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Minichino A, Davies C, Karpenko O, Christodoulou N, Ramalho R, Nandha S, Damiani S, Provenzani U, Esposito CM, Mensi MM, Borgatti R, Stefana A, McGuire P, Fusar-Poli P. Preventing psychosis in people at clinical high risk: an updated meta-analysis by the World Psychiatric Association Preventive Psychiatry section. Mol Psychiatry 2025:10.1038/s41380-025-02902-8. [PMID: 39953286 DOI: 10.1038/s41380-025-02902-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 09/19/2024] [Accepted: 01/17/2025] [Indexed: 02/17/2025]
Abstract
Recently published large-scale randomised controlled trials (RCTs) have questioned the efficacy of preventive interventions in individuals at clinical high risk for psychosis (CHR-P). We conducted a systematic review and meta-analysis to include this new evidence and provide future directions for the field. We followed the PRISMA guidelines and a pre-registered protocol, with a literature search conducted from inception to November 2023. We included RCTs that collected data on psychosis transition (the primary outcome) in CHR-P. Secondary outcomes were symptoms severity and functioning. Investigated time points were 6,12,24,36, and +36 months. We used odd ratios (ORs) and standardised mean differences (SMD) as summary outcomes. Heterogeneity was estimated with the Higgins I2. Twenty-four RCTs, involving 3236 CHR-P individuals, were included. Active interventions were Cognitive Behavioural Therapy (CBT), family-focused therapy, Integrated Psychological Therapy, antipsychotics, omega-3 fatty acids, CBT plus risperidone, minocycline, and other non-pharmacological approaches (cognitive remediation, sleep-targeted therapy, brain stimulation). Results showed no evidence that any of the investigated active interventions had a sustained and robust effect on any of the investigated outcomes in CHR-P, when compared to control interventions, including CBT on transition to psychosis at 12 months (9 RCTs; OR: 0.64; 95% CI: 0.39-1.06; I2: 21%; P = 0.08). These results highlight the need for novel treatment approaches in CHR-P. Future studies should consider the heterogeneity of this clinical population and prioritise stratification strategies and bespoke treatments.
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Affiliation(s)
| | - Cathy Davies
- EPIC Lab, Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
| | - Olga Karpenko
- Mental-health Clinic No. 1 named after N.A. Alexeev, Moscow, Russia
| | - Nikos Christodoulou
- Department of Psychiatry, Faculty of Medicine, University of Thessaly, Larisa, Greece
| | - Rodrigo Ramalho
- Department of Social and Community Health, School of Population Health, University of Auckland, Auckland, New Zealand
| | - Sunil Nandha
- Outreach And Support in South London (OASIS) Service, South London & Maudsley NHS Foundation Trust, London, UK
| | - Stefano Damiani
- Dipartimento di Scienze del Sistema Nervoso e del Comportamento, Università di Pavia, Pavia, Italy
| | - Umberto Provenzani
- Dipartimento di Scienze del Sistema Nervoso e del Comportamento, Università di Pavia, Pavia, Italy
| | - Cecilia Maria Esposito
- Dipartimento di Scienze del Sistema Nervoso e del Comportamento, Università di Pavia, Pavia, Italy
| | - Martina Maria Mensi
- Dipartimento di Scienze del Sistema Nervoso e del Comportamento, Università di Pavia, Pavia, Italy
- Child and Adolescent Neuropsichiatry Unit, IRCCS F. Mondino, Pavia, Italia
| | - Renato Borgatti
- Dipartimento di Scienze del Sistema Nervoso e del Comportamento, Università di Pavia, Pavia, Italy
- Child and Adolescent Neuropsichiatry Unit, IRCCS F. Mondino, Pavia, Italia
| | - Alberto Stefana
- Dipartimento di Scienze del Sistema Nervoso e del Comportamento, Università di Pavia, Pavia, Italy
| | - Philip McGuire
- Department of Psychiatry, University of Oxford, Oxford, UK
| | - Paolo Fusar-Poli
- EPIC Lab, Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
- Outreach And Support in South London (OASIS) Service, South London & Maudsley NHS Foundation Trust, London, UK.
- Dipartimento di Scienze del Sistema Nervoso e del Comportamento, Università di Pavia, Pavia, Italy.
- Department of Psychiatry and Psychotherapy, University Hospital, Ludwig-Maximilian-University (LMU), Munich, Germany.
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Rossier AT, Hallahan B. The therapeutic effect of omega-3 polyunsaturated fatty acids on symptom severity of psychosis: A systematic review and meta-analysis. Eur Psychiatry 2024; 67:e88. [PMID: 39697115 PMCID: PMC11733620 DOI: 10.1192/j.eurpsy.2024.1804] [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: 07/19/2024] [Revised: 11/10/2024] [Accepted: 11/16/2024] [Indexed: 12/20/2024] Open
Abstract
BACKGROUND While omega-3 polyunsaturated fatty acids (PUFAs) have shown promise as an adjunctive treatment for schizophrenia and other psychotic disorders, the overall consensus about their efficacy across studies is still lacking and findings to date are inconclusive. No clinical trials or systematic reviews have yet examined if omega-3 PUFAs are associated with differential levels of efficacy at various stages of psychosis. METHOD A systematic bibliographic search of randomized double-blind placebo-controlled trials (RCTs) examining the effect of omega-3 PUFAs as a monotherapy or adjunctive therapy versus a control group in adults and children at ultra-high risk (UHR) for psychosis, experiencing a first-episode psychosis (FEP), or diagnosed with an established psychotic disorder was conducted. Participants' clinical symptoms were evaluated using total and subscale scores on validated psychometric scales. RESULTS No beneficial effect of omega-3 PUFAs treatment was found in comparison with that of placebo (G = -0.26, 95% CI -0.55 to 0.03, p = 0.08). Treatment of omega-3 PUFAs did not prove any significant improvement in psychopathology in UHR (G = -0.09, 95% CI -0.45 to 0.27, p = 0.63), FEP (G = -1.20, 95% CI -5.63 to 3.22, p = 0.59), or schizophrenia patients (G = -0.17, 95% CI -0.38 to -0.03, p = 0.10). CONCLUSION These findings confirm previous evidence that disputes the original reported findings of the beneficial effect of omega-3 PUFAs in schizophrenia. Furthermore, accumulative evidence of the use of omega-3 as a preventive treatment option in UHR is not supported, suggesting that the need for future studies in this line of research should not be promoted.
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Affiliation(s)
- Alison T. Rossier
- Department of Pharmacology and Therapeutics, College of Medicine, Nursing and Health Sciences, University of Galway, Galway, Ireland
| | - Brian Hallahan
- Department of Psychiatry, College of Medicine, Nursing and Health Sciences, University of Galway, Galway, Ireland
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Rarinca V, Vasile A, Visternicu M, Burlui V, Halitchi G, Ciobica A, Singeap AM, Dobrin R, Burlui E, Maftei L, Trifan A. Relevance of diet in schizophrenia: a review focusing on prenatal nutritional deficiency, obesity, oxidative stress and inflammation. Front Nutr 2024; 11:1497569. [PMID: 39734678 PMCID: PMC11673491 DOI: 10.3389/fnut.2024.1497569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Accepted: 11/29/2024] [Indexed: 12/31/2024] Open
Abstract
BACKGROUND/OBJECTIVES Schizophrenia is a complex mental disorder influenced by genetic and environmental factors, including dietary habits. Oxidative stress and inflammation play a crucial role in the pathophysiology of schizophrenia. Emerging research suggests that diet may affect schizophrenia through different biological mechanisms beyond oxidative stress and inflammation. In particular, epigenetic changes may alter the expression of genes related to neurodevelopment and neurotransmitter systems, while neuroplasticity plays a crucial role in brain adaptation and resilience to psychiatric disorders. METHODS The literature search included the main available databases (Science Direct, PubMed and Google Scholar), considering the English language, and our screening was performed based on several words such as "schizophrenia", "diet", "nutrients", "obesity", "oxidative stress", "inflammation", "antioxidants" and "prenatal nutritional deficiency". The review focused specifically on studies examining the relevance of diet in schizophrenia, as well as prenatal nutritional deficiency, obesity, oxidative stress, and inflammation associated with this disorder. RESULTS Following a review of the literature, it was found that nutritional deficiencies, including lack of omega-3 fatty acids, vitamins D, and B, during the prenatal and postnatal periods can have a negative impact on neurodevelopment and increase the risk of schizophrenia. Patients with schizophrenia have imbalances in antioxidant enzymes, such as glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase (CAT), and reduced levels of antioxidants (vitamin E, vitamin C). These biochemical changes lead to an increase in markers of oxidative stress, including malondialdehyde (MDA). In addition, cytokine-mediated inflammation, microglial activation, and intestinal dysbiosis are associated with the onset of schizophrenia and the severity of schizophrenia symptoms. Currently, there is no universally accepted dietary regimen for control. However, various diets and nutritional methods are being researched and applied to alleviate the symptoms of schizophrenia and improve the overall health of patients, including the Mediterranean diet, the ketogenic diet, the gluten-free diet, and the DASH (Dietary Approaches to Stop Hypertension) diet. CONCLUSION A healthy diet, rich in anti-inflammatory nutrients and antioxidants, may help manage schizophrenia by reducing oxidative stress, preventing complications, and improving quality of life. Omega-3 fatty acids, vitamin D, and B vitamins are particularly important for brain development and function. In this review, we aim to analyze the literature on the influence of diet on schizophrenia, focusing on the role of prenatal nutritional deficiencies, obesity, oxidative stress, and inflammation.
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Affiliation(s)
- Viorica Rarinca
- Doctoral School of Geosciences, Faculty of Geography and Geology, Alexandru Ioan Cuza University of Iasi, Iași, Romania
- Doctoral School of Biology, Faculty of Biology, Alexandru Ioan Cuza University of Iași, Iași, Romania
- Preclinical Department, Apollonia University, Iași, Romania
| | - Amalia Vasile
- Faculty of Biology, “Alexandru Ioan Cuza” University of Iași, Iași, Romania
| | - Malina Visternicu
- Doctoral School of Biology, Faculty of Biology, Alexandru Ioan Cuza University of Iași, Iași, Romania
- Preclinical Department, Apollonia University, Iași, Romania
| | - Vasile Burlui
- Preclinical Department, Apollonia University, Iași, Romania
| | | | - Alin Ciobica
- Preclinical Department, Apollonia University, Iași, Romania
- Faculty of Biology, “Alexandru Ioan Cuza” University of Iași, Iași, Romania
- CENEMED Platform for Interdisciplinary Research, “Grigore T. Popa” University of Medicine and Pharmacy of Iasi, Iași, Romania
- Romanian Academy of Scientists, Bucharest, Romania
| | - Ana-Maria Singeap
- Department of Gastroenterology, “Grigore T. Popa” University of Medicine and Pharmacy, Iași, Romania
- Institute of Gastroenterology and Hepatology, “Sf. Spiridon”, Iași, Romania
| | - Romeo Dobrin
- “Socola” Psychiatric Institute, Iași, Romania
- “Grigore T. Popa” University of Medicine and Pharmacy, Iași, Romania
| | | | - Lucian Maftei
- SC MAKEUP SHOP SRL – Cosmetics Product Development Department, Iași, Romania
| | - Anca Trifan
- Department of Gastroenterology, “Grigore T. Popa” University of Medicine and Pharmacy, Iași, Romania
- Institute of Gastroenterology and Hepatology, “Sf. Spiridon”, Iași, Romania
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He Y, Zhao L, Chen X. Tracing the Trajectory: Polyunsaturated Fatty Acids and Early Adult Psychosis. Biol Psychiatry 2024; 96:768. [PMID: 39415394 DOI: 10.1016/j.biopsych.2024.08.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Accepted: 08/16/2024] [Indexed: 10/18/2024]
Affiliation(s)
- Ying He
- Department of Psychiatry, National Clinical Research Center for Mental Disorders, National Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Hunan, China
| | - Linlin Zhao
- Department of Psychiatry, National Clinical Research Center for Mental Disorders, National Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Hunan, China
| | - Xiaogang Chen
- Department of Psychiatry, National Clinical Research Center for Mental Disorders, National Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Hunan, China.
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Ni P, Ma Y, Chung S. Mitochondrial dysfunction in psychiatric disorders. Schizophr Res 2024; 273:62-77. [PMID: 36175250 DOI: 10.1016/j.schres.2022.08.027] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Revised: 08/25/2022] [Accepted: 08/30/2022] [Indexed: 11/30/2022]
Abstract
Psychiatric disorders are a heterogeneous group of mental disorders with abnormal mental or behavioral patterns, which severely distress or disable affected individuals and can have a grave socioeconomic burden. Growing evidence indicates that mitochondrial function plays an important role in developing psychiatric disorders. This review discusses the neuropsychiatric consequences of mitochondrial abnormalities in both animal models and patients. We also discuss recent studies associated with compromised mitochondrial function in various psychiatric disorders, such as schizophrenia (SCZ), major depressive disorder (MD), and bipolar disorders (BD). These studies employ various approaches including postmortem studies, imaging studies, genetic studies, and induced pluripotent stem cells (iPSCs) studies. We also summarize the evidence from animal models and clinical trials to support mitochondrial function as a potential therapeutic target to treat various psychiatric disorders. This review will contribute to furthering our understanding of the metabolic etiology of various psychiatric disorders, and help guide the development of optimal therapies.
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Affiliation(s)
- Peiyan Ni
- The Psychiatric Laboratory and Mental Health Center, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China.
| | - Yao Ma
- The Psychiatric Laboratory and Mental Health Center, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China
| | - Sangmi Chung
- Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY 10595, USA.
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6
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Slot MIE, Urquijo Castro MF, Winter-van Rossum I, van Hell HH, Dwyer D, Dazzan P, Maat A, De Haan L, Crespo-Facorro B, Glenthøj BY, Lawrie SM, McDonald C, Gruber O, van Amelsvoort T, Arango C, Kircher T, Nelson B, Galderisi S, Weiser M, Sachs G, Kirschner M, Fleischhacker WW, McGuire P, Koutsouleris N, Kahn RS. Multivariable prediction of functional outcome after first-episode psychosis: a crossover validation approach in EUFEST and PSYSCAN. SCHIZOPHRENIA (HEIDELBERG, GERMANY) 2024; 10:89. [PMID: 39375356 PMCID: PMC11458815 DOI: 10.1038/s41537-024-00505-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Accepted: 09/04/2024] [Indexed: 10/09/2024]
Abstract
Several multivariate prognostic models have been published to predict outcomes in patients with first episode psychosis (FEP), but it remains unclear whether those predictions generalize to independent populations. Using a subset of demographic and clinical baseline predictors, we aimed to develop and externally validate different models predicting functional outcome after a FEP in the context of a schizophrenia-spectrum disorder (FES), based on a previously published cross-validation and machine learning pipeline. A crossover validation approach was adopted in two large, international cohorts (EUFEST, n = 338, and the PSYSCAN FES cohort, n = 226). Scores on the Global Assessment of Functioning scale (GAF) at 12 month follow-up were dichotomized to differentiate between poor (GAF current < 65) and good outcome (GAF current ≥ 65). Pooled non-linear support vector machine (SVM) classifiers trained on the separate cohorts identified patients with a poor outcome with cross-validated balanced accuracies (BAC) of 65-66%, but BAC dropped substantially when the models were applied to patients from a different FES cohort (BAC = 50-56%). A leave-site-out analysis on the merged sample yielded better performance (BAC = 72%), highlighting the effect of combining data from different study designs to overcome calibration issues and improve model transportability. In conclusion, our results indicate that validation of prediction models in an independent sample is essential in assessing the true value of the model. Future external validation studies, as well as attempts to harmonize data collection across studies, are recommended.
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Grants
- 603196 EC | EC Seventh Framework Programm | FP7 Health (FP7-HEALTH - Specific Programme "Cooperation": Health)
- 603196 EC | EC Seventh Framework Programm | FP7 Health (FP7-HEALTH - Specific Programme "Cooperation": Health)
- Professor Birte Y. Glenthøj has been the leader of a Lundbeck Foundation Centre of Excellence for Clinical Intervention and Neuropsychiatric Schizophrenia Research (CINS) (January 2009 – December 2021), which was partially financed by an independent grant from the Lundbeck Foundation based on international review and partially financed by the Mental Health Services in the Capital Region of Denmark, the University of Copenhagen, and other foundations. All grants are the property of the Mental Health Services in the Capital Region of Denmark and administrated by them.
- Professor Silvana Galderisi received advisory board/consultant fees from the following drug companies: Angelini, Boehringer Ingelheim Italia, Gedeon Richter-Recordati, Janssen Pharmaceutica NV and ROVI. SG received honoraria/expenses from the following drug companies: Angelini, Gedeon Richter-Recordati, Janssen Australia and New Zealand, Janssen Pharmaceutica NV, Janssen-Cilag, Lundbeck A/S, Lundbeck Italia, Otsuka, Recordati Pharmaceuticals, ROVI, Sunovion Pharmaceuticals.
- EUFEST was funded by the European Group for Research in Schizophrenia (EGRIS) with grants from AstraZeneca, Pfizer and Sanofi Aventis. Professor Wolfgang Fleischhacker has received grants from Lundbeck and Otsuka and lecture honoraria from Sumitomo-Pharma and Forum Medizinische Fortbildung.
- Professor Nikolaos Koutsouleris received honoraria for talks presented at education meetings organized by Otsuka/Lundbeck.
- EUFEST was funded by the European Group for Research in Schizophrenia (EGRIS) with grants from AstraZeneca, Pfizer and Sanofi Aventis.
