity Index (IRI) was used to assess cognitive ('perspective taking'), affective ('empathic concern') and self-related ('personal distress') dimensions of empathy. No group differences in genotype frequencies were observed. MANCOVA revealed a significant main (F [1,282]?=?10.464; p<0.01) and interaction effect (genotype by diagnosis: F [1,282]?=?4.329; p<0.05) of OXTR SNP rs2254298(A>GG) with 'empathic concern'. Within the schizophrenia group, linear regression analysis determined OXTR rs2254298 genotype, PANSS negative and general symptom score, and age of disease onset as being significantly associated with 'empathic concern'. OXTR rs2254298 significantly impacted PANSS general psychopathology scores. No associations were found for OXTR rs53576, IRI 'perspective taking' or 'personal distress' ratings. Our preliminary findings support hypotheses about an involvement of OXTR rs2254298 in emotional empathy in schizophrenic and healthy individuals, warranting independent replication. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 5 | PLoS ONE 2012 -1 7: e51882 |
| PMID | 23284802 |
| Title | Association between oxytocin receptor gene polymorphisms and self-rated 'empathic concern' in schizophrenia. |
| Abstract | The nonapeptide oxytocin (OXT) and its receptor (OXTR) have been implicated in social cognition, empathy, emotion and stress regulation in humans. Previous studies reported associations between OXT and OXTR genetic polymorphisms and risk for disorders characterized by impaired socio-emotional functioning, such as schizophrenia and autism. Here we investigate the influence of two single nucleotide polymorphisms (SNPs) within the OXTR gene on a measure of socio-emotional functioning in schizophrenic patients. OXTR SNPs that were previously investigated in other studies were genotyped in 145 patients diagnosed with schizophrenia according to DSM-IV and 145 healthy controls matched for age and gender. The Interpersonal Reactivity Index (IRI) was used to assess cognitive ('perspective taking'), affective ('empathic concern') and self-related ('personal distress') dimensions of empathy. No group differences in genotype frequencies were observed. MANCOVA revealed a significant main (F [1,282]?=?10.464; p<0.01) and interaction effect (genotype by diagnosis: F [1,282]?=?4.329; p<0.05) of OXTR SNP rs2254298(A>GG) with 'empathic concern'. Within the schizophrenia group, linear regression analysis determined OXTR rs2254298 genotype, PANSS negative and general symptom score, and age of disease onset as being significantly associated with 'empathic concern'. OXTR rs2254298 significantly impacted PANSS general psychopathology scores. No associations were found for OXTR rs53576, IRI 'perspective taking' or 'personal distress' ratings. Our preliminary findings support hypotheses about an involvement of OXTR rs2254298 in emotional empathy in schizophrenic and healthy individuals, warranting independent replication. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 6 | World J. Biol. Psychiatry 2013 Sep 14: 500-8 |
| PMID | 22651577 |
| Title | Oxytocin and oxytocin receptor gene polymorphisms and risk for schizophrenia: a case-control study. |
| Abstract | Dysfunctions of the "social brain" belong to the core features of schizophrenia. The neurohormone oxytocin (OXT), mediated through its specific receptor (OXTR), is involved in the regulation of social behaviour and social cognition. Previous research has suggested a role of OXT system genes in disorders of social reciprocity. Preliminary evidence points to an association of peripheral OXT levels as well as OXT and OXTR gene polymorphisms with psychotic symptoms and treatment response in schizophrenia. This study aims to determine a possible contribution of OXT and OXTR genetic variations to schizophrenia susceptibility. Using n = 406 individuals diagnosed with schizophrenia according to DSM-IV and n = 406 healthy controls matched for age and gender in a case-control design, two single nucleotide polymorphisms (SNPs) within the OXT gene (rs2740204, rs2740210) and four SNPs within the OXTR gene (rs53576, rs237880, rs237885, rs237902) that were previously investigated in other studies were genotyped. Chi(2)-testing suggested significant associations of OXTR SNPs rs53576(A > G) (P = 0.008) and rs237885(T > G) (P = 0.025) with a diagnosis of schizophrenia. Post-hoc ANCOVA revealed significant associations of OXTR SNPs rs53576 with general psychopathology and rs237902 with negative symptom scores in schizophrenic patients. Our findings support hypotheses about an involvement of oxytocinergic gene variants in schizophrenia vulnerability and warrant independent replication. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 7 | World J. Biol. Psychiatry 2013 Sep 14: 500-8 |
