The kynurenine pathway in major depressive disorder, bipolar disorder, and schizophrenia: a meta-analysis of 101 studies.

Melissa Lane, Brisa S Fernandes, Jair C Soares, João Quevedo, André F Carvalho, Brendon Stubbs, Felice Jacka, Gerard Clarke, Ping-Tao Tseng, Alexandre P Diaz, Marsal Sanches, Michael Berk, Susana Gomes-da-Costa, Adam J Walker, Jasmine Cleminson, Anu Ruusunen, Tetyana Rocks, Wolfgang Marx, Amelia J McGuinness, Pao-Yen Lin, Adrienne O'Neil

Journal: Molecular psychiatry 2022;26(8):4158-4178

PMID: 33230205

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Abstract

The importance of tryptophan as a precursor for neuroactive compounds has long been acknowledged. The metabolism of tryptophan along the kynurenine pathway and its involvement in mental disorders is an emerging area in psychiatry. We performed a meta-analysis to examine the differences in kynurenine metabolites in major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ). Electronic databases were searched for studies that assessed metabolites involved in the kynurenine pathway (tryptophan, kynurenine, kynurenic acid, quinolinic acid, 3-hydroxykynurenine, and their associate ratios) in people with MDD, SZ, or BD, compared to controls. We computed the difference in metabolite concentrations between people with MDD, BD, or SZ, and controls, presented as Hedges' g with 95% confidence intervals. A total of 101 studies with 10,912 participants were included. Tryptophan and kynurenine are decreased across MDD, BD, and SZ; kynurenic acid and the kynurenic acid to quinolinic acid ratio are decreased in mood disorders (i.e., MDD and BD), whereas kynurenic acid is not altered in SZ; kynurenic acid to 3-hydroxykynurenine ratio is decreased in MDD but not SZ. Kynurenic acid to kynurenine ratio is decreased in MDD and SZ, and the kynurenine to tryptophan ratio is increased in MDD and SZ. Our results suggest that there is a shift in the tryptophan metabolism from serotonin to the kynurenine pathway, across these psychiatric disorders. In addition, a differential pattern exists between mood disorders and SZ, with a preferential metabolism of kynurenine to the potentially neurotoxic quinolinic acid instead of the neuroprotective kynurenic acid in mood disorders but not in SZ.

Address: Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia. [email protected].; Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia.; Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.; Department of Psychiatry, Kuopio University Hospital, Kuopio, Finland.; Bipolar and Depression Disorders Unit, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain.; Center of Excellence on Mood Disorders, Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA.; Translational Psychiatry Program, Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA.; Institute of Biomedical Sciences and Prospect Clinic for Otorhinolaryngology & Neurology, National Sun Yat-sen University, Kaohsiung, Taiwan.; Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.; Institute for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.; Department of Psychiatry and Neurobehavioural Science and APC Microbiome Ireland, University College Cork, Cork, Ireland.; Department of Psychological Medicine, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, UK.; South London and Maudsley NHS Foundation Trust, London, UK.; Department of Psychiatry, University of Toronto, Toronto, ON, Canada.; Centre for Addiction and Mental Health, Toronto, ON, Canada.; Center of Excellence on Mood Disorders, Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA. [email protected].; Translational Psychiatry Program, Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA. [email protected].

DOI: 10.1038/s41380-020-00951-9

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MeSH Terms: Bipolar Disorder, Depressive Disorder, Major, Humans, Kynurenic Acid, Kynurenine, Schizophrenia