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Affiliation(s)
- Margot I E Slot
- Department of Psychiatry, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, The Netherlands.
| | - Maria F Urquijo Castro
- Department of Psychiatry and Psychotherapy, Ludwig-Maximilian-University, Munich, Germany
| | - Inge Winter-van Rossum
- Department of Psychiatry, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, The Netherlands
- Department of Psychiatry, Icahn School of Medicine, Mount Sinai, New York, USA
- Department of Psychiatry, University of Oxford, Oxford, UK
| | - Hendrika H van Hell
- Department of Psychiatry, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Dominic Dwyer
- Centre for Youth Mental Health, University of Melbourne, Melbourne, VIC, Australia
- Orygen, Melbourne, VIC, Australia
| | - Paola Dazzan
- Department of Psychological Medicine, Institute of Psychiatry, Psychology & Neuroscience, King's College London, De Crespigny Park, Denmark 458 Hill, SE5 8AF, London, UK
| | - Arija Maat
- Department of Psychiatry, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Lieuwe De Haan
- Amsterdam UMC, University of Amsterdam, Psychiatry, Department Early Psychosis, Meibergdreef 9, Amsterdam, The Netherlands
| | - Benedicto Crespo-Facorro
- Department of Psychiatry, Marqués de Valdecilla University Hospital, IDIVAL. School of Medicine, University of Cantabria, Santander, Spain
- CIBERSAM, Centro Investigación Biomédica en Red Salud Mental, Madrid, Spain
| | - Birte Y Glenthøj
- Centre for Neuropsychiatric Schizophrenia Research (CNSR) & Centre for Clinical Intervention and Neuropsychiatric Schizophrenia Research (CINS), Mental Health Centre Glostrup, Glostrup, Denmark
- University of Copenhagen, Faculty of Health and Medical Sciences, Department of Clinical Medicine, Copenhagen, Denmark
| | - Stephen M Lawrie
- Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, EH10 5HF, UK
| | - Colm McDonald
- Centre for Neuroimaging & Cognitive Genomics (NICOG), NCBES Galway Neuroscience Centre, National University of Ireland Galway, H91 TK33, Galway, Ireland
| | - Oliver Gruber
- Section for Experimental Psychopathology and Neuroimaging, Department of General Psychiatry, Heidelberg University, Heidelberg, Germany
| | - Thérèse van Amelsvoort
- Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, The Netherlands
| | - Celso Arango
- Department of Child and Adolescent Psychiatry, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón, IiSGM, CIBERSAM, ISCIII, School of Medicine, Universidad Complutense, Madrid, Spain
| | - Tilo Kircher
- Department of Psychiatry, University of Marburg, Rudolf-Bultmann-Straße 8, D-35039, Marburg, Germany
| | - Barnaby Nelson
- Centre for Youth Mental Health, University of Melbourne, Melbourne, VIC, Australia
- Orygen, Melbourne, VIC, Australia
| | - Silvana Galderisi
- Department of Mental and Physical Health and Preventive Medicine, University of Campania Luigi Vanvitelli, Largo Madonna delle Grazie, 80138, Naples, Italy
| | - Mark Weiser
- Zachai Department of Psychiatry, Sheba Medical Center, Tel Hashomer, 52621, Israel
- Tel Aviv University School of Medicine, Ramat Aviv, Israel
| | - Gabriele Sachs
- Department of Psychiatry and Psychotherapy, 1090, Vienna, Austria
| | - Matthias Kirschner
- Division of Adult Psychiatry, Department of Psychiatry, University Hospitals of Geneva, Geneva, Switzerland
- Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Zurich, Switzerland
| | | | - Philip McGuire
- Department of Psychiatry, University of Oxford, Oxford, UK
| | - Nikolaos Koutsouleris
- Department of Psychiatry and Psychotherapy, Ludwig-Maximilian-University, Munich, Germany
- Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, De Crespigny Park, Denmark 458 Hill, London, SE5 8AF, UK
- Max Planck Institute of Psychiatry, Munich, Germany
| | - René S Kahn
- Department of Psychiatry, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, The Netherlands.
- Department of Psychiatry, Icahn School of Medicine, Mount Sinai, New York, USA.
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Raine A, Gur RC, Gur RE, Richmond TS, Hibbeln J, Liu J. Omega-3 Supplementation Reduces Schizotypal Personality in Children: A Randomized Controlled Trial. Schizophr Bull 2024; 50:1117-1126. [PMID: 38300759 PMCID: PMC11349019 DOI: 10.1093/schbul/sbae009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2024]
Abstract
BACKGROUND AND HYPOTHESIS Based on a childhood intervention from ages 3 to 5 years that included additional fish consumption and which resulted in reduced schizotypal personality at age 23, we had previously hypothesized that omega-3 could reduce schizotypy. The current study tests the hypothesis that omega-3 supplementation reduces schizotypy in children. STUDY DESIGN In this intention-to-treat, randomized, single-blind, stratified, factorial trial, a community sample of 290 children aged 11-12 years were randomized into Omega-3 Only, Cognitive Behavioral Therapy (CBT) Only, Omega-3 + CBT, and Control groups. Schizotypy was assessed using the SPQ-C (Schizotypal Personality Questionnaire for Children) at 0 months (baseline), 3 months (end of treatment), 6 months (3 months post-treatment), and 12 months (9 months post-treatment). STUDY RESULTS A significant group × time interaction (P = .013) indicated that, compared with Controls, total schizotypy scores were reduced in both Omega-3 Only and Omega-3 + CBT groups immediately post-treatment (d = 0.56 and 0.47, respectively), and also 3 months after supplementation terminated (d = 0.49, d = 0.70). Stronger findings were observed for the interpersonal schizotypy factor, with both omega-3 groups showing reductions 9 months post-treatment compared with the CBT Only group. Schizotypy reductions were significantly stronger for those with higher dietary intake of omega-3 at intake. Sensitivity analyses confirmed findings. CONCLUSIONS Results are unique in the field and suggest that omega-3 can help reduce schizotypal personality in community-residing children. From an epidemiological standpoint, if replicated and extended, these findings could have implications for early prevention of more significant schizotypal features developing later in adolescence. CLINICAL TRIAL REGISTRATION "Healthy Brains & Behavior: Understanding and Treating Youth Aggression (HBB)." ClinicalTrials.gov Identifier: NCT00842439, https://clinicaltrials.gov/ct2/show/NCT00842439.
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Affiliation(s)
- Adrian Raine
- Department of Criminology, University of Pennsylvania, Philadelphia, PA, USA
- Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA
- Department of Psychology, University of Pennsylvania, Philadelphia, PA, USA
| | - Ruben C Gur
- Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA
- Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA
- Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA
| | - Raquel E Gur
- Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA
- Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA
- Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA
| | | | | | - Jianghong Liu
- School of Nursing, University of Pennsylvania, Philadelphia, PA, USA
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Tang M, Zhao T, Liu T, Dang R, Cai H, Wang Y. Nutrition and schizophrenia: associations worthy of continued revaluation. Nutr Neurosci 2024; 27:528-546. [PMID: 37565574 DOI: 10.1080/1028415x.2023.2233176] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/12/2023]
Abstract
BACKGROUND Accumulating evidence have shown that diet and nutrition play significant roles in mental illness, such as depression, anxiety and bipolar disorder. However, comprehensive evaluation of the relationship between nutrition and schizophrenia is lacking. OBJECTIVE The present review aims to synthetic elaborate the associations between nutrition and schizophrenia. Relevant studies on dietary patterns, macronutrients, micronutrients were performed through a literature search to synthesize the extracted data. SUMMARY Dietary interventions may help prevent the occurrence of schizophrenia, or delay symptoms: Healthy diets like nutritious plant-based foods and high-quality protein, have been linked to reducing the risk or symptoms of schizophrenia. Moreover, diet high in saturated fat and sugar is linked to more serious outcomes of schizophrenia. Additionally, when N-acetylcysteine acts as an adjuvant therapy, the overall symptoms of schizophrenia are significantly reduced. Also nascent evidence showed mental disorders may be related to intestinal microbiota dysfunction. Our study offered important insights into the dietary habits of patients with schizophrenia and the potential impact of nutritional factors on the disease. We also emphasized the need for further research, particularly in the form of large randomized double-blind controlled trials, to better understand the effects of nutrients on schizophrenia symptoms in different populations and disease types.
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Affiliation(s)
- Mimi Tang
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, People's Republic of China
- Institute for Rational and Safe Medication Practices, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, People's Republic of China
| | - Tingyu Zhao
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, People's Republic of China
- Institute for Rational and Safe Medication Practices, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, People's Republic of China
| | - Ting Liu
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, People's Republic of China
- Institute for Rational and Safe Medication Practices, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, People's Republic of China
| | - Ruili Dang
- Institute of Clinical Pharmacy, Jining First People's Hospital, Jining Medical University, Jining, People's Republic of China
| | - Hualin Cai
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, People's Republic of China
- Institute of Clinical Pharmacy, Central South University, Changsha, People's Republic of China
| | - Ying Wang
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, People's Republic of China
- Institute of Clinical Pharmacy, Central South University, Changsha, People's Republic of China
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Chen C, Deng Y, Li Y, Zhang M, Yu T, Xie K, Bao W, Li P, Sun L, Zhang T, Zhu Y, Zhang B. Network Meta-Analysis Indicates Superior Effects of Omega-3 Polyunsaturated Fatty Acids in Preventing the Transition to Psychosis in Individuals at Clinical High-Risk. Int J Neuropsychopharmacol 2024; 27:pyae014. [PMID: 38408281 PMCID: PMC10949445 DOI: 10.1093/ijnp/pyae014] [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: 12/12/2023] [Accepted: 02/24/2024] [Indexed: 02/28/2024] Open
Abstract
BACKGROUND The efficacy of pharmacological and nutritional interventions in individuals at clinical high risk for psychosis (CHR-P) remains elusive. This study aims to investigate the efficacy of pharmacological and nutritional interventions in CHR-P and whether these interventions can enhance the efficacy of psychological treatments. METHODS We systematically reviewed data from 5 databases until July 24, 2021: PubMed, Web of Science, EMBASE, China National Knowledge Infrastructure, and WanFang Data. The primary outcome was the transition to psychosis. Network meta-analyses were conducted at 3 time points (6, 12, and ≥24 months) considering both pharmacological/nutritional interventions alone and its combination with psychotherapy. RESULTS Out of 11 417 identified references, 21 studies were included, comprising 1983 participants. CHR-P participants receiving omega-3 polyunsaturated fatty acids treatment were associated with a lower probability of transition compared with placebo/control at 6 months (odds ratio [OR] = 0.07, 95% confidence interval [CI] = .01 to .054), 12 months (OR = 0.14, 95% CI = .03 to .66), and ≥24 months (OR = 0.16, 95% CI = .05 to .54). Moreover, risperidone plus psychotherapy was associated with a lower likelihood of transition at 6 months compared with placebo/control plus psychotherapy, but this result was not sustained over longer durations. CONCLUSION Omega-3 polyunsaturated fatty acids helped in preventing transitions to psychosis compared with controls. PROSPERO REGISTRATION NUMBER CRD42021256209.
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Affiliation(s)
- Chengfeng Chen
- Department of Psychiatry, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, China
- Department of Psychiatry, Guangzhou Medical University, Guangzhou, China
| | - Yongyan Deng
- Peking University Sixth Hospital, Peking University Institute of Mental Health, Beijing, China
- NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, China
| | - Yuling Li
- Department of Psychiatry, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, China
- Department of Psychiatry, Guangzhou Medical University, Guangzhou, China
| | - Meiting Zhang
- Department of Psychiatry, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, China
- Department of Psychiatry, Guangzhou Medical University, Guangzhou, China
| | - Tong Yu
- Department of Psychiatry, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, China
- Department of Psychiatry, Guangzhou Medical University, Guangzhou, China
| | - Kun Xie
- Department of Psychiatry, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, China
- Department of Psychiatry, Guangzhou Medical University, Guangzhou, China
| | - Wuyou Bao
- Institute of Mental Health, Tianjin Anding Hospital, Tianjin Medical University, Tianjin, China
| | - Peiying Li
- Institute of Mental Health, Tianjin Anding Hospital, Tianjin Medical University, Tianjin, China
| | - Ling Sun
- Institute of Mental Health, Tianjin Anding Hospital, Tianjin Medical University, Tianjin, China
| | - Tianhong Zhang
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yikang Zhu
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bin Zhang
- Institute of Mental Health, Tianjin Anding Hospital, Tianjin Medical University, Tianjin, China
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10
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Caballero N, Machiraju S, Diomino A, Kennedy L, Kadivar A, Cadenhead KS. Recent Updates on Predicting Conversion in Youth at Clinical High Risk for Psychosis. Curr Psychiatry Rep 2023; 25:683-698. [PMID: 37755654 PMCID: PMC10654175 DOI: 10.1007/s11920-023-01456-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/05/2023] [Indexed: 09/28/2023]
Abstract
PURPOSE OF REVIEW This review highlights recent advances in the prediction and treatment of psychotic conversion. Over the past 25 years, research into the prodromal phase of psychotic illness has expanded with the promise of early identification of individuals at clinical high risk (CHR) for psychosis who are likely to convert to psychosis. RECENT FINDINGS Meta-analyses highlight conversion rates between 20 and 30% within 2-3 years using existing clinical criteria while research into more specific risk factors, biomarkers, and refinement of psychosis risk calculators has exploded, improving our ability to predict psychotic conversion with greater accuracy. Recent studies highlight risk factors and biomarkers likely to contribute to earlier identification and provide insight into neurodevelopmental abnormalities, CHR subtypes, and interventions that can target specific risk profiles linked to neural mechanisms. Ongoing initiatives that assess longer-term (> 5-10 years) outcome of CHR participants can provide valuable information about predictors of later conversion and diagnostic outcomes while large-scale international biomarker studies provide hope for precision intervention that will alter the course of early psychosis globally.
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Affiliation(s)
- Noe Caballero
- Department of Psychiatry, University of California San Diego, 9500 Gilman Dr., La Jolla, CA, 92093-0810, USA
| | - Siddharth Machiraju
- Department of Psychiatry, University of California San Diego, 9500 Gilman Dr., La Jolla, CA, 92093-0810, USA
| | - Anthony Diomino
- Department of Psychiatry, University of California San Diego, 9500 Gilman Dr., La Jolla, CA, 92093-0810, USA
| | - Leda Kennedy
- Department of Psychiatry, University of California San Diego, 9500 Gilman Dr., La Jolla, CA, 92093-0810, USA
| | - Armita Kadivar
- Department of Psychiatry, University of California San Diego, 9500 Gilman Dr., La Jolla, CA, 92093-0810, USA
| | - Kristin S Cadenhead
- Department of Psychiatry, University of California San Diego, 9500 Gilman Dr., La Jolla, CA, 92093-0810, USA.
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11
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Xu H, Sun Y, Francis M, Cheng CF, Modulla NT, Brenna JT, Chiang CWK, Ye K. Shared genetic basis informs the roles of polyunsaturated fatty acids in brain disorders. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2023.10.03.23296500. [PMID: 37873425 PMCID: PMC10593041 DOI: 10.1101/2023.10.03.23296500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2023]
Abstract
The neural tissue is rich in polyunsaturated fatty acids (PUFAs), components that are indispensable for the proper functioning of neurons, such as neurotransmission. PUFA nutritional deficiency and imbalance have been linked to a variety of chronic brain disorders, including major depressive disorder (MDD), anxiety, and anorexia. However, the effects of PUFAs on brain disorders remain inconclusive, and the extent of their shared genetic determinants is largely unknown. Here, we used genome-wide association summary statistics to systematically examine the shared genetic basis between six phenotypes of circulating PUFAs (N = 114,999) and 20 brain disorders (N = 9,725-762,917), infer their potential causal relationships, identify colocalized regions, and pinpoint shared genetic variants. Genetic correlation and polygenic overlap analyses revealed a widespread shared genetic basis for 77 trait pairs between six PUFA phenotypes and 16 brain disorders. Two-sample Mendelian randomization analysis indicated potential causal relationships for 16 pairs of PUFAs and brain disorders, including alcohol consumption, bipolar disorder (BIP), and MDD. Colocalization analysis identified 40 shared loci (13 unique) among six PUFAs and ten brain disorders. Twenty-two unique variants were statistically inferred as candidate shared causal variants, including rs1260326 (GCKR), rs174564 (FADS2) and rs4818766 (ADARB1). These findings reveal a widespread shared genetic basis between PUFAs and brain disorders, pinpoint specific shared variants, and provide support for the potential effects of PUFAs on certain brain disorders, especially MDD, BIP, and alcohol consumption.
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Affiliation(s)
- Huifang Xu
- Department of Genetics, University of Georgia, Athens, Georgia
| | - Yitang Sun
- Department of Genetics, University of Georgia, Athens, Georgia
| | - Michael Francis
- Institute of Bioinformatics, University of Georgia, Athens, Georgia
| | - Claire F. Cheng
- Department of Genetics, University of Georgia, Athens, Georgia
| | | | - J. Thomas Brenna
- Dell Pediatric Research Institute and Department of Pediatrics, The University of Texas at Austin, Texas
- Dell Pediatric Research Institute and Department of Chemistry, The University of Texas at Austin, Texas
- Department of Nutritional Sciences, College of Natural Sciences, The University of Texas at Austin, Texas
| | - Charleston W. K. Chiang
- Center for Genetic Epidemiology, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California
- Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, California
| | - Kaixiong Ye
- Department of Genetics, University of Georgia, Athens, Georgia
- Institute of Bioinformatics, University of Georgia, Athens, Georgia
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12
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Jobin ML, De Smedt-Peyrusse V, Ducrocq F, Baccouch R, Oummadi A, Pedersen MH, Medel-Lacruz B, Angelo MF, Villette S, Van Delft P, Fouillen L, Mongrand S, Selent J, Tolentino-Cortez T, Barreda-Gómez G, Grégoire S, Masson E, Durroux T, Javitch JA, Guixà-González R, Alves ID, Trifilieff P. Impact of membrane lipid polyunsaturation on dopamine D2 receptor ligand binding and signaling. Mol Psychiatry 2023; 28:1960-1969. [PMID: 36604603 DOI: 10.1038/s41380-022-01928-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 12/05/2022] [Accepted: 12/14/2022] [Indexed: 01/07/2023]
Abstract
Increasing evidence supports a relationship between lipid metabolism and mental health. In particular, the biostatus of polyunsaturated fatty acids (PUFAs) correlates with some symptoms of psychiatric disorders, as well as the efficacy of pharmacological treatments. Recent findings highlight a direct association between brain PUFA levels and dopamine transmission, a major neuromodulatory system implicated in the etiology of psychiatric symptoms. However, the mechanisms underlying this relationship are still unknown. Here we demonstrate that membrane enrichment in the n-3 PUFA docosahexaenoic acid (DHA), potentiates ligand binding to the dopamine D2 receptor (D2R), suggesting that DHA acts as an allosteric modulator of this receptor. Molecular dynamics simulations confirm that DHA has a high preference for interaction with the D2R and show that membrane unsaturation selectively enhances the conformational dynamics of the receptor around its second intracellular loop. We find that membrane unsaturation spares G protein activity but potentiates the recruitment of β-arrestin in cells. Furthermore, in vivo n-3 PUFA deficiency blunts the behavioral effects of two D2R ligands, quinpirole and aripiprazole. These results highlight the importance of membrane unsaturation for D2R activity and provide a putative mechanism for the ability of PUFAs to enhance antipsychotic efficacy.
