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Sui B, Li S, Wang P, Li X, Sun M, Bu Y, Li Z, Miao W, Cai L, Xi J, Song C, Zhu W. Niacin skin flushing response in patients with schizophrenia: Associations with the efficacy of modified electroconvulsive therapy and clinical symptoms. J Psychiatr Res 2025; 186:226-234. [PMID: 40252363 DOI: 10.1016/j.jpsychires.2025.04.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 03/18/2025] [Accepted: 04/14/2025] [Indexed: 04/21/2025]
Abstract
OBJECTIVE Schizophrenia (SZ) is a group of chronic neurodevelopmental disorders, and antipsychotic medication is the main clinical treatment. However, approximately one-third of patients demonstrate inadequate response to these medications, which is termed treatment-resistant schizophrenia (TRS). The primary objective of this study was to explore the clinical characteristics of patients with TRS, including positive, negative, general psychotic symptoms and niacin skin flushing response (NSFR), which is considered an auxiliary diagnostic biomarker for SZ, and the improvement of these characteristics after modified electroconvulsive therapy (MECT). METHODS This study included 32 patients with TRS, who received MECT combined with antipsychotic medication (SZ-MECT group), and 30 patients with non-treatment-resistant SZ (N-TRS), who received antipsychotic medication alone (SZ-N group). We assessed disease severity with the Positive and Negative Syndrome Scale (PANSS) and NSFR at baseline and at weeks 2, 4, and 6 in all patients. RESULTS At baseline, the SZ-MECT group had greater PANSS scores (P < 0.0001) and a more blunted NSFR (P = 0.020) than the SZ-N group did, and the PANSS-TOTAL scores were negatively correlated with the NSFR scores (r = -0.361, P = 0.0039). At week 6 after treatment, the SZ-MECT group presented significantly improved PANSS scores (P < 0.0001) and NSFR blunting (P = 0.010) that were comparable with those in the SZ-N group. CONCLUSION Compared with patients with N-TRS, patients with TRS presented more severe clinical symptoms and a more blunted NSFR, which significantly improved after MECT treatment. The NSFR may have good clinical application potential as an auxiliary assessment of severity and MECT efficacy in patients with schizophrenia.
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Affiliation(s)
- Bingbing Sui
- Bengbu Medical University, Bengbu, 233000, China
| | - Shuhui Li
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200030, China
| | - Pingsheng Wang
- The Fourth People's Hospital of Wuhu, Wuhu, 241000, China
| | - Xiaoyue Li
- The Fourth People's Hospital of Wuhu, Wuhu, 241000, China
| | | | - Yangying Bu
- The Fourth People's Hospital of Wuhu, Wuhu, 241000, China
| | - Zixiang Li
- Bengbu Medical University, Bengbu, 233000, China
| | - Wenwen Miao
- The Fourth People's Hospital of Wuhu, Wuhu, 241000, China
| | - Lei Cai
- The Fourth People's Hospital of Wuhu, Wuhu, 241000, China
| | - Jiawei Xi
- The Fourth People's Hospital of Wuhu, Wuhu, 241000, China
| | - Chuanfu Song
- The Fourth People's Hospital of Wuhu, Wuhu, 241000, China
| | - Wenli Zhu
- The Fourth People's Hospital of Wuhu, Wuhu, 241000, China.
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Wang J, Wang Q, Wang D, Gao Y, Li S, Wang T, Liu H, Wang H, Hu X, Wan C. Blunted Niacin Skin Flushing Response in Schizophrenia: A Meta-analysis. Schizophr Bull 2025:sbaf069. [PMID: 40401804 DOI: 10.1093/schbul/sbaf069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/23/2025]
Abstract
BACKGROUND AND HYPOTHESIS The multifactorial pathogenesis of schizophrenia (SZ) hinders the diagnosis and treatment of this disorder. Niacin skin flushing response (NSFR) has been identified as an endophenotype for SZ, but the proportion of blunted NSFR (BNR) varied between studies. This study aims to clarify the relationship between NSFR and SZ through a meta-analysis. STUDY DESIGN PubMed, Embase, Web of Science, Cochrane, and Scopus databases were searched for articles published until May 2024, and 32 studies were eligible. Using random-effects models, we examined the characteristics of NSFR in SZ, including the reaction degree, speed, sensitivity, and risk and prevalence of BNR. Subgroup analyses and regression analyses were performed to investigate the relevant effect factors of NSFR. STUDY RESULTS The reaction degree (SMD = -0.90; CI, -1.08 to -0.72), speed (SMD = 0.64; CI, 0.02-1.25), and sensitivity (SMD = 0.89; CI, 0.49-1.29) of NSFR was significantly reduced in SZ compared to healthy controls (HC). Moreover, we observed a positive association between BNR and SZ (OR = 8.50; CI, 5.93-12.19). The overall prevalence of BNR was 58.5% in SZ (CI, 49.3%-67.8%) compared to 11.8% in HC (CI, 7.7%-15.9%). In addition, NSFR detection method, geographical regions, and age were found to have effects on reaction degree and prevalence of BNR. CONCLUSIONS This study confirmed a significantly abnormal NSFR and higher prevalence of BNR in SZ, which highlights the potential facilitation of the diagnosis and personalized intervention of SZ subgroups. In addition, the study points to a need to establish a standardized method for NSFR assessment.
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Affiliation(s)
- Jinfeng Wang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - Qian Wang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - Dandan Wang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - Yan Gao
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - Shuhui Li
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - Tianqi Wang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - Hao Liu
- Department of Psychiatry, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Huiling Wang
- Department of Psychiatry, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Xiaowen Hu
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - Chunling Wan
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
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Oxenkrug G, Forester B. Anthranilic Acid, a GPR109A Agonist, and Schizophrenia. Int J Tryptophan Res 2024; 17:11786469241239125. [PMID: 38532858 PMCID: PMC10964450 DOI: 10.1177/11786469241239125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Accepted: 02/27/2024] [Indexed: 03/28/2024] Open
Abstract
Introduction Limited clinical efficiency of current medications warrants search for new antipsychotic agents. Deorphanized G-protein coupled receptor (GPR)109A has not attracted much of attention of schizophrenia researchers. We analyzed literature and our data on endogenous agonists of GPR109A, beta-hydroxybutyrate (BHB), anthranilic (AA), butyric (BA), and nicotinic (NA) acids, in individuals with schizophrenia. Data Sex specific differences: plasma AA levels were 27% higher in female than in male patients and correlated with PANSS before 6 weeks of antipsychotics treatment (r = .625, P < .019, Spearman's test). There was no sex specific differences of plasma AA levels after treatment. AA plasma levels inversely correlated (-.58, P < .005) with PANSS scores in responders to treatment (at least, 50% improvement) but not in nonresponders. Preclinical studies suggested antipsychotic effect of BHB and BA. Clinical studies observed antipsychotic effect of NA; benzoate sodium, an AA precursor; and interventions associated with BHB upregulation (eg, fasting and ketogenic diets). Discussion Upregulation of GPR109A, an anti-inflammatory and neuroprotective receptor, inhibits cytosolic phospholipase A2 (cPLA2), an enzyme that breakdown myelin, lipid-based insulating axonal sheath that protects and promotes nerve conduction. Brain cPLA2 is upregulated in individuals with schizophrenia and subjects at high-risk for development of psychosis. Lower myelin content is associated with cognitive decline in individuals with schizophrenia. Therefore, GPR109A might exert antipsychotic effect via suppression of cPLA2, and, consequently, preservation of myelin integrity. Future research might explore antipsychotic effects of (1) human pegylated kynureninase, an enzyme that catalyzes formation of AA from kynurenine (Kyn); (2) inhibitors of Kyn conversion into kynurenic acid, for example, KYN5356, to patients with already impaired Kyn conversion into 3-hydroxykynurenine; (3) synthetic GPR 109A agonists, for example, MK-1903 and SCH900271 and GSK256073, that underwent clinical trials as anti-dyslipidemia agents. GPR109A expression, that might be a new endophenotype of schizophrenia, especially associated with cognitive impairment, needs thorough assessment.
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Affiliation(s)
- Gregory Oxenkrug
- Department of Psychiatry, Tufts University School of Medicine, Boston MA, USA
| | - Brent Forester
- Department of Psychiatry, Tufts University School of Medicine, Boston MA, USA
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Jiang J, Wang D, Gao Y, Sun L, Li S, Hu X, Li Z, Zhang J, Ji F, Tian Y, Guan L, Li Z, He L, Wan C. Altered HCAR3 expression may underlying the blunted niacin responses of the psychiatric disorders and the risk of schizophrenia. Psychiatry Clin Neurosci 2024; 78:123-130. [PMID: 37984442 DOI: 10.1111/pcn.13617] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2023] [Revised: 10/24/2023] [Accepted: 11/09/2023] [Indexed: 11/22/2023]
Abstract
AIM Blunted niacin response (BNR) was an endophenotype of schizophrenia, but the underlying mechanism remains unclarified. The objective of this study was to verify whether genes associated with BNR pathway constitute the genetic basis and the pathological mechanism of BNR phenotypic psychiatric patients. METHODS Two independent sample sets consisting of 971 subjects were enrolled in this study. A total of 62 variants were genotyped in the discovery set, then the related variants were verified in the verification set. The published PGC GWAS data were used to validate the associations between the variants and psychiatry disorders. RT-PCR analysis, eQTL data, and Dual-Luciferase Reporter experiment were used to investigate the potential molecular mechanisms of the variants underlying BNR. RESULTS The results showed that two SNPs, rs56959712 in HCAR2 and rs2454721 in HCAR3 were significantly associated with niacin response. The risk allele T of rs2454721 could affect the niacin responses of psychiatric patients through elevated HCAR3 gene expression. These two genes, especially HCAR3, were significantly associated with the risk of schizophrenia, as identified in this study and verified using the published GWAS data. CONCLUSION HCAR3 is a novel schizophrenia susceptibility gene which is significantly associated with blunted niacin response in schizophrenia. In-depth investigation of HCAR3 is of great significance for uncovering the pathogenesis and propose new therapeutic targets for psychiatric disorders, especially for the BNR subgroup patients.
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Affiliation(s)
- Jie Jiang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - Dandan Wang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - Yan Gao
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - Liya Sun
- Shanghai Mental Health Center, Shanghai Key Laboratory of Psychiatry Disorders, Shanghai Jiao Tong University, Shanghai, China
| | - Shuhui Li
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaowen Hu
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - Zhuyun Li
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - Juan Zhang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - Feng Ji
- Institute of Mental Health, Jining Medical University, Jining, China
| | - Yusheng Tian
- National Clinical Research Center for Mental Disorders, Department of Psychiatry and Hunan Medical Center for Mental Health, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Lili Guan
- Peking University Sixth Hospital, Peking University Institute of Mental Health, Beijing, China
| | - Zhiqiang Li
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
- The Affiliated Hospital of Qingdao University and the Biomedical Sciences Institute of Qingdao University, Qingdao Branch of SJTU Bio-X Institutes, Qingdao University, Qingdao, China
| | - Lin He
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - Chunling Wan
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Mental Health Center, Shanghai Key Laboratory of Psychiatry Disorders, Shanghai Jiao Tong University, Shanghai, China
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Zhang T, Gan R, Zeng J, Ye J, Hu Y, Xu L, Wei Y, Tang X, Li C, Liu H, Chen T, Wang J. Attenuated niacin response is associated with a subtype of first-episode drug-naïve psychosis characterized as serious negative symptoms. Eur Arch Psychiatry Clin Neurosci 2023; 273:1725-1736. [PMID: 36688979 DOI: 10.1007/s00406-023-01556-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Accepted: 01/09/2023] [Indexed: 01/24/2023]
Abstract
Although the phenomenon of attenuated niacin response (ANR) has been widely replicated in some patients with first-episode psychosis (FEP), its relevance to the negative symptoms (NS) of psychosis remains unclear. Total of 240 patients with drug-naïve FEP and 101 healthy controls (HCs) were recruited, and 209 were followed up for 1 year. Psychotic symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS), and niacin-induced responses were measured using laser Doppler flowmetry. We calculated the log-transform EC50 [concentration of methyl nicotinate required to elicit a half-maximal blood flow (MBF) response] and MBF values. Core-NS was generated by factor analysis of the PANSS-NS subscale and cluster analysis to produce subtypes. Significant differences were found in the log10 (EC50) values between the FEP and HC groups (p < 0.001), supporting the ANR in patients with FEP. A higher NS severity was found in the ANR subgroup than that in other patients. Factor analysis determined that a two-dimensional model included core NS and rigidity of thinking. The log10 (EC50) value was significantly associated with only the core NS. Cluster analysis revealed three subtypes-36.7% (cluster-1, n = 88), 16.7% (cluster-2, n = 40), and 46.7% (cluster-3, n = 112). Cluster-2 characterized by extensive NS appeared to have a more remarkable ANR and less symptomatic improvement than those with other clusters during follow-up. No significant changes were found in the niacin response trajectories between the baseline and follow-up. Our findings indicate a significant correlation between ANR and core NS in patients with FEP. ANR may be a potential biomarker for certain subtypes with NS-dominated characteristics and poor symptomatic remission.
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Affiliation(s)
- TianHong Zhang
- Shanghai Intelligent Psychological Evaluation and Intervention Engineering Technology Research Center (20DZ2253800), Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, 600 Wanping Nan Road, Shanghai, 200030, China.
| | - RanPiao Gan
- Shanghai Intelligent Psychological Evaluation and Intervention Engineering Technology Research Center (20DZ2253800), Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, 600 Wanping Nan Road, Shanghai, 200030, China
| | - JiaHui Zeng
- Shanghai Intelligent Psychological Evaluation and Intervention Engineering Technology Research Center (20DZ2253800), Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, 600 Wanping Nan Road, Shanghai, 200030, China
| | - JiaYi Ye
- Shanghai Intelligent Psychological Evaluation and Intervention Engineering Technology Research Center (20DZ2253800), Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, 600 Wanping Nan Road, Shanghai, 200030, China
| | - YeGang Hu
- Shanghai Intelligent Psychological Evaluation and Intervention Engineering Technology Research Center (20DZ2253800), Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, 600 Wanping Nan Road, Shanghai, 200030, China
| | - LiHua Xu
- Shanghai Intelligent Psychological Evaluation and Intervention Engineering Technology Research Center (20DZ2253800), Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, 600 Wanping Nan Road, Shanghai, 200030, China
| | - YanYan Wei
- Shanghai Intelligent Psychological Evaluation and Intervention Engineering Technology Research Center (20DZ2253800), Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, 600 Wanping Nan Road, Shanghai, 200030, China
| | - XiaoChen Tang
- Shanghai Intelligent Psychological Evaluation and Intervention Engineering Technology Research Center (20DZ2253800), Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, 600 Wanping Nan Road, Shanghai, 200030, China
| | - ChunBo Li
- Shanghai Intelligent Psychological Evaluation and Intervention Engineering Technology Research Center (20DZ2253800), Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, 600 Wanping Nan Road, Shanghai, 200030, China
| | - HaiChun Liu
- Department of Automation, Shanghai Jiao Tong University, Shanghai, 200240, People's Republic of China
| | - Tao Chen
- Department of Automation, Shanghai Jiao Tong University, Shanghai, 200240, People's Republic of China
- Big Data Research Lab, University of Waterloo, Waterloo, ON, Canada
- Labor and Worklife Program, Harvard University, Cambridge, MA, USA
| | - JiJun Wang
- Shanghai Intelligent Psychological Evaluation and Intervention Engineering Technology Research Center (20DZ2253800), Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, 600 Wanping Nan Road, Shanghai, 200030, China.
- Center for Excellence in Brain Science and Intelligence Technology (CEBSIT), Chinese Academy of Science, Beijing, People's Republic of China.
- Brain Science and Technology Research Center, Shanghai Jiao Tong University, Shanghai, People's Republic of China.
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Nadalin S, Zatković L, Peitl V, Karlović D, Vidrih B, Puljić A, Pavlić SD, Buretić-Tomljanović A. Association between PLA2 gene polymorphisms and treatment response to antipsychotic medications: A study of antipsychotic-naïve first-episode psychosis patients and nonadherent chronic psychosis patients. Prostaglandins Leukot Essent Fatty Acids 2023; 194:102578. [PMID: 37290257 DOI: 10.1016/j.plefa.2023.102578] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 05/26/2023] [Accepted: 05/31/2023] [Indexed: 06/10/2023]
Abstract
Here we investigated whether antipsychotic treatment was influenced by three polymorphisms: rs10798059 (BanI) in the phospholipase A2 (PLA2)G4A gene, rs4375 in PLA2G6, and rs1549637 in PLA2G4C. A total of 186 antipsychotic-naïve first-episode psychosis patients or nonadherent chronic psychosis individuals (99 males and 87 females) were genotyped by polymerase chain reaction analysis/restriction fragment length polymorphism. At baseline, and after 8 weeks of treatment with various antipsychotic medications, we assessed patients' Positive and Negative Syndrome Scale (PANSS) scores, PANSS factors, and metabolic syndrome-related parameters (fasting plasma lipid and glucose levels, and body mass index). We found that PLA2G4A polymorphism influenced changes in PANSS psychopathology, and PLA2G6 polymorphism influenced changes in PANSS psychopathology and metabolic parameters. PLA2G4C polymorphism did not show any impact on PANSS psychopathology or metabolic parameters. The polymorphisms' effect sizes were estimated as moderate to strong, with contributions ranging from around 6.2-15.7%. Furthermore, the polymorphisms' effects manifested in a gender-specific manner.
