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  • 1.
    Bay-Richter, Cecilie
    et al.
    Aarhus University, Denmark.
    Linderholm, Klas R.
    Karolinska Institute, Sweden.
    Lim, Chai K.
    Macquarie University, Australia.
    Samuelsson, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry. Linköping University, Faculty of Medicine and Health Sciences.
    Traskman-Bendz, Lil
    Lund University, Sweden.
    Guillemin, Gilles J.
    Macquarie University, Australia.
    Erhardt, Sophie
    Karolinska Institute, Sweden.
    Brundin, Lena
    Michigan State University, MI USA; Van Andel Research Institute, MI USA.
    A role for inflammatory metabolites as modulators of the glutamate N-methyl-D-aspartate receptor in depression and suicidality2015In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 43, p. 110-117Article in journal (Refereed)
    Abstract [en]

    Background: Patients with depression and suicidality suffer from low-grade neuroinflammation. Proinflammatory cytokines activate indoleamine 2,3-dioxygenase, an initial enzyme of the kynurenine pathway. This pathway produces neuroactive metabolites, including quinolinic- and kynurenic acid, binding to the glutamate N-methyl-D-aspartate-receptor, which is hypothesized to be part of the neural mechanisms underlying symptoms of depression. We therefore hypothesized that symptoms of depression and suicidality would fluctuate over time in patients prone to suicidal behavior, depending on the degree of inflammation and kynurenine metabolite levels in the cerebrospinal fluid (CSF). Methods: We measured cytokines and kynurenine metabolites in CSF, collected from suicide attempters at repeated occasions over 2 years (total patient samples n = 143, individuals n = 30) and healthy controls (n = 36). The association between the markers and psychiatric symptoms was assessed using the Montgomery Asberg Depression Rating Scale and the Suicide Assessment Scale. Results: Quinolinic acid was increased and kynurenic acid decreased over time in suicidal patients versus healthy controls. Furthermore, we found a significant association between low kynurenic acid and severe depressive symptoms, as well as between high interleukin-6 levels and more severe suicidal symptoms. Conclusions: We demonstrate a long-term dysregulation of the kynurenine pathway in the central nervous system of suicide attempters. An increased load of inflammatory cytokines was coupled to more severe symptoms. We therefore suggest that patients with a dysregulated kynurenine pathway are vulnerable to develop depressive symptoms upon inflammatory conditions, as a result the excess production of the NMDA-receptor agonist quinolinic acid. This study provides a neurobiological framework supporting the use of NMDA-receptor antagonists in the treatment of suicidality and depression. (C) 2014 Elsevier Inc. All rights reserved.

  • 2.
    Erhardt, Sophie
    et al.
    Karolinska Institute, Sweden .
    Lim, Chai K.
    University of New S Wales, Australia .
    Linderholm, Klas R.
    Karolinska Institute, Sweden .
    Janelidze, Shorena
    Lund University, Sweden .
    Lindqvist, Daniel
    Lund University, Sweden .
    Samuelsson, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Psychiatry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Lundberg, Kristina
    Linköping University, Department of Clinical and Experimental Medicine, Psychiatry. Linköping University, Faculty of Health Sciences.
    Postolache, Teodor T
    University of Maryland, MD USA .
    Traskman-Bendz, Lil
    Lund University, Sweden .
    Guillemin, Gilles J
    University of New S Wales, Australia .
    Brundin, Lena
    Lund University, Sweden .
    Connecting Inflammation with Glutamate Agonism in Suicidality2013In: Neuropsychopharmacology, ISSN 0893-133X, E-ISSN 1740-634X, Vol. 38, no 5, p. 743-752Article in journal (Refereed)
    Abstract [en]

    The NMDA-receptor antagonist ketamine has proven efficient in reducing symptoms of suicidality, although the mechanisms explaining this effect have not been detailed in psychiatric patients. Recent evidence points towards a low-grade inflammation in brains of suicide victims. Inflammation leads to production of quinolinic acid (QUIN) and kynurenic acid (KYNA), an agonist and antagonist of the glutamatergic N-methyl-D-aspartate (NMDA) receptor, respectively. We here measured QUIN and KYNA in the cerebrospinal fluid (CSF) of 64 medication-free suicide attempters and 36 controls, using gas chromatography mass spectrometry and high-performance liquid chromatography. We assessed the patients clinically using the Suicide Intent Scale and the Montgomery Asberg Depression Rating Scale (MADRS). We found that QUIN, but not KYNA, was significantly elevated in the CSF of suicide attempters (Pandlt;0.001). As predicted, the increase in QUIN was associated with higher levels of CSF interleukin-6. Moreover, QUIN levels correlated with the total scores on Suicide Intent Scale. There was a significant decrease of QUIN in patients who came for follow-up lumbar punctures within 6 months after the suicide attempt. In summary, we here present clinical evidence of increased QUIN in the CSF of suicide attempters. An increased QUIN/KYNA quotient speaks in favor of an overall NMDA-receptor stimulation. The correlation between QUIN and the Suicide Intent Scale indicates that changes in glutamatergic neurotransmission could be specifically linked to suicidality. Our findings have important implications for the detection and specific treatment of suicidal patients, and might explain the observed remedial effects of ketamine. Neuropsychopharmacology (2013) 38, 743-752; doi:10.1038/npp.2012.248; published online 9 January 2013

  • 3.
    Janelidze, S.
    et al.
    Lund University, Sweden; Lund University, Sweden.
    Suchankova, P.
    University of Gothenburg, Sweden.
    Ekman, A.
    University of Gothenburg, Sweden.
    Erhardt, S.
    Karolinska Institute, Sweden.
    Sellgren, C.
    Karolinska Institute, Sweden.
    Samuelsson, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Westrin, A.
    Lund University, Sweden.
    Minthon, L.
    Lund University, Sweden.
    Hansson, O.
    Lund University, Sweden.
    Traskman-Bendz, L.
    Lund University, Sweden.
    Brundin, L.
    Michigan State University, MI USA; Van Andel Research Institute, MI USA.
    Low IL-8 is associated with anxiety in suicidal patients: genetic variation and decreased protein levels2015In: Acta Psychiatrica Scandinavica, ISSN 0001-690X, E-ISSN 1600-0447, Vol. 131, no 4, p. 269-278Article in journal (Refereed)
    Abstract [en]