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Affiliation(s)
- Marie-Lise Jobin
- Université de Bordeaux, INRAE, Bordeaux INP, NutriNeuro, 33000, Bordeaux, France
| | | | - Fabien Ducrocq
- Université de Bordeaux, INRAE, Bordeaux INP, NutriNeuro, 33000, Bordeaux, France
| | - Rim Baccouch
- Institute of Chemistry & Biology of Membranes & Nanoobjects, CNRS UMR 5248, Université de Bordeaux, Bordeaux INP, 33600, Pessac, France
| | - Asma Oummadi
- Université de Bordeaux, INRAE, Bordeaux INP, NutriNeuro, 33000, Bordeaux, France
| | - Maria Hauge Pedersen
- Department of Psychiatry, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, 10032, USA
- Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, 10032, USA
| | - Brian Medel-Lacruz
- Research Programme on Biomedical Informatics (GRIB), Hospital del Mar Medical Research Institute (IMIM)-Department of Experimental and Health Sciences, Pompeu Fabra University (UPF), 08003, Barcelona, Spain
| | | | - Sandrine Villette
- Institute of Chemistry & Biology of Membranes & Nanoobjects, CNRS UMR 5248, Université de Bordeaux, Bordeaux INP, 33600, Pessac, France
| | - Pierre Van Delft
- Laboratory of Membrane Biogenesis (LBM), Research Mix Unity (UMR) 5200, National Scientific Research Center (CNRS), University of Bordeaux, Bordeaux, France
| | - Laetitia Fouillen
- Laboratory of Membrane Biogenesis (LBM), Research Mix Unity (UMR) 5200, National Scientific Research Center (CNRS), University of Bordeaux, Bordeaux, France
| | - Sébastien Mongrand
- Laboratory of Membrane Biogenesis (LBM), Research Mix Unity (UMR) 5200, National Scientific Research Center (CNRS), University of Bordeaux, Bordeaux, France
| | - Jana Selent
- Research Programme on Biomedical Informatics (GRIB), Hospital del Mar Medical Research Institute (IMIM)-Department of Experimental and Health Sciences, Pompeu Fabra University (UPF), 08003, Barcelona, Spain
| | | | - Gabriel Barreda-Gómez
- Research Department, IMG Pharma Biotech S.L., BIC Bizkaia (612), 48160, Derio, Spain
| | - Stéphane Grégoire
- Centre des Sciences du Goût et de l'Alimentation, AgroSup Dijon, CNRS, INRAE, Université Bourgogne Franche-Comté, 21000, Dijon, France
| | - Elodie Masson
- Centre des Sciences du Goût et de l'Alimentation, AgroSup Dijon, CNRS, INRAE, Université Bourgogne Franche-Comté, 21000, Dijon, France
| | - Thierry Durroux
- Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France
| | - Jonathan A Javitch
- Department of Psychiatry, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, 10032, USA
- Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, 10032, USA
- Department of Molecular Pharmacology and Therapeutics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, 10032, USA
| | - Ramon Guixà-González
- Condensed Matter Theory Group, Paul Scherrer Institute (PSI), 5232, Villigen, PSI, Switzerland.
| | - Isabel D Alves
- Institute of Chemistry & Biology of Membranes & Nanoobjects, CNRS UMR 5248, Université de Bordeaux, Bordeaux INP, 33600, Pessac, France.
| | - Pierre Trifilieff
- Université de Bordeaux, INRAE, Bordeaux INP, NutriNeuro, 33000, Bordeaux, France.
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13
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Zailani H, Satyanarayanan SK, Liao WC, Liao HF, Huang SY, Gałecki P, Su KP, Chang JPC. Omega-3 Polyunsaturated Fatty Acids in Managing Comorbid Mood Disorders in Chronic Obstructive Pulmonary Disease (COPD): A Review. J Clin Med 2023; 12:jcm12072653. [PMID: 37048736 PMCID: PMC10095486 DOI: 10.3390/jcm12072653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 03/15/2023] [Accepted: 03/29/2023] [Indexed: 04/05/2023] Open
Abstract
Chronic obstructive pulmonary disease (COPD) is the third-leading cause of mortality globally, significantly affecting people over 40 years old. COPD is often comorbid with mood disorders; however, they are frequently neglected or undiagnosed in COPD management, thus resulting in unintended treatment outcomes and higher mortality associated with the disease. Although the exact link between COPD and mood disorders remains to be ascertained, there is a broader opinion that inflammatory reactions in the lungs, blood, and inflammation-induced changes in the brain could orchestrate the onset of mood disorders in COPD. Although the current management of mood disorders such as depression in COPD involves using antidepressants, their use has been limited due to tolerability issues. On the other hand, as omega-3 polyunsaturated fatty acids (n-3 PUFAs) play a vital role in regulating inflammatory responses, they could be promising alternatives in managing mood disorders in COPD. This review discusses comorbid mood disorders in COPD as well as their influence on the progression and management of COPD. The underlying mechanisms of comorbid mood disorders in COPD will also be discussed, along with the potential role of n-3 PUFAs in managing these conditions.
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Affiliation(s)
- Halliru Zailani
- Mind-Body Interface Laboratory (MBI-Lab), Department of Psychiatry, China Medical University Hospital, Taichung 404, Taiwan
- Graduate Institute of Nutrition, China Medical University, Taichung 404, Taiwan
| | - Senthil Kumaran Satyanarayanan
- Mind-Body Interface Laboratory (MBI-Lab), Department of Psychiatry, China Medical University Hospital, Taichung 404, Taiwan
| | - Wei-Chih Liao
- Division of Pulmonary and Critical Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung 404, Taiwan
| | - Hsien-Feng Liao
- Mind-Body Interface Laboratory (MBI-Lab), Department of Psychiatry, China Medical University Hospital, Taichung 404, Taiwan
| | - Shih-Yi Huang
- School of Nutrition and Health Sciences, Taipei Medical University, Taipei 110, Taiwan
- Nutrition Research Centre, Taipei Medical University Hospital, Taipei 110, Taiwan
| | - Piotr Gałecki
- Department of Adult Psychiatry, Medical University of Lodz, 91-229 Lodz, Poland
| | - Kuan-Pin Su
- Mind-Body Interface Laboratory (MBI-Lab), Department of Psychiatry, China Medical University Hospital, Taichung 404, Taiwan
- College of Medicine, China Medical University, Taichung 404, Taiwan
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan
- An-Nan Hospital, China Medical University, Tainan 833, Taiwan
| | - Jane Pei-Chen Chang
- Mind-Body Interface Laboratory (MBI-Lab), Department of Psychiatry, China Medical University Hospital, Taichung 404, Taiwan
- College of Medicine, China Medical University, Taichung 404, Taiwan
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14
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Bhatara VS, Daniel J, Whitman C, Vik T, Bernstein B, Simkin DR. Complementary/Integrative Medicine Treatment and Prevention of Youth Psychosis. Child Adolesc Psychiatr Clin N Am 2023; 32:273-296. [PMID: 37147040 DOI: 10.1016/j.chc.2022.08.009] [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] [Indexed: 05/07/2023]
Abstract
The rationale for CIM treatments in youth psychoses is to optimize treatment by targeting symptoms not resolved by antipsychotics, such as negative symptoms (major drivers of disability). Adjunctive omega-3 fatty acids (ω-3 FA) or N-acetyl cystine (NAC usage for > 24-week) can potentially reduce negative symptoms and improve function. ω-3 FA or exercise may prevent progression to psychosis in youth (in prodromal stage). Weekly 90-minute moderate to vigorous physical activity or aerobic exercise can reduce positive and negative symptoms. Awaiting better research, CIM agents are also recommended because they are devoid of any serious side-effects.
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Affiliation(s)
- Vinod S Bhatara
- Department of Psychiatry and Pediatrics, University of South Dakota, Sanford School of Medicine, 2601 W Nicole Drive, Sioux Falls, SD 57105-3329, USA.
| | - Jeremy Daniel
- South Dakota State University, College of Pharmacy and Allied Health Professions, Avera Behavioral Health
| | - Carol Whitman
- University of South Dakota Sanford School of Medicine, Sioux Falls, SD, USA
| | - Tamara Vik
- University of South Dakota Sanford School of Medicine, Sioux Falls, SD, USA
| | - Bettina Bernstein
- Philadelphia College of Osteopathic Medicine, Philadelphia, PA, USA; Clinical Affiliate Department of Child and Adolescent Psychiatry, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Deborah R Simkin
- Department of Psychiatry, Emory University School of Medicine, 8955 Highway 98 West, Suite 204, Miramar Beach, FL 32550, USA
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15
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Lin S, Li P, Qin J, Liu Q, Zhang J, Meng N, Jia C, Zhu K, Lv D, Sun L, Shang T, Lin Y, Niu W, Wang T. Exploring the key factors of schizophrenia relapse by integrating LC-MS/ 1H NMR metabolomics and weighted correlation network analysis. Clin Chim Acta 2023; 541:117252. [PMID: 36781041 DOI: 10.1016/j.cca.2023.117252] [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: 10/17/2022] [Revised: 02/08/2023] [Accepted: 02/09/2023] [Indexed: 02/13/2023]
Abstract
BACKGROUND Lack of comprehending key factors of schizophrenia relapse has impeded its effective treatment, indicating that the mechanism clarification and available intervention of schizophrenia relapse required further amelioration. METHOD Based on the integration of LC-MS and 1H NMR metabolomics, a weighted correlation network was established to screen pivotal factors of accelerating schizophrenia relapse. Then, the cluster most correlated with schizophrenia relapse was explored, and the biological function of cluster was investigated. Next, the key biomarker related to schizophrenia relapse was obtained through multiple algorithms. Moreover, the Lilikoi algorithm and correlation analysis were implemented to reveal the association between key biomarker and schizophrenia relapse. RESULT Results showed that 458 different forms of metabolites were identified for structuring the weighted correlation network. The module-trait correlation indicated that the turquoise module was the most highly correlated with schizophrenia relapse. Further, network analysis revealed that, in turquoise module, cluster 1 composed of 139 metabolites (involved in lipid metabolism and energy metabolism) was the most important subnetwork relevant to schizophrenia relapse. Finally, phenylalanylphenylalanine was recommended as the key biomarker related to schizophrenia relapse. Moreover, the correlation analysis indicated that phenylalanylphenylalanine might affect the progression of schizophrenia by intervening in energy metabolism. CONCLUSION In summary, critical factors of schizophrenia relapse have been revealed in our research, expounding the schizophrenia progression more systemically, which could shed some light on improving the intervention of schizophrenia relapse.
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Affiliation(s)
- Song Lin
- Basic Medical Science College, Qiqihar Medical University, Qiqihar, Heilongjiang Province 161006, China
| | - Ping Li
- School of Mental Health, Qiqihar Medical University, Qiqihar, Heilongjiang Province 161006, China
| | - Jinglei Qin
- Baiyupao Psychiatric Hospital of Harbin, Harbin, Heilongjiang Province 150000, China
| | - Qi Liu
- Research Institute of Medicine & Pharmacy, Qiqihar Medical University, Qiqihar, Heilongjiang Province 161006, China
| | - Jinling Zhang
- Research Institute of Medicine & Pharmacy, Qiqihar Medical University, Qiqihar, Heilongjiang Province 161006, China
| | - Nana Meng
- Basic Medical Science College, Qiqihar Medical University, Qiqihar, Heilongjiang Province 161006, China
| | - Cuicui Jia
- School of Mental Health, Qiqihar Medical University, Qiqihar, Heilongjiang Province 161006, China
| | - Kunjie Zhu
- Basic Medical Science College, Qiqihar Medical University, Qiqihar, Heilongjiang Province 161006, China
| | - Dan Lv
- School of Mental Health, Qiqihar Medical University, Qiqihar, Heilongjiang Province 161006, China
| | - Lei Sun
- School of Mental Health, Qiqihar Medical University, Qiqihar, Heilongjiang Province 161006, China
| | - Tinghuizi Shang
- School of Mental Health, Qiqihar Medical University, Qiqihar, Heilongjiang Province 161006, China
| | - Yan Lin
- Basic Medical Science College, Qiqihar Medical University, Qiqihar, Heilongjiang Province 161006, China
| | - Weipan Niu
- Baiyupao Psychiatric Hospital of Harbin, Harbin, Heilongjiang Province 150000, China
| | - Tianyang Wang
- School of Pharmacy, Qiqihar Medical University, Qiqihar, Heilongjiang Province 161006, China.
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16
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Adrien V, Bosc N, Fumat H, Tessier C, Ferreri F, Mouchabac S, Tareste D, Nuss P. Higher stress response and altered quality of life in schizophrenia patients with low membrane levels of docosahexaenoic acid. Front Psychiatry 2023; 14:1089724. [PMID: 36816405 PMCID: PMC9937080 DOI: 10.3389/fpsyt.2023.1089724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Accepted: 01/12/2023] [Indexed: 02/05/2023] Open
Abstract
Schizophrenia is a severe, chronic, and heterogeneous mental disorder that affects approximately 1% of the world population. Ongoing research aims at clustering schizophrenia heterogeneity into various "biotypes" to identify subgroups of individuals displaying homogeneous symptoms, etiopathogenesis, prognosis, and treatment response. The present study is in line with this approach and focuses on a biotype partly characterized by a specific membrane lipid composition. We have examined clinical and biological data of patients with stabilized schizophrenia, including the fatty acid content of their erythrocyte membranes, in particular the omega-3 docosahexaenoic acid (DHA). Two groups of patients of similar size were identified: the DHA- group (N = 19) with a lower proportion of membrane DHA as compared to the norm in the general population, and the DHAn group (N = 18) with a normal proportion of DHA. Compared to DHAn, DHA- patients had a higher number of hospitalizations and a lower quality of life in terms of perceived health and physical health. They also exhibited significant higher interleukin-6 and cortisol blood levels. These results emphasize the importance of measuring membrane lipid and immunoinflammatory biomarkers in stabilized patients to identify a specific subgroup and optimize non-pharmacological interventions. It could also guide future research aimed at proposing specific pharmacological treatments.
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Affiliation(s)
- Vladimir Adrien
- AP-HP, Sorbonne Université, Department of Psychiatry, Hôpital Saint-Antoine, Paris, France.,Infrastructure for Clinical Research in Neurosciences (iCRIN), Paris Brain Institute, Sorbonne Université, INSERM, CNRS, Paris, France.,Université Paris Cité, INSERM UMR-S 1266, Institut de Psychiatrie et Neurosciences de Paris, Paris, France
| | - Nicolas Bosc
- AP-HP, Sorbonne Université, Department of Psychiatry, Hôpital Saint-Antoine, Paris, France
| | - Hugo Fumat
- Université Paris Cité, INSERM UMR-S 1266, Institut de Psychiatrie et Neurosciences de Paris, Paris, France
| | - Cédric Tessier
- AP-HP, Sorbonne Université, Department of Psychiatry, Hôpital Saint-Antoine, Paris, France
| | - Florian Ferreri
- AP-HP, Sorbonne Université, Department of Psychiatry, Hôpital Saint-Antoine, Paris, France.,Infrastructure for Clinical Research in Neurosciences (iCRIN), Paris Brain Institute, Sorbonne Université, INSERM, CNRS, Paris, France
| | - Stéphane Mouchabac
- AP-HP, Sorbonne Université, Department of Psychiatry, Hôpital Saint-Antoine, Paris, France.,Infrastructure for Clinical Research in Neurosciences (iCRIN), Paris Brain Institute, Sorbonne Université, INSERM, CNRS, Paris, France
| | - David Tareste
- Université Paris Cité, INSERM UMR-S 1266, Institut de Psychiatrie et Neurosciences de Paris, Paris, France
| | - Philippe Nuss
- AP-HP, Sorbonne Université, Department of Psychiatry, Hôpital Saint-Antoine, Paris, France.,Centre de Recherche Saint-Antoine, INSERM UMR S938, Sorbonne Université, Paris, France
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17
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Evidence that complement and coagulation proteins are mediating the clinical response to omega-3 fatty acids: A mass spectrometry-based investigation in subjects at clinical high-risk for psychosis. Transl Psychiatry 2022; 12:454. [PMID: 36307392 PMCID: PMC9616837 DOI: 10.1038/s41398-022-02217-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 09/21/2022] [Accepted: 10/04/2022] [Indexed: 11/08/2022] Open
Abstract
Preliminary evidence indicates beneficial effects of omega-3 polyunsaturated fatty acids (PUFAs) in early psychosis. The present study investigates the molecular mechanism of omega-3 PUFA-associated therapeutic effects in clinical high-risk (CHR) participants. Plasma samples of 126 CHR psychosis participants at baseline and 6-months follow-up were included. Plasma protein levels were quantified using mass spectrometry and erythrocyte omega-3 PUFA levels were quantified using gas chromatography. We examined the relationship between change in polyunsaturated PUFAs (between baseline and 6-month follow-up) and follow-up plasma proteins. Using mediation analysis, we investigated whether plasma proteins mediated the relationship between change in omega-3 PUFAs and clinical outcomes. A 6-months change in omega-3 PUFAs was associated with 24 plasma proteins at follow-up. Pathway analysis revealed the complement and coagulation pathway as the main biological pathway to be associated with change in omega-3 PUFAs. Moreover, complement and coagulation pathway proteins significantly mediated the relationship between change in omega-3 PUFAs and clinical outcome at follow-up. The inflammatory protein complement C5 and protein S100A9 negatively mediated the relationship between change in omega-3 PUFAs and positive symptom severity, while C5 positively mediated the relationship between change in omega-3 and functional outcome. The relationship between change in omega-3 PUFAs and cognition was positively mediated through coagulation factor V and complement protein C1QB. Our findings provide evidence for a longitudinal association of omega-3 PUFAs with complement and coagulation protein changes in the blood. Further, the results suggest that an increase in omega-3 PUFAs decreases symptom severity and improves cognition in the CHR state through modulating effects of complement and coagulation proteins.
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18
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Cheng N, McLaverty A, Nelson B, Markulev C, Schäfer MR, Berger M, Mossaheb N, Schlögelhofer M, Smesny S, Hickie IB, Berger GE, Chen EYH, de Haan L, Nieman DH, Nordentoft M, Riecher-Rössler A, Verma S, Street R, Thompson A, Yuen HP, Hester R, Yung AR, McGorry PD, Allott K, Amminger GP. Effects of omega-3 polyunsaturated fatty acid supplementation on cognitive functioning in youth at ultra-high risk for psychosis: secondary analysis of the NEURAPRO randomised controlled trial. BJPsych Open 2022; 8:e165. [PMID: 36073014 PMCID: PMC9534907 DOI: 10.1192/bjo.2022.572] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND Cognitive impairments are well-established features of psychotic disorders and are present when individuals are at ultra-high risk for psychosis. However, few interventions target cognitive functioning in this population. AIMS To investigate whether omega-3 polyunsaturated fatty acid (n-3 PUFA) supplementation improves cognitive functioning among individuals at ultra-high risk for psychosis. METHOD Data (N = 225) from an international, multi-site, randomised controlled trial (NEURAPRO) were analysed. Participants were given omega-3 supplementation (eicosapentaenoic acid and docosahexaenoic acid) or placebo over 6 months. Cognitive functioning was assessed with the Brief Assessment of Cognition in Schizophrenia (BACS). Mixed two-way analyses of variance were computed to compare the change in cognitive performance between omega-3 supplementation and placebo over 6 months. An additional biomarker analysis explored whether change in erythrocyte n-3 PUFA levels predicted change in cognitive performance. RESULTS The placebo group showed a modest greater improvement over time than the omega-3 supplementation group for motor speed (ηp2 = 0.09) and BACS composite score (ηp2 = 0.21). After repeating the analyses without individuals who transitioned, motor speed was no longer significant (ηp2 = 0.02), but the composite score remained significant (ηp2 = 0.02). Change in erythrocyte n-3 PUFA levels did not predict change in cognitive performance over 6 months. CONCLUSIONS We found no evidence to support the use of omega-3 supplementation to improve cognitive functioning in ultra-high risk individuals. The biomarker analysis suggests that this finding is unlikely to be attributed to poor adherence or consumption of non-trial n-3 PUFAs.