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Affiliation(s)
- Sergej Nadalin
- Department of Psychiatry, General Hospital "Dr. Josip Benčević", Slavonski Brod, Croatia; School of Medicine, Catholic University of Croatia, Zagreb, Croatia.
| | - Lena Zatković
- Hospital pharmacy, Clinical Hospital Center Rijeka, Rijeka, Croatia
| | - Vjekoslav Peitl
- School of Medicine, Catholic University of Croatia, Zagreb, Croatia; Department of Psychiatry, Sestre Milosrdnice University Hospital Center, Zagreb, Croatia
| | - Dalibor Karlović
- School of Medicine, Catholic University of Croatia, Zagreb, Croatia; Department of Psychiatry, Sestre Milosrdnice University Hospital Center, Zagreb, Croatia
| | - Branka Vidrih
- School of Medicine, Catholic University of Croatia, Zagreb, Croatia; Department of Psychiatry, Sestre Milosrdnice University Hospital Center, Zagreb, Croatia
| | - Antonia Puljić
- School of Medicine, Catholic University of Croatia, Zagreb, Croatia; Department of Psychiatry, Sestre Milosrdnice University Hospital Center, Zagreb, Croatia
| | - Sanja Dević Pavlić
- Department of Medical Biology and Genetics, Faculty of Medicine, University of Rijeka, Rijeka, Croatia
| | - Alena Buretić-Tomljanović
- Department of Medical Biology and Genetics, Faculty of Medicine, University of Rijeka, Rijeka, Croatia
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Sitarz R, Juchnowicz D, Karakuła K, Forma A, Baj J, Rog J, Karpiński R, Machrowska A, Karakuła-Juchnowicz H. Niacin Skin Flush Backs-From the Roots of the Test to Nowadays Hope. J Clin Med 2023; 12:1879. [PMID: 36902666 PMCID: PMC10003235 DOI: 10.3390/jcm12051879] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Revised: 02/22/2023] [Accepted: 02/23/2023] [Indexed: 03/08/2023] Open
Abstract
The niacin skin flush test (NSFT) is a simple method used to assess the content of fatty acids in cell membranes and is a possible indicator of factors hidden behind various outcomes in patients. The purpose of this paper is to determine the potential usefulness of NSFT in mental disorder diagnostics along with the determination of factors that may affect its results. The authors reviewed articles from 1977 onwards, focusing on the history, variety of methodologies, influencing factors, and proposed mechanisms underlying its performance. Research indicated that NSFT could be applicable in early intervention, staging in psychiatry, and the search for new therapeutic methods and drugs based on the mechanisms of NSFT action. The NSFT can contribute to defining an individualized diet for patients and prevent the development of damaging disease effects at an early stage. There is promising evidence for supplementation with polyunsaturated fatty acids, which have a beneficial influence on the metabolic profile and are effective even in the subclinical phase of the disease. NSFT can contribute to the new classification of diseases and a better understanding of certain mental disorders' pathophysiology. However, there is a need to establish a validated method for assessing the NSFT results.
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Affiliation(s)
- Ryszard Sitarz
- 1st Department of Psychiatry, Psychotherapy and Early Intervention, Medical University of Lublin, Gluska Street 1, 20-439 Lublin, Poland
| | - Dariusz Juchnowicz
- Department of Psychiatry and Psychiatric Nursing, Medical University of Lublin, 20-059 Lublin, Poland
| | - Kaja Karakuła
- 1st Department of Psychiatry, Psychotherapy and Early Intervention, Medical University of Lublin, Gluska Street 1, 20-439 Lublin, Poland
- Department of Forensic Medicine, Medical University of Lublin, 20-059 Lublin, Poland
| | - Alicja Forma
- 1st Department of Psychiatry, Psychotherapy and Early Intervention, Medical University of Lublin, Gluska Street 1, 20-439 Lublin, Poland
- Department of Forensic Medicine, Medical University of Lublin, 20-059 Lublin, Poland
| | - Jacek Baj
- Department of Anatomy, Medical University of Lublin, 20-059 Lublin, Poland
| | - Joanna Rog
- Department of Dietetics, Institute of Human Nutrition Sciences, Warsaw University of Life Sciences (SGGW-WULS), 02-776 Warsaw, Poland
| | - Robert Karpiński
- 1st Department of Psychiatry, Psychotherapy and Early Intervention, Medical University of Lublin, Gluska Street 1, 20-439 Lublin, Poland
- Department of Machine Design and Mechatronics, Faculty of Mechanical Engineering, Lublin University of Technology, 20-618 Lublin, Poland
| | - Anna Machrowska
- Department of Machine Design and Mechatronics, Faculty of Mechanical Engineering, Lublin University of Technology, 20-618 Lublin, Poland
| | - Hanna Karakuła-Juchnowicz
- 1st Department of Psychiatry, Psychotherapy and Early Intervention, Medical University of Lublin, Gluska Street 1, 20-439 Lublin, Poland
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Yu YH, Su HM, Lin SH, Hsiao PC, Lin YT, Liu CM, Hwang TJ, Hsieh MH, Liu CC, Chien YL, Kuo CJ, Hwu HG, Chen WJ. Niacin skin flush and membrane polyunsaturated fatty acids in schizophrenia from the acute state to partial remission: a dynamic relationship. SCHIZOPHRENIA 2022; 8:38. [PMID: 35853900 PMCID: PMC9261101 DOI: 10.1038/s41537-022-00252-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Accepted: 03/28/2022] [Indexed: 11/13/2022]
Abstract
Despite the consistent finding of an attenuated niacin-induced flush response in schizophrenia, its long-term stability and relationship to the membrane polyunsaturated fatty acid (PUFA) levels remain unknown. We conducted niacin skin tests and measured the membrane PUFAs using gas chromatography among 46 schizophrenia inpatients and 37 healthy controls at the baseline and the 2-month follow-up. Attenuated flush responses were persistently observed in schizophrenia patients in both acute and partial remission states, whereas an increased flush response was found in the controls. A persistent decrease in both dihomo-gamma-linolenic acid and docosahexaenoic acid and an increased turnover of arachidonic acid (ARA) via endogenous biosynthesis were found in schizophrenia patients. A composite niacin flush score by combining those with a control-to-case ratio of >1.4 (i.e., scores at 5 min of 0.1 M, 0.01 M, and 0.001 M + 10 min of 0.01 M and 0.001 M + 15 min of 0.001 M) at the baseline was correlated positively with ARA levels among controls but not among schizophrenia patients, whereas the flush score at the 2-month follow-up was correlated positively with ARA levels among patients. The 2-month persistence of attenuated niacin-induced flush response in schizophrenia patients implies that the niacin skin test might tap a long-term vulnerability to schizophrenia beyond acute exacerbation.
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Gan R, Zhao Y, Wu G, Zeng J, Hu Y, Xu L, Wei Y, Tang X, Liu X, Liu H, Chen T, Wang J, Zhang T. Replication of the abnormal niacin response in first episode psychosis measured using laser Doppler flowmeter. Asia Pac Psychiatry 2022; 14:e12516. [PMID: 35652467 DOI: 10.1111/appy.12516] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 02/24/2022] [Accepted: 05/18/2022] [Indexed: 11/28/2022]
Abstract
INTRODUCTION Impaired sensitivity of the skin flush response to niacin is found in approximately 30% of patients with schizophrenia. Although the niacin response abnormality (NRA) may serve as a useful endophenotype for schizophrenia, few studies have directly replicated NRA in patients with first-episode psychosis (FEP). METHODS In total, 204 patients with FEP, 16 with psychotic mood disorder (PMD), and 68 healthy controls (HC) were included. The log10 (EC50 ) values represent the concentration of methyl nicotinate required to elicit a half-maximal blood flow (MBF) response, and the MBF value was calculated. The NRA was defined as having log10 (EC50 ) molar value above the 90% and an MBF value below the 60% of those in the HC group. RESULTS In total, 13.7% of the FEP, 12.5% of the PMD, and 7.4% of the HC group met the definition of NRA. Significant differences were found in the log10 (EC50 ) values between the FEP and HC groups (p = .014) and in the MBF between the FEP and PMD groups (p = .011). Patients with FEP and NRA had more severe negative symptoms than those with a normal niacin response. DISCUSSION These data represent the NRA in patients with FEP, defining a small subgroup of patients with early-phase psychosis possessing a clinically significant phospholipid-signaling defect.
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Affiliation(s)
- RanPiao Gan
- Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, Shanghai Key Laboratory of Psychotic Disorders, Shanghai, China
| | - YuanQiao Zhao
- Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, Shanghai Key Laboratory of Psychotic Disorders, Shanghai, China
| | - GuiSen Wu
- Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, Shanghai Key Laboratory of Psychotic Disorders, Shanghai, China
| | - JiaHui Zeng
- Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, Shanghai Key Laboratory of Psychotic Disorders, Shanghai, China
| | - YeGang Hu
- Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, Shanghai Key Laboratory of Psychotic Disorders, Shanghai, China
| | - LiHua Xu
- Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, Shanghai Key Laboratory of Psychotic Disorders, Shanghai, China
| | - YanYan Wei
- Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, Shanghai Key Laboratory of Psychotic Disorders, Shanghai, China
| | - XiaoChen Tang
- Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, Shanghai Key Laboratory of Psychotic Disorders, Shanghai, China
| | - XiaoHua Liu
- Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, Shanghai Key Laboratory of Psychotic Disorders, Shanghai, China
| | - HaiChun Liu
- Department of Automation, Shanghai Jiao Tong University, Shanghai, China.,Research and Development Department, Niacin (Shanghai) Technology Co., Ltd., Shanghai, China
| | - Tao Chen
- Department of Automation, Shanghai Jiao Tong University, Shanghai, China.,Research and Development Department, Niacin (Shanghai) Technology Co., Ltd., Shanghai, China.,Big Data Research Lab, University of Waterloo, Ontario, Canada.,Senior Research Fellow, Labor and Worklife Program, Harvard University, Harvard, Massachusetts, USA
| | - JiJun Wang
- Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, Shanghai Key Laboratory of Psychotic Disorders, Shanghai, China.,CAS Center for Excellence in Brain Science and Intelligence Technology (CEBSIT), Chinese Academy of Science, China.,Brain Science and Technology Research Center, Shanghai Jiao Tong University, Shanghai, China
| | - TianHong Zhang
- Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, Shanghai Key Laboratory of Psychotic Disorders, Shanghai, China
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10
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Gan R, Wei Y, Wu G, Zeng J, Hu Y, Xu L, Tang X, Liu X, Liu H, Chen T, Wang J, Zhang T. Attenuated niacin-induced skin flush response in individuals with clinical high risk for psychosis. Gen Psychiatr 2022; 35:e100748. [PMID: 35572776 PMCID: PMC9039376 DOI: 10.1136/gpsych-2022-100748] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 03/25/2022] [Indexed: 11/03/2022] Open
Abstract
Background Impaired sensitivity of the skin flush response to niacin is one of the most replicated findings in patients with schizophrenia. However, prior studies have usually focused on postonset psychosis, and little is known about the clinical high-risk (CHR) phase of niacin sensitivity in psychosis. Aims To profile and compare the niacin flush response among CHR individuals (converters and non-converters), patients with first-episode schizophrenia (FES) and healthy controls (HCs). Methods Sensitivity to four concentrations (0.1-0.0001 M) of aqueous methylnicotinate was tested in 105 CHR individuals, 57 patients with FES and 52 HCs. CHR individuals were further grouped as converters and non-converters according to the 2-year follow-up outcomes. Skin flush response scores were rated on a 4-point scale. Results Of the 105 CHR individuals, 21 individuals were lost during the study, leaving 84 CHR individuals; 16 (19.0%) converted to full psychosis at 2 years of follow-up. Flush response scores identified in the CHR samples were characterised as modest degree levels, intermediate between those of HC individuals and patients with FES. The flush responses in the CHR group mimicked the responses observed in the FES group at higher concentrations (0.01 M, 0.1 M) and longer time points (15 min, 20 min); however, these became comparable with the responses in the HC group at the shorter time points and at lower concentrations. The converters exhibited lower mean flush response scores than the non-converters. Conclusions Attenuated niacin-induced flushing emerged during the early phase of psychosis. New devices should be developed and verified for objective quantification of skin responses in the CHR population.
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Affiliation(s)
- Ranpiao Gan
- Shanghai Intelligent Psychological Evaluation and Intervention Engineering Technology Research Center, Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yanyan Wei
- Shanghai Intelligent Psychological Evaluation and Intervention Engineering Technology Research Center, Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Guisen Wu
- Shanghai Intelligent Psychological Evaluation and Intervention Engineering Technology Research Center, Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiahui Zeng
- Shanghai Intelligent Psychological Evaluation and Intervention Engineering Technology Research Center, Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yegang Hu
- Shanghai Intelligent Psychological Evaluation and Intervention Engineering Technology Research Center, Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lihua Xu
- Shanghai Intelligent Psychological Evaluation and Intervention Engineering Technology Research Center, Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaochen Tang
- Shanghai Intelligent Psychological Evaluation and Intervention Engineering Technology Research Center, Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaohua Liu
- Shanghai Intelligent Psychological Evaluation and Intervention Engineering Technology Research Center, Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Haichun Liu
- Department of Automation, Shanghai Jiao Tong University, Shanghai, China
| | - Tao Chen
- Big Data Research Lab, University of Waterloo, Waterloo, Ontario, Canada
| | - Jijun Wang
- Shanghai Intelligent Psychological Evaluation and Intervention Engineering Technology Research Center, Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Center for Excellence in Brain Science and Intelligence Technology (CEBSIT), Chinese Academy of Science, Shanghai, China.,Brain Science and Technology Research Center, Shanghai Jiao Tong University, Shanghai, China
| | - Tianhong Zhang
- Shanghai Intelligent Psychological Evaluation and Intervention Engineering Technology Research Center, Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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11
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Li N, Yang P, Tang M, Liu Y, Guo W, Lang B, Wang J, Wu H, Tang H, Yu Y, Wu X, Zeng C, Cao T, Cai H. Reduced erythrocyte membrane polyunsaturated fatty acid levels indicate diminished treatment response in patients with multi- versus first-episode schizophrenia. SCHIZOPHRENIA (HEIDELBERG, GERMANY) 2022; 8:7. [PMID: 35217671 PMCID: PMC8881498 DOI: 10.1038/s41537-022-00214-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 02/01/2022] [Indexed: 11/09/2022]
Abstract
Antipsychotic effects seem to decrease in relapsed schizophrenia patients and the underlying mechanisms remain to be elucidated. Based on the essential role of polyunsaturated fatty acids in brain function and the treatment of schizophrenia, we hypothesize that disordered fatty acid metabolism may contribute to treatment resistance in multi-episode patients. We analyzed the erythrocyte membrane fatty acids in 327 schizophrenia patients under various episodes (numbers of patients: first-episode drug naïve 89; 2–3 episodes 110; 4–6 episodes 80; over 6 episodes 48) and 159 age- and gender-matched healthy controls. Membrane fatty acid levels and PANSS scales were assessed at baseline of antipsychotic-free period and one-month of follow-up after treatment. Totally, both saturated and unsaturated fatty acids were reduced at baseline when compared to healthy controls. Subgroup analyses among different episodes indicated that in response to atypical antipsychotic treatment, the membrane fatty acids were only increased in patients within 3 episodes, and this therapeutic effects on omega-3 index were merely present in the first episode. Results of fatty acid ratios suggested that dysregulations of enzymes such as D6 desaturase, D5 desaturase, and elongases for polyunsaturated fatty acids in patients with multi-episode schizophrenia could account for the differences. Additionally, certain fatty acid level/ratio changes were positively correlated with symptom improvement. The alterations of C22:5n3 and omega-3 index, gender, and the number of episodes were significant risk factors correlated with treatment responsiveness. Using targeted metabolomic approach, we revealed the potential mechanisms underlying abnormal fatty acid metabolism responsible for reduced treatment response in patients with multi-episode schizophrenia.
