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Xie Y, Zhang T, Ma C, Guan M, Li C, Wang L, Lin X, Li Y, Wang Z, Wang H, Fang P. The underlying neurobiological basis of gray matter volume alterations in schizophrenia with auditory verbal hallucinations: A meta-analytic investigation. Prog Neuropsychopharmacol Biol Psychiatry 2025; 138:111331. [PMID: 40089004 DOI: 10.1016/j.pnpbp.2025.111331] [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: 11/17/2024] [Revised: 02/08/2025] [Accepted: 03/09/2025] [Indexed: 03/17/2025]
Abstract
Schizophrenia patients with auditory verbal hallucinations (AVH) frequently exhibit brain structural alterations, particularly reductions in gray matter volume (GMV).Understanding the neurobiological mechanisms underlying the changes is essential for advancing treatment strategies. To address this, a meta-analysis was conducted to identify GMV changes in schizophrenia patients with AVH and their associations with gene expression and neurotransmitter receptor profiles. The results indicated significant GMV reductions in the left and the right insula, as well as the left anterior cingulate cortex. Ontology analysis of genes associated with GMV alternations revealed enrichment in biological processes related to ion transport and synaptic transmission. Hub genes from the KCN, SCN, GN, and PRK families, along with neurotransmitter receptors such as D2, VAChT, and mGluR5, showed significant correlations with GMV changes. Furthermore, multivariate linear regression analysis demonstrated that GNB2, GNB4, PRKCG, D2, and mGluR5 significantly predicted GMV alternations. These findings suggest that GMV reductions in schizophrenia with AVH are linked to disruptions in neurobiological processes involving specific genes and neurotransmitter systems, highlighting the potential targets for therapeutic intervention.
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Affiliation(s)
- Yuanjun Xie
- Medical Innovation Center, Sichuan University of Science and Engineering, Zigong, China; Military Medical Psychology School, Air Force Medical University, Xi'an, China.
| | - Tian Zhang
- Military Medical Psychology School, Air Force Medical University, Xi'an, China
| | - Chaozong Ma
- Military Medical Psychology School, Air Force Medical University, Xi'an, China
| | - Muzhen Guan
- Deparment of Mental Health, Xi'an Medical College, Xi'an, China
| | - Chenxi Li
- Military Medical Psychology School, Air Force Medical University, Xi'an, China
| | - Lingling Wang
- Military Medical Psychology School, Air Force Medical University, Xi'an, China
| | - Xinxin Lin
- Military Medical Psychology School, Air Force Medical University, Xi'an, China
| | - Yijun Li
- Military Medical Psychology School, Air Force Medical University, Xi'an, China
| | - Zhongheng Wang
- Department of Psychiatry, Air Force Medical University, Xi'an, China
| | - Huaning Wang
- Department of Psychiatry, Air Force Medical University, Xi'an, China
| | - Peng Fang
- Military Medical Psychology School, Air Force Medical University, Xi'an, China; Innovation Research Institute, Xijing Hospital, Air Force Medical University, Xi'an, China; Military Medical Innovation Center, Air Force Medical University, Xi'an, China; Shaanxi Provincial Key Laboratory of Bioelectromagnetic Detection and Intelligent Perception, Xi'an, China.
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Fernández-Pereira C, Agís-Balboa RC. The Insulin-like Growth Factor Family as a Potential Peripheral Biomarker in Psychiatric Disorders: A Systematic Review. Int J Mol Sci 2025; 26:2561. [PMID: 40141202 PMCID: PMC11942524 DOI: 10.3390/ijms26062561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 02/13/2025] [Accepted: 02/17/2025] [Indexed: 03/28/2025] Open
Abstract
Psychiatric disorders (PDs), including schizophrenia (SZ), major depressive disorder (MDD), bipolar disorder (BD), autism spectrum disorder (ASD), among other disorders, represent a significant global health burden. Despite advancements in understanding their biological mechanisms, there is still no reliable objective and reliable biomarker; therefore, diagnosis remains largely reliant on subjective clinical assessments. Peripheral biomarkers in plasma or serum are interesting due to their accessibility, low cost, and potential to reflect central nervous system processes. Among these, the insulin-like growth factor (IGF) family, IGF-1, IGF-2, and IGF-binding proteins (IGFBPs), has gained attention for its roles in neuroplasticity, cognition, and neuroprotection, as well as for their capability to cross the blood-brain barrier. This review evaluates the evidence for IGF family alterations in PDs, with special focus on SZ, MDD, and BD, while also addressing other PDs covering almost 40 years of history. In SZ patients, IGF-1 alterations have been linked to metabolic dysregulation, treatment response, and hypothalamic-pituitary-adrenal axis dysfunction. In MDD patients, IGF-1 appears to compensate for impaired neurogenesis, although findings are inconsistent. Emerging studies on IGF-2 and IGFBPs suggest potential roles across PDs. While promising, heterogeneity among studies and methodological limitations highlights the need for further research to validate IGFs as reliable psychiatric biomarkers.
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Affiliation(s)
- Carlos Fernández-Pereira
- Neuro Epigenetics Lab, Health Research Institute of Santiago de Compostela (IDIS), Santiago University Hospital Complex, 15706 Santiago de Compostela, Spain;
- Translational Research in Neurological Diseases (ITEN) Group, Health Research Institute of Santiago de Compostela (IDIS), Santiago University Hospital Complex, SERGAS-USC, 15706 Santiago de Compostela, Spain
- Neurology Service, Santiago University Hospital Complex, 15706 Santiago de Compostela, Spain
| | - Roberto Carlos Agís-Balboa
- Neuro Epigenetics Lab, Health Research Institute of Santiago de Compostela (IDIS), Santiago University Hospital Complex, 15706 Santiago de Compostela, Spain;
- Translational Research in Neurological Diseases (ITEN) Group, Health Research Institute of Santiago de Compostela (IDIS), Santiago University Hospital Complex, SERGAS-USC, 15706 Santiago de Compostela, Spain
- Neurology Service, Santiago University Hospital Complex, 15706 Santiago de Compostela, Spain
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3
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Haussler SM, Zahid U, Day F, Ciufolini S, Petros N, Gifford G, Alameda L, Quattrone D, Dazzan P, Pariante C, Fisher HL, Laurens KR, Di Forti M, Wood SJ, Murray RM, McGuire P, Mondelli V, Cullen AE. Salivary cortisol measures across the clinical stages of psychosis: An individual participant data (IPD) meta-analysis. Psychoneuroendocrinology 2025; 173:107283. [PMID: 39869966 DOI: 10.1016/j.psyneuen.2025.107283] [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: 01/08/2025] [Accepted: 01/09/2025] [Indexed: 01/29/2025]
Abstract
BACKGROUND Studies of salivary cortisol levels in psychosis have yielded inconsistent findings, which may be attributable to heterogeneity in cortisol measurement, illness stage, and approaches to dealing with sampling factors and potential confounders. To address these issues, we performed an individual participant data (IPD) meta-analysis comparing individuals at different stages of psychosis to controls using five different salivary cortisol measures and explored potential effect modifiers. METHODS Salivary cortisol data from five London-based cohorts were used to derive the cortisol awakening response, total daytime cortisol output, basal cortisol, and diurnal slope measures (wake-to-evening and peak-to-evening). Linear regression models were first performed to obtain standardised beta coefficients (β), representing the difference in each cortisol metric between each clinical stage group (cases) and healthy individuals (controls) after accounting for relevant sampling factors; we then used random-effects meta-analyses and meta-regression models to investigate the effect of psychosis stage and sample characteristics on effect sizes. RESULTS Data were available for 352 individuals distributed across psychosis clinical stages (1a - distress disorder: N = 35; 1b - clinical high-risk for psychosis: N = 90; 2a - first-episode psychosis: N = 197; 2b - single episode remitted: N = 5; 3 - relapsing/remitting illness: N = 18; 4 - severe and persistent illness: N = 7) and 292 controls. A significant overall main effect of clinical stage on peak-to-evening diurnal slope was observed (χ2=12.83, p = 0.025), with both the clinical high-risk (β=0.21, 95 % CI: 0.06, 0.36) and first-episode psychosis (β=0.20, 95 % CI: 0.10, 0.31) groups characterised by flatter slopes than controls. The clinical stage groups and controls did not differ on any other cortisol measure. Several sample characteristics were significantly associated with diurnal slope effect sizes, but after accounting for clinical stage, only the association between mean age in cases and wake-to-evening diurnal slope retained significance. CONCLUSION Clinical high-risk and first-episode psychosis participants differed from healthy controls in the peak-to-evening diurnal cortisol slope. This measure has not been examined in these populations before, and its potential predictive and prognostic utility for psychotic disorders merits further investigation.
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Affiliation(s)
- Senta M Haussler
- King's College London, Institute of Psychiatry, Psychology & Neuroscience, Department of Psychosis Studies, London, UK; King's College London, Social, Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, London, UK; National Institute for Health and Care Research (NIHR) Maudsley Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London, London, UK
| | - Uzma Zahid
- King's College London, Institute of Psychiatry, Psychology & Neuroscience, Department of Psychosis Studies, London, UK; National Institute for Health and Care Research (NIHR) Maudsley Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London, London, UK
| | - Fern Day
- South London and Maudsley NHS Foundation Trust, London, UK
| | - Simone Ciufolini
- King's College London, Institute of Psychiatry, Psychology & Neuroscience, Department of Psychosis Studies, London, UK
| | - Natalia Petros
- King's College London, Institute of Psychiatry, Psychology & Neuroscience, Department of Psychosis Studies, London, UK; National Institute for Health and Care Research (NIHR) Maudsley Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London, London, UK
| | - George Gifford
- King's College London, Institute of Psychiatry, Psychology & Neuroscience, Department of Psychosis Studies, London, UK; National Institute for Health and Care Research (NIHR) Maudsley Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London, London, UK; Department of Psychiatry, University of Oxford, Oxford, UK; National Institute for Health and Care Research (NIHR) Oxford Health Biomedical Research Centre, Oxford Health NHS Foundation Trust, Oxford, UK
| | - Luis Alameda
- King's College London, Institute of Psychiatry, Psychology & Neuroscience, Department of Psychosis Studies, London, UK; South London and Maudsley NHS Foundation Trust, London, UK; Service of General Psychiatry, Treatment and Early Intervention in Psychosis Program, Lausanne University Hospital (CHUV), Lausanne, Switzerland; Instituto de Investigación Sanitaria de Sevilla, IbiS, Hospital Universitario Virgen del Rocío, Department of Psychiatry, Universidad de Sevilla, Spain
| | - Diego Quattrone
- King's College London, Social, Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, London, UK; National Institute for Health and Care Research (NIHR) Maudsley Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London, London, UK
| | - Paola Dazzan
- National Institute for Health and Care Research (NIHR) Maudsley Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London, London, UK; King's College London, Institute of Psychiatry, Psychology & Neuroscience, Department of Psychological Medicine, London, UK
| | - Carmine Pariante
- National Institute for Health and Care Research (NIHR) Maudsley Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London, London, UK; King's College London, Institute of Psychiatry, Psychology & Neuroscience, Department of Psychological Medicine, London, UK
| | - Helen L Fisher
- King's College London, Social, Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, London, UK; ESRC Centre for Society and Mental Health, King's College London, London, UK
| | - Kristin R Laurens
- King's College London, Social, Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, London, UK; Queensland University of Technology (QUT), School of Psychology and Counselling, Brisbane, Queensland, Australia
| | - Marta Di Forti
- King's College London, Social, Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, London, UK; National Institute for Health and Care Research (NIHR) Maudsley Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London, London, UK; South London and Maudsley NHS Foundation Trust, London, UK
| | - Stephen J Wood
- Orygen, Melbourne, Australia; Centre for Youth Mental Health, University of Melbourne, Melbourne, Australia; School of Psychology, University of Birmingham, Birmingham, UK
