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Peripheral and central kynurenine pathway abnormalities in major depression
Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
Karolinska Inst, Sweden.
Karolinska Inst, Sweden.
Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
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2022 (English)In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 101, p. 136-145Article in journal (Refereed) Published
Abstract [en]

Considerable data relate major depressive disorder (MDD) with aberrant immune system functioning. Pro inflammatory cytokines facilitate metabolism of tryptophan along the kynurenine pathway (KP) putatively resulting in reduced neuroprotective and increased neurotoxic KP metabolites in MDD, in addition to modulating metabolic and immune function. This central nervous system hypothesis has, however, only been tested in the periphery. Here, we measured KP-metabolite levels in both plasma and cerebrospinal fluid (CSF) of depressed patients (n = 63/36 respectively) and healthy controls (n = 48/33). Further, we assessed the relation between KP abnormalities and brain-structure volumes, as well as body mass index (BMI), an index of metabolic disturbance associated with atypical depression. Plasma levels of picolinic acid (PIC), the kynurenic/quinolinic acid ratio (KYNA/QUIN), and PIC/QUIN were lower in MDD, but QUIN levels were increased. In the CSF, we found lower PIC in MDD. Confirming previous work, MDD patients had lower hippocampal, and amygdalar volumes. Hippocampal and amygdalar volumes were correlated positively with plasma KYNA/QUIN ratio in MDD patients. BMI was increased in the MDD group relative to the control group. Moreover, BMI was inversely correlated with plasma and CSF PIC and PIC/QUIN, and positively correlated with plasma QUIN levels in MDD. Our results partially confirm previous peripheral KP findings and extend them to the CSF in MDD. We present the novel finding that abnormalities in KP metabolites are related to metabolic disturbances in depression, but the relation between KP metabolites and depression-associated brain atrophy might not be as direct as previously hypothesized.

Place, publisher, year, edition, pages
Academic Press Inc - Elsevier Science , 2022. Vol. 101, p. 136-145
Keywords [en]
Major depressive disorder; Kynurenine pathway; Inflammation; Central nervous system; Brain volumetry; Structural magnetic resonance imaging; Cerebrospinal fluid
National Category
Neurology
Identifiers
URN: urn:nbn:se:liu:diva-183765DOI: 10.1016/j.bbi.2022.01.002ISI: 000761260700005PubMedID: 34999196OAI: oai:DiVA.org:liu-183765DiVA, id: diva2:1646936
Note

Funding Agencies|Johnson & Johnson Innovation; Swedish Medical Research CouncilSwedish Medical Research Council (SMRC)European Commission [2017-00875, 2013-07434, 2019-01138]; ALF Grants, Region Ostergotland; National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01 CA193522, R01 NS073939]; MD Anderson Cancer Support Grant [P30 CA016672]

Available from: 2022-03-24 Created: 2022-03-24 Last updated: 2023-10-13
In thesis
1. Immunological Changes and Brain Function over a Psychotic-Depressive Spectrum
Open this publication in new window or tab >>Immunological Changes and Brain Function over a Psychotic-Depressive Spectrum
2023 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Psychotic and depressive disorders are severe psychiatric disorders that contribute significantly to the global burden of disease. They are distinct disorders with different symptom profiles according to both the Diagnostic and Statistical Manual and the International Classification of Diseases. However, these disorders share commonalities in various aspects, such as high comorbidity, prevalence of subclinical symptoms, and shared genetics. Furthermore, both disorders have been associated with a dysregulated immune system functioning.

In this thesis, we aimed to identify common biological dimensions of both depression and psychosis by first investigating proteins related to immune system activation in depression and psychosis separately, and then identifying biological underpinnings of psychotic-like symptoms in depression.Specifically, we first assessed in major depressive disorder central nervous system levels of metabolites along the kynurenine pathway, a pathway that is regulated by the immune system and implicated in depressive and psychotic disorders (paper I). We found an imbalance between neuroprotective versus neurotoxic metabolites in blood and decreased levels of a neuroprotective metabolite in cerebrospinal fluid of patients with depression.

Next, we assessed patterns of proteins implicated in immune-system function that distinguish first episode psychosis and healthy controls (paper II). Results indicate prominent changes in patients compared to controls, partially replicating previous findings and partially highlighting proteins that have not previously been assessed in psychosis.

Lastly, we investigated psychotic-like symptoms in patients with major depressive disorder, finding a relation to immune system markers (paper III) and changes in connectivity between brain structures that integrate information about the physical body and autobiographic information into a sense of self (paper IV).

In summary, the results from this thesis suggest that both in major depressive disorder and first episode psychosis there might be a dysregulation of the immune system and closely related systems such as the kynurenine pathway. These commonalities could further underlie the prevalence of subclinical psychotic-like symptoms in major depressive disorder. Ultimately, a better understanding of the underlying biological mechanisms of psychiatric disorders and, transdiagnostically, their symptoms will help formulate empiricallyinformed frameworks to guide clinical diagnostic processes and treatments.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2023. p. 87
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1867
National Category
Psychiatry
Identifiers
urn:nbn:se:liu:diva-198464 (URN)10.3384/9789180753098 (DOI)9789180753081 (ISBN)9789180753098 (ISBN)
Public defence
2023-11-24, Berzeliussalen, Building 463, Campus US, Linköping, 09:00 (English)
Opponent
Supervisors
Note

Funding agencies: Drottning Silvias Jubileumsfond, Fonden för Psykisk Hälsa, Swedish Research Council, Region Östergötland (ALF), Medical Research Council of Southeast Sweden (ALF), Horizon 2020, Warren Foundation, Johnson & Johnson Innovation, National Institutes of Health, MD Anderson Cancer Support Grant, The Finnish Society of Sciences, Hjärnfonden, Liv and Hälsa Foundation, Finska Läkarsällskapet, Magnus Ehrnrooth Foundation, Sigrid Jusélius Foundation, Minerva Foundation, European Regional Development Fund, Estonian Research Foundation

Available from: 2023-10-13 Created: 2023-10-13 Last updated: 2023-12-28Bibliographically approved

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Paul, ElisabethBoda, SandraKämpe, RobinAsratian, AnnaHolm, LovisaYngve, AdamHeilig, MarkusHamilton, Paul J.Samuelsson, Martin

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Paul, ElisabethBoda, SandraKämpe, RobinAsratian, AnnaHolm, LovisaYngve, AdamHeilig, MarkusHamilton, Paul J.Samuelsson, Martin
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Center for Social and Affective NeuroscienceFaculty of Medicine and Health SciencesDivision of Cell BiologyPsykiatriska kliniken i LinköpingCenter for Medical Image Science and Visualization (CMIV)
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