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Affiliation(s)
- Nana Li
- Department of Pharmacy, the Second Xiangya Hospital of Central South University, Changsha, Hunan Province, China.,Institute of Clinical Pharmacy, Central South University, Changsha, Hunan Province, China
| | - Ping Yang
- Department of Psychiatry, the Second People's Hospital of Hunan Province, Changsha, Hunan Province, China
| | - Mimi Tang
- Department of Pharmacy, Xiangya Hospital of Central South University, Changsha, Hunan Province, China.,Institute of Hospital Pharmacy, Xiangya Hospital of Central South University, Changsha, Hunan Province, China
| | - Yong Liu
- Department of Psychiatry, The Second Xiangya Hospital of Central South University, Changsha, Hunan Province, China.,National Clinical Research Center on Mental Disorders, Changsha, Hunan Province, China
| | - Wenbin Guo
- Department of Psychiatry, The Second Xiangya Hospital of Central South University, Changsha, Hunan Province, China.,National Clinical Research Center on Mental Disorders, Changsha, Hunan Province, China
| | - Bing Lang
- Department of Psychiatry, The Second Xiangya Hospital of Central South University, Changsha, Hunan Province, China.,National Clinical Research Center on Mental Disorders, Changsha, Hunan Province, China
| | - Jianjian Wang
- Department of Psychiatry, The Second Xiangya Hospital of Central South University, Changsha, Hunan Province, China.,National Clinical Research Center on Mental Disorders, Changsha, Hunan Province, China
| | - Haishan Wu
- Department of Psychiatry, The Second Xiangya Hospital of Central South University, Changsha, Hunan Province, China.,National Clinical Research Center on Mental Disorders, Changsha, Hunan Province, China
| | - Hui Tang
- Department of Psychiatry, The Second Xiangya Hospital of Central South University, Changsha, Hunan Province, China.,National Clinical Research Center on Mental Disorders, Changsha, Hunan Province, China
| | - Yan Yu
- Department of Psychiatry, Changsha Psychiatric Hospital, Changsha, Hunan Province, China
| | - Xiangxin Wu
- Department of Pharmacy, the Second Xiangya Hospital of Central South University, Changsha, Hunan Province, China.,Institute of Clinical Pharmacy, Central South University, Changsha, Hunan Province, China
| | - Cuirong Zeng
- Department of Pharmacy, the Second Xiangya Hospital of Central South University, Changsha, Hunan Province, China.,Institute of Clinical Pharmacy, Central South University, Changsha, Hunan Province, China
| | - Ting Cao
- Department of Pharmacy, the Second Xiangya Hospital of Central South University, Changsha, Hunan Province, China.,Institute of Clinical Pharmacy, Central South University, Changsha, Hunan Province, China
| | - Hualin Cai
- Department of Pharmacy, the Second Xiangya Hospital of Central South University, Changsha, Hunan Province, China. .,Institute of Clinical Pharmacy, Central South University, Changsha, Hunan Province, China.
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12
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Png G, Barysenka A, Repetto L, Navarro P, Shen X, Pietzner M, Wheeler E, Wareham NJ, Langenberg C, Tsafantakis E, Karaleftheri M, Dedoussis G, Mälarstig A, Wilson JF, Gilly A, Zeggini E. Mapping the serum proteome to neurological diseases using whole genome sequencing. Nat Commun 2021; 12:7042. [PMID: 34857772 PMCID: PMC8640022 DOI: 10.1038/s41467-021-27387-1] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Accepted: 11/11/2021] [Indexed: 12/12/2022] Open
Abstract
Despite the increasing global burden of neurological disorders, there is a lack of effective diagnostic and therapeutic biomarkers. Proteins are often dysregulated in disease and have a strong genetic component. Here, we carry out a protein quantitative trait locus analysis of 184 neurologically-relevant proteins, using whole genome sequencing data from two isolated population-based cohorts (N = 2893). In doing so, we elucidate the genetic landscape of the circulating proteome and its connection to neurological disorders. We detect 214 independently-associated variants for 107 proteins, the majority of which (76%) are cis-acting, including 114 variants that have not been previously identified. Using two-sample Mendelian randomisation, we identify causal associations between serum CD33 and Alzheimer's disease, GPNMB and Parkinson's disease, and MSR1 and schizophrenia, describing their clinical potential and highlighting drug repurposing opportunities.
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Affiliation(s)
- Grace Png
- Institute of Translational Genomics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany. .,TUM School of Medicine, Technical University of Munich and Klinikum Rechts der Isar, Munich, Germany.
| | - Andrei Barysenka
- grid.4567.00000 0004 0483 2525Institute of Translational Genomics, Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany
| | - Linda Repetto
- grid.4305.20000 0004 1936 7988Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, UK
| | - Pau Navarro
- grid.4305.20000 0004 1936 7988MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
| | - Xia Shen
- grid.4305.20000 0004 1936 7988Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, UK ,grid.8547.e0000 0001 0125 2443Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, Guangzhou, China ,grid.4714.60000 0004 1937 0626Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden
| | - Maik Pietzner
- grid.5335.00000000121885934MRC Epidemiology Unit, University of Cambridge, Cambridge, UK
| | - Eleanor Wheeler
- grid.5335.00000000121885934MRC Epidemiology Unit, University of Cambridge, Cambridge, UK
| | - Nicholas J. Wareham
- grid.5335.00000000121885934MRC Epidemiology Unit, University of Cambridge, Cambridge, UK
| | - Claudia Langenberg
- grid.5335.00000000121885934MRC Epidemiology Unit, University of Cambridge, Cambridge, UK ,grid.484013.aComputational Medicine, Berlin Institute of Health (BIH), Charité University Medicine, Berlin, Germany
| | | | | | - George Dedoussis
- grid.15823.3d0000 0004 0622 2843Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University of Athens, Athens, Greece
| | - Anders Mälarstig
- grid.4714.60000 0004 1937 0626Department of Medicine, Karolinska Institute, Solna, Sweden ,Emerging Science & Innovation, Pfizer Worldwide Research, Development and Medical, Cambridge, MA USA
| | - James F. Wilson
- grid.4305.20000 0004 1936 7988Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, UK ,grid.4305.20000 0004 1936 7988MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
| | - Arthur Gilly
- grid.4567.00000 0004 0483 2525Institute of Translational Genomics, Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany
| | - Eleftheria Zeggini
- Institute of Translational Genomics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany. .,TUM School of Medicine, Technical University of Munich and Klinikum Rechts der Isar, Munich, Germany.
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13
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Increased PLA 2 activity in individuals at ultra-high risk for psychosis. Eur Arch Psychiatry Clin Neurosci 2021; 271:1593-1599. [PMID: 33677687 DOI: 10.1007/s00406-021-01246-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Accepted: 02/24/2021] [Indexed: 10/22/2022]
Abstract
Phospholipase A2 is the main enzyme in the metabolism of membrane phospholipids. It comprises a family of enzymes divided into iPLA2, cPLA2 and sPLA2. Studies have reported increased PLA2 activity in psychotic patients, which suggests an accelerated breakdown of membrane phospholipids. In the present study we investigated whether increased PLA2 activity is also present in individuals at ultra-high risk (UHR) for psychosis. One-hundred fifty adults were included in this study (85 UHR and 65 controls). UHR was assessed using the "structured interview for prodromal syndromes". PLA2 activity was determined in platelets by a radio-enzymatic assay. We found in UHR individuals increased activities of iPLA2 (p < 0.001) and cPLA2 (p = 0.012) as compared to controls. No correlations were found between socio-demographic and clinical parameters and PLA2 activity. Our findings suggest that increased PLA2 activities may be useful as a biological risk-marker for psychotic disorders.
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14
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Wang DD, Hu XW, Jiang J, Sun LY, Qing Y, Yang XH, Gao Y, Cui GP, Li MH, Wang PK, Zhang J, Zhuang Y, Li ZZ, Li J, Guan LL, Zhang TH, Wang JJ, Ji F, Wan CL. Attenuated and delayed niacin skin flushing in schizophrenia and affective disorders: A potential clinical auxiliary diagnostic marker. Schizophr Res 2021; 230:53-60. [PMID: 33677199 DOI: 10.1016/j.schres.2021.02.009] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Revised: 01/19/2021] [Accepted: 02/13/2021] [Indexed: 11/27/2022]
Abstract
AIM Schizophrenia and affective disorders all show high heterogeneity in clinical manifestations. A lack of objective biomarkers has long been a challenge in the clinical diagnosis of these diseases. In this study, we aimed to investigate the performance of niacin skin flushing in schizophrenia and affective disorders and determine its clinical potential as an auxiliary diagnostic marker. METHODS In this case-control study, niacin skin-flushing tests were conducted in 613 patients (including 307 schizophrenia patients, 179 bipolar disorder patients, and 127 unipolar depression patients) and 148 healthy controls (HCs) with a modified method. Differences in niacin skin-flushing responses were compared with adjustment for gender, BMI, age, nicotine dependence, alcohol consumption and educational status. A diagnostic model was established based on a bivariate cut-off. RESULTS Schizophrenia and affective disorders showed similar performance of niacin bluntness, characterized by attenuated flushing extent and reduced flushing rate. An innovative bivariate cut-off was established according to these two features, by which we could identify -patients with either schizophrenia or affective disorders from HCs with a sensitivity of 55.28%, a specificity of 83.56% and a positive predictive value of 93.66%. CONCLUSIONS The niacin-induced skin flushing was prevalently blunted in patients with schizophrenia or affective disorders, indicating a promising potential as an auxiliary diagnostic marker in risk prediction and clinical management of these disorders. Additionally, the niacin-blunted subgroup implies a common biological basis in the investigated disorders, which provokes new thoughts in elucidating the pathological mechanisms.
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Affiliation(s)
- Dan-Dan Wang
- Bio-X Institutes, Shanghai Mental Health Center, Shanghai Jiao Tong University, Shanghai, China; Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Key Laboratory of Psychiatry Disorders, Shanghai Jiao Tong University, Shanghai, China
| | - Xiao-Wen Hu
- Bio-X Institutes, Shanghai Mental Health Center, Shanghai Jiao Tong University, Shanghai, China; Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Key Laboratory of Psychiatry Disorders, Shanghai Jiao Tong University, Shanghai, China
| | - Jie Jiang
- Bio-X Institutes, Shanghai Mental Health Center, Shanghai Jiao Tong University, Shanghai, China; Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Key Laboratory of Psychiatry Disorders, Shanghai Jiao Tong University, Shanghai, China
| | - Li-Ya Sun
- Bio-X Institutes, Shanghai Mental Health Center, Shanghai Jiao Tong University, Shanghai, China; Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Key Laboratory of Psychiatry Disorders, Shanghai Jiao Tong University, Shanghai, China
| | - Ying Qing
- Bio-X Institutes, Shanghai Mental Health Center, Shanghai Jiao Tong University, Shanghai, China; Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Key Laboratory of Psychiatry Disorders, Shanghai Jiao Tong University, Shanghai, China
| | - Xu-Han Yang
- Bio-X Institutes, Shanghai Mental Health Center, Shanghai Jiao Tong University, Shanghai, China; Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Key Laboratory of Psychiatry Disorders, Shanghai Jiao Tong University, Shanghai, China
| | - Yan Gao
- Bio-X Institutes, Shanghai Mental Health Center, Shanghai Jiao Tong University, Shanghai, China; Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Key Laboratory of Psychiatry Disorders, Shanghai Jiao Tong University, Shanghai, China
| | - Gao-Ping Cui
- Bio-X Institutes, Shanghai Mental Health Center, Shanghai Jiao Tong University, Shanghai, China; Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Key Laboratory of Psychiatry Disorders, Shanghai Jiao Tong University, Shanghai, China
| | - Ming-Hui Li
- Bio-X Institutes, Shanghai Mental Health Center, Shanghai Jiao Tong University, Shanghai, China; Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Key Laboratory of Psychiatry Disorders, Shanghai Jiao Tong University, Shanghai, China
| | - Peng-Kun Wang
- Bio-X Institutes, Shanghai Mental Health Center, Shanghai Jiao Tong University, Shanghai, China; Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Key Laboratory of Psychiatry Disorders, Shanghai Jiao Tong University, Shanghai, China
| | - Juan Zhang
- Bio-X Institutes, Shanghai Mental Health Center, Shanghai Jiao Tong University, Shanghai, China; Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Key Laboratory of Psychiatry Disorders, Shanghai Jiao Tong University, Shanghai, China
| | - Yan Zhuang
- Department of Obstetrics and Gyneocology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ze-Zhi Li
- Department of Neurology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jing Li
- Department of Bioinformatics and Biostatistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
| | - Li-Li Guan
- Peking University Sixth Hospital and Institute of Mental Health, Beijing, China
| | - Tian-Hong Zhang
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ji-Jun Wang
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Feng Ji
- Institute of Mental Health, Jining Medical University, Jining, Shandong, China.
| | - Chun-Ling Wan
- Bio-X Institutes, Shanghai Mental Health Center, Shanghai Jiao Tong University, Shanghai, China; Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Key Laboratory of Psychiatry Disorders, Shanghai Jiao Tong University, Shanghai, China.
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15
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Yang X, Li M, Jiang J, Hu X, Qing Y, Sun L, Yang T, Wang D, Cui G, Gao Y, Zhang J, Li X, Shen Y, Qin S, Wan C. Dysregulation of phospholipase and cyclooxygenase expression is involved in Schizophrenia. EBioMedicine 2021; 64:103239. [PMID: 33581645 PMCID: PMC7892797 DOI: 10.1016/j.ebiom.2021.103239] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 01/22/2021] [Accepted: 01/26/2021] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Schizophrenia (SZ) is a severe mental disease with highly heterogeneous clinical manifestations and pathological mechanisms. Schizophrenia is linked to abnormalities in cell membrane phospholipids and blunting of the niacin skin flush response, but the associations between these phenotypes and its molecular pathogenesis remain unclear. This study aimed to describe the PLA2/COX pathway, the key link between phospholipids and niacin flush, and to illustrate the pathogenic mechanisms in schizophrenia that mediate the above phenotypes. METHODS A total of 166 patients with schizophrenia and 54 healthy controls were recruited in this study and assigned to a discovery set and a validation set. We assessed the mRNA levels of 19 genes related to the PLA2/COX cascade in leukocytes by real-time PCR. Plasma IL-6 levels were measured with an ELISA kit. Genetic association analysis was performed on PLA2G4A and PTGS2 to investigate their potential relationship with blunted niacin-skin response in an independent sample set. FINDINGS Six of the 19 genes in the PLA2/COX pathway exhibited significant differences between schizophrenia and healthy controls. The disturbance of the pathway indicates the activation of arachidonic acid (AA) hydrolysis and metabolization, resulting in the abnormalities of membrane lipid homeostasis and immune function, further increasing the risk of schizophrenia. On the other hand, the active process of AA hydrolysis from cell membrane phospholipids and decreased transcription of CREB1, COX-2 and PTGER4 may explain the reported findings of a blunted niacin response in schizophrenia. The significant genetic associations between PLA2G4A and PTGS2 with the niacin-skin responses further support the inference. INTERPRETATION These results suggested that the activation of AA hydrolysis and the imbalance in COX-1 and COX-2 expression are involved in the pathogenesis of schizophrenia and blunting of the niacin flush response. FUNDING This work was supported by the National Key R&D Program of China (2016YFC1306900, 2016YFC1306802); the National Natural Science Foundation of China (81971254, 81771440, 81901354); Interdisciplinary Program of Shanghai Jiao Tong University (ZH2018ZDA40, YG2019GD04, YG2016MS48); Grants of Shanghai Brain-Intelligence Project from STCSM (16JC1420500); Shanghai Key Laboratory of Psychotic Disorders (13DZ2260500); and Shanghai Municipal Science and Technology Major Project (2017SHZDZX01); China Postdoctoral Science Foundation (2018M642029, 2018M630442, 2019M661526, 2020T130407); Natural Science Foundation of Shanghai (20ZR1426700); and Startup Fund for Youngman Research at SJTU (19 × 100040033).
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Affiliation(s)
- Xuhan Yang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - Minghui Li
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - Jie Jiang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaowen Hu
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - Ying Qing
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - Liya Sun
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - Tianqi Yang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - Dandan Wang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - Gaoping Cui
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - Yan Gao
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - Juan Zhang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - Xingwang Li
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - Yuhua Shen
- The Fourth People's Hospital of Wuhu, Wuhu, China
| | - Shengying Qin
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China; Shanghai Mental Health Center, Shanghai Key Laboratory of Psychiatry Disorders, Shanghai Jiao Tong University, Shanghai, China
| | - Chunling Wan
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China; Shanghai Mental Health Center, Shanghai Key Laboratory of Psychiatry Disorders, Shanghai Jiao Tong University, Shanghai, China.
