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  • 1.
    Aoun, E. G.
    et al.
    Brown Univ, RI 02912 USA.
    Jimenez, V. A.
    Oregon Hlth and Sci Univ, OR 97201 USA.
    Vendruscolo, L. F.
    Scripps Res Inst, CA 92037 USA; NIDA, MD 20892 USA.
    Walter, N. A. R.
    Oregon Hlth and Sci Univ, OR 97201 USA.
    Barbier, Estelle
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Ferrulli, A.
    Univ Cattolica Sacro Cuore, Italy.
    Haass-Koffler, C. L.
    Brown Univ, RI 02912 USA; NIAAA, MD 20892 USA; NIDA, MD 20892 USA.
    Darakjian, P.
    Oregon Hlth and Sci Univ, OR 97201 USA.
    Lee, M. R.
    NIAAA, MD 20892 USA; NIDA, MD 20892 USA.
    Addolorato, G.
    Univ Cattolica Sacro Cuore, Italy.
    Heilig, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Hitzemann, R.
    Oregon Hlth and Sci Univ, OR 97201 USA.
    Koob, G. F.
    Scripps Res Inst, CA 92037 USA; NIAAA, MD 20852 USA.
    Grant, K. A.
    Oregon Hlth and Sci Univ, OR 97201 USA.
    Leggio, L.
    Brown Univ, RI 02912 USA; NIAAA, MD 20892 USA; NIDA, MD 20892 USA.
    A relationship between the aldosterone-mineralocorticoid receptor pathway and alcohol drinking: preliminary translational findings across rats, monkeys and humans2018In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 23, no 6, p. 1466-1473Article in journal (Refereed)
    Abstract [en]

    Aldosterone regulates electrolyte and fluid homeostasis through binding to the mineralocorticoid receptors (MRs). Previous work provides evidence for a role of aldosterone in alcohol use disorders (AUDs). We tested the hypothesis that high functional activity of the mineralocorticoid endocrine pathway contributes to vulnerability for AUDs. In Study 1, we investigated the relationship between plasma aldosterone levels, ethanol self-administration and the expression of CYP11B2 and MR (NR3C2) genes in the prefrontal cortex area (PFC) and central nucleus of the amygdala (CeA) in monkeys. Aldosterone significantly increased after 6- and 12-month ethanol self-administration. NR3C2 expression in the CeA was negatively correlated to average ethanol intake during the 12 months. In Study 2, we measured Nr3c2 mRNA levels in the PFC and CeA of dependent and nondependent rats and the correlates with ethanol drinking during acute withdrawal. Low Nr3c2 expression levels in the CeA were significantly associated with increased anxiety-like behavior and compulsive-like drinking in dependent rats. In Study 3, the relationship between plasma aldosterone levels, alcohol drinking and craving was investigated in alcohol-dependent patients. Non-abstinent patients had significantly higher aldosterone levels than abstinent patients. Aldosterone levels positively correlated with the number of drinks consumed, craving and anxiety scores. These findings support a relationship between ethanol drinking and the aldosterone/MR pathway in three different species.

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  • 2.
    Barbier, Estelle
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Johnstone, A. L.
    University of Miami, FL 33136 USA.
    Khomtchouk, B. B.
    University of Miami, FL 33136 USA.
    Tapocik, J. D.
    NIAAA, MD USA.
    Pitcairn, C.
    NIAAA, MD USA.
    Rehman, F.
    NIAAA, MD USA.
    Augier, Eric
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Borich, A.
    NIAAA, MD USA.
    Schank, J. R.
    University of Georgia, GA 30602 USA.
    Rienas, C. A.
    University of Miami, FL 33136 USA.
    Van Booven, D. J.
    University of Miami, FL 33136 USA.
    Sun, H.
    NIAAA, MD USA.
    Nätt, Daniel
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Wahlestedt, C.
    University of Miami, FL 33136 USA; University of Miami, FL 33136 USA.
    Heilig, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry. NIAAA, MD USA.
    Dependence-induced increase of alcohol self-administration and compulsive drinking mediated by the histone methyltransferase PRDM22017In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 22, no 12, p. 1746-1758Article in journal (Refereed)
    Abstract [en]

    Epigenetic processes have been implicated in the pathophysiology of alcohol dependence, but the specific molecular mechanisms mediating dependence-induced neuroadaptations remain largely unknown. Here, we found that a history of alcohol dependence persistently decreased the expression of Prdm2, a histone methyltransferase that monomethylates histone 3 at the lysine 9 residue (H3K9me1), in the rat dorsomedial prefrontal cortex (dmPFC). Downregulation of Prdm2 was associated with decreased H3K9me1, supporting that changes in Prdm2 mRNA levels affected its activity. Chromatin immunoprecipitation followed by massively parallel DNA sequencing showed that genes involved in synaptic communication are epigenetically regulated by H3K9me1 in dependent rats. In non-dependent rats, viral-vector-mediated knockdown of Prdm2 in the dmPFC resulted in expression changes similar to those observed following a history of alcohol dependence. Prdm2 knockdown resulted in increased alcohol self-administration, increased aversion-resistant alcohol intake and enhanced stress-induced relapse to alcohol seeking, a phenocopy of postdependent rats. Collectively, these results identify a novel epigenetic mechanism that contributes to the development of alcohol-seeking behavior following a history of dependence.

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  • 3.
    Barchiesi, Riccardo
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Chanthongdee, Kanat
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Mahidol Univ, Thailand.
    Petrella, Michele
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Xu, Li
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Söderholm, Simon
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Domi, Esi
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Augier, Gaëlle
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Coppola, Andrea
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Wiskerke, Joost
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Szczot, Ilona
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Domi, Ana
    Univ Gothenburg, Sweden.
    Adermark, Louise
    Univ Gothenburg, Sweden.
    Augier, Eric
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Cantù, Claudio
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Heilig, Markus
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Psykiatricentrum, Psykiatriska kliniken i Linköping.
    Barbier, Estelle
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    An epigenetic mechanism for over-consolidation of fear memories2022In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 27, no 12, p. 4893-4904Article in journal (Refereed)
    Abstract [en]

    Excessive fear is a hallmark of anxiety disorders, a major cause of disease burden worldwide. Substantial evidence supports a role of prefrontal cortex-amygdala circuits in the regulation of fear and anxiety, but the molecular mechanisms that regulate their activity remain poorly understood. Here, we show that downregulation of the histone methyltransferase PRDM2 in the dorsomedial prefrontal cortex enhances fear expression by modulating fear memory consolidation. We further show that Prdm2 knock-down (KD) in neurons that project from the dorsomedial prefrontal cortex to the basolateral amygdala (dmPFC-BLA) promotes increased fear expression. Prdm2 KD in the dmPFC-BLA circuit also resulted in increased expression of genes involved in synaptogenesis, suggesting that Prdm2 KD modulates consolidation of conditioned fear by modifying synaptic strength at dmPFC-BLA projection targets. Consistent with an enhanced synaptic efficacy, we found that dmPFC Prdm2 KD increased glutamatergic release probability in the BLA and increased the activity of BLA neurons in response to fear-associated cues. Together, our findings provide a new molecular mechanism for excessive fear responses, wherein PRDM2 modulates the dmPFC -BLA circuit through specific transcriptomic changes.

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  • 4.
    Biazus, Tais Boeira
    et al.
    Univ Sao Paulo, Brazil.
    Beraldi, Gabriel Henrique
    Univ Sao Paulo, Brazil.
    Tokeshi, Lucas
    Univ Sao Paulo, Brazil.
    Rotenberg, Luisa de Siqueira
    Univ Sao Paulo, Brazil.
    Dragioti, Elena
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center. Univ Ioannina, Greece.
    Carvalho, Andre F.
    Deakin Univ, Australia.
    Solmi, Marco
    Univ Ottawa, Canada; Charite, Germany.
    Lafer, Beny
    Univ Sao Paulo, Brazil.
    All-cause and cause-specific mortality among people with bipolar disorder: a large-scale systematic review and meta-analysis2023In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 28, no 6, p. 2508-2524Article, review/survey (Refereed)
    Abstract [en]

    ObjectiveBipolar disorder (BD) is associated with premature mortality. All-cause and specific mortality risks in this population remain unclear, and more studies are still needed to further understand this issue and guide individual and public strategies to prevent mortality in bipolar disorder Thus, a systematic review and meta-analysis of studies assessing mortality risk in people with BD versus the general population was conducted. The primary outcome was all-cause mortality, whilst secondary outcomes were mortality due to suicide, natural, unnatural, and specific-causes mortality.ResultsFifty-seven studies were included (BD; n = 678,353). All-cause mortality was increased in people with BD (RR = 2.02, 95% CI: 1.89-2.16, k = 39). Specific-cause mortality was highest for suicide (RR = 11.69, 95% CI: 9.22-14.81, k = 25). Risk of death due to unnatural causes (RR = 7.29, 95% CI: 6.41-8.28, k = 17) and natural causes (RR = 1.90, 95% CI: 1.75-2.06, k = 17) were also increased. Among specific natural causes analyzed, infectious causes had the higher RR (RR = 4,38, 95%CI: 1.5-12.69, k = 3), but the analysis was limited by the inclusion of few studies. Mortality risk due to respiratory (RR = 3.18, 95% CI: 2.55-3.96, k = 6), cardiovascular (RR = 1.76, 95% CI: 1.53-2.01, k = 27), and cerebrovascular (RR = 1.57, 95% CI: 1.34-1.84, k = 13) causes were increased as well. No difference was identified in mortality by cancer (RR = 0.99, 95% CI: 0.88-1.11, k = 16). Subgroup analyses and meta-regression did not affect the findings.ConclusionResults presented in this meta-analysis show that risk of premature death in BD is not only due to suicide and unnatural causes, but somatic comorbidities are also implicated. Not only the prevention of suicide, but also the promotion of physical health and the prevention of physical conditions in individuals with BD may mitigate the premature mortality in this population. Notwithstanding this is to our knowledge the largest synthesis of evidence on BD-related mortality, further well-designed studies are still warranted to inform this field.

