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  • 51.
    Holmes, Emily A.
    et al.
    Department for Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Bonsall, M B
    Hales, S A
    Mitchell, H
    Renner, F
    Blackwell, S E
    Watson, P
    Goodwin, G M
    Di Simplicio, M
    Applications of time-series analysis to mood fluctuations in bipolar disorder to promote treatment innovation: a case series.2016In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 6, article id e720Article in journal (Refereed)
    Abstract [en]

    Treatment innovation for bipolar disorder has been hampered by a lack of techniques to capture a hallmark symptom: ongoing mood instability. Mood swings persist during remission from acute mood episodes and impair daily functioning. The last significant treatment advance remains Lithium (in the 1970s), which aids only the minority of patients. There is no accepted way to establish proof of concept for a new mood-stabilizing treatment. We suggest that combining insights from mood measurement with applied mathematics may provide a step change: repeated daily mood measurement (depression) over a short time frame (1 month) can create individual bipolar mood instability profiles. A time-series approach allows comparison of mood instability pre- and post-treatment. We test a new imagery-focused cognitive therapy treatment approach (MAPP; Mood Action Psychology Programme) targeting a driver of mood instability, and apply these measurement methods in a non-concurrent multiple baseline design case series of 14 patients with bipolar disorder. Weekly mood monitoring and treatment target data improved for the whole sample combined. Time-series analyses of daily mood data, sampled remotely (mobile phone/Internet) for 28 days pre- and post-treatment, demonstrated improvements in individuals' mood stability for 11 of 14 patients. Thus the findings offer preliminary support for a new imagery-focused treatment approach. They also indicate a step in treatment innovation without the requirement for trials in illness episodes or relapse prevention. Importantly, daily measurement offers a description of mood instability at the individual patient level in a clinically meaningful time frame. This costly, chronic and disabling mental illness demands innovation in both treatment approaches (whether pharmacological or psychological) and measurement tool: this work indicates that daily measurements can be used to detect improvement in individual mood stability for treatment innovation (MAPP).

  • 52.
    Hoppe, Johanna M
    et al.
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Frick, Andreas
    Department of Psychology, Uppsala University, Uppsala, Sweden. Department of Psychology, Stockholm University, Stockholm, Sweden.
    Åhs, Fredrik
    Department of Psychology, Uppsala University, Uppsala, Sweden. Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Linnman, Clas
    Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children’s Hospital, and Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States.
    Appel, Lieuwe
    Nuclear Medicine and PET, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
    Jonasson, My
    Nuclear Medicine and PET, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden. Medical Physics, Uppsala University Hospital, Uppsala, Sweden.
    Lubberink, Mark
    Nuclear Medicine and PET, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden. Medical Physics, Uppsala University Hospital, Uppsala, Sweden.
    Långström, Bengt
    Medical Physics, Uppsala University Hospital, Uppsala, Sweden.
    Frans, Örjan
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    von Knorring, Lars
    Department of Neuroscience, Psychiatry, Uppsala University, Uppsala, Sweden.
    Fredrikson, Mats
    Department of Psychology, Uppsala University, Uppsala, Sweden. Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Furmark, Tomas
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Association between amygdala neurokinin-1 receptor availability and anxiety-related personality traits2018In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 8, no 1, article id 168Article in journal (Refereed)
    Abstract [en]

    Animal studies indicate that substance P (SP) and its preferred neurokinin-1 (NK1) receptor modulate stress and anxiety-related behavior. Alterations in the SP-NK1 system have also been observed in human anxiety disorders, yet little is known about the relation between this system and individual differences in personality traits associated with anxiety propensity and approach-avoidance behavior, including trait anxiety, neuroticism, and extraversion. Exploring this relation could provide important insights into the neurobiological underpinnings of human anxiety and the etiology of anxiety disorders, as anxious traits are associated with increased susceptibility to develop psychopathological conditions. Here we examined the relationship between central NK1 receptor availability and self-rated measures of trait anxiety, neuroticism, and extraversion. The amygdala was chosen as the primary region of interest since this structure has been suggested to mediate the effect of the SP-NK1 system on anxiety. Anxious traits and NK1 receptor availability, determined with positron emission tomography and the radiotracer [11C]GR205171, were measured in 17 healthy individuals. Voxel-wise analyses showed a significant positive correlation between bilateral amygdala NK1 receptor availability and trait anxiety, and a trend in similar direction was observed for neuroticism. Conversely, extraversion was found to be negatively associated with amygdala NK1 receptor availability. Extraversion also correlated negatively with the NK1 measure in the cuneus/precuneus and fusiform gyrus according to exploratory whole-brain analyses. In conclusion, our findings indicate that amygdala NK1 receptor availability is associated with anxiety-related personality traits in healthy subjects, consistent with a modulatory role for the SP-NK1 system in human anxiety.

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  • 53. Hoppe, Johanna M.
    et al.
    Frick, Andreas
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Biological psychology. Stockholm University, Sweden.
    Åhs, Fredrik
    Linnman, Clas
    Appel, Lieuwe
    Jonasson, My
    Lubberink, Mark
    Långström, Bengt
    Frans, Örjan
    von Knorring, Lars
    Fredrikson, Mats
    Furmark, Tomas
    Association between amygdala neurokinin-1 receptor availability and anxiety-related personality traits2018In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 8, article id 168Article in journal (Refereed)
    Abstract [en]

    Animal studies indicate that substance P (SP) and its preferred neurokinin-1 (NK1) receptor modulate stress and anxiety-related behavior. Alterations in the SP-NK1 system have also been observed in human anxiety disorders, yet little is known about the relation between this system and individual differences in personality traits associated with anxiety propensity and approach-avoidance behavior, including trait anxiety, neuroticism, and extraversion. Exploring this relation could provide important insights into the neurobiological underpinnings of human anxiety and the etiology of anxiety disorders, as anxious traits are associated with increased susceptibility to develop psychopathological conditions. Here we examined the relationship between central NK1 receptor availability and selfrated measures of trait anxiety, neuroticism, and extraversion. The amygdala was chosen as the primary region of interest since this structure has been suggested to mediate the effect of the SP-NK1 system on anxiety. Anxious traits and NK1 receptor availability, determined with positron emission tomography and the radiotracer [C-11]GR205171, were measured in 17 healthy individuals. Voxel-wise analyses showed a significant positive correlation between bilateral amygdala NK1 receptor availability and trait anxiety, and a trend in similar direction was observed for neuroticism. Conversely, extraversion was found to be negatively associated with amygdala NK1 receptor availability. Extraversion also correlated negatively with the NK1 measure in the cuneus/precuneus and fusiform gyrus according to exploratory whole-brain analyses. In conclusion, our findings indicate that amygdala NK1 receptor availability is associated with anxiety-related personality traits in healthy subjects, consistent with a modulatory role for the SP-NK1 system in human anxiety.

  • 54. Hou, J.
    et al.
    Hess, J. L.
    Armstrong, N.
    Bis, J. C.
    Grenier-Boley, B.
    Karlsson, Ida K.
    Jönköping University, School of Health and Welfare, HHJ, Institute of Gerontology. Jönköping University, School of Health and Welfare, HHJ. ARN-J (Aging Research Network - Jönköping).
    Leonenko, G.
    Numbers, K.
    O’Brien, E. K.
    Shadrin, A.
    Thalamuthu, A.
    Yang, Q.
    Andreassen, O. A.
    Brodaty, H.
    Gatz, M.
    Kochan, N. A.
    Lambert, J. -C
    Laws, S. M.
    Masters, C. L.
    Mather, K. A.
    Pedersen, N. L.
    Posthuma, D.
    Sachdev, P. S.
    Williams, J.
    Fan, C. C.
    Faraone, S. V.
    Fennema-Notestine, C.
    Lin, S. -J
    Escott-Price, V.
    Holmans, P.
    Seshadri, S.
    Tsuang, M. T.
    Kremen, W. S.
    Glatt, S. J.
    Polygenic resilience scores capture protective genetic effects for Alzheimer’s disease2022In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 12, no 1, article id 296Article in journal (Refereed)
    Abstract [en]

    Polygenic risk scores (PRSs) can boost risk prediction in late-onset Alzheimer’s disease (LOAD) beyond apolipoprotein E (APOE) but have not been leveraged to identify genetic resilience factors. Here, we sought to identify resilience-conferring common genetic variants in (1) unaffected individuals having high PRSs for LOAD, and (2) unaffected APOE-ε4 carriers also having high PRSs for LOAD. We used genome-wide association study (GWAS) to contrast “resilient” unaffected individuals at the highest genetic risk for LOAD with LOAD cases at comparable risk. From GWAS results, we constructed polygenic resilience scores to aggregate the addictive contributions of risk-orthogonal common variants that promote resilience to LOAD. Replication of resilience scores was undertaken in eight independent studies. We successfully replicated two polygenic resilience scores that reduce genetic risk penetrance for LOAD. We also showed that polygenic resilience scores positively correlate with polygenic risk scores in unaffected individuals, perhaps aiding in staving off disease. Our findings align with the hypothesis that a combination of risk-independent common variants mediates resilience to LOAD by moderating genetic disease risk.

  • 55.
    Ip, Hill F.
    et al.
    Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Boomsma, Dorret I
    Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands; Amsterdam Public Health Research Institute, Amsterdam, The Netherlands.
    Genetic association study of childhood aggression across raters, instruments, and age2021In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 11, no 1, article id 413Article in journal (Refereed)
    Abstract [en]

    Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association meta-analysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis (AGGoverall) was 3.31% (SE = 0.0038). We found no genome-wide significant SNPs for AGGoverall. The gene-based analysis returned three significant genes: ST3GAL3 (P = 1.6E-06), PCDH7 (P = 2.0E-06), and IPO13 (P = 2.5E-06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations (rg) among rater-specific assessment of AGG ranged from rg = 0.46 between self- and teacher-assessment to rg = 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong rgs with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range [Formula: see text]: 0.19-1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (rg = ~-0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range [Formula: see text]: 0.46-0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.

  • 56. Isung, J
    et al.
    Aeinehband, S
    Mobarrez, F
    Mårtensson, B
    Nordström, P
    Asberg, M
    Piehl, F
    Jokinen, Jussi
    Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
    Low vascular endothelial growth factor and interleukin-8 in cerebrospinal fluid of suicide attempters2012In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 2, p. e196-Article in journal (Refereed)
    Abstract [en]

    A dysregulated immune system influencing pathways for cytokine regulation and growth factor expression is implicated in the pathophysiology of several neuropsychiatric disorders. Here, we analyzed cerebrospinal fluid (CSF) cytokines and growth factors with an ultra-sensitive immunoassay system in 43 medication-free suicide attempters and 20 healthy male volunteers. CSF vascular endothelial growth factor (VEGF) and CSF interleukin-8 (IL-8) levels were significantly lower in suicide attempters compared with healthy controls. Further, CSF VEGF showed a significant negative correlation with depression severity. CSF IL-6 levels did not differ between suicide attempters and healthy controls. Low CSF levels of VEGF may represent a lack of trophic support to neurons and downregulation of neurogenesis in the hippocampus reflecting more severe depressive states. IL-8 has also been reported as important in neuroprotection as well as having chemokine activity in the innate immune response. The results support a role for an impaired innate immunity and dysregulation of neuroprotection in the pathophysiology of depression and suicidal behavior.

  • 57. Isung, J
    et al.
    Aeinehband, S
    Mobarrez, F
    Nordström, P
    Runeson, B
    Asberg, M
    Piehl, F
    Jokinen, Jussi
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry. Department of Clinical Neuroscience/Psychiatry, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    High interleukin-6 and impulsivity: determining the role of endophenotypes in attempted suicide2014In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 4, no e470Article in journal (Refereed)
    Abstract [en]

    The dysregulation of inflammation has been associated with depression and, more recently, with suicidal behaviors. The reports regarding the relationship between interleukin-6 (IL-6) and suicide attempts are inconsistent. Personality traits such as impulsivity and aggression are considered endophenotypes and important factors that underlie suicidal behaviors. The aim of the current study was to assess whether plasma and cerebrospinal fluid (CSF) levels of IL-6 are associated with personality traits among suicide attempters. We assessed the relationships among personality traits, IL-6 and violent suicide attempts. The plasma and CSF levels of IL-6 were measured in suicide attempters (plasma=58, CSF=39) using antibody-based immunoassay systems. Personality domains were assessed using the Karolinska Scale of Personality (KSP). IL-6 levels in plasma and CSF were used to predict personality domains via regression models. Plasma IL-6 was significantly and positively correlated with extraversion as well as the KSP subscales impulsivity and monotony avoidance. CSF IL-6 was positively correlated with monotony avoidance. Violent suicide attempts tended to be associated with high plasma IL-6 levels. Plasma and CSF levels of IL-6 were not significantly associated with each other. These results indicate that impulsivity and the choice of a violent suicide attempt method might be related to higher levels of IL-6 in individuals who attempt suicide. The neuroinflammation hypothesis of suicidal behavior on the basis of elevated IL-6 levels might be partly explained by the positive association between IL-6 and impulsivity, which is a key element of the suicidal phenotype.

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  • 58.
    Isung, Josef
    et al.
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Stockholm County Council, Stockholm.
    Isomura, Kayoko
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden.
    Almqvist, Catarina
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Wester, Tomas
    Division of Pediatric Surgery, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
    Rück, Christian
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden.
    Fernández de la Cruz, Lorena
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden.
    Sidorchuk, Anna
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden.
    Mataix-Cols, David
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden.
    Association of chronic and acute inflammation of the mucosa-associated lymphoid tissue with psychiatric disorders and suicidal behavior2019In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 9, no 1, article id 227Article in journal (Refereed)
    Abstract [en]

    Immune dysregulation due to chronic inflammation is a hypothesized risk factor underlying psychiatric disorders and suicidal behavior. Whether tonsillectomy and acute appendicitis used, respectively, as proxies for chronic and acute inflammation within the mucosa-associated lymphoid tissue (MALT) are associated with psychiatric disorders and suicidal behavior is currently unknown. A birth cohort study was conducted including 3,052,875 individuals born in Sweden between 1973 and 2003. We identified 210,686 individuals ever exposed to tonsillectomy and 86,928 individuals ever exposed to acute appendicitis, as well as 317,214 clusters of siblings discordant for tonsillectomy, and 160,079 sibling clusters discordant for acute appendicitis. Outcomes were an aggregate risk of 'any psychiatric disorder', 'any suicidal behavior', 12 individual psychiatric disorders, suicide attempts and deaths by suicide. Tonsillectomy was associated with increased odds of 'any psychiatric disorder' (adjusted odds ratio [aOR] = 1.39; 95% confidence interval (CI) = 1.38-1.41) and 'any suicidal behavior' (aOR = 1.41; 95% CI = 1.37-1.44), and most individual disorders. Acute appendicitis also increased the odds of 'any psychiatric disorder' and 'any suicidal behavior' (aOR = 1.23; 95% CI = 1.20-1.25, and aOR = 1.32; 95% CI = 1.28-1.37, respectively). Exposure to both tonsillectomy and appendicitis was associated with the highest odds of 'any psychiatric disorder' (aOR = 1.70; 95% CI = 1.59-1.82) and 'any suicidal behavior' (aOR = 1.90; 95% CI = 1.70-2.12). In sibling comparisons, the associations were attenuated but remained significant. We conclude that inflammation within the MALT, particularly when chronic, is robustly associated with a broad range of psychiatric disorders and suicidal behavior.