    ObjectiveRecent studies indicate that inflammation may play a role in the pathophysiology of suicidality. Interleukin-8 (IL-8) is a chemokine that in addition to its function in the immune system also exert neuroprotective properties. The involvement of this chemokine in neuropsychiatric conditions is incompletely known. MethodWe measured plasma and cerebrospinal fluid (CSF) IL-8, as well as the genotype frequency of a single nucleotide polymorphism (-251A/T, rs4073) in the promoter region of the IL8 gene, in suicide attempters (n=206) and healthy controls (n=578). ResultsPlasma and CSF levels of IL-8 were significantly lower in suicide attempters with anxiety than in healthy controls. IL-8 in both plasma and CSF correlated negatively with symptoms of anxiety. Compared with the population-based cohort, the IL-8-251T allele was more prevalent among female suicide attempters. Furthermore, suicide attempters carrying this allele showed more severe anxiety. This correlative study warrants further mechanistic studies on the effects of IL-8 in the central nervous system. ConclusionWe suggest that IL-8 might be involved in the biological mechanisms mediating resilience to anxiety. Thus, our findings highlight the chemokine IL-8 as a potential target for future development of anti-anxiety treatments and suicide prevention.

  • 4.
    Janelidze, Shorena
    et al.
    Lund University, Sweden .
    Ventorp, Filip
    Lund University, Sweden .
    Erhardt, Sophie
    Karolinska Institute, Sweden .
    Hansson, Oskar
    Lund University, Sweden .
    Minthon, Lennart
    Lund University, Sweden .
    Flax, John
    PrecisionMedical Inc, CA USA .
    Samuelsson, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Psychiatry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Traskman-Bendz, Lil
    Lund University, Sweden .
    Brundin, Lena
    Lund University, Sweden Michigan State University, MI USA .
    Altered chemokine levels in the cerebrospinal fluid and plasma of suicide attempters2013In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 38, no 6, p. 853-862Article in journal (Refereed)
    Abstract [en]

    Chemokines constitute a class of small inflammatory proteins that control the chemotaxis of leukocytes. They are also present in the central nervous system (CNS) and contribute to diverse physiological functions, such as the regulation of cell migration, axonal growth and neuronal survival. It is to date not known whether chemokines in the CNS are affected in psychiatric disorders. In this study, chemokine levels were measured in the cerebrospinal fluid (CSF) of 137 psychiatric patients in conjunction to a suicide attempt, and 43 healthy controls. A subgroup of patients (n = 42) was followed up with blood samples 12 years after the initial CSF collection, when they did not show suicidal behavior. The follow-up chemokine levels were compared to those of psychiatric patients (n = 17) who had never attempted suicide. Ultrasensitive chemokine multiplex immunoassay was used to quantify eotaxin-1 (CCL11), interferon gamma-induced protein-10 (IP-10, CXCL10), macrophage inflammatory protein-1 beta (MIP-1 beta, CCL4), monocyte chemotactic protein-1 (MCP-1, CCL2), MCP-4 (CCL13) and thymus and activation regulated chemokine (TARC, CCL17). Patients were diagnosed using DSM-III-R/DSM-IV, and assessed using the Comprehensive Psychopathological Rating Scale (CPRS), including subscales, and the Suicidal Intent Scale (SIS). CSF eotaxin-1, MIP-1 beta, MCP-1, MCP-4 and TARC were significantly lower in suicide attempters than in healthy controls. Low chemokine levels were specifically associated with psychotic symptoms and pain. In the samples collected at follow-up, TARC was significantly lower in suicide attempters compared to psychiatric patients who had never attempted suicide. We also found a positive correlation between blood TARC and brain-derived neurotrophic factor (BDNF) levels. Our study thus provides evidence of reduced chemokine levels in suicide attempters, both in the acute suicidal setting, and at long-term, compared to non-attempters. These results warrant future studies on the detailed neurobiological functions of chemokines in psychiatric patients. (C) 2012 Elsevier Ltd. All rights reserved.

  • 5.
    Kegel, Magdalena E.
    et al.
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Bhat, Maria
    AstraZeneca, Research and Development, Innovative Medicines, Personalised Healthcare and Biomarkers, Translational Science Centre, Science for Life Laboratory, Solna, Sweden / Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Skogh, Elisabeth
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Samuelsson, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Lundberg, Kristina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences.
    Dahl, Marja-Liisa
    Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Sellgren, Carl
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Schwieler, Lilly
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Engberg, Göran
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Schuppe-Koistinen, Ina
    AstraZeneca, Research and Development, Innovative Medicines, Personalised Healthcare and Biomarkers, Translational Science Centre, Science for Life Laboratory, Solna, Sweden / Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Erhardt, Sophie
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Imbalanced Kynurenine Pathway in Schizophrenia2014In: International Journal of Tryptophan Research, ISSN 1178-6469, Vol. 7, p. 15-22Article in journal (Refereed)
    Abstract [en]

    Several studies suggest a role for kynurenic acid (KYNA) in the pathophysiology of schizophrenia. It has been proposed that increased brain KYNA levels in schizophrenia result from a pathological shift in the kynurenine pathway toward enhanced KYNA formation, away from the other branch of the pathway leading to quinolinic acid (QUIN). Here we investigate the levels of QUIN in cerebrospinal fluid (CSF) of patients with schizophrenia and healthy controls, and relate those to CSF levels of KYNA and other kynurenine metabolites from the same individuals. CSF QUIN levels from stable outpatients treated with olanzapine (n = 22) and those of controls (n = 26) were analyzed using liquid chromatography-mass spectrometry. No difference in CSF QUIN levels between patients and controls was observed (20.6 ± 1.5 nM vs. 18.2 ± 1.1 nM, P = 0.36). CSF QUIN was positively correlated to CSF kynurenine and CSF KYNA in patients but not in controls. The CSF QUIN/KYNA ratio was lower in patients than in controls (P = 0.027). In summary, the present study offers support for an over-activated and imbalanced kynurenine pathway, favoring the production of KYNA over QUIN in patients with schizophrenia.

