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Dietrich-Muszalska A, Wachowicz B. Platelet haemostatic function in psychiatric disorders: Effects of antidepressants and antipsychotic drugs. World J Biol Psychiatry 2017; 18:564-574. [PMID: 27112326 DOI: 10.3109/15622975.2016.1155748] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Objectives Platelets, the smallest anucleated blood cells, play an essential role in the first step of complex haemostatic process. This review presents the haemostatic function of blood platelets related to their activation in psychiatric disorders (schizophrenia, depression), the role of antipsychotic and antidepressant medication, and introduces the mechanisms by which activated platelets may be involved in the pathophysiology of these disorders. Methods Platelets are interesting and easily accessible blood cells to study biochemical pathways related to schizophrenia and other psychiatric disorders, and their complex activation process might be useful as a diagnostic peripheral marker for studying psychiatric disorders and haemostatic complications. Results The excessive activation of platelets observed in patients with depression and schizophrenia is involved in cardiovascular diseases, stroke and increased risk of thrombotic complications that may be major causes of morbidity and mortality of patients. The use of antidepressants or antipsychotic drugs in depression and schizophrenia treatment is often associated with haematological side effects such as bleeding, venous thromboembolism and impaired platelet function. Conclusions Understanding the role of platelet activation in psychiatric disorders such as schizophrenia or depression and medication may improve therapies in the future.
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Affiliation(s)
- Anna Dietrich-Muszalska
- a Department of Biological Psychiatry of the Chair of Experimental and Clinical Physiology , Medical University of Lodz , Lodz , Poland
| | - Barbara Wachowicz
- b Department of General Biochemistry , University of Lodz , Lodz , Poland
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Yenilmez C, Ozdemir Koroglu Z, Kurt H, Yanas M, Colak E, Degirmenci I, Gunes HV. A study of the possible association of plasminogen activator inhibitor type 1 4G/5G insertion/deletion polymorphism with susceptibility to schizophrenia and in its subtypes. J Clin Pharm Ther 2016; 42:103-107. [PMID: 27796029 DOI: 10.1111/jcpt.12470] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2016] [Accepted: 09/26/2016] [Indexed: 11/29/2022]
Abstract
WHAT IS KNOWN AND OBJECTIVE Inhibition of the fibrinolytic system may occur at the level of plasminogen activation, mainly by PAI-1. Mental and physical stress caused to alterations of platelet function, and also decreased to fibrinolytic activity. Furthermore, stress-induced thrombosis regulation was proposed to be by PAI-1 in schizophrenia patients. In this study, the distribution of genotypes and frequency of alleles of the plasminogen activator inhibitor type 1 (PAI-1) gene 4G/5G polymorphism in different Turkish clinical schizophrenia subtypes was investigated for its role in schizophrenia development. METHODS The clinical schizophrenia subtypes include paranoid, catatonic, disorganized, undifferentiated and residual, as diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition IV (DSM-IV). Samples of genomic DNA (250 total, including 150 schizophrenia patients and 100 healthy subjects) were analysed. PAI-1 4G/5G genotyping was performed by polymerase chain reaction-allele-specific amplification. PCR products were separated by 2% agarose gel electrophoresis and then visualized. RESULTS AND DISCUSSION The genotype distributions (P = 0·136) and allele frequencies (P = 0·721 for 4G, P = 0. 097 for 5G) were not significantly different between patients with schizophrenia and control subjects for the 4G/5G polymorphism. Similar results were also found for the genotype distributions (P = 0·640) and allele frequencies (P = 0·763 for 4G, P = 0·448 for 5G) in the clinical schizophrenia subtypes compared to the each other. WHAT IS NEW AND CONCLUSION We conclude that PAI-1 4G/5G polymorphism was not significantly associated with schizophrenia or its subtypes in the Turkish population. However, we recognize that with our sample sizes, we cannot exclude weak associations.