| | - Robin M Murray
- King's College London, Institute of Psychiatry, Psychology & Neuroscience, Department of Psychosis Studies, London, UK; National Institute for Health and Care Research (NIHR) Maudsley Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London, London, UK
| | - Philip McGuire
- South London and Maudsley NHS Foundation Trust, London, UK; Department of Psychiatry, University of Oxford, Oxford, UK
| | - Valeria Mondelli
- National Institute for Health and Care Research (NIHR) Maudsley Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London, London, UK; King's College London, Institute of Psychiatry, Psychology & Neuroscience, Department of Psychological Medicine, London, UK
| | - Alexis E Cullen
- King's College London, Institute of Psychiatry, Psychology & Neuroscience, Department of Psychosis Studies, London, UK; National Institute for Health and Care Research (NIHR) Maudsley Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London, London, UK; Division of Insurance Medicine, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
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Van Den Noortgate M, Van Den Eede F, Coppens V, Giltay EJ, De Picker L, Morrens M. Immune-neuroendocrine crosstalk in mood and psychotic disorders: A meta-analysis and systematic review. Brain Behav Immun Health 2025; 44:100965. [PMID: 40040865 PMCID: PMC11879693 DOI: 10.1016/j.bbih.2025.100965] [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: 03/05/2024] [Revised: 02/09/2025] [Accepted: 02/10/2025] [Indexed: 03/06/2025] Open
Abstract
Background Bidirectional interactions between immune and neuroendocrine mechanisms are involved in mood and psychotic disorders, although individual studies report inconsistent and even contradictory findings on the nature of this crosstalk. Our objective was to perform an up to date systematic review and meta-analysis of the association between hypothalamic-pituitary-adrenal (HPA) axis and immune system functioning in mood and psychotic disorders. Methods We searched the Pubmed, Web of Science and Embase databases for studies reporting correlations between one or more HPA- and immune markers (IM) in patients with mood or psychotic disorders. We analyzed unchallenged correlations as well as challenge studies investigating the HPA-immune interaction through dexamethasone (DEX) and/or CRH suppression, HPA-mediated challenge of immune cell proliferation, immune challenges, or psychological stressors. Finally, genetic studies focusing on HPA x immune interrelation were evaluated. For meta-analyzable data, three primary outcome measures were defined for immune functioning, namely the pro-inflammatory index (PII) and anti-inflammatory index (AII) for the molecular IM and a composite cellular immune marker score (CCIM) for the cellular IM. Secondary analyses were performed for the individual molecular and cellular IM. Heterogeneity was evaluated with the I2 statistic. Meta-regression analyses were performed to evaluate the impact of potential covariates (publication year, gender, age, symptom severity) on the primary outcome analyses. Results 93 studies (n = 8226) were included, of which 50 (n = 5649) contained meta-analyzable data. The majority of the included studies (k = 72) investigated major depressive disorder (MDD) patients, nineteen schizophrenia spectrum disorders (SSD) and six bipolar disorder (BD). Under physiological conditions, a poor association was found between cortisol and the PII only in the unmedicated subsample of MDD (k = 8; n = 425; r = .205; z = 2.151; p = .031) and the medicated subsample of SSD (k = 4; n = 152; r = .0.237; z = 2.314; p = .021). No significant correlation was found in MDD between the AII and cortisol (k = 3; n = 1243; r = .005; z = .188; p = .851). Similar results were found for the association between immune cell numbers and cortisol in both MDD (k = 10; n = 773; r = -.005; z = -.113; p = .894) and SSD (k = 4; n = 99; r = .167; z = 1.356; p = .175). A total of 42 studies discussed post-challenge associations between immune alterations and HPA disturbances, of which 12 (n = 389; all MDD) contained meta-analyzable data and 37 entered the systematic review (n = 1783). No post-DEX correlations were found between cortisol and PII (k = 3; n = 105; r = .074; z = .355; p = .722) or CCIM (k = 5; n = 259; r = -.153; z = -1.294; p = .196). However, a significant association was found between post-DEX cortisol/ACTH and PII produced by stimulated blood cells in vitro (k = 3; n = 61; r = .508; z = 4.042; p < .001) as well as for cortisol and CCIM score in MDD after in vitro mitogen stimulation (k = 4; n = 90; r = -.309; z = -2498; p = .012). Following a psychological stressor (k = 6; n = 121), cortisol responses tended to be blunted in all included pathologies, while immune activation was comparable to healthy controls. Genetic studies (k = 7; n = 464) demonstrate altered gene expression of glucocorticoid receptors (GR) in peripheral immune cells in MDD. Heterogeneity over studies tended to be moderate to high. Discussion The main limitations are the heterogeneity of outcome measures (both HPA and IM) and small sample sizes of the included studies. We conclude that, in physiological conditions, associations between HPA-axis and molecular or cellular IM are absent or poor in both MDD and SSD and psychotropic medication may influence this crosstalk differently in both patient groups. Studies using challenge paradigms in MDD populations did reveal differences in the HPA-immune crosstalk. The normally expected decrease in lymphocytes after DEX distribution tended to be less pronounced in MDD, especially in glucocorticoid-insensitive non-suppressors. It is recommended that future studies should be properly powered and assess HPA functioning using multiple cortisol assessments. Challenge studies are probably more useful than baseline biomarker studies and cellular IM are more informative than molecular IM. It is recommended to broadly assess leucocyte function and, when possible, perform subgroup analyses based on HPA- and/or immune function.
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Affiliation(s)
- Minne Van Den Noortgate
- Collaborative Antwerp Psychiatric Research Institute (CAPRI), Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
| | - Filip Van Den Eede
- Collaborative Antwerp Psychiatric Research Institute (CAPRI), Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
- University Department of Psychiatry, Campus Antwerp University Hospital, Edegem, Belgium
| | - Violette Coppens
- Collaborative Antwerp Psychiatric Research Institute (CAPRI), Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
| | - Erik J. Giltay
- Collaborative Antwerp Psychiatric Research Institute (CAPRI), Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
- Department of Psychiatry, Leiden University Medical Center, Leiden, the Netherlands
- Department of Public Health and Primary Care, Health Campus the Hague, Leiden University Medical Center, The Hague, the Netherlands
| | - Livia De Picker
- Collaborative Antwerp Psychiatric Research Institute (CAPRI), Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
- Scientific Initiative of Neuropsychiatric and Psychopharmacological Studies (SINAPS), University Psychiatric Centre Campus Duffel, Duffel, Belgium
| | - Manuel Morrens
- Collaborative Antwerp Psychiatric Research Institute (CAPRI), Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
- Scientific Initiative of Neuropsychiatric and Psychopharmacological Studies (SINAPS), University Psychiatric Centre Campus Duffel, Duffel, Belgium
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Kogler L, Wang R, Luther T, Hofer A, Frajo-Apor B, Derntl B. Cortisol in schizophrenia spectrum disorders: A comprehensive meta-analysis. Front Neuroendocrinol 2025; 77:101186. [PMID: 39986355 DOI: 10.1016/j.yfrne.2025.101186] [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: 08/01/2024] [Revised: 01/10/2025] [Accepted: 02/15/2025] [Indexed: 02/24/2025]
Abstract
Schizophrenia spectrum disorders (SSD) are characterized by alterations in cortisol levels across various parameters, including stress reactivity, hair cortisol, and baseline levels, which may be influenced by antipsychotic treatment. To provide a comprehensive overview of cortisol dysregulation in SSD, we conducted meta-analyses assessing (1) the effects of antipsychotic treatment in SSD patients, and additionally comparing cortisol in SSD patients versus healthy controls (HC) (2) following stress induction (metabolic, physiological, psychological stressors), (3) in hair and (4) baseline levels. Systematic literature searches in PubMed, Web of Science, and PsycINFO (November 2024) identified 121 studies (9049 SSD patients) for inclusion. Meta-analytic results revealed that antipsychotic treatment significantly reduced cortisol levels in SSD (k = 16, g = -0.480, 95 % CI [-0.818, -0.142], p = 0.005). Additionally, compared to HC, SSD was associated with reduced cortisol suppression following dexamethasone exposure (k = 9, g = 0.299, 95 % CI [0.091, 0.507], p = 0.005) and with elevated baseline cortisol levels in the morning (k = 71, g = 0.38, 95 % CI [0.210, 0.546], p < 0.001) and evening (k = 11, g = 0.368, 95 % CI [0.076, 0.661], p = 0.014). However, there were no significant group differences in afternoon baseline cortisol, hair cortisol or cortisol reactivity to stress (p > 0.05). These findings offer a detailed understanding of cortisol alterations in SSD and improve our understanding of HPA axis dysregulation in SSD.
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Affiliation(s)
- Lydia Kogler
- Department of Psychiatry and Psychotherapy, Tübingen Centre for Mental Health (TüCMH), Medical Faculty, University of Tübingen, Calwerstrasse 14, 72076 Tübingen, Germany; German Center for Mental Health (DZPG) Partner Site Tübingen 72076 Tübingen, Germany.
| | - Rui Wang
- Department of Psychiatry and Psychotherapy, Tübingen Centre for Mental Health (TüCMH), Medical Faculty, University of Tübingen, Calwerstrasse 14, 72076 Tübingen, Germany
| | - Teresa Luther
- Leibniz-Institut für Wissensmedien, Knowledge Construction Lab, Schleichstraße 6, 72076 Tübingen, Germany
| | - Alex Hofer
- Department of Psychiatry, Psychotherapy, Psychosomatics and Medical Psychology, Division of Psychiatry I, Medical University Innsbruck, Innsbruck, Austria
| | - Beatrice Frajo-Apor
- Department of Psychiatry, Psychotherapy, Psychosomatics and Medical Psychology, Division of Psychiatry I, Medical University Innsbruck, Innsbruck, Austria
| | - Birgit Derntl
- Department of Psychiatry and Psychotherapy, Tübingen Centre for Mental Health (TüCMH), Medical Faculty, University of Tübingen, Calwerstrasse 14, 72076 Tübingen, Germany; German Center for Mental Health (DZPG) Partner Site Tübingen 72076 Tübingen, Germany
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Song YN, Xia S, Sun Z, Chen YC, Jiao L, Wan WH, Zhang HW, Guo X, Guo H, Jia SF, Li XX, Cao SX, Fu LB, Liu MM, Zhou T, Zhang LF, Jia QQ. Metabolic pathway modulation by olanzapine: Multitarget approach for treating violent aggression in patients with schizophrenia. World J Psychiatry 2025; 15:101186. [PMID: 39831024 PMCID: PMC11684224 DOI: 10.5498/wjp.v15.i1.101186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2024] [Revised: 11/05/2024] [Accepted: 12/05/2024] [Indexed: 12/18/2024] Open
Abstract
BACKGROUND The use of network pharmacology and blood metabolomics to study the pathogenesis of violent aggression in patients with schizophrenia and the related drug mechanisms of action provides new directions for reducing the risk of violent aggression and optimizing treatment plans. AIM To explore the metabolic regulatory mechanism of olanzapine in treating patients with schizophrenia with a moderate to high risk of violent aggression. METHODS Metabolomic technology was used to screen differentially abundant metabolites in patients with schizophrenia with a moderate to high risk of violent aggression before and after olanzapine treatment, and the related metabolic pathways were identified. Network pharmacology was used to establish protein-protein interaction networks of the core targets of olanzapine. Gene Ontology functional analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were subsequently performed. RESULTS Compared with the healthy group, the patients with schizophrenia group presented significant changes in the levels of 24 metabolites related to the disruption of 9 metabolic pathways, among which the key pathways were the alanine, aspartate and glutamate metabolism and arginine biosynthesis pathways. After treatment with olanzapine, the levels of 10 differentially abundant metabolites were significantly reversed in patients with schizophrenia. Olanzapine effectively regulated six metabolic pathways, among which the key pathways were alanine, aspartate and glutamate metabolism and arginine biosynthesis pathways. Ten core targets of olanzapine were involved in several key pathways. CONCLUSION The metabolic pathways of alanine, aspartate, and glutamate metabolism and arginine biosynthesis are the key pathways involved in olanzapine treatment for aggressive schizophrenia.