  • 6.
    Linderholm, Klas R
    et al.
    Department of Physiology and Pharmacology, Karolinska Institutet.
    Skogh, Elisabeth
    Linköping University, Department of Clinical and Experimental Medicine, Psychiatry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Olsson, Sara K
    Department of Physiology and Pharmacology, Karolinska Institutet.
    Dahl, Marja-Liisa
    Department of Medical Sciences, Clinical Pharmacology, Uppsala University.
    Holtze, Maria
    Department of Physiology and Pharmacology, Karolinska Institutet.
    Engberg, Göran
    Department of Physiology and Pharmacology, Karolinska Institutet.
    Samuelsson, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Psychiatry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Erhardt, Sophie
    Department of Physiology and Pharmacology, Karolinska Institutet.
    Increased Levels of Kynurenine and Kynurenic Acid in the CSF of Patients With Schizophrenia2012In: Schizophrenia Bulletin, ISSN 0586-7614, E-ISSN 1745-1701, Vol. 38, no 3, p. 426-432Article in journal (Refereed)
    Abstract [en]

    Background: The kynurenic acid (KYNA) hypothesis for schizophrenia is partly based on studies showing increased brain levels of KYNA in patients. KYNA is an endogenous metabolite of tryptophan (TRP) produced in astrocytes and antagonizes N-methyl-D-aspartate and alpha7* nicotinic receptors. Methods: The formation of KYNA is determined by the availability of substrate, and hence, we analyzed KYNA and its precursors, kynurenine (KYN) and TRP, in the cerebrospinal fluid (CSF) of patients with schizophrenia. CSF from male patients with schizophrenia on olanzapine treatment (n = 16) was compared with healthy male volunteers (n = 29). Results: KYN and KYNA concentrations were higher in patients with schizophrenia (60.7 +/- 4.37nM and 2.03 +/- 0.23nM, respectively) compared with healthy volunteers (28.6 +/- 1.44nM and 1.36 +/- 0.08nM, respectively), whereas TRP did not differ between the groups. In all subjects, KYN positively correlated to KYNA. Conclusion: Our results demonstrate increased levels of CSF KYN and KYNA in patients with schizophrenia and further support the hypothesis that KYNA is involved in the pathophysiology of schizophrenia.

  • 7.
    Lindqvist, Daniel
    et al.
    Lund University Hospital.
    Janelidze, Shorena
    Lund University Hospital.
    Hagell, Peter
    Lund University Hospital.
    Erhardt, Sophie
    Karolinska Institute.
    Samuelsson, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Psychiatry . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Minthon, Lennart
    Lund University Hospital.
    Hansson, Oskar
    Lund University Hospital.
    Bjorkqvist, Maria
    Lund University Hospital.
    Traskman-Bendz, Lil
    Lund University Hospital.
    Brundin, Lena
    Lund University Hospital.
    Interleukin-6 Is Elevated in the Cerebrospinal Fluid of Suicide Attempters and Related to Symptom Severity2009In: BIOLOGICAL PSYCHIATRY, ISSN 0006-3223, Vol. 66, no 3, p. 287-292Article in journal (Refereed)
    Abstract [en]

    Background: Depressive disorders are associated with immune system alterations that can be detected in the blood. Cytokine concentrations in cerebrospinal fluid (CSF) and their relationship to aspects of suicidality have previously not been investigated. Methods: We measured interleukin-1 beta interleukin-6 (IL-6), interleukin-8, and tumor necrosis factor-a (TNF-alpha) in CSF and plasma of suicide attempters (n = 63) and healthy control subjects (n = 47). Patients were classified according to diagnosis and violent or nonviolent suicide attempt. We evaluated suicidal ideation and depressive symptoms using the Suicide Assessment Scale and the Montgomery-Asberg Depression Rating Scale (MADRS). We also analyzed the relation between cytokines and monoamine metabolites 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) in CSF, as well as the integrity of the blood-brain barrier as reflected by the CSF:serum albumin ratio. Results: IL-6 in CSF was significantly higher in suicide attempters than in healthy control subjects. Patients who performed violent suicide attempts displayed the highest IL-6. Furthermore, there was a significant positive correlation between MANS scores and CSF IL-6 levels in all patients. IL-6 and TNF-a correlated significantly with 5-HIAA and HVA in CSF, but not with MHPG. Cytokine levels in plasma and CSF were not associated, and patients with increased blood-brain barrier permeability did not exhibit elevated cytokine levels. Conclusions: We propose a role for CSF IL-6 in the symptomatology of suicidal behavior, possibly through mechanisms involving alterations of dopamine and serotonin metabolism.

  • 8.
    Nordin, Conny
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Dahl, M-L
    Gupta, R C
    Samuelsson, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Psychiatry. Linköping University, Faculty of Health Sciences.
    Taurine In Plasma And CSF-A Study In Healthy Male Volunteers2007In: : EUROPEAN NEUROPSYCHOPHARMACOLOGY   , 2007, p. 307-308Conference paper (Refereed)
  • 9.
    Olsson, Sara K
    et al.
    Karolinska Institute.
    Samuelsson, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Psychiatry . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Saetre, Peter
    Karolinska Institute and Hospital.
    Lindstrom, Leif
    Uppsala University.
    Jonsson, Erik G
    Karolinska Institute and Hospital.
    Nordin, Conny
    Linköping University, Department of Clinical and Experimental Medicine, Psychiatry . Linköping University, Faculty of Health Sciences.
    Engberg, Goran
    Karolinska Institute.
    Erhardt, Sophie
    Karolinska Institute.
    Landen, Mikael
    Karolinska Institute.
    Elevated levels of kynurenic acid in the cerebrospinal fluid of patients with bipolar disorder2010In: JOURNAL OF PSYCHIATRY and NEUROSCIENCE, ISSN 1180-4882, Vol. 35, no 3, p. 195-199Article in journal (Refereed)
    Abstract [en]