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Ansarey SH. Inflammation and JNK's Role in Niacin-GPR109A Diminished Flushed Effect in Microglial and Neuronal Cells With Relevance to Schizophrenia. Front Psychiatry 2021; 12:771144. [PMID: 34916973 PMCID: PMC8668869 DOI: 10.3389/fpsyt.2021.771144] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Accepted: 11/02/2021] [Indexed: 12/28/2022] Open
Abstract
Schizophrenia is a neuropsychiatric illness with no single definitive aetiology, making its treatment difficult. Antipsychotics are not fully effective because they treat psychosis rather than the cognitive or negative symptoms. Antipsychotics fail to alleviate symptoms when patients enter the chronic stage of illness. Topical application of niacin showed diminished skin flush in the majority of patients with schizophrenia compared to the general population who showed flushing. The niacin skin flush test is useful for identifying patients with schizophrenia at their ultra-high-risk stage, and understanding this pathology may introduce an effective treatment. This review aims to understand the pathology behind the diminished skin flush response, while linking it back to neurons and microglia. First, it suggests that there are altered proteins in the GPR109A-COX-prostaglandin pathway, inflammatory imbalance, and kinase signalling pathway, c-Jun N-terminal kinase (JNK), which are associated with diminished flush. Second, genes from the GPR109A-COX-prostaglandin pathway were matched against the 128-loci genome wide association study (GWAS) for schizophrenia using GeneCards, suggesting that G-coupled receptor-109A (GPR109A) may have a genetic mutation, resulting in diminished flush. This review also suggests that there may be increased pro-inflammatory mediators in the GPR109A-COX-prostaglandin pathway, which contributes to the diminished flush pathology. Increased levels of pro-inflammatory markers may induce microglial-activated neuronal death. Lastly, this review explores the role of JNK on pro-inflammatory mediators, proteins in the GPR109A-COX-prostaglandin pathway, microglial activation, and neuronal death. Inhibiting JNK may reverse the changes observed in the diminished flush response, which might make it a good therapeutic target.
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Affiliation(s)
- Sabrina H Ansarey
- Department of Neuroscience and Psychology, University of Glasgow, Glasgow, United Kingdom
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17
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Hsu MC, Huang YS, Ouyang WC. Beneficial effects of omega-3 fatty acid supplementation in schizophrenia: possible mechanisms. Lipids Health Dis 2020; 19:159. [PMID: 32620164 PMCID: PMC7333328 DOI: 10.1186/s12944-020-01337-0] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 06/24/2020] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Schizophrenia is a serious long-term psychotic disorder marked by positive and negative symptoms, severe behavioral problems and cognitive function deficits. The cause of this disorder is not completely clear, but is suggested to be multifactorial, involving both inherited and environmental factors. Since human brain regulates all behaviour, studies have focused on identifying changes in neurobiology and biochemistry of brain in schizophrenia. Brain is the most lipid rich organ (approximately 50% of brain dry weight). Total brain lipids is constituted of more than 60% of phospholipids, in which docosahexaenoic acid (DHA, 22:6n-3) is the most abundant (more than 40%) polyunsaturated fatty acid (PUFA) in brain membrane phospholipids. Results from numerous studies have shown significant decreases of PUFAs, in particular, DHA in peripheral blood (plasma and erythrocyte membranes) as well as brain of schizophrenia patients at different developmental phases of the disorder. PUFA deficiency has been associated to psychotic symptoms and cognitive deficits in schizophrenia. These findings have led to a number of clinical trials examining whether dietary omega-3 fatty acid supplementation could improve the course of illness in patients with schizophrenia. Results are inconsistent. Some report beneficial whereas others show not effective. The discrepancy can be attributed to the heterogeneity of patient population. METHODS In this review, results from recent experimental and clinical studies, which focus on illustrating the role of PUFAs in the development of schizophrenia were examined. The rationale why omega-3 supplementation was beneficial on symptoms (presented by subscales of the positive and negative symptom scale (PANSS), and cognitive functions in certain patients but not others was reviewed. The potential mechanisms underlying the beneficial effects were discussed. RESULTS Omega-3 fatty acid supplementation reduced the conversion rate to psychosis and improved both positive and negative symptoms and global functions in adolescents at ultra-high risk for psychosis. Omega-3 fatty acid supplementation could also improve negative symptoms and global functions in the first-episode patients with schizophrenia, but improve mainly total or general PANSS subscales in chronic patients. Patients with low PUFA (particularly DHA) baseline in blood were more responsive to the omega-3 fatty acid intervention. CONCLUSION Omega-3 supplementation is more effective in reducing psychotic symptom severity in young adults or adolescents in the prodromal phase of schizophrenia who have low omega-3 baseline. Omega-3 supplementation was more effective in patients with low PUFA baseline. It suggests that patients with predefined lipid levels might benefit from lipid treatments, but more controlled clinical trials are warranted.
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Affiliation(s)
- Mei-Chi Hsu
- Department of Nursing, I-Shou University, No.8, Yida Road, Jiaosu Village Yanchao District, Kaohsiung, 82445 Taiwan
| | - Yung-Sheng Huang
- College of Medicine, I-Shou University, No.8, Yida Road, Jiaosu Village Yanchao District, Kaohsiung, 82445 Taiwan
| | - Wen-Chen Ouyang
- Department of Geriatric Psychiatry, Jianan Psychiatric Center, Ministry of Health and Welfare, No.539, Yuzhong Rd., Rende Dist., Tainan City, 71742 Taiwan
- Department of Nursing, Shu-Zen Junior College of Medicine and Management, No.452, Huanqiu Rd. Luzhu Dist, Kaohsiung, 82144 Taiwan
- Department of Psychiatry, College of Medicine, Kaohsiung Medical University, No.100, Shin-Chuan 1st Road, Sanmin Dist., Kaohsiung, 80708 Taiwan
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18
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Emanuele E, Carlin MV, D'Angelo A, Peros E, Barale F, Geroldi D, Politi P. Elevated plasma levels of lipoprotein(a) in psychiatric patients: a possible contribution to increased vascular risk. Eur Psychiatry 2020; 21:129-33. [PMID: 16516110 DOI: 10.1016/j.eurpsy.2004.10.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2004] [Accepted: 10/29/2004] [Indexed: 11/19/2022] Open
Abstract
AbstractAn increased incidence of adverse cardiovascular events has been reported in psychiatric patients, but the exact mechanisms underlying this association are still uncertain. Elevated plasma level of lipoprotein(a) [Lp(a)] is an independent risk factor for atherothrombotic disease in the general population. To study the implications of Lp(a) in psychiatric patients, we measured the plasma levels of Lp(a) in 74 patients with psychiatric disorders (39 schizophrenia, 10 major depression, 13 bipolar disorder and 12 personality disorder) and 74 healthy controls. The Lp(a) levels of the patient groups with schizophrenia, major depression and bipolar disorder were significantly higher than that of the control group. The median Lp(a) value of these diagnostic groups was comparable with those reported in patients with prior atherothrombotic events. On the other hand, no differences were found among personality disorder and controls. Our findings suggest that the elevation of plasma Lp(a) may contribute to increased cardiovascular risk in several patients with psychiatric disorders.
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Affiliation(s)
- Enzo Emanuele
- Molecular Medicine Laboratory, Clinica Medica 2, IRCCS Policlinico San Matteo, University of Pavia, Piazzale Golgi, 2, 27100 Pavia, Italy.
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19
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Nadalin S, Jonovska S, Šendula Jengić V, Buretić-Tomljanović A. An association between niacin skin flush response and plasma triglyceride levels in patients with schizophrenia. Prostaglandins Leukot Essent Fatty Acids 2020; 155:102084. [PMID: 32126479 DOI: 10.1016/j.plefa.2020.102084] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 02/03/2020] [Accepted: 02/18/2020] [Indexed: 01/31/2023]
Abstract
The available data suggest that abnormalities of arachidonic acid-related signaling may be of relevance in attenuated niacin-induced flush responses and lipid and glucose metabolism disturbances, which are all common among individuals with schizophrenia. We previously demonstrated attenuated skin flush responses to niacin in patients with schizophrenia. Here we investigated whether these niacin responses might be associated with elevated plasma lipid and glucose concentrations in this patient group. We found that higher plasma triglyceride levels were associated with higher total volumetric niacin response (VNR) values and that the VNR accounted for ~14.2% of the variability in triglyceride levels. Triglyceride levels were significantly higher in patients with a positive niacin skin flush response compared to those with absent niacin skin flushing at the 5-minute interval with niacin concentrations of 0.1 and 0.01 M, and at the 10- and 15-minute intervals with a niacin concentration of 0.001 M.
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Affiliation(s)
- Sergej Nadalin
- Department of Medical Biology and Genetics, School of Medicine, University of Rijeka, Braće Branchetta 20, 51000 Rijeka, Croatia.
| | | | | | - Alena Buretić-Tomljanović
- Department of Medical Biology and Genetics, School of Medicine, University of Rijeka, Braće Branchetta 20, 51000 Rijeka, Croatia
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20
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Nadalin S, Rebić J, Šendula Jengić V, Peitl V, Karlović D, Buretić-Tomljanović A. Association between PLA2G6 gene polymorphism for calcium-independent phospholipase A2 and nicotine dependence among males with schizophrenia. Prostaglandins Leukot Essent Fatty Acids 2019; 148:9-15. [PMID: 31492433 DOI: 10.1016/j.plefa.2019.07.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 06/03/2019] [Accepted: 07/02/2019] [Indexed: 01/08/2023]
Abstract
We investigated the relationship between the rs10798059 (BanI) and rs4375 polymorphisms in the phospholipase A2 (PLA2)G4A and PLA2G6 genes and the risk of nicotine dependence in 263 Croatian patients with schizophrenia. We also examined whether interactions between these polymorphisms and smoking contributed to schizophrenia onset and Positive and Negative Syndrome Scale (PANSS) psychopathology. We found no significant differences in the distribution of PLA2G4A genotypes and alleles according to smoking status, and no effect of the PLA2G4A genotype-smoking interaction on disease onset or PANSS. The PLA2G6-TT homozygous genotype was significantly overrepresented in male smokers compared to nonsmokers (34.7% vs. 17.1%, p < 0.05). These patients had ∼2.6-fold higher risk of becoming smokers than males with heterozygous PLA2G6-CT and homozygous PLA2G6-CC genotypes. In addition, male smokers without the PLA2G6-C allele (PLA2G6-TT homozygous) experienced earlier onset than nonsmoking homozygous PLA2G6-TT males. Thus, the PLA2G6 polymorphism affected the risk of nicotine dependence in male patients and the PLA2G6 genotype-smoking interaction was linked to the age of disease onset.
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Affiliation(s)
- Sergej Nadalin
- Department of Medical Biology and Genetics, Faculty of Medicine, University of Rijeka, Braće Branchetta 20, 51000, Rijeka, Croatia.
| | - Jelena Rebić
- Psychiatry Clinic, Clinical Hospital Center Rijeka, Rijeka, Croatia
| | | | - Vjekoslav Peitl
- Department of Psychiatry, Sestre Milosrdnice University Hospital Center and Catholic University of Croatia, Zagreb, Croatia
| | - Dalibor Karlović
- Department of Psychiatry, Sestre Milosrdnice University Hospital Center and Catholic University of Croatia, Zagreb, Croatia
| | - Alena Buretić-Tomljanović
- Department of Medical Biology and Genetics, Faculty of Medicine, University of Rijeka, Braće Branchetta 20, 51000, Rijeka, Croatia
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21
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Ciappolino V, Mazzocchi A, Botturi A, Turolo S, Delvecchio G, Agostoni C, Brambilla P. The Role of Docosahexaenoic Acid (DHA) on Cognitive Functions in Psychiatric Disorders. Nutrients 2019; 11:nu11040769. [PMID: 30986970 PMCID: PMC6520996 DOI: 10.3390/nu11040769] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Revised: 03/25/2019] [Accepted: 03/28/2019] [Indexed: 02/07/2023] Open
Abstract
Cognitive impairment is strongly associated with functional outcomes in psychiatric patients. Involvement of n-3 long chain polyunsaturated fatty acid (n-3 LC-PUFA), in particular docosahexaenoic acid (DHA), in brain functions is largely documented. DHA is incorporated into membrane phospholipids as structural component, especially in the central nervous system where it also has important functional effects. The aim of this review is to investigate the relationship between DHA and cognitive function in relation to mental disorders. Results from few randomized controlled trials (RCTs) on the effects of DHA (alone or in combination) in psychotic, mood and neurodevelopmental disorders, respectively, suggest that no conclusive remarks can be drawn.
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Affiliation(s)
- Valentina Ciappolino
- Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Department of Neurosciences and Mental Health, 20122 Milan, Italy.
| | - Alessandra Mazzocchi
- Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy.
| | - Andrea Botturi
- Neurologic Clinic, Fondazione IRCCS Istituto neurologico Carlo Besta, 20122 Milan, Italy.
| | - Stefano Turolo
- Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Pediatric Nephrology, Dialysis and Transplant Unit, 20122 Milan, Italy.
| | - Giuseppe Delvecchio
- Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, Italy.
| | - Carlo Agostoni
- Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy.
- Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Pediatric Intermediate Care Unit, 20122 Milan, Italy.
| | - Paolo Brambilla
- Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Department of Neurosciences and Mental Health, 20122 Milan, Italy.
- Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, Italy.
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22
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Xu C, Yang X, Sun L, Yang T, Cai C, Wang P, Jiang J, Qing Y, Hu X, Wang D, Wang P, Cui G, Zhang J, Li Y, Ji F, Liu C, Wan C. An investigation of calcium-independent phospholipase A2 (iPLA2) and cytosolic phospholipase A2 (cPLA2) in schizophrenia. Psychiatry Res 2019; 273:782-787. [PMID: 31207866 DOI: 10.1016/j.psychres.2019.01.095] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Revised: 12/24/2018] [Accepted: 01/29/2019] [Indexed: 11/20/2022]
Abstract
Evidence indicates that abnormal phospholipase A2 (PLA2) levels and niacin insensitivity are present in individuals with schizophrenia. This study was designed to determine whether differences in plasma calcium-independent phospholipase A2 (iPLA2) and cytosolic phospholipase A2 (cPLA2) exist between those with schizophrenia and healthy controls, and to explore the correlation between PLA2s and the niacin skin reaction in schizophrenic patients. We performed ELISA experiments to measure the concentrations of plasma iPLA2 and cPLA2 and we conducted a series of niacin skin tests on schizophrenic patients from the Chinese Han population. In addition, a meta-analysis of the relationship between PLA2 and schizophrenia was conducted. The plasma concentration of iPLA2 in patients with schizophrenia was significantly higher than that in healthy controls while the plasma concentration of cPLA2 did not differ. The meta-analysis also revealed that the activity level of iPLA2 in individuals with schizophrenia was higher than that in healthy controls, whereas that of cPLA2 was not. Furthermore, a significant positive correlation was found between the concentration of iPLA2 and the score for the skin flushing response within 20 min. The abnormal plasma iPLA2 concentration and its relationship with the niacin skin test in schizophrenic patients has contributed to a deeper understanding of the pathology of schizophrenia, which may in turn provide new insights into the clinical diagnoses and treatment of schizophrenia.
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Affiliation(s)
- Chuangye Xu
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University, Shanghai, China
| | - Xuhan Yang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University, Shanghai, China
| | - Liya Sun
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University, Shanghai, China
| | - Tianqi Yang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University, Shanghai, China
| | - Changqun Cai
- The Fourth People's Hospital of Wuhu, Wuhu 241002, China
| | - Peng Wang
- The Fourth People's Hospital of Wuhu, Wuhu 241002, China
| | - Jie Jiang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University, Shanghai, China
| | - Ying Qing
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaowen Hu
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University, Shanghai, China
| | - Dandan Wang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University, Shanghai, China
| | - Pengkun Wang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University, Shanghai, China
| | - Gaoping Cui
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University, Shanghai, China
| | - Juan Zhang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University, Shanghai, China
| | - Yan Li
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University, Shanghai, China
| | - Feng Ji
- School of Mental Health, Jining Medical University, Jining, China
| | - Chuanxin Liu
- School of Mental Health, Jining Medical University, Jining, China
| | - Chunling Wan
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University, Shanghai, China; Collaborative Innovation Center of Genetics and Development, Shanghai, China.
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23
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Psychodermatology: An Association of Primary Psychiatric Disorders With Skin. ACTA ACUST UNITED AC 2019; 48:50-57. [DOI: 10.1016/j.rcp.2017.07.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2017] [Revised: 05/26/2017] [Accepted: 07/10/2017] [Indexed: 02/02/2023]
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24
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Messamore E. The niacin response biomarker as a schizophrenia endophenotype: A status update. Prostaglandins Leukot Essent Fatty Acids 2018; 136:95-97. [PMID: 28688777 DOI: 10.1016/j.plefa.2017.06.014] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Revised: 05/03/2017] [Accepted: 06/29/2017] [Indexed: 11/20/2022]
Abstract
Increasingly, it is recognized that the behavioral syndrome of schizophrenia is not a unitary disease with a single underlying cause. Rather, it may have several possible etiologies, and its symptoms may arise from multiple causes. Such heterogeneity could account for some of the difficulties in elucidating its genetics, and may also explain clinical observations of variable medication response in schizophrenia. The ability to categorize schizophrenia using objectively recognizable, physiologically-based subtypes promises to make our understanding of schizophrenia more comprehensive and could provide some clues for more personalized treatment. This paper will review the extent to which an abnormally blunted skin flush response to niacin satisfies the criteria for a schizophrenia endophenotype.