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  • 5.
    Cortese, Samuele
    et al.
    Univ Southampton, England; Solent NHS Trust, England; NYU, NY 10012 USA; Univ Nottingham, England.
    Song, Minjin
    Yonsei Univ, South Korea.
    Farhat, Luis C.
    Univ Sao Paulo, Brazil.
    Yon, Dong Keon
    Kyung Hee Univ, South Korea.
    Lee, Seung Won
    Sungkyunkwan Univ, South Korea.
    Kim, Min Seo
    Sungkyunkwan Univ, South Korea.
    Park, Seoyeon
    Yonsei Univ, South Korea.
    Oh, Jae Won
    Yonsei Univ, South Korea.
    Lee, San
    Yonsei Univ, South Korea.
    Cheon, Keun-Ah
    Yonsei Univ, South Korea.
    Smith, Lee
    Anglia Ruskin Univ, England.
    Gosling, Corentin J.
    Univ Southampton, England; Paris Nanterre Univ, France; Univ Paris, France.
    Polanczyk, Guilherme V.
    Univ Sao Paulo, Brazil.
    Larsson, Henrik
    Orebro Univ, Sweden; Karolinska Inst, Sweden.
    Rohde, Luis A.
    Univ Fed Rio Grande do Sul, Brazil; Natl Inst Dev Psychiat, Brazil.
    Faraone, Stephen V.
    SUNY Upstate Med Univ, NY USA.
    Koyanagi, Ai
    ISCIII, Spain; ICREA, Spain.
    Dragioti, Elena
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center. Univ Ioannina, Greece.
    Radua, Joaquim
    Univ Barcelona, Spain.
    Carvalho, Andre F.
    Deakin Univ, Australia.
    Shin, Jae Il
    Yonsei Univ, South Korea.
    Solmi, Marco
    Univ Southampton, England; Univ Ottawa, Canada; Ottawa Hosp, Canada; Charite, Germany.
    Incidence, prevalence, and global burden of ADHD from 1990 to 2019 across 204 countries: data, with critical re-analysis, from the Global Burden of Disease study2023In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 28, p. 4823-4830Article in journal (Refereed)
    Abstract [en]

    Data on incidence, prevalence and burden of ADHD are crucial for clinicians, patients, and stakeholders. We present the incidence, prevalence, and burden of ADHD globally and across countries from 1990 to 2019 from the Global Burden of Disease (GBD) study. We also: (1) calculated the ADHD prevalence based on data actually collected as opposed to the prevalence estimated by the GBD with data imputation for countries without prevalence data; (2) discussed the GBD estimated ADHD burden in the light of recent meta-analytic evidence on ADHD-related mortality. In 2019, GBD estimated global age-standardized incidence and prevalence of ADHD across the lifespan at 0.061% (95%UI = 0.040-0.087) and 1.13% (95%UI = 0.831-1.494), respectively. ADHD accounted for 0.8% of the global mental disorder DALYs, with mortality set at zero by the GBD. From 1990 to 2019 there was a decrease of -8.75% in the global age-standardized prevalence and of -4.77% in the global age-standardized incidence. The largest increase in incidence, prevalence, and burden from 1990 to 2019 was observed in the USA; the largest decrease occurred in Finland. Incidence, prevalence, and DALYs remained approximately 2.5 times higher in males than females from 1990 to 2019. Incidence peaked at age 5-9 years, and prevalence and DALYs at age 10-14 years. Our re-analysis of data prior to 2013 showed a prevalence in children/adolescents two-fold higher (5.41%, 95% CI: 4.67-6.15%) compared to the corresponding GBD estimated prevalence (2.68%, 1.83-3.72%), with no significant differences between low- and middle- and high-income countries. We also found meta-analytic evidence of significantly increased ADHD-related mortality due to unnatural causes. While it provides the most detailed evidence on temporal trends, as well as on geographic and sex variations in incidence, prevalence, and burden of ADHD, the GBD may have underestimated the ADHD prevalence and burden. Given the influence of the GBD on research and policies, methodological issues should be addressed in its future editions.

  • 6.
    Dragioti, Elena
    et al.
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center.
    Radua, Joaquim
    Kings Coll London, England; Inst Invest Biomed August Pi & Sunyer, Spain; Karolinska Inst, Sweden.
    Solmi, Marco
    Kings Coll London, England; Univ Ottawa, Canada; Ottawa Hosp, Canada; Univ Southampton, England.
    Arango, Celso
    Hosp Gen Univ Gregorio Maranon, Spain; Univ Complutense Madrid, Spain; Biomed Res Ctr Mental Hlth CIBERSAM, Spain.
    Oliver, Dominic
    Kings Coll London, England.
    Cortese, Samuele
    Univ Southampton, England; Univ Southampton, England; Solent NHS Trust, England; Hassenfeld Childrens Hosp NYU Langone, NY USA; Univ Nottingham, England.
    Jones, Peter B.
    Univ Cambridge, England; Cambridgeshire & Peterborough Natl Hlth Serv Fdn, England.
    Il Shin, Jae
    Yonsei Univ, South Korea; Severance Childrens Hosp, South Korea.
    Correll, Christoph U.
    Northwell Hlth, NY USA; Zucker Sch Med Hofstra Northwell, NY USA; Feinstein Inst Med Res, NY USA; Charite, Germany.
    Fusar-Poli, Paolo
    Kings Coll London, England; South London & Maudsley NHS Fdn Trust, England; Univ Pavia, Italy.
    Global population attributable fraction of potentially modifiable risk factors for mental disorders: a meta-umbrella systematic review2022In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 27, no 8, p. 3510-3519Article in journal (Refereed)
    Abstract [en]

    Numerous risk factors for mental disorders have been identified. However, we do not know how many disorders we could prevent and to what extent by modifying these risk factors. This study quantifies the Population Attributable Fraction (PAF) of potentially modifiable risk factors for mental disorders. We conducted a PRISMA 2020-compliant (Protocol: https://osf.io/hk2ag) meta-umbrella systematic review (Web of Science/PubMed/Cochrane Central Register of Reviews/Ovi/PsycINFO, until 05/12/2021) of umbrella reviews reporting associations between potentially modifiable risk factors and ICD/DSM mental disorders, restricted to highly convincing (class I) and convincing (class II) evidence from prospective cohorts. The primary outcome was the global meta-analytical PAF, complemented by sensitivity analyses across different settings, the meta-analytical Generalised Impact Fraction (GIF), and study quality assessment (AMSTAR). Seven umbrella reviews (including 295 meta-analyses and 547 associations) identified 28 class I-II risk associations (23 risk factors; AMSTAR: 45.0% high-, 35.0% medium-, 20.0% low quality). The largest global PAFs not confounded by indication were 37.84% (95% CI = 26.77-48.40%) for childhood adversities and schizophrenia spectrum disorders, 24.76% (95% CI = 13.98-36.49%) for tobacco smoking and opioid use disorders, 17.88% (95% CI = not available) for job strain and depression, 14.60% (95% CI = 9.46-20.52%) for insufficient physical activity and Alzheimers disease, 13.40% (95% CI = 7.75-20.15%) for childhood sexual abuse and depressive disorders, 12.37% (95% CI = 5.37-25.34%) for clinical high-risk state for psychosis and any non-organic psychotic disorders, 10.00% (95% CI = 5.62-15.95%) for three metabolic factors and depression, 9.73% (95% CI = 4.50-17.30%) for cannabis use and schizophrenia spectrum disorders, and 9.30% (95% CI = 7.36-11.38%) for maternal pre-pregnancy obesity and ADHD. The GIFs confirmed the preventive capacity for these factors. Addressing several potentially modifiable risk factors, particularly childhood adversities, can reduce the global population-level incidence of mental disorders.

