| 1 | Biol. Psychiatry 2005 Sep 58: 401-7 |
|---|---|
| PMID | 15978554 |
| Title | Association of an orexin 1 receptor 408Val variant with polydipsia-hyponatremia in schizophrenic subjects. |
| Abstract | Primary polydipsia is a common complication in patients with chronic psychoses, particularly schizophrenia. Disease pathogenesis is poorly understood, but one contributory factor is thought to be dopamine dysregulation caused by prolonged treatment with neuroleptics. Both angiotensin-converting enzyme (ACE) and orexin (hypocretin) signaling can modulate drinking behavior through interactions with the dopaminergic system. We performed association studies on the insertion/deletion (I/D) sequence polymorphism of ACE and single nucleotide polymorphisms within the prepro-orexin (HCRT), orexin receptor 1 (HCRTR1), and orexin receptor 2 (HCRTR2) genes. Genotypes were determined by polymerase chain reaction amplification, followed by either electrophoretic separation or direct sequencing. The ACE I/D polymorphism showed no association with polydipsic schizophrenia. Screening of the orexin signaling system detected a 408 isoleucine to valine mutation in HCRTR1 that showed significant genotypic association with polydipsic-hyponatremic schizophrenia (p = .012). The accumulation of this mutation was most pronounced in polydipsic versus nonpolydipsic schizophrenia (p = .0002 and p = .008, for the respective genotypic and allelic associations). The calcium mobilization properties and the protein localization of mutant HCRTR1 seem to be unaltered. Our preliminary data suggest that mutation carriers might have an increased susceptibility to polydipsia through an undetermined mechanism. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 2 | Biol. Psychiatry 2005 Sep 58: 401-7 |
| PMID | 15978554 |
| Title | Association of an orexin 1 receptor 408Val variant with polydipsia-hyponatremia in schizophrenic subjects. |
| Abstract | Primary polydipsia is a common complication in patients with chronic psychoses, particularly schizophrenia. Disease pathogenesis is poorly understood, but one contributory factor is thought to be dopamine dysregulation caused by prolonged treatment with neuroleptics. Both angiotensin-converting enzyme (ACE) and orexin (hypocretin) signaling can modulate drinking behavior through interactions with the dopaminergic system. We performed association studies on the insertion/deletion (I/D) sequence polymorphism of ACE and single nucleotide polymorphisms within the prepro-orexin (HCRT), orexin receptor 1 (HCRTR1), and orexin receptor 2 (HCRTR2) genes. Genotypes were determined by polymerase chain reaction amplification, followed by either electrophoretic separation or direct sequencing. The ACE I/D polymorphism showed no association with polydipsic schizophrenia. Screening of the orexin signaling system detected a 408 isoleucine to valine mutation in HCRTR1 that showed significant genotypic association with polydipsic-hyponatremic schizophrenia (p = .012). The accumulation of this mutation was most pronounced in polydipsic versus nonpolydipsic schizophrenia (p = .0002 and p = .008, for the respective genotypic and allelic associations). The calcium mobilization properties and the protein localization of mutant HCRTR1 seem to be unaltered. Our preliminary data suggest that mutation carriers might have an increased susceptibility to polydipsia through an undetermined mechanism. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 3 | Front Neurosci 2014 -1 8: 57 |
| PMID | 24834023 |
| Title | OX1 and OX2 orexin/hypocretin receptor pharmacogenetics. |
| Abstract | Orexin/hypocretin peptide mutations are rare in humans. Even though human narcolepsy is associated with orexin deficiency, this is only extremely rarely due to mutations in the gene coding prepro-orexin, the precursor for both orexin peptides. In contrast, coding and non-coding variants of the OX1 and OX2 orexin receptors have been identified in many human populations; sometimes, these have been associated with disease phenotype, although most confer a relatively low risk. In most cases, these studies have been based on a candidate gene hypothesis that predicts the involvement of orexins in the relevant pathophysiological processes. In the current review, the known human OX1/HCRTR1 and OX2/HCRTR2 genetic variants/polymorphisms as well as studies concerning their involvement in disorders such as narcolepsy, excessive daytime sleepiness, cluster headache, polydipsia-hyponatremia in schizophrenia, and affective disorders are discussed. In most