  • 59.
    Iyadurai, Lalitha
    et al.
    P1vital Prod Ltd, Wallingford, Oxon, England..
    Highfield, Julie
    Intens Care Soc, 7-9-Breams Bldg, London, England..
    Kanstrup, Marie
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Markham, Alfred
    P1vital Prod Ltd, Wallingford, Oxon, England..
    Ramineni, Varsha
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. P1vital Prod Ltd, Wallingford, Oxon, England..
    Guo, Boliang
    NIHR ARC East Midlands, Nottingham, England..
    Jaki, Thomas
    Univ Cambridge, MRC Biostat Unit, Cambridge, Cambs, England.;Univ Regensburg, Regensburg, Bavaria, Germany..
    Kingslake, Jonathan
    P1vital Prod Ltd, Wallingford, Oxon, England..
    Goodwin, Guy M.
    Univ Oxford, Dept Psychiat, Oxford, Oxon, England..
    Summers, Charlotte
    Univ Cambridge, Heart & Lung Res Inst, Cambridge, Cambs, England..
    Bonsall, Michael B.
    Univ Oxford, Dept Biol, Oxford, Oxon, England..
    Holmes, Emily A.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Reducing intrusive memories after trauma via an imagery-competing task intervention in COVID-19 intensive care staff: a randomised controlled trial2023In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 13, no 1, article id 290Article in journal (Refereed)
    Abstract [en]

    Intrusive memories (IMs) after traumatic events can be distressing and disrupt mental health and functioning. We evaluated the impact of a brief remotely-delivered digital imagery-competing task intervention on the number of IMs for intensive care unit (ICU) staff who faced repeated trauma exposure during the COVID-19 pandemic using a two-arm, parallel-group, single-blind randomised controlled trial, with the comparator arm receiving delayed access to active treatment (crossover). Eligible participants worked clinically in a UK NHS ICU during the pandemic and had at least 3 IMs of work-related traumatic events in the week before recruitment. Participants were randomly assigned (1:1) to immediate (weeks 1-4) or delayed (weeks 5-8) intervention access. Sequential Bayesian analyses to optimise the intervention and increase trial efficiency are reported elsewhere [1]. The primary endpoint for the pre-specified frequentist analysis of the final study population compared the number of IMs experienced in week 4 between the immediate and delayed access arms. Secondary outcomes included clinical symptoms, work functioning and wellbeing. Safety was assessed throughout the trial by scheduled questions and free report. All analyses were undertaken on an intention-to-treat basis (86 randomised participants). There were significantly fewer intrusive memories during week 4 in the immediate (median = 1, IQR = 0-3, n = 43), compared to the comparator delayed arm (median = 10, IQR = 6-17, n = 43), IRR 0.31, 95% CI: 0.20-0.48, p < 0.001. After crossover, the delayed arm also showed a significant reduction in IMs at week 8 compared to week 4. There were convergent findings for symptoms of PTSD, insomnia and anxiety, work engagement and burnout, general functioning and quality of life. The intervention was found safe and acceptable to participants. All adverse events were unrelated to the study. Our study provides the first evidence of a benefit on reducing IMs, improving other clinical symptoms, work functioning and wellbeing, as well as safety of a brief remotely-delivered digital imagery-competing task intervention. An efficacy trial with an active control and longer follow-up is warranted. The trial is registered at ClinicalTrials.gov (NCT04992390).

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  • 60.
    Javaheripour, Nooshin
    et al.
    Jena Univ Hosp, Germany; Clin Affect Neuroimaging Lab CANLAB, Germany.
    Li, Meng
    Jena Univ Hosp, Germany; Clin Affect Neuroimaging Lab CANLAB, Germany.
    Chand, Tara
    Jena Univ Hosp, Germany; Clin Affect Neuroimaging Lab CANLAB, Germany.
    Krug, Axel
    Univ Bonn, Germany; Philipps Univ Marburg, Germany.
    Kircher, Tilo
    Philipps Univ Marburg, Germany.
    Dannlowski, Udo
    Univ Munster, Germany.
    Nenadic, Igor
    Philipps Univ Marburg, Germany.
    Hamilton, Paul
    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).
    Sacchet, Matthew D.
    Harvard Med Sch, MA USA.
    Gotlib, Ian H.
    Stanford Univ, CA 94305 USA.
    Walter, Henrik
    Charite Univ Med Berlin, Germany; Free Univ Berlin, Germany; Berlin Inst Hlth, Germany; Humboldt Univ, Germany.
    Frodl, Thomas
    Otto von Guericke Univ, Germany.
    Grimm, Simone
    Charite Univ Med Berlin, Germany.
    Harrison, Ben J.
    Univ Melbourne, Australia.
    Wolf, Christian Robert
    Heidelberg Univ, Germany.
    Olbrich, Sebastian
    Dept Psychiat Psychotherapy & Psychosomat, Switzerland.
    van Wingen, Guido
    Univ Amsterdam, Netherlands.
    Pezawas, Lukas
    Med Univ Vienna, Austria.
    Parker, Gordon
    Univ New South Wales, Australia.
    Hyett, Matthew P.
    Univ Western Australia, Australia.
    Saemann, Philipp G.
    Max Planck Inst Psychiat, Germany.
    Hahn, Tim
    Univ Munster, Germany.
    Steinstraeter, Olaf
    Philipps Univ Marburg, Germany.
    Jansen, Andreas
    Philipps Univ Marburg, Germany; Philipps Univ Marburg, Germany.
    Yuksel, Dilara
    SRI Int, CA USA.
    Kämpe, Robin
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Davey, Christopher G.
    Univ Melbourne, Australia.
    Meyer, Bernhard
    Med Univ Vienna, Austria.
    Bartova, Lucie
    Med Univ Vienna, Austria.
    Croy, Ilona
    Friedrich Schiller Univ Jena, Germany; Tech Univ Dresden, Germany.
    Walter, Martin
    Jena Univ Hosp, Germany; Clin Affect Neuroimaging Lab CANLAB, Germany; Leibniz Inst Neurobiol, Germany; Univ Tubingen, Germany.
    Wagner, Gerd
    Jena Univ Hosp, Germany.
    Altered resting-state functional connectome in major depressive disorder: a mega-analysis from the PsyMRI consortium2021In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 11, no 1, article id 511Article in journal (Refereed)
    Abstract [en]

    Major depressive disorder (MDD) is associated with abnormal neural circuitry. It can be measured by assessing functional connectivity (FC) at resting-state functional MRI, that may help identifying neural markers of MDD and provide further efficient diagnosis and monitor treatment outcomes. The main aim of the present study is to investigate, in an unbiased way, functional alterations in patients with MDD using a large multi-center dataset from the PsyMRI consortium including 1546 participants from 19 centers (). After applying strict exclusion criteria, the final sample consisted of 606 MDD patients (age: 35.8 +/- 11.9 y.o.; females: 60.7%) and 476 healthy participants (age: 33.3 +/- 11.0 y.o.; females: 56.7%). We found significant relative hypoconnectivity within somatosensory motor (SMN), salience (SN) networks and between SMN, SN, dorsal attention (DAN), and visual (VN) networks in MDD patients. No significant differences were detected within the default mode (DMN) and frontoparietal networks (FPN). In addition, alterations in network organization were observed in terms of significantly lower network segregation of SMN in MDD patients. Although medicated patients showed significantly lower FC within DMN, FPN, and SN than unmedicated patients, there were no differences between medicated and unmedicated groups in terms of network organization in SMN. We conclude that the network organization of cortical networks, involved in processing of sensory information, might be a more stable neuroimaging marker for MDD than previously assumed alterations in higher-order neural networks like DMN and FPN.

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  • 61.
    Jayaram-Lindstrom, N.
    et al.
    Stockholm Cty Council, Dept Clin Neurosci, Karolinska Inst, Ctr Psychiat Res, Stockholm, Sweden.;Stockholm Cty Council, Stockholm Hlth Care Serv, Stockholm, Sweden..
    Guterstam, J.
    Stockholm Cty Council, Dept Clin Neurosci, Karolinska Inst, Ctr Psychiat Res, Stockholm, Sweden.;Stockholm Cty Council, Stockholm Hlth Care Serv, Stockholm, Sweden..
    Haggkvist, J.
    Stockholm Cty Council, Dept Clin Neurosci, Karolinska Inst, Ctr Psychiat Res, Stockholm, Sweden.;Stockholm Cty Council, Stockholm Hlth Care Serv, Stockholm, Sweden..
    Ericson, M.
    Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, Gothenburg, Sweden..
    Malmlof, T.
    Karolinska Inst, Sect Neuropsychopharmacol, Dept Physiol & Pharmacol, Stockholm, Sweden..
    Schilstrom, B.
    Karolinska Inst, Sect Neuropsychopharmacol, Dept Physiol & Pharmacol, Stockholm, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, Gothenburg, Sweden..
    Halldin, C.
    Stockholm Cty Council, Dept Clin Neurosci, Karolinska Inst, Ctr Psychiat Res, Stockholm, Sweden.;Stockholm Cty Council, Stockholm Hlth Care Serv, Stockholm, Sweden..
    Cervenka, Simon
    Stockholm Cty Council, Dept Clin Neurosci, Karolinska Inst, Ctr Psychiat Res, Stockholm, Sweden.;Stockholm Cty Council, Stockholm Hlth Care Serv, Stockholm, Sweden..
    Saijo, T.
    Stockholm Cty Council, Dept Clin Neurosci, Karolinska Inst, Ctr Psychiat Res, Stockholm, Sweden.;Stockholm Cty Council, Stockholm Hlth Care Serv, Stockholm, Sweden..
    Nordstrom, A-L
    Stockholm Cty Council, Dept Clin Neurosci, Karolinska Inst, Ctr Psychiat Res, Stockholm, Sweden.;Stockholm Cty Council, Stockholm Hlth Care Serv, Stockholm, Sweden..
    Franck, J.
    Stockholm Cty Council, Dept Clin Neurosci, Karolinska Inst, Ctr Psychiat Res, Stockholm, Sweden.;Stockholm Cty Council, Stockholm Hlth Care Serv, Stockholm, Sweden..
    Naltrexone modulates dopamine release following chronic, but not acute amphetamine administration: a translational study2017In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 7, article id e1104Article in journal (Refereed)
    Abstract [en]

    The opioid antagonist naltrexone has been shown to attenuate the subjective effects of amphetamine. However, the mechanisms behind this modulatory effect are currently unknown. We hypothesized that naltrexone would diminish the striatal dopamine release induced by amphetamine, which is considered an important mechanism behind many of its stimulant properties. We used positron emission tomography and the dopamine D2-receptor radioligand [C-11]raclopride in healthy subjects to study the dopaminergic effects of an amphetamine injection after pretreatment with naltrexone or placebo. In a rat model, we used microdialysis to study the modulatory effects of naltrexone on dopamine levels after acute and chronic amphetamine exposure. In healthy humans, naltrexone attenuated the subjective effects of amphetamine, confirming our previous results. Amphetamine produced a significant reduction in striatal radioligand binding, indicating increased levels of endogenous dopamine. However, there was no statistically significant effect of naltrexone on dopamine release. The same pattern was observed in rats, where an acute injection of amphetamine caused a significant rise in striatal dopamine levels, with no effect of naltrexone pretreatment. However, in a chronic model, naltrexone significantly attenuated the dopamine release caused by reinstatement of amphetamine. Collectively, these data suggest that the opioid system becomes engaged during the more chronic phase of drug use, evidenced by the modulatory effect of naltrexone on dopamine release following chronic amphetamine administration. The importance of opioid-dopamine interactions in the reinforcing and addictive effects of amphetamine is highlighted by the present findings and may help to facilitate medication development in the field of stimulant dependence.

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  • 62.
    Jernbom Falk, August
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Galletly, Cherrie
    Univ Adelaide, Adelaide Med Sch, Discipline Psychiat, Adelaide, SA, Australia.;SA Hlth, Northern Adelaide Mental Hlth Serv, Adelaide, SA, Australia.;Adelaide Clin, Ramsay Hlth Care SA Mental Hlth, Adelaide, SA, Australia..
    Just, David
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics.
    Toben, Catherine
    Univ Adelaide, Adelaide Med Sch, Discipline Psychiat, Adelaide, SA, Australia..
    Baune, Bernhard T.
    Univ Adelaide, Adelaide Med Sch, Discipline Psychiat, Adelaide, SA, Australia.;Univ Munster, Dept Mental Hlth, Munster, Germany.;Univ Munster, Lab Div Mol Neurobiol Mental Hlth, Munster, Germany.;Univ Melbourne, Melbourne Med Sch, Dept Psychiat, Melbourne, Vic, Australia.;Univ Melbourne, Florey Inst Neurosci & Mental Hlth, Parkville, Vic, Australia.;SUNY Upstate Med Univ, Dept Psychiat, Syracuse, NY 13210 USA.;Univ New South Wales, Sch Psychiat, Sydney, NSW, Australia..
    Clark, Scott R.
    Univ Adelaide, Adelaide Med Sch, Discipline Psychiat, Adelaide, SA, Australia..
    Liu, Dennis
    Univ Adelaide, Adelaide Med Sch, Discipline Psychiat, Adelaide, SA, Australia.;SA Hlth, Northern Adelaide Mental Hlth Serv, Adelaide, SA, Australia..
    Nilsson, Peter
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics.
    Månberg, Anna
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics.
    Schubert, K. Oliver
    Univ Adelaide, Adelaide Med Sch, Discipline Psychiat, Adelaide, SA, Australia.;SA Hlth, Northern Adelaide Mental Hlth Serv, Adelaide, SA, Australia..
    Autoantibody profiles associated with clinical features in psychotic disorders2021In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 11, no 1, article id 474Article in journal (Refereed)
    Abstract [en]

    Autoimmune processes are suspected to play a role in the pathophysiology of psychotic disorders. Better understanding of the associations between auto-immunoglobulin G (IgG) repertoires and clinical features of mental illness could yield novel models of the pathophysiology of psychosis, and markers for biological patient stratification. We undertook cross-sectional detection and quantification of auto-IgGs in peripheral blood plasma of 461 people (39% females) with established psychotic disorder diagnoses. Broad screening of 24 individuals was carried out on group level in eight clinically defined groups using planar protein microarrays containing 42,100 human antigens representing 18,914 proteins. Autoantibodies indicated by broad screening and in the previous literature were measured using a 380-plex bead-based array for autoantibody profiling of all 461 individuals. Associations between autoantibody profiles and dichotomized clinical characteristics were assessed using a stepwise selection procedure. Broad screening and follow-up targeted analyses revealed highly individual autoantibody profiles. Females, and people with family histories of obesity or of psychiatric disorders other than schizophrenia had the highest overall autoantibody counts. People who had experienced subjective thought disorder and/or were treated with clozapine (trend) had the lowest overall counts. Furthermore, six autoantibodies were associated with specific psychopathology symptoms: anti-AP3B2 (persecutory delusions), anti-TDO2 (hallucinations), anti-CRYGN (initial insomnia); anti-APMAP (poor appetite), anti-OLFM1 (above-median cognitive function), and anti-WHAMMP3 (anhedonia and dysphoria). Future studies should clarify whether there are causal biological relationships, and whether autoantibodies could be used as clinical markers to inform diagnostic patient stratification and choice of treatment.