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Affiliation(s)
- C Yenilmez
- Department of Psychiatry, Medical Faculty, Eskisehir Osmangazi University, Eskisehir, Turkey
| | - Z Ozdemir Koroglu
- Department of Medical Laboratory, Vocational School of Health Services, Eskisehir Osmangazi University, Eskisehir, Turkey
| | - H Kurt
- Department of Medical Biology, Medical Faculty, Eskisehir Osmangazi University, Eskisehir, Turkey
| | - M Yanas
- Department of Psychiatry, Medical Faculty, Eskisehir Osmangazi University, Eskisehir, Turkey
| | - E Colak
- Department of Biostatistics, Medical Faculty, Eskisehir Osmangazi University, Eskisehir, Turkey
| | - I Degirmenci
- Department of Medical Biology, Medical Faculty, Eskisehir Osmangazi University, Eskisehir, Turkey
| | - H V Gunes
- Department of Medical Biology, Medical Faculty, Eskisehir Osmangazi University, Eskisehir, Turkey
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Wachowicz B. Blood Platelet as a Peripheral Cell in Oxidative Stress in Psychiatric Disorders. OXIDATIVE STRESS IN APPLIED BASIC RESEARCH AND CLINICAL PRACTICE 2015. [DOI: 10.1007/978-1-4939-0440-2_16] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
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Wesseling H, Gottschalk MG, Bahn S. Targeted multiplexed selected reaction monitoring analysis evaluates protein expression changes of molecular risk factors for major psychiatric disorders. Int J Neuropsychopharmacol 2014; 18:pyu015. [PMID: 25539505 PMCID: PMC4368865 DOI: 10.1093/ijnp/pyu015] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Extensive research efforts have generated genomic, transcriptomic, proteomic, and functional data hoping to elucidate psychiatric pathophysiology. Selected reaction monitoring, a recently developed targeted proteomic mass spectrometric approach, has made it possible to evaluate previous findings and hypotheses with high sensitivity, reproducibility, and quantitative accuracy. METHODS Here, we have developed a labelled multiplexed selected reaction monitoring assay, comprising 56 proteins previously implicated in the aetiology of major psychiatric disorders, including cell type markers or targets and effectors of known psychopharmacological interventions. We analyzed postmortem anterior prefrontal cortex (Brodmann area 10) tissue of patients diagnosed with schizophrenia (n=22), bipolar disorder (n=23), and major depressive disorder with (n=11) and without (n=11) psychotic features compared with healthy controls (n=22). RESULTS Results agreed with several previous studies, with the finding of alterations of Wnt-signalling and glutamate receptor abundance predominately in bipolar disorder and abnormalities in energy metabolism across the neuropsychiatric disease spectrum. Calcium signalling was predominantly affected in schizophrenia and affective psychosis. Interestingly, we were able to show a decrease of all 4 tested oligodendrocyte specific proteins (MOG, MBP, MYPR, CNPase) in bipolar disorder and to a lesser extent in schizophrenia and affective psychosis. Finally, we provide new evidence linking ankyrin 3 specifically to affective psychosis and the 22q11.2 deletion syndrome-associated protein septin 5 to schizophrenia. CONCLUSIONS Our study highlights the potential of selected reaction monitoring to evaluate the protein abundance levels of candidate markers of neuropsychiatric spectrum disorders, providing a high throughput multiplex platform for validation of putative disease markers and drug targets.
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Affiliation(s)
| | | | - Sabine Bahn
- Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge CB2 1QT, United Kingdom (Wesseling, Gottschalk, and Bahn); Department of Neuroscience, Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands (Dr Bahn).H.W. and M.G.G. contributed equally to this work.
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Goubau C, Buyse GM, Van Geet C, Freson K. The contribution of platelet studies to the understanding of disease mechanisms in complex and monogenetic neurological disorders. Dev Med Child Neurol 2014; 56:724-31. [PMID: 24579816 DOI: 10.1111/dmcn.12421] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/05/2014] [Indexed: 01/03/2023]
Abstract
Platelets, known for their role in primary haemostasis, prevent excessive bleeding after injury. The study of platelets has, therefore, traditionally focused on bleeding disorders. It has recently become evident, however, that platelet research can contribute to unravelling the disease mechanisms that underlie neuropathological disorders that have a subtle subclinical platelet phenotype. Platelets and neurosecretory cells have common gene expression profiles and share several biological features. This review provides a literature update on the use of platelets as easily accessible cells to study neurological disorders. We provide examples of the use of different platelet-based tests to understand the underlying pathophysiological mechanisms for both complex and monogenetic neuropathological disorders. In addition to the well-studied regulated granule secretion and serotonin metabolism, more recent studies have shown that defects in transcription factors, membrane transporters, G-protein signal transduction, and cytoskeletal proteins can be investigated using platelets to gain information on their role in neuropathology.