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Affiliation(s)
- Yan-Ning Song
- Department of Pharmacy, The Affiliated Encephalopathy Hospital of Zhengzhou University (Zhumadian Second People's Hospital), Zhumadian 463000, Henan Province, China
| | - Shuang Xia
- Department of Pharmacy, The Affiliated Encephalopathy Hospital of Zhengzhou University (Zhumadian Second People's Hospital), Zhumadian 463000, Henan Province, China
| | - Zhi Sun
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Yong-Chao Chen
- Department of Pharmacy, Zhumadian First People's Hospital, Zhumadian 463000, Henan Province, China
| | - Lu Jiao
- Department of Pharmacy, The Affiliated Encephalopathy Hospital of Zhengzhou University (Zhumadian Second People's Hospital), Zhumadian 463000, Henan Province, China
| | - Wen-Hua Wan
- Department of Pharmacy, The Affiliated Encephalopathy Hospital of Zhengzhou University (Zhumadian Second People's Hospital), Zhumadian 463000, Henan Province, China
| | - Hong-Wei Zhang
- Scientific Education Section, The Affiliated Encephalopathy Hospital of Zhengzhou University (Zhumadian Second People's Hospital), Zhumadian 463000, Henan Province, China
| | - Xiao Guo
- Department of Psychiatry, The Affiliated Encephalopathy Hospital of Zhengzhou University (Zhumadian Second People's Hospital), Zhumadian 463000, Henan Province, China
| | - Hua Guo
- Department of Psychiatry, The Affiliated Encephalopathy Hospital of Zhengzhou University (Zhumadian Second People's Hospital), Zhumadian 463000, Henan Province, China
| | - Shou-Feng Jia
- Department of Psychiatry, The Affiliated Encephalopathy Hospital of Zhengzhou University (Zhumadian Second People's Hospital), Zhumadian 463000, Henan Province, China
| | - Xiao-Xin Li
- Department of Pharmacy, The Affiliated Encephalopathy Hospital of Zhengzhou University (Zhumadian Second People's Hospital), Zhumadian 463000, Henan Province, China
| | - Shi-Xian Cao
- Department of Pharmacy, The Affiliated Encephalopathy Hospital of Zhengzhou University (Zhumadian Second People's Hospital), Zhumadian 463000, Henan Province, China
| | - Li-Bin Fu
- Department of Pharmacy, The Affiliated Encephalopathy Hospital of Zhengzhou University (Zhumadian Second People's Hospital), Zhumadian 463000, Henan Province, China
| | - Meng-Meng Liu
- Clinical Laboratory, The Affiliated Encephalopathy Hospital of Zhengzhou University (Zhumadian Second People's Hospital), Zhumadian 463000, Henan Province, China
| | - Tian Zhou
- Publicity Division, The Affiliated Encephalopathy Hospital of Zhengzhou University (Zhumadian Second People's Hospital), Zhumadian 463000, Henan Province, China
| | - Lv-Feng Zhang
- Department of Psychiatry, The Affiliated Encephalopathy Hospital of Zhengzhou University (Zhumadian Second People's Hospital), Zhumadian 463000, Henan Province, China
| | - Qing-Quan Jia
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
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Künzel RG, Elgazzar M, Bain PA, Kirschbaum C, Papatheodorou S, Gelaye B. The association between maternal prenatal hair cortisol concentration and preterm birth: A systematic review and meta-analysis. Psychoneuroendocrinology 2024; 165:107041. [PMID: 38581747 DOI: 10.1016/j.psyneuen.2024.107041] [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: 02/02/2024] [Revised: 03/30/2024] [Accepted: 03/31/2024] [Indexed: 04/08/2024]
Abstract
BACKGROUND The risk of preterm birth (PTB) increases when experiencing stress during pregnancy. Chronic stress has been associated with a dysregulation of the hypothalamic-pituitary-adrenal axis, for which hair cortisol concentration (HCC) is a promising biomarker. However, previous studies on the association between HCC and PTB yielded inconsistent results. This systematic review and meta-analysis synthesized previous studies on the association between maternal HCC before and during pregnancy and spontaneous PTB. METHODS Data was extracted from N = 11 studies with k = 19 effect sizes retrieved from PubMed, Embase, Web of Science, CINAHL and citation searching by hand in June 2023 and updated in October 2023. Standardized mean differences were calculated, and a random-effects three-level meta-analysis was conducted. Effect heterogeneity was assessed using Q and I2. RESULTS HCC during pregnancy was higher among PTB than term groups, but effects were not statistically significant (z = 0.11, 95% CI: - 0.28, 0.51, p = .54) and total heterogeneity was high (Q16 = 60.01, p < .001, I2Total = 92.30%). After leaving out two possible outlier studies in sensitivity analyses, HCC was lower among preterm compared to term delivering groups, although not statistically significant (z = - 0.06, 95% CI: - 0.20, 0.08, p = .39) but with a substantially reduced total heterogeneity (Q12 = 16.45, p = .17, I2Total = 42.15%). No moderators affected the estimates significantly, but an effect of trimester and gestational age at delivery is likely. CONCLUSION There is currently no evidence of prenatal HCC differences between PTB and term groups as effects were small, imprecise, and not significant. Low statistical power and methodological weaknesses of the small-scale studies challenge possible biological inferences from the small effects, but further research on HCC during pregnancy is highly encouraged.
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Affiliation(s)
- Richard G Künzel
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, 677 Huntington Avenue, Boston, MA 02115, USA; Katholische Universität Eichstätt-Ingolstadt, Ostenstr. 28a, Eichstätt 85072, Germany.
| | | | - Paul A Bain
- Countway Library, Harvard Medical School, 10 Shattuck St, Boston, MA 02115, USA
| | - Clemens Kirschbaum
- Technische Universität Dresden, Zellescher Weg 19, Dresden 01062, Germany
| | - Stefania Papatheodorou
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, 677 Huntington Avenue, Boston, MA 02115, USA
| | - Bizu Gelaye
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, 677 Huntington Avenue, Boston, MA 02115, USA; The Chester M. Pierce M.D. Division of Global Psychiatry, Department of Psychiatry, Massachusetts General Hospital, 55 Fruit St, Boston, MA 02114, USA
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8
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Oliver D, Chesney E, Cullen AE, Davies C, Englund A, Gifford G, Kerins S, Lalousis PA, Logeswaran Y, Merritt K, Zahid U, Crossley NA, McCutcheon RA, McGuire P, Fusar-Poli P. Exploring causal mechanisms of psychosis risk. Neurosci Biobehav Rev 2024; 162:105699. [PMID: 38710421 PMCID: PMC11250118 DOI: 10.1016/j.neubiorev.2024.105699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 02/17/2024] [Accepted: 04/28/2024] [Indexed: 05/08/2024]
Abstract
Robust epidemiological evidence of risk and protective factors for psychosis is essential to inform preventive interventions. Previous evidence syntheses have classified these risk and protective factors according to their strength of association with psychosis. In this critical review we appraise the distinct and overlapping mechanisms of 25 key environmental risk factors for psychosis, and link these to mechanistic pathways that may contribute to neurochemical alterations hypothesised to underlie psychotic symptoms. We then discuss the implications of our findings for future research, specifically considering interactions between factors, exploring universal and subgroup-specific factors, improving understanding of temporality and risk dynamics, standardising operationalisation and measurement of risk and protective factors, and developing preventive interventions targeting risk and protective factors.
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Affiliation(s)
- Dominic Oliver
- Department of Psychiatry, University of Oxford, Oxford, UK; NIHR Oxford Health Biomedical Research Centre, Oxford, UK; OPEN Early Detection Service, Oxford Health NHS Foundation Trust, Oxford, UK; Early Psychosis: Interventions and Clinical-Detection (EPIC) Lab, Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
| | - Edward Chesney
- Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK; Addictions Department, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 4 Windsor Walk, London SE5 8AF, UK
| | - Alexis E Cullen
- Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK; Department of Clinical Neuroscience, Karolinska Institutet, Sweden
| | - Cathy Davies
- Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK; Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
| | - Amir Englund
- Addictions Department, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 4 Windsor Walk, London SE5 8AF, UK
| | - George Gifford
- Department of Psychiatry, University of Oxford, Oxford, UK
| | - Sarah Kerins
- Early Psychosis: Interventions and Clinical-Detection (EPIC) Lab, Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK; Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
| | - Paris Alexandros Lalousis
- Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK; Department of Psychiatry and Psychotherapy, Ludwig-Maximilian-University Munich, Munich, Germany
| | - Yanakan Logeswaran
- Early Psychosis: Interventions and Clinical-Detection (EPIC) Lab, Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK; Department of Biostatistics & Health Informatics, King's College London, London, UK
| | - Kate Merritt
- Division of Psychiatry, Institute of Mental Health, UCL, London, UK
| | - Uzma Zahid
- Department of Psychology, King's College London, London, UK
| | - Nicolas A Crossley
- Department of Psychiatry, University of Oxford, Oxford, UK; Department of Psychiatry, School of Medicine, Pontificia Universidad Católica de Chile, Chile
| | - Robert A McCutcheon
- Department of Psychiatry, University of Oxford, Oxford, UK; Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK; Oxford Health NHS Foundation Trust, Oxford, UK
| | - Philip McGuire
- Department of Psychiatry, University of Oxford, Oxford, UK; NIHR Oxford Health Biomedical Research Centre, Oxford, UK; OPEN Early Detection Service, Oxford Health NHS Foundation Trust, Oxford, UK
| | - Paolo Fusar-Poli
- Early Psychosis: Interventions and Clinical-Detection (EPIC) Lab, Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK; Department of Psychiatry and Psychotherapy, Ludwig-Maximilian-University Munich, Munich, Germany; Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy; OASIS Service, South London and Maudsley NHS Foundation Trust, London SE11 5DL, UK
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9
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Qi D, Wang W, Chu L, Wu Y, Wang W, Zhu M, Yuan L, Gao W, Deng H. Associations of schizophrenia with the activities of the HPA and HPG axes and their interactions characterized by hair-based biomarkers. Psychoneuroendocrinology 2024; 165:107049. [PMID: 38657340 DOI: 10.1016/j.psyneuen.2024.107049] [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: 01/02/2024] [Revised: 03/11/2024] [Accepted: 04/10/2024] [Indexed: 04/26/2024]
Abstract
BACKGROUND Past studies on schizophrenia (SCZ) and the stress-sensitive neuroendocrine systems have mostly focused on a single system and traditionally utilized acute biomarkers (e.g., biomarkers from blood, urine and saliva) that poorly match the chronic course of schizophrenia in time span. Using eight biomarkers in hair, this study aimed to explore the functional characteristics of SCZ patients in the hypothalamic-pituitary-adrenocortical (HPA) and hypothalamic-pituitary-gonadal (HPG) axes and the interaction between the two axes. METHODS Hair samples were taken from 137 SCZ patients and 73 controls. The SCZ patients were diagnosed by their attending physician according to the Diagnostic and Statistical Manual of Mental Disorders IV and were clinically stable after treatment. Gender, age, BMI, frequency of hair washing, marital status, education level, family history of mental illness and clozapine dosage were concurrently collected as covariates. The 10-item perceived stress scale (PSS-10) and the social readjustment rating scale were used to assess chronic stress status in SCZ patients. Eight hair biomarkers, cortisol, cortisone, dehydroepiandrosterone (DHEA), testosterone, progesterone, cortisol/cortisone, cortisol/DHEA and cortisol/testosterone, were measured by high performance liquid chromatography tandem mass spectrometer. Among them, cortisol, cortisone, DHEA and cortisol/DHEA reflected the functional activity of the HPA axis, and testosterone and progesterone reflected the functional activity of the HPG axis, and cortisol/cortisone reflected the activity of 11β-hydroxysteroid dehydrogenase types 2 (11β-HSD 2), and cortisol/testosterone reflected the HPA-HPG interaction. RESULTS SCZ patients showed significantly higher cortisone and cortisol/testosterone than controls (p<0.001, η²p=0.180 and p=0.015, η²p=0.031), lower testosterone (p=0.009, η²p=0.034), progesterone (p<0.001, η²p=0.069) and cortisol/cortisone (p=0.001, η²p=0.054). There were significant intergroup differences in male and female progesterone (p=0.003, η²p=0.088 and p=0.030, η²p=0.049) and female testosterone (p=0.028, η²p=0.051). In SCZ patients, cortisol, cortisol/cortisone, cortisol/DHEA and cortisol/testosterone were positively associated with PSS-10 score (ps<0.05, 0.212 CONCLUSION The function of the HPA and HPG axes, the activity of 11β-HSD 2 and the HPA-HPG interaction were abnormal in SCZ patients. The abnormality of neuroendocrine systems was associated with chronic stress status in SCZ patients. This study provided evidence for abnormalities in the neuroendocrine systems in SCZ patients.
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Affiliation(s)
- Deyi Qi
- Department of Brain and Learning Science, School of Biological Science & Medical Engineering, Southeast University, Nanjing 211189, China; Key Laboratory of Child Development and Learning Science (Southeast University), Ministry of Education, Nanjing 211189, China; Institute of Child Development and Education, Southeast University, Nanjing 211189, China
| | - Weiliang Wang
- School of Nursing, Harbin Medical University, Harbin 163319, China.
| | - Liuxi Chu
- Department of Brain and Learning Science, School of Biological Science & Medical Engineering, Southeast University, Nanjing 211189, China; Key Laboratory of Child Development and Learning Science (Southeast University), Ministry of Education, Nanjing 211189, China; Institute of Child Development and Education, Southeast University, Nanjing 211189, China
| | - Yan Wu
- Department of Brain and Learning Science, School of Biological Science & Medical Engineering, Southeast University, Nanjing 211189, China; Key Laboratory of Child Development and Learning Science (Southeast University), Ministry of Education, Nanjing 211189, China; Institute of Child Development and Education, Southeast University, Nanjing 211189, China
| | - Wei Wang
- Department of Brain and Learning Science, School of Biological Science & Medical Engineering, Southeast University, Nanjing 211189, China; Key Laboratory of Child Development and Learning Science (Southeast University), Ministry of Education, Nanjing 211189, China; Institute of Child Development and Education, Southeast University, Nanjing 211189, China
| | - Minhui Zhu
- Department of Brain and Learning Science, School of Biological Science & Medical Engineering, Southeast University, Nanjing 211189, China; Key Laboratory of Child Development and Learning Science (Southeast University), Ministry of Education, Nanjing 211189, China; Institute of Child Development and Education, Southeast University, Nanjing 211189, China
| | - Lin Yuan
- Department of Brain and Learning Science, School of Biological Science & Medical Engineering, Southeast University, Nanjing 211189, China; Key Laboratory of Child Development and Learning Science (Southeast University), Ministry of Education, Nanjing 211189, China; Institute of Child Development and Education, Southeast University, Nanjing 211189, China
| | - Wei Gao
- Institute of Child Development and Education, Southeast University, Nanjing 211189, China; School of Psychology, Nanjing Normal University, Nanjing 210024, China
| | - Huihua Deng
- Department of Brain and Learning Science, School of Biological Science & Medical Engineering, Southeast University, Nanjing 211189, China; Key Laboratory of Child Development and Learning Science (Southeast University), Ministry of Education, Nanjing 211189, China; Institute of Child Development and Education, Southeast University, Nanjing 211189, China.