  • 63.
    Johansson, Therese
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, WoMHeR (Centre for Women’s Mental Health during the Reproductive Lifespan). Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Birgegard, Andreas
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Zhang, Ruyue
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Bergen, Sarah E.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Landen, Mikael
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.;Univ Gothenburg, Inst Neurosci & Physiol, Gothenburg, Sweden..
    Petersen, Liselotte, V
    Aarhus Univ, Natl Ctr Register Based Res, Dept Econ & Business Econ, Aarhus, Denmark..
    Bulik, Cynthia M.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.;Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27515 USA.;Univ N Carolina, Dept Nutr, Chapel Hill, NC 27515 USA..
    Hubel, Christopher
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.;Aarhus Univ, Natl Ctr Register Based Res, Dept Econ & Business Econ, Aarhus, Denmark.;Kings Coll London, Inst Psychiat Psychol & Neurosci, Social Genet & Dev Psychiat Ctr, London, England.;South London & Maudsley Hosp, UK Natl Inst Hlth Res NIHR Biomed Res Ctr Mental, London, England..
    Polygenic association with severity and long-term outcome in eating disorder cases2022In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 12, no 1, article id 61Article in journal (Refereed)
    Abstract [en]

    About 20% of individuals with anorexia nervosa (AN) remain chronically ill. Therefore, early identification of poor outcome could improve care. Genetic research has identified regions of the genome associated with AN. Patients with anorexia nervosa were identified via the Swedish eating disorder quality registers Stepwise and Riksat and invited to participate in the Anorexia Nervosa Genetics Initiative. First, we associated genetic information longitudinally with eating disorder severity indexed by scores on the Clinical Impairment Assessment (CIA) in 2843 patients with lifetime AN with or without diagnostic migration to other forms of eating disorders followed for up to 16 years (mean = 5.3 years). Second, we indexed the development of a severe and enduring eating disorder (SEED) by a high CIA score plus a follow-up time >= 5 years. We associated individual polygenic scores (PGSs) indexing polygenic liability for AN, schizophrenia, and body mass index (BMI) with severity and SEED. After multiple testing correction, only the BMI PGS when calculated with traditional clumping and p value thresholding was robustly associated with disorder severity (beta(PGS) = 1.30; 95% CI: 0.72, 1.88; p = 1.2 x 10(-5)) across all p value thresholds at which we generated the PGS. However, using the alternative PGS calculation method PRS-CS yielded inconsistent results for all PGS. The positive association stands in contrast to the negative genetic correlation between BMI and AN. Larger discovery GWASs to calculate PGS will increase power, and it is essential to increase sample sizes of the AN GWASs to generate clinically meaningful PGS as adjunct risk prediction variables. Nevertheless, this study provides the first evidence of potential clinical utility of PGSs for eating disorders.

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  • 64.
    Jokinen, Jussi
    et al.
    Umeå Univ, Dept Clin Sci Psychiat, Umeå, Sweden.;Karolinska Inst, Dept Clin Neurosci Psychol, Stockholm, Sweden..
    Andersson, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Center for Clinical Research Dalarna. Karolinska Inst, Dept Clin Neurosci Psychol, Stockholm, Sweden.
    Chatzittofis, Andreas
    Umeå Univ, Dept Clin Sci Psychiat, Umeå, Sweden.;Univ Cyprus, Med Sch, Nicosia, Cyprus..
    Savard, Josephine
    Umeå Univ, Dept Clin Sci Psychiat, Umeå, Sweden..
    Rask-Andersen, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Åsberg, Marie
    Karolinska Inst, Dept Clin Neurosci Psychol, Stockholm, Sweden..
    Boström, Adrian Desai E.
    Umeå Univ, Dept Clin Sci Psychiat, Umeå, Sweden.;Karolinska Inst, Dept Womens & Childrens Hlth Neuropediat, Stockholm, Sweden..
    Accelerated epigenetic aging in suicide attempters uninfluenced by high intent-to-die and choice of lethal methods2022In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 12, no 1, article id 224Article in journal (Refereed)
    Abstract [en]

    Suicide attempts (SA) are associated with excess non-suicidal mortality, putatively mediated in part by premature cellular senescence. Epigenetic age (EA) estimators of biological age have been previously demonstrated to strongly predict physiological dysregulation and mortality risk. Herein, we investigate if violent SA with high intent-to-die is predictive of epigenetics-derived estimates of biological aging. The genome-wide methylation pattern was measured using the Illumina Infinium Methylation EPIC BeadChip in whole blood of 88 suicide attempters. Subjects were stratified into two groups based on the putative risk of later committed suicide (low- [n = 58] and high-risk [n = 30]) in dependency of SA method (violent or non-violent) and/or intent-to-die (high/low). Estimators of intrinsic and extrinsic EA acceleration, one marker optimized to predict physiological dysregulation (DNAmPhenoAge/AgeAccelPheno) and one optimized to predict lifespan (DNAmGrimAge/AgeAccelGrim) were investigated for associations to severity of SA, by univariate and multivariate analyses. The study was adequately powered to detect differences of 2.2 years in AgeAccelGrim in relation to SA severity. Baseline DNAmGrimAge exceeded chronological age by 7.3 years on average across all samples, conferring a mean 24.6% increase in relation to actual age. No individual EA acceleration marker was differentiated by suicidal risk group (p > 0.1). Thus, SA per se but not severity of SA is related to EA, implicating that excess non-suicidal mortality in SA is unrelated to risk of committed suicide. Preventative healthcare efforts aimed at curtailing excess mortality after SA may benefit from acting equally powerful to recognize somatic comorbidities irrespective of the severity inherent in the act itself.

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  • 65.
    Jokinen, Jussi
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry. Department of Clinical Neuroscience/Psychology, Karolinska Institute, Stockholm, Sweden.
    Andersson, Peter
    Department of Clinical Neuroscience/Psychology, Karolinska Institute, Stockholm, Sweden; Centre for Clinical Research Dalarna, Uppsala University, Falun, Sweden.
    Chatzittofis, Andreas
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry. Medical School, University of Cyprus, Nicosia, Cyprus.
    Savard, Josephine
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Rask-Andersen, Mathias
    Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Åsberg, Marie
    Department of Clinical Neuroscience/Psychology, Karolinska Institute, Stockholm, Sweden.
    Boström, Adrian Desai E.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry. Department of Women’s and Children’s Health/Neuropediatrics, Karolinska Institutet, Stockholm, Sweden.
    Accelerated epigenetic aging in suicide attempters uninfluenced by high intent-to-die and choice of lethal methods2022In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 12, no 1, article id 224Article in journal (Refereed)
    Abstract [en]

    Suicide attempts (SA) are associated with excess non-suicidal mortality, putatively mediated in part by premature cellular senescence. Epigenetic age (EA) estimators of biological age have been previously demonstrated to strongly predict physiological dysregulation and mortality risk. Herein, we investigate if violent SA with high intent-to-die is predictive of epigenetics-derived estimates of biological aging. The genome-wide methylation pattern was measured using the Illumina Infinium Methylation EPIC BeadChip in whole blood of 88 suicide attempters. Subjects were stratified into two groups based on the putative risk of later committed suicide (low- [n = 58] and high-risk [n = 30]) in dependency of SA method (violent or non-violent) and/or intent-to-die (high/low). Estimators of intrinsic and extrinsic EA acceleration, one marker optimized to predict physiological dysregulation (DNAmPhenoAge/AgeAccelPheno) and one optimized to predict lifespan (DNAmGrimAge/AgeAccelGrim) were investigated for associations to severity of SA, by univariate and multivariate analyses. The study was adequately powered to detect differences of 2.2 years in AgeAccelGrim in relation to SA severity. Baseline DNAmGrimAge exceeded chronological age by 7.3 years on average across all samples, conferring a mean 24.6% increase in relation to actual age. No individual EA acceleration marker was differentiated by suicidal risk group (p > 0.1). Thus, SA per se but not severity of SA is related to EA, implicating that excess non-suicidal mortality in SA is unrelated to risk of committed suicide. Preventative healthcare efforts aimed at curtailing excess mortality after SA may benefit from acting equally powerful to recognize somatic comorbidities irrespective of the severity inherent in the act itself.

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    fulltext
  • 66.
    Just, David
    et al.
    KTH Royal Inst Technol, SciLifeLab, Dept Prot Sci, Stockholm, Sweden.;Uppsala Univ, Dept Neurosci, Psychiat, Uppsala, Sweden..
    Manberg, Anna
    KTH Royal Inst Technol, SciLifeLab, Dept Prot Sci, Stockholm, Sweden..
    Mitsios, Nicholas
    Karolinska Inst, Dept Neurosci, Stockholm, Sweden..
    Stockmeier, Craig A.
    Univ Mississippi, Med Ctr, Dept Psychiat & Human Behav, Jackson, MS 39216 USA..
    Rajkowska, Grazyna
    Univ Mississippi, Med Ctr, Dept Psychiat & Human Behav, Jackson, MS 39216 USA..
    Uhlen, Mathias
    KTH Royal Inst Technol, SciLifeLab, Dept Prot Sci, Stockholm, Sweden.;Karolinska Inst, Dept Neurosci, Stockholm, Sweden..
    Mulder, Jan
    Karolinska Inst, Dept Neurosci, Stockholm, Sweden..
    Feuk, Lars
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Cunningham, Janet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Ekselius: Psychiatry.
    Nilsson, Peter
    KTH Royal Inst Technol, SciLifeLab, Dept Prot Sci, Stockholm, Sweden..
    Carlström, Eva Lindholm
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Exploring autoantibody signatures in brain tissue from patients with severe mental illness2020In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 10, no 1, article id 401Article in journal (Refereed)
    Abstract [en]

    In recent years, studies have shown higher prevalence of autoantibodies in patients with schizophrenia compared to healthy individuals. This study applies an untargeted and a targeted affinity proteomics approach to explore and characterize the autoantibody repertoire in brain tissues from 73 subjects diagnosed with schizophrenia and 52 control subjects with no psychiatric or neurological disorders. Selected brain tissue lysates were first explored for IgG reactivity on planar microarrays composed of 11,520 protein fragments representing 10,820 unique proteins. Based on these results of ours and other previous studies of autoantibodies related to psychosis, we selected 226 fragments with an average length of 80 amino acids, representing 127 unique proteins. Tissue-based analysis of IgG reactivities using antigen suspension bead arrays was performed in a multiplex and parallel fashion for all 125 subjects. Among the detected autoantigens, higher IgG reactivity in subjects with schizophrenia, as compared to psychiatrically healthy subjects, was found against the glutamate ionotropic receptor NMDA type subunit 2D (anti-GluN2D). In a separate cohort with serum samples from 395 young adults with a wider spectrum of psychiatric disorders, higher levels of serum autoantibodies targeting GluN2D were found when compared to 102 control individuals. By further validating GluN2D and additional potential autoantigens, we will seek insights into how these are associated with severe mental illnesses.

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  • 67.
    Just, David
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science. KTH, Centres, Science for Life Laboratory, SciLifeLab. Uppsala Univ, Dept Neurosci, Psychiat, Uppsala, Sweden..
    Månberg, Anna
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science.
    Mitsios, Nicholas
    Karolinska Inst, Dept Neurosci, Stockholm, Sweden..
    Stockmeier, Craig A.
    Univ Mississippi, Med Ctr, Dept Psychiat & Human Behav, Jackson, MS 39216 USA..
    Rajkowska, Grazyna
    Univ Mississippi, Med Ctr, Dept Psychiat & Human Behav, Jackson, MS 39216 USA..
    Uhlén, Mathias
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science. Karolinska Inst, Dept Neurosci, Stockholm, Sweden..
    Mulder, Jan
    Karolinska Inst, Dept Neurosci, Stockholm, Sweden..
    Feuk, Lars
    Uppsala Univ, Dept Immunol Genet & Pathol, Sci Life Lab, Uppsala, Sweden..
    Cunningham, Janet L.
    Uppsala Univ, Dept Neurosci, Psychiat, Uppsala, Sweden..
    Nilsson, Peter
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics.
    Carlstrom, Eva Lindholm
    Uppsala Univ, Dept Immunol Genet & Pathol, Sci Life Lab, Uppsala, Sweden..
    Exploring autoantibody signatures in brain tissue from patients with severe mental illness2020In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 10, no 1, article id 401Article in journal (Refereed)
    Abstract [en]

    In recent years, studies have shown higher prevalence of autoantibodies in patients with schizophrenia compared to healthy individuals. This study applies an untargeted and a targeted affinity proteomics approach to explore and characterize the autoantibody repertoire in brain tissues from 73 subjects diagnosed with schizophrenia and 52 control subjects with no psychiatric or neurological disorders. Selected brain tissue lysates were first explored for IgG reactivity on planar microarrays composed of 11,520 protein fragments representing 10,820 unique proteins. Based on these results of ours and other previous studies of autoantibodies related to psychosis, we selected 226 fragments with an average length of 80 amino acids, representing 127 unique proteins. Tissue-based analysis of IgG reactivities using antigen suspension bead arrays was performed in a multiplex and parallel fashion for all 125 subjects. Among the detected autoantigens, higher IgG reactivity in subjects with schizophrenia, as compared to psychiatrically healthy subjects, was found against the glutamate ionotropic receptor NMDA type subunit 2D (anti-GluN2D). In a separate cohort with serum samples from 395 young adults with a wider spectrum of psychiatric disorders, higher levels of serum autoantibodies targeting GluN2D were found when compared to 102 control individuals. By further validating GluN2D and additional potential autoantigens, we will seek insights into how these are associated with severe mental illnesses.