| PMID | 22651577 |
| Title | Oxytocin and oxytocin receptor gene polymorphisms and risk for schizophrenia: a case-control study. |
| Abstract | Dysfunctions of the "social brain" belong to the core features of schizophrenia. The neurohormone oxytocin (OXT), mediated through its specific receptor (OXTR), is involved in the regulation of social behaviour and social cognition. Previous research has suggested a role of OXT system genes in disorders of social reciprocity. Preliminary evidence points to an association of peripheral OXT levels as well as OXT and OXTR gene polymorphisms with psychotic symptoms and treatment response in schizophrenia. This study aims to determine a possible contribution of OXT and OXTR genetic variations to schizophrenia susceptibility. Using n = 406 individuals diagnosed with schizophrenia according to DSM-IV and n = 406 healthy controls matched for age and gender in a case-control design, two single nucleotide polymorphisms (SNPs) within the OXT gene (rs2740204, rs2740210) and four SNPs within the OXTR gene (rs53576, rs237880, rs237885, rs237902) that were previously investigated in other studies were genotyped. Chi(2)-testing suggested significant associations of OXTR SNPs rs53576(A > G) (P = 0.008) and rs237885(T > G) (P = 0.025) with a diagnosis of schizophrenia. Post-hoc ANCOVA revealed significant associations of OXTR SNPs rs53576 with general psychopathology and rs237902 with negative symptom scores in schizophrenic patients. Our findings support hypotheses about an involvement of oxytocinergic gene variants in schizophrenia vulnerability and warrant independent replication. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 8 | Expert Opin Ther Pat 2014 Jan 24: 29-46 |
| PMID | 24094047 |
| Title | Novel oxytocin receptor agonists and antagonists: a patent review (2002 - 2013). |
| Abstract | Oxytocin is a nine amino acid cyclic peptide hormone with a high degree of uterotonic activity. The oxytocin receptor (OXTR) is most strongly expressed in the uterus and mammary gland, but can also be found in regions of the brain, showing a neurotransmitter-like activity. The OXTR knockout mice have no obvious defects in fertility or sexual behavior, but display aberrant social behavior. All of these suggest that OXTR may become an important therapeutic target for the treatment of a wide range of conditions. This article will highlight the significant progress that has been made in the discovery and development of OXTR agonists and antagonists in the patent literature between January 2002 and May 2013. In the past decade, cumulative evidence supports the idea that activation of the OXTR can have a positive effect upon human cognition and social behavior. The authors suggest that new agonists and antagonists may play an important role in the treatment of disorders such as anxiety, autism or schizophrenia. It may even be that older OXTR agonists and antagonists, which were used to overcome labor-related dysfunction, may also have a significant impact on human social behavior. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 9 | Psychoneuroendocrinology 2014 Jul 45: 128-41 |
| PMID | 24845184 |
| Title | The neuroanatomical distribution of oxytocin receptor binding and mRNA in the male rhesus macaque (Macaca mulatta). |
| Abstract | The rhesus macaque (Macaca mulatta) is an important primate model for social cognition, and recent studies have begun to explore the impact of oxytocin on social cognition and behavior. Macaques have great potential for elucidating the neural mechanisms by which oxytocin modulates social cognition, which has implications for oxytocin-based pharmacotherapies for psychiatric disorders such as autism and schizophrenia. Previous attempts to localize oxytocin receptors (OXTR) in the rhesus macaque brain have failed due to reduced selectivity of radioligands, which in primates bind to both OXTR and the structurally similar vasopressin 1a receptor (AVPR1A). We have developed a pharmacologically-informed competitive binding autoradiography protocol that selectively reveals OXTR and AVPR1A binding sites in primate brain sections. Using this protocol, we describe the neuroanatomical distribution of OXTR in the macaque. Finally, we use in situ hybridization to localize OXTR mRNA. Our results demonstrate that OXTR expression in the macaque brain is much more restricted than AVPR1A. OXTR is largely limited to the nucleus basalis of Meynert, pedunculopontine tegmental nucleus, the superficial gray layer of the superior colliculus, the trapezoid body, and the ventromedial hypothalamus. These regions are involved in a variety of functions relevant to social cognition, including modulating visual attention, processing auditory and multimodal sensory stimuli, and controlling orienting responses to visual stimuli. These results provide insights into the neural mechanisms by which oxytocin modulates social cognition and behavior in this species, which, like humans, uses vision and audition as the primary modalities for social communication. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 10 | Schizophr. Res. 2014 Nov 159: 353-7 |
| PMID | 25244972 |
| Title | Associations between oxytocin receptor genotypes and social cognitive performance in individuals with schizophrenia. |
| Abstract | Individuals with schizophrenia often show substantial deficits in social cognitive abilities, which are strongly associated with social functioning. To advance our understanding of the genetic variation that is associated with social cognitive deficits in schizophrenia, we genotyped 74 schizophrenia outpatients who completed social cognitive performance measures assessing mentalizing, social perception, and emotional intelligence, as well as clinical symptoms. We assessed seven single nucleotide polymorphisms (SNPs) of the oxytocin receptor (OXTR) previously found to show replicable associations with socio-emotional processes. For one of the seven SNPs, rs2268493, the 'T' allele was significantly associated with poorer performance on a composite social cognition index, as well as specific tests of mentalizing and social perception. None of the SNPs were associated with clinical symptoms. Though the sample size is small, these findings provide initial support for the involvement of genetic variants of the OXTR in social cognitive impairments in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 11 | Genes Brain Behav. 2014 Jan 13: 104-17 |
| PMID | 23927712 |
| Title | Theory of mind and the social brain: implications for understanding the genetic basis of schizophrenia. |
| Abstract | Genome-wide association studies in schizophrenia have recently made significant progress in our understanding of the complex genetic architecture of this disorder. Many genetic loci have been identified and now require functional investigation. One approach involves studying their correlation with neuroimaging and neurocognitive endophenotypes. Theory of Mind (ToM) deficits are well established in schizophrenia and they appear to fulfill criteria for being considered an endophenotype. We aim to review the behavioral and neuroimaging-based studies of ToM in schizophrenia, assess its suitability as an endophenotype, discuss current findings, and propose future research directions. Suitable research articles were sourced from a comprehensive literature search and from references identified through other studies. ToM deficits are repeatable, stable, and heritable: First-episode patients, those in remission and unaffected relatives all show deficits. Activation and structural differences in brain regions believed important for ToM are also consistently reported in schizophrenia patients at all stages of illness, although no research to date has examined unaffected relatives. Studies using ToM as an endophenotype are providing interesting genetic associations with both single nucleotide polymorphisms (SNPs) and specific copy number variations (CNVs) such as the 22q11.2 deletion syndrome. We conclude that ToM is an important cognitive endophenotype for consideration in future studies addressing the complex genetic architecture of schizophrenia, and may help identify more homogeneous clinical sub-types for further study. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 12 | Psychoneuroendocrinology 2014 Apr 42: 225-36 |
| PMID | 24636519 |
| Title | Dose-dependent effects of chronic central infusion of oxytocin on anxiety, oxytocin receptor binding and stress-related parameters in mice. |