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10
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Tandon R, Nasrallah H, Akbarian S, Carpenter WT, DeLisi LE, Gaebel W, Green MF, Gur RE, Heckers S, Kane JM, Malaspina D, Meyer-Lindenberg A, Murray R, Owen M, Smoller JW, Yassin W, Keshavan M. The schizophrenia syndrome, circa 2024: What we know and how that informs its nature. Schizophr Res 2024; 264:1-28. [PMID: 38086109 DOI: 10.1016/j.schres.2023.11.015] [Citation(s) in RCA: 43] [Impact Index Per Article: 43.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 11/23/2023] [Accepted: 11/29/2023] [Indexed: 03/01/2024]
Abstract
With new data about different aspects of schizophrenia being continually generated, it becomes necessary to periodically revisit exactly what we know. Along with a need to review what we currently know about schizophrenia, there is an equal imperative to evaluate the construct itself. With these objectives, we undertook an iterative, multi-phase process involving fifty international experts in the field, with each step building on learnings from the prior one. This review assembles currently established findings about schizophrenia (construct, etiology, pathophysiology, clinical expression, treatment) and posits what they reveal about its nature. Schizophrenia is a heritable, complex, multi-dimensional syndrome with varying degrees of psychotic, negative, cognitive, mood, and motor manifestations. The illness exhibits a remitting and relapsing course, with varying degrees of recovery among affected individuals with most experiencing significant social and functional impairment. Genetic risk factors likely include thousands of common genetic variants that each have a small impact on an individual's risk and a plethora of rare gene variants that have a larger individual impact on risk. Their biological effects are concentrated in the brain and many of the same variants also increase the risk of other psychiatric disorders such as bipolar disorder, autism, and other neurodevelopmental conditions. Environmental risk factors include but are not limited to urban residence in childhood, migration, older paternal age at birth, cannabis use, childhood trauma, antenatal maternal infection, and perinatal hypoxia. Structural, functional, and neurochemical brain alterations implicate multiple regions and functional circuits. Dopamine D-2 receptor antagonists and partial agonists improve psychotic symptoms and reduce risk of relapse. Certain psychological and psychosocial interventions are beneficial. Early intervention can reduce treatment delay and improve outcomes. Schizophrenia is increasingly considered to be a heterogeneous syndrome and not a singular disease entity. There is no necessary or sufficient etiology, pathology, set of clinical features, or treatment that fully circumscribes this syndrome. A single, common pathophysiological pathway appears unlikely. The boundaries of schizophrenia remain fuzzy, suggesting the absence of a categorical fit and need to reconceptualize it as a broader, multi-dimensional and/or spectrum construct.
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Affiliation(s)
- Rajiv Tandon
- Department of Psychiatry, WMU Homer Stryker School of Medicine, Kalamazoo, MI 49008, United States of America.
| | - Henry Nasrallah
- Department of Psychiatry, University of Cincinnati College of Medicine Cincinnati, OH 45267, United States of America
| | - Schahram Akbarian
- Department of Psychiatry, Icahn School of Medicine at Mt. Sinai, New York, NY 10029, United States of America
| | - William T Carpenter
- Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD 21201, United States of America
| | - Lynn E DeLisi
- Department of Psychiatry, Cambridge Health Alliance and Harvard Medical School, Cambridge, MA 02139, United States of America
| | - Wolfgang Gaebel
- Department of Psychiatry and Psychotherapy, LVR-Klinikum Dusseldorf, Heinrich-Heine University, Dusseldorf, Germany
| | - Michael F Green
- Department of Psychiatry and Biobehavioral Sciences, Jane and Terry Semel Institute of Neuroscience and Human Behavior, UCLA, Los Angeles, CA 90024, United States of America; Greater Los Angeles Veterans' Administration Healthcare System, United States of America
| | - Raquel E Gur
- Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, United States of America
| | - Stephan Heckers
- Department of Psychiatry, Vanderbilt University Medical Center, Nashville, TN 37232, United States of America
| | - John M Kane
- Department of Psychiatry, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Glen Oaks, NY 11004, United States of America
| | - Dolores Malaspina
- Department of Psychiatry, Neuroscience, Genetics, and Genomics, Icahn School of Medicine at Mt. Sinai, New York, NY 10029, United States of America
| | - Andreas Meyer-Lindenberg
- Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Mannhein/Heidelberg University, Mannheim, Germany
| | - Robin Murray
- Institute of Psychiatry, Psychology, and Neuroscience, Kings College, London, UK
| | - Michael Owen
- Centre for Neuropsychiatric Genetics and Genomics, and Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK
| | - Jordan W Smoller
- Center for Precision Psychiatry, Department of Psychiatry, Psychiatric and Neurodevelopmental Unit, Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, United States of America
| | - Walid Yassin
- Department of Psychiatry, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, United States of America
| | - Matcheri Keshavan
- Department of Psychiatry, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, United States of America
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11
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Bahlinger K, Lincoln TM, Clamor A. Do deficits in subjective stress recovery predict subsequent stress sensitivity and symptoms in schizophrenia spectrum disorders? Schizophr Res 2024; 264:170-177. [PMID: 38150849 DOI: 10.1016/j.schres.2023.12.021] [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: 03/15/2023] [Revised: 11/23/2023] [Accepted: 12/17/2023] [Indexed: 12/29/2023]
Abstract
High levels of stress play a crucial role in the development of psychotic symptoms, such as paranoia, and may stem in part from recovery deficits after stress exposure. However, it remains unclear whether deficient recovery causes a build-up of heightened stress levels that increases stress sensitivity and symptoms when exposed to another stressor. To test this, we investigated the effect of subjective stress recovery on the response to a subsequent stressor and paranoia. We applied two consecutive runs of the same combined physical and cognitive stressor separated by a recovery phase of 60 min in individuals with schizophrenia spectrum disorders (n = 49). We repeatedly assessed self-reported stress, negative affect, heart rate, heart rate variability, salivary cortisol, and paranoia. Recovery of self-reported stress was defined as the geometric mean of the percentage changes of self-reported stress during recovery after the first stressor, and was regressed on the response to the second stressor controlling for self-reported stress during the first stressor. Lower subjective stress recovery predicted higher levels of self-reported stress, negative affect, and paranoia in response to the second stressor. The subjective stress recovery was not predictive of the physiological stress response (heart rate, heart rate variability, or salivary cortisol). Taken together, the findings indicate that recovery deficits could contribute to high levels of self-reported stress, negative affect, and paranoia in schizophrenia spectrum disorders and that the improvement of stress recovery could be a promising approach for interventions.
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Affiliation(s)
- Katrin Bahlinger
- Clinical Psychology and Psychotherapy, Institute of Psychology, Faculty of Psychology and Human Movement Sciences, Universität Hamburg, Germany.
| | - Tania M Lincoln
- Clinical Psychology and Psychotherapy, Institute of Psychology, Faculty of Psychology and Human Movement Sciences, Universität Hamburg, Germany
| | - Annika Clamor
- Clinical Psychology and Psychotherapy, Institute of Psychology, Faculty of Psychology and Human Movement Sciences, Universität Hamburg, Germany
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12
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Cullen AE, Labad J, Oliver D, Al-Diwani A, Minichino A, Fusar-Poli P. The Translational Future of Stress Neurobiology and Psychosis Vulnerability: A Review of the Evidence. Curr Neuropharmacol 2024; 22:350-377. [PMID: 36946486 PMCID: PMC10845079 DOI: 10.2174/1570159x21666230322145049] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 12/17/2022] [Accepted: 12/27/2022] [Indexed: 03/23/2023] Open
Abstract
Psychosocial stress is a well-established risk factor for psychosis, yet the neurobiological mechanisms underlying this relationship have yet to be fully elucidated. Much of the research in this field has investigated hypothalamic-pituitary-adrenal (HPA) axis function and immuno-inflammatory processes among individuals with established psychotic disorders. However, as such studies are limited in their ability to provide knowledge that can be used to develop preventative interventions, it is important to shift the focus to individuals with increased vulnerability for psychosis (i.e., high-risk groups). In the present article, we provide an overview of the current methods for identifying individuals at high-risk for psychosis and review the psychosocial stressors that have been most consistently associated with psychosis risk. We then describe a network of interacting physiological systems that are hypothesised to mediate the relationship between psychosocial stress and the manifestation of psychotic illness and critically review evidence that abnormalities within these systems characterise highrisk populations. We found that studies of high-risk groups have yielded highly variable findings, likely due to (i) the heterogeneity both within and across high-risk samples, (ii) the diversity of psychosocial stressors implicated in psychosis, and (iii) that most studies examine single markers of isolated neurobiological systems. We propose that to move the field forward, we require well-designed, largescale translational studies that integrate multi-domain, putative stress-related biomarkers to determine their prognostic value in high-risk samples. We advocate that such investigations are highly warranted, given that psychosocial stress is undoubtedly a relevant risk factor for psychotic disorders.
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Affiliation(s)
- Alexis E. Cullen
- Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, United Kingdom
- Department of Clinical Neuroscience, Division of Insurance Medicine, Karolinska Institutet, Solna, Sweden
- Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, United Kingdom
| | - Javier Labad
- CIBERSAM, Sabadell, Barcelona, Spain
- Department of Mental Health and Addictions, Consorci Sanitari del Maresme, Mataró, Spain
| | - Dominic Oliver
- Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, United Kingdom
- Early Psychosis: Interventions and Clinical-Detection (EPIC) Lab, Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, United Kingdom
| | - Adam Al-Diwani
- Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, United Kingdom
| | - Amedeo Minichino
- Early Psychosis: Interventions and Clinical-Detection (EPIC) Lab, Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, United Kingdom
| | - Paolo Fusar-Poli
- Early Psychosis: Interventions and Clinical-Detection (EPIC) Lab, Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, United Kingdom
- Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy
- OASIS Service, South London and Maudsley NHS Foundation Trust, London, United Kingdom
- National Institute of Health Research Maudsley Biomedical Research Centre, South London and Maudsley NHS Foundation Trust, London, UK
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13
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Obdržálková M, Ustohal L, Hlaváčová N, Mayerová M, Češková E, Kašpárek T, Ježová D. Selected neuroendocrine factors as potential molecular biomarkers of early non-affective psychosis course in relation to treatment outcome: A pilot study. Heliyon 2023; 9:e21173. [PMID: 37916075 PMCID: PMC10616415 DOI: 10.1016/j.heliyon.2023.e21173] [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: 08/22/2022] [Revised: 10/16/2023] [Accepted: 10/17/2023] [Indexed: 11/03/2023] Open
Abstract
The aim of this pilot study was to find whether the dysregulation of neuroendocrine biomarker signaling pathways in the first episode of non-affective psychosis is a predictive factor of treatment outcome. Patients with the first episode of non-affective psychosis (N = 29) were examined at admission, at discharge, and at follow-up (N = 23). The biomarkers included serum aldosterone, cortisol, free thyroxine, thyroid stimulating hormone, and prolactin. We revealed lower baseline aldosterone and higher baseline cortisol concentrations in patients with very good outcome compared to those with good outcome after one year. We failed to reveal any significant association between treatment outcome and neurohumoral biomarkers in the whole sample at 1-year follow-up. However, baseline aldosterone concentrations negatively correlated with total PANSS scores at the discharge. Lower baseline aldosterone and higher baseline cortisol concentrations have the potential to predict a more favorable outcome for patients with the first episode of psychosis.
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Affiliation(s)
- Marie Obdržálková
- Department of Psychiatry, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Libor Ustohal
- Department of Psychiatry, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Masaryk University, Brno, Czech Republic
| | - Nataša Hlaváčová
- Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Michaela Mayerová
- Department of Psychiatry, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Eva Češková
- Department of Psychiatry, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Tomáš Kašpárek
- Department of Psychiatry, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Daniela Ježová
- Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia
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Gine-Serven E, Martinez-Ramirez M, Boix-Quintana E, Davi-Loscos E, Guanyabens N, Casado V, Muriana D, Torres-Rivas C, Cuesta M, Labad J. Association between free thyroxine levels and clinical phenotype in first-episode psychosis: a prospective observational study. PeerJ 2023; 11:e15347. [PMID: 37283900 PMCID: PMC10241168 DOI: 10.7717/peerj.15347] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 04/13/2023] [Indexed: 06/08/2023] Open
Abstract
Aim To determine whether thyroid hormone levels are associated with a specific clinical phenotype in patients with first-episode psychosis (FEP). Methods Ninety-eight inpatients experiencing FEP and with less than 6 weeks of antipsychotic treatment were included in the study and were followed up for one year. Baseline psychiatric evaluation included assessment of prodromal symptoms, positive and negative symptoms, depressive symptoms, stressful life events and cycloid psychosis criteria. Thyroid function (thyroid-stimulating hormone (TSH) and free thyroxin (FT4)) was determined at admission. Partial correlation analysis was conducted to analyse the correlation between levels of TSH/FT4 and symptoms. Logistic regression was performed to explore the association between psychopathological symptoms, 12-month diagnoses and thyroid hormones while adjusting for covariates. Results Patients with prodromal symptomatology showed lower baseline FT4 levels (OR = 0.06; p = 0.018). The duration of untreated psychosis (DUP) was inversely associated with FT4 concentrations (r = - 0.243; p = 0.039). FEP patients with sudden onset of psychotic symptoms (criteria B, cycloid psychosis) showed higher FT4 levels at admission (OR = 10.49; p = 0.040). Patients diagnosed with affective psychotic disorders (BD or MDD) at the 12-month follow-up showed higher FT4 levels at admission than patients diagnosed with nonaffective psychosis (schizophrenia, schizoaffective) (OR = 8.57; p = 0.042). Conclusions Our study suggests that higher free-thyroxine levels are associated with a specific clinical phenotype of FEP patients (fewer prodromal symptoms, shorter DUP duration and sudden onset of psychosis) and with affective psychosis diagnoses at the 12-month follow-up.