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  • 7.
    Gallo, Selene
    et al.
    Amsterdam UMC, Netherlands; Amsterdam Neurosci, Netherlands.
    El-Gazzar, Ahmed
    Amsterdam UMC, Netherlands; Amsterdam Neurosci, Netherlands.
    Zhutovsky, Paul
    Amsterdam UMC, Netherlands; Amsterdam Neurosci, Netherlands.
    Thomas, Rajat M.
    Amsterdam UMC, Netherlands; Amsterdam Neurosci, Netherlands.
    Javaheripour, Nooshin
    Jena Univ Hosp, Germany.
    Li, Meng
    Jena Univ Hosp, Germany.
    Bartova, Lucie
    Med Univ Vienna, Austria.
    Bathula, Deepti
    Indian Inst Technol IIT, India.
    Dannlowski, Udo
    Univ Munster, Germany.
    Davey, Christopher
    Univ Melbourne, Australia.
    Frodl, Thomas
    Otto von Guericke Univ, Germany; German Ctr Mental Hlth, Germany.
    Gotlib, Ian
    Stanford Univ, CA 94305 USA.
    Grimm, Simone
    Charite Univ Med Berlin, Germany.
    Grotegerd, Dominik
    Univ Munster, Germany.
    Hahn, Tim
    Univ Munster, Germany.
    Hamilton, Paul J.
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Harrison, Ben J.
    Univ Melbourne, Australia.
    Jansen, Andreas
    Univ Marburg, Germany.
    Kircher, Tilo
    Meyer, Bernhard
    Med Univ Vienna, Austria.
    Nenadic, Igor
    Univ Marburg, Germany.
    Olbrich, Sebastian
    Univ Hosp Zurich, Switzerland.
    Paul, Elisabeth
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Pezawas, Lukas
    Med Univ Vienna, Austria.
    Sacchet, Matthew D.
    Harvard Med Sch, MA USA.
    Saemann, Philipp
    Max Planck Inst Psychiat, Germany.
    Wagner, Gerd
    Jena Univ Hosp, Germany.
    Walter, Henrik
    Charite Univ Med Berlin, Germany.
    Walter, Martin
    Otto von Guericke Univ, Germany; German Ctr Mental Hlth, Germany.
    PsyMRI, Guido
    van Wingen, Guido
    Amsterdam UMC, Netherlands; Amsterdam Neurosci, Netherlands.
    Functional connectivity signatures of major depressive disorder: machine learning analysis of two multicenter neuroimaging studies2023In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 28, no 7, p. 3013-3022Article in journal (Refereed)
    Abstract [en]

    The promise of machine learning has fueled the hope for developing diagnostic tools for psychiatry. Initial studies showed high accuracy for the identification of major depressive disorder (MDD) with resting-state connectivity, but progress has been hampered by the absence of large datasets. Here we used regular machine learning and advanced deep learning algorithms to differentiate patients with MDD from healthy controls and identify neurophysiological signatures of depression in two of the largest resting-state datasets for MDD. We obtained resting-state functional magnetic resonance imaging data from the REST-meta-MDD (N = 2338) and PsyMRI (N = 1039) consortia. Classification of functional connectivity matrices was done using support vector machines (SVM) and graph convolutional neural networks (GCN), and performance was evaluated using 5-fold cross-validation. Features were visualized using GCN-Explainer, an ablation study and univariate t-testing. The results showed a mean classification accuracy of 61% for MDD versus controls. Mean accuracy for classifying (non-)medicated subgroups was 62%. Sex classification accuracy was substantially better across datasets (73-81%). Visualization of the results showed that classifications were driven by stronger thalamic connections in both datasets, while nearly all other connections were weaker with small univariate effect sizes. These results suggest that whole brain resting-state connectivity is a reliable though poor biomarker for MDD, presumably due to disease heterogeneity as further supported by the higher accuracy for sex classification using the same methods. Deep learning revealed thalamic hyperconnectivity as a prominent neurophysiological signature of depression in both multicenter studies, which may guide the development of biomarkers in future studies.

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  • 8.
    Gray, J. D.
    et al.
    Rockefeller Univ, NY 10021 USA.
    Rubin, T. G.
    Albert Einstein Coll Med, NY 10467 USA.
    Kogan, J. F.
    Rockefeller Univ, NY 10021 USA.
    Marrocco, J.
    Rockefeller Univ, NY 10021 USA.
    Weidmann, J.
    Linköping University.
    Lindkvist, S.
    Linköping University.
    Lee, F. S.
    Weill Cornell Med Coll, NY USA.
    Schmidt, E. F.
    Rockefeller Univ, NY 10021 USA.
    McEwen, B. S.
    Rockefeller Univ, NY 10021 USA.
    Translational profiling of stress-induced neuroplasticity in the CA3 pyramidal neurons of BDNF Val66Met mice2018In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 23, no 4, p. 904-913Article in journal (Refereed)
    Abstract [en]

    Genetic susceptibility and environmental factors (such as stress) can interact to affect the likelihood of developing a mood disorder. Stress-induced changes in the hippocampus have been implicated in mood disorders, and mutations in several genes have now been associated with increased risk, such as brain-derived neurotrophic factor (BDNF). The hippocampus has important anatomical subdivisions, and pyramidal neurons of the vulnerable CA3 region show significant remodeling after chronic stress, but the mechanisms underlying their unique plasticity remain unknown. This study characterizes stress-induced changes in the in vivo translating mRNA of this cell population using a CA3-specific enhanced green fluorescent protein (EGFP) reporter fused to the L10a large ribosomal subunit (EGFPL10a). RNA-sequencing after isolation of polysome-bound mRNAs allows for cell-type-specific, genome-wide characterization of translational changes after stress. The data demonstrate that acute and chronic stress produce unique translational profiles and that the stress history of the animal can alter future reactivity of CA3 neurons. CA3-specific EGFPL10a mice were then crossed to the stress-susceptible BDNF Val66Met mouse line to characterize how a known genetic susceptibility alters both baseline translational profiles and the reactivity of CA3 neurons to stress. Not only do Met allele carriers exhibit distinct levels of baseline translation in genes implicated in ion channel function and cytoskeletal regulation, but they also activate a stress response profile that is highly dissimilar from wild-type mice. Closer examination of genes implicated in the mechanisms of neuroplasticity, such as the NMDA and AMPA subunits and the BDNF pathway, reveal how wild-type mice upregulate many of these genes in response to stress, but Met allele carriers fail to do so. These profiles provide a roadmap of stress-induced changes in a genetically homogenous population of hippocampal neurons and illustrate the profound effects of gene-environment interactions on the translational profile of these cells.

  • 9.
    Johansson Capusan, Andrea
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Psykiatricentrum, Psykiatriska kliniken i Linköping.
    Gustafsson, Per
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Psykiatricentrum, Department of Child and Adolescent Psychiatry in Linköping.
    Kuja-Halkola, Ralf
    Karolinska Inst, Sweden.
    Igelström, Kajsa
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Psykiatricentrum, Department of Child and Adolescent Psychiatry in Linköping.
    Mayo, Leah
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Heilig, Markus
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Psykiatricentrum, Psykiatriska kliniken i Linköping.
    Re-examining the link between childhood maltreatment and substance use disorder: a prospective, genetically informative study2021In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 26, no 7, p. 3201-3209Article in journal (Refereed)
    Abstract [en]

    Childhood maltreatment is considered a risk factor for substance use disorders (SUD), but this is largely based on retrospective self-reports that are subject to recall bias, designs that do not control for familial confounding, or both. The specific contribution of childhood maltreatment to SUD risk thus remains unclear. Here, we evaluated this contribution in a prospective cohort with objectively recorded childhood maltreatment, using a design that allows controlling for familial confounding. We used medical records and registers to study 525 young adults (20-37 years) with prospectively and objectively documented severe maltreatment exposure, 1979 clinical controls (unexposed former child and adolescent psychiatry patients), 1388 matched healthy controls; and their siblings and cousins. We examined the association between maltreatment and SUD using Cox regression models in the population, as well as stratified within siblings in the same family. SUD risk was significantly increased with childhood maltreatment exposure (crude HR: 6.61, 95% CI: 5.81-7.53; HR adjusted for sex, birthyear, externalizing problems, parents SUD and socioeconomic factors: 3.50, 95% CI 2.95, 4.16). An approximately threefold elevated SUD risk remained when comparing exposed individuals with their unexposed siblings (adjusted HR: 3.12, 95% CI 2.21, 4.42). We provide estimates of the association between childhood maltreatment and SUD accounting for possible confounds of both recall bias and familial factors. When familial confounding is controlled for, SUD risk attributable to severe childhood maltreatment is decreased, but nevertheless considerable. These findings establish a specific contribution of childhood maltreatment to SUD, underscoring the need for SUD prevention in young people exposed to maltreatment.