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Affiliation(s)
- Christophe Goubau
- Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium; Department of Child Neurology, University Hospitals Leuven, Leuven, Belgium
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Asor E, Ben-Shachar D. Platelets: A possible glance into brain biological processes in schizophrenia. World J Psychiatry 2012; 2:124-33. [PMID: 24175178 PMCID: PMC3782191 DOI: 10.5498/wjp.v2.i6.124] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2011] [Revised: 07/02/2012] [Accepted: 07/23/2012] [Indexed: 02/05/2023] Open
Abstract
Schizophrenia is a severe mental disorder, characterized by behavioral, emotional and cognitive disturbances, which commonly follows a chronic course. Diagnostic accuracy, management plans, treatment evaluation and prognosis are dependent on relatively subjective assessments. Despite extensive research and improvement in imaging technology, as well as modern genetic and molecular methodologies, the biological basis of this disease is still unclear. Therefore, there is a need for objective and valid biological markers. Platelets have often been used as a model in neurobiological research. The accessibility of platelets and their similarities with neurons turns them into an attractive candidate to search for biological markers for diagnosis and for unraveling pathophysiological processes relevant to the etiology of brain disorders, including schizophrenia. The present review addresses the main changes in platelet physiology observed in schizophrenia and its response to antipsychotic medication. We summarize numerous studies demonstrating impaired metabolism, uptake and receptor kinetics of schizophrenia-relevant neurotransmitters, abnormalities in membrane derived phospholipids and polyunsaturated fatty acids, as well as dysfunctions in the mitochondria. These changes fit with the various hypotheses raised for the etiology of schizophrenia, including the dopamine-glutamate hypothesis, the autoimmune hypothesis, the polyunsaturated fatty acid hypothesis and the impaired energy metabolism hypothesis. Despite extensive research in platelets, no conclusive reliable biomarker has been identified yet. This review suggests that the clinical heterogeneity and the biological complexity of schizophrenia lead to the inevitable conclusion that biomarkers will be identified only for subgroups characterized according to the different diagnostic criteria. Moreover, any biomarker would have to be an array of interrelated factors or even a set of several such arrays.
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Affiliation(s)
- Eyal Asor
- Eyal Asor, Dorit Ben-Shachar, Laboratory of Psychobiology, Department of Psychiatry, Rambam Medical Center and B. Rappaport Faculty of Medicine, Rappaport Family Institute for Research in the Medical Sciences, Technion, PO Box 9649, Haifa 31096, Israel
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Dietrich-Muszalska A, Rabe-Jablonska J, Nowak P, Kontek B. The first- and second-generation antipsychotic drugs affect ADP-induced platelet aggregation. World J Biol Psychiatry 2010; 11:268-75. [PMID: 20218792 DOI: 10.3109/15622970802505792] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
OBJECTIVE Blood platelets play an important role in haemostasis and their hyperaggregability may lead to thrombosis and cardiovascular diseases. Increased incidence of mortality, caused by cardiovascular disease, and the increased risk of thrombotic complication in schizophrenic patients treated with antipsychotics have been reported. The effects of antipsychotic drugs on blood platelet function are not fully explained, therefore the purpose of the present study was to examine and compare the effects of the second-generation antipsychotic drugs used in schizophrenia (clozapine, risperidone and olanzapine), with the effects of the first generation antipsychotic, haloperidol, on the platelet aggregation induced by ADP in vitro. METHODS Blood obtained from healthy volunteers (n=25) collected into sodium citrate was centrifuged (250xg, 10 min) at room temperature to obtain platelet-rich plasma. Aggregation of blood platelets (10 microM ADP) was recorded (Chrono-log aggregometer) in platelet-rich plasma preincubated with antipsychotic drugs (final concentration: clozapine 420 ng/ml, risperidone 65 ng/ml, olanzapine 40 ng/ml, haloperidol 20 ng/ml) for 30 min. RESULTS Our results showed that all tested drugs inhibit platelet aggregation induced by ADP in vitro. Among studied antipsychotic drugs clozapine and olanzapine significantly reduced platelet aggregability in vitro. In comparison with control platelets (without the drug), clozapine inhibited ADP-induced platelet aggregation by 21% (P=3.7x10(-6)) and olanzapine by 18% (P=2.8x10(-4)), respectively. CONCLUSION The obtained results indicate that antipsychotic drugs, especially clozapine and olanzapine, contrary to haloperidol, reduced response of blood platelets to ADP measured as platelet aggregation. This suggests that therapy with such antipsychotics, particularly with second-generation antipsychotics, may partly reduce prothrombotic events associated with the increased platelet activation observed in schizophrenic patients. The mechanism of antiaggregatory influence of antipsychotics requires further studies.