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Affiliation(s)
- Erik Messamore
- Best Practices in Schizophrenia Treatment (BeST) Center, Department of Psychiatry, Northeast Ohio Medical University, Rootstown, OH, USA.
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25
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Nadalin S, Buretić-Tomljanović A. An association between the BanI polymorphism of the PLA2G4A gene for calcium-dependent phospholipase A2 and plasma glucose levels among females with schizophrenia. Prostaglandins Leukot Essent Fatty Acids 2018; 135:39-41. [PMID: 30103930 DOI: 10.1016/j.plefa.2018.06.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2017] [Revised: 06/27/2018] [Accepted: 06/28/2018] [Indexed: 11/21/2022]
Abstract
Abnormal glucose and lipid metabolism may be associated with altered cytosolic Ca2+-dependent phospholipase A2 (cPLA2) signaling in patients with schizophrenia. The relationship between schizophrenia and the functional BanI polymorphism (rs10798059 variant, A/G polymorphism) of the PLA2G4A gene for cPLA2 has been extensively investigated. We previously reported that it can influence several clinical features of schizophrenia, and it was shown to contribute to schizophrenia risk in several population studies. We performed PCR/RFLP genotyping of 263 Croatian patients (males/females: 139/124) to investigate the relationship between the BanI polymorphism and fasting plasma glucose and lipid levels in patients with schizophrenia. Our results indicate that the BanI polymorphic variant contributes significantly to plasma glucose levels in female patients. Females carrying the PLA2G4A-G allele (PLA2G4A-GG homozygous and PLA2G4A-AG heterozygous) presented with lower glucose levels than PLA2G4A-AA homozygous carriers, and the PLA2G4A genotype contributed approximately 6% of plasma glucose level variability in this group of patients.
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Affiliation(s)
- Sergej Nadalin
- Department of Biology and Medical Genetics, School of Medicine, University of Rijeka, Braće Branchetta 20, 51 000 Rijeka, Croatia.
| | - Alena Buretić-Tomljanović
- Department of Biology and Medical Genetics, School of Medicine, University of Rijeka, Braće Branchetta 20, 51 000 Rijeka, Croatia
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26
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Sun L, Yang X, Jiang J, Hu X, Qing Y, Wang D, Yang T, Yang C, Zhang J, Yang P, Wang P, Cai C, Wang J, He L, Wan C. Identification of the Niacin-Blunted Subgroup of Schizophrenia Patients from Mood Disorders and Healthy Individuals in Chinese Population. Schizophr Bull 2018; 44:896-907. [PMID: 29077970 PMCID: PMC6007359 DOI: 10.1093/schbul/sbx150] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Schizophrenia (SZ) is a devastating mental disease caused by complex genetic and environmental factors. The pathological process and clinical manifestation of SZ are heterogeneous among patients, which hampers precise diagnosis and treatment of the disease. Since no objective marker for SZ has been established today, to identify a subgroup of the patients with homogeneous biochemical traits will provide a new angle for both researchers and clinicians to understand and manage the disease. In this study, we employed the niacin skin-flushing test in Chinese population and confirmed a niacin-blunted subgroup of SZ patients distinguishable from mood disorders (MD) and normal individuals. This subgroup accounted for 30.67% of the total SZ patients with a specificity of 88.37% in male subjects and 83.75% in female subjects. We support the notion that bluntness in niacin skin test might reflect abnormalities in membrane fatty acid composition, which could be induced by increased PLA2 enzyme activity, in vivo oxidative stress or lipid metabolism imbalance in SZ. Further studies are encouraged to clarify the molecular origins of niacin-bluntness in SZ, which would provide extra clues for etiological research in schizophrenia and for new targeted treatment.
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Affiliation(s)
- Liya Sun
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Centre, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Center for Women and Children's Health, Shanghai, China
| | - Xuhan Yang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Centre, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jie Jiang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Centre, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaowen Hu
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Centre, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ying Qing
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Centre, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Dandan Wang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Centre, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Tianqi Yang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Centre, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chao Yang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China
| | - Juan Zhang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Centre, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ping Yang
- The Fourth People’s Hospital of Wuhu, Wuhu, China
| | - Peng Wang
- The Fourth People’s Hospital of Wuhu, Wuhu, China
| | - Changqun Cai
- The Fourth People’s Hospital of Wuhu, Wuhu, China
| | - Jijun Wang
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Centre, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lin He
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China
| | - Chunling Wan
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Centre, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Hui L, Yin XL, Chen J, Zhu HL, Zhang GY, Wang XQ, Liu JH, Zhu C, Xu DW, Yu X, Yin GZ. Association between PLA2G12A polymorphism and patients with schizophrenia in a southern Chinese Han population. Hum Psychopharmacol 2018. [PMID: 29527719 DOI: 10.1002/hup.2654] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
BACKGROUND Elevated phospholipase A2 (PLA2) activity is reported to be involved in the development of schizophrenia. Further study revealed an association between PLA2 groups XIIA (PLA2G12A) polymorphism and patients with schizophrenia in a northeast Chinese Han population. OBJECTIVE This study will further examine whether PLA2G12A rs3087494 polymorphism is associated with patients with schizophrenia in a southern Chinese Han population. METHODS This polymorphism was genotyped in 438 patients with schizophrenia (diagnosed according to Diagnostic and Statistical Manual of Mental Disorders-IV) and 876 healthy controls using a case-control design. Demographic and clinical data were collected in all subjects. RESULTS The allele and genotype frequencies of PLA2G12A rs3087494 polymorphism significantly differed between groups (both, p < .001). These differences still were significant by adjusting for sex and age. However, there was no difference in age at onset among 3 genotype groups in patients with schizophrenia by adjusting for the variables (F = 0.22, p = .80). Stepwise multivariate regression analysis showed that this polymorphism was not associated with age at onset in patients with schizophrenia (β = .008, t = .07, p = .94). CONCLUSIONS Our results indicated that even though PLA2G12A rs3087494 polymorphism did not influence age at onset in patients with schizophrenia, it may play an important role in the susceptibility to schizophrenia in a southern Chinese Han population.
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Affiliation(s)
- Li Hui
- Institute of Mental Health, Suzhou Psychiatric Hospital, The Affiliated Guangji Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Xiao Li Yin
- Kangning Hospital attached to Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jie Chen
- Institute of Mental Health, Suzhou Psychiatric Hospital, The Affiliated Guangji Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Hong Liang Zhu
- Institute of Mental Health, Suzhou Psychiatric Hospital, The Affiliated Guangji Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Guang Ya Zhang
- Institute of Mental Health, Suzhou Psychiatric Hospital, The Affiliated Guangji Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Xiao Qiong Wang
- Kangning Hospital attached to Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jia Hong Liu
- Kangning Hospital attached to Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Cheng Zhu
- Kangning Hospital attached to Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Dong Wu Xu
- School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xin Yu
- School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang, China.,Institute of Mental Health, Peking University, Beijing, China
| | - Guang Zhong Yin
- Institute of Mental Health, Suzhou Psychiatric Hospital, The Affiliated Guangji Hospital of Soochow University, Suzhou, Jiangsu, China
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Langbein K, Schmidt U, Schack S, Biesel NJ, Rudzok M, Amminger GP, Berger M, Sauer H, Smesny S. State marker properties of niacin skin sensitivity in ultra-high risk groups for psychosis - An optical reflection spectroscopy study. Schizophr Res 2018; 192:377-384. [PMID: 28602647 DOI: 10.1016/j.schres.2017.06.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2017] [Revised: 05/15/2017] [Accepted: 06/03/2017] [Indexed: 11/30/2022]
Abstract
Impaired niacin sensitivity (NS) is one of the most replicated findings in untreated schizophrenia, and reflects a disturbance of prostaglandin-mediated pathways in association with deregulated arachidonic acid metabolism, pro-inflammatory activation, and vasomotor function. In ultra-high risk individuals (UHR) increased NS was reported recently, pointing towards dynamic alterations of the underlying pathomechanisms in the period preceding psychosis. However, these characteristics are still unresolved in the diverse UHR groups. We tested the hypothesis that NS is attenuated in patients who have transitioned to psychosis and in the Brief Limited Intermittent Psychotic Symptoms (BLIPS, UHR-B) and/or the attenuated symptoms (UHR-A) groups, while it is unchanged or increased in the genetic risk group (UHR-G). Sensitivity to three concentrations (0.1-0.001M) of aqueous methylnicotinate was tested in 84 UHR patients, 105 first-episode psychosis patients (FEP) and 180 healthy individuals (HC), using optical reflection spectroscopy (ORS). The UHR subgroup and transition/non-transition outcomes were assessed according to PACE criteria using the CAARMS. Psychopathology was assessed using SANS, SAPS, and BPRS or SCL-90-R self-ratings. In 0.001M data, decreased NS was found in the UHR-B (n=12), UHR-A (n=45) and the transition groups (n=13), similar to the result in FEP. NS in the UHR-G (n=27) and HC groups did not differ. In the UHR-B and FEP groups, NS and positive symptom scores were inversely correlated. These state marker properties could be used to characterize the intensity of the underlying pathomechanisms during the onset of psychosis or to identify UHR individuals that might benefit from related indicated prevention strategies.
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Affiliation(s)
- Kerstin Langbein
- Department of Psychiatry and Psychotherapy, Jena University Hospital, Philosophenweg 3, 07743 Jena, Germany.
| | - Ulrike Schmidt
- Department of Psychiatry and Psychotherapy, Jena University Hospital, Philosophenweg 3, 07743 Jena, Germany
| | - Stephan Schack
- Department of Psychiatry and Psychotherapy, Jena University Hospital, Philosophenweg 3, 07743 Jena, Germany
| | - Natalie J Biesel
- Department of Psychiatry and Psychotherapy, Jena University Hospital, Philosophenweg 3, 07743 Jena, Germany
| | - Maria Rudzok
- Department of Psychiatry and Psychotherapy, Jena University Hospital, Philosophenweg 3, 07743 Jena, Germany
| | - G Paul Amminger
- Orygen - The National Centre of Excellence in Youth Mental Health, The University of Melbourne, 35 Poplar Road, Parkville, Victoria 3052, Australia
| | - Maximus Berger
- College of Public Health, Medical and Veterinary Science, James Cook University, 1 James Cook Drive, Townsville, QLD 4811, Australia; Laboratory of Psychiatric Neuroscience, Australian Institute of Tropical Health and Medicine (AITHM), 1 James Cook Drive, Townsville, QLD 4811, Australia
| | - Heinrich Sauer
- Department of Psychiatry and Psychotherapy, Jena University Hospital, Philosophenweg 3, 07743 Jena, Germany
| | - Stefan Smesny
- Department of Psychiatry and Psychotherapy, Jena University Hospital, Philosophenweg 3, 07743 Jena, Germany
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Zuccoli GS, Saia-Cereda VM, Nascimento JM, Martins-de-Souza D. The Energy Metabolism Dysfunction in Psychiatric Disorders Postmortem Brains: Focus on Proteomic Evidence. Front Neurosci 2017; 11:493. [PMID: 28936160 PMCID: PMC5594406 DOI: 10.3389/fnins.2017.00493] [Citation(s) in RCA: 87] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2017] [Accepted: 08/22/2017] [Indexed: 12/27/2022] Open
Abstract
Psychiatric disorders represent a great medical and social challenge and people suffering from these conditions face many impairments regarding personal and professional life. In addition, a mental disorder will manifest itself in approximately one quarter of the world's population at some period of their life. Dysfunction in energy metabolism is one of the most consistent scientific findings associated with these disorders. With this is mind, this review compiled data on disturbances in energy metabolism found by proteomic analyses of postmortem brains collected from patients affected by the most prevalent psychiatric disorders: schizophrenia (SCZ), bipolar disorder (BPD), and major depressive disorder (MDD). We searched in the PubMed database to gather the studies and compiled all the differentially expressed proteins reported in each work. SCZ studies revealed 92 differentially expressed proteins related to energy metabolism, while 95 proteins were discovered in BPD, and 41 proteins in MDD. With the compiled data, it was possible to determine which proteins related to energy metabolism were found to be altered in all the disorders as well as which ones were altered exclusively in one of them. In conclusion, the information gathered in this work could contribute to a better understanding of the impaired metabolic mechanisms and hopefully bring insights into the underlying neuropathology of psychiatric disorders.
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Affiliation(s)
- Giuliana S Zuccoli
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of CampinasCampinas, Brazil.,Instituto Nacional de Biomarcadores em Neuropsiquiatria (INBION), Conselho Nacional de Desenvolvimento Cientifico e TecnologicoSão Paulo, Brazil
| | - Verônica M Saia-Cereda
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of CampinasCampinas, Brazil.,Instituto Nacional de Biomarcadores em Neuropsiquiatria (INBION), Conselho Nacional de Desenvolvimento Cientifico e TecnologicoSão Paulo, Brazil
| | - Juliana M Nascimento
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of CampinasCampinas, Brazil.,Instituto Nacional de Biomarcadores em Neuropsiquiatria (INBION), Conselho Nacional de Desenvolvimento Cientifico e TecnologicoSão Paulo, Brazil
| | - Daniel Martins-de-Souza
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of CampinasCampinas, Brazil.,Instituto Nacional de Biomarcadores em Neuropsiquiatria (INBION), Conselho Nacional de Desenvolvimento Cientifico e TecnologicoSão Paulo, Brazil
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Schmitt A, Martins-de-Souza D, Akbarian S, Cassoli JS, Ehrenreich H, Fischer A, Fonteh A, Gattaz WF, Gawlik M, Gerlach M, Grünblatt E, Halene T, Hasan A, Hashimoto K, Kim YK, Kirchner SK, Kornhuber J, Kraus TFJ, Malchow B, Nascimento JM, Rossner M, Schwarz M, Steiner J, Talib L, Thibaut F, Riederer P, Falkai P. Consensus paper of the WFSBP Task Force on Biological Markers: Criteria for biomarkers and endophenotypes of schizophrenia, part III: Molecular mechanisms. World J Biol Psychiatry 2017; 18:330-356. [PMID: 27782767 DOI: 10.1080/15622975.2016.1224929] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES Despite progress in identifying molecular pathophysiological processes in schizophrenia, valid biomarkers are lacking for both the disease and treatment response. METHODS This comprehensive review summarises recent efforts to identify molecular mechanisms on the level of protein and gene expression and epigenetics, including DNA methylation, histone modifications and micro RNA expression. Furthermore, it summarises recent findings of alterations in lipid mediators and highlights inflammatory processes. The potential that this research will identify biomarkers of schizophrenia is discussed. RESULTS Recent studies have not identified clear biomarkers for schizophrenia. Although several molecular pathways have emerged as potential candidates for future research, a complete understanding of these metabolic pathways is required to reveal better treatment modalities for this disabling condition. CONCLUSIONS Large longitudinal cohort studies are essential that pair a thorough phenotypic and clinical evaluation for example with gene expression and proteome analysis in blood at multiple time points. This approach might identify biomarkers that allow patients to be stratified according to treatment response and ideally also allow treatment response to be predicted. Improved knowledge of molecular pathways and epigenetic mechanisms, including their potential association with environmental influences, will facilitate the discovery of biomarkers that could ultimately be effective tools in clinical practice.