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  • 10.
    Kang, Jiseung
    et al.
    Gwangju Inst Sci & Technol, South Korea; Massachusetts Gen Hosp, MA USA; Harvard Med Sch, MA USA.
    Lee, Hyeri
    Kyung Hee Univ, South Korea; Kyung Hee Univ, South Korea.
    Yu, Seungyeong
    Gwangju Inst Sci & Technol, South Korea.
    Lee, Myeongcheol
    Kyung Hee Univ, South Korea.
    Kim, Hyeon Jin
    Kyung Hee Univ, South Korea.
    Kwon, Rosie
    Kyung Hee Univ, South Korea.
    Kim, Sunyoung
    Kyung Hee Univ, South Korea.
    Fond, Guillaume
    Aix Marseille Univ, France.
    Boyer, Laurent
    Aix Marseille Univ, France.
    Rahmati, Masoud
    Aix Marseille Univ, France; Lorestan Univ, Iran; Vali E Asr Univ Rafsanjan, Iran.
    Koyanagi, Ai
    Parc Sanitari Sant Joan De Deu, Spain.
    Smith, Lee
    Anglia Ruskin Univ, England.
    Nehs, Christa J.
    Massachusetts Gen Hosp, MA USA; Harvard Med Sch, MA USA.
    Kim, Min Seo
    Broad Inst MIT & Harvard, MA USA.
    Sanchez, Guillermo F. Lopez
    Univ Murcia, Spain.
    Dragioti, Elena
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center. Univ Ioannina, Greece.
    Kim, Tae
    Gwangju Inst Sci & Technol, South Korea.
    Yon, Dong Keon
    Kyung Hee Univ, South Korea; Kyung Hee Univ, South Korea; Kyung Hee Univ, South Korea.
    Effects and safety of transcranial direct current stimulation on multiple health outcomes: an umbrella review of randomized clinical trials2024In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578Article, review/survey (Refereed)
    Abstract [en]

    Transcranial direct current stimulation (tDCS), which delivers a direct current to the brain, emerged as a non-invasive potential therapeutic in treating a range of neurological and neuropsychiatric disorders. However, a comprehensive quantitative evidence synthesis on the effects of tDCS on a broad range of mental illnesses is lacking. Here, we systematically assess the certainty of the effects and safety of tDCS on several health outcomes using an umbrella review of randomized controlled trials (RCTs). The methodological quality of each included original meta-analysis was assessed by the A Measurement Tool for Assessing Systematic Reviews 2 (AMSTAR2), and the certainty of the evidence for each effect was evaluated with Grading of Recommendations, Assessment, Development, and Evaluation (GRADE). We followed an a priori protocol (PROSPERO CRD42023458700). We identified 15 meta-analyses of RCTs (AMSTAR 2; high 3, moderate 3, and low 9) that included 282 original articles, covering 22 unique health endpoints across 22 countries and six continents. From meta-analyses of RCTs supported by very low to high certainty of evidence, it was found that tDCS improved symptoms related to post-stroke, including post-stroke depression scale score (equivalent standardized mean difference [eSMD], 1.61 [95% confidence level, 0.72-2.50]; GRADE=moderate), activities of daily living independence (7.04 [3.41-10.67]; GRADE=high), motor recovery of upper and lower extremity (upper extremity: 0.15 [0.06-0.24], GRADE=high; lower extremity: 0.10 [0.03-0.16], GRADE=high), swallowing performance (GRADE=low), and spasticity (GRADE=moderate). In addition, tDCS had treatment effects on symptoms of several neurological and neuropsychiatric disorders, including obsessive-compulsive disorder (0.81 [0.44-1.18]; GRADE=high), pain in fibromyalgia (GRADE=low), disease of consciousness (GRADE=low), insight score (GRADE=moderate) and working memory (0.34 [0.01-0.67]; GRADE=high) in schizophrenia, migraine-related pain (-1.52 [-2.91 to -0.13]; GRADE=high), attention-deficit/hyperactivity disorder (reduction in overall symptom severity: 0.24 [0.04-0.45], GRADE=low; reduction in inattention: 0.56 [0.02-1.11], GRADE=low; reduction in impulsivity: 0.28 [0.04-0.51], GRADE=low), depression (GRADE=low), cerebellar ataxia (GRADE=low), and pain (GRADE=very low). Importantly, tDCS induced an increased number of reported cases of treatment-emergent mania or hypomania (0.88 [0.62-1.13]; GRADE=moderate). We found varied levels of evidence for the effects of tDCS with multiple neurological and neuropsychiatric conditions, from very low to high certainty of evidence. tDCS was effective for people with stroke, obsessive-compulsive disorder, fibromyalgia, disease of consciousness, schizophrenia, migraine, attention-deficit/hyperactivity disorder, depression, cerebellar ataxia, and pain. Therefore, these findings suggest the benefit of tDCS for several neurological and neuropsychiatric disorders; however, further studies are needed to understand the underlying mechanism and optimize its therapeutic potential.

  • 11.
    Lee, Mary R.
    et al.
    NIAAA, MD 20892 USA; NIDA, MD 20892 USA.
    Tapocik, Jenica D.
    NIDA, MD 20892 USA.
    Ghareeb, Mwlod
    Univ Rhode Isl, RI 02881 USA.
    Schwandt, Melanie L.
    NIAAA, MD USA.
    Dias, Alexandra A.
    NIAAA, MD 20892 USA; NIDA, MD 20892 USA.
    Le, April N.
    NIAAA, MD 20892 USA; NIDA, MD 20892 USA.
    Cobbina, Enoch
    Univ Rhode Isl, RI 02881 USA.
    Farinelli, Lisa A.
    NIAAA, MD 20892 USA; NIDA, MD 20892 USA.
    Bouhlal, Sofia
    NIAAA, MD 20892 USA; NIDA, MD 20892 USA.
    Farokhnia, Mehdi
    NIAAA, MD 20892 USA; NIDA, MD 20892 USA.
    Heilig, Markus
    Section on Molecular Pathophysiology, Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, USA.
    Akhlaghi, Fatemeh
    Univ Rhode Isl, RI 02881 USA.
    Leggio, Lorenzo
    NIAAA, MD 20892 USA; NIDA, MD 20892 USA; Brown Univ, RI 02912 USA.
    The novel ghrelin receptor inverse agonist PF-5190457 administered with alcohol: preclinical safety experiments and a phase 1b human laboratory study2020In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 25, no 2, p. 461-475Article in journal (Refereed)
    Abstract [en]

    Rodent studies indicate that ghrelin receptor blockade reduces alcohol consumption. However, no ghrelin receptor blockers have been administered to heavy alcohol drinking individuals. Therefore, we evaluated the safety, tolerability, pharmacokinetic (PK), pharmacodynamic (PD) and behavioral effects of a novel ghrelin receptor inverse agonist, PF-5190457, when co-administered with alcohol. We tested the effects of PF-5190457 combined with alcohol on locomotor activity, loss-of-righting reflex (a measure of alcohol sedative actions), and on blood PF-5190457 concentrations in rats. Then, we performed a single-blind, placebo-controlled, within-subject human study with PF-5190457 (placebo/0 mg b.i.d., 50 mg b.i.d., 100 mg b.i.d.). Twelve heavy drinkers during three identical visits completed an alcohol administration session, subjective assessments, and an alcohol cue-reactivity procedure, and gave blood samples for PK/PD testing. In rats, PF-5190457 did not interact with the effects of alcohol on locomotor activity or loss-of-righting reflex. Alcohol did not affect blood PF-5190457 concentrations. In humans, all adverse events were mild or moderate and did not require discontinuation or dose reductions. Drug dose did not alter alcohol concentration or elimination, alcohol-induced stimulation or sedation, or mood during alcohol administration. Potential PD markers of PF-5190457 were acyl-to-total ghrelin ratio and insulin-like growth factor-1. PF-5190457 (100 mg b.i.d.) reduced alcohol craving during the cue-reactivity procedure. This study provides the first translational evidence of safety and tolerability of the ghrelin receptor inverse agonist PF-5190457 when co-administered with alcohol. PK/PD/behavioral findings support continued research of PF-5190457 as a potential pharmacological agent to treat alcohol use disorder.