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Tseng WL, Huang CL, Chong KY, Liao CH, Stern A, Cheng JC, Tseng CP. Reelin is a platelet protein and functions as a positive regulator of platelet spreading on fibrinogen. Cell Mol Life Sci 2010; 67:641-53. [PMID: 19936619 PMCID: PMC11115871 DOI: 10.1007/s00018-009-0201-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2009] [Revised: 10/06/2009] [Accepted: 11/02/2009] [Indexed: 12/21/2022]
Abstract
Abnormalities of platelet functions have been linked to reelin-impaired neuronal disorders. However, little attention has been given to understanding the interplay between reelin and platelet. In this study, reelin was found to present in the human platelets and megakaryocyte-like leukemic cells. Reelin-binding assays revealed that extracellular reelin can interact with platelets through the receptor belonging to the low density lipoprotein receptor gene family. The reelin-to-platelet interactions enhance platelet spreading on fibrinogen concomitant with the augmentation of lamellipodia formation and F-actin bundling. In contrast, reelin has no effect on integrin alphaIIbbeta3 activation and agonist-induced platelet aggregation. Molecular analysis revealed that the up-regulation of Rac1 activity and the inhibition of protein kinase C delta-Thr505 phosphorylation are important for reelin-mediated enhancement of platelet spreading on fibrinogen. These findings demonstrate for the first time that reelin is present in platelets and the reelin-to-platelet interactions play a novel role in platelet signaling and functions.
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Affiliation(s)
- Wei-Lien Tseng
- Graduate Institute of Biomedical Sciences, Chang Gung University, Kweishan, Taoyuan, 333 Taiwan, ROC
| | - Chien-Ling Huang
- Department of Medical Biotechnology and Laboratory Science, Chang Gung University, 259 Wen-Hwa 1st Road, Kweishan, Taoyuan, 333 Taiwan, ROC
| | - Kowit-Yu Chong
- Department of Medical Biotechnology and Laboratory Science, Chang Gung University, 259 Wen-Hwa 1st Road, Kweishan, Taoyuan, 333 Taiwan, ROC
| | - Chang-Huei Liao
- Graduate Institute of Natural Products, Chang Gung University, Kweishan, Taoyuan, 333 Taiwan, ROC
| | - Arnold Stern
- Department of Pharmacology, New York University School of Medicine, New York, NY USA
| | - Ju-Chien Cheng
- Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, 404 Taiwan, ROC
| | - Ching-Ping Tseng
- Graduate Institute of Biomedical Sciences, Chang Gung University, Kweishan, Taoyuan, 333 Taiwan, ROC
- Department of Medical Biotechnology and Laboratory Science, Chang Gung University, 259 Wen-Hwa 1st Road, Kweishan, Taoyuan, 333 Taiwan, ROC
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Dietrich-Muszalska A, Olas B. The changes of aggregability of blood platelets in schizophrenia. World J Biol Psychiatry 2009; 10:171-6. [PMID: 19514099 DOI: 10.1080/15622970701557993] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
OBJECTIVE Oxidative stress in schizophrenia may be responsible for the changes of platelet function and reactivity. Therefore, the aim of our present study was to evaluate the response of platelets from patients with schizophrenia to platelet agonists such as ADP and collagen. RESULTS Platelet aggregation of schizophrenic patients and healthy subjects stimulated by collagen or ADP showed significant differences. Aggregation of platelets stimulated by collagen was significantly lower in schizophrenic patients (about 86%) than in healthy subjects (P=0.022), but when this process was induced by ADP, aggregation of platelets was significantly higher in schizophrenic patients (increase to about 112%) than in healthy subjects (P=0.018). We also observed that antipsychotic drugs (clozapine, risperidone, olanzapine, haloperidol) reduce aggregation of platelets of schizophrenic patients and healthy group in vitro. CONCLUSION The obtained results indicate that the response of platelets from schizophrenic patients to ADP and collagen is different than in healthy subjects.