    Background: Patients with schizophrenia show elevated brain levels of the neuroactive tryptophan metabolite kynurenic acid (KYNA) This astrocyte] derived mediator acts as a neuroprotectant and modulates sensory gating and cognitive functiona We measured the levels of KYNA in the cerebrospinal fluid T vSyU of patients with bipolar disorder and healthy volunteers to investigate the putative involvement of KYNA in bipolar disorder. Methods: We obtained CSF by lumbar puncture from 23 healthy men and 31 euthymic men with bipolar disorder. We analyzed the samples using high] performance liquid chromatography. Results: Patients with bipolar disorder had increased levels of KYNA in their CSF compared with healthy volunteers (1.71 nM, standard error of the mean [SEM] cad, va dad, nM, SEM cacln p = 0.002. The levels of KYNA were positively correlated with age among bipolar patients but not healthy volunteersa Limitations: The influence of ongoing drug treatment among patients cannot be ruled outa We conducted our study during the euthymic phase of the diseasea Conclusion: Brain KYNA levels are increased in euthymic men with bipolar disorder. In addition, KYNA levels increased with age in these patientsa These findings indicate shared mechanisms between bipolar disorder and schizophrenia. Elevated levels of brain KYNA may provide further insight to the pathophysiology and progression of bipolar disordera

  • 10. Olsson, SK
    et al.
    Erhardt, S
    Samuelsson, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Psychiatry. Linköping University, Faculty of Health Sciences.
    Nordin, Conny
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Elevated levels of kynurenic acid in the cerebrospinal fluid of patients with bipolar disorder2008Conference paper (Refereed)
  • 11.
    Samuelsson, Martin
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Psychiatry. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Spelberoende - synen på behandlingsansvar och behandling2006In: Medicinska Riksstämman,2006, 2006, p. 86-86Conference paper (Other academic)
    Abstract [sv]

      

  • 12.
    Samuelsson, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Psychiatry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Taurine and Glutathione in cerebrospinal fluid and plasma from patients with psychiatric disorders and healthy controls2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    A growing body of results indicate that immunological alterations and oxidative stress are of importance in various mental disorders. The inflammatory changes are possible to detect both in plasma and cerebrospinal fluid (CSF), and different psychiatric disorder exhibit similar changes indicating a common underlying mechanism. The antioxidants are of importance to regulate the redox balance and control the inflammatory processes but the causal relationship between psychiatric disorders and increased oxidative stress is however not fully clarified. Two important antioxidants; taurine and glutathione (GSH), have been suggested to have central nervous system (CNS)-protective properties. They have been found to fluctuate in several mental disorders including schizophrenia and depression but the clinical relevance need further studies.

    The general aim of this thesis was to increase the understanding of taurine and the GSH in depression and schizophrenia, two major mental disorders, in comparison to healthy controls.

    Correlations between glutathione and taurine levels in blood and CSF were analyzed in healthy male volunteers and we identified a complex pattern of associations showing that the CSF concentration was influenced by body mass index (BMI), age, intraspinal pressure, plasma concentrations the previous day and possible genetic factors. Electroconvulsive therapy (ECT) is used in the treatment of severely depressed patients. In blood collected before the first and after the third ECT, we found a significant decrease in plasma taurine in patients responding to the treatment, while total glutathione was unaltered. In a group of olanzapine treated patients with schizophrenia or schizoaffective disorders, we analysed taurine and glutathione in plasma and CSF and compared with healthy male and female volunteers. We observed increased plasma taurine levels in patients compared with controls, but no difference in CSF taurine and no alteration in glutathione.

    This thesis indicates that taurine might play a role in mental disorders such as depression and schizophrenia. Increased knowledge about the complex regulation of taurine and glutathione might provide new insights into the impact of redox balance in the pathophysiology of psychiatric disorder and contribute to a future personalization of the treatment.

    List of papers
    1. Taurine in plasma and CSF: a study in healthy male volunteers
    Open this publication in new window or tab >>Taurine in plasma and CSF: a study in healthy male volunteers
    2009 (English)In: Amino Acids, ISSN 0939-4451, E-ISSN 1438-2199, Vol. 36, no 3, p. 529-533Article in journal (Refereed) Published
    Abstract [en]

    In order to explore the interrelationship between plasma and cerebrospinal fluid taurine concentrations, three consecutive 6-ml fractions of cerebrospinal fluid were drawn from 30 healthy male volunteers in the early morning after 8 h in the fasting condition. Repeated plasma samples were drawn over 24 h the day before lumbar puncture. Taurine in plasma and cerebrospinal fluid was determined by high performance liquid chromatography. The subjects were categorized as extensive or poor metabolizers with respect to the cytochrome P450 2D6 genotype. The taurine cerebrospinal fluid/plasma ratio at 8 a.m. was negatively influenced by the plasma taurine concentration at 4 p.m. the previous day. It was also negatively influenced by body mass index and positively by the intraspinal pressure. Three poor metabolizers of cytochrome P450 2D6 had higher plasma taurine areas under the curve than 27 extensive metabolizers. Hypothetically, cytochrome P450 2D6 influences the transport of taurine across the blood-brain barrier.