  • 68.
    Kanina, Aleksandra
    et al.
    Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Sjölander, Arvid
    Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Butwicka, Agnieszka
    Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Division of Mental Health Services, Akershus University Hospital, Lørenskog, Norway; Department of Biostatistics and Translational Medicine, Medical University of Lodz, Lodz, Poland.
    Taylor, Mark J.
    Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Martini, Miriam I.
    Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lundberg, Frida E.
    Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    D'Onofrio, Brian M.
    Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA.
    Rosenqvist, Mina A.
    Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Association between cumulative psychosocial adversity in the family and ADHD and autism: a family-based cohort study2023In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 13, no 1, article id 282Article in journal (Refereed)
    Abstract [en]

    Cumulative exposure to psychosocial adversity at an early age has been shown to be a risk factor for attention-deficit hyperactivity disorder (ADHD) and autism that often co-occur. However, it is not clear if this association reflects a causal effect or familial confounding. We aimed to assess whether cumulative psychosocial adversity in the family increases the risk for ADHD and autism in offspring while accounting for unmeasured familial confounding. We used a population-based cohort of 1,877,901 individuals born in Sweden between 1990 and 2009. Participants were followed from the age of 3 until 2013, with a median follow up time of 13.8 years. We created a cumulative index based on 7 psychosocial adversity factors. We used Cox regression to estimate the hazard ratios (HRs) relating neurodevelopmental conditions to cumulative psychosocial adversity. To address familial confounding, the analyses were repeated in groups of relatives of different kinship: siblings and half-siblings and cousins. A dose-response relationship was observed between cumulative exposure to psychosocial adversity and ADHD at a general population level (covariate adjusted HRs (aHRs) with 95% confidence intervals ranged from 1.55 [one adversity; 1.53-1.58] to 2.65 [ ≥ 4 adversities; 1.98-3.54]). No clear dose-response relation was seen for autism (aHRs ranged from 1.04 [.59-1.84] to 1.37 [1.30-1.45]). HRs of ADHD and autism decreased with increasing level of kinship in the analysis of relatives. Cumulative exposure to psychosocial adversity was associated with both ADHD and autism in the general population, these associations were partly explained by unmeasured familial confounding between relatives. This highlights the need for using family-based designs in studies of psychosocial adversity and ADHD and autism.

  • 69. Kanstrup, Marie
    et al.
    Singh, Laura
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Göransson, Katarina E.
    Widoff, Julia
    Taylor, Rod S.
    Gamble, Beau
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Iyadurai, Lalitha
    Moulds, Michelle M.
    Holmes, Emily A.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Division of Psychology, Department of Clinical Neuroscience, Karolinska Institutet.
    Reducing intrusive memories after trauma via a brief cognitive task intervention in the hospital emergency department: an exploratory pilot randomised controlled trial2021In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 11, no 1, article id 30Article in journal (Refereed)
    Abstract [en]

    Intrusive memories are common after trauma, and can cause significant distress. Interventions to prevent/reduce the occurrence of this core clinical feature of posttraumatic stress disorder are needed; they should be easy to deliver, readily disseminated and scalable. A novel one-session intervention by Iyadurai et al. 2018, Molecular Psychiatry, resulted in intrusion reduction over the subsequent week. Its feasibility in a different setting and longer-term effects (>1 month) need investigation. We conducted an exploratory open-label pilot randomised controlled trial (RCT) to investigate the feasibility and effects of a brief behavioural intervention to reduce intrusive memories in trauma-exposed patients in a Swedish hospital emergency department (ED). Participants (final N = 41) were randomly allocated to either intervention (including memory reminder cue then visuospatial cognitive task “Tetris” with mental rotation instructions) or active control (podcast) condition within 72 h of presenting to the ED (both conditions using their smartphone). Findings were examined descriptively. We estimated between-group effect sizes for the number of intrusive memories post-intervention at week 1 (primary outcome) and week 5 (secondary outcome). Compared to the control condition, participants in the intervention condition reported fewer intrusive memories of trauma, both at week 1 and week 5. Findings extend the previous evaluation in the UK. The intervention was readily implemented in a different international context, with a mixed trauma sample, with treatment gains maintained at 1 month and associated with some functional improvements. Findings inform future trials to evaluate the capacity of the cognitive task intervention to reduce the occurrence of intrusive memories after traumatic events.

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  • 70. Kanstrup, Marie
    et al.
    Singh, Laura
    Göransson, Katarina
    Karolinska Institutet, Stockholm, Sweden.
    Widoff, Julia
    Taylor, Rod S
    Gamble, Beau
    Iyadurai, Lalitha
    Moulds, Michelle L
    Holmes, Emily A
    Reducing intrusive memories after trauma via a brief cognitive task intervention in the hospital emergency department: an exploratory pilot randomised controlled trial2021In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 11, no 1, p. 30-30Article in journal (Refereed)
    Abstract [en]

    Intrusive memories are common after trauma, and can cause significant distress. Interventions to prevent/reduce the occurrence of this core clinical feature of posttraumatic stress disorder are needed; they should be easy to deliver, readily disseminated and scalable. A novel one-session intervention by Iyadurai et al. 2018, Molecular Psychiatry, resulted in intrusion reduction over the subsequent week. Its feasibility in a different setting and longer-term effects (>1 month) need investigation. We conducted an exploratory open-label pilot randomised controlled trial (RCT) to investigate the feasibility and effects of a brief behavioural intervention to reduce intrusive memories in trauma-exposed patients in a Swedish hospital emergency department (ED). Participants (final N = 41) were randomly allocated to either intervention (including memory reminder cue then visuospatial cognitive task "Tetris" with mental rotation instructions) or active control (podcast) condition within 72 h of presenting to the ED (both conditions using their smartphone). Findings were examined descriptively. We estimated between-group effect sizes for the number of intrusive memories post-intervention at week 1 (primary outcome) and week 5 (secondary outcome). Compared to the control condition, participants in the intervention condition reported fewer intrusive memories of trauma, both at week 1 and week 5. Findings extend the previous evaluation in the UK. The intervention was readily implemented in a different international context, with a mixed trauma sample, with treatment gains maintained at 1 month and associated with some functional improvements. Findings inform future trials to evaluate the capacity of the cognitive task intervention to reduce the occurrence of intrusive memories after traumatic events.

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  • 71.
    Karlsson, Ida K.
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Ploner, A.
    Song, C.
    Gatz, M.
    Pedersen, Nancy L.
    Hägg, S.
    Genetic susceptibility to cardiovascular disease and risk of dementia2017In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 7, no 5Article in journal (Refereed)
    Abstract [en]

    Several studies have shown cardiovascular disease (CVD) to be associated with dementia, but it is not clear whether CVD per se increases the risk of dementia or whether the association is due to shared risk factors. We tested how a genetic risk score (GRS) for coronary artery disease (CAD) affects dementia risk after CVD in 13 231 Swedish twins. We also utilized summarized genome-wide association data to study genetic overlap between CAD and Alzheimer´s disease (AD), and additionally between shared risk factors and each disease. There was no direct effect of a CAD GRS on dementia (hazard ratio 0.99, 95% confidence interval (CI): 0.98-1.01). However, the GRS for CAD modified the association between CVD and dementia within 3 years of CVD diagnosis, ranging from a hazard ratio of 1.59 (95% CI: 1.05-2.41) in the first GRS quartile to 1.91 (95% CI: 1.28-2.86) in the fourth GRS quartile. Using summary statistics, we found no genetic overlap between CAD and AD. We did, however, find that both AD and CAD share a significant genetic overlap with lipids, but that the overlap arose from clearly distinct gene clusters. In conclusion, genetic susceptibility to CAD was found to modify the association between CVD and dementia, most likely through associations with shared risk factors.

  • 72. Karpyak, V. M.
    et al.
    Biernacka, J. M.
    Geske, J. R.
    Jenkins, G. D.
    Cunningham, J. M.
    Rueegg, J.
    Kononenko, Olga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Leontovich, A. A.
    Abulseoud, O. A.
    Hall-Flavin, D. K.
    Loukianova, L. L.
    Schneekloth, T. D.
    Skime, M. K.
    Frank, J.
    Noethen, M. M.
    Rietschel, M.
    Kiefer, F.
    Mann, K. F.
    Weinshilboum, R. M.
    Frye, M. A.
    Choi, D. S.
    Genetic markers associated with abstinence length in alcohol-dependent subjects treated with acamprosate2014In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 4, p. e462-Article in journal (Refereed)
    Abstract [en]

    Acamprosate supports abstinence in some alcohol-dependent subjects, yet predictors of response are unknown. To identify response biomarkers, we investigated associations of abstinence length with polymorphisms in candidate genes in glycine and glutamate neurotransmission pathways and genes previously implicated in acamprosate response. Association analyses were conducted in the discovery sample of 225 alcohol-dependent subjects treated with acamprosate for 3 months in community-based treatment programs in the United States. Data from 110 alcohol-dependent males treated with acamprosate in the study PREDICT were used for replication of the top association findings. Statistical models were adjusted for relevant covariates, including recruitment site and baseline clinical variables associated with response. In the discovery sample, shorter abstinence was associated with increased intensity of alcohol craving and lower number of days between the last drink and initiation of acamprosate treatment. After adjustment for covariates, length of abstinence was associated with the GRIN2B rs2058878 (P = 4.6 x 10(-5)). In the replication sample, shorter abstinence was associated with increased craving, increased depressive mood score and higher alcohol consumption. Association of abstinence length with GRIN2B rs2058878 was marginally significant (P = 0.0675); as in the discovery sample, the minor A allele was associated with longer abstinence. Furthermore, rs2300272, which is in strong linkage disequilibrium with rs2058878, was also associated with abstinence length (P = 0.049). This is the first report of a replicated association of genetic markers with the length of abstinence in acamprosate-treated alcoholics. Investigation of the underlying mechanisms of this association and its usefulness for individualized treatment selection should follow.

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  • 73.
    Kastrati, G.
    et al.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Department of Psychology and Social Work, Mid Sweden University, Östersund, Sweden.
    Rosén, J.
    Department of Psychology and Social Work, Mid Sweden University, Östersund, Sweden.
    Fredrikson, M.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Chen, X.
    Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, the Netherlands.
    Kuja-Halkola, R.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences.
    Jensen, K. B.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Åhs, F.
    Department of Psychology and Social Work, Mid Sweden University, Östersund, Sweden.
    Genetic influences on central and peripheral nervous system activity during fear conditioning2022In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 12, no 1, article id 95Article in journal (Refereed)
    Abstract [en]

    Fear conditioning is an evolutionarily conserved type of learning serving as a model for the acquisition of situationally induced anxiety. Brain function supporting fear conditioning may be genetically influenced, which in part could explain genetic susceptibility for anxiety following stress exposure. Using a classical twin design and functional magnetic resonance imaging, we evaluated genetic influences (h2) on brain activity and standard autonomic measures during fear conditioning. We found an additive genetic influence on mean brain activation (h2 = 0.34) and autonomic responses (h2 = 0.24) during fear learning. The experiment also allowed estimation of the genetic influence on brain activation during safety learning (h2 = 0.55). The mean safety, but not fear, related brain activation was genetically correlated with autonomic responses. We conclude that fear and safety learning processes, both involved in anxiety development, are moderately genetically influenced as expressed both in the brain and the body.

  • 74.
    Kastrati, Gránit
    et al.
    Mid Sweden University, Faculty of Human Sciences, Department of Psychology and Social Work. Karolinska Institutet.
    Rosén, Jörgen
    Mid Sweden University, Faculty of Human Sciences, Department of Psychology and Social Work.
    Fredrikson, M
    Chen, X
    Kuja-Halkola, R
    Larsson, H
    Jensen, K B
    Åhs, Fredrik
    Mid Sweden University, Faculty of Human Sciences, Department of Psychology and Social Work.
    Genetic influences on central and peripheral nervous system activity during fear conditioning.2022In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 12, no 1, article id 95Article in journal (Refereed)
    Abstract [en]

    Fear conditioning is an evolutionarily conserved type of learning serving as a model for the acquisition of situationally induced anxiety. Brain function supporting fear conditioning may be genetically influenced, which in part could explain genetic susceptibility for anxiety following stress exposure. Using a classical twin design and functional magnetic resonance imaging, we evaluated genetic influences (h2) on brain activity and standard autonomic measures during fear conditioning. We found an additive genetic influence on mean brain activation (h2 = 0.34) and autonomic responses (h2 = 0.24) during fear learning. The experiment also allowed estimation of the genetic influence on brain activation during safety learning (h2 = 0.55). The mean safety, but not fear, related brain activation was genetically correlated with autonomic responses. We conclude that fear and safety learning processes, both involved in anxiety development, are moderately genetically influenced as expressed both in the brain and the body.

  • 75.
    Kauppi, Karolina
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Department of Medical Epidemiology and Biostatistics, Karolinska Institutet,Stockholm, Sweden.
    Rönnlund, Michael
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Nordin Adolfsson, Annelie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Pudas, Sara
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Effects of polygenic risk for Alzheimer's disease on rate of cognitive decline in normal aging2020In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 10, no 1, article id 250Article in journal (Refereed)
    Abstract [en]

    Most people's cognitive abilities decline with age, with significant and partly genetically driven, individual differences in rate of change. Although APOE 4 and genetic scores for late-onset Alzheimer's disease (LOAD) have been related to cognitive decline during preclinical stages of dementia, there is limited knowledge concerning genetic factors implied in normal cognitive aging. In the present study, we examined three potential genetic predictors of age-related cognitive decline as follows: (1) the APOE 4 allele, (2) a polygenic score for general cognitive ability (PGS-cog), and (3) a polygenic risk score for late-onset AD (PRS-LOAD). We examined up to six time points of cognitive measurements in the longitudinal population-based Betula study, covering a 25-year follow-up period. Only participants that remained alive and non-demented until the most recent dementia screening (1-3 years after the last test occasion) were included (n=1087). Individual differences in rate of cognitive change (composite score) were predicted by the PRS-LOAD and APOE 4, but not by PGS-cog. To control for the possibility that the results reflected a preclinical state of Alzheimer's disease in some participants, we re-ran the analyses excluding cognitive data from the last test occasion to model cognitive change up-until a minimum of 6 years before potential onset of clinical Alzheimers. Strikingly, the association of PRS-LOAD, but not APOE 4, with cognitive change remained. The results indicate that PRS-LOAD predicts individual difference in rate of cognitive decline in normal aging, but it remains to be determined to what extent this reflects preclinical Alzheimer's disease brain pathophysiology and subsequent risk to develop the disease.