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Affiliation(s)
- Nicholas Cheng
- Orygen, Centre for Youth Mental Health, The University of Melbourne, Australia
| | - Alison McLaverty
- Melbourne School of Psychological Sciences, The University of Melbourne, Australia
| | - Barnaby Nelson
- Orygen, Centre for Youth Mental Health, The University of Melbourne, Australia
| | - Connie Markulev
- Orygen, Centre for Youth Mental Health, The University of Melbourne, Australia
| | - Miriam R Schäfer
- Orygen, Centre for Youth Mental Health, The University of Melbourne, Australia
| | - Maximus Berger
- Orygen, Centre for Youth Mental Health, The University of Melbourne, Australia; and Department of Psychiatry and Psychotherapy, University of Bern, Switzerland
| | - Nilufar Mossaheb
- Department of Psychiatry and Psychotherapy, Medical University of Vienna, Austria
| | | | - Stefan Smesny
- Department of Psychiatry and Psychotherapy, Jena University Hospital, Germany
| | - Ian B Hickie
- Brain and Mind Centre, The University of Sydney, Australia
| | - Gregor E Berger
- Child and Adolescent Psychiatric Service, Canton of Zurich, Switzerland
| | - Eric Y H Chen
- Department of Psychiatry, University of Hong Kong, Hong Kong
| | - Lieuwe de Haan
- Department of Psychiatry, Academic Medical Center, The Netherlands
| | - Dorien H Nieman
- Department of Psychiatry, Academic Medical Center, The Netherlands
| | - Merete Nordentoft
- Mental Health Centre Copenhagen, Department of Clinical Medicine, Copenhagen University Hospital, Denmark
| | | | - Swapna Verma
- Early Psychosis Intervention, Institute of Mental Health, Singapore
| | - Rebekah Street
- Orygen, Centre for Youth Mental Health, The University of Melbourne, Australia
| | - Andrew Thompson
- Orygen, Centre for Youth Mental Health, The University of Melbourne, Australia
| | - Hok Pan Yuen
- Orygen, Centre for Youth Mental Health, The University of Melbourne, Australia
| | - Robert Hester
- Melbourne School of Psychological Sciences, The University of Melbourne, Australia
| | - Alison Ruth Yung
- Institute for Mental and Physical Health and Clinical Translation (IMPACT), Deakin University, Australia; and School of Health Sciences, University of Manchester, UK
| | - Patrick D McGorry
- Orygen, Centre for Youth Mental Health, The University of Melbourne, Australia
| | - Kelly Allott
- Orygen, Centre for Youth Mental Health, The University of Melbourne, Australia; and Melbourne School of Psychological Sciences, The University of Melbourne, Australia
| | - G Paul Amminger
- Orygen, Centre for Youth Mental Health, The University of Melbourne, Australia
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19
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Scale-Up to Pilot of a Non-Axenic Culture of Thraustochytrids Using Digestate from Methanization as Nitrogen Source. Mar Drugs 2022; 20:md20080499. [PMID: 36005502 PMCID: PMC9410245 DOI: 10.3390/md20080499] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Revised: 07/27/2022] [Accepted: 07/28/2022] [Indexed: 12/02/2022] Open
Abstract
The production of non-fish based docosahexaenoic acid (DHA) for feed and food has become a critical need in our global context of over-fishing. The industrial-scale production of DHA–rich Thraustochytrids could be an alternative, if costs turned out to be competitive. In order to reduce production costs, this study addresses the feasibility of the non-axenic (non-sterile) cultivation of Aurantiochytrium mangrovei on industrial substrates (as nitrogen and mineral sources and glucose syrup as carbon and energy sources), and its scale-up from laboratory (250 mL) to 500 L cultures. Pilot-scale reactors were airlift cylinders. Batch and fed-batch cultures were tested. Cultures over 38 to 62 h achieved a dry cell weight productivity of 3.3 to 5.5 g.L−1.day−1, and a substrate to biomass yield of up to 0.3. DHA productivity ranged from 10 to 0.18 mg.L−1.day−1. Biomass productivity appears linearly related to oxygen transfer rate. Bacterial contamination of cultures was low enough to avoid impacts on fatty acid composition of the biomass. A specific work on microbial risks assessment (in supplementary files) showed that the biomass can be securely used as feed. However, to date, there is a law void in EU legislation regarding the recycling of nitrogen from digestate from animal waste for microalgae biomass and its usage in animal feed. Overall, the proposed process appears similar to the industrial yeast production process (non-axenic heterotrophic process, dissolved oxygen supply limiting growth, similar cell size). Such similarity could help in further industrial developments.
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20
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Dash S, Syed YA, Khan MR. Understanding the Role of the Gut Microbiome in Brain Development and Its Association With Neurodevelopmental Psychiatric Disorders. Front Cell Dev Biol 2022; 10:880544. [PMID: 35493075 PMCID: PMC9048050 DOI: 10.3389/fcell.2022.880544] [Citation(s) in RCA: 76] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Accepted: 03/28/2022] [Indexed: 12/12/2022] Open
Abstract
The gut microbiome has a tremendous influence on human physiology, including the nervous system. During fetal development, the initial colonization of the microbiome coincides with the development of the nervous system in a timely, coordinated manner. Emerging studies suggest an active involvement of the microbiome and its metabolic by-products in regulating early brain development. However, any disruption during this early developmental process can negatively impact brain functionality, leading to a range of neurodevelopment and neuropsychiatric disorders (NPD). In this review, we summarize recent evidence as to how the gut microbiome can influence the process of early human brain development and its association with major neurodevelopmental psychiatric disorders such as autism spectrum disorders, attention-deficit hyperactivity disorder, and schizophrenia. Further, we discuss how gut microbiome alterations can also play a role in inducing drug resistance in the affected individuals. We propose a model that establishes a direct link of microbiome dysbiosis with the exacerbated inflammatory state, leading to functional brain deficits associated with NPD. Based on the existing research, we discuss a framework whereby early diet intervention can boost mental wellness in the affected subjects and call for further research for a better understanding of mechanisms that govern the gut-brain axis may lead to novel approaches to the study of the pathophysiology and treatment of neuropsychiatric disorders.
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Affiliation(s)
- Somarani Dash
- Life Sciences Division, Institute of Advanced Study in Science and Technology (IASST), Guwahati, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Yasir Ahmed Syed
- School of Biosciences and Neuroscience and Mental Health Research Institute, Cardiff University, Hadyn Ellis Building, Cardiff, United Kingdom
| | - Mojibur R. Khan
- Life Sciences Division, Institute of Advanced Study in Science and Technology (IASST), Guwahati, India
- *Correspondence: Mojibur R. Khan,
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21
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Amminger GP, Lin A, Kerr M, Weller A, Spark J, Pugh C, O'Callaghan S, Berger M, Clark SR, Scott JG, Baker A, McGregor I, Cotter D, Sarnyai Z, Thompson A, Yung AR, O'Donoghue B, Killackey E, Mihalopoulos C, Yuen HP, Nelson B, McGorry PD. Cannabidiol for at risk for psychosis youth: A randomized controlled trial. Early Interv Psychiatry 2022; 16:419-432. [PMID: 34190422 DOI: 10.1111/eip.13182] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 06/04/2021] [Accepted: 06/07/2021] [Indexed: 12/21/2022]
Abstract
BACKGROUND No biological treatment has been firmly established for the at-risk stage of psychotic disorder. In this study we aim to test if subthreshold psychotic symptoms can be effectively treated with cannabidiol (CBD), a non-psychoactive compound of the plant Cannabis sativa. The question has taken on increased importance in the wake of evidence questioning both the need and efficacy of specific pharmacological interventions in the ultra-high risk (UHR) for psychosis group. METHODS Three-arm randomized controlled trial of 405 patients (135 per arm) aged 12-25 years who meet UHR for psychosis criteria. The study includes a 6-week lead-in phase during which 10% of UHR individuals are expected to experience symptom remission. Participants will receive CBD (per oral) at doses 600 or 1000 mg per day (fixed schedule) for 12 weeks. Participants in the third arm of the trial will receive matching placebo capsules. Primary outcome is severity of positive psychotic symptoms as measured by the Comprehensive Assessment of At-Risk Mental States at 12 weeks. We hypothesize that CBD will be significantly more effective than placebo in improving positive psychotic symptoms in UHR patients. All participants will also be followed up 6 months post baseline to evaluate if treatment effects are sustained. CONCLUSION This paper reports on the rationale and protocol of the Cannabidiol for At Risk for psychosis Youth (CanARY) study. This study will test CBD for the first time in the UHR phase of psychotic disorder.
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Affiliation(s)
- G Paul Amminger
- Orygen, Melbourne, Australia.,The Centre for Youth Mental Health, The University of Melbourne, Melbourne, Australia
| | - Ashleigh Lin
- Telethon Kids Institute, The University of Western Australia, Perth, Australia
| | - Melissa Kerr
- Orygen, Melbourne, Australia.,The Centre for Youth Mental Health, The University of Melbourne, Melbourne, Australia
| | - Amber Weller
- Orygen, Melbourne, Australia.,The Centre for Youth Mental Health, The University of Melbourne, Melbourne, Australia
| | - Jessica Spark
- Orygen, Melbourne, Australia.,The Centre for Youth Mental Health, The University of Melbourne, Melbourne, Australia
| | - Charlotte Pugh
- Telethon Kids Institute, The University of Western Australia, Perth, Australia
| | - Sally O'Callaghan
- Orygen, Melbourne, Australia.,The Centre for Youth Mental Health, The University of Melbourne, Melbourne, Australia
| | - Maximus Berger
- Orygen, Melbourne, Australia.,The Centre for Youth Mental Health, The University of Melbourne, Melbourne, Australia
| | - Scott R Clark
- Discipline of Psychiatry, University of Adelaide, Adelaide, Australia
| | - James G Scott
- QIMR Berghofer Medical Research Institute, Brisbane, Australia.,Queensland Centre for Mental Health Research, The Park Centre for Mental Health, Brisbane, Australia.,Metro North Mental Health Service, Herston, Australia
| | - Andrea Baker
- QIMR Berghofer Medical Research Institute, Brisbane, Australia.,Queensland Centre for Mental Health Research, The Park Centre for Mental Health, Brisbane, Australia
| | - Iain McGregor
- Lambert Initiative for Cannabinoid Therapeutics, University of Sydney, Sydney, Australia
| | | | | | - Andrew Thompson
- Orygen, Melbourne, Australia.,The Centre for Youth Mental Health, The University of Melbourne, Melbourne, Australia
| | - Alison R Yung
- Orygen, Melbourne, Australia.,The Centre for Youth Mental Health, The University of Melbourne, Melbourne, Australia.,School of Health Science, University of Manchester, Manchester, UK
| | - Brian O'Donoghue
- Orygen, Melbourne, Australia.,The Centre for Youth Mental Health, The University of Melbourne, Melbourne, Australia
| | - Eoin Killackey
- Orygen, Melbourne, Australia.,The Centre for Youth Mental Health, The University of Melbourne, Melbourne, Australia
| | | | - Hok Pan Yuen
- Orygen, Melbourne, Australia.,The Centre for Youth Mental Health, The University of Melbourne, Melbourne, Australia
| | - Barnaby Nelson
- Orygen, Melbourne, Australia.,The Centre for Youth Mental Health, The University of Melbourne, Melbourne, Australia
| | - Patrick D McGorry
- Orygen, Melbourne, Australia.,The Centre for Youth Mental Health, The University of Melbourne, Melbourne, Australia
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22
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Bozali E, Yalinbas D. Analysis of the Thickness of the Outer Retinal Layer Using Optical Coherence Tomography - A Predictor of Visual Acuity in Schizophrenia. Klin Monbl Augenheilkd 2022; 239:1232-1238. [PMID: 35320864 DOI: 10.1055/a-1741-7988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
BACKGROUND The aim of this study was to evaluate the thickness of the outer retinal layer (ORL) together with macular thickness and changes in the retinal nerve fiber layer (RNFL) in patients with schizophrenia in comparison with healthy controls. METHODS This study included 114 eyes of 57 patients diagnosed with schizophrenia and 114 eyes of 57 healthy controls. Central foveal thickness (CFT), central macular thickness (CMT), and ORL thickness were measured in both groups via the images obtained by spectral-domain optical coherence tomography (SD-OCT). RNFL was also assessed in four quadrants (inferior, superior, temporal, nasal). CMT measurements were presented as the average thickness of the macula in the central 1 mm area on the Early Treatment Diabetic Retinopathy Study (ETDRS) grid. The ORL thickness was defined as the distance between the external limiting membrane and retinal pigment epithelium at the center of the foveal pit. RESULTS The mean age of 57 patients was 37 ± 10 years, of whom 34 (60%) were male and 23 (40%) female. No statistically significant difference was found between groups in terms of age and gender (p = 0.8 for age, p = 0.9 for gender). There was no statistically significant difference in the mean CMT between the two groups (p = 0.1). The mean ORL thickness in the two groups was 99.8 ± 8.3 and 103.7 ± 6.2, respectively, and was significantly decreased in the schizophrenia group (p = 0.005). RNFL analysis demonstrated significant thinning in the inferior and superior quadrants compared to healthy controls (p < 0.001 and p = 0.017, respectively). CONCLUSIONS SD-OCT findings - especially ORL and RNFL thickness - may be related to the neurodegenerational changes in schizophrenia.
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Affiliation(s)
- Erman Bozali
- Sivas Cumhuriyet University Faculty of Medicine, Department of Ophthalmology, Sivas, Turkey
| | - Duygu Yalinbas
- Sivas Cumhuriyet University Faculty of Medicine, Department of Ophthalmology, Sivas, Turkey
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23
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Ansari Z, Pawar S, Seetharaman R. Neuroinflammation and oxidative stress in schizophrenia: are these opportunities for repurposing? Postgrad Med 2022; 134:187-199. [PMID: 34766870 DOI: 10.1080/00325481.2021.2006514] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 11/11/2021] [Indexed: 10/19/2022]
Abstract
PURPOSE To summarize the main findings on the subject of neuroinflammation and oxidative stress in patients with Schizophrenia (SCZ). METHODS A narrative review of all the relevant papers known to the authors was conducted. RESULTS SCZ is a chronic, debilitating, neuropsychiatric disorder associated with an immense and adverse impact on both the patient and the caregiver, and impairs the overall quality of life. The current modality of treatment involves the use of antipsychotics to balance the disturbances in the neurotransmitters in the dopaminergic and serotonin pathways in the brain, which have a role to play in SCZ. Contemporary management of SCZ focuses mainly on symptomatic control due to the lack of effective curative treatments.Despite the optimum use of antipsychotics, there is a considerable proportion of the patient population who are poor responders. This has necessitated the exploration of new etiopathologies in order to evolve new modalities of treatment. This narrative review, conducted over a period of 3 months, throws light on the large-scale evidence pointing toward neuroinflammation and oxidative stress as key etiopathological markers that merit further consideration in SCZ, and may even be the basis for devising novel pharmacotherapies for SCZ. CONCLUSIONS This review discusses the various plausible hypotheses, viz., cytokine hypothesis of peripheral inflammation, acute-phase reactants in SCZ, microglial hypothesis of central inflammation, neurogenesis in relation to neuroinflammation, and oxidative stress in SCZ. It also highlights the many opportunities available for repurposing already marketed drugs with anti-inflammatory and antioxidant properties with a view to devising more effective and comprehensive therapies to manage SCZ.
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Affiliation(s)
- Zarrin Ansari
- Department of Pharmacology, Lokmanya Tilak Municipal Medical College and General Hospital, Mumbai, India
| | - Sudhir Pawar
- Department of Pharmacology, Lokmanya Tilak Municipal Medical College and General Hospital, Mumbai, India
| | - Rajmohan Seetharaman
- Department of Pharmacology, Lokmanya Tilak Municipal Medical College and General Hospital, Mumbai, India
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24
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Susai SR, Mongan D, Healy C, Cannon M, Nelson B, Markulev C, Schäfer MR, Berger M, Mossaheb N, Schlögelhofer M, Smesny S, Hickie IB, Berger GE, Chen EYH, de Haan L, Nieman DH, Nordentoft M, Riecher-Rössler A, Verma S, Thompson A, Yung AR, McGorry PD, Föcking M, Cotter D, Amminger GP. The association of plasma inflammatory markers with omega-3 fatty acids and their mediating role in psychotic symptoms and functioning: An analysis of the NEURAPRO clinical trial. Brain Behav Immun 2022; 99:147-156. [PMID: 34624483 DOI: 10.1016/j.bbi.2021.09.018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 09/17/2021] [Accepted: 09/25/2021] [Indexed: 12/12/2022] Open
Abstract
There is increasing evidence that dysregulation of polyunsaturated fatty acids (FAs) mediated membrane function plays a role in the pathophysiology of schizophrenia. Even though preclinical findings have supported the anti-inflammatory properties of omega-3 FAs on brain health, their biological roles as anti-inflammatory agents and their therapeutic role on clinical symptoms of psychosis risk are not well understood. In the current study, we investigated the relationship of erythrocyte omega-3 FAs with plasma immune markers in a clinical high risk for psychosis (CHR) sample. In addition, a mediation analysis was performed to examine whether previously reported associations between omega-3 FAs and clinical outcomes were mediated via plasma immune markers. Clinical outcomes for CHR participants in the NEURAPRO clinical trial were measured using the Brief Psychiatric Rating Scale (BPRS), Schedule for the Scale of Assessment of Negative Symptoms (SANS) and Social and Occupational Functioning Assessment Scale (SOFAS) scales. The erythrocyte omega-3 index [eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA)] and plasma concentrations of inflammatory markers were quantified at baseline (n = 268) and 6 month follow-up (n = 146) by gas chromatography and multiplex immunoassay, respectively. In linear regression models, the baseline plasma concentrations of Interleukin (IL)-15, Intercellular adhesion molecule (ICAM)-1 and Vascular cell adhesion molecule (VCAM)-1 were negatively associated with baseline omega-3 index. In addition, 6-month change in IL-12p40 and TNF-α showed a negative association with change in omega-3 index. In longitudinal analyses, the baseline and 6 month change in omega-3 index was negatively associated with VCAM-1 and TNF-α respectively at follow-up. Mediation analyses provided little evidence for mediating effects of plasma immune markers on the relationship between omega-3 FAs and clinical outcomes (psychotic symptoms and functioning) in CHR participants. Our results indicate a predominantly anti-inflammatory relationship of omega-3 FAs on plasma inflammatory status in CHR individuals, but this did not appear to convey clinical benefits at 6 month and 12 month follow-up. Both immune and non-immune biological effects of omega-3 FAs would be resourceful in understanding the clinical benefits of omega-3 FAs in CHR papulation.