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Affiliation(s)
- Eloi Gine-Serven
- Department of Mental Health, Hospital de Mataró, Consorci Sanitari del Maresme, Mataró, Spain
| | - Maria Martinez-Ramirez
- Department of Mental Health, Hospital de Mataró, Consorci Sanitari del Maresme, Mataró, Spain
| | - Ester Boix-Quintana
- Department of Mental Health, Hospital de Mataró, Consorci Sanitari del Maresme, Mataró, Spain
| | - Eva Davi-Loscos
- Department of Mental Health, Hospital de Mataró, Consorci Sanitari del Maresme, Mataró, Spain
| | - Nicolau Guanyabens
- Department of Neurology, Hospital de Mataró, Consorci Sanitari del Maresme, Mataró, Spain
| | - Virginia Casado
- Department of Neurology, Hospital de Mataró, Consorci Sanitari del Maresme, Mataró, Spain
| | - Desiree Muriana
- Department of Neurology, Hospital de Mataró, Consorci Sanitari del Maresme, Mataró, Spain
| | - Cristina Torres-Rivas
- Department of Mental Health, Hospital de Mataró, Consorci Sanitari del Maresme, Mataró, Spain
| | - M.J. Cuesta
- Department of Psychiatry, Complejo Hospitalario de Navarra, Pamplona, Spain
- IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
| | - Javier Labad
- Department of Mental Health, Hospital de Mataró, Consorci Sanitari del Maresme, Mataró, Spain
- Translational Neuroscience Research Unit I3PT-INc-UAB, Institut de Innovació i Investigació Parc Taulí (I3PT), Institut de Neurociències, Universitat Autònoma de Barcelona, Barcelona, Spain
- Centro de Investigación en Red de Salud Mental (CIBERSAM), Madrid, Spain
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15
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Ristanovic I, Vargas TG, Damme KSF, Mittal VA. Hippocampal subfields, daily stressors, and resting cortisol in individuals at clinical high-risk for psychosis. Psychoneuroendocrinology 2023; 148:105996. [PMID: 36495626 PMCID: PMC9898196 DOI: 10.1016/j.psyneuen.2022.105996] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 10/17/2022] [Accepted: 11/28/2022] [Indexed: 12/03/2022]
Abstract
INTRODUCTION The hippocampus, comprised of functionally distinct subfields, both regulates stress and is affected by it during psychosis pathogenesis. Hippocampal abnormalities are evident across psychosis spectrum and are associated with aberrant cortisol levels and greater environmental stressors exposure. These associations, particularly at the subfield-level, are poorly understood in individuals at clinical high-risk (CHR) for psychosis. This represents a significant literature gap given this critical pathogenetic period is characterized by an interplay between environmental stressors and biological susceptibility. METHODS A total of 121 participants including 51 CHR (mean age=18.61) and 70 healthy controls (HC; mean age=18.3) were enrolled in the study. Participants completed a structural scan, salivary cortisol assays, and a self-report measure assessing distress from daily stressors exposure (DSI). Hippocampal subfield segmentation was conducted using Freesurfer. RESULTS Smaller hippocampal subfields were associated with greater stress levels. Greater DSI was associated with lower volumes in CA1 (r = -0.38) and CA2/3 (r = -0.29), but not in CA4/DG (r = -0.28), presubiculum (r = -0.09), or subiculum (r = -0.17). Higher resting cortisol was associated with lower volumes in presubiculum (r = -0.4) but not subiculum (r = -0.22), CA1 (r = 0.08), CA2/3 (r = 0.1), or CA4/DG (r = -0.005). Regressions indicated effects for CA1 and DSI (β = 0.57, p = .03) and presubiculum and cortisol (β = 0.61, p = .02) are specific to CHR participants relative to HCs. CONCLUSIONS The findings provided insights into links between stress and brain vulnerability during psychosis-risk period. Regional differences highlighted potentially different mechanisms by which stress impacts specific subfields. Presubiculum may be more susceptible to the impact of early stress on HPA-axis and cornu amonis to acute stressors.
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Affiliation(s)
- Ivanka Ristanovic
- Northwestern University, Department of Psychology, Evanston, IL 60208, USA; Institute for Innovations in Developmental Sciences (DevSci), Northwestern University, Evanston, Chicago, IL, USA.
| | - Teresa G Vargas
- Northwestern University, Department of Psychology, Evanston, IL 60208, USA; Institute for Innovations in Developmental Sciences (DevSci), Northwestern University, Evanston, Chicago, IL, USA
| | - Katherine S F Damme
- Northwestern University, Department of Psychology, Evanston, IL 60208, USA; Institute for Innovations in Developmental Sciences (DevSci), Northwestern University, Evanston, Chicago, IL, USA
| | - Vijay Anand Mittal
- Northwestern University, Department of Psychology, Evanston, IL 60208, USA; Institute for Innovations in Developmental Sciences (DevSci), Northwestern University, Evanston, Chicago, IL, USA; Northwestern University, Department of Psychiatry, Chicago, IL 60611, USA; Northwestern University, Medical Social Sciences, Chicago IL 60611, USA; Norhtwestern University, Institute for Policy Research, Evanston, IL 60208, USA
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16
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Barendse MEA, Lara GA, Guyer AE, Swartz JR, Taylor SL, Shirtcliff EA, Lamb ST, Miller C, Ng J, Yu G, Tully LM. Sex and pubertal influences on the neurodevelopmental underpinnings of schizophrenia: A case for longitudinal research on adolescents. Schizophr Res 2023; 252:231-241. [PMID: 36682313 PMCID: PMC10725041 DOI: 10.1016/j.schres.2022.12.011] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 11/08/2022] [Accepted: 12/10/2022] [Indexed: 01/21/2023]
Abstract
Sex is a significant source of heterogeneity in schizophrenia, with more negative symptoms in males and more affective symptoms and internalizing comorbidity in females. In this narrative review, we argue that there are likely sex differences in the pathophysiological mechanisms of schizophrenia-spectrum disorders (SZ) that originate during puberty and relate to the sex-specific impacts of pubertal maturation on brain development. Pubertal maturation might also trigger underlying (genetic or other) vulnerabilities in at-risk individuals, influencing brain development trajectories that contribute to the emergence of SZ. This review is the first to integrate links between pubertal development and neural development with cognitive neuroscience research in SZ to form and evaluate these hypotheses, with a focus on the frontal-striatal and frontal-limbic networks and their hypothesized contribution to negative and mood symptoms respectively. To test these hypotheses, longitudinal research with human adolescents is needed that examines the role of sex and pubertal development using large cohorts or high risk samples. We provide recommendations for such studies, which will integrate the fields of psychiatry, developmental cognitive neuroscience, and developmental endocrinology towards a more nuanced understanding of the role of pubertal factors in the hypothesized sex-specific pathophysiological mechanisms of schizophrenia.
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Affiliation(s)
- M E A Barendse
- Department of Psychiatry and Behavioral Sciences, UC Davis, CA, USA
| | - G A Lara
- Department of Psychiatry and Behavioral Sciences, UC Davis, CA, USA
| | - A E Guyer
- Department of Human Ecology, UC Davis, CA, USA; Center for Mind and Brain, UC Davis, CA, USA
| | - J R Swartz
- Center for Mind and Brain, UC Davis, CA, USA
| | - S L Taylor
- Division of Biostatistics, Department of Public Health Sciences, UC Davis, CA, USA
| | - E A Shirtcliff
- Human Development and Family Studies, Iowa State University, Ames, IA, USA
| | - S T Lamb
- Department of Psychiatry and Behavioral Sciences, UC Davis, CA, USA
| | - C Miller
- Department of Psychiatry and Behavioral Sciences, UC Davis, CA, USA
| | - J Ng
- Department of Psychiatry and Behavioral Sciences, UC Davis, CA, USA
| | - G Yu
- Department of Psychiatry and Behavioral Sciences, UC Davis, CA, USA
| | - L M Tully
- Department of Psychiatry and Behavioral Sciences, UC Davis, CA, USA.
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17
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Arinami H, Watanabe Y, Suzuki Y, Tajiri M, Tsuneyama N, Someya T. Serum cortisol and insulin-like growth factor 1 levels in major depressive disorder and schizophrenia. Sci Rep 2023; 13:1148. [PMID: 36670169 PMCID: PMC9859801 DOI: 10.1038/s41598-023-28449-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Accepted: 01/18/2023] [Indexed: 01/22/2023] Open
Abstract
The pathophysiology underlying major depressive disorder (MDD) and schizophrenia is related to endocrine system functions and includes changes in the blood levels of cortisol and insulin-like growth factor 1 (IGF-1). However, these hormones have not been investigated simultaneously in patients with MDD and schizophrenia. We investigated the differences in serum cortisol and IGF-1 levels among patients with MDD and schizophrenia and controls. We included 129 patients with MDD, 71 patients with schizophrenia, and 71 healthy volunteers. Blood tests were performed between 6:00 am and 11:00 am after fasting. Serum cortisol levels were significantly higher in patients with schizophrenia than in patients with MDD and controls. Serum cortisol levels were significantly higher in patients with MDD than in controls. Serum IGF-1 levels were higher in both patient groups than in controls, whereas there was no significant difference between patients with MDD and schizophrenia. Both cortisol and IGF-1 levels were positively correlated with the Hamilton Rating Scale for Depression score in patients with MDD, whereas cortisol level was positively correlated and IGF-1 level was negatively correlated with the Brief Psychiatric Rating Scale score in patients with schizophrenia. The differences in the level of these hormones suggest pathophysiological differences between these disorders.
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Affiliation(s)
- Hiroshi Arinami
- Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, 757 Asahimachidori-Ichibancho, Chuo-ku, Niigata, 951-8510, Japan
| | - Yuichiro Watanabe
- Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, 757 Asahimachidori-Ichibancho, Chuo-ku, Niigata, 951-8510, Japan.
| | - Yutaro Suzuki
- Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, 757 Asahimachidori-Ichibancho, Chuo-ku, Niigata, 951-8510, Japan
| | - Misuzu Tajiri
- Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, 757 Asahimachidori-Ichibancho, Chuo-ku, Niigata, 951-8510, Japan
| | - Nobuto Tsuneyama
- Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, 757 Asahimachidori-Ichibancho, Chuo-ku, Niigata, 951-8510, Japan
| | - Toshiyuki Someya
- Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, 757 Asahimachidori-Ichibancho, Chuo-ku, Niigata, 951-8510, Japan
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18
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The Placentas of Women Who Suffer an Episode of Psychosis during Pregnancy Have Increased Lipid Peroxidation with Evidence of Ferroptosis. Biomolecules 2023; 13:biom13010120. [PMID: 36671505 PMCID: PMC9855415 DOI: 10.3390/biom13010120] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2022] [Revised: 01/04/2023] [Accepted: 01/05/2023] [Indexed: 01/11/2023] Open
Abstract
Psychosis is a complex entity characterized by psychological, behavioral, and motor alterations resulting in a loss of contact with reality. Although it is not common, pregnancy can be a period in which a first episode of psychosis can manifest, entailing detrimental consequences for both the fetus and the mother. The pathophysiological basis and study of maternofetal wellbeing need to be further elucidated. Lipid peroxidation and ferroptosis are two phenomena that are tightly linked to the placental dysfunction commonly observed in different complications of pregnancy. In the present study, we aim to explore the histopathological and gene expression of different markers of lipid peroxidation and ferroptosis in the placentas of women who underwent a first episode of psychosis during their pregnancy (n = 22). The aim is to then compare them with healthy pregnant women (n = 20). In order to achieve this goal, iron deposits were studied using Prussian Blue staining. In addition, the protein/gene expression of a transferrin receptor (TFRC), as well as an acyl-CoA synthetase long-chain family member 4 (ACSL-4), arachidonate lipoxygenase-5 (ALOX-5), malondialdehyde (MDA), and glutathione peroxidase 4 (GPX4) were all analyzed through gene expression (RT-qPCR) and immunohistochemical procedures. Our results demonstrate an increased presence of iron deposits that are accompanied by a further expression of TFRC, ACSL-4, ALOX-5, MDA, and GPX4-all of which are observed in the placenta tissue of women who have suffered from a first episode of psychosis. Therefore, in our study, a histopathological increase in lipid peroxidation and ferroptosis markers in the affected women is suggested. However, further studies are needed in order to validate our results and to establish possible consequences for the reported alterations.