  • 12.
    Mayo, Leah M.
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Asratian, Anna
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Lindé, Johan
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Holm, Lovisa
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Nätt, Daniel
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Augier, Gaëlle
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Stensson, Niclas
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center.
    Vecchiarelli, Haley A.
    Hotchkiss Brain Institute and Mathison Centre for Mental Health Research and Education, Departments of Cell Biology and Anatomy and Psychiatry, University of Calgary, Canada.
    Balsevich, Georgia
    Hotchkiss Brain Institute and Mathison Centre for Mental Health Research and Education, Departments of Cell Biology and Anatomy and Psychiatry, University of Calgary, Canada.
    Aukema, Robert J.
    Hotchkiss Brain Institute and Mathison Centre for Mental Health Research and Education, Departments of Cell Biology and Anatomy and Psychiatry, University of Calgary, Canada.
    Ghafouri, Bijar
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center. Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine.
    Spagnolo, Primavera A.
    National Institute on Alcohol Abuse and Alcoholism and National Institute of Neurological Disorders and Stroke, NIH, Bethesda, USA.
    Lee, Francis S.
    Institute for Developmental Psychobiology, Weill Cornell Medical College of Cornell University, New York, USA.
    Hill, Matthew N.
    Hotchkiss Brain Institute and Mathison Centre for Mental Health Research and Education, Departments of Cell Biology and Anatomy and Psychiatry, University of Calgary, Canada.
    Heilig, Markus
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Psykiatricentrum, Psykiatriska kliniken i Linköping.
    Protective effects of elevated anandamide on stress and fear-related behaviors: translational evidence from humans and mice2020In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 25, no 5, p. 993-1005Article in journal (Refereed)
    Abstract [en]

    Post-traumatic stress disorder (PTSD) is a common, debilitating condition with limited treatment options. Extinction of fear memories through prolonged exposure therapy, the primary evidence-based behavioral treatment for PTSD, has only partial efficacy. In mice, pharmacological inhibition of fatty acid amide hydrolase (FAAH) produces elevated levels of anandamide (AEA) and promotes fear extinction, suggesting that FAAH inhibitors may aid fear extinction-based treatments. A human FAAH 385C-greater thanA substitution encodes an FAAH enzyme with reduced catabolic efficacy. Individuals homozygous for the FAAH 385A allele may therefore offer a genetic model to evaluate the impact of elevations in AEA signaling in humans, helping to inform whether FAAH inhibitors have the potential to facilitate fear extinction therapy for PTSD. To overcome the challenge posed by low frequency of the AA genotype (appr. 5%), we prospectively genotyped 423 individuals to examine the balanced groups of CC, AC, and AA individuals (n = 25/group). Consistent with its loss-of-function nature, the A allele was dose dependently associated with elevated basal AEA levels, facilitated fear extinction, and enhanced the extinction recall. Moreover, the A-allele homozygotes were protected against stress-induced decreases in AEA and negative emotional consequences of stress. In a humanized mouse model, AA homozygous mice were similarly protected against stress-induced decreases in AEA, both in the periphery, and also in the amygdala and prefrontal cortex, brain structures critically involved in fear extinction and regulation of stress responses. Collectively, these data suggest that AEA signaling can temper aspects of the stress response and that FAAH inhibition may aid the treatment for stress-related psychiatric disorders, such as PTSD.

  • 13.
    Palmer, Elizabeth E.
    et al.
    Sydney Childrens Hosp Network, Australia; Univ New South Wales, Australia.
    Pusch, Michael
    CNR, Italy.
    Picollo, Alessandra
    CNR, Italy.
    Forwood, Caitlin
    Sydney Childrens Hosp Network, Australia.
    Nguyen, Matthew H.
    Univ New South Wales, Australia; Liverpool Hosp, Australia.
    Suckow, Vanessa
    Max Planck Inst Mol Genet, Germany.
    Gibbons, Jessica
    Max Planck Inst Mol Genet, Germany.
    Hoff, Alva
    Linköping University, Department of Biomedical and Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. CNR, Italy.
    Sigfrid, Lisa
    Linköping University, Department of Biomedical and Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. CNR, Italy.
    Megarbane, Andre
    Lebanese Amer Univ, Lebanon; Inst Jerome Lejeune, France.
    Nizon, Mathilde
    Nantes Univ, France; Nantes Univ, France.
    Cogne, Benjamin
    Nantes Univ, France; Nantes Univ, France.
    Beneteau, Claire
    Nantes Univ, France.
    Alkuraya, Fowzan S.
    King Faisal Specialist Hosp & Res Ctr, Saudi Arabia.
    Chedrawi, Aziza
    King Faisal Specialist Hosp & Res Ctr, Saudi Arabia.
    Hashem, Mais O.
    King Faisal Specialist Hosp & Res Ctr, Saudi Arabia.
    Stamberger, Hannah
    VIB, Belgium; Antwerp Univ Hosp, Belgium.
    Weckhuysen, Sarah
    VIB, Belgium; Antwerp Univ Hosp, Belgium; Univ Antwerp, Belgium.
    Vanlander, Arnaud
    Ghent Univ Hosp, Belgium.
    Ceulemans, Berten
    Univ Antwerp, Belgium.
    Rajagopalan, Sulekha
    Liverpool Hosp, Australia.
    Nunn, Kenneth
    Childrens Hosp Westmead, Australia.
    Arpin, Stephanie
    Ctr Hosp Reg Univ Tours, France.
    Raynaud, Martine
    Ctr Hosp Reg Univ Tours, France.
    Motter, Constance S.
    Akron Childrens Hosp, OH 44308 USA.
    Ward-Melver, Catherine
    Akron Childrens Hosp, OH 44308 USA.
    Janssens, Katrien
    Univ Antwerp, Belgium.
    Meuwissen, Marije
    Univ Antwerp, Belgium.
    Beysen, Diane
    Univ Antwerp, Belgium.
    Dikow, Nicola
    Heidelberg Univ, Germany.
    Grimmel, Mona
    Univ Tubingen, Germany.
    Haack, Tobias B.
    Univ Tubingen, Germany.
    Clement, Emma
    Great Ormond St Hosp Sick Children, England.
    McTague, Amy
    UCL Great Ormond St Inst Child Hlth, England; Great Ormond St Hosp Sick Children, England.
    Hunt, David
    Princess Anne Hosp, England.
    Townshend, Sharron
    King Edward Mem Hosp, Australia.
    Ward, Michelle
    King Edward Mem Hosp, Australia.
    Richards, Linda J.
    Washington Univ, MI USA; Univ Queensland, Australia.
    Simons, Cas
    Murdoch Childrens Res Inst, Australia; UNSW, Australia.
    Costain, Gregory
    Hosp Sick Children, Canada.
    Dupuis, Lucie
    Hosp Sick Children, Canada.
    Mendoza-Londono, Roberto
    Hosp Sick Children, Canada.
    Dudding-Byth, Tracy
    Genet Learning Disabil Serv, Australia; Univ Newcastle, Australia.
    Boyle, Jackie
    Genet Learning Disabil Serv, Australia.
    Saunders, Carol
    Childrens Mercy Hosp & Clin, MI USA; Univ Missouri, MI USA.
    Fleming, Emily
    Childrens Mercy Hosp & Clin, MI USA.
    El Chehadeh, Salima
    Hop Univ Strasbourg, France; Univ Strasbourg, France; INSERM, France.
    Spitz, Marie-Aude
    Hop Univ Strasbourg, France.
    Piton, Amelie
    Hop Univ Strasbourg, France.
    Gerard, Benedicte
    Hop Univ Strasbourg, France.
    Warde, Marie-Therese Abi
    Hop Univ Strasbourg, France; CHU Strasbourg, France.
    Rea, Gillian
    Northern Ireland Reg Genet Serv, North Ireland.
    McKenna, Caoimhe
    Northern Ireland Reg Genet Serv, North Ireland.
    Douzgou, Sofia
    Haukeland Hosp, Norway; Univ Manchester, England.
    Banka, Siddharth
    Univ Manchester, England; Manchester Univ NHS Fdn Trust, England.
    Akman, Cigdem
    Columbia Univ, NY USA.
    Bain, Jennifer M.
    Columbia Univ, NY USA.
    Sands, Tristan T.
    Columbia Univ, NY USA.
    Wilson, Golder N.
    Texas Tech Hlth Sci Ctr Lubbock, TX USA; KinderGenome Med Genet, TX USA.
    Silvertooth, Erin J.
    Texas Sports Psychiat & Integrat Hlth, TX USA.
    Miller, Lauren
    Hillcrest Internal Med, TX USA.
    Lederer, Damien
    Inst Pathol & Genet ASBL, Belgium.
    Sachdev, Rani
    Sydney Childrens Hosp Network, Australia; Univ New South Wales, Australia.
    Macintosh, Rebecca
    Sydney Childrens Hosp Network, Australia; Univ New South Wales, Australia.
    Monestier, Olivier
    Inst Pathol & Genet ASBL, Belgium.
    Karadurmus, Deniz
    Inst Pathol & Genet ASBL, Belgium.
    Collins, Felicity
    Royal Prince Alfred Hosp, Australia.
    Carter, Melissa
    Childrens Hosp Eastern Ontario, Canada.
    Rohena, Luis
    San Antonio Mil Med Ctr, TX USA; UT Hlth San Antonio, TX USA.
    Willemsen, Marjolein H.
    Radboud Univ Nijmegen Med Ctr, Netherlands.
    Ockeloen, Charlotte W.
    Radboud Univ Nijmegen Med Ctr, Netherlands.
    Pfundt, Rolph
    Radboud Univ Nijmegen Med Ctr, Netherlands.
    Kroft, Sanne D.
    Pluryn, Netherlands.
    Field, Michael
    Genet Learning Disabil Serv, Australia.
    Laranjeira, Francisco E. R.
    Ctr Hosp Univ Porto, Portugal.
    Fortuna, Ana M.
    Univ Porto, Portugal.
    Soares, Ana R.
    Univ Porto, Portugal.
    Michaud, Vincent
    CHU Bordeaux, France; Bordeaux Univ, France.
    Naudion, Sophie
    CHU Bordeaux, France.
    Golla, Sailaja
    CHOC Hosp, CA USA.
    Weaver, David D.
    Indiana Univ Sch Med, IN 46202 USA.
    Bird, Lynne M.
    Univ Calif San Diego, CA 92103 USA.
    Friedman, Jennifer
    Univ Calif San Diego, CA 92103 USA.
    Clowes, Virginia
    London North West Univ Healthcare NHS Trust, England; Imperial Coll London, England.
    Joss, Shelagh
    Queen Elizabeth Univ Hosp, Scotland.
    Polsler, Laura
    Univ Ziekenhuis Brussel, Belgium.
    Campeau, Philippe M.
    Univ Montreal, Canada.
    Blazo, Maria
    Texas A&M Univ, TX USA.
    Bijlsma, Emilia K.
    Leiden Univ Med Ctr, Netherlands.
    Rosenfeld, Jill A.
    Baylor Coll Med, TX 77030 USA; Baylor Genet Labs, TX USA.
    Beetz, Christian
    Centogene GmbH, Germany.
    Powis, Zoe
    Ambry Genet, CA USA.
    McWalter, Kirsty
    GeneDx LLC, MA USA.
    Brandt, Tracy
    GeneDx LLC, MA USA.
    Torti, Erin
    GeneDx LLC, MA USA.
    Mathot, Mikael
    CHU UCL Namur, Belgium.
    Mohammad, Shekeeb S.
    Childrens Hosp Westmead, Australia.
    Armstrong, Ruth
    Addenbrookes Hosp, England.
    Kalscheuer, Vera M.
    Max Planck Inst Mol Genet, Germany.
    Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition2023In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 28, no 2, p. 668-697Article in journal (Refereed)
    Abstract [en]

    Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a "shift" of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.

  • 14.
    Peng, Shi-Yu
    et al.
    Shanghai Jiao Tong Univ, Peoples R China.
    Shi, Zhe
    Hunan Univ Chinese Med, Peoples R China.
    Zhou, Dong-Sheng
    Ningbo Kangning Hosp, Peoples R China.
    Wang, Xin-Yue
    Shanghai Jiao Tong Univ, Peoples R China.
    Li, Xing-Xing
    Ningbo Kangning Hosp, Peoples R China.
    Liu, Xiao-Li
    Ningbo Kangning Hosp, Peoples R China.
    Wang, Wei-Di
    Shanghai Jiao Tong Univ, Peoples R China.
    Lin, Guan-Ning
    Shanghai Jiao Tong Univ, Peoples R China; Shanghai Jiao Tong Univ, Peoples R China.
    Pan, Bing-Xing
    Nanchang Univ, Peoples R China.
    Voon, Valerie
    Univ Cambridge, England.
    Grace, Anthony A.
    Univ Pittsburgh, PA USA.
    Heilig, Markus
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Region Östergötland, Psykiatricentrum, Psykiatriska kliniken i Linköping.
    Wong, Ma-Li
    SUNY Upstate Med Univ, NY 13210 USA.
    Yuan, Ti-Fei
    Shanghai Jiao Tong Univ, Peoples R China; Nantong Univ, Peoples R China; TianQiao & Chrissy Chen Inst Translat Res, Peoples R China; Univ Hong Kong, Peoples R China.
    Reduced motor cortex GABABR function following chronic alcohol exposure2021In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 26, no 2, p. 383-395Article in journal (Refereed)
    Abstract [en]

    The GABA(B) receptor (GABA(B)R) agonist baclofen has been used to treat alcohol and several other substance use disorders (AUD/SUD), yet its underlying neural mechanism remains unclear. The present study aimed to investigate cortical GABA(B)R dynamics following chronic alcohol exposure. Ex vivo brain slice recordings from mice chronically exposed to alcohol revealed a reduction in GABA(B)R-mediated currents, as well as a decrease of GABA(B1/2)R and G-protein-coupled inwardly rectifying potassium channel 2 (GIRK2) activities in the motor cortex. Moreover, our data indicated that these alterations could be attributed to dephosphorylation at the site of serine 783 (ser-783) in GABA(B2) subunit, which regulates the surface expression of GABA(B)R. Furthermore, a human study using paired-pulse-transcranial magnetic stimulation (TMS) analysis further demonstrated a reduced cortical inhibition mediated by GABA(B)R in patients with AUD. Our findings provide the first evidence that chronic alcohol exposure is associated with significantly impaired cortical GABA(B)R function. The ability to promote GABA(B)R signaling may account for the therapeutic efficacy of baclofen in AUD.

  • 15.
    Perini, Irene
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Mayo, Leah M.
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Johansson Capusan, Andrea
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Psykiatricentrum, Psykiatriska kliniken i Linköping.
    Paul, Elisabeth
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Yngve, Adam
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Kämpe, Robin
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Gauffin, Emelie
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Psykiatricentrum, Psykiatriska kliniken i Linköping.
    Mazurka, Raegan Mary Rose
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Ghafouri, Bijar
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center.
    Stensson, Niclas
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center.
    Asratian, Anna
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Hamilton, J. Paul
    Univ Bergen, Norway.
    Kastbom, Åsa
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Psykiatricentrum, Psykiatriska kliniken i Linköping.
    Gustafsson, Per A
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Psykiatricentrum, Department of Child and Adolescent Psychiatry in Linköping.
    Heilig, Markus
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Psykiatricentrum, Psykiatriska kliniken i Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Resilience to substance use disorder following childhood maltreatment: association with peripheral biomarkers of endocannabinoid function and neural indices of emotion regulation2023In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, no 6, p. 2563-2571Article in journal (Refereed)
    Abstract [en]

    Childhood maltreatment (CM) is a risk factor for substance use disorders (SUD) in adulthood. Understanding the mechanisms by which people are susceptible or resilient to developing SUD after exposure to CM is important for improving intervention. This case-control study investigated the impact of prospectively assessed CM on biomarkers of endocannabinoid function and emotion regulation in relation to the susceptibility or resilience to developing SUD. Four groups were defined across the dimensions of CM and lifetime SUD (N = 101 in total). After screening, participants completed two experimental sessions on separate days, aimed at assessing the behavioral, physiological, and neural mechanisms involved in emotion regulation. In the first session, participants engaged in tasks assessing biochemical (i.e., cortisol, endocannabinoids), behavioral, and psychophysiological indices of stress and affective reactivity. During the second session, the behavioral and brain mechanisms associated with emotion regulation and negative affect were investigated using magnetic resonance imaging. CM-exposed adults who did not develop SUD, operationally defined as resilient to developing SUD, had higher peripheral levels of the endocannabinoid anandamide at baseline and during stress exposure, compared to controls. Similarly, this group had increased activity in salience and emotion regulation regions in task-based measures of emotion regulation compared to controls, and CM-exposed adults with lifetime SUD. At rest, the resilient group also showed significantly greater negative connectivity between ventromedial prefrontal cortex and anterior insula compared to controls and CM-exposed adults with lifetime SUD. Collectively, these peripheral and central findings point to mechanisms of potential resilience to developing SUD after documented CM exposure.

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  • 16.
    Ramchandani, V A
    et al.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Umhau, J
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Pavon, F J
    The Scripps Research Institute, La Jolla, CA, USA.
    Ruiz-Velasco, V
    PennState College of Medicin, Hershey, PA, USA.
    Margas, W
    PennState College of Medicin, Hershey, PA, USA.
    Sun, H
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Damadzic, R
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Eskay, R
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Schoor, M
    TaconicArtemis GmbH, Köln, Germany.
    Thorsell, Annika
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Schwandt, M L
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Sommer, W H
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    George, D T
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Parsons, L H
    The Scripps Research Institute, La Jolla, CA, USA.
    Herscovitch, P
    National Institutes of Health, Bethesda, MD, USA.
    Hommer, D
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Heilig, Marcus
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    A genetic determinant of the striatal dopamine response to alcohol in men2011In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 16, no 8, p. 809-817Article in journal (Refereed)
    Abstract [en]

    Excessive alcohol use, a major cause of morbidity and mortality, is less well understood than other addictive disorders. Dopamine release in ventral striatum is a common element of drug reward, but alcohol has an unusually complex pharmacology, and humans vary greatly in their alcohol responses. This variation is related to genetic susceptibility for alcoholism, which contributes more than half of alcoholism risk. Here, we report that a functional OPRM1 A118G polymorphism is a major determinant of striatal dopamine responses to alcohol. Social drinkers recruited based on OPRM1 genotype were challenged in separate sessions with alcohol and placebo under pharmacokinetically controlled conditions, and examined for striatal dopamine release using positron emission tomography and [(11)C]-raclopride displacement. A striatal dopamine response to alcohol was restricted to carriers of the minor 118G allele. To directly establish the causal role of OPRM1 A118G variation, we generated two humanized mouse lines, carrying the respective human sequence variant. Brain microdialysis showed a fourfold greater peak dopamine response to an alcohol challenge in h/mOPRM1-118GG than in h/mOPRM1-118AA mice. OPRM1 A118G variation is a genetic determinant of dopamine responses to alcohol, a mechanism by which it likely modulates alcohol reward.