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Affiliation(s)
- Subash Raj Susai
- Department of Psychiatry, RCSI University of Medicine and Health Sciences, Dublin, Ireland.
| | - David Mongan
- Department of Psychiatry, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Colm Healy
- Department of Psychiatry, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Mary Cannon
- Department of Psychiatry, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Barnaby Nelson
- Centre for Youth Mental Health, The University of Melbourne, Melbourne, Victoria, Australia; Orygen, 35 Poplar Rd, Parkville 3052, Australia
| | - Connie Markulev
- Centre for Youth Mental Health, The University of Melbourne, Melbourne, Victoria, Australia; Orygen, 35 Poplar Rd, Parkville 3052, Australia
| | - Miriam R Schäfer
- Centre for Youth Mental Health, The University of Melbourne, Melbourne, Victoria, Australia; Orygen, 35 Poplar Rd, Parkville 3052, Australia
| | - Maximus Berger
- Centre for Youth Mental Health, The University of Melbourne, Melbourne, Victoria, Australia; Orygen, 35 Poplar Rd, Parkville 3052, Australia
| | - Nilufar Mossaheb
- Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria
| | - Monika Schlögelhofer
- BioPsyC-Biopsychosocial Corporation - Non-Profit Association for Research Funding, Austria; Department of Child and Adolescent Psychiatry, Medical University Vienna, Austria
| | - Stefan Smesny
- Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany
| | - Ian B Hickie
- Brain and Mind Centre, The University of Sydney, Sydney, New South Wales, Australia
| | - Gregor E Berger
- Child and Adolescent Psychiatric Service of the Canton of Zurich, Zürich, Switzerland
| | - Eric Y H Chen
- Department of Psychiatry, University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Lieuwe de Haan
- Department of Psychiatry, Academic Medical Center, Amsterdam, the Netherlands
| | - Dorien H Nieman
- Department of Psychiatry, Academic Medical Center, Amsterdam, the Netherlands
| | - Merete Nordentoft
- Mental Health Center Copenhagen, Department of Clinical Medicine, Copenhagen University Hospital, Denmark
| | | | - Swapna Verma
- Institute of Mental Health, Singapore, Singapore
| | - Andrew Thompson
- Centre for Youth Mental Health, The University of Melbourne, Melbourne, Victoria, Australia; Orygen, 35 Poplar Rd, Parkville 3052, Australia
| | - Alison Ruth Yung
- Centre for Youth Mental Health, The University of Melbourne, Melbourne, Victoria, Australia; Orygen, 35 Poplar Rd, Parkville 3052, Australia; Institute for Mental and Physical Health and Clinical Translation (IMPACT), Deakin University, Geelong, Australia; School of Health Sciences, University of Manchester, UK
| | - Patrick D McGorry
- Centre for Youth Mental Health, The University of Melbourne, Melbourne, Victoria, Australia; Orygen, 35 Poplar Rd, Parkville 3052, Australia
| | - Melanie Föcking
- Department of Psychiatry, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - David Cotter
- Department of Psychiatry, RCSI University of Medicine and Health Sciences, Dublin, Ireland.
| | - G Paul Amminger
- Centre for Youth Mental Health, The University of Melbourne, Melbourne, Victoria, Australia; Orygen, 35 Poplar Rd, Parkville 3052, Australia; Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria
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25
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Increased PLA 2 activity in individuals at ultra-high risk for psychosis. Eur Arch Psychiatry Clin Neurosci 2021; 271:1593-1599. [PMID: 33677687 DOI: 10.1007/s00406-021-01246-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Accepted: 02/24/2021] [Indexed: 10/22/2022]
Abstract
Phospholipase A2 is the main enzyme in the metabolism of membrane phospholipids. It comprises a family of enzymes divided into iPLA2, cPLA2 and sPLA2. Studies have reported increased PLA2 activity in psychotic patients, which suggests an accelerated breakdown of membrane phospholipids. In the present study we investigated whether increased PLA2 activity is also present in individuals at ultra-high risk (UHR) for psychosis. One-hundred fifty adults were included in this study (85 UHR and 65 controls). UHR was assessed using the "structured interview for prodromal syndromes". PLA2 activity was determined in platelets by a radio-enzymatic assay. We found in UHR individuals increased activities of iPLA2 (p < 0.001) and cPLA2 (p = 0.012) as compared to controls. No correlations were found between socio-demographic and clinical parameters and PLA2 activity. Our findings suggest that increased PLA2 activities may be useful as a biological risk-marker for psychotic disorders.
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26
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Jones HJ, Borges MC, Carnegie R, Mongan D, Rogers PJ, Lewis SJ, Thompson AD, Zammit S. Associations between plasma fatty acid concentrations and schizophrenia: a two-sample Mendelian randomisation study. Lancet Psychiatry 2021; 8:1062-1070. [PMID: 34735824 DOI: 10.1016/s2215-0366(21)00286-8] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 06/21/2021] [Accepted: 07/22/2021] [Indexed: 12/30/2022]
Abstract
BACKGROUND Although studies suggest that concentrations of omega-3 and omega-6 fatty acids are lower in individuals with schizophrenia, evidence for beneficial effects of fatty acid supplementation is scarce. Therefore, in this study, we aimed to determine whether omega-3 and omega-6 fatty acid concentrations are causally related to schizophrenia. METHODS We did a two-sample Mendelian randomisation study, using deidentified summary-level data that were publicly available. Exposure-outcome relationships were evaluated using the inverse variance weighted two-sample Mendelian randomisation method using results from genome-wide association studies (GWASs) of fatty acid concentrations and schizophrenia. GWAS results were available for European (fatty acids) and European and Asian (schizophrenia) ancestry samples. Overall age and gender information were not calculable from the summary-level GWAS results. Weighted median, weighted mode, and Mendelian randomisation Egger regression methods were used as sensitivity analyses. To address underlying mechanisms, further analyses were done using single instruments within the FADS gene cluster and ELOVL2 gene locus. FADS gene cluster and ELOVL2 gene causal effects on schizophrenia were calculated by dividing the single nucleotide polymorphism (SNP)-schizophrenia effect estimate by the SNP-fatty acid effect estimate with standard errors derived using the first term from a delta method expansion for the ratio estimate. Multivariable Mendelian randomisation was used to estimate direct effects of omega-3 fatty acids on schizophrenia, independent of omega-6 fatty acids, lipoproteins (ie, HDL and LDL), and triglycerides. FINDINGS Mendelian randomisation analyses indicated that long-chain omega-3 and long-chain omega-6 fatty acid concentrations were associated with a lower risk of schizophrenia (eg, inverse variance weighted odds ratio [OR] 0·83 [95% CI 0·75-0·92] for docosahexaenoic acid). By contrast, there was weak evidence that short-chain omega-3 and short-chain omega-6 fatty acids were associated with an increased risk of schizophrenia (eg, inverse variance weighted OR 1·07 [95% CI 0·98-1·18] for α-linolenic acid). Effects were consistent across the sensitivity analyses and the FADS single-SNP analyses, suggesting that long-chain omega-3 and long-chain omega-6 fatty acid concentrations were associated with lower risk of schizophrenia (eg, OR 0·74 [95% CI 0·58-0·96] for docosahexaenoic acid) whereas short-chain omega-3 and short-chain omega-6 fatty acid concentrations were associated with an increased risk of schizophrenia (eg, OR 1·08 [95% CI 1·02-1·15] for α-linolenic acid). By contrast, estimates from the ELOVL2 single-SNP analyses were more imprecise and compatible with both risk-increasing and protective effects for each of the fatty acid measures. Multivariable Mendelian randomisation indicated that the protective effect of docosahexaenoic acid on schizophrenia persisted after conditioning on other lipids, although evidence was slightly weaker (multivariable inverse variance weighted OR 0·84 [95% CI 0·71-1·01]). INTERPRETATION Our results are compatible with the protective effects of long-chain omega-3 and long-chain omega-6 fatty acids on schizophrenia, suggesting that people with schizophrenia might have difficulty converting short-chain polyunsaturated fatty acids to long-chain polyunsaturated fatty acids. Further studies are required to determine whether long-chain polyunsaturated fatty acid supplementation or diet enrichment might help prevent onset of schizophrenia. FUNDING National Institute for Health Research Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol.
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Affiliation(s)
- Hannah J Jones
- Centre for Academic Mental Health, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK; MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK; National Institute for Health Research Bristol Biomedical Research Centre, University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol, Bristol, UK.
| | - Maria Carolina Borges
- MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Rebecca Carnegie
- Centre for Academic Mental Health, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - David Mongan
- Department of Psychiatry, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Peter J Rogers
- Nutrition and Behaviour Unit, School of Psychological Science, University of Bristol, Bristol, UK; National Institute for Health Research Bristol Biomedical Research Centre, University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol, Bristol, UK
| | - Sarah J Lewis
- MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK; Bristol Dental School, University of Bristol, Bristol, UK
| | - Andrew D Thompson
- Division of Mental Health and Wellbeing, University of Warwick, Coventry, UK; Orygen, Centre of Youth Mental Health, Melbourne, Australia
| | - Stanley Zammit
- Centre for Academic Mental Health, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK; National Institute for Health Research Bristol Biomedical Research Centre, University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol, Bristol, UK; MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Cardiff University, Cardiff, UK
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Keefe RSE, Woods SW, Cannon TD, Ruhrmann S, Mathalon DH, McGuire P, Rosenbrock H, Daniels K, Cotton D, Roy D, Pollentier S, Sand M. A randomized Phase II trial evaluating efficacy, safety, and tolerability of oral BI 409306 in attenuated psychosis syndrome: Design and rationale. Early Interv Psychiatry 2021; 15:1315-1325. [PMID: 33354862 PMCID: PMC8451588 DOI: 10.1111/eip.13083] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 09/23/2020] [Accepted: 11/14/2020] [Indexed: 12/17/2022]
Abstract
AIM Attenuated psychosis syndrome (APS), a condition for further study in the Diagnostic and Statistical Manual of Mental Disorders-5, comprises psychotic symptoms that are qualitatively similar to those observed in schizophrenia but are less severe. Patients with APS are at high risk of converting to first-episode psychosis (FEP). As evidence for effective pharmacological interventions in APS is limited, novel treatments may provide symptomatic relief and delay/prevent psychotic conversion. This trial aims to investigate the efficacy, safety, and tolerability of BI 409306, a potent and selective phosphodiesterase-9 inhibitor, versus placebo in APS. Novel biomarkers of psychosis are being investigated. METHODS In this Phase II, multinational, double-blind, parallel-group trial, randomized (1:1) patients will receive BI 409306 50 mg or placebo twice daily for 52 weeks. Patients (n = 300) will be enrolled to determine time to remission of APS, time to FEP, change in everyday functional capacity (Schizophrenia Cognition Rating Scale), and change from baseline in Brief Assessment of Cognition composite score and Positive and Negative Syndrome Scale scores. Potential biomarkers of psychosis under investigation include functional measures of brain activity and automated speech analyses. Safety is being assessed throughout. CONCLUSIONS This trial will determine whether BI 409306 is superior to placebo in achieving sustainable remission of APS and improvements in cognition and functional capacity. These advances may provide evidence-based treatment options for symptomatic relief in APS. Furthermore, the study will assess the effect of BI 409306 on psychotic conversion and explore the identification of patients at risk for conversion using novel biomarkers.
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Affiliation(s)
- Richard S. E. Keefe
- Department of Psychiatry and Behavioral SciencesDuke UniversityDurhamNorth CarolinaUSA
- VeraSciDurhamNCUSA
| | - Scott W. Woods
- Department of PsychiatryYale UniversityNew HavenConnecticutUSA
| | - Tyrone D. Cannon
- Department of PsychiatryYale UniversityNew HavenConnecticutUSA
- Department of PsychologyYale UniversityNew HavenConnecticutUSA
| | - Stephan Ruhrmann
- Department of Psychiatry and PsychotherapyUniversity of CologneCologneGermany
| | - Daniel H. Mathalon
- Department of PsychologyUCSF School of MedicineSan FranciscoCaliforniaUSA
| | - Philip McGuire
- Department of Psychosis Studies, Institute of Psychiatry, Psychology and NeuroscienceKing's College LondonLondonUK
| | | | - Kristen Daniels
- Boehringer Ingelheim Pharmaceuticals Inc.RidgefieldConnecticutUSA
| | - Daniel Cotton
- Boehringer Ingelheim Pharmaceuticals Inc.RidgefieldConnecticutUSA
| | - Dooti Roy
- Boehringer Ingelheim Pharmaceuticals Inc.RidgefieldConnecticutUSA
| | | | - Michael Sand
- Boehringer Ingelheim Pharmaceuticals Inc.RidgefieldConnecticutUSA
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Sadamura Y, Thapa S, Mizunuma R, Kambe Y, Hirasawa A, Nakamoto K, Tokuyama S, Yoshimoto K, Arita K, Miyata A, Oyoshi T, Kurihara T. FFAR1/GPR40 Contributes to the Regulation of Striatal Monoamine Releases and Facilitation of Cocaine-Induced Locomotor Activity in Mice. Front Pharmacol 2021; 12:699026. [PMID: 34489696 PMCID: PMC8417570 DOI: 10.3389/fphar.2021.699026] [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: 04/22/2021] [Accepted: 07/19/2021] [Indexed: 11/13/2022] Open
Abstract
The free fatty acid receptor 1 (FFAR1) is suggested to function as a G protein-coupled receptor (GPR40) for medium-to-long-chain free fatty acids. Previous studies on the expression of FFAR1 revealed that the nigrostriatal region is one of the areas which express abundant FFAR1 mRNA/protein in the central nervous system (CNS). However, the role of FFAR1 in the CNS has been still largely unclarified. Here, we examined a possible functional role of FFAR1 in the control of extracellular concentrations of striatal monoamines and cocaine-induced locomotor activity. Microdialysis analysis revealed that the basal level of extracellular dopamine (DA) was significantly elevated, while the basal serotonin (5-HT) level tended to be reduced in the striatum of FFAR1 knockout (-/-) mice. Interestingly, local application of a FFAR1 agonist, GW9508, markedly augmented the striatal 5-HT release in FFAR1 wild-type (+/+) mice, whereas topical application of a FFAR1 antagonist, GW1100, significantly reduced the 5-HT release. However, the enhanced 5-HT release was completely lost in -/- mice. Although acute administration of cocaine enhanced the locomotor activity in both +/+ and -/- mice, the magnitude of the enhancement was significantly reduced in -/- mice. In addition, intraperitoneal injection of GW1100 significantly decreased the cocaine-induced locomotor enhancement. These results suggest that FFAR1 has a facilitatory role in striatal 5-HT release, and the evoked 5-HT release might contribute to enhance cocaine-induced locomotor activity.
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Affiliation(s)
- Yuko Sadamura
- Department of Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.,Department of Neurosurgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Shanta Thapa
- Department of Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.,Department of Neurosurgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Ryota Mizunuma
- Department of Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Yuki Kambe
- Department of Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Akira Hirasawa
- Department of Genomic Drug Discovery Science, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
| | - Kazuo Nakamoto
- Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Kobe Gakuin University, Hyogo, Japan
| | - Shogo Tokuyama
- Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Kobe Gakuin University, Hyogo, Japan
| | - Koji Yoshimoto
- Department of Neurosurgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Kazunori Arita
- Department of Neurosurgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Atsuro Miyata
- Department of Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Tatsuki Oyoshi
- Department of Neurosurgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Takashi Kurihara
- Department of Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
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Nutrition, Exercise, and Stress Management for Treatment and Prevention of Psychiatric Disorders. A Narrative Review Psychoneuroendocrineimmunology-Based. ENDOCRINES 2021. [DOI: 10.3390/endocrines2030022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Psychoneuroendocrineimmunology (PNEI) brings together knowledge acquired since the 1930s from endocrinology, immunology, neuroscience, and psychology. With PNEI, a model of research and interpretation of health and disease is emerging, which sees the human body as a structured and interconnected unit, where the psychological and biological systems are mutually coordinated. In the PNEI view, many factors could influence mental health, with the endocrine system involved in mediating the effects of environmental stress on mental health and inflammation in the onset and course of psychiatric disorders as a result of individual and collective conditions and behaviors. Among these, nutrition is one way by which the environment impacts physiology: indeed, many pieces of research showed that several elements (e.g., probiotics, fish oil, zinc) have a positive effect on mental disorders thus being potentially augmentation agents in treatment. Still, physical activity can moderate depressive symptoms, while prolonged stress increases the risk of psychopathology. Taken together, the PNEI-based approach may inform prevention and treatment strategies, also in the field of mental health care.
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Shared Biological Pathways between Antipsychotics and Omega-3 Fatty Acids: A Key Feature for Schizophrenia Preventive Treatment? Int J Mol Sci 2021; 22:ijms22136881. [PMID: 34206945 PMCID: PMC8269187 DOI: 10.3390/ijms22136881] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 06/18/2021] [Accepted: 06/23/2021] [Indexed: 12/25/2022] Open
Abstract
Schizophrenia typically emerges during adolescence, with progression from an ultra-high risk state (UHR) to the first episode of psychosis (FEP) followed by a chronic phase. The detailed pathophysiology of schizophrenia and the factors leading to progression across these stages remain relatively unknown. The current treatment relies on antipsychotics, which are effective for FEP and chronic schizophrenia but ineffective for UHR patients. Antipsychotics modulate dopaminergic and glutamatergic neurotransmission, inflammation, oxidative stress, and membrane lipids pathways. Many of these biological pathways intercommunicate and play a role in schizophrenia pathophysiology. In this context, research of preventive treatment in early stages has explored the antipsychotic effects of omega-3 supplementation in UHR and FEP patients. This review summarizes the action of omega-3 in various biological systems involved in schizophrenia. Similar to antipsychotics, omega-3 supplementation reduces inflammation and oxidative stress, improves myelination, modifies the properties of cell membranes, and influences dopamine and glutamate pathways. Omega-3 supplementation also modulates one-carbon metabolism, the endocannabinoid system, and appears to present neuroprotective properties. Omega-3 has little side effects compared to antipsychotics and may be safely prescribed for UHR patients and as an add-on for FEP patients. This could to lead to more efficacious individualised treatments, thus contributing to precision medicine in psychiatry.