    Keywords
    Taurine, Cerebrospinal fluid, Plasma, Cytochrome P450 2D6, Genotype
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-17389 (URN)10.1007/s00726-008-0115-9 (DOI)
    Available from: 2009-03-21 Created: 2009-03-21 Last updated: 2017-12-13
    2. Glutathione in the blood and cerebrospinal fluid: A study in healthy male volunteers
    Open this publication in new window or tab >>Glutathione in the blood and cerebrospinal fluid: A study in healthy male volunteers
    2011 (English)In: Neuropeptides, ISSN 0143-4179, E-ISSN 1532-2785, Vol. 45, no 4, p. 287-292Article in journal (Refereed) Published
    Abstract [en]

    Glutathione (GSH) is an important regulator of intracellular redox homeostasis. In the brain, glutathione is considered a major antioxidant, which is also found at high concentrations in the extracellular environment. Altered GSH balance in plasma, blood and cerebrospinal fluid (CSF) has been observed in several disorders suggesting that an impaired antioxidant function is part of the pathophysiology. The aim of the present study was to investigate a possible relationship between glutathione in plasma and CSF. Blood samples were collected from 26 healthy male volunteers at 8 a.m., noon, 4 p.m. and 8 p.m. At 8 a.m. the following morning, blood was drawn and three 6-ml fractions of CSF were collected by lumbar puncture. In CSF, a disrupted gradient was found showing the highest glutathione concentration in the second compared to the first and third fraction (P andlt; 0.002). Moreover, correlation and regression analyses between glutathione in plasma and CSF revealed an association between the third fraction CSF and plasma glutathione 8 p.m. the day before lumbar puncture. Thus, if carefully standardised due to the disrupted gradient in CSF, it might be possible to estimate glutathione levels in CSF by analysing plasma in healthy males.

    Place, publisher, year, edition, pages
    Elsevier, 2011
    Keywords
    Glutathione, Plasma, Blood, Cerebrospinal fluid, Lumbar puncture
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-71560 (URN)10.1016/j.npep.2011.05.004 (DOI)000295349600005 ()
    Note
    Funding Agencies|Ostergotland County Council||Available from: 2011-10-21 Created: 2011-10-21 Last updated: 2017-12-08
    3. Taurine and glutathione levels in plasma before and after ECT treatment
    Open this publication in new window or tab >>Taurine and glutathione levels in plasma before and after ECT treatment
    2012 (English)In: Psychiatry Research, ISSN 0165-1781, E-ISSN 1872-7123, Vol. 198, no 1, p. 53-57Article in journal (Refereed) Published
    Abstract [en]

    Taurine has been shown to be elevated in plasma and lymphocytes of depressed patients, but the level normalises after successful drug therapy. During depression, levels of glutathione (GSH) are decreased in the plasma and blood. This study was performed to examine taurine and GSH levels in depressed patients before and after electroconvulsive therapy (ECT). Fasting blood samples were collected from 23 patients before the first and after the third ECT treatment. The severity of depression was estimated with the Montgomery–Åsberg Depression Rating Scale (MADRS). We analysed GSH in blood and the levels of taurine and total GSH in plasma. After three ECTs, a significant decrease in MADRS scores was found for the entire group. Simultaneously, the decrease in the plasma taurine levels was significant for the seven responders but not for the sixteen non-responders. We observed no differences in blood or plasma GSH levels after three ECT treatments when compared to values before the therapy. Plasma taurine levels decrease significantly after three ECT treatments in patients who respond to treatment. GSH levels were not affected by ECT treatment. The results indicate that taurine may play a role in the pathophysiology of depression.

    Place, publisher, year, edition, pages
    Elsevier Science B.V., Amsterdam., 2012
    Keywords
    ECT; Taurine; Glutathione; Depression
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-84600 (URN)10.1016/j.psychres.2012.02.016 (DOI)000313848200010 ()
    Available from: 2012-10-15 Created: 2012-10-15 Last updated: 2017-12-07Bibliographically approved
    4. Taurine and glutathione in plasma and cerebrospinal fluid in olanzapine treated patients with schizophrenia
    Open this publication in new window or tab >>Taurine and glutathione in plasma and cerebrospinal fluid in olanzapine treated patients with schizophrenia
    Show others...
    2013 (English)In: Psychiatry Research, ISSN 0165-1781, E-ISSN 1872-7123, Vol. 210, no 3, p. 819-824Article in journal (Refereed) Published
    Abstract [en]

    Objectives: Oxidative stress has been implicated in the pathophysiology of schizophrenia. Taurine and glutathione (GSH) have antioxidant and central nervous system protective properties and are proposed to be involved in the pathology of schizophrenia. The aim of this study was to compare the blood and cerebrospinal fluid (CSF) levels of taurine and GSH in patients with schizophrenia medicated with oral olanzapine compared with controls.

    Methods: In total, 37 patients with schizophrenia being medicated with olanzapine and 45 healthy volunteers were recruited. Taurine and GSH levels were analysed in plasma and CSF and correlated to symptoms and level of function.

    Results: Plasma taurine levels were elevated in patients compared with controls (p=0.000003). No differences were found between patients and controls regarding taurine in CSF or GSH concentrations in plasma and CSF.

    Conclusion: The significantly higher levels of plasma but not CSF taurine in patients with schizophrenia treated with olanzapine compared with controls may implicate the involvement of taurine in the pathophysiology of the disease. The absence of GSH differences in plasma and CSF between patients and controls is interesting in the perspective of earlier research proposing a dysregulation of GSH metabolism as a vulnerability factor for the development of schizophrenia.

    Place, publisher, year, edition, pages
    Elsevier, 2013
    Keywords
    Glutathione; taurine; schizophrenia; cerebrospinal fluid; olanzapine
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-84601 (URN)10.1016/j.psychres.2013.09.014 (DOI)000329417500024 ()
    Available from: 2012-10-15 Created: 2012-10-15 Last updated: 2017-12-07Bibliographically approved
  • 13.
    Samuelsson, Martin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Psychiatry . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Dahl, M-L
    Uppsala University Hospital.
    Gupta, Ramesh
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Nordin, Conny
    Linköping University, Department of Clinical and Experimental Medicine, Psychiatry . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Taurine in plasma and CSF: a study in healthy male volunteers2009In: Amino Acids, ISSN 0939-4451, E-ISSN 1438-2199, Vol. 36, no 3, p. 529-533Article in journal (Refereed)
    Abstract [en]

    In order to explore the interrelationship between plasma and cerebrospinal fluid taurine concentrations, three consecutive 6-ml fractions of cerebrospinal fluid were drawn from 30 healthy male volunteers in the early morning after 8 h in the fasting condition. Repeated plasma samples were drawn over 24 h the day before lumbar puncture. Taurine in plasma and cerebrospinal fluid was determined by high performance liquid chromatography. The subjects were categorized as extensive or poor metabolizers with respect to the cytochrome P450 2D6 genotype. The taurine cerebrospinal fluid/plasma ratio at 8 a.m. was negatively influenced by the plasma taurine concentration at 4 p.m. the previous day. It was also negatively influenced by body mass index and positively by the intraspinal pressure. Three poor metabolizers of cytochrome P450 2D6 had higher plasma taurine areas under the curve than 27 extensive metabolizers. Hypothetically, cytochrome P450 2D6 influences the transport of taurine across the blood-brain barrier.