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Oruch R, Hodneland E, Pryme IF, Holmsen H. In thrombin stimulated human platelets Citalopram, Promethazine, Risperidone, and Ziprasidone, but not Diazepam, may exert their pharmacological effects also through intercalation in membrane phospholipids in a receptor-independent manner. J Chem Biol 2009; 2:89-103. [PMID: 19568786 PMCID: PMC2701490 DOI: 10.1007/s12154-009-0018-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2009] [Accepted: 03/31/2009] [Indexed: 10/31/2022] Open
Abstract
Intercalation of drugs in the platelet membrane affects phospholipid-requiring enzymatic processes according to the drugs' intercalation capability. We investigated effects of Promethazine, Citalopram, Ziprasidone, Risperidone, and Diazepam on phospholipase A(2) (PLA(2)) and polyphosphoinositide (PPI) metabolism in thrombin-stimulated human platelets. We also examined effects of the drugs on monolayers of glycerophospholipids using the Langmuir technique. Diazepam did not influence PLA( 2 ) activity, had no effects on PPI cycle, and caused no change in mean molecular area of phospholipid monolayers. The remaining psychotropic drugs affected these parameters in different ways and levels of potency suggesting that they act by being intercalated between the molecules of adjacent membrane phospholipids, thus causing changes in substrate availability for phospholipid-hydrolyzing enzymes (PLA(2) and Phospholipase C). We show that several psychotropic drugs can also have other cellular effects than receptor antagonism. These effects may be implicated in the psychotropic effects of the drugs and/or their side effects.
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Affiliation(s)
- Ramadhan Oruch
- Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009, Bergen, Norway,
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Reddy RD, Keshavan MS, Yao JK. Reduced platelet serotonergic responsivity as assessed by dense granule secretion in first-episode psychosis. Clin Biochem 2007; 40:1081-3. [PMID: 17601524 PMCID: PMC2064870 DOI: 10.1016/j.clinbiochem.2007.04.019] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2006] [Revised: 04/18/2007] [Accepted: 04/30/2007] [Indexed: 10/23/2022]
Abstract
OBJECTIVES To determine whether blunted serotonergic responsivity, indicated by decreased platelet dense granule secretion (DGS), occurs in neuroleptic-naïve patients with schizophrenia, as observed previously in chronic schizophrenia. DESIGN AND METHODS Serotonin (5-HT)-amplified DGS was examined in 40 first-episode neuroleptic-naïve patients (24 with schizophrenia and 16 with mood disorders) and 24 healthy subjects. RESULTS Healthy controls showed robustly increased DGS. Schizophrenic patients showed very modest DGS increases; mood disorder patients showed intermediate response. CONCLUSIONS Blunted DGS appears to a characteristic of schizophrenia that is observed in the treatment-naïve condition.