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Affiliation(s)
- Andrea Schmitt
- a Department of Psychiatry and Psychotherapy , LMU Munich , Germany.,b Laboratory of Neuroscience (LIM27) , Institute of Psychiatry, University of Sao Paulo , Sao Paulo , Brazil
| | - Daniel Martins-de-Souza
- b Laboratory of Neuroscience (LIM27) , Institute of Psychiatry, University of Sao Paulo , Sao Paulo , Brazil.,c Laboratory of Neuroproteomics, Department of Biochemistry , Institute of Biology University of Campinas (UNICAMP), Campinas , SP , Brazil
| | - Schahram Akbarian
- d Division of Psychiatric Epigenomics, Departments of Psychiatry and Neuroscience , Mount Sinai School of Medicine , New York , USA
| | - Juliana S Cassoli
- c Laboratory of Neuroproteomics, Department of Biochemistry , Institute of Biology University of Campinas (UNICAMP), Campinas , SP , Brazil
| | - Hannelore Ehrenreich
- e Clinical Neuroscience , Max Planck Institute of Experimental Medicine, DFG Centre for Nanoscale Microscopy & Molecular Physiology of the Brain , Göttingen , Germany
| | - Andre Fischer
- f Research Group for Epigenetics in Neurodegenerative Diseases , German Centre for Neurodegenerative Diseases (DZNE), Göttingen , Germany.,g Department of Psychiatry and Psychotherapy , University Medical Centre Göttingen , Germany
| | - Alfred Fonteh
- h Neurosciences , Huntington Medical Research Institutes , Pasadena , CA , USA
| | - Wagner F Gattaz
- b Laboratory of Neuroscience (LIM27) , Institute of Psychiatry, University of Sao Paulo , Sao Paulo , Brazil
| | - Michael Gawlik
- i Department of Psychiatry and Psychotherapy , University of Würzburg , Germany
| | - Manfred Gerlach
- j Centre for Mental Health, Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy , University of Würzburg , Germany
| | - Edna Grünblatt
- i Department of Psychiatry and Psychotherapy , University of Würzburg , Germany.,k Department of Child and Adolescent Psychiatry and Psychotherapy , Psychiatric Hospital, University of Zürich , Switzerland.,l Neuroscience Centre Zurich , University of Zurich and the ETH Zurich , Switzerland.,m Zurich Centre for Integrative Human Physiology , University of Zurich , Switzerland
| | - Tobias Halene
- d Division of Psychiatric Epigenomics, Departments of Psychiatry and Neuroscience , Mount Sinai School of Medicine , New York , USA
| | - Alkomiet Hasan
- a Department of Psychiatry and Psychotherapy , LMU Munich , Germany
| | - Kenij Hashimoto
- n Division of Clinical Neuroscience , Chiba University Centre for Forensic Mental Health , Chiba , Japan
| | - Yong-Ku Kim
- o Department of Psychiatry , Korea University, College of Medicine , Republic of Korea
| | | | - Johannes Kornhuber
- p Department of Psychiatry and Psychotherapy , Friedrich-Alexander-University Erlangen-Nuremberg , Erlangen , Germany
| | | | - Berend Malchow
- a Department of Psychiatry and Psychotherapy , LMU Munich , Germany
| | - Juliana M Nascimento
- c Laboratory of Neuroproteomics, Department of Biochemistry , Institute of Biology University of Campinas (UNICAMP), Campinas , SP , Brazil
| | - Moritz Rossner
- r Department of Psychiatry, Molecular and Behavioural Neurobiology , LMU Munich , Germany.,s Research Group Gene Expression , Max Planck Institute of Experimental Medicine , Göttingen , Germany
| | - Markus Schwarz
- t Institute for Laboratory Medicine, LMU Munich , Germany
| | - Johann Steiner
- u Department of Psychiatry , University of Magdeburg , Magdeburg , Germany
| | - Leda Talib
- b Laboratory of Neuroscience (LIM27) , Institute of Psychiatry, University of Sao Paulo , Sao Paulo , Brazil
| | - Florence Thibaut
- v Department of Psychiatry , University Hospital Cochin (site Tarnier), University of Paris-Descartes, INSERM U 894 Centre Psychiatry and Neurosciences , Paris , France
| | - Peter Riederer
- w Center of Psychic Health; Department of Psychiatry, Psychosomatics and Psychotherapy , University Hospital of Würzburg , Germany
| | - Peter Falkai
- a Department of Psychiatry and Psychotherapy , LMU Munich , Germany
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Scifo E, Calza G, Fuhrmann M, Soliymani R, Baumann M, Lalowski M. Recent advances in applying mass spectrometry and systems biology to determine brain dynamics. Expert Rev Proteomics 2017; 14:545-559. [PMID: 28539064 DOI: 10.1080/14789450.2017.1335200] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
INTRODUCTION Neurological disorders encompass various pathologies which disrupt normal brain physiology and function. Poor understanding of their underlying molecular mechanisms and their societal burden argues for the necessity of novel prevention strategies, early diagnostic techniques and alternative treatment options to reduce the scale of their expected increase. Areas covered: This review scrutinizes mass spectrometry based approaches used to investigate brain dynamics in various conditions, including neurodegenerative and neuropsychiatric disorders. Different proteomics workflows for isolation/enrichment of specific cell populations or brain regions, sample processing; mass spectrometry technologies, for differential proteome quantitation, analysis of post-translational modifications and imaging approaches in the brain are critically deliberated. Future directions, including analysis of cellular sub-compartments, targeted MS platforms (selected/parallel reaction monitoring) and use of mass cytometry are also discussed. Expert commentary: Here, we summarize and evaluate current mass spectrometry based approaches for determining brain dynamics in health and diseases states, with a focus on neurological disorders. Furthermore, we provide insight on current trends and new MS technologies with potential to improve this analysis.
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Affiliation(s)
- Enzo Scifo
- a Department of Psychiatry, and of Pharmacology and Toxicology , University of Toronto, Campbell Family Mental Health Research Institute of CAMH , Toronto , Canada
| | - Giulio Calza
- b Medicum, Meilahti Clinical Proteomics Core Facility, Biochemistry/Developmental Biology, Faculty of Medicine , FI-00014 University of Helsinki , Helsinki , Finland
| | - Martin Fuhrmann
- c Neuroimmunology and Imaging Group , German Center for Neurodegenerative Diseases (DZNE) , Bonn , Germany
| | - Rabah Soliymani
- b Medicum, Meilahti Clinical Proteomics Core Facility, Biochemistry/Developmental Biology, Faculty of Medicine , FI-00014 University of Helsinki , Helsinki , Finland
| | - Marc Baumann
- b Medicum, Meilahti Clinical Proteomics Core Facility, Biochemistry/Developmental Biology, Faculty of Medicine , FI-00014 University of Helsinki , Helsinki , Finland
| | - Maciej Lalowski
- b Medicum, Meilahti Clinical Proteomics Core Facility, Biochemistry/Developmental Biology, Faculty of Medicine , FI-00014 University of Helsinki , Helsinki , Finland
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32
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Vendramini PH, Gattaz WF, Schmitt A, Falkai P, Eberlin MN, Martins-de-Souza D. Pioneering ambient mass spectrometry imaging in psychiatry: Potential for new insights into schizophrenia. Schizophr Res 2016; 177:67-69. [PMID: 26545296 DOI: 10.1016/j.schres.2015.10.019] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2015] [Revised: 10/06/2015] [Accepted: 10/11/2015] [Indexed: 11/28/2022]
Affiliation(s)
- Pedro H Vendramini
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil; ThoMSon Mass Spectrometry Laboratory, Institute of Chemistry, University of Campinas (UNICAMP), Campinas, SP, Brazil
| | - Wagner F Gattaz
- Laboratory of Neurosciences (LIM-27), Institute of Psychiatry, University of São Paulo (USP), São Paulo, Brazil
| | - Andrea Schmitt
- Laboratory of Neurosciences (LIM-27), Institute of Psychiatry, University of São Paulo (USP), São Paulo, Brazil; Department of Psychiatry and Psychotherapy, Ludwig Maximilian University (LMU), Munich, Germany
| | - Peter Falkai
- Department of Psychiatry and Psychotherapy, Ludwig Maximilian University (LMU), Munich, Germany
| | - Marcos N Eberlin
- ThoMSon Mass Spectrometry Laboratory, Institute of Chemistry, University of Campinas (UNICAMP), Campinas, SP, Brazil
| | - Daniel Martins-de-Souza
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil; Laboratory of Neurosciences (LIM-27), Institute of Psychiatry, University of São Paulo (USP), São Paulo, Brazil; UNICAMP's Neurobiology Center, Campinas, Brazil.
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Mury FB, da Silva WC, Barbosa NR, Mendes CT, Bonini JS, Sarkis JES, Cammarota M, Izquierdo I, Gattaz WF, Dias-Neto E. Lithium activates brain phospholipase A2 and improves memory in rats: implications for Alzheimer's disease. Eur Arch Psychiatry Clin Neurosci 2016; 266:607-18. [PMID: 26661385 DOI: 10.1007/s00406-015-0665-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2015] [Accepted: 11/30/2015] [Indexed: 02/07/2023]
Abstract
Phospholipase A2 (Pla2) is required for memory retrieval, and its inhibition in the hippocampus has been reported to impair memory acquisition in rats. Moreover, cognitive decline and memory deficits showed to be reduced in animal models after lithium treatment, prompting us to evaluate possible links between Pla2, lithium and memory. Here, we evaluated the possible modulation of Pla2 activity by a long-term treatment of rats with low doses of lithium and its impact in memory. Wistar rats were trained for the inhibitory avoidance task, treated with lithium for 100 days and tested for perdurability of long-term memory. Hippocampal samples were used for quantifying the expression of 19 brain-expressed Pla2 genes and for evaluating the enzymatic activity of Pla2 using group-specific radio-enzymatic assays. Our data pointed to a significant perdurability of long-term memory, which correlated with increased transcriptional and enzymatic activities of certain members of the Pla2 family (iPla2 and sPla2) after the chronic lithium treatment. Our data suggest new possible targets of lithium, add more information on its pharmacological activity and reinforce the possible use of low doses of lithium for the treatment of neurodegenerative conditions such as the Alzheimer's disease.
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Affiliation(s)
- Fábio B Mury
- Laboratório de Neurociências (LIM27), Instituto de Psiquiatria, Faculdade de Medicina da Universidade de São Paulo, Rua Ovídio Pires de Campos, 785, 05403-010, São Paulo, SP, Brazil
- Pós-Graduação Interunidades em Biotecnologia, Universidade de São Paulo, São Paulo, SP, Brazil
| | - Weber C da Silva
- Centro de Memória, Instituto de Pesquisas Biomédicas, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS, Brazil
- Departamento de Farmácia, Universidade Estadual do Centro-Oeste, Guarapuava, PR, Brazil
| | - Nádia R Barbosa
- Laboratório de Neurociências (LIM27), Instituto de Psiquiatria, Faculdade de Medicina da Universidade de São Paulo, Rua Ovídio Pires de Campos, 785, 05403-010, São Paulo, SP, Brazil
| | - Camila T Mendes
- Laboratório de Neurociências (LIM27), Instituto de Psiquiatria, Faculdade de Medicina da Universidade de São Paulo, Rua Ovídio Pires de Campos, 785, 05403-010, São Paulo, SP, Brazil
- Pós-Graduação Interunidades em Biotecnologia, Universidade de São Paulo, São Paulo, SP, Brazil
| | - Juliana S Bonini
- Centro de Memória, Instituto de Pesquisas Biomédicas, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS, Brazil
- Departamento de Farmácia, Universidade Estadual do Centro-Oeste, Guarapuava, PR, Brazil
| | - Jorge Eduardo Souza Sarkis
- Instituto de Pesquisas Energéticas e Nucleares-IPEN-CNEN/SP, Grupo de Caracterização Química e Isotópica, Universidade de São Paulo, São Paulo, SP, Brazil
| | - Martin Cammarota
- Laboratório de Pesquisa de Memória, Instituto do Cérebro, Universidade Federal do Rio Grande do Norte, Natal, RN, Brazil
| | - Ivan Izquierdo
- Centro de Memória, Instituto de Pesquisas Biomédicas, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Wagner F Gattaz
- Laboratório de Neurociências (LIM27), Instituto de Psiquiatria, Faculdade de Medicina da Universidade de São Paulo, Rua Ovídio Pires de Campos, 785, 05403-010, São Paulo, SP, Brazil.
| | - Emmanuel Dias-Neto
- Laboratório de Neurociências (LIM27), Instituto de Psiquiatria, Faculdade de Medicina da Universidade de São Paulo, Rua Ovídio Pires de Campos, 785, 05403-010, São Paulo, SP, Brazil.
- Laboratório de Genômica Médica, Centro Internacional de Pesquisas, AC Camargo Cancer Center, São Paulo, SP, Brazil.
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Yang G, Xu H, Zhang H, Yu Q, Wu Y, Shi J, Rao W, You Y, Kou C, Yu Y. Association between PLA2G12A Polymorphisms and Schizophrenia in a Han Chinese Population from Northeast China. PLoS One 2016; 11:e0159584. [PMID: 27434078 PMCID: PMC4951095 DOI: 10.1371/journal.pone.0159584] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2016] [Accepted: 07/04/2016] [Indexed: 01/14/2023] Open
Abstract
Objective The purpose of this study was to explore the association between single nucleotide polymorphisms (SNPs) in the phospholipase A2 (PLA2), group XIIA gene (PLA2G12A) and schizophrenia. Methods This study included 1,063 schizophrenia patients and 1,103 healthy controls from a Han Chinese Population in Northeast China. Four tagSNPs (rs11728699 in intron 1, synonymous rs2285714 in exon 3, rs3087494 in the 3’ UTR, and rs7694620 in the downstream region) in PLA2G12A were selected, and they were genotyped by the MALDI-TOF-MS technology. The Chi-square (χ2) test and haplotype analysis were performed to analyze the association of PLA2G12A SNPs and schizophrenia using the software packages SPSS 16.0 and Haploview 4.2. Results Among the four tagSNPs, only SNP rs3087494 in the 3’ UTR of PLA2G12A showed significant differences in both allele frequencies (χ2 = 20.136, P<0.001) compared to healthy controls. The minor allele G of SNP rs3087494 is potentially a predictive factor for schizophrenia (OR = 0.753, 95% CI: 0.665–0.882). The frequency distribution of haplotypes consisting of specific alleles of two SNPs (rs7694620-rs3087494 or rs3087494-rs2285714), three SNPs (rs7694620-rs3087494-rs2285714 or rs3087494-rs2285714-rs11728699), or all four SNPs (rs7694620-rs3087494-rs2285714-rs11728699) was significantly different between schizophrenia patients and control subjects (P<0.001). Conclusions Our study demonstrated that PLA2G12A SNPs or haplotypes might influence the susceptibility to schizophrenia in the Han Chinese population from Northeast China.
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Affiliation(s)
- Guang Yang
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, 1163 Xinmin Street, Changchun, 130021, Jilin province, China
| | - Hongqin Xu
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, 1163 Xinmin Street, Changchun, 130021, Jilin province, China
- Department of Hepatology, First Hospital of Jilin University, Jilin University, Changchun, Jilin, 130021, China
| | - Huiping Zhang
- Department of Psychiatry, Yale University School of Medicine, New Haven, United States of America
- VA Medical Center, VA Connecticut Healthcare System, West Haven, United States of America
| | - Qiong Yu
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, 1163 Xinmin Street, Changchun, 130021, Jilin province, China
| | - Yanhua Wu
- Division of Clinical Epidemiology, First Hospital of Jilin University, Changchun, Jilin, 130021, China
| | - Jieping Shi
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, 1163 Xinmin Street, Changchun, 130021, Jilin province, China
| | - Wenwang Rao
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, 1163 Xinmin Street, Changchun, 130021, Jilin province, China
| | - Yueyue You
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, 1163 Xinmin Street, Changchun, 130021, Jilin province, China
| | - Changgui Kou
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, 1163 Xinmin Street, Changchun, 130021, Jilin province, China
- * E-mail: (YQY); (CGK)
| | - Yaqin Yu
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, 1163 Xinmin Street, Changchun, 130021, Jilin province, China
- * E-mail: (YQY); (CGK)
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35
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Yao JK, Dougherty GG, Gautier CH, Haas GL, Condray R, Kasckow JW, Kisslinger BL, Gurklis JA, Messamore E. Prevalence and Specificity of the Abnormal Niacin Response: A Potential Endophenotype Marker in Schizophrenia. Schizophr Bull 2016; 42:369-76. [PMID: 26371338 PMCID: PMC4753599 DOI: 10.1093/schbul/sbv130] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
The skin flush response to niacin is abnormally blunted among a subset of patients with schizophrenia (SZ), preferentially associates with SZ compared to other mental illnesses, occurs frequently in nonpsychotic members of SZ-affected families, appears heritable, and shows evidence of genetic association. The niacin response abnormality (NRA) may prove to be a useful SZ endophenotype. Using a laser Doppler flowmeter, we undertook this study to estimate the prevalence of NRA in SZ (n = 70), bipolar disorder (BP, n = 59), and healthy control (HC, n = 87) groups, and to estimate its specificity for the illness. From the dose-response curves, we calculated the concentration of methylnicotinate required to elicit a half-maximal blood flow (MBF) response (EC50 value) and MBF value for each subject. The median log10EC50 of the SZ was above the third quartile of log10EC50 of either the HC or BP groups, whereas the MBF was significantly lower in the SZ than in the HC or BP groups. With a definition of NRA of having both EC50 above the ninetieth percentile of the control samples and MBF response below the sixtieth percentile for the control range, the NRA predicted SZ with 31% sensitivity and 97% specificity. Moreover, the NRA was not influenced by age, gender, race, and cigarette smoking. In summary, the NRA may define a SZ subtype with a clinically significant phospholipid signaling defect. Understanding its molecular origins may shed light on the pathophysiology of SZ and suggest new tools for its early diagnosis and treatment.