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19
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van den Heuvel LL, Smit AM, Stalder T, Kirschbaum C, Seedat S, Emsley R. Hair cortisol levels in schizophrenia and metabolic syndrome. Early Interv Psychiatry 2022; 16:902-911. [PMID: 34978366 DOI: 10.1111/eip.13238] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 08/16/2021] [Accepted: 10/19/2021] [Indexed: 11/28/2022]
Abstract
AIM Individuals with schizophrenia demonstrate higher rates of metabolic syndrome (MetS) than the general population. Hair cortisol concentrations (HCC) reflect longer-term cortisol secretion and can provide additional insights into the role of the hypothalamic pituitary adrenal (HPA) axis in schizophrenia and co-occurring MetS. METHODS In a case-control study of 16 patients with schizophrenia (11 first episode psychosis [FEP] and 5 chronic) and 21 controls hair samples, representing a 3-month retrospective window of cortisol, were collected and analysed utilizing liquid chromatography tandem mass spectrometry. We investigated whether schizophrenia and MetS co-occurrence were associated with HCC utilizing multivariate regression models. We also explored the longitudinal trajectory of HCC in FEP patients by conducting a mixed models analysis. RESULTS At baseline HCC were significantly lower (Cohen's d = 0.88) in patients with schizophrenia than in controls (p = .014). HCC increased from baseline to month-12 in FEP patients compared to controls, demonstrating a trend towards significance (p = .097). MetS was not associated with HCC at baseline, but HCC increased significantly from baseline to month-12 in relation to MetS (p = .037). CONCLUSIONS In a subgroup of schizophrenia patients, psychosis may be associated with a blunted HPA axis with lower long-term cortisol output. MetS was associated with an increase in HCC and elevated cortisol levels observed in schizophrenia may be related to increased rates of MetS in schizophrenia patients.
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Affiliation(s)
- Leigh Luella van den Heuvel
- Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa.,South African Medical Research Council, Stellenbosch University Genomics of Brain Disorders Research Unit, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Anna Margaretha Smit
- Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa
| | - Tobias Stalder
- Clinical Psychology, University of Siegen, Siegen, Germany
| | - Clemens Kirschbaum
- Biological Psychology, Dresden University of Technology, Dresden, Germany
| | - Soraya Seedat
- Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa.,South African Medical Research Council, Stellenbosch University Genomics of Brain Disorders Research Unit, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Robin Emsley
- Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa.,South African Medical Research Council, Stellenbosch University Genomics of Brain Disorders Research Unit, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
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20
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Yue W, Huang H, Duan J. Potential diagnostic biomarkers for schizophrenia. MEDICAL REVIEW (BERLIN, GERMANY) 2022; 2:385-416. [PMID: 37724326 PMCID: PMC10388817 DOI: 10.1515/mr-2022-0009] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 06/20/2022] [Indexed: 09/20/2023]
Abstract
Schizophrenia (SCH) is a complex and severe mental disorder with high prevalence, disability, mortality and carries a heavy disease burden, the lifetime prevalence of SCH is around 0.7%-1.0%, which has a profound impact on the individual and society. In the clinical practice of SCH, key problems such as subjective diagnosis, experiential treatment, and poor overall prognosis are still challenging. In recent years, some exciting discoveries have been made in the research on objective biomarkers of SCH, mainly focusing on genetic susceptibility genes, metabolic indicators, immune indices, brain imaging, electrophysiological characteristics. This review aims to summarize the biomarkers that may be used for the prediction and diagnosis of SCH.
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Affiliation(s)
- Weihua Yue
- Institute of Mental Health, Peking University Sixth Hospital, Beijing, China
- National Clinical Research Center for Mental Disorders & NHC Key Laboratory of Mental Health (Peking University) and Chinese Academy of Medical Sciences Research Unit, Beijing, China
- PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, China
- Chinese Institute for Brain Research, Beijing, China
| | - Hailiang Huang
- Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Jubao Duan
- Center for Psychiatric Genetics, NorthShore University Health System, Evanston, IL, USA
- Department of Psychiatry and Behavioral Neurosciences, University of Chicago, Chicago, IL, USA
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21
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Miller CL. The Epigenetics of Psychosis: A Structured Review with Representative Loci. Biomedicines 2022; 10:561. [PMID: 35327363 PMCID: PMC8945330 DOI: 10.3390/biomedicines10030561] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 02/24/2022] [Accepted: 02/26/2022] [Indexed: 02/04/2023] Open
Abstract
The evidence for an environmental component in chronic psychotic disorders is strong and research on the epigenetic manifestations of these environmental impacts has commenced in earnest. In reviewing this research, the focus is on three genes as models for differential methylation, MCHR1, AKT1 and TDO2, each of which have been investigated for genetic association with psychotic disorders. Environmental factors associated with psychotic disorders, and which interact with these model genes, are explored in depth. The location of transcription factor motifs relative to key methylation sites is evaluated for predicted gene expression results, and for other sites, evidence is presented for methylation directing alternative splicing. Experimental results from key studies show differential methylation: for MCHR1, in psychosis cases versus controls; for AKT1, as a pre-existing methylation pattern influencing brain activation following acute administration of a psychosis-eliciting environmental stimulus; and for TDO2, in a pattern associated with a developmental factor of risk for psychosis, in all cases the predicted expression impact being highly dependent on location. Methylation induced by smoking, a confounding variable, exhibits an intriguing pattern for all three genes. Finally, how differential methylation meshes with Darwinian principles is examined, in particular as it relates to the "flexible stem" theory of evolution.
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22
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Cortisol Levels in Childhood Associated With Emergence of Attenuated Psychotic Symptoms in Early Adulthood. Biol Psychiatry 2022; 91:226-235. [PMID: 34715990 PMCID: PMC7612877 DOI: 10.1016/j.biopsych.2021.08.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Revised: 08/08/2021] [Accepted: 08/11/2021] [Indexed: 12/19/2022]
Abstract
BACKGROUND In individuals at clinical high-risk for psychosis, elevated cortisol levels predict subsequent onset of psychotic disorder. However, it is unclear whether cortisol alterations are evident at an earlier clinical stage and promote progression of psychosis expression. This study aimed to address this issue by investigating whether cortisol levels in childhood were associated with the emergence of attenuated psychotic symptoms in early adulthood. In exploratory analyses, we examined whether cortisol and psychosocial stress measures interacted in predicting attenuated psychotic symptoms. METHODS A sample of children (N = 109) enriched for psychosis risk factors were recruited at age 9-12 years and assessed at age 11-14 years (T1) and 17-21 years (T2). Measures of psychopathology, psychosocial stressors, and salivary cortisol were obtained at T1. Attenuated psychotic symptoms were assessed at T2 using the Prodromal Questionnaire. RESULTS Diurnal cortisol (β = 0.915, 95% CI: 0.062-1.769) and daily stressors (β = 0.379, 95% CI: 0.034-0.723) at T1 were independently associated with total Prodromal Questionnaire scores at T2 after accounting for demographic factors and T1 psychopathology. Exploratory analyses indicated a significant interaction between T1 diurnal cortisol and daily stressors (β = 0.743, 95% CI: 0.081-1.405), with the highest predicted T2 total Prodromal Questionnaire scores occurring when both diurnal cortisol and daily stressors were increased. CONCLUSIONS Our findings suggest that daily stressors and elevations in diurnal cortisol in late childhood/early adolescence increases risk for developing attenuated psychotic symptoms. These findings emphasize the importance of assessing environmental and biological risk factors for psychosis during neurodevelopmentally vulnerable time periods.
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23
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Thyroid hormones in persons with schizophrenia: A systematic review and meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry 2021; 111:110402. [PMID: 34274416 DOI: 10.1016/j.pnpbp.2021.110402] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 07/09/2021] [Accepted: 07/12/2021] [Indexed: 01/14/2023]
Abstract
There is accumulating evidence that individuals with schizophrenia show altered levels of thyroid hormones. However, a qualitative and quantitative synthesis of findings in this field has not been performed so far. Therefore, we aimed to perform a systematic review and meta-analysis of studies investigating the levels of thyroid-stimulating hormone (TSH), free thyroxine (fT4), total thyroxine (tT4), free triiodothyronine (fT3) and total triiodothyronine (tT3) in multiple-episode schizophrenia (MES) and first-episode psychosis (FEP). Electronic databases were searched from their inception until 30th May 2020 by two independent reviewers. Random-effects meta-analyses and meta-regression analyses were performed. Altogether, 19 studies were included. Persons with FEP had significantly lower TSH levels (5 studies, g = -0.26, 95%CI: -0.47 to -0.06, p = 0.013, I2 = 21.3%), higher fT4 levels (3 studies, g = 0.58, 95%CI: 0.15-1.01, p = 0.008, I2 = 64.6%) and lower tT3 levels (2 studies, g = -0.60, 95%CI: -0.82 to -0.37, p < 0.001, I2 = 0%) compared to controls. Elevated TSH levels were found in persons with MES (13 studies, g = 0.20, 95%CI: 0.02-0.39, p = 0.031, I2 = 50.0%). Our findings imply that the levels of TSH might be decreased in persons with FEP and increased in those with MES. Other alterations need to be confirmed by additional studies. These findings imply the need to monitor the levels of TSH and thyroid hormones from the onset of psychosis.
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24
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Dawidowski B, Górniak A, Podwalski P, Lebiecka Z, Misiak B, Samochowiec J. The Role of Cytokines in the Pathogenesis of Schizophrenia. J Clin Med 2021; 10:jcm10173849. [PMID: 34501305 PMCID: PMC8432006 DOI: 10.3390/jcm10173849] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 08/21/2021] [Accepted: 08/24/2021] [Indexed: 02/07/2023] Open
Abstract
Schizophrenia is a chronic mental illness of unknown etiology. A growing and compelling body of evidence implicates immunologic dysfunction as the key element in its pathomechanism. Cytokines, whose altered levels have been increasingly reported in various patient populations, are the major mediators involved in the coordination of the immune system. The available literature reports both elevated levels of proinflammatory as well as reduced levels of anti-inflammatory cytokines, and their effects on clinical status and neuroimaging changes. There is evidence of at least a partial genetic basis for the association between cytokine alterations and schizophrenia. Two other factors implicated in its development include early childhood trauma and disturbances in the gut microbiome. Moreover, its various subtypes, characterized by individual symptom severity and course, such as deficit schizophrenia, seem to differ in terms of changes in peripheral cytokine levels. While the use of a systematic review methodology could be difficult due to the breadth and diversity of the issues covered in this review, the applied narrative approach allows for a more holistic presentation. The aim of this narrative review was to present up-to-date evidence on cytokine dysregulation in schizophrenia, its effect on the psychopathological presentation, and links with antipsychotic medication. We also attempted to summarize its postulated underpinnings, including early childhood trauma and gut microbiome disturbances, and propose trait and state markers of schizophrenia.
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Affiliation(s)
- Bartosz Dawidowski
- Department of Psychiatry, Pomeranian Medical University, 71-460 Szczecin, Poland; (B.D.); (A.G.); (J.S.)
| | - Adrianna Górniak
- Department of Psychiatry, Pomeranian Medical University, 71-460 Szczecin, Poland; (B.D.); (A.G.); (J.S.)
| | - Piotr Podwalski
- Department of Psychiatry, Pomeranian Medical University, 71-460 Szczecin, Poland; (B.D.); (A.G.); (J.S.)
- Correspondence: ; Tel.: +48-510-091-466
| | - Zofia Lebiecka
- Department of Health Psychology, Pomeranian Medical University, 71-210 Szczecin, Poland;
| | - Błażej Misiak
- Department of Psychiatry, Division of Consultation Psychiatry and Neuroscience, Medical University, 50-367 Wroclaw, Poland;
| | - Jerzy Samochowiec
- Department of Psychiatry, Pomeranian Medical University, 71-460 Szczecin, Poland; (B.D.); (A.G.); (J.S.)