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31
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Higher Dietary Inflammation in Patients with Schizophrenia: A Case-Control Study in Korea. Nutrients 2021; 13:nu13062033. [PMID: 34199231 PMCID: PMC8231973 DOI: 10.3390/nu13062033] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 06/07/2021] [Accepted: 06/09/2021] [Indexed: 11/16/2022] Open
Abstract
Inflammation is a risk factor for the onset and progression of schizophrenia, and dietary factors are related to chronic inflammation. We investigated whether the dietary inflammatory index (DII) is associated with schizophrenia in the Korean population. Of the 256 subjects who responded to the questionnaire, 184 subjects (117 controls; 67 individuals with schizophrenia) were included in this case-control study. A semi-quantitative food frequency questionnaire was used to evaluate the dietary intakes of the study participants. The energy-adjusted DII (E-DII) was used to assess the inflammatory potential of the participants' diets. Dietary intakes of vitamin C, niacin, and folate were significantly reduced in the patients with schizophrenia. The patients with schizophrenia had higher E-DII scores than the controls (p = 0.011). E-DII was positively associated with schizophrenia (odds ratio = 1.254, p = 0.010). The additional analysis confirmed that E-DII was significantly associated with schizophrenia, especially in the third tertile group of E-DII scores (odds ratio = 2.731, p = 0.016). Our findings suggest that patients with schizophrenia have more pro-inflammatory diets.
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32
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Mei C, van der Gaag M, Nelson B, Smit F, Yuen HP, Berger M, Krcmar M, French P, Amminger GP, Bechdolf A, Cuijpers P, Yung AR, McGorry PD. Preventive interventions for individuals at ultra high risk for psychosis: An updated and extended meta-analysis. Clin Psychol Rev 2021; 86:102005. [PMID: 33810885 DOI: 10.1016/j.cpr.2021.102005] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 01/14/2021] [Accepted: 03/01/2021] [Indexed: 02/06/2023]
Abstract
Intervention at the earliest illness stage, in ultra or clinical high-risk individuals, or indicated prevention, currently represents the most promising strategy to ameliorate, delay or prevent psychosis. We review the current state of evidence and conduct a broad-spectrum meta-analysis of various outcomes: transition to psychosis, attenuated positive and negative psychotic symptoms, mania, depression, anxiety, general psychopathology, symptom-related distress, functioning, quality of life, and treatment acceptability. 26 randomized controlled trials were included. Meta-analytically pooled interventions reduced transition rate (risk ratio [RR] = 0.57, 95%CI 0.41-0.81) and attenuated positive psychotic symptoms at 12-months (standardized mean difference = -0.15, 95%CI = -0.28--0.01). When stratified by intervention type (pharmacological, psychological), only the pooled effect of psychological interventions on transition rate was significant. Cognitive behavioral therapy (CBT) was associated with a reduction in incidence at 12-months (RR = 0.52, 95%CI = 0.33-0.82) and 18-48-months (RR = 0.60, 95%CI = 0.42-0.84), but not 6-months. Findings at 12-months and 18-48-months were robust in sensitivity and subgroup analyses. All other outcomes were non-significant. To date, effects of trialed treatments are specific to transition and, a lesser extent, attenuated positive symptoms, highlighting the future need to target other symptom domains and functional outcomes. Sound evidence supports CBT in reducing transition and the value of intervening at this illness stage. STUDY REGISTRATION: Research Registry ID: reviewregistry907.
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Affiliation(s)
- Cristina Mei
- Orygen, Parkville, VIC, Australia; Centre for Youth Mental Health, The University of Melbourne, Parkville, VIC, Australia
| | - Mark van der Gaag
- Department of Clinical, Neuro and Developmental Psychology, Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands; Parnassia Psychiatric Institute, The Hague, the Netherlands.
| | - Barnaby Nelson
- Orygen, Parkville, VIC, Australia; Centre for Youth Mental Health, The University of Melbourne, Parkville, VIC, Australia
| | - Filip Smit
- Department of Clinical, Neuro and Developmental Psychology, Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands; Trimbos Institute, Netherlands Institute of Mental Health and Addiction, Centre of Mental Health and Prevention, Utrecht, the Netherlands; Department of Epidemiology and Biostatistics, Amsterdam University Medical Centres, Amsterdam, the Netherlands
| | - Hok Pan Yuen
- Orygen, Parkville, VIC, Australia; Centre for Youth Mental Health, The University of Melbourne, Parkville, VIC, Australia
| | - Maximus Berger
- Orygen, Parkville, VIC, Australia; Centre for Youth Mental Health, The University of Melbourne, Parkville, VIC, Australia
| | - Marija Krcmar
- Orygen, Parkville, VIC, Australia; Centre for Youth Mental Health, The University of Melbourne, Parkville, VIC, Australia
| | - Paul French
- School of Health Sciences, University of Manchester, Manchester, UK
| | - G Paul Amminger
- Orygen, Parkville, VIC, Australia; Centre for Youth Mental Health, The University of Melbourne, Parkville, VIC, Australia
| | - Andreas Bechdolf
- Department of Psychiatry, Psychotherapy and Psychosomatic Medicine, Vivantes Klinikum am Urban, Charite-Universitätsmedizin, Berlin, Germany; Department of Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany
| | - Pim Cuijpers
- Department of Clinical, Neuro and Developmental Psychology, Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Alison R Yung
- Orygen, Parkville, VIC, Australia; Centre for Youth Mental Health, The University of Melbourne, Parkville, VIC, Australia; School of Health Sciences, University of Manchester, Manchester, UK
| | - Patrick D McGorry
- Orygen, Parkville, VIC, Australia; Centre for Youth Mental Health, The University of Melbourne, Parkville, VIC, Australia.
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da Costa AEM, Gomes NS, Gadelha Filho CVJ, Linhares MGOES, da Costa RO, Chaves Filho AJM, Cordeiro RC, Vasconcelos GS, da Silva FER, Araujo TDS, Vasconcelos SMM, Lucena DF, Macêdo DS. Sex influences in the preventive effects of peripubertal supplementation with N-3 polyunsaturated fatty acids in mice exposed to the two-hit model of schizophrenia. Eur J Pharmacol 2021; 897:173949. [PMID: 33607108 DOI: 10.1016/j.ejphar.2021.173949] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 01/30/2021] [Accepted: 02/11/2021] [Indexed: 01/05/2023]
Abstract
Schizophrenia is a devastating neurodevelopmental disorder. The animal model based on perinatal immune activation, as first-hit, combined with peripubertal stress, as a second hit, has gained evidence in recent years. Omega-3 polyunsaturated fatty acids (n3-PUFAs) is being a promise for schizophrenia prevention. Nevertheless, the influence of sex in schizophrenia neurobiology and prevention has been neglected. Thus, the present study evaluates the preventive effects of n3-PUFAs in both sexes' mice submitted to the two-hit model and the participation of oxidative changes in this mechanism. The two-hit consisted of polyI:C administration from postnatal days (PNs) 5-7, and unpredictable stress from PNs35-43. n3-PUFAs were administered from PNs30-60. Prepulse inhibition of the startle reflex (PPI), social interaction, and Y-maze tests were conducted between PNs70-72 to evaluate positive-, negative-, and cognitive-like schizophrenia symptoms. We assessed brain oxidative changes in brain areas and plasma. Both sexes' two-hit mice presented deficits in PPI, social interaction, and working memory that were prevented by n3-PUFAs. In two-hit females, n3-PUFAs prevented increments in nitrite levels in the prefrontal cortex (PFC), hippocampus, striatum, and plasma TBARS levels. In two-hit males, n3-PUFAs prevented the increase in TBARS in the PFC, hippocampus, and striatum. Notably, male mice that received only n3-PUFAs without hit exposure presented impairments in working memory and social interaction. These results add further preclinical evidence for n3-PUFAs as an accessible and effective alternative in preventing behavioral and oxidative changes related to schizophrenia but call attention to the need for precaution in this indication due to hit- and sex-sensitive issues.
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Affiliation(s)
- Ayane Edwiges Moura da Costa
- Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil
| | - Nayana Soares Gomes
- Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil
| | - Carlos Venício Jatai Gadelha Filho
- Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil
| | | | - Roberta Oliveira da Costa
- Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil
| | - Adriano José Maia Chaves Filho
- Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil
| | - Rafaela Carneiro Cordeiro
- Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil
| | - Germana Silva Vasconcelos
- Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil
| | - Francisco Eliclécio Rodrigues da Silva
- Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil
| | - Tatiane da Silva Araujo
- Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil
| | - Silvânia Maria Mendes Vasconcelos
- Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil
| | - David Freitas Lucena
- Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil
| | - Danielle S Macêdo
- Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil; National Institute for Translational Medicine (INCT-TM, CNPq), Ribeirão Preto, SP, Brazil.
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McGorry PD, Mei C, Hartmann J, Yung AR, Nelson B. Intervention strategies for ultra-high risk for psychosis: Progress in delaying the onset and reducing the impact of first-episode psychosis. Schizophr Res 2021; 228:344-356. [PMID: 33545668 DOI: 10.1016/j.schres.2020.12.026] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Revised: 10/02/2020] [Accepted: 12/31/2020] [Indexed: 12/26/2022]
Abstract
Over a quarter of a century ago, the formulation of the "at risk mental state" and operational criteria to prospectively identify individuals at "clinical" or "ultra-high risk" (UHR) for psychosis created a global wave of research momentum aimed at predicting and preventing first-episode psychosis. A substantial number of randomized controlled trials (RCTs) were conducted to determine if transition to psychosis could be delayed or even prevented. The efficacy of a range of interventions was examined, with standard meta-analyses clearly indicating that these could at least delay transition for 1-2 years and that outcomes improve. Recently, network meta-analyses have attempted to identify the most effective intervention. These highlighted the fact that no one form of intervention is superior to the rest, a finding interpreted in such a way as to create doubts concerning the value of intervening. These doubts have been reinforced by a subsequent Cochrane review which judged the quality of the evidence as low or very low. Here, we report a narrative review of findings from RCTs and meta-analyses on the efficacy of interventions in UHR. We also critique the network meta-analyses and the Cochrane review, and indicate that many of the trials were of the highest possible quality for such research, and were published in top ranked psychiatry journals, which demand such quality. Although outcomes vary, and the UHR group is clearly heterogeneous, we highlight the clinical benefits of psychosocial treatment. The next generation of clinical trials seek to elucidate the optimal type, duration and sequence of interventions.
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Affiliation(s)
- Patrick D McGorry
- Orygen, Parkville, Victoria, Australia; Centre for Youth Mental Health, The University of Melbourne, Parkville, Victoria, Australia.
| | - Cristina Mei
- Orygen, Parkville, Victoria, Australia; Centre for Youth Mental Health, The University of Melbourne, Parkville, Victoria, Australia
| | - Jessica Hartmann
- Orygen, Parkville, Victoria, Australia; Centre for Youth Mental Health, The University of Melbourne, Parkville, Victoria, Australia
| | - Alison R Yung
- Orygen, Parkville, Victoria, Australia; Centre for Youth Mental Health, The University of Melbourne, Parkville, Victoria, Australia; School of Health Sciences, University of Manchester, Manchester, UK
| | - Barnaby Nelson
- Orygen, Parkville, Victoria, Australia; Centre for Youth Mental Health, The University of Melbourne, Parkville, Victoria, Australia
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Ducrocq F, Trifilieff P. [Motivational deficits and polyunsaturated fatty acids]. Med Sci (Paris) 2021; 37:15-18. [PMID: 33492212 DOI: 10.1051/medsci/2020250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Affiliation(s)
- Fabien Ducrocq
- Université de Bordeaux, INRAE, Bordeaux INP Aquitaine, NutriNeuro, 146 rue Léo Saignat, 33000 Bordeaux, France
| | - Pierre Trifilieff
- Université de Bordeaux, INRAE, Bordeaux INP Aquitaine, NutriNeuro, 146 rue Léo Saignat, 33000 Bordeaux, France
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Challenges in researching the immune pathways between early life adversity and psychopathology. Dev Psychopathol 2021; 32:1597-1624. [DOI: 10.1017/s0954579420001157] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
AbstractExposure to childhood adversity is a critical risk factor for the development of psychopathology. A growing field of research examines how exposure to childhood adversity is translated into biological risk for psychopathology through alterations in immune system functioning, most notably heightened levels of inflammation biomarkers. Though our knowledge about how childhood adversity can instantiate biological risk for psychopathology is growing, there remain many challenges and gaps in the field to understand how inflammation from childhood adversity contributes to psychopathology. This paper reviews research on the inflammatory outcomes arising from childhood adversity and presents four major challenges that future research must address: (a) the measurement of childhood adversity, (b) the measurement of inflammation, (c) the identification of mediators between childhood adversity and inflammation, and (d) the identification of moderators of inflammatory outcomes following childhood adversity. We discuss synergies and inconsistencies in the literature to summarize the current understanding of the association between childhood adversity, a proinflammatory phenotype, and the biological risk for psychopathology. We discuss the clinical implications of the inflammatory links between childhood adversity and psychopathology, including possibilities for intervention. Finally, this review conclude by delineates future directions for research, including issues of how best to detect, prevent, and understand these “hidden wounds” of childhood adversity.
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Efficacy of Polyunsaturated Fatty Acids (PUFAs) on Impulsive Behaviours and Aggressiveness in Psychiatric Disorders. Int J Mol Sci 2021; 22:ijms22020620. [PMID: 33435512 PMCID: PMC7826871 DOI: 10.3390/ijms22020620] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 01/06/2021] [Accepted: 01/07/2021] [Indexed: 02/08/2023] Open
Abstract
It is the focus of increasing interest to investigate the effects of long-chain n-3 and long-chain n-6 polyunsaturated fatty acids (LC n-3 PUFAs; LC n-6 PUFAs) on psychiatric symptoms in a transdiagnostic perspective. There is some evidence that low levels of LC n-3 PUFAs and a higher ratio of LC n-6 to LC n-3 PUFAs in plasma and blood cells are associated with aggressive and impulsive behaviours. Therefore, implementation of LC n-3 PUFAs may produce positive effects on hostility, aggression, and impulsivity in both psychiatric and non-psychiatric samples across different stages of life. A possible mechanism of action of LC n-3 PUFAs in conditions characterized by a high level of impulsivity and aggression is due to the effect of these compounds on the serotonin system and membrane stability. Studies that evaluated the effects of LC n-3 PUFAs on impulsivity and aggressiveness indicated that addition of rather low doses of these agents to antipsychotic treatment might reduce agitation and violent behaviours in psychosis, attention deficit hyperactivity disorder, personality disorders, and impulsive control and conduct disorders. The present review is aimed at examining and discussing available data from recent trials on this topic.
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Supplementation with the omega-3 long chain polyunsaturated fatty acids: Changes in the concentrations of omega-3 index, fatty acids and molecular phospholipids of people at ultra high risk of developing psychosis. Schizophr Res 2020; 226:52-60. [PMID: 31606244 DOI: 10.1016/j.schres.2019.08.033] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 08/26/2019] [Accepted: 08/29/2019] [Indexed: 01/03/2023]
Abstract
Omega-3 long chain polyunsaturated fatty acids (n-3 LCPUFA) are necessary for optimum mental health, with recent studies showing low n-3 LCPUFA in people at ultra-high risk (UHR) of developing psychosis. Furthermore, people at UHR of psychosis had increased erythrocyte sphingomyelin (SM) and reduced phosphatidylethanolamine (PE) concentrations as well as 27 erythrocyte phospholipid species that differed when compared to erythrocytes from age matched people not at UHR of psychosis. The aim of this analysis was to evaluate the effect of n-3 supplementation on the different erythrocyte lipid species (including SM and PE concentrations) in people at UHR of psychosis. Participants were randomly assigned to fish oil (containing 840 mg EPA and 560 mg DHA per day) or placebo (paraffin oil) for 6 months. Fasted blood samples were taken at baseline and post intervention. Mass spectrometry was used to analyse the molecular phospholipids and fatty acid composition of erythrocytes for both groups. The n-3 index was significantly increased from 3.0% to 4.12% after 6 months of receiving n-3 capsules. Fish oil capsules increased the phospholipid molecular species containing n-3 LCPUFA, and concomitant decreases in n-6 LCPUFA species. SM species did not show any significant changes in n-3 LCPUFA group however, three SM species (SM 16:0, SM 18:0, SM 18:1) significantly increased after 6 months of supplementation with placebo. N-3 supplementation for 6 months led to higher n-3 incorporation into erythrocytes, at the expense of n-6 PUFA across all phospholipid classes analyzed and may have prevented the increase in SM seen in the placebo group.
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Alqarni A, Mitchell TW, McGorry PD, Nelson B, Markulev C, Yuen HP, Schäfer MR, Berger M, Mossaheb N, Schlögelhofer M, Smesny S, Hickie IB, Berger GE, Chen EYH, de Haan L, Nieman DH, Nordentoft M, Riecher-Rössler A, Verma S, Thompson A, Yung AR, Amminger GP, Meyer BJ. Comparison of erythrocyte omega-3 index, fatty acids and molecular phospholipid species in people at ultra-high risk of developing psychosis and healthy people. Schizophr Res 2020; 226:44-51. [PMID: 31301881 DOI: 10.1016/j.schres.2019.06.020] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Revised: 06/19/2019] [Accepted: 06/22/2019] [Indexed: 12/12/2022]
Abstract
People classified as ultra-high risk (UHR) of developing psychosis have reduced cellular membrane omega-3 and omega-6 polyunsaturated fatty acids (PUFA). We aimed to compare omega-3 index, fatty acids and molecular phospholipid species from erythrocytes of people with UHR (n = 285) with age-matched healthy controls (n = 120) assessed by mass spectrometry. Lower proportions of PUFA were observed in the UHR group compared to healthy controls; specifically, eicosapentaenoic acid (EPA) was 29.3% lower, docosahexaenoic acid (DHA) was 27.2% lower, arachidonic acid (AA) was 15.8% lower and the omega-3 index was 26.9% lower. The AA to EPA ratio was higher in the UHR group compared to the healthy group. Smoking status had no significant effect on PUFA levels in healthy or the UHR groups. BMI was associated with PUFA levels in the UHR group only and the statistical model only explains 2% of the variance of the PUFA levels. The proportion of nervonic acid was 64.4% higher in the UHR group compared to healthy controls. At a lipid class level, the UHR group had 16% higher concentrations of sphingomyelin (SM) and 46% lower concentrations phosphatidylethanolamine (PE) compared to healthy group. Of the 49 individual molecular phospholipids, twenty-seven phospholipid species were lower in the UHR group. In conclusion, there are clear differences in the proportions of erythrocyte fatty acids and phospholipids between UHR and healthy controls and UHR had higher concentrations of SM and lower concentrations of PE. These differences may represent a promising prodromal risk biomarker in the UHR population to aid clinical diagnosis.