  • 17.
    Soderlund, J
    et al.
    Karolinska Institute.
    Schroeder, J
    University of Heidelberg.
    Nordin, C
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Samuelsson, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Psychiatry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Walther-Jallow, L
    Karolinska University.
    Karlsson, H
    Karolinska Institute.
    Erhardt, S
    Karolinska Institute.
    Engberg, G
    Karolinska Institute.
    Letter: Activation of brain interleukin-1 beta in schizophrenia2009In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 14, no 12, p. 1069-1071Article in journal (Other academic)
    Abstract [en]

    n/a

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  • 18.
    Solmi, Marco
    et al.
    Charite Univ Med Berlin, Germany; Univ Ottawa, Canada.
    Cortese, Samuele
    Univ Southampton, England; Solent NHS Trust, England; NYU, NY USA; Univ Nottingham, England; Univ Bari Aldo Moro, Italy.
    Vita, Giovanni
    Univ Verona, Italy.
    De Prisco, Michele
    Hosp Clin Barcelona, Spain; Inst Invest Biomed August Pi & Sunyer IDIBAPS, Spain; Inst Salud Carlos III, Spain.
    Radua, Joaquim
    Univ Barcelona, Spain.
    Dragioti, Elena
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center. Univ Ioannina, Greece.
    Kohler-Forsberg, Ole
    Aarhus Univ Hosp Psychiat, Denmark; Aarhus Univ, Denmark.
    Madsen, Nanna M.
    Aarhus Univ Hosp Psychiat, Denmark; Aarhus Univ, Denmark.
    Rohde, Christopher
    Aarhus Univ, Denmark; Aarhus Univ Hosp Psychiat, Denmark.
    Eudave, Luis
    Univ Navarra, Spain.
    Aymerich, Claudia
    Univ Basque Country UPV EHU, Spain.
    Pedruzo, Borja
    Basurto Univ Hosp, Spain.
    Rodriguez, Victoria
    Kings Coll London, England.
    Rosson, Stella
    Local Hlth Unit ULSS3 Serenissima, Italy.
    Sabe, Michel
    Univ Hosp Geneva, Switzerland.
    Hojlund, Mikkel
    Reg Southern Denmark, Denmark; Univ Southern Denmark, Denmark; Capital Reg Denmark, Denmark.
    Catalan, Ana
    Univ Basque Country UPV EHU, Spain.
    de Luca, Beatrice
    Univ Verona, Italy.
    Fornaro, Michele
    Federico II Naples, Italy.
    Ostuzzi, Giovanni
    Univ Verona, Italy.
    Barbui, Corrado
    Univ Verona, Italy.
    Salazar-de-Pablo, Gonzalo
    Kings Coll London, England; South London & Maudsley NHS Fdn Trust, England; Univ Complutense, Spain.
    Fusar-Poli, Paolo
    Kings Coll London, England; Univ Pavia, Italy; NHS South London & Maudsley Fdn Trust, England; Ludwig Maximilian Univ Munich, Germany.
    Correll, Christoph U.
    Charite Univ Med Berlin, Germany; Northwell Hlth, NY 10011 USA; Donald & Barbara Zucker Sch Med Hofstra Northwell, NY 11549 USA; Feinstein Inst Med Res, NY 11030 USA.
    An umbrella review of candidate predictors of response, remission, recovery, and relapse across mental disorders2023In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 28, p. 3671-3687Article, review/survey (Refereed)
    Abstract [en]

    We aimed to identify diagnosis-specific/transdiagnostic/transoutcome multivariable candidate predictors (MCPs) of key outcomes in mental disorders. We conducted an umbrella review (protocol link), searching MEDLINE/Embase (19/07/2022), including systematic reviews of studies reporting on MCPs of response, remission, recovery, or relapse, in DSM/ICD-defined mental disorders. From published predictors, we filtered MCPs, validating MCP criteria. AMSTAR2/PROBAST measured quality/risk of bias of systematic reviews/individual studies. We included 117 systematic reviews, 403 studies, 299,888 individuals with mental disorders, testing 796 prediction models. Only 4.3%/1.2% of the systematic reviews/individual studies were at low risk of bias. The most frequently targeted outcome was remission (36.9%), the least frequent was recovery (2.5%). Studies mainly focused on depressive (39.4%), substance-use (17.9%), and schizophrenia-spectrum (11.9%) disorders. We identified numerous MCPs within disorders for response, remission and relapse, but none for recovery. Transdiagnostic MCPs of remission included lower disease-specific symptoms (disorders = 5), female sex/higher education (disorders = 3), and quality of life/functioning (disorders = 2). Transdiagnostic MCPs of relapse included higher disease-specific symptoms (disorders = 5), higher depressive symptoms (disorders = 3), and younger age/higher anxiety symptoms/global illness severity/ number of previous episodes/negative life events (disorders = 2). Finally, positive trans-outcome MCPs for depression included less negative life events/depressive symptoms (response, remission, less relapse), female sex (response, remission) and better functioning (response, less relapse); for schizophrenia, less positive symptoms/higher depressive symptoms (remission, less relapse); for substance use disorder, marital status/higher education (remission, less relapse). Male sex, younger age, more clinical symptoms and comorbid mental/physical symptoms/disorders were poor prognostic factors, while positive factors included social contacts and employment, absent negative life events, higher education, early access/intervention, lower disease-specific and comorbid mental and physical symptoms/conditions, across mental disorders. Current data limitations include high risk of bias of studies and extraction of single predictors from multivariable models. Identified MCPs can inform future development, validation or refinement of prediction models of key outcomes in mental disorders.

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  • 19.
    Solmi, Marco
    et al.
    Univ Ottawa, Canada; Ottawa Hosp, Canada; Univ Ottawa, Canada; Univ Ottawa, Canada; Univ Southampton, England; Charite Univ Med Berlin, Germany.
    Seitidis, Georgios
    Univ Ioannina, Greece.
    Mavridis, Dimitris
    Univ Ioannina, Greece; Paris Descartes Univ, France.
    Correll, Christoph U. U.
    Charite Univ Med Berlin, Germany; Zucker Hillside Hosp, NY USA; Donald & Barbara Zucker Sch Med Hofstra Northwell, NY USA; Feinstein Inst Med Res, NY USA.
    Dragioti, Elena
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center.
    Guimond, Synthia
    Univ Quebec Outaouais, Canada; Univ Ottawa, Canada.
    Tuominen, Lauri
    Univ Ottawa, Canada; Univ Ottawa, Canada.
    Dargel, Aroldo
    Univ Ottawa, Canada; Ottawa Hosp, Canada; Univ Ottawa, Canada; Univ Ottawa, Canada.
    Carvalho, Andre F. F.
    Deakin Univ, Australia.
    Fornaro, Michele
    Federico II Univ Naples, Italy.
    Maes, Michael
    Univ Elect Sci & Technol China, Peoples R China; Chulalongkorn Univ, Thailand; King Chulalongkorn Mem Hosp, Thailand; Med Univ Plovdiv, Bulgaria; Med Univ Plovdiv, Bulgaria.
    Monaco, Francesco
    ASL Salerno, Italy; European Biomed Res Inst Salerno EBRIS, Italy.
    Song, Minjin
    Yonsei Univ, South Korea.
    Shin, Jae Il
    Yonsei Univ, South Korea.
    Cortese, Samuele
    Univ Southampton, England; Univ Southampton, England; NYU, NY USA; Solent NHS Trust, England.
    Incidence, prevalence, and global burden of schizophrenia-data, with critical appraisal, from the Global Burden of Disease (GBD) 20192023In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 28, no 5319, article id 5327Article in journal (Refereed)
    Abstract [en]

    Schizophrenia substantially contributes to the burden of mental disorders. Schizophrenias burden and epidemiological estimates in some countries have been published, but updated estimates of prevalence, incidence, and schizophrenia-related disability at the global level are lacking. Here, we present the data from and critically discuss the Global Burden of Diseases, Injuries, and Risk Factors Study data, focusing on temporal changes in schizophrenias prevalence, incidence, and disability-adjusted life years (DALYs) globally. From 1990 to 2019, schizophrenia raw prevalence (14.2 to 23.6 million), incidence (941,000 to 1.3 million), and DALYs (9.1 to 15.1 million) increased by over 65%, 37%, and 65% respectively, while age-standardized estimates remained stable globally. In countries with high socio-demographic index (SDI), both prevalence and DALYs increased, while in those with low SDI, the age-standardized incidence decreased and DALYs remained stable. The male/female ratio of burden of schizophrenia has remained stable in the overall population over the past 30 years (i.e., M/F = 1.1), yet decreasing from younger to older age groups (raw prevalence in females higher than males after age 65, with males having earlier age of onset, and females longer life expectancy). Results of this work suggest that schizophrenias raw prevalence, incidence, and burden have been increasing since 1990. Age-adjusted estimates did not reduce. Schizophrenia detection in low SDI countries is suboptimal, and its prevention/treatment in high SDI countries should be improved, considering its increasing prevalence. Schizophrenia sex ratio inverts throughout the lifespan, suggesting different age of onset and survival by sex. However, prevalence and burden estimates for schizophrenia are probably underestimated. GBD does not account for mortality from schizophrenia (and other mental disorders, apart from anorexia nervosa).