cases, the functional cellular or pharmacological correlates of orexin variants have not been investigated-with the exception of the possible impact of an amino acid 10 Pro/Ser variant of OX2 on orexin potency-leaving conclusions on the nature of the receptor variant effects speculative. Nevertheless, we present perspectives that could shape the basis for further studies. The pharmacology and other properties of the orexin receptor variants are discussed in the context of GPCR signaling. Since orexinergic therapeutics are emerging, the impact of receptor variants on the affinity or potency of ligands deserves consideration. This perspective (pharmacogenetics) is also discussed in the review. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 4 | Sleep Med. 2014 Jan 15: 15-22 |
| PMID | 24268496 |
| Title | Narcolepsy-cataplexy and schizophrenia in adolescents. |
| Abstract | Despite advances in the understanding of narcolepsy, little information the on association between narcolepsy and psychosis is available, except for amphetamine-related psychotic reactions. Our case-control study aimed to compare clinical differences and analyze risk factors in children who developed narcolepsy with cataplexy (N-C), schizophrenia, and N-C followed by schizophrenia. Three age- and gender-matched groups of children with N-C schizophrenia (study group), N-C (control group 1), and schizophrenia only (control group 2) were investigated. Subjects filled out sleep questionnaires, sleep diaries, and quality of life scales, followed by polysomnography (PSG), multiple sleep latency tests (MSLT), routine blood tests, HLA typing, genetic analysis of genes of interest, and psychiatric evaluation. The risk factors for schizophrenia also were analyzed. The study group was significantly overweight when measuring body mass index (BMI) (P=.016), at narcolepsy onset compared to control group 1, and the study group developed schizophrenia after a mean of 2.55±1.8 years. Compared to control group 2, psychotic symptoms were significantly more severe in the study group, with a higher frequency of depressive symptoms and acute ward hospitalization in 8 out of 10 of the subjects. They also had poorer long-term response to treatment, despite multiple treatment trials targeting their florid psychotic symptoms. All subjects with narcolepsy were HLA DQ B1(?)0602 positive. The study group had a significantly higher frequency of DQ B1(?)-03:01/06:02 (70%) than the two other groups, without any significant difference in HLA-DR typing, tumor necrosis factor ? (TNF-?) levels, hypocretin (orexin) receptor 1 gene, HCRTR1, and the hypocretin (orexin) receptor 2 gene, HCRTR2, or blood infectious titers. BMI and weight at onset of narcolepsy as well as a higher frequency of DQ B1(?)-03:01/06:02 antigens were the only significant differences in the N-C children with secondary schizophrenia; such an association is a therapeutic challenge with long-term persistence of severe psychotic symptoms. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 5 | World J. Biol. Psychiatry 2016 Apr 17: 221-9 |
| PMID | 26447462 |
| Title | Association of orexin receptor polymorphisms with antipsychotic-induced weight gain. |
| Abstract | Antipsychotic-induced weight gain (AIWG) is a common side effect of treatment with antipsychotics such as clozapine and olanzapine. The orexin gene and its receptors are expressed in the hypothalamus and have been associated with maintenance of energy homeostasis. In this study, we have analysed tagging single nucleotide polymorphisms (SNPs) in orexin receptors 1 and 2 (HCRTR1 and HCRTR2) for association with AIWG. schizophrenia or schizoaffective disorder subjects (n?=?218), treated mostly with clozapine and olanzapine for up to 14 weeks, were included. Replication was conducted in a subset of CATIE samples (n?=?122) treated with either olanzapine or risperidone for up to 190 days. Association between SNPs and AIWG was assessed using analysis of covariance (ANCOVA) with baseline weight and duration of treatment as covariates. Several SNPs in HCRTR2 were nominally associated with AIWG in patients of European ancestry treated with either clozapine or olanzapine (P<0.05). In the replication analysis two SNPs rs3134701 (P?=?0.043) and rs12662510 (P?=?0.012) were nominally associated with AIWG. None of the SNPs in HCRTR1 were associated with AIWG. This study provides preliminary evidence supporting the role of HCRTR2 in AIWG. However, these results need to be confirmed in large study samples. |
| SCZ Keywords | schizophrenia, schizophrenic |