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Affiliation(s)
- Ayedh Alqarni
- School of Medicine, Molecular Horizons, Lipid Research Centre, University of Wollongong, and Illawarra Health & Medical Research Institute, Wollongong, Australia; King Fahad Specialist Hospital, Dammam City, Saudi Arabia
| | - Todd W Mitchell
- School of Medicine, Molecular Horizons, Lipid Research Centre, University of Wollongong, and Illawarra Health & Medical Research Institute, Wollongong, Australia
| | - Patrick D McGorry
- Orygen - The National Centre of Excellence in Youth Mental Health, Parkville, Australia; The Centre for Youth Mental Health, The University of Melbourne, Melbourne, Australia
| | - Barnaby Nelson
- Orygen - The National Centre of Excellence in Youth Mental Health, Parkville, Australia; The Centre for Youth Mental Health, The University of Melbourne, Melbourne, Australia
| | - Connie Markulev
- Orygen - The National Centre of Excellence in Youth Mental Health, Parkville, Australia; The Centre for Youth Mental Health, The University of Melbourne, Melbourne, Australia
| | - Hok Pan Yuen
- Orygen - The National Centre of Excellence in Youth Mental Health, Parkville, Australia; The Centre for Youth Mental Health, The University of Melbourne, Melbourne, Australia
| | - Miriam R Schäfer
- Orygen - The National Centre of Excellence in Youth Mental Health, Parkville, Australia; The Centre for Youth Mental Health, The University of Melbourne, Melbourne, Australia
| | - Maximus Berger
- Orygen - The National Centre of Excellence in Youth Mental Health, Parkville, Australia; The Centre for Youth Mental Health, The University of Melbourne, Melbourne, Australia
| | - Nilufar Mossaheb
- Department of Psychiatry, Medical University of Vienna, Vienna, Austria
| | | | - Stefan Smesny
- Department of Psychiatry, University Hospital Jena, Jena, Germany
| | - Ian B Hickie
- Brain and Mind Research Institute, University of Sydney, Sydney, Australia
| | - Gregor E Berger
- Department of Child and Adolescent Psychiatry and Psychotherapy, University Hospital of Psychiatry Zurich, University of Zurich, Zurich, Switzerland
| | - Eric Y H Chen
- Department of Psychiatry, University of Hong Kong, Hong Kong
| | - Lieuwe de Haan
- Department of Psychiatry, Amsterdam University Medical Centers (location AMC), Amsterdam, the Netherlands
| | - Dorien H Nieman
- Department of Psychiatry, Amsterdam University Medical Centers (location AMC), Amsterdam, the Netherlands
| | | | | | - Swapna Verma
- Institute of Mental Health, Singapore, Singapore
| | - Andrew Thompson
- Division of Mental Health and Wellbeing, Warwick Medical School, University of Warwick, Coventry, England, United Kingdom of Great Britain and Northern Ireland; North Warwickshire Early Intervention in Psychosis Service, Coventry and Warwickshire National Health Service Partnership Trust, Coventry, England, United Kingdom of Great Britain and Northern Ireland
| | - Alison Ruth Yung
- Institute of Brain, Behaviour, and Mental Health, University of Manchester, Manchester, England, United Kingdom of Great Britain and Northern Ireland; Greater Manchester West National Health Service Mental Health Foundation Trust, Manchester, England, United Kingdom of Great Britain and Northern Ireland
| | - G Paul Amminger
- Orygen - The National Centre of Excellence in Youth Mental Health, Parkville, Australia; The Centre for Youth Mental Health, The University of Melbourne, Melbourne, Australia
| | - Barbara J Meyer
- School of Medicine, Molecular Horizons, Lipid Research Centre, University of Wollongong, and Illawarra Health & Medical Research Institute, Wollongong, Australia.
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Jung T, Hudson R, Rushlow W, Laviolette SR. Functional interactions between cannabinoids, omega-3 fatty acids, and peroxisome proliferator-activated receptors: Implications for mental health pharmacotherapies. Eur J Neurosci 2020; 55:1088-1100. [PMID: 33108021 DOI: 10.1111/ejn.15023] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 09/08/2020] [Accepted: 10/16/2020] [Indexed: 12/18/2022]
Abstract
Cannabis contains a plethora of phytochemical constituents with diverse neurobiological effects. Cannabidiol (CBD) is the main non-psychotropic component found in cannabis that is capable of modulating mesocorticolimbic DA transmission and may possess therapeutic potential for several neuropsychiatric disorders. Emerging evidence also suggests that, similar to CBD, omega-3 polyunsaturated fatty acids may regulate DA transmission and possess therapeutic potential for similar neuropsychiatric disorders. Although progress has been made to elucidate the mechanisms underlying the therapeutic properties of CBD and omega-3s, it remains unclear through which receptor mechanisms they may produce their purported effects. Peroxisome proliferator-activated receptors are a group of nuclear transcription factors with multiple isoforms. PPARγ is an isoform activated by both CBD and omega-3, whereas the PPARα isoform is activated by omega-3. Interestingly, the activation of PPARγ and PPARα with selective agonists has been shown to decrease mesocorticolimbic DA activity and block neuropsychiatric symptoms similar to CBD and omega-3s, raising the possibility that CBD and omega-3s produce their effects through PPAR signaling. This review will examine the relationship between CBD, omega-3s, and PPARs and how they may be implicated in the modulation of mesocorticolimbic DAergic abnormalities and associated neuropsychiatric symptoms.
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Affiliation(s)
- Tony Jung
- Addiction Research Group, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON, Canada.,Department of Anatomy & Cell Biology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON, Canada
| | - Roger Hudson
- Addiction Research Group, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON, Canada.,Department of Anatomy & Cell Biology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON, Canada
| | - Walter Rushlow
- Addiction Research Group, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON, Canada.,Department of Anatomy & Cell Biology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON, Canada.,Department of Psychiatry, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON, Canada
| | - Steven R Laviolette
- Addiction Research Group, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON, Canada.,Department of Anatomy & Cell Biology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON, Canada.,Department of Psychiatry, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON, Canada
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Thompson AD, Jones HJ, Heron J, Hibbeln J, Sullivan S, Zammit S. Omega-3 and Omega-6 fatty acids and risk of psychotic outcomes in the ALSPAC birth cohort. Schizophr Res 2020; 224:108-115. [PMID: 33067055 PMCID: PMC7738752 DOI: 10.1016/j.schres.2020.09.018] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Revised: 06/12/2020] [Accepted: 09/23/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND Long chain polyunsaturated fatty acid (PUFA) levels have been implicated in the pathology of psychotic disorders. We investigated the relationship between childhood PUFA levels and later psychotic experiences (PE's) in a large birth cohort. METHODS Plasma levels of Ω-3 and Ω-6 fatty acids (FA's) were assayed at ages 7 and 16 years. PE's were assessed at ages 12 and 18 years using a semi-structured interview. Primary outcome was any PE's at 18 years; sensitivity analyses examined incident PE's between ages 12 and 18 years, persistent PE's (at 12 and 18) and psychotic disorder at 18 years. Genetic instruments for Ω-3 and Ω-6 were derived and used in a multivariable Mendelian Randomization analysis. RESULTS Higher levels of Ω-6 FA's AA, OA and AdA at age 7 years were weakly associated with a reduced risk for PE's at 18 years, however, effect sizes were small and attenuated after adjusting for confounders (strongest evidence for OA; adjusted OR, 0.842; 95% CI, 0.711, 0.998; p, 0.048). Total Ω-6 levels at age 16 years were associated with an increased odds of psychotic disorder at age 18 years. However, there was no association between Ω-6/Ω-3 ratio and psychosis outcomes, nor with genetic instruments of total Ω-3 or Ω-6 levels. CONCLUSIONS There is no strong evidence that total plasma Ω-3 FA levels or Ω-6/Ω-3 ratios in childhood and mid-adolescence are associated with increased risk for PE's or psychotic disorder, but very marginal evidence that alterations in the Ω-6 pathway at developmental time points might influence risk2.
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Affiliation(s)
- A D Thompson
- Division of Mental Health and Wellbeing, University of Warwick, UK; Orygen, the Centre of Excellence in Youth Mental Health, 35 Poplar Rd, Parkville, VIC 3250, Australia.
| | - H J Jones
- Centre for Academic Mental Health, Bristol Medical School, University of Bristol, Bristol, UK; NIHR Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust, University of Bristol, UK
| | - J Heron
- Centre for Academic Mental Health, Bristol Medical School, University of Bristol, Bristol, UK
| | - J Hibbeln
- Laboratory of Membrane Biochemistry and Biophysics, Section of Nutritional Neuroscience, National Institute for Health, Bethesda, USA
| | - S Sullivan
- Centre for Academic Mental Health, Bristol Medical School, University of Bristol, Bristol, UK; NIHR CLAHRC West, Whitefriars, Lewins Mead, Bristol, UK
| | - S Zammit
- Centre for Academic Mental Health, Bristol Medical School, University of Bristol, Bristol, UK; NIHR Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust, University of Bristol, UK; MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK
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Bozzatello P, De Rosa ML, Rocca P, Bellino S. Effects of Omega 3 Fatty Acids on Main Dimensions of Psychopathology. Int J Mol Sci 2020; 21:ijms21176042. [PMID: 32839416 PMCID: PMC7504659 DOI: 10.3390/ijms21176042] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 08/11/2020] [Accepted: 08/19/2020] [Indexed: 12/12/2022] Open
Abstract
The usefulness of polyunsaturated fatty acids on inflammatory, cardiovascular, and the nervous system was studied in the last decades, but the mechanisms underlying their benefic properties are still partially unknown. These agents seem to express their action on the membrane phospholipid composition and permeability and modulation of second messenger cascades. In psychiatry, the efficacy and tolerability of omega-3 fatty acids were investigated in several psychiatric disorders, including major depression, bipolar disorder, personality disorders, high-risk conditions to develop psychosis, attention-deficit hyperactivity disorder, and autism spectrum disorders. Initial findings in this field are promising, and some relevant questions need to be addressed. In particular, the effects of these agents on the main symptom dimensions have to be investigated in a trans-diagnostic perspective. The present systematic review is aimed to examine the available data on the efficacy of omega-3 fatty acids on domains of psychotic symptoms, affective symptoms, impulsivity, and aggressiveness, and harmful behaviors, and suicide risk.
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Affiliation(s)
- Paola Bozzatello
- Department of Neuroscience, Faculty of Medicine, University of Turin, 10126 Turin, Italy; (P.B.); (M.L.D.R.); (P.R.)
- Center for Personality Disorders, Psychiatric Clinic, 10126 Turin, Italy
| | - Maria Laura De Rosa
- Department of Neuroscience, Faculty of Medicine, University of Turin, 10126 Turin, Italy; (P.B.); (M.L.D.R.); (P.R.)
- Center for Personality Disorders, Psychiatric Clinic, 10126 Turin, Italy
| | - Paola Rocca
- Department of Neuroscience, Faculty of Medicine, University of Turin, 10126 Turin, Italy; (P.B.); (M.L.D.R.); (P.R.)
| | - Silvio Bellino
- Department of Neuroscience, Faculty of Medicine, University of Turin, 10126 Turin, Italy; (P.B.); (M.L.D.R.); (P.R.)
- Center for Personality Disorders, Psychiatric Clinic, 10126 Turin, Italy
- Correspondence: ; Tel.: +39-011-6634848; Fax: +39-011-673473
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Hsu MC, Huang YS, Ouyang WC. Beneficial effects of omega-3 fatty acid supplementation in schizophrenia: possible mechanisms. Lipids Health Dis 2020; 19:159. [PMID: 32620164 PMCID: PMC7333328 DOI: 10.1186/s12944-020-01337-0] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 06/24/2020] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Schizophrenia is a serious long-term psychotic disorder marked by positive and negative symptoms, severe behavioral problems and cognitive function deficits. The cause of this disorder is not completely clear, but is suggested to be multifactorial, involving both inherited and environmental factors. Since human brain regulates all behaviour, studies have focused on identifying changes in neurobiology and biochemistry of brain in schizophrenia. Brain is the most lipid rich organ (approximately 50% of brain dry weight). Total brain lipids is constituted of more than 60% of phospholipids, in which docosahexaenoic acid (DHA, 22:6n-3) is the most abundant (more than 40%) polyunsaturated fatty acid (PUFA) in brain membrane phospholipids. Results from numerous studies have shown significant decreases of PUFAs, in particular, DHA in peripheral blood (plasma and erythrocyte membranes) as well as brain of schizophrenia patients at different developmental phases of the disorder. PUFA deficiency has been associated to psychotic symptoms and cognitive deficits in schizophrenia. These findings have led to a number of clinical trials examining whether dietary omega-3 fatty acid supplementation could improve the course of illness in patients with schizophrenia. Results are inconsistent. Some report beneficial whereas others show not effective. The discrepancy can be attributed to the heterogeneity of patient population. METHODS In this review, results from recent experimental and clinical studies, which focus on illustrating the role of PUFAs in the development of schizophrenia were examined. The rationale why omega-3 supplementation was beneficial on symptoms (presented by subscales of the positive and negative symptom scale (PANSS), and cognitive functions in certain patients but not others was reviewed. The potential mechanisms underlying the beneficial effects were discussed. RESULTS Omega-3 fatty acid supplementation reduced the conversion rate to psychosis and improved both positive and negative symptoms and global functions in adolescents at ultra-high risk for psychosis. Omega-3 fatty acid supplementation could also improve negative symptoms and global functions in the first-episode patients with schizophrenia, but improve mainly total or general PANSS subscales in chronic patients. Patients with low PUFA (particularly DHA) baseline in blood were more responsive to the omega-3 fatty acid intervention. CONCLUSION Omega-3 supplementation is more effective in reducing psychotic symptom severity in young adults or adolescents in the prodromal phase of schizophrenia who have low omega-3 baseline. Omega-3 supplementation was more effective in patients with low PUFA baseline. It suggests that patients with predefined lipid levels might benefit from lipid treatments, but more controlled clinical trials are warranted.
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Affiliation(s)
- Mei-Chi Hsu
- Department of Nursing, I-Shou University, No.8, Yida Road, Jiaosu Village Yanchao District, Kaohsiung, 82445 Taiwan
| | - Yung-Sheng Huang
- College of Medicine, I-Shou University, No.8, Yida Road, Jiaosu Village Yanchao District, Kaohsiung, 82445 Taiwan
| | - Wen-Chen Ouyang
- Department of Geriatric Psychiatry, Jianan Psychiatric Center, Ministry of Health and Welfare, No.539, Yuzhong Rd., Rende Dist., Tainan City, 71742 Taiwan
- Department of Nursing, Shu-Zen Junior College of Medicine and Management, No.452, Huanqiu Rd. Luzhu Dist, Kaohsiung, 82144 Taiwan
- Department of Psychiatry, College of Medicine, Kaohsiung Medical University, No.100, Shin-Chuan 1st Road, Sanmin Dist., Kaohsiung, 80708 Taiwan
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Post RM, Goldstein BI, Birmaher B, Findling RL, Frey BN, DelBello MP, Miklowitz DJ. Toward prevention of bipolar disorder in at-risk children: Potential strategies ahead of the data. J Affect Disord 2020; 272:508-520. [PMID: 32553395 PMCID: PMC8986089 DOI: 10.1016/j.jad.2020.03.025] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Revised: 02/03/2020] [Accepted: 03/05/2020] [Indexed: 01/03/2023]
Abstract
BACKGROUND Despite the well-documented negative impact of untreated bipolar illness, approaches to early intervention in childhood-onset bipolar and related disorders are not well delineated. METHODS We reviewed the extant treatment literature on children at high risk for bipolar disorder, with definitions based on family history, childhood adversity, and prodromal symptoms. RESULTS A panoply of approaches have been described, but most interventions are based on an inadequate database to support their routine implementation. We classify early stage interventions as a function of their safety and tolerability with the hope that these might generate more rigorous study and a stronger database. LIMITATIONS Critics may rightly argue that identifying viable treatment methods is premature given our lack of ability to reliably predict illness trajectory in very young children. However, many of the psychosocial and pharmacological interventions we present could have nonspecific positive effects across a variety of symptoms, syndromes, and diagnoses, further enhancing the rationale for more rigorous study. CONCLUSIONS Early stage interventions have the potential to improve functioning in prodromal illness and exert long-term positive effects on the course of illness. Many of the safest interventions deserve consideration for implementation and dissemination studies.
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Affiliation(s)
- Robert M Post
- Bipolar Collaborative Network, Professor of Psychiatry George Washington Medical School, Bethesda, MD, Washington, DC, United States.
| | - Benjamin I Goldstein
- Departments of Psychiatry and Pharmacology, University of Toronto; Centre for Youth Bipolar Disorder, Sunnybrook Health Sciences Centre, Canada
| | - Boris Birmaher
- University of Pittsburgh School of Medicine, Psychiatry Research Pathway, United States
| | - Robert L Findling
- Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, United States
| | - Benicio N Frey
- Mood Disorders Program, Department of Psychiatry and Behavioural Neurosciences, Women's Health Concerns Clinic, St. Joseph's Healthcare Hamilton, ON, Canada
| | - Melissa P DelBello
- University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - David J Miklowitz
- Psychiatry and Biobehavioral Sciences, UCLA Semel Institute for Neuroscience and Behavior, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
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Farris MS, Shakeel MK, Addington J. Cannabis use in individuals at clinical high-risk for psychosis: a comprehensive review. Soc Psychiatry Psychiatr Epidemiol 2020; 55:527-537. [PMID: 31796983 DOI: 10.1007/s00127-019-01810-x] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Accepted: 11/28/2019] [Indexed: 12/16/2022]
Abstract
PURPOSE The objectives of this review were to understand the prevalence of cannabis use and how cannabis is associated with transition to psychosis, symptoms, cognition, trauma and family history in clinical high risk (CHR) for psychosis individuals. METHOD A systematic literature review was conducted to find studies that examined cannabis use in CHR individuals, with no limitations on the geographical area, and included publications up to November 2018. Studies were screened for inclusion based on detailed criteria, and data were extracted on cannabis use and associated outcomes. A quantitative synthesis by meta-analysis was performed where appropriate, otherwise, a qualitative synthesis was conducted. RESULTS Overall, 36 studies met inclusion criteria with an average age of 20.1 years and 58.4% males. Prevalence of lifetime cannabis use was 48.7%, whereas current cannabis use was 25.8% and the prevalence of cannabis use disorder/abuse or dependence was 14.9% across the studies. All cannabis use results had statistically significant heterogeneity ranging from 75.7 to 92.8%. The most commonly reported association with cannabis use was transition to psychosis, although the pooled relative risk (RR) was not statistically significant (RR = 1.11, 95% confidence interval = 0.89-1.37). For all other outcomes including symptoms, cognition, trauma, and family history, the evidence was limited, and therefore, the results were synthesized qualitatively. CONCLUSION Almost half of CHR individuals have ever used cannabis. However, cannabis use has not been thoroughly researched regarding frequency and dose of use, and how other factors, such as symptoms, are associated with cannabis in CHR individuals.