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Affiliation(s)
- Jeffrey K. Yao
- *To whom correspondence should be addressed; VA Pittsburgh Healthcare System, B1-2E-140, University Drive C, Pittsburgh, PA 15240, US; tel: 412-360-6781, fax: 412-360-1159, e-mail:
| | - George G. Dougherty
- Medical Research Service, VA Pittsburgh Healthcare System, Pittsburgh, PA;,Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Clara H. Gautier
- Medical Research Service, VA Pittsburgh Healthcare System, Pittsburgh, PA
| | - Gretchen L. Haas
- Medical Research Service, VA Pittsburgh Healthcare System, Pittsburgh, PA;,Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Ruth Condray
- Medical Research Service, VA Pittsburgh Healthcare System, Pittsburgh, PA
| | - John W. Kasckow
- Medical Research Service, VA Pittsburgh Healthcare System, Pittsburgh, PA;,Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | | | - John A. Gurklis
- Medical Research Service, VA Pittsburgh Healthcare System, Pittsburgh, PA
| | - Erik Messamore
- Department of Psychiatry, University of Cincinnati and Lindner Center for Hope, Cincinnati, OH
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36
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Berger GE, Smesny S, Schäfer MR, Milleit B, Langbein K, Hipler UC, Milleit C, Klier CM, Schlögelhofer M, Holub M, Holzer I, Berk M, McGorry PD, Sauer H, Amminger GP. Niacin Skin Sensitivity Is Increased in Adolescents at Ultra-High Risk for Psychosis. PLoS One 2016; 11:e0148429. [PMID: 26894921 PMCID: PMC4764507 DOI: 10.1371/journal.pone.0148429] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2015] [Accepted: 01/18/2016] [Indexed: 12/14/2022] Open
Abstract
Background Most studies provide evidence that the skin flush response to nicotinic acid (niacin) stimulation is impaired in schizophrenia. However, only little is known about niacin sensitivity in the ultra-high risk (UHR) phase of psychotic disorders. Methods We compared visual ratings of niacin sensitivity between adolescents at UHR for psychosis according to the one year transition outcome (UHR-T n = 11; UHR-NT n = 55) with healthy controls (HC n = 25) and first episode schizophrenia patients (FEP n = 25) treated with atypical antipsychotics. Results Contrary to our hypothesis niacin sensitivity of the entire UHR group was not attenuated, but significantly increased compared to the HC group, whereas no difference could be found between the UHR-T and UHR-NT groups. As expected, niacin sensitivity of FEP was attenuated compared to HC group. In UHR individuals niacin sensitivity was inversely correlated with omega-6 and -9 fatty acids (FA), but positively correlated with phospholipase A2 (inPLA2) activity, a marker of membrane lipid repair/remodelling. Conclusions Increased niacin sensitivity in UHR states likely indicates an impaired balance of eicosanoids and omega-6/-9 FA at a membrane level. Our findings suggest that the emergence of psychosis is associated with an increased mobilisation of eicosanoids prior to the transition to psychosis possibly reflecting a “pro-inflammatory state”, whereas thereafter eicosanoid mobilisation seems to be attenuated. Potential treatment implications for the UHR state should be further investigated.
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Affiliation(s)
- Gregor E. Berger
- University Hospital of Child and Adolescent Psychiatry, University of Zurich, Neumünsterallee 9, 8032 Zurich, Switzerland
- Orygen Youth Health Research Centre, The University of Melbourne, Locked Bag 10, 35 Poplar Road Parkville, Victoria 3052, Melbourne, Australia
| | - Stefan Smesny
- Department of Psychiatry, Jena University Hospital, Philosophenweg 3, D-07743 Jena, Germany
- * E-mail:
| | - Miriam R. Schäfer
- Orygen Youth Health Research Centre, The University of Melbourne, Locked Bag 10, 35 Poplar Road Parkville, Victoria 3052, Melbourne, Australia
- Department of Child and Adolescent Psychiatry, Medical University of Vienna, Währingergürtel 18–20, A–1090 Vienna, Austria
| | - Berko Milleit
- Department of Psychiatry, Jena University Hospital, Philosophenweg 3, D-07743 Jena, Germany
| | - Kerstin Langbein
- Department of Psychiatry, Jena University Hospital, Philosophenweg 3, D-07743 Jena, Germany
| | - Uta-Christina Hipler
- Department of Dermatology, University Hospital Jena, Erfurter Straße 35, D-07743 Jena, Germany
| | - Christine Milleit
- Department of Psychiatry, Jena University Hospital, Philosophenweg 3, D-07743 Jena, Germany
| | - Claudia M. Klier
- Department of Child and Adolescent Psychiatry, Medical University of Vienna, Währingergürtel 18–20, A–1090 Vienna, Austria
| | - Monika Schlögelhofer
- Department of Child and Adolescent Psychiatry, Medical University of Vienna, Währingergürtel 18–20, A–1090 Vienna, Austria
| | - Magdalena Holub
- Department of Nutritional Sciences, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria
| | - Ingrid Holzer
- Department of Nutritional Sciences, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria
| | - Michael Berk
- Deakin University of Melbourne, School of Medicine, Barwon Health, Geelong, Australia
- Florey Institute for Neuroscience and Mental Health, Parkville, Australia
| | - Patrick D. McGorry
- Orygen Youth Health Research Centre, The University of Melbourne, Locked Bag 10, 35 Poplar Road Parkville, Victoria 3052, Melbourne, Australia
| | - Heinrich Sauer
- Department of Psychiatry, Jena University Hospital, Philosophenweg 3, D-07743 Jena, Germany
| | - G. Paul Amminger
- Orygen Youth Health Research Centre, The University of Melbourne, Locked Bag 10, 35 Poplar Road Parkville, Victoria 3052, Melbourne, Australia
- Department of Child and Adolescent Psychiatry, Medical University of Vienna, Währingergürtel 18–20, A–1090 Vienna, Austria
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Nadalin S, Radović I, Buretić-Tomljanović A. Polymorphisms in PLA2G6 and PLA2G4C genes for calcium-independent phospholipase A2 do not contribute to attenuated niacin skin flush response in schizophrenia patients. Prostaglandins Leukot Essent Fatty Acids 2015; 100:29-32. [PMID: 26160611 DOI: 10.1016/j.plefa.2015.06.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2015] [Revised: 05/11/2015] [Accepted: 06/18/2015] [Indexed: 11/18/2022]
Abstract
We hypothesized that attenuated niacin skin flushing in schizophrenia patients might be associated with polymorphic variants in PLA2G6 and PLA2G4C genes (rs4375 and rs1549637 variations) which encode calcium-independent phospholipase A2 beta (iPLA2β) and cytosolic phospholipase A2 gamma (cPLA2γ) enzymes. The iPLA2β and cPLA2γ may play an important role in niacin-mediated signaling; in addition to their major role - mediating phospholipids remodeling, which alters membrane receptors and signal transduction, they regulate the reservoir of arachidonic acid for prostaglandins synthesis. Skin response to topical niacin of 0.1M, 0.01M, 0.001M and 0.0001M concentrations in 75 schizophrenia patients was rated using the method of volumetric niacin response (VNR). Neither PLA2G6 nor PLA2G4C gene polymorphisms were significantly associated with VNR values. Furthermore, polymorphisms׳ synergy on niacin skin flushing was also not detected.
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Affiliation(s)
- S Nadalin
- Department of Biology and Medical Genetics, School of Medicine, University of Rijeka, Rijeka, Croatia.
| | - I Radović
- School of Medicine, University of Rijeka, Rijeka, Croatia
| | - A Buretić-Tomljanović
- Department of Biology and Medical Genetics, School of Medicine, University of Rijeka, Rijeka, Croatia
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38
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Ikenaga EH, Talib LL, Ferreira AS, Machado-Vieira R, Forlenza OV, Gattaz WF. Reduced activities of phospholipases A2 in platelets of drug-naïve bipolar disorder patients. Bipolar Disord 2015; 17:97-101. [PMID: 25041493 DOI: 10.1111/bdi.12229] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2013] [Accepted: 12/27/2013] [Indexed: 01/05/2023]
Abstract
OBJECTIVE Phospholipases A2 (PLA2 ) comprise a family of hydrolytic enzymes that cleave membrane phospholipids and play a key role in cellular homeostasis. Alterations in enzymatic activity have been hypothesized in bipolar disorder (BD). Recent studies suggest that PLA2 activity in platelets may reflect PLA2 activity in the brain. The aim of this study was to determine PLA2 activity in platelets of BD patients. METHODS We determined the activity of PLA2 subtypes [extracellular, calcium-dependent PLA2 (sPLA2 ), intracellular, calcium-dependent PLA2 (cPLA2 ), and intracellular, calcium-independent PLA2 (iPLA2 )] by a radioenzymatic method in platelets from 20 patients with BD (15 drug-naïve and five drug-free) and from 16 age- and gender-matched healthy controls. RESULTS We found that iPLA2 , cPLA2 , and sPLA2 activities were lower in drug-naïve patients with BD when compared to the control group (p = 0.017, p < 0.001, and p < 0.001, respectively). CONCLUSIONS Reduced PLA2 activity at the early stage of BD may disrupt brain function and increase the risk for the disease. Moreover, epidemiological studies show that patients with BD have a fivefold increased risk for developing Alzheimer's disease. Because patients with Alzheimer's disease also have reduced PLA2 activity, the present finding of reduced PLA2 in the BD group may be related to the risk factor for these individuals developing Alzheimer's disease in advanced age.
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Affiliation(s)
- Eliza Hiromi Ikenaga
- Laboratory of Neuroscience, Department and Institute of Psychiatry, Faculty of Medicine, University of Sao Paulo, Sao Paulo, Brazil
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39
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Nilsson BM, Holm G, Hultman CM, Ekselius L. Cognition and autonomic function in schizophrenia: inferior cognitive test performance in electrodermal and niacin skin flush non-responders. Eur Psychiatry 2014; 30:8-13. [PMID: 25169443 DOI: 10.1016/j.eurpsy.2014.06.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2014] [Revised: 06/13/2014] [Accepted: 06/29/2014] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Patients with schizophrenia suffer from a broad range of cognitive disturbances. The impact in terms of functional outcome is significant. There are also several reports of disturbed autonomic regulation in the disease. The present study examined cognitive function as well as psychophysiological parameters in patients with schizophrenia and healthy controls. METHODS Twenty-five patients and 14 controls were investigated with electrodermal activity (EDA), an oral niacin skin flush test and a comprehensive neurocognitive test program including the Wechsler battery (WAIS-R), Fingertapping Test, Trail Making Test, Verbal Fluency, Benton Visual Retention Test, Wisconsin Card Sorting Test and Rey Auditory Verbal Learning Test. RESULTS The patients generally had inferior test results compared to controls. Further analysis revealed that the EDA non-responding patient group explained this variation with significant lower test results than controls. On executive tests, EDA non-responders also performed significantly worse than EDA responding patients. The small group of niacin non-responding patients exhibited an even lower overall test performance. Delayed niacin flush also correlated inversely with psychomotor function and IQ in the patients. CONCLUSION The findings support the hypothesis of a neurodevelopment disturbance affecting both autonomic function and higher cortical function in schizophrenia.
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Affiliation(s)
- B M Nilsson
- Department of Neuroscience, Psychiatry, Uppsala University, SE-751 85 Uppsala, Sweden.
| | - G Holm
- Department of Neuroscience, Psychiatry, Uppsala University, SE-751 85 Uppsala, Sweden
| | - C M Hultman
- Department of Medical Epidemiology and Biostatistics, Karolinska Institute, SE-17177 Stockholm, Sweden
| | - L Ekselius
- Department of Neuroscience, Psychiatry, Uppsala University, SE-751 85 Uppsala, Sweden
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40
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Smesny S, Milleit B, Hipler UC, Milleit C, Schäfer MR, Klier CM, Holub M, Holzer I, Berger GE, Otto M, Nenadic I, Berk M, McGorry PD, Sauer H, Amminger GP. Omega-3 fatty acid supplementation changes intracellular phospholipase A2 activity and membrane fatty acid profiles in individuals at ultra-high risk for psychosis. Mol Psychiatry 2014; 19:317-24. [PMID: 23478748 DOI: 10.1038/mp.2013.7] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2011] [Revised: 12/10/2012] [Accepted: 01/02/2013] [Indexed: 02/07/2023]
Abstract
The identification of an ultra-high risk (UHR) profile for psychosis and a greater understanding of its prodrome have led to increasing interest in early intervention to delay or prevent the onset of psychotic illness. In a randomized placebo-controlled trial, we have identified long-chain ω-3 (ω-3) polyunsaturated fatty acid (PUFA) supplementation as potentially useful, as it reduced the rate of transition to psychosis by 22.6% 1 year after baseline in a cohort of 81 young people at UHR of transition to psychosis. However, the mechanisms whereby the ω-3 PUFAs might be neuroprotective are incompletely understood. Here, we report on the effects of ω-3 PUFA supplementation on intracellular phospholipase A2 (inPLA(2)) activity, the main enzymes regulating phospholipid metabolism, as well as on peripheral membrane lipid profiles in the individuals who participated in this randomized placebo-controlled trial. Patients were studied cross-sectionally (n=80) and longitudinally (n=65) before and after a 12-week intervention with 1.2 g per day ω-3 PUFAs or placebo, followed by a 40-week observation period to establish the rates of transition to psychosis. We investigated inPLA(2) and erythrocyte membrane FAs in the treatment groups (ω-3 PUFAs vs placebo) and the outcome groups (psychotic vs non-psychotic). The levels of membrane ω-3 and ω-6 PUFAs and inPLA(2) were significantly related. Some of the significant associations (that is, long-chain ω-6 PUFAs, arachidonic acid) with inPLA(2) activity were in opposite directions in individuals who did (a positive correlation) and who did not (a negative correlation) transition to psychosis. Supplementation with ω-3 PUFA resulted in a significant decrease in inPLA(2) activity. We conclude that ω-3 PUFA supplementation may act by normalizing inPLA(2) activity and δ-6-desaturase-mediated metabolism of ω-3 and ω-6 PUFAs, suggesting their role in neuroprogression of psychosis.
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Affiliation(s)
- S Smesny
- Department of Psychiatry, University Hospital Jena, Jena, Germany
| | - B Milleit
- Department of Psychiatry, University Hospital Jena, Jena, Germany
| | - U-C Hipler
- Department of Dermatology, University Hospital Jena, Jena, Germany
| | - C Milleit
- 1] Department of Psychiatry, University Hospital Jena, Jena, Germany [2] Department of Dermatology, University Hospital Jena, Jena, Germany
| | - M R Schäfer
- 1] Department of Child and Adolescent Psychiatry, Medical University Vienna, Vienna, Austria [2] Orygen Youth Health Research Centre, University of Melbourne, Melbourne, VIC, Australia
| | - C M Klier
- Department of Child and Adolescent Psychiatry, Medical University Vienna, Vienna, Austria
| | - M Holub
- Department of Nutritional Sciences, University of Vienna, Vienna, Austria
| | - I Holzer
- Department of Nutritional Sciences, University of Vienna, Vienna, Austria
| | - G E Berger
- Department of Adolescent Psychiatry Winterthur-Zürcher Unterland, Switzerland
| | - M Otto
- Department of Psychiatry, University Hospital Jena, Jena, Germany
| | - I Nenadic
- Department of Psychiatry, University Hospital Jena, Jena, Germany
| | - M Berk
- 1] Orygen Youth Health Research Centre, University of Melbourne, Melbourne, VIC, Australia [2] Deakin University of Melbourne, School of Medicine, Barwon Health, Geelong, VIC, Australia [3] Florey Institute for Neuroscience and Mental Health, Melbourne, VIC, Australia
| | - P D McGorry
- Orygen Youth Health Research Centre, University of Melbourne, Melbourne, VIC, Australia
| | - H Sauer
- Department of Psychiatry, University Hospital Jena, Jena, Germany
| | - G P Amminger
- 1] Department of Child and Adolescent Psychiatry, Medical University Vienna, Vienna, Austria [2] Orygen Youth Health Research Centre, University of Melbourne, Melbourne, VIC, Australia
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Talib LL, Valente KD, Vincentiis S, Gattaz WF. Correlation between platelet and brain PLA(2) activity. Prostaglandins Leukot Essent Fatty Acids 2013; 89:265-8. [PMID: 23880350 DOI: 10.1016/j.plefa.2013.07.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2013] [Revised: 06/26/2013] [Accepted: 07/02/2013] [Indexed: 11/17/2022]
Abstract
The phospholipase A2 (PLA2) enzymes have been implicated in several neuropsychiatry disorders and activity alterations have been described in brain and platelet. Since brain tissue is not readily available for the measurement of PLA2 activity, it would be of interest to test directly whether PLA2 activities in both tissues are correlated. We performed this task assessing PLA2 activity in platelets and hippocampus collected simultaneously from 19 patients undergoing temporal lobectomy for treatment of refractory epilepsy. Our findings suggest that total PLA2 activity in platelets may reflect the total activity of the enzyme in the brain (rs=0.59, p=0.008). However in our sample no correlations were found between the subgroups of the enzyme in brain and in platelets. This lack of correlations may be due to different effects of drug treatment on the PLA2 subtypes. In face of the difficulty to obtain brain tissues from living patients, further studies with larger drug-free samples are warranted to clarify whether the use of platelets is a reliable strategy to reflect the subtypes of PLA2 activity in the brain.