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  • 76.
    Kimmel, Mary C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Obstetrics and Reproductive Health Research. Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27515 USA..
    Fransson, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Obstetrics and Reproductive Health Research.
    Cunningham, Janet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Cervenka: Psychiatry.
    Bränn, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Obstetrics and Reproductive Health Research.
    Grewen, Karen
    Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27515 USA..
    Boschiero, Dario
    BIOTEKNA, Venice, Italy..
    Chrousos, George P.
    Natl & Kapodistrian Univ Athens, Univ Res Inst Maternal & Child Hlth & Precis Med, Med Sch, UNESCO Chair Adolescent Hlth Care, Athens, Greece..
    Meltzer-Brody, Samantha
    Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27515 USA..
    Skalkidou, Alkistis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Obstetrics and Reproductive Health Research.
    Heart rate variability in late pregnancy: exploration of distinctive patterns in relation to maternal mental health2021In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 11, article id 286Article in journal (Refereed)
    Abstract [en]

    Exploration of photoplethysmography (PPG), a technique that can be translated to the clinic, has the potential to assess the autonomic nervous system (ANS) through heart rate variable (HRV) in pregnant individuals. This novel study explores the complexity of mental health of individuals in a clinical sample responding to a task in late pregnancy; finding those with several types of past or current anxiety disorders, greater trait anxiety, or greater exposure to childhood traumatic events had significantly different HRV findings from the others in the cohort. Lower high frequency (HF), a measure of parasympathetic activity, was found for women who met the criteria for the history of obsessive-compulsive disorder (OCD) (p = 0.004) compared with women who did not meet the criteria for OCD, and for women exposed to greater than five childhood traumatic events (p = 0.006) compared with those exposed to four or less childhood traumatic events. Conversely higher low frequency (LF), a measure thought to be impacted by sympathetic system effects, and the LF/HF ratio was found for those meeting criteria for a panic disorder (p = 0.006), meeting criteria for social phobia (p = 0.002), had elevated trait anxiety (p = 0.006), or exposure to greater than five childhood traumatic events (p = 0.004). This study indicates further research is needed to understand the role of PPG and in assessing ANS functioning in late pregnancy. Study of the impact of lower parasympathetic functioning and higher sympathetic functioning separately and in conjunction at baseline and in relation to tasks during late pregnancy has the potential to identify individuals that require more support and direct intervention.

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  • 77.
    Koch, Elise
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Lundquist, Anders
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Pudas, Sara
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Kauppi, Karolina
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Solna, Sweden.
    Sex-specific effects of polygenic risk for schizophrenia on lifespan cognitive functioning in healthy individuals2021In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 11, no 1, article id 520Article in journal (Refereed)
    Abstract [en]

    Polygenic risk for schizophrenia has been associated with lower cognitive ability and age-related cognitive change in healthy individuals. Despite well-established neuropsychological sex differences in schizophrenia patients, genetic studies on sex differences in schizophrenia in relation to cognitive phenotypes are scarce. Here, we investigated whether the effect of a polygenic risk score (PRS) for schizophrenia on childhood, midlife, and late-life cognitive function in healthy individuals is modified by sex, and if PRS is linked to accelerated cognitive decline. Using a longitudinal data set from healthy individuals aged 25–100 years (N = 1459) spanning a 25-year period, we found that PRS was associated with lower cognitive ability (episodic memory, semantic memory, visuospatial ability), but not with accelerated cognitive decline. A significant interaction effect between sex and PRS was seen on cognitive task performance, and sex-stratified analyses showed that the effect of PRS was male-specific. In a sub-sample, we observed a male-specific effect of the PRS on school performance at age 12 (N = 496). Our findings of sex-specific effects of schizophrenia genetics on cognitive functioning across the lifespan indicate that the effects of underlying disease genetics on cognitive functioning is dependent on biological processes that differ between the sexes.

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  • 78.
    Kohshour, Mojtaba Oraki
    et al.
    Ludwig Maximilians Univ Munchen, Inst Psychiat Phen & Genom IPPG, Univ Hosp, Munich, Germany.;Ahvaz Jundishapur Univ Med Sci, Fac Med, Dept Immunol, Ahvaz, Iran..
    Kannaiyan, Nirmal R.
    Ludwig Maximilians Univ Munchen, Dept Psychiat & Psychotherapy, Univ Hosp, Munich, Germany..
    Jernbom Falk, August
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Papiol, Sergi
    Ludwig Maximilians Univ Munchen, Inst Psychiat Phen & Genom IPPG, Univ Hosp, Munich, Germany.;Ludwig Maximilians Univ Munchen, Dept Psychiat & Psychotherapy, Univ Hosp, Munich, Germany..
    Heilbronner, Urs
    Ludwig Maximilians Univ Munchen, Inst Psychiat Phen & Genom IPPG, Univ Hosp, Munich, Germany..
    Budde, Monika
    Ludwig Maximilians Univ Munchen, Inst Psychiat Phen & Genom IPPG, Univ Hosp, Munich, Germany..
    Kalman, Janos L.
    Ludwig Maximilians Univ Munchen, Inst Psychiat Phen & Genom IPPG, Univ Hosp, Munich, Germany.;Ludwig Maximilians Univ Munchen, Dept Psychiat & Psychotherapy, Univ Hosp, Munich, Germany.;Max Planck Inst Psychiat, Int Max Planck Res Sch Translat Psychiat IMPRS TP, Munich, Germany..
    Schulte, Eva C.
    Ludwig Maximilians Univ Munchen, Inst Psychiat Phen & Genom IPPG, Univ Hosp, Munich, Germany.;Ludwig Maximilians Univ Munchen, Dept Psychiat & Psychotherapy, Univ Hosp, Munich, Germany..
    Rietschel, Marcella
    Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Dept Genet Epidemiol Psychiat, Mannheim, Germany..
    Witt, Stephanie
    Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Dept Genet Epidemiol Psychiat, Mannheim, Germany..
    Forstner, Andreas J.
    Univ Bonn, Sch Med, Inst Human Genet, Bonn, Germany.;Univ Hosp Bonn, Bonn, Germany..
    Heilmann-Heimbach, Stefanie
    Univ Bonn, Sch Med, Inst Human Genet, Bonn, Germany.;Univ Hosp Bonn, Bonn, Germany..
    Nöthen, Markus M.
    Univ Bonn, Sch Med, Inst Human Genet, Bonn, Germany.;Univ Hosp Bonn, Bonn, Germany..
    Spitzer, Carsten
    Univ Med Ctr Rostock, Dept Psychosomat Med & Psychotherapy, Rostock, Germany..
    Malchow, Berend
    Univ Med Ctr Gottingen, Dept Psychiat & Psychotherapy, Gottingen, Germany..
    Müller, Thorsten
    Ludwig Maximilians Univ Munchen, Inst Psychiat Phen & Genom IPPG, Univ Hosp, Munich, Germany..
    Wiltfang, Jens
    Univ Med Ctr Gottingen, Dept Psychiat & Psychotherapy, Gottingen, Germany.;German Ctr Neurodegenerat Dis DZNE, Gottingen, Germany.;Univ Aveiro, Med Sci Dept, iBiMED, Aveiro, Portugal..
    Falkai, Peter
    Ludwig Maximilians Univ Munchen, Dept Psychiat & Psychotherapy, Univ Hosp, Munich, Germany..
    Schmitt, Andrea
    Ludwig Maximilians Univ Munchen, Dept Psychiat & Psychotherapy, Univ Hosp, Munich, Germany.;Univ Sao Paulo, Inst Psychiat, Lab Neurosci LIM27, Sao Paulo, SP, Brazil..
    Rossner, Moritz J.
    Ludwig Maximilians Univ Munchen, Dept Psychiat & Psychotherapy, Univ Hosp, Munich, Germany..
    Nilsson, Peter
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics.
    Schulze, Thomas G.
    Ludwig Maximilians Univ Munchen, Inst Psychiat Phen & Genom IPPG, Univ Hosp, Munich, Germany.;SUNY Upstate Med Univ, Dept Psychiat & Behav Sci, Syracuse, NY 13210 USA.;Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA..
    Comparative serum proteomic analysis of a selected protein panel in individuals with schizophrenia and bipolar disorder and the impact of genetic risk burden on serum proteomic profiles2022In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 12, no 1, article id 471Article in journal (Refereed)
    Abstract [en]

    The diagnostic criteria for schizophrenia (SCZ) and bipolar disorder (BD) are based on clinical assessments of symptoms. In this pilot study, we applied high-throughput antibody-based protein profiling to serum samples of healthy controls and individuals with SCZ and BD with the aim of identifying differentially expressed proteins in these disorders. Moreover, we explored the influence of polygenic burden for SCZ and BD on the serum levels of these proteins. Serum samples from 113 individuals with SCZ and 125 with BD from the PsyCourse Study and from 44 healthy controls were analyzed by using a set of 155 antibodies in an antibody-based assay targeting a selected panel of 95 proteins. For the cases, genotyping and imputation were conducted for DNA samples and SCZ and BD polygenic risk scores (PRS) were calculated. Univariate linear and logistic models were used for association analyses. The comparison between SCZ and BD revealed two serum proteins that were significantly elevated in BD after multiple testing adjustment: "complement C9" and "Interleukin 1 Receptor Accessory Protein". Moreover, the first principal component of variance in the proteomics dataset differed significantly between SCZ and BD. After multiple testing correction, SCZ-PRS, BD-PRS, and SCZ-vs-BD-PRS were not significantly associated with the levels of the individual proteins or the values of the proteome principal components indicating no detectable genetic effects. Overall, our findings contribute to the evidence suggesting that the analysis of circulating proteins could lead to the identification of distinctive biomarkers for SCZ and BD. Our investigation warrants replication in large-scale studies to confirm these findings.

  • 79.
    Korhonen, Laura
    et al.
    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.
    Paul, Elisabeth
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Wåhlén, Karin
    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.
    Haring, Liina
    5 Institute of Clinical Medicine University of Tartu; Psychiatry Clinic of Tartu University Hospital, Tartu, Estonia.
    Vasar, Eero
    Institute of Biomedicine and Translational Medicine, University of Tartu, Estonia.
    Vaheri, Antti
    7 Department of Virology, Medicum, University of Helsinki, Finland.
    Lindholm, Dan
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Department of Biochemistry and Developmental Biology, Medicum, University of Helsinki, Finland; 9 Minerva Foundation Institute for Medical Research, Biomedicum Helsinki 2U, Finland.
    Multivariate analyses of immune markers reveal increases in plasma EN-RAGE in first-episode psychosis patients2023In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 13, no 1, article id 326Article in journal (Refereed)
    Abstract [en]

    Immune cells and cytokines are largely recognized as significant factors in the pathophysiology of neuropsychiatric disorders. The possible role of other blood cells such as leukocytes in events of acute psychosis is in contrast only emerging. To study blood-born markers in acute psychosis we here evaluated plasma proteins in drug-naive first-episode psychosis (FEP) patients and healthy controls using a multiplex proximity extension assay technique. We analyzed a panel of 92 immune markers and plasma samples from 60 FEP patients and 50 controls and evaluated the changes obtained using multivariate statistical methods followed by protein pathway analyses. Data showed that 11 proteins are significantly different between FEP patients and healthy controls We observed increases in pro-inflammatory proteins such as interleukin-6, oncostatin-M, and transforming growth factor-alpha in FEP patients compared with controls. Likewise, the extracellular newly identified RAGE-binding protein (EN-RAGE) that regulates the expression of various cytokines was also elevated in the plasma of FEP patients. The results indicate that neutrophil-derived EN-RAGE could play an important role during the early phase of acute psychosis by stimulating cytokines and the immune response targeting thereby likely also the brain vasculature.

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  • 80.
    Kowalec, Kaarina
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; College of Pharmacy, University of Manitoba, Winnipeg, MN, Canada.
    Lu, Yi
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Song, Jie
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Dalman, Christina
    Department of Global Public Health Sciences, Karolinska Institutet, Stockholm, Sweden.
    Hultman, Christina M.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Icahn School of Medicine, Department of Psychiatry, Mt Sinai Hospital, New York, NY, USA.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Sullivan, Patrick F.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Departments of Genetics and Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
    The association between family history and genomic burden with schizophrenia mortality: a Swedish population-based register and genetic sample study2021In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 11, no 1, article id 163Article in journal (Refereed)
    Abstract [en]

    Individuals with schizophrenia (SCZ) have a 2-3-fold higher risk of mortality than the general population. Heritability of mortality in psychiatric disorders has been proposed; however, few have investigated SCZ family history and genetic variation, with all-cause and specific causes of death. We aimed to identify correlates of SCZ mortality using genetic epidemiological and genetic modelling in two samples: a Swedish national population sample and a genotyped subsample. In the Swedish national population sample followed from the first SCZ treatment contact until emigration, death or end of the follow-up, we investigated a standardised measure of SCZ family history. In a subgroup with comprehensive genetic data, we investigated the impact of common and rare genetic variation. Cox proportional hazards regression was used to estimate the association between various factors and mortality (all and specific causes). A total of 13727 SCZ cases fulfilled criteria for the population-based analyses (1268 deaths, 9.2%). The genomic subset contained 4991 cases (1353 deaths, 27.1%). Somatic mutations associated with clonal hematopoiesis with unknown drivers were associated with all-cause mortality (HR 1.77, 95% CI: 1.26-2.49). No other heritable measures were associated with all-cause mortality nor with any specific causes of death. Future studies in larger, comparable cohorts are warranted to further understand the association between hereditary measures and mortality in SCZ.

  • 81.
    Kunovac Kallak, Theodora
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Reproductive Health.
    Fransson, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Reproductive Health Research.
    Bränn, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Reproductive Health Research.
    Berglund, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Lager, Susanne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Reproductive Health Research.
    Comasco, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Reproductive Health. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lyle, Robert
    Oslo Univ Hosp, Ctr Fertil & Hlth, Norwegian Inst Publ Hlth, Dept Med Genet, Oslo, Norway.;Oslo Univ Hosp, Ctr Fertil & Hlth, Norwegian Inst Publ Hlth, Norwegian Sequencing Ctr NSC, Oslo, Norway..
    Skalkidou, Alkistis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Reproductive Health Research.
    Maternal prenatal depressive symptoms and toddler behavior: an umbilical cord blood epigenome-wide association study2022In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 12, article id 186Article in journal (Refereed)
    Abstract [en]

    Children of mothers with prenatal depressive symptoms (PND) have a higher risk of behavioral problems; fetal programming through DNA methylation is a possible underlying mechanism. This study investigated DNA methylation in cord blood to identify possible "at birth" signatures that may indicate susceptibility to behavioral problems at 18 months of age. Cord blood was collected from 256 children of mothers who had self-reported on symptoms of depression during pregnancy and the behavior of their child at 18 months of age. Whole genome DNA methylation was assessed using Illumina MethylationEPIC assay. The mother and child pairs were categorized into four groups, based on both self-reported depressive symptoms, PND or Healthy control (HC), and scores from the Child Behavior checklist (high or low for internalizing, externalizing, and total scores). Adjustments were made for batch effects, cell-type, and clinical covariates. Differentially methylated sites were identified using Kruskal-Wallis test, and Benjamini-Hochberg adjusted p values < 0.05 were considered significant. The analysis was also stratified by sex of the child. Among boys, we observed higher and correlated DNA methylation of one CpG-site in the promoter region of TPP1 in the HC group, with high externalizing scores compared to HC with low externalizing scores. Boys in the PND group showed lower DNA methylation in NUDT15 among those with high, compared to low, internalizing scores; the DNA methylation levels of CpGs in this gene were positively correlated with the CBCL scores. Hence, the differentially methylated CpG sites could be of interest for resilience, regardless of maternal mental health during pregnancy. The findings are in a relatively healthy study cohort, thus limiting the possibility of detecting strong effects associated with behavioral difficulties. This is the first investigation of cord blood DNA methylation signs of fetal programming of PND on child behavior at 18 months of age and thus calls for independent replications.