  • 20.
    Solmi, Marco
    et al.
    Univ Ottawa, Canada; Ottawa Hosp, Canada; Univ Ottawa, Canada; Kings Coll London, England; Univ Southampton, England.
    Song, Minjin
    Yonsei Univ, South Korea.
    Yon, Dong Keon
    Kyung Hee Univ, South Korea; Kyung Hee Univ, South Korea.
    Lee, Seung Won
    Sejong Univ, South Korea; Sungkyunkwan Univ, South Korea.
    Fombonne, Eric
    Oregon Hlth & Sci Univ, OR 97201 USA; Oregon Hlth & Sci Univ, OR 97201 USA.
    Kim, Min Seo
    Sungkyunkwan Univ, South Korea.
    Park, Seoyeon
    Yonsei Univ, South Korea.
    Lee, Min Ho
    Yonsei Univ, South Korea.
    Hwang, Jimin
    Johns Hopkins Bloomberg Sch Publ Hlth, MD USA.
    Keller, Roberto
    Adult Autism Ctr, Italy.
    Koyanagi, Ai
    Univ Barcelona, Spain; ICREA, Spain.
    Jacob, Louis
    Univ Barcelona, Spain; Univ Versailles St Quentin En Yvelines, France.
    Dragioti, Elena
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center. Univ Ioannina, Greece.
    Smith, Lee
    Anglia Ruskin Univ, England.
    Correll, Christoph U.
    Zucker Hillside Hosp, NY USA; Donald & Barbara Zucker Sch Med Hofstra Northwell, NY USA; Feinstein Inst Med Res, NY USA; Charite Univ Med Berlin, Germany.
    Fusar-Poli, Paolo
    Kings Coll London, England; Univ Pavia, Italy; South London & Maudsley NHS Fdn Trust, England; Maudsley Biomed Res Ctr, England.
    Croatto, Giovanni
    AULSS3 Serenissima, Italy.
    Carvalho, Andre F.
    Deakin Univ, Australia.
    Oh, Jae Won
    Yonsei Univ, South Korea.
    Lee, San
    Yonsei Univ, South Korea; Yonsei Univ, South Korea; Yonsei Univ, South Korea.
    Gosling, Corentin J.
    Univ Southampton, England; Nanterre Univ, France; Univ Paris, France.
    Cheon, Keun-Ah
    Yonsei Univ, South Korea.
    Mavridis, Dimitris
    Univ Ioannina, Greece; Paris Descartes Univ, France.
    Chu, Che-Sheng
    Kaohsiung Vet Gen Hosp, Taiwan; Kaohsiung Vet Gen Hosp, Taiwan; Kaohsiung Med Univ, Taiwan.
    Liang, Chih-Sung
    Triserv Gen Hosp, Taiwan; Natl Def Med Ctr, Taiwan.
    Radua, Joaquim
    Kings Coll London, England; Ctr Invest Biomed Red Salud Mental CIBERSAM, Spain; Karolinska Inst, Sweden.
    Boyer, Laurent
    Aix Marseille Univ, France.
    Fond, Guillaume
    Aix Marseille Univ, France.
    Shin, Jae Il
    Yonsei Univ, South Korea.
    Cortese, Samuele
    Univ Southampton, England; Univ Southampton, England; Univ Nottingham, England; NYU, NY USA; Child & Adolescent Mental Hlth Serv CAMHS, England.
    Incidence, prevalence, and global burden of autism spectrum disorder from 1990 to 2019 across 204 countries2022In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 27, no 10, p. 4172-4180Article in journal (Refereed)
    Abstract [en]

    Autism spectrum disorder (ASD) substantially contributes to the burden of mental disorders. Improved awareness and changes in diagnostic criteria of ASD may have influenced the diagnostic rates of ASD. However, while data on trends in diagnostic rates in some individual countries have been published, updated estimates of diagnostic rate trends and ASD-related disability at the global level are lacking. Here, we used the Global Burden of Diseases, Injuries, and Risk Factors Study data to address this gap, focusing on changes in prevalence, incidence, and disability-adjusted life years (DALYs) of ASD across the world. From 1990 to 2019, overall age-standardized estimates remained stable globally. Both prevalence and DALYs increased in countries with high socio-demographic index (SDI). However, the age-standardized incidence decreased in some low SDI countries, indicating a need to improve awareness. The male/female ratio decreased between 1990 and 2019, possibly accounted for by increasing clinical attention to ASD in females. Our results suggest that ASD detection in low SDI countries is suboptimal, and that ASD prevention/treatment in countries with high SDI should be improved, considering the increasing prevalence of the disorder. Additionally, growing attention is being paid to ASD diagnosis in females, who might have been left behind by ASD epidemiologic and clinical research previously. ASD burden estimates are underestimated as GBD does not account for mortality in ASD.

  • 21.
    Yoon, Sojung
    et al.
    Yonsei Univ, South Korea.
    Kim, Sung Eun
    Yonsei Univ, South Korea.
    Ko, Younhee
    HankEngland Univ Foreign Studies, South Korea.
    Jeong, Gwang Hun
    Gyeongsang Natl Univ, South Korea.
    Lee, Keum Hwa
    Yonsei Univ, South Korea.
    Lee, Jinhee
    Yonsei Univ, South Korea.
    Solmi, Marco
    Univ Ottawa, Canada; Ottawa Hosp, Canada; Ottawa Hosp Res Inst OHRI, Canada; Univ Ottawa, Canada.
    Jacob, Louis
    Univ Versailles St Quentin En Yvelines, France; Univ Barcelona, Spain.
    Smith, Lee
    Anglia Ruskin Univ, England.
    Stickley, Andrew
    Natl Ctr Neurol & Psychiat, Japan; Sodertorn Univ, Sweden.
    Carvalho, Andre F.
    Ctr Addict & Mental Hlth CAMH, Canada; Univ Toronto, Canada.
    Dragioti, Elena
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center.
    Kronbichler, Andreas
    Univ Cambridge, England.
    Koyanagi, Ai
    Univ Barcelona, Spain; ICREA, Spain.
    Hong, Sung Hwi
    Yonsei Univ, South Korea.
    Thompson, Trevor
    Univ Greenwich, England.
    Oh, Hans
    Univ Southern Calif, CA 90015 USA.
    de Pablo, Gonzalo Salazar
    Kings Coll London, England; Kings Coll London, England; Univ Complutense, Spain.
    Radua, Joaquim
    Kings Coll London, England; CIBERSAM, Spain; Karolinska Inst, Sweden.
    Shin, Jae Il
    Yonsei Univ, South Korea.
    Fusar-Poli, Paolo
    Kings Coll London, England; Univ Pavia, Italy; South London & Maudsley NHS Fdn Trust, England; South London & Maudsley NHS Fdn Trust, England.
    Differential expression of MicroRNAs in Alzheimers disease: a systematic review and meta-analysis2022In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 27, no 5, p. 2405-2413Article, review/survey (Refereed)
    Abstract [en]

    Alzheimers disease (AD) results in progressive cognitive decline owing to the accumulation of amyloid plaques and hyperphosphorylated tau. MicroRNAs (miRNAs) have attracted attention as a putative diagnostic and therapeutic target for neurodegenerative diseases. However, existing meta-analyses on AD and its association with miRNAs have produced inconsistent results. The primary objective of this study is to evaluate the magnitude and consistency of differences in miRNA levels between AD patients, mild cognitive impairment (MCI) patients and healthy controls (HC). Articles investigating miRNA levels in blood, brain tissue, or cerebrospinal fluid (CSF) of AD and MCI patients versus HC were systematically searched in PubMed/Medline from inception to February 16(th), 2021. Fixed- and random-effects meta-analyses were complemented with the I-2 statistic to measure the heterogeneity, assessment of publication bias, sensitivity subgroup analyses (AD severity, brain region, post-mortem versus ante-mortem specimen for CSF and type of analysis used to quantify miRNA) and functional enrichment pathway analysis. Of the 1512 miRNAs included in 61 articles, 425 meta-analyses were performed on 334 miRNAs. Fifty-six miRNAs were significantly upregulated (n = 40) or downregulated (n = 16) in AD versus HC and all five miRNAs were significantly upregulated in MCI versus HC. Functional enrichment analysis confirmed that pathways related to apoptosis, immune response and inflammation were statistically enriched with upregulated pathways in participants with AD relative to HC. This study confirms that miRNAs expression is altered in AD and MCI compared to HC. These findings open new diagnostic and therapeutic perspectives for this disorder.

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