  • 14.
    Samuelsson, Martin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Psychiatry . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Gerdin, G.
    Linköping University, Department of Clinical and Experimental Medicine, Psychiatry . Linköping University, Faculty of Health Sciences.
    Vrethem, Magnus
    Linköping University, Department of Clinical and Experimental Medicine, Neurology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Neurology.
    Taurine levels in plasma before and after three ECT treatments in EUROPEAN NEUROPSYCHOPHARMACOLOGY, vol 20, issue , pp S426-S4262010In: EUROPEAN NEUROPSYCHOPHARMACOLOGY, Elsevier Science B.V., Amsterdam. , 2010, Vol. 20, p. S426-S426Conference paper (Refereed)
    Abstract [en]

    n/a

  • 15.
    Samuelsson, Martin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Psychiatry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Gerdin, George
    Linköping University, Department of Clinical and Experimental Medicine, Psychiatry. Linköping University, Faculty of Health Sciences.
    Öllinger, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Vrethem, Magnus
    Linköping University, Department of Clinical and Experimental Medicine, Neurology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Neurology.
    Taurine and glutathione levels in plasma before and after ECT treatment2012In: Psychiatry Research, ISSN 0165-1781, E-ISSN 1872-7123, Vol. 198, no 1, p. 53-57Article in journal (Refereed)
    Abstract [en]

    Taurine has been shown to be elevated in plasma and lymphocytes of depressed patients, but the level normalises after successful drug therapy. During depression, levels of glutathione (GSH) are decreased in the plasma and blood. This study was performed to examine taurine and GSH levels in depressed patients before and after electroconvulsive therapy (ECT). Fasting blood samples were collected from 23 patients before the first and after the third ECT treatment. The severity of depression was estimated with the Montgomery–Åsberg Depression Rating Scale (MADRS). We analysed GSH in blood and the levels of taurine and total GSH in plasma. After three ECTs, a significant decrease in MADRS scores was found for the entire group. Simultaneously, the decrease in the plasma taurine levels was significant for the seven responders but not for the sixteen non-responders. We observed no differences in blood or plasma GSH levels after three ECT treatments when compared to values before the therapy. Plasma taurine levels decrease significantly after three ECT treatments in patients who respond to treatment. GSH levels were not affected by ECT treatment. The results indicate that taurine may play a role in the pathophysiology of depression.

  • 16.
    Samuelsson, Martin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Psychiatry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Skogh, Elisabeth
    Linköping University, Department of Clinical and Experimental Medicine, Psychiatry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Lundberg, Kristina
    Linköping University, Department of Clinical and Experimental Medicine, Psychiatry. Linköping University, Faculty of Health Sciences.
    Vrethem, Magnus
    Linköping University, Department of Clinical and Experimental Medicine, Neurology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Neurology.
    Öllinger, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Taurine and glutathione in plasma and cerebrospinal fluid in olanzapine treated patients with schizophrenia2013In: Psychiatry Research, ISSN 0165-1781, E-ISSN 1872-7123, Vol. 210, no 3, p. 819-824Article in journal (Refereed)
    Abstract [en]

    Objectives: Oxidative stress has been implicated in the pathophysiology of schizophrenia. Taurine and glutathione (GSH) have antioxidant and central nervous system protective properties and are proposed to be involved in the pathology of schizophrenia. The aim of this study was to compare the blood and cerebrospinal fluid (CSF) levels of taurine and GSH in patients with schizophrenia medicated with oral olanzapine compared with controls.

    Methods: In total, 37 patients with schizophrenia being medicated with olanzapine and 45 healthy volunteers were recruited. Taurine and GSH levels were analysed in plasma and CSF and correlated to symptoms and level of function.

    Results: Plasma taurine levels were elevated in patients compared with controls (p=0.000003). No differences were found between patients and controls regarding taurine in CSF or GSH concentrations in plasma and CSF.

    Conclusion: The significantly higher levels of plasma but not CSF taurine in patients with schizophrenia treated with olanzapine compared with controls may implicate the involvement of taurine in the pathophysiology of the disease. The absence of GSH differences in plasma and CSF between patients and controls is interesting in the perspective of earlier research proposing a dysregulation of GSH metabolism as a vulnerability factor for the development of schizophrenia.

  • 17.
    Samuelsson, Martin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Psychiatry. Linköping University, Faculty of Health Sciences.
    Vainikka, Linda
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Nordin, Conny
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Öllinger, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Glutathione In Blood And Cerebrospinal Fluid2008Conference paper (Refereed)
  • 18.
    Samuelsson, Martin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Psychiatry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Vainikka, Linda
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Öllinger, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Glutathione in the blood and cerebrospinal fluid: A study in healthy male volunteers2011In: Neuropeptides, ISSN 0143-4179, E-ISSN 1532-2785, Vol. 45, no 4, p. 287-292Article in journal (Refereed)
    Abstract [en]

    Glutathione (GSH) is an important regulator of intracellular redox homeostasis. In the brain, glutathione is considered a major antioxidant, which is also found at high concentrations in the extracellular environment. Altered GSH balance in plasma, blood and cerebrospinal fluid (CSF) has been observed in several disorders suggesting that an impaired antioxidant function is part of the pathophysiology. The aim of the present study was to investigate a possible relationship between glutathione in plasma and CSF. Blood samples were collected from 26 healthy male volunteers at 8 a.m., noon, 4 p.m. and 8 p.m. At 8 a.m. the following morning, blood was drawn and three 6-ml fractions of CSF were collected by lumbar puncture. In CSF, a disrupted gradient was found showing the highest glutathione concentration in the second compared to the first and third fraction (P andlt; 0.002). Moreover, correlation and regression analyses between glutathione in plasma and CSF revealed an association between the third fraction CSF and plasma glutathione 8 p.m. the day before lumbar puncture. Thus, if carefully standardised due to the disrupted gradient in CSF, it might be possible to estimate glutathione levels in CSF by analysing plasma in healthy males.