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Affiliation(s)
- Leda L Talib
- Laboratory of Neuroscience-LIM 27, Department and Institute of Psychiatry, Faculty of Medicine, University of Sao Paulo, Brazil
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42
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43
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Nadalin S, Giacometti J, Jonovska S, Tomljanović D, Buretić-Tomljanović A. The impact of PLA2G4A and PTGS2 gene polymorphisms, and red blood cell PUFAs deficit on niacin skin flush response in schizophrenia patients. Prostaglandins Leukot Essent Fatty Acids 2013; 88:185-90. [PMID: 23219238 DOI: 10.1016/j.plefa.2012.11.005] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2012] [Revised: 09/14/2012] [Accepted: 11/15/2012] [Indexed: 11/23/2022]
Abstract
We investigated the etiology of the attenuated niacin skin flush response in schizophrenia patients. Skin response to topical niacin of 0.1M, 0.01 M, 0.001 M, and 0.0001 M concentrations was rated using method of volumetric niacin response (VNR) and correlated to two functional A/G polymorphisms in genes: phospholipase A2 group IVA (BanI of the PLA2G4A), and rs689466 of the prostaglandin synthase-2 (PTGS2). We further tested the possible correlation between niacin response and fatty acid (FA) content of red blood cells (RBCs). We detected statistically significant but weak impact of both polymorphisms on niacin flush response in schizophrenia patients. The dosage of the G alleles of both polymorphisms was associated with higher VNR values, although each polymorphic variant accounted for only 1% of the overall flush response variability. Regarding FA content, both n-3 and n-6 polyunsaturated FAs (PUFAs) were significantly reduced in the patient group, but an association with niacin sensitivity was not detected.
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Affiliation(s)
- Sergej Nadalin
- Department of Biology and Medical Genetics, School of Medicine, University of Rijeka, Braće Branchetta 20, Rijeka 51000, Croatia
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Lien YJ, Huang SS, Liu CM, Hwu HG, Faraone SV, Tsuang MT, Chen WJ. A genome-wide quantitative linkage scan of niacin skin flush response in families with schizophrenia. Schizophr Bull 2013; 39:68-76. [PMID: 21653277 PMCID: PMC3523922 DOI: 10.1093/schbul/sbr054] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Schizophrenia patients frequently display reduced niacin flush responses, and similar characteristics are also observed in their nonpsychotic relatives. This study aimed to identify loci influencing flush response to niacin in schizophrenia using genome-wide quantitative linkage scan. In a nationwide sample of families with at least 2 siblings affected with schizophrenia in each family, 115 families that had at least 2 affected siblings with information on the niacin skin test were subjected to quantitative trait loci linkage analysis, either involving affected individuals only or the whole family. Nonparametric linkage z (NPL-Z) scores were calculated for each of 386 microsatellite markers spaced at an average of 9-cM intervals. Niacin patches of 3 concentrations (0.001 M, 0.01, and 0.1 M) were applied to forearm skin, and the flush response was rated at 5, 10, and 15 minutes, respectively, with a 4-point scale. Determination of genome-wide empirical significance was implemented using 1000 simulated genome scans. One linkage peak attaining genome-wide significance was identified at chromosomal region 14q32.12 for 0.01 M concentration at 5 minutes (NPL-Z scores = 3.39, genome-wide empirical P = .03) in affected individuals, and the corresponding linkage signal remained strong (NPL-Z scores = 2.87) for the analyses of the whole family. This locus is distinct from the chromosomal region identified in the previous genome-wide scan for the diagnosis of schizophrenia, and the signal was higher than the peak linkage signal in that study. These findings indicate that there might be modifier or susceptibility-modifier genes at 14q32.12 for schizophrenia-related attenuation of flush response to niacin.
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Affiliation(s)
- Yin-Ju Lien
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, 17 Xu-Zhou Road, Taipei 100, Taiwan,Department of Public Health, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Sih-Syuan Huang
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, 17 Xu-Zhou Road, Taipei 100, Taiwan
| | - Chih-Min Liu
- Department of Psychiatry, National Taiwan University Hospital, and College of Medicine, Taipei, Taiwan
| | - Hai-Gwo Hwu
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, 17 Xu-Zhou Road, Taipei 100, Taiwan,Department of Psychiatry, National Taiwan University Hospital, and College of Medicine, Taipei, Taiwan,Neurobiology and Cognitive Center, National Taiwan University, Taipei, Taiwan
| | - Stephen V. Faraone
- Department of Psychiatry, SUNY Upstate Medical University, Syracuse, NY,Department of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY
| | - Ming T. Tsuang
- Department of Psychiatry, Center for Behavioral Genomics, University of California, San Diego, CA,Harvard Department of Psychiatry, Harvard Institute of Psychiatric Epidemiology and Genetics, Boston, MA
| | - Wei J. Chen
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, 17 Xu-Zhou Road, Taipei 100, Taiwan,Department of Public Health, College of Public Health, National Taiwan University, Taipei, Taiwan,Genetic Epidemiology Core Laboratory, Center of Genomic Medicine, National Taiwan University, Taipei, Taiwan,To whom correspondence should be addressed; tel: 886-2-33668010, fax: 886-2-33668004, e-mail:
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Yang J, Chen T, Sun L, Zhao Z, Qi X, Zhou K, Cao Y, Wang X, Qiu Y, Su M, Zhao A, Wang P, Yang P, Wu J, Feng G, He L, Jia W, Wan C. Potential metabolite markers of schizophrenia. Mol Psychiatry 2013; 18:67-78. [PMID: 22024767 PMCID: PMC3526727 DOI: 10.1038/mp.2011.131] [Citation(s) in RCA: 193] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Schizophrenia is a severe mental disorder that affects 0.5-1% of the population worldwide. Current diagnostic methods are based on psychiatric interviews, which are subjective in nature. The lack of disease biomarkers to support objective laboratory tests has been a long-standing bottleneck in the clinical diagnosis and evaluation of schizophrenia. Here we report a global metabolic profiling study involving 112 schizophrenic patients and 110 healthy subjects, who were divided into a training set and a test set, designed to identify metabolite markers. A panel of serum markers consisting of glycerate, eicosenoic acid, β-hydroxybutyrate, pyruvate and cystine was identified as an effective diagnostic tool, achieving an area under the receiver operating characteristic curve (AUC) of 0.945 in the training samples (62 patients and 62 controls) and 0.895 in the test samples (50 patients and 48 controls). Furthermore, a composite panel by the addition of urine β-hydroxybutyrate to the serum panel achieved a more satisfactory accuracy, which reached an AUC of 1 in both the training set and the test set. Multiple fatty acids and ketone bodies were found significantly (P<0.01) elevated in both the serum and urine of patients, suggesting an upregulated fatty acid catabolism, presumably resulting from an insufficiency of glucose supply in the brains of schizophrenia patients.
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Affiliation(s)
- J Yang
- Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Bio-X Center, Shanghai Jiao Tong University, Shanghai, China,Institutes for Nutritional Sciences, Shanghai Institute of Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - T Chen
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China
| | - L Sun
- Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Bio-X Center, Shanghai Jiao Tong University, Shanghai, China,Institutes for Nutritional Sciences, Shanghai Institute of Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Z Zhao
- Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN, USA,Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - X Qi
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
| | - K Zhou
- Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Bio-X Center, Shanghai Jiao Tong University, Shanghai, China,Institutes for Nutritional Sciences, Shanghai Institute of Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Y Cao
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China
| | - X Wang
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China
| | - Y Qiu
- Department of Nutrition, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC, USA
| | - M Su
- Department of Nutrition, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC, USA
| | - A Zhao
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
| | - P Wang
- Wuhu No. 4 People's Hospital, Wuhu, China
| | - P Yang
- Wuhu No. 4 People's Hospital, Wuhu, China
| | - J Wu
- Instrumental Analysis Center, Shanghai Jiao Tong University, Shanghai, China
| | - G Feng
- Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Bio-X Center, Shanghai Jiao Tong University, Shanghai, China,Institutes for Nutritional Sciences, Shanghai Institute of Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - L He
- Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Bio-X Center, Shanghai Jiao Tong University, Shanghai, China,Institutes for Nutritional Sciences, Shanghai Institute of Biological Sciences, Chinese Academy of Sciences, Shanghai, China,Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - W Jia
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China,Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China. E-mail:
| | - C Wan
- Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Bio-X Center, Shanghai Jiao Tong University, Shanghai, China,Institutes for Nutritional Sciences, Shanghai Institute of Biological Sciences, Chinese Academy of Sciences, Shanghai, China,Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Bio-X Center, Shanghai Jiao Tong University, 1954 Huashan Road, Shanghai 200030, China. E-mail:
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Talib LL, Joaquim HP, Forlenza OV. Platelet biomarkers in Alzheimer’s disease. World J Psychiatry 2012; 2:95-101. [PMID: 24175175 PMCID: PMC3782189 DOI: 10.5498/wjp.v2.i6.95] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2011] [Revised: 10/23/2012] [Accepted: 11/17/2012] [Indexed: 02/05/2023] Open
Abstract
The search for diagnostic and prognostic markers in Alzheimer’s disease (AD) has been an area of active research in the last decades. Biochemical markers are correlates of intracerebral changes that can be identified in biological fluids, namely: peripheral blood (total blood, red and white blood cells, platelets, plasma and serum), saliva, urine and cerebrospinal fluid. An important feature of a biomarker is that it can be measured objectively and evaluated as (1) an indicator of disease mechanisms (markers of core pathogenic processes or the expression of downstream effects of these processes), or (2) biochemical responses to pharmacological or therapeutic intervention, which can be indicative of disease modification. Platelets have been used in neuropharmacological models since the mid-fifties, as they share several homeostatic functions with neurons, such as accumulation and release of neurotransmitters, responsiveness to variations in calcium concentration, and expression of membrane-bound compounds. Recent studies have shown that platelets also express several components related to the pathogenesis of AD, in particular to the amyloid cascade and the regulation of oxidative stress: thus they can be used in the search for biomarkers of the disease process. For instance, platelets are the most important source of circulating forms of the amyloid precursor protein and other important proteins such as Tau and glycogen synthase kinase-3B. Moreover, platelets express enzymes involved in membrane homeostasis (e.g., phospholipase A2), and markers of the inflammatory process and oxidative stress. In this review we summarize the available literature and discuss evidence concerning the potential use of platelet markers in AD.
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Affiliation(s)
- Leda L Talib
- Leda L Talib, Helena PG Joaquim, Orestes V Forlenza, Laboratory of Neuroscience (LIM-27), Department and Institute of Psychiatry, Faculty of Medicine, University of São Paulo, 05403-010 São Paulo, SP, Brazil
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Niacin subsensitivity is associated with functional impairment in schizophrenia. Schizophr Res 2012; 137:180-4. [PMID: 22445461 DOI: 10.1016/j.schres.2012.03.001] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2011] [Revised: 02/29/2012] [Accepted: 03/02/2012] [Indexed: 11/23/2022]
Abstract
OBJECTIVE Sensitivity to the skin flush effect of niacin is reduced in a portion of patients with schizophrenia. Though this peripheral physiological abnormality has been widely replicated, its relevance to neuropsychiatric manifestations of the illness has been unclear. The goal of this study was to determine if the niacin response abnormality in schizophrenia is associated with functional impairment. METHODS Following psychiatric assessment, a Global Assessment of Functioning (GAF) score was assigned to each of 40 volunteers with schizophrenia. For each subject, the blood flow responses to several concentrations of topical methylnicotinate were recorded. Blood flow was measured objectively, using laser Doppler flowmetry. From the dose-response data, EC(50) values were derived. GAF scores were assigned without knowledge of the participants' niacin response data. RESULTS There was a significant negative correlation between GAF scores and EC(50) values for methylnicotinate (Pearson r=-0.42; p=0.007). CONCLUSIONS Reduced niacin sensitivity is associated with greater functional impairment among patients with schizophrenia. These findings raise the possibility that a subset of schizophrenia patients possesses a biochemical abnormality that reduces niacin sensitivity in the skin and contributes to functional impairment from the disease.
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Talib LL, Diniz BS, Zainaghi IA, Forlenza OV, Gattaz WF. A radioenzymatic assay to identify three groups of phospholipase A(2) in platelets. Prostaglandins Leukot Essent Fatty Acids 2012; 86:149-53. [PMID: 22498046 DOI: 10.1016/j.plefa.2012.02.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2011] [Revised: 02/10/2012] [Accepted: 02/11/2012] [Indexed: 11/25/2022]
Abstract
Phospholipases A(2) (PLA(2)) are key enzymes in membrane metabolism. The release of fatty acids and lysophospholipids by PLA(2) activates several intra-cellular second messenger cascades that regulate a wide variety of physiological responses. The aim of the present study is to describe a radioenzymatic assay to determine the activity of three main PLA(2) subtypes in platelets, namely extracellular calcium-dependent PLA(2) (sPLA(2)) and intracellular calcium-dependent (cPLA(2)) and calcium-independent PLA(2) (iPLA(2)). The differentiation of these distinct PLA(2) subtypes was based on the enzyme substrate preference (arachdonic acid or palmitoyl acid) and calcium concentration. Our results indicate that this new assay is feasible, precise and specific to measure the activity of the aforementioned subtypes of PLA(2). Therefore, this protocol can be used to investigate modifications of PLA(2) homeostasis in distinct biological models addressing the pathophysiology of many medical and neuropsychiatric disorders such as schizophrenia and Alzheimer's disease.
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Affiliation(s)
- Leda L Talib
- Laboratory of Neuroscience-LIM 27, Department and Institute of Psychiatry, University of Sao Paulo, Brazil
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Abstract
Molecular biomarkers for antipsychotic treatments have been conceptually linked to the measurements of dopamine functions, mostly D(2) receptor occupancy, either by imaging using selective PET/SPECT radioactive tracers or by assessing plasma prolactin levels. A quest for novel biomarkers was recently proposed by various academic, health service, and industrial institutions driven by the need for better treatments of psychoses. In this review we conceptualize biomarkers within the Translational Medicine paradigm whose goal was to provide support to critical decision-making in drug discovery. At first we focused on biomarkers as outcome measure of clinical studies by searching into the database clinicaltrial.gov. The results were somewhat disappointing, showing that out of 1,659 antipsychotic trials only 18 used a biomarker as an outcome measure. Several of these trials targeted plasma lipids as sentinel marker for metabolic adverse effects associated with the use of atypical antipsychotics, while only few studies were aimed to new disease specific biological markers. As an example of a mechanistic biomarker, we described the work done to progress the novel class of glycine transporter inhibitors as putative treatment for negative symptoms of schizophrenia. We also review how large-scale multiplex biological assays were applied to samples from tissues of psychiatric patients, so to learn from changes of numerous analytes (metabolic products, lipids, proteins, RNA transcripts) about the substrates involved in the disease. We concluded that a stringent implementation of these techniques could contribute to the endophenotypic characterization of patients, helping in the identification of key biomarkers to drive personalized medicine and new treatment development.
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Affiliation(s)
- Emilio Merlo Pich
- Respiratory Therapeutic Area, GlaxoSmithKline R&D, King of Prussia, PA, USA.
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Gattaz WF, Valente KD, Raposo NRB, Vincentiis S, Talib LL. Increased PLA2 activity in the hippocampus of patients with temporal lobe epilepsy and psychosis. J Psychiatr Res 2011; 45:1617-20. [PMID: 21813137 DOI: 10.1016/j.jpsychires.2011.07.005] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2011] [Revised: 06/22/2011] [Accepted: 07/07/2011] [Indexed: 11/18/2022]
Abstract
OBJECTIVE The aim of this work was to investigate whether increased activity of the enzyme phospholipase A(2) (PLA(2)) in the brain, as frequently reported in schizophrenia, is also related to psychosis in epilepsy. Our working hypothesis was based on the increased prevalence of schizophrenia-like psychosis in patients with temporal lobe epilepsy (TLE) secondary to mesial temporal sclerosis (MTS), as compared to patients with other forms of epilepsy. METHODS We determined PLA(2) activity in hippocampal tissue from 7 patients with TLE-MTS and psychosis, as compared to 9 TLE-MTS patients without psychosis. Hippocampal tissue was obtained from patients who underwent an anterior temporal lobectomy due to therapy-resistant epilepsy. RESULTS We found that patients with TLE-MTS and psychosis had a significantly increased calcium-independent PLA(2) activity as compared to patients without psychosis (p = 0.016). CONCLUSION Our finding suggest that an increment in brain PLA(2) activity is not specific for schizophrenia, but rather may be associated to the manifestation of schizophrenia-like psychotic symptoms in general.
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Affiliation(s)
- Wagner F Gattaz
- Laboratory of Neuroscience (LIM27), Department and Institute of Psychiatry, Faculty of Medicine, University of Sao Paulo, Rua Dr. Ovídio Pires de Campos 785, 05403-010 São Paulo, Brazil.
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