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25
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Kasznia J, Pytel A, Stańczykiewicz B, Samochowiec J, Preś J, Rachubińska K, Misiak B. Adverse Childhood Experiences and Neurocognition in Schizophrenia Spectrum Disorders: Age at First Exposure and Multiplicity Matter. Front Psychiatry 2021; 12:684099. [PMID: 34305680 PMCID: PMC8295342 DOI: 10.3389/fpsyt.2021.684099] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 06/08/2021] [Indexed: 12/14/2022] Open
Abstract
Adverse childhood experiences (ACEs) might be related to cognitive impairments observed in schizophrenia spectrum disorders (SSD). However, it remains unknown what aspects of ACEs are associated with cognitive impairments in SSD. Therefore, we aimed to investigate the association between various characteristics of ACEs (age at first exposure, severity, and multiplicity) and cognition in SSD and healthy controls (HCs). We enrolled 127 individuals with SSD and 56 HCs. Cognitive performance was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). The Childhood Experience of Care and Abuse Questionnaire was administered to record a history of ACEs. The following characteristics of ACEs were analyzed: multiplicity, severity, and age at first exposure. Individuals with SSD had significantly lower scores on all RBANS domains. Multiplicity and severity of ACEs were significantly higher in patients with SSD compared to HCs. In both groups, greater multiplicity of ACEs was associated with lower scores of global cognition and delayed memory. Additionally, in subjects with SSD, greater multiplicity and younger age at first exposure were associated with lower scores of attention. The present findings indicate that greater multiplicity and younger age at first exposure are the most important aspects of ACEs contributing to cognitive impairments observed in SSD. Moreover, ACEs might exert differential impact on cognition in SSD and HCs.
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Affiliation(s)
- Justyna Kasznia
- Inpatient Psychiatric Unit, Municipal General Hospital, Ostrów Wielkopolski, Poland
| | - Aleksandra Pytel
- Department of Nervous System Diseases, Wroclaw Medical University, Wroclaw, Poland
| | | | - Jerzy Samochowiec
- Department of Psychiatry, Pomeranian Medical University, Szczecin, Poland
| | - Joanna Preś
- Department of Psychiatry, Pomeranian Medical University, Szczecin, Poland
| | | | - Błażej Misiak
- Division of Consultation Psychiatry and Neuroscience, Department of Psychiatry, Wroclaw Medical University, Wroclaw, Poland
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Misiak B, Pruessner M, Samochowiec J, Wiśniewski M, Reginia A, Stańczykiewicz B. A meta-analysis of blood and salivary cortisol levels in first-episode psychosis and high-risk individuals. Front Neuroendocrinol 2021; 62:100930. [PMID: 34171354 DOI: 10.1016/j.yfrne.2021.100930] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Revised: 06/10/2021] [Accepted: 06/19/2021] [Indexed: 11/18/2022]
Abstract
Dysregulated cortisol responses and glucose metabolism have been reported in psychosis. We performed a random-effects meta-analysis of cortisol responses in first-episode psychosis (FEP) and psychosis risk states, taking into consideration glucose metabolism. A total of 47 studies were included. Unstimulated blood cortisol levels were significantly higher (g = 0.48, 95 %CI: 0.25-0.70, p < 0.001) in FEP, but not in psychosis risk states (g = 0.39, 95 %CI: -0.42-1.21, p = 0.342), compared to controls. Cortisol awakening response (CAR) was attenuated in FEP (g = -0.40, 95 %CI: -0.68 - -0.12, p = 0.006), but not in psychosis risk states (p = 0.433). Glucose and insulin levels were positively correlated with unstimulated blood cortisol levels in FEP. Our meta-analysis supports previous findings of elevated blood cortisol levels and attenuated CAR in FEP. Future research should focus on identifying the common denominators for alterations in stress hormones and glucose metabolism.
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Affiliation(s)
- Błażej Misiak
- Department of Psychiatry, Division of Consultation Psychiatry and Neuroscience, Wroclaw Medical University, Pasteura 10 Street, 50-367 Wroclaw, Poland.
| | - Marita Pruessner
- Prevention and Early Intervention Program for Psychosis, Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montreal, Canada; Department of Clinical Psychology, University of Konstanz, Konstanz, Germany
| | - Jerzy Samochowiec
- Department of Psychiatry, Pomeranian Medical University, Broniewskiego 26 Street, 71-457 Szczecin, Poland
| | | | - Artur Reginia
- Department of Psychiatry, Pomeranian Medical University, Broniewskiego 26 Street, 71-457 Szczecin, Poland
| | - Bartłomiej Stańczykiewicz
- Department of Nervous System Diseases, Wroclaw Medical University, Bartla 5 Street, 51-618 Wroclaw, Poland
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Ciobanu AM, Geza L, David IG, Popa DE, Buleandra M, Ciucu AA, Dehelean L. Actualities in immunological markers and electrochemical sensors for determination of dopamine and its metabolites in psychotic disorders (Review). Exp Ther Med 2021; 22:888. [PMID: 34194566 PMCID: PMC8237259 DOI: 10.3892/etm.2021.10320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 05/26/2021] [Indexed: 12/03/2022] Open
Abstract
Psychotic disorders represent a serious health concern. At this moment, anamnestic data, international criteria for diagnosis/classification from the Diagnostic and Statistical Manual of Mental Disorders-5 and the International Classification of Diseases-10 and diagnostic scales are used to establish a diagnosis. The most commonly used biomarkers in psychotic illnesses are those regarding the neuroimmune system, metabolic abnormalities, neurotrophins and neurotransmitter systems and proteomics. A current issue faced by clinicians is the lack of biomarkers to help develop a more accurate diagnosis, with the possibility of initiating the most effective treatment. The detection of biological markers for psychosis has the potential to contribute to improvements in its diagnosis, prognosis and treatment effectiveness. The mixture of multiple biomarkers may improve the ability to differentiate and classify these patients. In this sense, the aim of this study was to analyze the literature concerning the potential biomarkers that could be used in medical practice and to review the newest developments in electrochemical sensors used for dopamine detection, one of the most important exploited biomarkers.
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Affiliation(s)
- Adela Magdalena Ciobanu
- Department of Psychiatry, 'Prof. Dr. Alexandru Obregia' Clinical Psychiatric Hospital, 041914 Bucharest, Romania.,Discipline of Psychiatry, Neurosciences Department, 'Carol Davila' University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Luana Geza
- Department of Psychiatry, 'Prof. Dr. Alexandru Obregia' Clinical Psychiatric Hospital, 041914 Bucharest, Romania.,Discipline of Psychiatry, Neurosciences Department, 'Carol Davila' University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Iulia Gabriela David
- Department of Analytical Chemistry, Faculty of Chemistry, University of Bucharest, 050663 Bucharest, Romania
| | - Dana Elena Popa
- Department of Analytical Chemistry, Faculty of Chemistry, University of Bucharest, 050663 Bucharest, Romania
| | - Mihaela Buleandra
- Department of Analytical Chemistry, Faculty of Chemistry, University of Bucharest, 050663 Bucharest, Romania
| | - Anton Alexandru Ciucu
- Department of Analytical Chemistry, Faculty of Chemistry, University of Bucharest, 050663 Bucharest, Romania
| | - Liana Dehelean
- Department of Neurosciences-Psychiatry, Centre for Cognitive Research in Neuropsychiatric Pathology, 'Victor Babes' University of Medicine and Pharmacy of Timisoara, 300041 Timisoara, Romania
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The Impact of the FKBP5 Gene Polymorphisms on the Relationship between Traumatic Life Events and Psychotic-Like Experiences in Non-Clinical Adults. Brain Sci 2021; 11:brainsci11050561. [PMID: 33925151 PMCID: PMC8144983 DOI: 10.3390/brainsci11050561] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Accepted: 04/24/2021] [Indexed: 01/30/2023] Open
Abstract
Common variations of the FKBP5 gene are implicated in psychotic disorders, by modulating the hypothalamic–pituitary–adrenal axis reactivity to stress. It has been demonstrated that some of them might moderate the effects of childhood trauma on psychosis proneness. However, these associations have not been investigated with respect to traumatic life events (TLEs). Therefore, we aimed to explore whether the FKBP5 polymorphisms moderate the effects of TLEs on the level of psychotic-like experiences (PLEs). A total of 535 non-clinical adults were approached for participation, and genotyping of six FKBP5 polymorphisms (rs3800373, rs9470080, rs4713902, rs737054, rs1360780 and rs9296158) was performed. The Prodromal Questionnaire-16 (PQ-16) and the Traumatic Events Checklist (TEC) were administered to assess PLEs and TLEs, respectively. Among the rs1360780 CC homozygotes, a history of physical abuse was associated with significantly higher PQ-16 scores. This difference was not significant in the rs1360780 T allele carriers. Similarly, a history of physical abuse was associated with significantly higher PQ-16 scores in the rs9296158 GG homozygotes but not in the rs9296158 A allele carriers. Finally, emotional neglect was related to significantly higher PQ-16 scores in the rs737054 T allele carriers but not in the rs737054 CC homozygotes. The present study indicates that variation in the FKBP5 gene might moderate the effects of lifetime traumatic events on psychosis proneness.
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29
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Lis M, Stańczykiewicz B, Liśkiewicz P, Misiak B. Impaired hormonal regulation of appetite in schizophrenia: A narrative review dissecting intrinsic mechanisms and the effects of antipsychotics. Psychoneuroendocrinology 2020; 119:104744. [PMID: 32534330 DOI: 10.1016/j.psyneuen.2020.104744] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Revised: 05/25/2020] [Accepted: 05/30/2020] [Indexed: 12/14/2022]
Abstract
Cardiometabolic diseases are the main contributor of reduced life expectancy in patients with schizophrenia. It is now widely accepted that antipsychotic treatment plays an important role in the development of obesity and its consequences. However, some intrinsic mechanisms need to be taken into consideration. One of these mechanisms might be related to impaired hormonal regulation of appetite in this group of patients. In this narrative review, we aimed to dissect impairments of appetite-regulating hormones attributable to intrinsic mechanisms and those related to medication effects. Early hormonal alterations that might be associated with intrinsic mechanisms include low levels of leptin and glucagon-like peptide-1 (GLP-1) together with elevated insulin levels in first-episode psychosis (FEP) patients. However, evidence regarding low GLP-1 levels in FEP patients is based on one large study. In turn, multiple-episode schizophrenia patients show elevated levels of insulin, leptin and orexin A together with decreased levels of adiponectin. In addition, patients receiving olanzapine may present with low ghrelin levels. Post mortem studies have also demonstrated reduced number of neuropeptide Y neurons in the prefrontal cortex of patients with schizophrenia. Treatment with certain second-generation antipsychotics may also point to these alterations. Although our understanding of hormonal regulation of appetite in schizophrenia has largely been improved, several limitations and directions for future studies need to be addressed. This is of particular importance since several novel pharmacological interventions for obesity and diabetes have already been developed and translation of these developments to the treatment of cardiometabolic comorbidities in schizophrenia patients is needed.
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Affiliation(s)
- Michał Lis
- Clinical Department of Internal Diseases, Endocrinology and Diabetology, The Central Clinical Hospital of the Ministry of the Interior in Warsaw, Wołoska 137 Street, 02-507 Warsaw, Poland
| | - Bartłomiej Stańczykiewicz
- Department of Nervous System Diseases, Wroclaw Medical University, Bartla 5 Street, 51-618, Wroclaw, Poland
| | - Paweł Liśkiewicz
- Department of Psychiatry, Pomeranian Medical University, Broniewskiego 26 Street, 71-460, Szczecin, Poland
| | - Błażej Misiak
- Department of Genetics, Wroclaw Medical University, Marcinkowskiego 1 Street, 50-368 Wroclaw, Poland.
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30
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Jackson AJ, Miller BJ. Meta-analysis of total and differential white blood cell counts in schizophrenia. Acta Psychiatr Scand 2020; 142:18-26. [PMID: 31850530 DOI: 10.1111/acps.13140] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/08/2019] [Indexed: 12/18/2022]
Abstract
OBJECTIVE Schizophrenia is associated with alterations in blood inflammatory markers, including cytokines. Total white blood cell (WBC) count is a marker of low-grade inflammation. We conducted a meta-analysis of total and differential WBC counts in patients with schizophrenia. METHOD Articles were identified through a systematic search of PsycINFO, Pub Med, Web of Science, and the associated references. Data were analyzed using a random effects approach. RESULTS Twenty-four studies met the inclusion criteria. Blood total WBC, monocytes, and neutrophils were significantly higher in schizophrenia vs. controls with small-to-medium effect sizes (standardized mean difference [SMD] = 0.39-0.53, P < 0.01 for each). In first-episode psychosis compared with controls, neutrophils and monocytes were significantly increased with similar effect sizes (SMD = 0.40-0.41, P ≤ 0.01 for each), and there was a trend for higher total WBC (SMD = 0.46, P = 0.05). CONCLUSIONS Consistent with studies of other inflammatory markers, we found evidence for increased total and differential WBC counts in schizophrenia. Our results complement other studies of WBC counts in schizophrenia. These findings are relevant to the pathophysiology and potentially the treatment of schizophrenia.