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Affiliation(s)
- Ravinder D Reddy
- Department of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, PA 15213, USA
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Gurguis GN. Psychiatric Disorders. Platelets 2007. [DOI: 10.1016/b978-012369367-9/50806-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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McNamara RK, Ostrander M, Abplanalp W, Richtand NM, Benoit SC, Clegg DJ. Modulation of phosphoinositide-protein kinase C signal transduction by omega-3 fatty acids: implications for the pathophysiology and treatment of recurrent neuropsychiatric illness. Prostaglandins Leukot Essent Fatty Acids 2006; 75:237-57. [PMID: 16935483 DOI: 10.1016/j.plefa.2006.07.009] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
The phosphoinositide (PI)-protein kinase C (PKC) signal transduction pathway is initiated by pre- and postsynaptic Galphaq-coupled receptors, and regulates several clinically relevant neurochemical events, including neurotransmitter release efficacy, monoamine receptor function and trafficking, monoamine transporter function and trafficking, axonal myelination, and gene expression. Mounting evidence for PI-PKC signaling hyperactivity in the peripheral (platelets) and central (premortem and postmortem brain) tissues of patients with schizophrenia, bipolar disorder, and major depressive disorder, coupled with evidence that PI-PKC signal transduction is down-regulated in rat brain following chronic, but not acute, treatment with antipsychotic, mood-stabilizer, and antidepressant medications, suggest that PI-PKC hyperactivity is central to an underlying pathophysiology. Evidence that membrane omega-3 fatty acids act as endogenous antagonists of the PI-PKC signal transduction pathway, coupled with evidence that omega-3 fatty acid deficiency is observed in peripheral and central tissues of patients with schizophrenia, bipolar disorder, and major depressive disorder, support the hypothesis that omega-3 fatty acid deficiency may contribute to elevated PI-PKC activity in these illnesses. The data reviewed in this paper outline a potential molecular mechanism by which omega-3 fatty acids could contribute to the pathophysiology and treatment of recurrent neuropsychiatric illness.
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Affiliation(s)
- Robert K McNamara
- Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0559, USA.
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Yao JK, Magan S, Sonel AF, Gurklis JA, Sanders R, Reddy RD. Effects of omega-3 fatty acid on platelet serotonin responsivity in patients with schizophrenia. Prostaglandins Leukot Essent Fatty Acids 2004; 71:171-6. [PMID: 15253886 DOI: 10.1016/j.plefa.2004.03.011] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2003] [Indexed: 10/26/2022]
Abstract
Studies suggest that the omega-3 fatty acid supplementation may be beneficial in reducing symptom severity in schizophrenia. The mechanism(s) underlying the clinical effect is not known. Serotonin (5-HT) has been implicated in the pathophysiology of schizophrenia and in the mechanism of some antipsychotic agents. 5-HT receptors are known to be modified by omega-3 fatty acids. We examined whether supplementation with the omega-3 fatty acid eicosapentaenoic acid (EPA)-modified 5-HT amplified ADP-induced platelet aggregation in patients with schizophrenia. Two grams of ethyl-EPA was administered daily for 6 months supplementally to ongoing antipsychotic treatment in 12 patients with chronic schizophrenia, using an open-label design. Red blood cell membrane fatty acids and platelet functions (platelet aggregation and dense granule secretion) were monitored at baseline, 1-, 3- and 6-months. The EPA levels were elevated more than five-fold in RBC membranes of all patients after 3 months supplementation, indicating a high degree of compliance. Consistent with previous reports, there was inhibition of ADP-induced platelet aggregation by EPA supplementation. Moreover, EPA markedly enhanced the 5-HT responsivity as measured by the magnitude of 5-HT amplification on ADP-induced platelet aggregation. Previously, we have demonstrated a significant inverse correlation between 5-HT responsivity and psychosis severity in unmedicated patients with schizophrenia. Taken together, the present data support the notion that EPA may be mediating its therapeutic effects in schizophrenia via modulation of the 5-HT2 receptor complex.
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Affiliation(s)
- Jeffrey K Yao
- VA Pittsburgh Healthcare System, Pittsburgh, PA, USA.
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Abstract
The prevalence of diabetes is increased in patients with schizophrenia. Although many reasons, including hereditary and lifestyle factors, contribute to this association, recently there has been heightened interest in the subject because of the link between the use of the newer atypical anti-psychotic drugs and the development of diabetes. These drugs cause significant weight gain and this may be one of the mechanisms by which they increase incident diabetes. The increased prevalence of diabetes among people with schizophrenia has implications for the delivery of care by psychiatrists, diabetologists and primary care.