| Abstract | Chronic psychosocial stress is a recognized risk factor for various affective and somatic disorders. In an established murine model of chronic psychosocial stress, exposure to chronic subordinate colony housing (CSC) results in an alteration of physiological, behavioral, neuroendocrine and immunological parameters, including a long-lasting increase in anxiety, adrenal hypertrophy and thymus atrophy. Based on the stress-protective and anxiolytic properties of oxytocin (OXT) after acute administration in rodents and humans, the major aims of our study were to assess whether chronic administration of OXT dose-dependently affects the behavior and physiology of male mice, as for therapeutic use in humans, mostly chronic treatment approaches will be used. Further, we studied, whether chronic administration during CSC prevents stress-induced consequences. Our results indicate that chronic intracerebroventricular (ICV) infusion of OXT (15 days) at high (10ng/h), but not at low (1ng/h) dose, induces an anxiogenic phenotype with a concomitant reduction of OXT receptor (OXTR) binding within the septum, the basolateral and medial amygdala, as well as the median raphe nucleus. Further, we demonstrate that chronic ICV infusion of OXT (1ng/h) during a 19-day CSC exposure prevents the hyper-anxiety, thymus atrophy, adrenal hypertrophy, and decreased in vitro adrenal ACTH sensitivity. Thus, given both negative, but also beneficial effects seen after chronic OXT treatment, which appear to be dose-dependent, a deeper understanding of long-lasting treatment effects is required before OXT can be considered for long-term therapeutic use for the treatment of psychopathologies such as autism, schizophrenia or anxiety-disorders. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 13 | Front Hum Neurosci 2015 -1 9: 9 |
| PMID | 25667571 |
| Title | Association between Genetic Variation in the Oxytocin Receptor Gene and Emotional Withdrawal, but not between Oxytocin Pathway Genes and Diagnosis in Psychotic Disorders. |
| Abstract | Social dysfunction is common in patients with psychotic disorders. Oxytocin is a neuropeptide with a central role in social behavior. This study aims to explore the relationship between oxytocin pathway genes and symptoms related to social dysfunction in patients with psychotic disorders. We performed association analyses between four oxytocin pathway genes (OXT, OXTR, AVP, and CD38) and four areas of social behavior-related psychopathology as measured by Positive and Negative Syndrome Scale. For this purpose, we used both a polygenic risk score (PGRS) and single OXTR candidate single nucleotide polymorphism previously reported in the literature (rs53576, rs237902, and rs2254298). A total of 734 subjects with DSM-IV psychotic spectrum disorders and 420 healthy controls were included. Oxytocin pathway PGRSs were calculated based on the independent Psychiatric Genomics Consortium study sample. There was a significant association between symptom of Emotional Withdrawal and the previously reported OXTR risk allele A in rs53576. No significant associations between oxytocin pathway gene variants and a diagnosis of psychotic disorder were found. Our findings indicate that while oxytocin pathway genes do not appear to contribute to the susceptibility to psychotic disorders, variations in the OXTR gene might play a role in the development of impaired social behavior. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 14 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2015 Oct 168: 609-16 |
| PMID | 26174935 |
| Title | Oxytocin system social function impacts in children with attention-deficit/hyperactivity disorder. |
| Abstract | To investigate relationships between the polymorphisms and social functioning of children with Attention Deficit/Hyperactivity Disorder (ADHD), according to the polymorphism of three oxytocin receptor (OXTR) genes (rs53576, rs13316193, and and rs2268493). A total of 198 children-studying in the same primary and secondary school and matched in terms of age and gender (99 ADHD, 99 control)-were included in this study. The Schedule for Affective Disorders and schizophrenia for School-Age Children-Present and Lifetime Version was administered to establish the clinical diagnosis. The Social Reciprocity Scale (SRS) was applied to evaluate social functioning. The total genomic DNA was isolated from buccal mucosa samples. No significant differences were determined between the ADHD and control groups in terms of rs2268493, rs13316193, and rs53576 genotype distribution (P = 0.078, P = 0.330, and P = 0.149, respectively). However, the control group T allele frequency in the OXTR Single Nucleotide Polymorphism (SNP) rs2268493 was significantly higher than the ADHD group (P = 0.024). Compared to the control group, the ADHD group had a higher score on the SRS scale (SRS total; Z =?-21,135, P < 0.001). No significant difference existed in the SRS scale scores between the children with the T/T genotype and the C allele in the ADHD group (SRS total; Z =?-0.543, P = 0.587). The allele distribution of the OXTR gene SNP rs2268493 was significantly different in the ADHD group, compared to the control group. This observation is important in understanding the underlying biological infrastructure in ADHD and developing treatment modalities. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 15 | Biol. Psychiatry 2016 Feb 79: 174-84 |