  • 19.
    Schwieler, Lilly
    et al.
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Markus K
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Skogh, Elisabeth
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Kegel, Magdalena E
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Orhan, Funda
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Abdelmoaty, Sally
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Finn, Anja
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Bhat, Maria
    AstraZeneca, Research & Development, Innovative Medicines, Personalised Healthcare & Biomarkers, Science for Life Laboratory, Solna, Sweden / Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Samuelsson, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Lundberg, Kristina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Dahl, Marja-Liisa
    Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Sellgren, Carl
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Schuppe-Koistinen, Ina
    AstraZeneca, Research & Development, Innovative Medicines, Personalised Healthcare & Biomarkers, Science for Life Laboratory, Solna, Sweden / Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Svensson, Camilla
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Erhardt, Sophie
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Engberg, Göran
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Increased levels of IL-6 in the cerebrospinal fluid of patients with chronic schizophrenia - significance for activation of the kynurenine pathway.2015In: Journal of Psychiatry & Neuroscience, ISSN 1180-4882, E-ISSN 1488-2434, Vol. 40, no 2, p. 126-13Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Accumulating evidence indicates that schizophrenia is associated with brain immune activation. While a number of reports suggest increased cytokine levels in patients with schizophrenia, many of these studies have been limited by their focus on peripheral cytokines or confounded by various antipsychotic treatments. Here, well-characterized patients with schizophrenia, all receiving olanzapine treatment, and healthy volunteers were analyzed with regard to cerebrospinal fluid (CSF) levels of cytokines. We correlated the CSF cytokine levels to previously analyzed metabolites of the kynurenine (KYN) pathway.

    METHODS: We analyzed the CSF from patients and controls using electrochemiluminescence detection with regard to cytokines. Cell culture media from human cortical astrocytes were analyzed for KYN and kynurenic acid (KYNA) using high-pressure liquid chromatography or liquid chromatography/mass spectrometry.

    RESULTS: We included 23 patients and 37 controls in our study. Patients with schizophrenia had increased CSF levels of interleukin (IL)-6 compared with healthy volunteers. In patients, we also observed a positive correlation between IL-6 and the tryptophan:KYNA ratio, indicating that IL-6 activates the KYN pathway. In line with this, application of IL-6 to cultured human astrocytes increased cell medium concentration of KYNA.

    LIMITATIONS: The CSF samples had been frozen and thawed twice before analysis of cytokines. Median age differed between patients and controls. When appropriate, all present analyses were adjusted for age.

    CONCLUSION: We have shown that IL-6, KYN and KYNA are elevated in patients with chronic schizophrenia, strengthening the idea of brain immune activation in patients with this disease. Our concurrent cell culture and clinical findings suggest that IL-6 induces the KYN pathway, leading to increased production of the N-methyl-D-aspartate receptor antagonist KYNA in patients with schizophrenia.

  • 20.
    Schwieler, Lilly
    et al.
    Karolinska Institute, Sweden.
    Samuelsson, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Institute, Sweden.
    Frye, Mark A.
    Mayo Clin, MN USA.
    Bhat, Maria
    AstraZeneca, Sweden; Karolinska Institute, Sweden.
    Schuppe-Koistinen, Ina
    Karolinska Institute, Sweden; Karolinska Institute, Sweden.
    Jungholm, Oscar
    Karolinska Institute, Sweden.
    Johansson, Anette G.
    Karolinska Institute, Sweden.
    Landen, Mikael
    Gothenburg University, Sweden; Karolinska Institute, Sweden.
    Sellgren, Carl M.
    Karolinska Institute, Sweden; Broad Institute MIT and Harvard, MA USA; Harvard University, MA 02115 USA.
    Erhardt, Sophie
    Karolinska Institute, Sweden.
    Electroconvulsive therapy suppresses the neurotoxic branch of the kynurenine pathway in treatment-resistant depressed patients2016In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 13, no 51Article in journal (Refereed)
    Abstract [en]

    Background: Neuroinflammation is increasingly recognized as contributing to the pathogenesis of depression. Key inflammatory markers as well as kynurenic acid (KYNA) and quinolinic acid (QUIN), both tryptophan metabolites, have been associated with depressive symptoms and suicidality. The aim of the present study is to investigate the peripheral concentration of cytokines and tryptophan and kynurenine metabolites in patients with unipolar treatment-resistant depression before and after electroconvulsive therapy (ECT), the most effective treatment for depression. Methods: Cytokines in plasma from patients with major depressive disorder (MDD; n = 19) and healthy volunteers (n = 14) were analyzed with electrochemiluminescence detection. Tryptophan and kynurenine metabolites were detected with high-performance liquid chromatography (HPLC) and LC/MS. KYNA was analyzed in a second healthy control cohort (n = 22). Results: Patients with MDD had increased plasma levels of interleukin (IL)-6 compared to healthy volunteers (P < 0.05). We also found an altered kynurenine metabolism in these patients displayed by decreased plasma levels of KYNA (P < 0.0001) as well as a significantly increased QUIN/KYNA ratio (P < 0.001). Plasma levels of tryptophan, kynurenine, and QUIN did not differ between patients and controls. Treatment with ECT was associated with a significant decrease in the plasma levels of tryptophan (P < 0.05), kynurenine (P < 0.01), and QUIN (P < 0.001), whereas plasma levels of KYNA did not change. The QUIN/KYNA ratio was found to significantly decrease in ECT-treated patients (P < 0.05). There was a significant inverse correlation between symptom severity and kynurenine levels at baseline (r = -0.67, P = 0.002). Conclusions: This study confirms an imbalanced kynurenine pathway in MDD supporting the hypothesis of a netstimulation of N-methyl-D-aspartic acid (NMDA) receptors in the disorder. Treatment with ECT profoundly decreased QUIN, an NMDA-receptor agonist previously suggested to be implicated in the pathogenesis of depression, an effect that might have bearing for the good clinical outcome of ECT.