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  • 82. Kuzmin, A.
    et al.
    Chefer, V.
    Bazov, Igor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Meis, J.
    Ogren, S. O.
    Shippenberg, T.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Upregulated dynorphin opioid peptides mediate alcohol-induced learning and memory impairment2013In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 3, p. e310-Article in journal (Refereed)
    Abstract [en]

    The dynorphin opioid peptides control glutamate neurotransmission in the hippocampus. Alcohol-induced dysregulation of this circuit may lead to impairments in spatial learning and memory. This study examines whether changes in the hippocampal dynorphin and glutamate systems are related, and contribute to impairment of spatial learning and memory in a rat model of cognitive deficit associated with alcohol binge drinking. Hippocampal dynorphins (radioimmunoassay) and glutamate (in vivo microdialysis) were analyzed in Wistar rats exposed to repeated moderate-dose ethanol bouts that impair spatial learning and memory in the Water Maze Task (WMT). The highly selective, long-acting k-opioid receptor (KOR) antagonist nor-binaltorphimine (nor-BNI) was administered systemically or into the hippocampal CA3 region to test a role of dynorphins in alcohol-induced dysregulations in glutamate neurotransmission and behavior in the WMT. The ethanol treatment impaired learning and memory, upregulated dynorphins and increased glutamate overflow in the CA3 region. Administration of nor-BNI after cessation of ethanol exposure reversed ethanol-induced changes in glutamate neurotransmission in animals exposed to ethanol and normalized their performance in the WMT. The findings suggest that impairments of spatial learning and memory by binge-like ethanol exposure are mediated through the KOR activation by upregulated dynorphins resulting in elevation in glutamate levels. Selective KOR antagonists may correct alcohol-induced pathological processes, thus representing a novel pharmacotherapy for treating of ethanol-related cognitive deficits.

  • 83.
    Kuzmin, A.
    et al.
    Karolinska Institute, Stockholm, Sweden; Stockholms Läns Landsting Stockholm, Sweden.
    Chefer, V.
    U.S. Department of Health and Human Services, Baltimore, MD, USA.
    Bazov, Igor
    Uppsala University, Uppsala, Sweden.
    Meis, J.
    U.S. Department of Health and Human Services, Baltimore, MD, USA.
    Ögren, S. O.
    Karolinska Institute, Stockholm, Sweden.
    Shippenberg, T.
    U.S. Department of Health and Human Services, Baltimore, MD, USA.
    Bakalkin, G.
    Uppsala University, Uppsala, Sweden.
    Upregulated dynorphin opioid peptides mediate alcohol-induced learning and memory impairment2013In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 3, no 10, article id e310Article in journal (Refereed)
    Abstract [en]

    The dynorphin opioid peptides control glutamate neurotransmission in the hippocampus. Alcohol-induced dysregulation of this circuit may lead to impairments in spatial learning and memory. This study examines whether changes in the hippocampal dynorphin and glutamate systems are related, and contribute to impairment of spatial learning and memory in a rat model of cognitive deficit associated with alcohol binge drinking. Hippocampal dynorphins (radioimmunoassay) and glutamate (in vivo microdialysis) were analyzed in Wistar rats exposed to repeated moderate-dose ethanol bouts that impair spatial learning and memory in the Water Maze Task (WMT). The highly selective, long-acting κ-opioid receptor (KOR) antagonist nor-binaltorphimine (nor-BNI) was administered systemically or into the hippocampal CA3 region to test a role of dynorphins in alcohol-induced dysregulations in glutamate neurotransmission and behavior in the WMT. The ethanol treatment impaired learning and memory, upregulated dynorphins and increased glutamate overflow in the CA3 region. Administration of nor-BNI after cessation of ethanol exposure reversed ethanol-induced changes in glutamate neurotransmission in animals exposed to ethanol and normalized their performance in the WMT. The findings suggest that impairments of spatial learning and memory by binge-like ethanol exposure are mediated through the KOR activation by upregulated dynorphins resulting in elevation in glutamate levels. Selective KOR antagonists may correct alcohol-induced pathological processes, thus representing a novel pharmacotherapy for treating of ethanol-related cognitive deficits.

  • 84. Lindner, P.
    et al.
    Savic, I.
    Sitnikov, R.
    Budhiraja, M.
    Liu, Y.
    Jokinen, Jussi
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry. Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
    Tiihonen, J.
    Hodgins, S.
    Conduct disorder in females is associated with reduced corpus callosum structural integrity independent of comorbid disorders and exposure to maltreatment2016In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 6, article id e714Article in journal (Refereed)
    Abstract [en]

    The behavioral phenotype and genotype of conduct disorder (CD) differ in males and females. Abnormalities of white matter integrity have been reported among males with CD and antisocial personality disorder (ASPD). Little is known about white matter integrity in females with CD. The present study aimed to determine whether abnormalities of white matter are present among young women who presented CD before the age of 15, and whether abnormalities are independent of the multiple comorbid disorders and experiences of maltreatment characterizing females with CD that may each in themselves be associated with alterations of the white matter. Three groups of women, aged on average 24 years, were scanned using diffusion tensor imaging and compared: 28 with prior CD, three of whom presented ASPD; a clinical comparison (CC) group of 15 women with no history of CD but with similar proportions who presented alcohol dependence, drug dependence, anxiety disorders, depression disorders and physical and sexual abuse as the CD group; and 24 healthy women. Whole-brain, tract-based spatial statistics were computed to investigate differences in fractional anisotropy, axial diffusivity and radial diffusivity. Compared with healthy women, women with prior CD showed widespread reductions in axial diffusivity primarily in frontotemporal regions. After statistically adjusting for comorbid disorders and maltreatment, group differences in the corpus callosum body and genu (including forceps minor) remained significant. Compared with the CC group, women with CD showed reduced fractional anisotropy in the body and genu of the corpus callosum. No differences were detected between the CD and healthy women in the uncinate fasciculus.

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  • 85.
    Lindqvist, D.
    et al.
    Department of Clinical Sciences Lund, Psychiatry, Lund University, Lund, Sweden; Department of Psychiatry, School of Medicine, University of California San Francisco, School of Medicine, San Francisco, CA, USA; Psychiatric Clinic, Lund, Division of Psychiatry, Lund, Sweden.
    Fernström, J.
    Department of Clinical Sciences Lund, Psychiatry, Lund University, Lund, Sweden; Psychiatric Clinic, Lund, Division of Psychiatry, Lund, Sweden.
    Grudet, C.
    Department of Clinical Sciences Lund, Psychiatry, Lund University, Lund, Sweden.
    Ljunggren, Lennart
    Malmö högskola, Faculty of Health and Society (HS), Department of Biomedical Science (BMV).
    Träskman-Bendz, L.
    Department of Clinical Sciences Lund, Psychiatry, Lund University, Lund, Sweden.
    Ohlsson, Lars
    Malmö högskola, Faculty of Health and Society (HS), Department of Biomedical Science (BMV).
    Westrin, Åsa
    Department of Clinical Sciences Lund, Psychiatry, Lund University, Lund, Sweden; Psychiatric Clinic, Lund, Division of Psychiatry, Lund, Sweden.
    Increased plasma levels of circulating cell-free mitochondrial DNA in suicide attempters: associations with HPA-axis hyperactivity2016In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 6, no 12, article id e971Article in journal (Refereed)
    Abstract [en]

    Preclinical data suggest that chronic stress may cause cellular damage and mitochondrial dysfunction, potentially leading to the release of mitochondrial DNA (mtDNA) into the bloodstream. Major depressive disorder has been associated with an increased amount of mtDNA in leukocytes from saliva samples and blood; however, no previous studies have measured plasma levels of free-circulating mtDNA in a clinical psychiatric sample. In this study, free circulating mtDNA was quantified in plasma samples from 37 suicide attempters, who had undergone a dexamethasone suppression test (DST), and 37 healthy controls. We hypothesized that free circulating mtDNA would be elevated in the suicide attempters and would be associated with hypothalamic-pituitary-adrenal (HPA)-axis hyperactivity. Suicide attempters had significantly higher plasma levels of free-circulating mtDNA compared with healthy controls at different time points (pre- and post-DST; all P-values < 2.98E - 12, Cohen's d ranging from 2.55 to 4.01). Pre-DST plasma levels of mtDNA were positively correlated with post-DST cortisol levels (rho = 0.49, P < 0.003). Suicide attempters may have elevated plasma levels of free-circulating mtDNA, which are related to impaired HPA-axis negative feedback. This peripheral index is consistent with an increased cellular or mitochondrial damage. The specific cells and tissues contributing to plasma levels of free-circulating mtDNA are not known, as is the specificity of this finding for suicide attempters. Future studies are needed in order to better understand the relevance of increased free-circulating mtDNA in relation to the pathophysiology underlying suicidal behavior and depression.

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  • 86. Liu, T.
    et al.
    Li, S-C.
    Papenberg, Goran
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Max Planck Institute for Human Development, Germany.
    Schröder, J.
    Roehr, J. T.
    Nietfeld, W.
    Lindenberger, U.
    Bertram, L.
    No association between CTNNBL1 and episodic memory performance2014In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 4, article id e454Article in journal (Refereed)
    Abstract [en]

    Polymorphisms in the gene encoding catenin-β-like 1 (CTNNBL1) were recently reported to be associated with verbal episodic memory performance--in particular, delayed verbal free recall assessed between 5 and 30 min after encoding--in a genome-wide association study on healthy young adults. To further examine the genetic effects of CTNNBL1, we tested for association between 455 single-nucleotide polymorphisms (SNPs) in or near CTNNBL1 and 14 measures of episodic memory performance from three different tasks in 1743 individuals. Probands were part of a population-based study of mentally healthy adult men and women, who were between 20 and 70 years old and were recruited as participants for the Berlin Aging Study II. Associations were assessed using linear regression analysis. Despite having sufficient power to detect the previously reported effect sizes, we found no evidence for statistically significant associations between the tested CTNNBL1 SNPs and any of the 14 measures of episodic memory. The previously reported effects of genetic polymorphisms in CTNNBL1 on episodic memory performance do not generalize to the broad range of tasks assessed in our cohort. If not altogether spurious, the effects may be limited to a very narrow phenotypic domain (that is, verbal delayed free recall between 5 and 30 min). More studies are needed to further clarify the role of CTNNBL1 in human memory.

  • 87.
    Mansson, K. N. T.
    et al.
    Linkoping Univ, Div Psychol, Dept Behav Sci & Learning, SE-58183 Linkoping, Sweden..
    Frick, Andreas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Boraxbekk, C-J
    Umea Univ, Ctr Populat Studies Ageing & Living Condit, Umea, Sweden.;Umea Univ, Umea Ctr Funct Brain Imaging UFBI, Umea, Sweden..
    Marquand, A. F.
    Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, NL-6525 ED Nijmegen, Netherlands.;Kings Coll London, Inst Psychiat, Ctr Neuroimaging Sci, Dept Neuroimaging, London WC2R 2LS, England..
    Williams, S. C. R.
    Kings Coll London, Inst Psychiat, Ctr Neuroimaging Sci, Dept Neuroimaging, London WC2R 2LS, England..
    Carlbring, P.
    Stockholm Univ, Dept Psychol, S-10691 Stockholm, Sweden..
    Andersson, G.
    Linkoping Univ, Div Psychol, Dept Behav Sci & Learning, SE-58183 Linkoping, Sweden.;Karolinska Inst, Dept Clin Neurosci, Psychiat Sect, Stockholm, Sweden..
    Furmark, Tomas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Predicting long-term outcome of Internet-delivered cognitive behavior therapy for social anxiety disorder using fMRI and support vector machine learning2015In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 5, article id e530Article in journal (Refereed)
    Abstract [en]

    Cognitive behavior therapy (CBT) is an effective treatment for social anxiety disorder (SAD), but many patients do not respond sufficiently and a substantial proportion relapse after treatment has ended. Predicting an individual's long-term clinical response therefore remains an important challenge. This study aimed at assessing neural predictors of long-term treatment outcome in participants with SAD 1 year after completion of Internet-delivered CBT (iCBT). Twenty-six participants diagnosed with SAD underwent iCBT including attention bias modification for a total of 13 weeks. Support vector machines (SVMs), a supervised pattern recognition method allowing predictions at the individual level, were trained to separate long-term treatment responders from nonresponders based on blood oxygen level-dependent (BOLD) responses to self-referential criticism. The Clinical Global Impression-Improvement scale was the main instrument to determine treatment response at the 1-year follow-up. Results showed that the proportion of long-term responders was 52% (12/23). From multivariate BOLD responses in the dorsal anterior cingulate cortex (dACC) together with the amygdala, we were able to predict long-term response rate of iCBT with an accuracy of 92% (confidence interval 95% 73.2-97.6). This activation pattern was, however, not predictive of improvement in the continuous Liebowitz Social Anxiety Scale-Self-report version. Follow-up psychophysiological interaction analyses revealed that lower dACC-amygdala coupling was associated with better long-term treatment response. Thus, BOLD response patterns in the fear-expressing dACC-amygdala regions were highly predictive of long-term treatment outcome of iCBT, and the initial coupling between these regions differentiated long-term responders from nonresponders. The SVM-neuroimaging approach could be of particular clinical value as it allows for accurate prediction of treatment outcome at the level of the individual.