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Affiliation(s)
- Megan S Farris
- Hotchkiss Brain Institute, Department of Psychiatry, Mathison Centre for Mental Health Research and Education, University of Calgary, 3280 Hospital Drive NW, Calgary, AB, T2N 4Z6, Canada
| | - Mohammed K Shakeel
- Hotchkiss Brain Institute, Department of Psychiatry, Mathison Centre for Mental Health Research and Education, University of Calgary, 3280 Hospital Drive NW, Calgary, AB, T2N 4Z6, Canada
| | - Jean Addington
- Hotchkiss Brain Institute, Department of Psychiatry, Mathison Centre for Mental Health Research and Education, University of Calgary, 3280 Hospital Drive NW, Calgary, AB, T2N 4Z6, Canada.
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Ni P, Chung S. Mitochondrial Dysfunction in Schizophrenia. Bioessays 2020; 42:e1900202. [PMID: 32338416 DOI: 10.1002/bies.201900202] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Revised: 02/29/2020] [Indexed: 02/05/2023]
Abstract
Schizophrenia (SCZ) is a severe neurodevelopmental disorder affecting 1% of populations worldwide with a grave disability and socioeconomic burden. Current antipsychotic medications are effective treatments for positive symptoms, but poorly address negative symptoms and cognitive symptoms, warranting the development of better treatment options. Further understanding of SCZ pathogenesis is critical in these endeavors. Accumulating evidence has pointed to the role of mitochondria and metabolic dysregulation in SCZ pathogenesis. This review critically summarizes recent studies associating a compromised mitochondrial function with people with SCZ, including postmortem studies, imaging studies, genetic studies, and induced pluripotent stem cell studies. This review also discusses animal models with mitochondrial dysfunction resulting in SCZ-relevant neurobehavioral abnormalities, as well as restoration of mitochondrial function as potential therapeutic targets. Further understanding of mitochondrial dysfunction in SCZ may open the door to develop novel therapeutic strategies that can address the symptoms that cannot be adequately addressed by current antipsychotics alone.
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Affiliation(s)
- Peiyan Ni
- Psychiatric Laboratory and Mental Health Center, The State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Sangmi Chung
- Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY, 10595, USA
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47
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Ducrocq F, Walle R, Contini A, Oummadi A, Caraballo B, van der Veldt S, Boyer ML, Aby F, Tolentino-Cortez T, Helbling JC, Martine L, Grégoire S, Cabaret S, Vancassel S, Layé S, Kang JX, Fioramonti X, Berdeaux O, Barreda-Gómez G, Masson E, Ferreira G, Ma DWL, Bosch-Bouju C, De Smedt-Peyrusse V, Trifilieff P. Causal Link between n-3 Polyunsaturated Fatty Acid Deficiency and Motivation Deficits. Cell Metab 2020; 31:755-772.e7. [PMID: 32142670 DOI: 10.1016/j.cmet.2020.02.012] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Revised: 12/02/2019] [Accepted: 02/13/2020] [Indexed: 01/11/2023]
Abstract
Reward-processing impairment is a common symptomatic dimension of several psychiatric disorders. However, whether the underlying pathological mechanisms are common is unknown. Herein, we asked if the decrease in the n-3 polyunsaturated fatty acid (PUFA) lipid species, consistently described in these pathologies, could underlie reward-processing deficits. We show that reduced n-3 PUFA biostatus in mice leads to selective motivational impairments. Electrophysiological recordings revealed increased collateral inhibition of dopamine D2 receptor-expressing medium spiny neurons (D2-MSNs) onto dopamine D1 receptor-expressing MSNs in the nucleus accumbens, a main brain region for the modulation of motivation. Strikingly, transgenically preventing n-3 PUFA deficiency selectively in D2-expressing neurons normalizes MSN collateral inhibition and enhances motivation. These results constitute the first demonstration of a causal link between a behavioral deficit and n-3 PUFA decrease in a discrete neuronal population and suggest that lower n-3 PUFA biostatus in psychopathologies could participate in the etiology of reward-related symptoms.
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Affiliation(s)
- Fabien Ducrocq
- Université Bordeaux, INRAE, Bordeaux INP, NutriNeuro, 33000, Bordeaux, France.
| | - Roman Walle
- Université Bordeaux, INRAE, Bordeaux INP, NutriNeuro, 33000, Bordeaux, France
| | - Andrea Contini
- Université Bordeaux, INRAE, Bordeaux INP, NutriNeuro, 33000, Bordeaux, France
| | - Asma Oummadi
- Université Bordeaux, INRAE, Bordeaux INP, NutriNeuro, 33000, Bordeaux, France
| | - Baptiste Caraballo
- Université Bordeaux, INRAE, Bordeaux INP, NutriNeuro, 33000, Bordeaux, France
| | | | - Marie-Lou Boyer
- Université Bordeaux, INRAE, Bordeaux INP, NutriNeuro, 33000, Bordeaux, France
| | - Frank Aby
- Université Bordeaux, INRAE, Bordeaux INP, NutriNeuro, 33000, Bordeaux, France
| | | | | | - Lucy Martine
- Centre des Sciences du Goût et de l'Alimentation, AgroSup Dijon, CNRS, INRAE, Université Bourgogne Franche-Comté, 21000 Dijon, France
| | - Stéphane Grégoire
- Centre des Sciences du Goût et de l'Alimentation, AgroSup Dijon, CNRS, INRAE, Université Bourgogne Franche-Comté, 21000 Dijon, France
| | - Stéphanie Cabaret
- Centre des Sciences du Goût et de l'Alimentation, AgroSup Dijon, CNRS, INRAE, Université Bourgogne Franche-Comté, 21000 Dijon, France
| | - Sylvie Vancassel
- Université Bordeaux, INRAE, Bordeaux INP, NutriNeuro, 33000, Bordeaux, France
| | - Sophie Layé
- Université Bordeaux, INRAE, Bordeaux INP, NutriNeuro, 33000, Bordeaux, France
| | - Jing Xuan Kang
- Laboratory for Lipid Medicine and Technology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA
| | - Xavier Fioramonti
- Université Bordeaux, INRAE, Bordeaux INP, NutriNeuro, 33000, Bordeaux, France
| | - Olivier Berdeaux
- Centre des Sciences du Goût et de l'Alimentation, AgroSup Dijon, CNRS, INRAE, Université Bourgogne Franche-Comté, 21000 Dijon, France
| | | | - Elodie Masson
- Centre des Sciences du Goût et de l'Alimentation, AgroSup Dijon, CNRS, INRAE, Université Bourgogne Franche-Comté, 21000 Dijon, France
| | - Guillaume Ferreira
- Université Bordeaux, INRAE, Bordeaux INP, NutriNeuro, 33000, Bordeaux, France
| | - David W L Ma
- Department of Human Health and Nutritional Sciences, University of Guelph, 50 Stone Road E., Guelph, ON N1G2W1, Canada
| | | | | | - Pierre Trifilieff
- Université Bordeaux, INRAE, Bordeaux INP, NutriNeuro, 33000, Bordeaux, France.
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Montemagni C, Bellino S, Bracale N, Bozzatello P, Rocca P. Models Predicting Psychosis in Patients With High Clinical Risk: A Systematic Review. Front Psychiatry 2020; 11:223. [PMID: 32265763 PMCID: PMC7105709 DOI: 10.3389/fpsyt.2020.00223] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Accepted: 03/06/2020] [Indexed: 11/25/2022] Open
Abstract
OBJECTIVE The present study reviews predictive models used to improve prediction of psychosis onset in individuals at clinical high risk for psychosis (CHR), using clinical, biological, neurocognitive, environmental, and combinations of predictors. METHODS A systematic literature search on PubMed was carried out (from 1998 through 2019) to find all studies that developed or validated a model predicting the transition to psychosis in CHR subjects. RESULTS We found 1,406 records. Thirty-eight of them met the inclusion criteria; 11 studies using clinical predictive models, seven studies using biological models, five studies using neurocognitive models, five studies using environmental models, and 18 studies using combinations of predictive models across different domains. While the highest positive predictive value (PPV) in clinical, biological, neurocognitive, and combined predictive models were relatively high (all above 83), the highest PPV across environmental predictive models was modest (63%). Moreover, none of the combined models showed a superiority when compared with more parsimonious models (using only neurocognitive, clinical, biological, or environmental factors). CONCLUSIONS The use of predictive models may allow high prognostic accuracy for psychosis prediction in CHR individuals. However, only ten studies had performed an internal validation of their models. Among the models with the highest PPVs, only the biological and neurocognitive but not the combined models underwent validation. Further validation of predicted models is needed to ensure external validity.
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Affiliation(s)
| | | | | | | | - Paola Rocca
- Department of Neuroscience, School of Medicine, University of Turin, Turin, Italy
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Frajerman A, Kebir O, Chaumette B, Tessier C, Lamazière A, Nuss P, Krebs MO. [Membrane lipids in schizophrenia and early phases of psychosis: Potential biomarkers and therapeutic targets?]. Encephale 2020; 46:209-216. [PMID: 32151446 DOI: 10.1016/j.encep.2019.11.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 11/22/2019] [Accepted: 11/28/2019] [Indexed: 01/02/2023]
Abstract
The various roles of membrane lipids in human health has urged researchers to study their impact in neuropsychiatric diseases, especially in schizophrenia spectrum disorders and more recently in early stages of psychosis. The progress in mass spectrometry technologies now allows a more comprehensive analysis of phospholipids (PL) and their fatty acid (FA) molecular species. FA are defined by a carbon chain of variable length and are said to be unsaturated when their chain has one or more carbon-carbon double bonds. The PL are composed of a hydrophilic polar head with a phosphoric acid group and an hydrophobic part with FAs; they encompass glycerophospholipids and sphingolipids. The plasma membrane is a complex and dynamic structure consisting of a lipid bilayer composed of an outer layer and an inner layer of specific lipid composition. The permanent remodeling of membrane lipids involves phospholipases especially the phospholipase A2. Seventy percent of the brain consists of lipids from different classes and molecular species. Most of the brain lipids are composed of polyunsaturated fatty acid (PUFA)-enriched diacyl classes where omega-3 and omega-6 molecular species predominate. The balance between omega-3 and omega-6 is important for the neurodevelopment. PUFA are also involved in neurogenesis and neurotransmission. Sphingomyelin (SM) is a sphingolipid that influences inflammation, cell proliferation and lipid rafts formation. It is an important component of myelin sheaths of white matter and therefore is involved in cerebral connectivity. In rat models, deficiency in omega-3 causes abnormalities in dopaminergic neurotransmission, impacts on the functioning of some receptors (including cannabinoids CB1, glutamatergic N-methyl-D-aspartate receptor, NMDA), and increases sensitivity to hallucinogens. In contrast, omega-3 supplementation improves cognitive function and prevents psychotic-like behavior in some animal models for schizophrenia. It also reduces oxidative stress and prevents demyelination. The historical membrane hypothesis of schizophrenia has led to explore the lipids abnormality in this disorder. This hypothesis was initially based on the observation of an abnormal membrane prostaglandin production in schizophrenia caused by a membrane arachidonic acid deficiency. It has evolved emphasizing the various PUFA membrane's roles in particular regarding oxidative stress, inflammation and regulation of the NMDA receptors. In patients with mental disorders, low omega-3 index is more frequent than in the general population. This lipid abnormality could lead to myelination abnormalities and cognitive deficits observed in patients. It could also participate in oxidative stress abnormalities and inflammation reported in schizophrenia. On the other hand, low omega-3 index deficit was reported to be associated with an increased cardiovascular risk, and omega-3 supplementation may also have a positive cardiovascular impact in psychiatric patients, even more than in the general population. The presence of membrane lipid abnormalities is also found in patients during the first psychotic episode (FEP). The omega-3 supplementation improved the recovery rate and prevented the loss of gray matter in FEP. In patients at ultra-high risk to develop a psychotic disorder (UHR), omega-3 supplementation has been associated with a reduction of the rate of conversion to psychosis and with metabolic changes, such as decreased activity of phospholipase A2. However, this study has not as yet been replicated. Not all patients exhibit lipid abnormalities. Several studies, including studies from our team, have found a bimodal distribution of lipids in patients with schizophrenia. But some studies have found differences (in PUFA) in the acute phase whereas our studies (on phospholipids) are in chronic phases. It will be interesting to study in more depth the links between these two parameters. Furthermore, we identified a subgroup which was identified with a deficit in sphingomyelin and PUFA whereas others have found an increase of sphingomyelin. Individuals with this abnormal lipid cluster had more cognitive impairments and more severe clinical symptoms. Because the niacin test is an indirect reflection of arachidonic acid levels, it has been proposed to identify a subset of patients with membrane lipids anomalies. Niacin test response is influenced by several factors related to lipid metabolism, including cannabis use and phospholipase A2 activity. Despite progress, the function and impact of membrane lipids are still poorly understood in schizophrenia. They could serve as biomarkers for identifying biological subgroups among patients with schizophrenia. In UHR patients, their predictive value on the conversion to psychosis should be tested. Omega-3 supplementation could be a promising treatment thanks to its good tolerance and acceptability. It could be more appropriate for patients with PUFA anomalies in a more personalized medical approach.
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Affiliation(s)
- A Frajerman
- Inserm U1266 - GDR 3557, institut de psychiatrie et neurosciences de Paris, Institut de Psychiatrie, Paris, France.
| | - O Kebir
- Inserm U1266 - GDR 3557, institut de psychiatrie et neurosciences de Paris, Institut de Psychiatrie, Paris, France; GHU Paris psychiatrie et neurosciences, Paris, France
| | - B Chaumette
- Inserm U1266 - GDR 3557, institut de psychiatrie et neurosciences de Paris, Institut de Psychiatrie, Paris, France; GHU Paris psychiatrie et neurosciences, Paris, France; Université Paris Descartes, Université de Paris, Paris, France
| | - C Tessier
- ERL 1157, laboratoire de spectrométrie de masse, CHU de Saint-Antoine, Paris, France
| | - A Lamazière
- Inserm UMR_S 938, département METOMICS, centre de recherche Saint-Antoine, Sorbonne Université, AP-HP, Paris, France
| | - P Nuss
- Inserm UMR_S 938, département METOMICS, centre de recherche Saint-Antoine, Sorbonne Université, AP-HP, Paris, France; Service de psychiatrie et de psychologie médicale, Hôpital Saint-Antoine, Sorbonne Université, AP-HP, Paris, France
| | - M-O Krebs
- Inserm U1266 - GDR 3557, institut de psychiatrie et neurosciences de Paris, Institut de Psychiatrie, Paris, France; GHU Paris psychiatrie et neurosciences, Paris, France; Université Paris Descartes, Université de Paris, Paris, France
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50
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Post RM, Altshuler LL, Kupka R, McElroy SL, Frye MA, Rowe M, Grunze H, Suppes T, Keck PE, Nolen WA. More assortative mating in US compared to European parents and spouses of patients with bipolar disorder: implications for psychiatric illness in the offspring. Eur Arch Psychiatry Clin Neurosci 2020; 270:237-245. [PMID: 30099616 DOI: 10.1007/s00406-018-0934-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Accepted: 07/30/2018] [Indexed: 02/08/2023]
Abstract
The effect of assortative mating on offspring is often not considered. Here, we present data on illness in the spouse and the parents of patients with bipolar disorder as they affect illness in the offspring. A history of psychiatric illness (depression, bipolar disorder, suicide attempt, alcohol abuse, drug abuse, and "other" illness) was elicited for the parents, spouse, and the offspring of 968 patients with bipolar disorder (540 of whom had children) who gave informed consent for participation in a treatment outcome network. Assortative mating for a mood disorder in the spouse and parents in those from the United States (US) was compared to those from the Netherlands and Germany and related to illnesses in the offspring. There was more illness and assortative mating for a mood disorder in both the spouse and patient's parents from the US compared to Europe. In the parents of the US patients, assortative mating for a mood disorder was associated with more depression, bipolar disorder, alcohol, and "other" illness in the offspring. Compared to the Europeans, there was more assortative mating for mood and other disorders in two generations of those from the US. This bilineal positivity for a parental mood disorder was related to more depression a second generation later in the patients' offspring. In clinical assessment of risk of illness in the offspring, the history of psychiatric illness in the spouse and patient's parents might provide additional information.
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Affiliation(s)
- Robert M Post
- Bipolar Collaborative Network, 5415 W. Cedar Lane
Suite 201-B, Bethesda, MD, 20814, USA.
- Department of Psychiatry and Behavioral Sciences, George Washington University, Washington, DC, USA.
| | - Lori L Altshuler
- Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
- Department of Psychiatry, VA Greater Los Angeles Healthcare System, West Los Angeles Healthcare Center, Los Angeles, CA, USA
| | - Ralph Kupka
- Department of Psychiatry, VU University Medical Center, Amsterdam, The Netherlands
| | - Susan L McElroy
- Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Lindner Center of HOPE, Mason, OH, USA
| | - Mark A Frye
- Department of Psychiatry, Mayo Clinic, Rochester, MI, USA
| | - Michael Rowe
- Bipolar Collaborative Network, 5415 W. Cedar Lane
Suite 201-B, Bethesda, MD, 20814, USA
| | - Heinz Grunze
- Department of Psychiatry and Psychotherapy, Christian Doppler Klinik, Paracelsus Medical University Salzburg, Salzburg, Austria
| | - Trisha Suppes
- Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, CA, USA
- V.A. Palo Alto Health Care System, Palo Alto, CA, USA
| | - Paul E Keck
- Lindner Center of HOPE, Mason, OH, USA
- Biological Psychiatry Program, University of Cincinnati Medical College, Cincinnati, OH, USA
| | - Willem A Nolen
- University Medical Center, University of Groningen, Groningen, The Netherlands
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