| PMID | 26392129 |
| Title | Oxytocin Pathway Genes: Evolutionary Ancient System Impacting on Human Affiliation, Sociality, and Psychopathology. |
| Abstract | Oxytocin (OT), a nonapeptide signaling molecule originating from an ancestral peptide, appears in different variants across all vertebrate and several invertebrate species. Throughout animal evolution, neuropeptidergic signaling has been adapted by organisms for regulating response to rapidly changing environments. The family of OT-like molecules affects both peripheral tissues implicated in reproduction, homeostasis, and energy balance, as well as neuromodulation of social behavior, stress regulation, and associative learning in species ranging from nematodes to humans. After describing the OT-signaling pathway, we review research on the three genes most extensively studied in humans: the OT receptor (OXTR), the structural gene for OT (OXT/neurophysin-I), and CD38. Consistent with the notion that sociality should be studied from the perspective of social life at the species level, we address human social functions in relation to OT-pathway genes, including parenting, empathy, and using social relationships to manage stress. We then describe associations between OT-pathway genes with psychopathologies involving social dysfunctions such as autism, depression, or schizophrenia. Human research particularly underscored the involvement of two OXTR single nucleotide polymorphisms (rs53576, rs2254298) with fewer studies focusing on other OXTR (rs7632287, rs1042778, rs2268494, rs2268490), OXT (rs2740210, rs4813627, rs4813625), and CD38 (rs3796863, rs6449197) single nucleotide polymorphisms. Overall, studies provide evidence for the involvement of OT-pathway genes in human social functions but also suggest that factors such as gender, culture, and early environment often confound attempts to replicate first findings. We conclude by discussing epigenetics, conceptual implications within an evolutionary perspective, and future directions, especially the need to refine phenotypes, carefully characterize early environments, and integrate observations of social behavior across ecological contexts. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 16 | Biol Psychiatry Cogn Neurosci Neuroimaging 2016 Mar 1: 141-151 |
| PMID | 26977453 |
| Title | Sex and diagnosis specific associations between DNA methylation of the oxytocin receptor gene with emotion processing and temporal-limbic and prefrontal brain volumes in psychotic disorders. |
| Abstract | The oxytocin (OT) system, including receptor epigenetic mechanisms, has been shown to influence emotion processing, especially in females. Whether OT receptor (OXTR) epigenetic alterations occur across psychotic disorders in relation to illness-related disturbances in social cognition and brain anatomy is unknown. Participants with affective and nonaffective psychotic disorders (92 women, 75 men) and healthy controls (38 women, 37 men) from the Chicago site of the BSNIP study completed the Penn Emotion Recognition Test (ER-40), a facial emotion recognition task. We measured cytosine methylation at site -934 upstream of the OXTR start codon in DNA from whole blood, and for the first time their relationship with plasma OT levels assessed by enzyme-immunoassay. Volumes of brain regions supporting social cognition were measured from MRI scans using FreeSurfer. Patients with prototypic schizophrenia features showed higher levels of DNA methylation than those with prototypic bipolar features. Methylation was higher in women than men, and was associated with poorer emotion recognition only in female patients and controls. Greater methylation was associated with smaller volumes in temporal-limbic and prefrontal regions associated previously with social cognition, but only in healthy women and females with schizophrenia. DNA methylation of the OXTR site -934 was higher in schizophrenia spectrum than bipolar patients. Among patients, it was linked to behavioral deficits in social cognition and neuroanatomic structures known to support emotion processing only in schizophrenia spectrum individuals. |
| SCZ Keywords | schizophrenia, schizophrenic |