  • 21.
    Soderlund, J
    et al.
    Karolinska Institute.
    Schroeder, J
    University of Heidelberg.
    Nordin, C
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Samuelsson, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Psychiatry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Walther-Jallow, L
    Karolinska University.
    Karlsson, H
    Karolinska Institute.
    Erhardt, S
    Karolinska Institute.
    Engberg, G
    Karolinska Institute.
    Letter: Activation of brain interleukin-1 beta in schizophrenia2009In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 14, no 12, p. 1069-1071Article in journal (Other academic)
    Abstract [en]

    n/a

  • 22.
    Soderlund, Johan
    et al.
    Karolinska Institute.
    Olsson, Sara K
    Karolinska Institute.
    Samuelsson, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Psychiatry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Walther-Jallow, Lilian
    Karolinska Institute.
    Johansson, Christian
    Karolinska Institute.
    Landen, Mikael
    Karolinska Institute.
    Engberg, Goran
    Karolinska Institute.
    Elevation of cerebrospinal fluid interleukin-1 beta in bipolar disorder2011In: JOURNAL OF PSYCHIATRY and NEUROSCIENCE, ISSN 1180-4882, Vol. 36, no 2, p. 114-118Article in journal (Refereed)
    Abstract [en]

    Background: In recent years, a role for the immune system in the pathogenesis of psychiatric diseases has gained increased attention. Although bipolar disorder appears to be associated with altered serum cytokine levels, a putative immunological contribution to its pathophysiology remains to be established. Hitherto, no direct analyses of cerebrospinal fluid (CSF) cytokines in patients with bipolar disorder have been performed. Methods: We analyzed CSF cytokine concentrations in euthymic patients with diagnosed bipolar disorder type I (n = 15) or type II (n = 15) and healthy volunteers (n = 30) using an immunoassay-based protein array multiplex system. Results: The mean interleukin (IL)-1 beta level (4.2 pg/mL, standard error of the mean [SEMI 0.5) was higher and the IL-6 level (1.5 pg/mL, SEM 0.2) was lower in euthymic bipolar patients than in healthy volunteers (0.8 pg/mL, SEM 0.04, and 2.6 pg/mL, SEM 0.2, respectively). Patients with 1 or more manic/hypomanic episodes during the last year showed significantly higher levels of IL-1 beta (6.2 pg/mL, SEM 0.8; n = 9) than patients without a recent manic/hypomanic episode (3.1 pg/mL, SEM 1.0; n = 10). Limitations: All patients were in an euthymic state at the time of sampling. Owing to the large variety of drugs prescribed to patients in the present study, influence of medication on the cytokine profile cannot be ruled out. Conclusion: Our findings show an altered brain cytokine profile associated with the manifestation of recent manic/hypomanic episodes in patients with bipolar disorder. Although the causality remains to be established, these findings may suggest a pathophysiological role for IL-1 beta in bipolar disorder.

  • 23.
    Ventorp, F.
    et al.
    Lund University, Sweden; Michigan State University, MI USA.
    Barzilay, R.
    Tel Aviv University, Israel; Geha Mental Health Centre, Israel.
    Erhardt, S.
    Karolinska Institute, Sweden.
    Samuelsson, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry. Linköping University, Faculty of Medicine and Health Sciences.
    Traskman-Bendz, L.
    Lund University, Sweden.
    Janelidze, S.
    Lund University, Sweden.
    Weizman, A.
    Geha Mental Health Centre, Israel; Tel Aviv University, Israel.
    Offen, D.
    Tel Aviv University, Israel.
    Brundin, L.
    Lund University, Sweden; Michigan State University, MI USA; Van Andel Research Institute, MI USA.
    The CD44 ligand hyaluronic acid is elevated in the cerebrospinal fluid of suicide attempters and is associated with increased blood-brain barrier permeability2016In: Journal of Affective Disorders, ISSN 0165-0327, E-ISSN 1573-2517, Vol. 193, p. 349-354Article in journal (Refereed)
    Abstract [en]

    Background: The glycosaminoglycan hyaluronic acid (HA) is an important component of the extracellular matrix (ECM) in the brain. CD44 is a cell adhesion molecule that binds to HA in the ECM and is present on astrocytes, microglia and certain neurons. Cell adhesion molecules have been reported to be involved in anxiety and mood disorders. CD44 levels are decreased in the cerebrospinal fluid (CSF) of depressed individuals, and the CD44 gene has been identified in brain GWAS studies as a possible risk gene for suicidal behavior. Method: We measured the CSF levels of HA and the soluble CD44 (sCD44) in suicide attempters (n=94) and in healthy controls (n=45) using ELISA and electrochemiluminescence assays. We also investigated other proteins known to interact with CD44, such as osteopontin and the matrix metalloproteinases MMP1, MMP3 and MMP9. Results: The suicide attempters had higher CSF levels of HA (p=.003) and MMP9 (p=.004). The CSF levels of HA correlated with BBB-permeability (rho=0.410, p<.001) and MMP9 correlated with sCD44 levels (rho=0.260, p=.005). Limitations: Other relevant biological contributors to suicidal behavior is not addressed in parallel to the specific role of CD44-HA signaling. The gender distribution of the patients from whom CSF was analyzed was uneven. Conclusions: Increased BBB-permeability and HA levels might be a results of increased neuroinflammation and can play a role in the pathobiology of suicidal behavior. The CD44 signaling pathway might be considered a novel target for intervention in mood disorders. (C) 2016 Elsevier B.V. All rights reserved.

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