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  • 88.
    Mansson, Kristoffer N. T.
    et al.
    Karolinska Inst, Sweden; Stockholm Univ, Sweden; Uppsala Univ, Sweden.
    Lindqvist, Daniel
    Lund Univ, Sweden.
    Yang, Liu L.
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Svanborg, Cecilia
    Karolinska Inst, Sweden; Stockholm Hlth Care Serv, Sweden.
    Isung, Josef
    Karolinska Inst, Sweden; Stockholm Hlth Care Serv, Sweden.
    Nilsonne, Gustav
    Karolinska Inst, Sweden; Stockholm Univ, Sweden.
    Bergman-Nordgren, Lise
    Karolinska Inst, Sweden; Stockholm Hlth Care Serv, Sweden.
    El Alaoui, Samir
    Karolinska Inst, Sweden; Stockholm Hlth Care Serv, Sweden.
    Hedman-Lagerlof, Erik
    Karolinska Inst, Sweden.
    Kraepelien, Martin
    Karolinska Inst, Sweden; Stockholm Hlth Care Serv, Sweden.
    Hogstrom, Jens
    Karolinska Inst, Sweden; Stockholm Hlth Care Serv, Sweden.
    Andersson, Gerhard
    Linköping University, Department of Behavioural Sciences and Learning, Psychology. Linköping University, Faculty of Arts and Sciences. Karolinska Inst, Sweden; Stockholm Hlth Care Serv, Sweden.
    Boraxbekk, Carl-Johan
    Umea Univ, Sweden; Copenhagen Univ Hosp, Denmark.
    Fischer, Hakan
    Stockholm Univ, Sweden.
    Lavebratt, Catharina
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Wolkowitz, Owen M.
    Univ Calif San Francisco, CA USA.
    Furmark, Tomas
    Uppsala Univ, Sweden.
    Improvement in indices of cellular protection after psychological treatment for social anxiety disorder2019In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 9, no 1, article id 340Article in journal (Refereed)
    Abstract [en]

    Telomere attrition is a hallmark of cellular aging and shorter telomeres have been reported in mood and anxiety disorders. Telomere shortening is counteracted by the enzyme telomerase and cellular protection is also provided by the antioxidant enzyme glutathione peroxidase (GPx). Here, telomerase, GPx, and telomeres were investigated in 46 social anxiety disorder (SAD) patients in a within-subject design with repeated measures before and after cognitive behavioral therapy. Treatment outcome was assessed by the Liebowitz Social Anxiety Scale ( self-report), administered three times before treatment to control for time and regression artifacts, and posttreatment. Venipunctures were performed twice before treatment, separated by 9 weeks, and once posttreatment. Telomerase activity and telomere length were measured in peripheral blood mononuclear cells and GPx activity in plasma. All patients contributed with complete data. Results showed that social anxiety symptom severity was significantly reduced from pretreatment to posttreatment (Cohens d = 1.46). There were no significant alterations in telomeres or cellular protection markers before treatment onset. Telomere length and telomerase activity did not change significantly after treatment, but an increase in telomerase over treatment was associated with reduced social anxiety. Also, lower pretreatment telomerase activity predicted subsequent symptom improvement. GPx activity increased significantly during treatment, and increases were significantly associated with symptom improvement. The relationships between symptom improvement and putative protective enzymes remained significant also after controlling for body mass index, sex, duration of SAD, smoking, concurrent psychotropic medication, and the proportion of lymphocytes to monocytes. Thus, indices of cellular protection may be involved in the therapeutic mechanisms of psychological treatment for anxiety.

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  • 89. Melas, P. A.
    et al.
    Lennartsson, A.
    Vakifahmetoglu-Norberg, H.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Developmental Biology.
    Wei, Y.
    Åberg, E.
    Werme, M.
    Rogdaki, M.
    Mannervik, Mattias
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Developmental Biology.
    Wegener, G.
    Brene, S.
    Mathe, A. A.
    Lavebratt, C.
    Allele-specific programming of Npy and epigenetic effects of physical activity in a genetic model of depression2013In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 3, p. e255-Article in journal (Refereed)
    Abstract [en]

    Neuropeptide Y (NPY) has been implicated in depression, emotional processing and stress response. Part of this evidence originates from human single-nucleotide polymorphism (SNP) studies. In the present study, we report that a SNP in the rat Npy promoter (C/T; rs105431668) affects in vitro transcription and DNA-protein interactions. Genotyping studies showed that the C-allele of rs105431668 is present in a genetic rat model of depression (Flinders sensitive line; FSL), while the SNP's T-allele is present in its controls (Flinders resistant line; FRL). In vivo experiments revealed binding of a transcription factor (CREB2) and a histone acetyltransferase (Ep300) only at the SNP locus of the FRL. Accordingly, the FRL had increased hippocampal levels of Npy mRNA and H3K18 acetylation; a gene-activating histone modification maintained by Ep300. Next, based on previous studies showing antidepressant-like effects of physical activity in the FSL, we hypothesized that physical activity may affect Npy's epigenetic status. In line with this assumption, physical activity was associated with increased levels of Npy mRNA and H3K18 acetylation. Physical activity was also associated with reduced mRNA levels of a histone deacetylase (Hdac5). Conclusively, the rat rs105431668 appears to be a functional Npy SNP that may underlie depression-like characteristics. In addition, the achieved epigenetic reprogramming of Npy provides molecular support for the putative effectiveness of physical activity as a non-pharmacological antidepressant.

  • 90.
    Momeni, N
    et al.
    School of Natural Sciences, Linnaeus University, Kalmar, Sweden.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Brudin, L
    Department of Clinical Physiology, Kalmar County Hospital, Kalmar, Sweden.
    Behnia, F
    Department of Occupational Therapy, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
    Sivberg, B
    Department of Health Sciences, Lund University, Lund, Sweden.
    Joghataei, M T
    Cellular and Molecular Research Centre, Tehran Medical University, Tehran, Iran.
    Persson, B L
    School of Natural Sciences, Linnaeus University, Kalmar, Sweden.
    A novel blood-based biomarker for detection of autism spectrum disorders2012In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 2, article id e91Article in journal (Refereed)
    Abstract [en]

    Autism spectrum disorders (ASD) are classified as neurological developmental disorders. Several studies have been carried out to find a candidate biomarker linked to the development of these disorders, but up to date no reliable biomarker is available. Mass spectrometry techniques have been used for protein profiling of blood plasma of children with such disorders in order to identify proteins/peptides that may be used as biomarkers for detection of the disorders. Three differentially expressed peptides with mass–charge (m/z) values of 2020±1, 1864±1 and 1978±1 Da in the heparin plasma of children with ASD that were significantly changed as compared with the peptide pattern of the non-ASD control group are reported here. This novel set of biomarkers allows for a reliable blood-based diagnostic tool that may be used in diagnosis and potentially, in prognosis of ASD.

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  • 91.
    Momeni, Naghi
    et al.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Bergquist, Jonas
    Uppsala University.
    Brudin, Lars
    Kalmar County Hospital.
    Behnia, Fatemeh
    University of Social Welfare and Rehabilitation Sciences, Iran.
    Sivberg, Bengt
    Lund University.
    Joghataei, Mohammad
    Tehran Medical University, Iran.
    Persson, Bengt L.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    A novel blood-based biomarker for detection of autism spectrum disorders2012In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 2, article id e91Article in journal (Refereed)
    Abstract [en]

    Autism Spectrum Disorders (ASD) are classified as neurological developmental disorders. Several studies have been carried out to find a candidate biomarker linked to development of these disorders, but up to date no reliable biomarker is available. Mass spectrometry techniques have been used for protein profiling of blood plasma of children with such disorders in order to identify proteins/peptides which may be used as biomarkers for detection of the disorders. Three differentially expressed peptides with mass charged (m/z) values of 2,020 ± 1, 1,864 ± 1, and 1,978 ± 1 Da in heparin plasma of children with ASD which were significantly changed as compared to the peptide pattern of the non-ASD control group are reported here. This novel set of biomarkers allows for a reliable blood based diagnostic tool that may be used in diagnosis and potentially, in prognosis of ASD. 

  • 92.
    Motilla Hoppe, Johanna
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Frick, Andreas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Åhs, Fredrik
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Linnman, Clas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Appel, Lieuwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Jonasson, My
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Frans, Örjan
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    von Knorring, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Fredriksson, M
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Furmark, Tomas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Association between amygdala neurokinin-1 receptor availability and anxiety-related personality traits2018In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 8, no 1, p. 168-Article in journal (Refereed)
    Abstract [en]

    Animal studies indicate that substance P (SP) and its preferred neurokinin-1 (NK1) receptor modulate stress and anxiety-related behavior. Alterations in the SP-NK1 system have also been observed in human anxiety disorders, yet little is known about the relation between this system and individual differences in personality traits associated with anxiety propensity and approach-avoidance behavior, including trait anxiety, neuroticism, and extraversion. Exploring this relation could provide important insights into the neurobiological underpinnings of human anxiety and the etiology of anxiety disorders, as anxious traits are associated with increased susceptibility to develop psychopathological conditions. Here we examined the relationship between central NK1 receptor availability and self-rated measures of trait anxiety, neuroticism, and extraversion. The amygdala was chosen as the primary region of interest since this structure has been suggested to mediate the effect of the SP-NK1 system on anxiety. Anxious traits and NK1 receptor availability, determined with positron emission tomography and the radiotracer [11C]GR205171, were measured in 17 healthy individuals. Voxel-wise analyses showed a significant positive correlation between bilateral amygdala NK1 receptor availability and trait anxiety, and a trend in similar direction was observed for neuroticism. Conversely, extraversion was found to be negatively associated with amygdala NK1 receptor availability. Extraversion also correlated negatively with the NK1 measure in the cuneus/precuneus and fusiform gyrus according to exploratory whole-brain analyses. In conclusion, our findings indicate that amygdala NK1 receptor availability is associated with anxiety-related personality traits in healthy subjects, consistent with a modulatory role for the SP-NK1 system in human anxiety.

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  • 93.
    Munk-Olsen, Trine
    et al.
    Univ Southern Denmark, Dept Clin Res, Odense, Denmark.;Aarhus Univ, Natl Ctr Register Based Res, Aarhus BSS, Aarhus, Denmark..
    Liu, Xiaoqin
    Aarhus Univ, Natl Ctr Register Based Res, Aarhus BSS, Aarhus, Denmark..
    Madsen, Kathrine Bang
    Aarhus Univ, Natl Ctr Register Based Res, Aarhus BSS, Aarhus, Denmark..
    Kjeldsen, Mette-Marie Zacher
    Aarhus Univ, Natl Ctr Register Based Res, Aarhus BSS, Aarhus, Denmark..
    Petersen, Liselotte Vogdrup
    Aarhus Univ, Natl Ctr Register Based Res, Aarhus BSS, Aarhus, Denmark..
    Bergink, Veerle
    Erasmus MC, Dept Psychiat, Rotterdam, Netherlands.;Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY USA..
    Skalkidou, Alkistis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Reproductive Health Research.
    Vigod, Simone N.
    Univ Toronto, Dept Psychiat, Womens Coll Hosp, Toronto, ON, Canada..
    Frokjaer, Vibe G.
    Univ Toronto, Dept Psychiat, Womens Coll Res Inst, Toronto, ON, Canada.;Capital Reg Denmark, Mental Hlth Serv, Copenhagen, Denmark.;Copenhagen Univ Hosp, Neurobiol Res Unit, Copenhagen, Denmark..
    Pedersen, Carsten B.
    Aarhus Univ, Natl Ctr Register Based Res, Aarhus BSS, Aarhus, Denmark.;Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, Copenhagen, Denmark.;Aarhus Univ, Ctr Integrated Register Based Res, CIRRAU, Aarhus, Denmark..
    Maegbaek, Merete L.
    Aarhus Univ, Natl Ctr Register Based Res, Aarhus BSS, Aarhus, Denmark..
    Postpartum depression: a developed and validated model predicting individual risk in new mothers2022In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 12, no 1, article id 419Article in journal (Refereed)
    Abstract [en]

    Postpartum depression (PPD) is a serious condition associated with potentially tragic outcomes, and in an ideal world PPDs should be prevented. Risk prediction models have been developed in psychiatry estimating an individual's probability of developing a specific condition, and recently a few models have also emerged within the field of PPD research, although none are implemented in clinical care. For the present study we aimed to develop and validate a prediction model to assess individualized risk of PPD and provide a tentative template for individualized risk calculation offering opportunities for additional external validation of this tool. Danish population registers served as our data sources and PPD was defined as recorded contact to a psychiatric treatment facility (ICD-10 code DF32-33) or redeemed antidepressant prescriptions (ATC code N06A), resulting in a sample of 6,402 PPD cases (development sample) and 2,379 (validation sample). Candidate predictors covered background information including cohabitating status, age, education, and previous psychiatric episodes in index mother (Core model), additional variables related to pregnancy and childbirth (Extended model), and further health information about the mother and her family (Extended+ model). Results indicated our recalibrated Extended model with 14 variables achieved highest performance with satisfying calibration and discrimination. Previous psychiatric history, maternal age, low education, and hyperemesis gravidarum were the most important predictors. Moving forward, external validation of the model represents the next step, while considering who will benefit from preventive PPD interventions, as well as considering potential consequences from false positive and negative test results, defined through different threshold values.

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  • 94. Månsson, K. N. T.
    et al.
    Frick, A.
    Boraxbekk, C-J
    Marquand, A. F.
    Williams, S. C. R.
    Carlbring, Per
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Andersson, G.
    Furmark, T.
    Predicting long-term outcome of Internet-delivered cognitive behavior therapy for social anxiety disorder using fMRI and support vector machine learning2015In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 5, article id e530Article in journal (Refereed)
    Abstract [en]

    Cognitive behavior therapy (CBT) is an effective treatment for social anxiety disorder (SAD), but many patients do not respond sufficiently and a substantial proportion relapse after treatment has ended. Predicting an individual’s long-term clinical response therefore remains an important challenge. This study aimed at assessing neural predictors of long-term treatment outcome in participants with SAD 1 year after completion of Internet-delivered CBT (iCBT). Twenty-six participants diagnosed with SAD underwent iCBT including attention bias modification for a total of 13 weeks. Support vector machines (SVMs), a supervised pattern recognition method allowing predictions at the individual level, were trained to separate long-term treatment responders from nonresponders based on blood oxygen level-dependent (BOLD) responses to self-referential criticism. The Clinical Global Impression-Improvement scale was the main instrument to determine treatment response at the 1-year follow-up. Results showed that the proportion of long-term responders was 52%(12/23). From multivariate BOLD responses in the dorsal anterior cingulate cortex (dACC) together with the amygdala, we were able to predict long-term response rate of iCBT with an accuracy of 92% (confidence interval 95% 73.2–97.6). This activation pattern was, however, not predictive of improvement in the continuous Liebowitz Social Anxiety Scale—Self-report version. Follow-up psychophysiological interaction analyses revealed that lower dACC–amygdala coupling was associated with better long-term treatment response. Thus, BOLD response patterns in the fear-expressing dACC–amygdala regions were highly predictive of long-term treatment outcome of iCBT, and the initial coupling between these regions differentiated long-term responders from nonresponders. The SVM-neuroimaging approach could be of particular clinical value as it allows for accurate prediction of treatment outcome at the level of the individual.