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Affiliation(s)
| | - Brian J Miller
- Department of Psychiatry, Augusta University, Augusta, GA, USA
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31
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Cullen AE, Addington J, Bearden CE, Stone WS, Seidman LJ, Cadenhead KS, Cannon TD, Cornblatt BA, Mathalon DH, McGlashan TH, Perkins DO, Tsuang MT, Woods SW, Walker EF. Stressor-Cortisol Concordance Among Individuals at Clinical High-Risk for Psychosis: Novel Findings from the NAPLS Cohort. Psychoneuroendocrinology 2020; 115:104649. [PMID: 32197198 PMCID: PMC7193890 DOI: 10.1016/j.psyneuen.2020.104649] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Revised: 02/19/2020] [Accepted: 03/04/2020] [Indexed: 01/02/2023]
Abstract
Whilst elevations in basal cortisol levels have been reported among individuals at-risk for psychosis, the extent to which this represents hyperresponsivity of the hypothalamic-pituitary-adrenal (HPA) axis to psychosocial stressors encountered in the natural environment is currently unclear. We aimed to examine stressor-cortisol concordance among youth at clinical high-risk (CHR) for psychosis in the North American Prodrome Longitudinal Study 2 (NAPLS 2) and the relationship with clinical outcome. At baseline, CHR (N = 457) and healthy (N = 205) individuals provided salivary cortisol samples and completed daily stressor, life event, and childhood trauma measures. CHR youth were categorised as remitted, symptomatic, progression of positive symptoms, or psychosis conversion at the two-year follow-up. Within-group regression models tested associations between psychosocial stressors and cortisol; standardised beta coefficients (Stβ) were subsequently derived to enable within-group pooling of effect sizes across stressor types. After adjustment for potential confounders, all CHR subgroups reported greater exposure to life events and daily stressors, and more distress in relation to these events, relative to controls. All CHR groups were also more likely to experience childhood trauma; only CHR converters, however, were characterised by elevated basal cortisol. Daily stressor distress was significantly associated with cortisol in controls (β = 0.60, 95% CI: 0.12-1.08) and CHR youth who converted to psychosis (β = 0.91, 95% CI: 0.05-1.78). In controls only, life event exposure was associated with cortisol (β = 0.45, 95% CI: 0.08-0.83). When pooled across stressors, stressor-cortisol concordance was substantially higher among CHR converters (Stβ = 0.26, 95% CI: 0.07 to 0.44) relative to CHR progressed (Stβ = 0.02, 95% CI: -0.11 to 0.15), symptomatic (Stβ = 0.01, 95% CI: -0.11 to 0.12), and remitted groups (Stβ = 0.00, 95% CI: -0.13 to 0.13); however, unexpectedly, healthy controls showed intermediate levels of concordance (Stβ = 0.15, 95% CI: 0.05 to 0.26). In conclusion, whilst all CHR subgroups showed increased psychosocial stress exposure and distress relative to controls, only those who later converted to psychosis were characterised by significantly elevated basal cortisol levels. Moreover, only CHR converters showed a higher magnitude of stressor-cortisol concordance compared to controls, although confidence intervals overlapped considerably between these two groups. These findings do not support the notion that all individuals at CHR for psychosis show HPA hyperresponsiveness to psychosocial stressors. Instead, CHR individuals vary in their response to stressor exposure/distress, perhaps driven by genetic or other vulnerability factors.
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Affiliation(s)
- Alexis E. Cullen
- Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, United Kingdom,Corresponding author at: Institute of Psychiatry, Psychology & Neuroscience (PO67), 16 De Crespigny Park, Denmark Hill, London, SE5 8AF, United Kingdom.
| | - Jean Addington
- Department of Psychiatry, University of Calgary, Calgary, Alberta, Canada
| | - Carrie E. Bearden
- Department of Psychiatry and Behavioural Sciences and Psychology, UCLA, Los Angeles, United States
| | - William S. Stone
- Harvard Medical School, Departments of Psychiatry at Massachusetts Mental Health Center Public Psychiatry Division, Beth Israel Deaconess Medical Center, Massachusetts, General Hospital, Boston, MA, United States
| | - Larry J. Seidman
- Harvard Medical School, Departments of Psychiatry at Massachusetts Mental Health Center Public Psychiatry Division, Beth Israel Deaconess Medical Center, Massachusetts, General Hospital, Boston, MA, United States
| | - Kristin S. Cadenhead
- Department of Psychiatry, University of California, San Diego, CA, United States
| | - Tyrone D. Cannon
- Department of Psychiatry, Yale University, New Haven, Connecticut, United States
| | - Barbara A. Cornblatt
- Department of Psychiatry, Zucker Hillside Hospital, Long Island, NY, United States
| | - Daniel H. Mathalon
- Department of Psychiatry, University of California, San Francisco Veterans Affairs Medical Center, San Francisco, CA, United States
| | | | - Diana O. Perkins
- Department of Psychiatry, University of North Carolina, Chapel Hill, NC, United States
| | - Ming T. Tsuang
- Department of Psychiatry, University of California, San Diego, CA, United States
| | - Scott W. Woods
- Department of Psychiatry, Yale University, New Haven, CT, United States
| | - Elaine F. Walker
- Department of Psychology, Emory University, Atlanta, GA, United States,Department of Psychiatry, Emory University, Atlanta, GA, United States,Corresponding author at: 487 PAIS Building, 36 Eagle Row, Emory University, Atlanta, GA, 30322, United States.
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32
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Noiriel A, Verneuil L, Osmond I, Manolios E, Revah-Levy A, Sibeoni J. The Lived Experience of First-Episode Psychosis: A Systematic Review and Metasynthesis of Qualitative Studies. Psychopathology 2020; 53:223-238. [PMID: 33120385 DOI: 10.1159/000510865] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Accepted: 08/11/2020] [Indexed: 11/19/2022]
Abstract
Both research and care have focused on first episodes of psychosis (FEPs) as a way to address the issue of early stages of schizophrenia and to reduce the duration of untreated psychosis. The objective of this study was to explore specifically the lived experience of FEP from the point of view of patients and their families by applying a metasynthetic approach, including a systematic review of the literature and analyses of qualitative studies on the subject. This metasynthesis follows thematic synthesis procedures. Four databases were systematically searched for qualitative studies reporting FEP from the patient or family's perspective. Article quality was assessed with the Critical Appraisal Skills Program. Thematic analysis was used to identify key themes and synthesize them. Thirty-eight articles were included, covering data from 554 participants (378 patients and 176 relatives). Three themes emerged from the analyses: (1) When and how does a FEP start? (2) What are its negative and positive aspects? (3) How do patients and families recount FEPs? Our results found important discrepancies between the experiences of patients and those of their families, especially regarding positive aspects. In light of the confusion reported by patients and notable in our results, we also discuss the gap between the name, FEP, and the lived experience of patients and family members in order to explore its practical implications.
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Affiliation(s)
| | | | - Ingrid Osmond
- Service Universitaire de Psychiatrie de l'Adolescent, Argenteuil Hospital Centre, Argenteuil, France
| | - Emilie Manolios
- ECSTRA Team, UMR-1153, Inserm, Université de Paris, Paris, France.,Service de Psychologie et Psychiatrie de Liaison et d'Urgences, Hôpital Européen Georges Pompidou AP-HP, Hôpitaux Universitaires Paris Ouest, Paris, France
| | - Anne Revah-Levy
- ECSTRA Team, UMR-1153, Inserm, Université de Paris, Paris, France.,Service Universitaire de Psychiatrie de l'Adolescent, Argenteuil Hospital Centre, Argenteuil, France
| | - Jordan Sibeoni
- ECSTRA Team, UMR-1153, Inserm, Université de Paris, Paris, France, .,Service Universitaire de Psychiatrie de l'Adolescent, Argenteuil Hospital Centre, Argenteuil, France,
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Boiko AS, Mednova IA, Kornetova EG, Bokhan NA, Semke AV, Loonen AJM, Ivanova SA. Cortisol and DHEAS Related to Metabolic Syndrome in Patients with Schizophrenia. Neuropsychiatr Dis Treat 2020; 16:1051-1058. [PMID: 32368067 PMCID: PMC7184116 DOI: 10.2147/ndt.s247161] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Accepted: 03/28/2020] [Indexed: 02/01/2023] Open
Abstract
BACKGROUND Both dehydroepiandrosterone (DHEAS) and cortisol are secreted by the adrenal glands and may modulate metabolic syndrome (MetS), which often affects the health of patients with schizophrenia. The relationship between the serum levels of these hormones and MetS has not been established. PURPOSE In this pilot study, we investigated the serum levels in schizophrenia patients with and without MetS and compared them with those in healthy volunteers. PATIENTS AND METHODS After obtaining informed consent, 110 patients with acute paranoid schizophrenia were recruited directly after admission to the Mental Health Research Institute. The control group consisted of 51 persons reported on questioning to be mentally and somatically healthy. Blood samples to prepare serum were drawn after an 8-h overnight fast during one of the first days of admission. Serum cortisol and DHEAS concentrations were quantified by enzyme-linked immunosorbent assay. RESULTS A total of 42 patients had MetS and 68 patients were without MetS. The cortisol blood level was significantly (p = 0.012) higher in schizophrenia patients without MetS in comparison to healthy controls, while patients with schizophrenia and a MetS have significantly (p = 0.014) lower DHEAS levels than healthy volunteers. These differences could, however, exclusively be attributed to female participants. Analysis of covariance adjusted for gender and age demonstrated a significant relationship between age and DHEAS levels (F = 9.512, р = 0.003). CONCLUSION Lower DHEAS serum levels in relationship to MetS become evident in women, but not in men, and have age differences as a confounding factor.
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Affiliation(s)
- Anastasiia S Boiko
- Mental Health Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, Tomsk, Russian Federation
| | - Irina A Mednova
- Mental Health Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, Tomsk, Russian Federation
| | - Elena G Kornetova
- Mental Health Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, Tomsk, Russian Federation.,Hospital, Siberian State Medical University, Tomsk, Russian Federation
| | - Nikolay A Bokhan
- Mental Health Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, Tomsk, Russian Federation.,Psychiatry, Addictology and Psychotherapy, Siberian State Medical University, Russian Federation
| | - Arkadiy V Semke
- Mental Health Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, Tomsk, Russian Federation
| | - Anton J M Loonen
- PharmacoTherapy, -Epidemiology and -Economics, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands
| | - Svetlana A Ivanova
- Mental Health Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, Tomsk, Russian Federation.,Psychiatry, Addictology and Psychotherapy, Siberian State Medical University, Russian Federation
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Cullen AE, Rai S, Vaghani MS, Mondelli V, McGuire P. Cortisol Responses to Naturally Occurring Psychosocial Stressors Across the Psychosis Spectrum: A Systematic Review and Meta-Analysis. Front Psychiatry 2020; 11:513. [PMID: 32595532 PMCID: PMC7300294 DOI: 10.3389/fpsyt.2020.00513] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 05/19/2020] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Individuals with established psychosis and those at high-risk for the disorder have been found to show abnormalities within the hypothalamic-pituitary-adrenal (HPA) axis, including elevations in basal and diurnal cortisol, but a blunted cortisol awakening response. However, the extent to which these features are associated with psychosocial stressors encountered in the natural environment (which are known to be more commonly experienced by these groups, and more distressing) is currently unclear. We therefore conducted a systematic review and meta-analysis to investigate the concordance between naturally-occurring psychosocial stressors and cortisol levels in these populations. METHODS PubMed, PsycINFO, and EMBASE were searched up to November 2019 to identify studies examining the concordance between psychosocial stressors and cortisol in healthy controls and individuals on the psychosis spectrum (patients with established psychosis and/or high-risk individuals). An overall meta-analysis (including data for all stressor-cortisol pairings) was performed to determine the degree of concordance irrespective of group status, with meta-regression employed to test whether the degree of concordance differed in established psychosis and high-risk groups compared to controls. Planned stratified analyses were then performed to examine group differences (where established psychosis and high-risk groups were combined) within individual stressor-cortisol pairings. RESULTS Eighteen studies (16 datasets) were eligible for inclusion. The overall model, comprising 134 effect sizes, showed that stressors and cortisol measures were only weakly correlated [r=0.05 (95% CI: -0.00 to 0.10), p=0.059] and that neither established psychosis status (r=0.01, p=0.838) nor high-risk status (r=0.02, p=0.477) had a significant effect of the strength of correlation. In stratified analyses, significant differences between healthy controls and psychosis spectrum groups were observed for only one of the six stressor-cortisol pairings examined, where life event exposure and diurnal cortisol were positively correlated in controls [r=0.25 (95% CI: 0.01 to 0.46)], but negatively correlated in the psychosis spectrum group [r=-0.28 (95% CI: -0.49 to -0.04)]. CONCLUSIONS Overall, we observed poor concordance between naturally-occurring psychosocial stressors and cortisol irrespective of stressor type, cortisol measure, or group status. We consider a range of methodological factors that may have obscured the ability to detect "true" associations and provide recommendations for future studies in this field.
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Affiliation(s)
- Alexis E Cullen
- Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom
| | - Sushma Rai
- Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom
| | - Meghna S Vaghani
- Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom
| | - Valeria Mondelli
- Department of Psychological Medicine, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom.,NIHR Biomedical Research Centre, South London and Maudsley NHS Foundation Trust, London, United Kingdom
| | - Philip McGuire
- Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom.,NIHR Biomedical Research Centre, South London and Maudsley NHS Foundation Trust, London, United Kingdom
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