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Affiliation(s)
- R I G Holt
- Endocrinology & Metabolism Sub-division, Fetal Origins of Adult Disease Division, School of Medicine, University of Southampton, Southampton, UK.
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Walsh MT, Ryan M, Hillmann A, Condren R, Kenny D, Dinan T, Thakore JH. Elevated expression of integrin alpha(IIb) beta(IIIa) in drug-naïve, first-episode schizophrenic patients. Biol Psychiatry 2002; 52:874-9. [PMID: 12399140 DOI: 10.1016/s0006-3223(02)01400-2] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
BACKGROUND Patients with schizophrenia have an increased risk over the general public of developing cardiovascular illness. It is unknown if there are functional changes in platelet surface receptors in schizophrenia. We therefore analyzed the surface expression of glycoprotein (GP)Ib, the integrin receptor alpha(IIb)beta(IIIa), CD62 (P-selectin), and CD63, and investigated platelet function in schizophrenic patients compared with healthy volunteers. METHODS Nineteen drug-naive, first-episode patients with a DSM IV diagnosis of paranoid schizophrenia were compared with matched healthy controls. Flow cytometry was used to assess platelet surface expression levels of GPIb, alpha(IIb)beta(IIIa), CD62, and CD63. Adenosine diphosphate-induced platelet aggregation was assayed. RESULTS The schizophrenic patients had a significantly (p < .0001) increased number of 68,145 +/- 8,260.1 alpha(IIb)beta(IIIa) receptors, platelet compared with 56,235 +/- 8,079.4 receptors, platelet in healthy controls. CONCLUSIONS Patients with schizophrenia have increased platelet expression of alpha(IIb)beta(IIIa), which may contribute to their increased risk of cardiovascular illness compared with the general population.
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Affiliation(s)
- Marie Thérèse Walsh
- Respiratory Research Group, Smurfit Building, Beaumont Hospital, Beaumont, Ireland
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Abstract
Schizophrenia is a life shortening illness. Unnatural causes and natural causes are put forward as reasons for this excess mortality. In terms of the latter, a host of different physical disorders occur with increased frequency in schizophrenia. When taken together, some of these illnesses such as type 2 diabetes mellitus and cardiovascular disorders constitute the Metabolic Syndrome; a characteristic phenotype of those with this syndrome is excessive visceral fat distribution. The exact reasons why this particular syndrome occurs in schizophrenia is as yet unclear though factors such as life style, poor diet and lack of exercise may contribute to it's development. Alternatively, overactivity of the hypothalamic-pituitary-adrenal axis leading to hypercortisolaemia can also result in excessive visceral fat accumulation. This minireview aims to explore the potential role of these issues and medication in terms of the increased morbidity and mortality observed in schizophrenia.
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Affiliation(s)
- Martina C M Ryan
- Neuroscience Centre, St. Vincent's Hospital, Richmond Rd, Fairview, Dublin 3, Ireland
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Abstract
Previous studies in schizophrenia have shown alterations in membrane phospholipids and polyunsaturated fatty acids. However, these studies have primarily examined peripheral (non-neuronal) cell types. The purpose of the present study was to examine whether the membrane deficits seen in peripheral tissues are also observed in the brain. The caudate was the primary region of interest for this study. Using high-pressure liquid chromatography in conjunction with an evaporative light-scattering detector, we first measured the level of various membrane phospholipids (PL) in schizophrenic (n=11) and control groups with (n=7) and without (n=14) other mental disorders. Polyunsaturated fatty acids (PUFAs) were then determined by capillary gas chromatography. Within groups, there are no significant correlations between membrane PL levels and other collection and demographic parameters including age, postmortem interval, storage time and brain weight. Significantly lower amounts of phosphatidylcholine and phosphatidylethanolamine were found in postmortem brain tissue from schizophrenic patients than in those from control groups, even after accounting for potential confounds. In addition, strong reductions of total PUFAs and saturated fatty acids were found in schizophrenic brains, relative to control brains. Specifically, the reduced PUFAs were largely attributable to decreases in arachidonic acid (AA) and, to a lesser extent, its precursors, linoleic and eicosadienoic acids. There are no significant differences between the control groups with and without other mental disorders. The present findings suggest that deficits identified in peripheral membranes may also be present in the brain from schizophrenic patients. Such a deficit in membrane AA may contribute to the many biological, physiological, and clinical phenomena observed in schizophrenia.