  • 95. Månsson, K. N. T.
    et al.
    Salami, A.
    Frick, A.
    Carlbring, Per
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Clinical psychology.
    Andersson, G.
    Furmark, T.
    Boraxbekk, C.-J.
    Neuroplasticity in response to cognitive behavior therapy for social anxiety disorder2016In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 6, article id e727Article in journal (Refereed)
    Abstract [en]

    Patients with anxiety disorders exhibit excessive neural reactivity in the amygdala, which can be normalized by effective treatment like cognitive behavior therapy (CBT). Mechanisms underlying the brain’s adaptation to anxiolytic treatments are likely related both to structural plasticity and functional response alterations, but multimodal neuroimaging studies addressing structure–function interactions are currently missing. Here, we examined treatment-related changes in brain structure (gray matter (GM) volume) and function (blood–oxygen level dependent, BOLD response to self-referential criticism) in 26 participants with social anxiety disorder randomly assigned either to CBT or an attention bias modification control treatment. Also, 26 matched healthy controls were included. Significant time × treatment interactions were found in the amygdala with decreases both in GM volume (family-wise error (FWE) corrected PFWE=0.02) and BOLD responsivity (PFWE=0.01) after successful CBT. Before treatment, amygdala GM volume correlated positively with anticipatory speech anxiety (PFWE=0.04), and CBT-induced reduction of amygdala GM volume (pre–post) correlated positively with reduced anticipatory anxiety after treatment (PFWE0.05). In addition, we observed greater amygdala neural responsivity to self-referential criticism in socially anxious participants, as compared with controls (PFWE=0.029), before but not after CBT. Further analysis indicated that diminished amygdala GM volume mediated the relationship between decreased neural responsivity and reduced social anxiety after treatment (P=0.007). Thus, our results suggest that improvement-related structural plasticity impacts neural responsiveness within the amygdala, which could be essential for achieving anxiety reduction with CBT.

  • 96. Månsson, K N T
    et al.
    Salami, A
    Frick, Andreas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Carlbring, P
    Andersson, G
    Furmark, Tomas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Boraxbekk, C-J
    Neuroplasticity in response to cognitive behavior therapy for social anxiety disorder2016In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 6, article id e727Article in journal (Refereed)
    Abstract [en]

    Patients with anxiety disorders exhibit excessive neural reactivity in the amygdala, which can be normalized by effective treatment like cognitive behavior therapy (CBT). Mechanisms underlying the brain's adaptation to anxiolytic treatments are likely related both to structural plasticity and functional response alterations, but multimodal neuroimaging studies addressing structure-function interactions are currently missing. Here, we examined treatment-related changes in brain structure (gray matter (GM) volume) and function (blood-oxygen level dependent, BOLD response to self-referential criticism) in 26 participants with social anxiety disorder randomly assigned either to CBT or an attention bias modification control treatment. Also, 26 matched healthy controls were included. Significant time × treatment interactions were found in the amygdala with decreases both in GM volume (family-wise error (FWE) corrected P(FWE) = 0.02) and BOLD responsivity (P(FWE) = 0.01) after successful CBT. Before treatment, amygdala GM volume correlated positively with anticipatory speech anxiety (P(FWE)=0.04), and CBT-induced reduction of amygdala GM volume (pre-post) correlated positively with reduced anticipatory anxiety after treatment (P(FWE) ⩽ 0.05). In addition, we observed greater amygdala neural responsivity to self-referential criticism in socially anxious participants, as compared with controls (P(FWE) = 0.029), before but not after CBT. Further analysis indicated that diminished amygdala GM volume mediated the relationship between decreased neural responsivity and reduced social anxiety after treatment (P=0.007). Thus, our results suggest that improvement-related structural plasticity impacts neural responsiveness within the amygdala, which could be essential for achieving anxiety reduction with CBT.

    Download full text (pdf)
    fulltext
  • 97.
    Månsson, Kristoffer N T
    et al.
    Linköping University, Department of Behavioural Sciences and Learning, Psychology. Linköping University, Faculty of Arts and Sciences.
    Frick, A
    Uppsala Univ, Dept Psychol, Uppsala, Sweden.
    Boraxbekk, C-J
    Umea Univ, Umea, Sweden.
    Marquand, A F
    Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands, Kings Coll London, Inst Psychiat, Ctr Neuroimaging Sci, Dept Neuroimaging, London, England.
    Williams, S C R
    Kings Coll London, Inst Psychiat, Ctr Neuroimaging Sci, Dept Neuroimaging, London WC2R 2LS, England.
    Carlbring, P
    Stockholm Univ, Dept Psychol, S-10691 Stockholm, Sweden.
    Andersson, Gerhard
    Linköping University, Department of Behavioural Sciences and Learning, Psychology. Linköping University, Faculty of Arts and Sciences.
    Furmark, T
    Uppsala Univ, Dept Psychol, Uppsala, Sweden.
    Predicting long-term outcome of Internet-delivered cognitive behavior therapy for social anxiety disorder using fMRI and support vector machine learning.2015In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 5, p. e530-Article in journal (Refereed)
    Abstract [en]

    Cognitive behavior therapy (CBT) is an effective treatment for social anxiety disorder (SAD), but many patients do not respond sufficiently and a substantial proportion relapse after treatment has ended. Predicting an individual's long-term clinical response therefore remains an important challenge. This study aimed at assessing neural predictors of long-term treatment outcome in participants with SAD 1 year after completion of Internet-delivered CBT (iCBT). Twenty-six participants diagnosed with SAD underwent iCBT including attention bias modification for a total of 13 weeks. Support vector machines (SVMs), a supervised pattern recognition method allowing predictions at the individual level, were trained to separate long-term treatment responders from nonresponders based on blood oxygen level-dependent (BOLD) responses to self-referential criticism. The Clinical Global Impression-Improvement scale was the main instrument to determine treatment response at the 1-year follow-up. Results showed that the proportion of long-term responders was 52% (12/23). From multivariate BOLD responses in the dorsal anterior cingulate cortex (dACC) together with the amygdala, we were able to predict long-term response rate of iCBT with an accuracy of 92% (confidence interval 95% 73.2-97.6). This activation pattern was, however, not predictive of improvement in the continuous Liebowitz Social Anxiety Scale-Self-report version. Follow-up psychophysiological interaction analyses revealed that lower dACC-amygdala coupling was associated with better long-term treatment response. Thus, BOLD response patterns in the fear-expressing dACC-amygdala regions were highly predictive of long-term treatment outcome of iCBT, and the initial coupling between these regions differentiated long-term responders from nonresponders. The SVM-neuroimaging approach could be of particular clinical value as it allows for accurate prediction of treatment outcome at the level of the individual.

  • 98.
    Månsson, Kristoffer N. T.
    et al.
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Department of Psychology, Stockholm University, Stockholm, Sweden; Department of Psychology, Uppsala University, Uppsala, Sweden.
    Lindqvist, Daniel
    Department of Clinical Sciences Lund, Psychiatry, Lund University, Lund.
    Yang, Liu L.
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
    Svanborg, Cecilia
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, & Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden.
    Isung, Josef
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, & Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden.
    Nilsonne, Gustav
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Stress Research Institute, Stockholm University, Stockholm, Sweden.
    Bergman Nordgren, Lise
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, & Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden.
    El Alaoui, Samir
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, & Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden.
    Hedman-Lagerlöf, Erik
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Kraepelien, Martin
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, & Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden.
    Högström, Jens
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, & Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden.
    Andersson, Gerhard
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, & Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden; Department of Behavioural Sciences and Learning, Linköping University, Linköping, Sweden.
    Boraxbekk, Carl-Johan
    Centre for Demographic and Ageing Research, Umeå University, Umeå, Sweden; Center for Magnetic Resonance (DRCMR), Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital, Hvidovre, Denmark.
    Fischer, Håkan
    Department of Psychology, Stockholm University, Stockholm, Sweden.
    Lavebratt, Catharina
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
    Wolkowitz, Owen M.
    Department of Psychiatry, University of California, San Francisco, CA, USA.
    Furmark, Tomas
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Improvement in indices of cellular protection after psychological treatment for social anxiety disorder2019In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 9, no 1, article id 340Article in journal (Refereed)
    Abstract [en]

    Telomere attrition is a hallmark of cellular aging and shorter telomeres have been reported in mood and anxiety disorders. Telomere shortening is counteracted by the enzyme telomerase and cellular protection is also provided by the antioxidant enzyme glutathione peroxidase (GPx). Here, telomerase, GPx, and telomeres were investigated in 46 social anxiety disorder (SAD) patients in a within-subject design with repeated measures before and after cognitive behavioral therapy. Treatment outcome was assessed by the Liebowitz Social Anxiety Scale (self-report), administered three times before treatment to control for time and regression artifacts, and posttreatment. Venipunctures were performed twice before treatment, separated by 9 weeks, and once posttreatment. Telomerase activity and telomere length were measured in peripheral blood mononuclear cells and GPx activity in plasma. All patients contributed with complete data. Results showed that social anxiety symptom severity was significantly reduced from pretreatment to posttreatment (Cohen's d = 1.46). There were no significant alterations in telomeres or cellular protection markers before treatment onset. Telomere length and telomerase activity did not change significantly after treatment, but an increase in telomerase over treatment was associated with reduced social anxiety. Also, lower pretreatment telomerase activity predicted subsequent symptom improvement. GPx activity increased significantly during treatment, and increases were significantly associated with symptom improvement. The relationships between symptom improvement and putative protective enzymes remained significant also after controlling for body mass index, sex, duration of SAD, smoking, concurrent psychotropic medication, and the proportion of lymphocytes to monocytes. Thus, indices of cellular protection may be involved in the therapeutic mechanisms of psychological treatment for anxiety. 

  • 99. Månsson, Kristoffer N. T.
    et al.
    Lindqvist, Daniel
    Yang, Liu L.
    Svanborg, Cecilia
    Isung, Josef
    Nilsonne, Gustav
    Bergman-Nordgren, Lise
    El Alaoui, Samir
    Hedman-Lagerlöf, Erik
    Kraepelien, Martin
    Högström, Jens
    Andersson, Gerhard
    Boraxbekk, Carl-Johan
    Umeå University, Faculty of Social Sciences, Centre for Demographic and Ageing Research (CEDAR). Center for Magnetic Resonance (DRCMR), Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital, Hvidovre, Denmark.
    Fischer, Håkan
    Lavebratt, Catharina
    Wolkowitz, Owen M.
    Furmark, Tomas
    Improvement in indices of cellular protection after psychological treatment for social anxiety disorder2019In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 9, article id 340Article in journal (Refereed)
    Abstract [en]

    Telomere attrition is a hallmark of cellular aging and shorter telomeres have been reported in mood and anxiety disorders. Telomere shortening is counteracted by the enzyme telomerase and cellular protection is also provided by the antioxidant enzyme glutathione peroxidase (GPx). Here, telomerase, GPx, and telomeres were investigated in 46 social anxiety disorder (SAD) patients in a within-subject design with repeated measures before and after cognitive behavioral therapy. Treatment outcome was assessed by the Liebowitz Social Anxiety Scale (self-report), administered three times before treatment to control for time and regression artifacts, and posttreatment. Venipunctures were performed twice before treatment, separated by 9 weeks, and once posttreatment. Telomerase activity and telomere length were measured in peripheral blood mononuclear cells and GPx activity in plasma. All patients contributed with complete data. Results showed that social anxiety symptom severity was significantly reduced from pretreatment to posttreatment (Cohen’s d = 1.46). There were no significant alterations in telomeres or cellular protection markers before treatment onset. Telomere length and telomerase activity did not change significantly after treatment, but an increase in telomerase over treatment was associated with reduced social anxiety. Also, lower pretreatment telomerase activity predicted subsequent symptom improvement. GPx activity increased significantly during treatment, and increases were significantly associated with symptom improvement. The relationships between symptom improvement and putative protective enzymes remained significant also after controlling for body mass index, sex, duration of SAD, smoking, concurrent psychotropic medication, and the proportion of lymphocytes to monocytes. Thus, indices of cellular protection may be involved in the therapeutic mechanisms of psychological treatment for anxiety.

    Download full text (pdf)
    fulltext
  • 100.
    Månsson, Kristoffer N. T.
    et al.
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Clinical psychology. Karolinska Institutet, Sweden; Uppsala University, Sweden.
    Lindqvist, Daniel
    Yang, Liu L.
    Svanborg, Cecilia
    Isung, Josef
    Nilsonne, Gustav
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Bergman-Nordgren, Lise
    El Alaoui, Samir
    Hedman-Lagerlöf, Erik
    Kraepelien, Martin
    Högström, Jens
    Andersson, Gerhard
    Boraxbekk, Carl-Johan
    Fischer, Håkan
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Biological psychology.
    Lavebratt, Catharina
    Wolkowitz, Owen M.
    Furmark, Tomas
    Improvement in indices of cellular protection after psychological treatment for social anxiety disorder2019In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 9, no 1, article id 340Article in journal (Refereed)
    Abstract [en]

    Telomere attrition is a hallmark of cellular aging and shorter telomeres have been reported in mood and anxiety disorders. Telomere shortening is counteracted by the enzyme telomerase and cellular protection is also provided by the antioxidant enzyme glutathione peroxidase (GPx). Here, telomerase, GPx, and telomeres were investigated in 46 social anxiety disorder (SAD) patients in a within-subject design with repeated measures before and after cognitive behavioral therapy. Treatment outcome was assessed by the Liebowitz Social Anxiety Scale (self-report), administered three times before treatment to control for time and regression artifacts, and posttreatment. Venipunctures were performed twice before treatment, separated by 9 weeks, and once posttreatment. Telomerase activity and telomere length were measured in peripheral blood mononuclear cells and GPx activity in plasma. All patients contributed with complete data. Results showed that social anxiety symptom severity was significantly reduced from pretreatment to posttreatment (Cohen’s d = 1.46). There were no significant alterations in telomeres or cellular protection markers before treatment onset. Telomere length and telomerase activity did not change significantly after treatment, but an increase in telomerase over treatment was associated with reduced social anxiety. Also, lower pretreatment telomerase activity predicted subsequent symptom improvement. GPx activity increased significantly during treatment, and increases were significantly associated with symptom improvement. The relationships between symptom improvement and putative protective enzymes remained significant also after controlling for body mass index, sex, duration of SAD, smoking, concurrent psychotropic medication, and the proportion of lymphocytes to monocytes. Thus, indices of cellular protection may be involved in the therapeutic mechanisms of psychological treatment for anxiety.

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