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Affiliation(s)
- J K Yao
- VA Pittsburgh Healthcare System, Pittsburgh, PA 15206, USA.
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Moss HB, Yao JK. Platelet dense granule secretion in adolescents with conduct disorder and substance abuse: preliminary evidence for variation in signal transduction. Biol Psychiatry 1996; 40:892-8. [PMID: 8896776 DOI: 10.1016/0006-3223(95)00521-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Platelet aggregation responses to agonists have been employed as peripheral indices of the physiological responsiveness and density of neurotransmitter receptors, and in investigations of membrane functioning in psychopathological conditions. In particular, there are mechanistic similarities between neuronal secretory and receptor dynamics, and those involved in platelet dense granule secretion. Consequently, we have explored the platelet dense granule secretory responses to various agonists in abstinent male adolescents who meet current psychiatric diagnostic criteria for Conduct Disorder and Psychoactive Substance. Use Disorder (CD+/PSUD+) in contrast to controls (CD-/PSUD-). The results showed a significant hyporesponsivity among experimental subjects to collagen, thrombin, adenosine diphosphate (ADP), ADP plus 0.2 microgram of serotonin, and ADP plus 1.0 microgram of serotonin. Only dense granule responses to arachidonic acid did not differentiate the groups. Taken together, the lack of agonist specificity suggests that a variation in signal transduction mechanisms could account for the observed reduction in dense granule secretion among CD+/PSUD+ adolescents. Association between dense granule secretory responses and substance use behavior, and comorbid psychiatric conditions are also examined.
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Affiliation(s)
- H B Moss
- Center for Education and Drug Abuse Research, Western Psychiatry Institute and Clinic, University of Pittsburgh School of Medicine, PA 15213, USA
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Yao JK, van Kammen DP, Moss HB, Sokulski DE. Decreased serotonergic responsivity in platelets of drug-free patients with schizophrenia. Psychiatry Res 1996; 63:123-32. [PMID: 8878308 DOI: 10.1016/0165-1781(96)02862-4] [Citation(s) in RCA: 22] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
We have recently developed a simplified and time-saving method to measure the magnitude of serotonin (5-hydroxytryptamine, 5HT)-amplified platelet aggregation and dense granule secretion (DGS) responses. To study the effects of neuroleptics on peripheral serotonergic function, we measured physiologic responsivity of the platelet 5HT2 receptor complex in schizophrenic patients (n = 27), both before and after haloperidol withdrawal, and also in normal volunteers (n = 18). In human platelets, 5HT amplifies the adenosine diphosphate (ADP)-induced platelet aggregation and DGS. Such an amplification was significantly enhanced in platelets from both normal volunteers and haloperidol-stabilized patients. Following haloperidol withdrawal, however, the magnitude of 5HT-amplified DGS response was no longer significant in drug-free patients, demonstrating a decreased serotonergic responsivity in schizophrenia. Moreover, in drug-free patients, the net changes of ADP-induced DGS, with and without the presence of 5HT, were correlated significantly and negatively with both Bunney-Hamburg psychosis ratings and Brief Psychiatric Rating Scale (total) scores, but not with scores on the Scale for the Assessment of Negative Symptoms. In the drug-free group, no significant difference of 5HT amplification was demonstrated between relapsed and nonrelapsed patients. The present finding thus suggests that drug-free schizophrenic patients may have a reduced physiologic responsivity mediated through the platelet 5HT2 receptor complex, which can be modified by haloperidol treatment. The pharmacologic action of haloperidol may derive in part from serotonergic mechanisms. The magnitude of 5HT-amplified DGS may be useful in the prediction of therapeutic outcome after haloperidol treatment.
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Affiliation(s)
- J K Yao
- Pathology & Laboratory Medicine Service, Department of Veterans Affairs Medical Center, Pittsburgh, PA 15206, USA
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