Elevated Levels of Kynurenic Acid in the Cerebrospinal Fluid of Patients with Bipolar Disorder

Overview

Journal J Psychiatry Neurosci

Specialty Psychiatry

Date 2010 Apr 28

PMID 20420770

Citations 53

Authors

Sara K Olsson

Martin Samuelsson

Peter Saetre

Leif Lindstrom

Erik G Jonsson

Conny Nordin

Goran Engberg

Sophie Erhardt

Mikael Landen

Affiliations

Soon will be listed here.

Abstract

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 function. We measured the levels of KYNA in the cerebrospinal fluid (CSF) 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] 0.13 v. 1.13 nM, SEM 0.09; p = 0.002. The levels of KYNA were positively correlated with age among bipolar patients but not healthy volunteers.

Limitations: The influence of ongoing drug treatment among patients cannot be ruled out. We conducted our study during the euthymic phase of the disease.

Conclusion: Brain KYNA levels are increased in euthymic men with bipolar disorder. In addition, KYNA levels increased with age in these patients. 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 disorder.

Citing Articles

Neuroactive Kynurenines as Pharmacological Targets: New Experimental Tools and Exciting Therapeutic Opportunities.

Pocivavsek A, Schwarcz R, Erhardt S Pharmacol Rev. 2024; 76(6):978-1008.

PMID: 39304346 PMC: 11549936. DOI: 10.1124/pharmrev.124.000239.

The steroid hormone ADIOL promotes learning by reducing neural kynurenic acid levels.

Lemieux G, Yoo S, Lin L, Vohra M, Ashrafi K Genes Dev. 2023; 37(21-24):998-1016.

PMID: 38092521 PMC: 10760639. DOI: 10.1101/gad.350745.123.

Kynurenine pathway abnormalities are state-specific but not diagnosis-specific in schizophrenia and bipolar disorder.

Skorobogatov K, Autier V, Foiselle M, Richard J, Boukouaci W, Wu C Brain Behav Immun Health. 2023; 27:100584.

PMID: 36685639 PMC: 9852293. DOI: 10.1016/j.bbih.2022.100584.

The tryptophan catabolite or kynurenine pathway in major depressive and bipolar disorder: A systematic review and meta-analysis.

Almulla A, Thipakorn Y, Vasupanrajit A, Algon A, Tunvirachaisakul C, Hashim Aljanabi A Brain Behav Immun Health. 2022; 26:100537.

PMID: 36339964 PMC: 9630622. DOI: 10.1016/j.bbih.2022.100537.

Is Poor Lithium Response in Individuals with Bipolar Disorder Associated with Increased Degradation of Tryptophan along the Kynurenine Pathway? Results of an Exploratory Study.

Fellendorf F, Manchia M, Squassina A, Pisanu C, DallAcqua S, Sut S J Clin Med. 2022; 11(9).

PMID: 35566641 PMC: 9103936. DOI: 10.3390/jcm11092517.

References

Erhardt S, Olsson S, Engberg G . Pharmacological manipulation of kynurenic acid: potential in the treatment of psychiatric disorders. CNS Drugs. 2009; 23(2):91-101. DOI: 10.2165/00023210-200923020-00001. View

Ceresoli-Borroni G, Rassoulpour A, Wu H, Guidetti P, Schwarcz R . Chronic neuroleptic treatment reduces endogenous kynurenic acid levels in rat brain. J Neural Transm (Vienna). 2006; 113(10):1355-65. DOI: 10.1007/s00702-005-0432-z. View

Erhardt S, Blennow K, Nordin C, Skogh E, Lindstrom L, Engberg G . Kynurenic acid levels are elevated in the cerebrospinal fluid of patients with schizophrenia. Neurosci Lett. 2001; 313(1-2):96-8. DOI: 10.1016/s0304-3940(01)02242-x. View

Bearden C, Hoffman K, Cannon T . The neuropsychology and neuroanatomy of bipolar affective disorder: a critical review. Bipolar Disord. 2001; 3(3):106-50; discussion 151-3. DOI: 10.1034/j.1399-5618.2001.030302.x. View

Parsons C, Danysz W, Quack G, Hartmann S, Lorenz B, Wollenburg C . Novel systemically active antagonists of the glycine site of the N-methyl-D-aspartate receptor: electrophysiological, biochemical and behavioral characterization. J Pharmacol Exp Ther. 1998; 283(3):1264-75. View

Perry W, Minassian A, Feifel D, Braff D . Sensorimotor gating deficits in bipolar disorder patients with acute psychotic mania. Biol Psychiatry. 2001; 50(6):418-24. DOI: 10.1016/s0006-3223(01)01184-2. View

Clark L, Iversen S, Goodwin G . Sustained attention deficit in bipolar disorder. Br J Psychiatry. 2002; 180:313-9. DOI: 10.1192/bjp.180.4.313. View

Martinez-Aran A, Vieta E, Reinares M, Colom F, Torrent C, Sanchez-Moreno J . Cognitive function across manic or hypomanic, depressed, and euthymic states in bipolar disorder. Am J Psychiatry. 2004; 161(2):262-70. DOI: 10.1176/appi.ajp.161.2.262. View

Miklowitz D, Johnson S . The psychopathology and treatment of bipolar disorder. Annu Rev Clin Psychol. 2007; 2:199-235. PMC: 2813703. DOI: 10.1146/annurev.clinpsy.2.022305.095332. View

10.

Gramsbergen J, Schmidt W, Turski W, Schwarcz R . Age-related changes in kynurenic acid production in rat brain. Brain Res. 1992; 588(1):1-5. DOI: 10.1016/0006-8993(92)91337-e. View

11.

Birch P, Grossman C, Hayes A . Kynurenic acid antagonises responses to NMDA via an action at the strychnine-insensitive glycine receptor. Eur J Pharmacol. 1988; 154(1):85-7. DOI: 10.1016/0014-2999(88)90367-6. View

12.

Robbins T, Murphy E . Behavioural pharmacology: 40+ years of progress, with a focus on glutamate receptors and cognition. Trends Pharmacol Sci. 2006; 27(3):141-8. PMC: 1867319. DOI: 10.1016/j.tips.2006.01.009. View

13.

Erhardt S, Schwieler L, Emanuelsson C, Geyer M . Endogenous kynurenic acid disrupts prepulse inhibition. Biol Psychiatry. 2004; 56(4):255-60. DOI: 10.1016/j.biopsych.2004.06.006. View

14.

Heyes M, Saito K, Crowley J, Davis L, Demitrack M, Der M . Quinolinic acid and kynurenine pathway metabolism in inflammatory and non-inflammatory neurological disease. Brain. 1992; 115 ( Pt 5):1249-73. DOI: 10.1093/brain/115.5.1249. View

15.

Chess A, Bucci D . Increased concentration of cerebral kynurenic acid alters stimulus processing and conditioned responding. Behav Brain Res. 2006; 170(2):326-32. DOI: 10.1016/j.bbr.2006.03.006. View

16.

Cavanagh J, Van Beck M, Muir W, Blackwood D . Case-control study of neurocognitive function in euthymic patients with bipolar disorder: an association with mania. Br J Psychiatry. 2002; 180:320-6. DOI: 10.1192/bjp.180.4.320. View

17.

Ryden E, Thase M, Straht D, Aberg-Wistedt A, Bejerot S, Landen M . A history of childhood attention-deficit hyperactivity disorder (ADHD) impacts clinical outcome in adult bipolar patients regardless of current ADHD. Acta Psychiatr Scand. 2009; 120(3):239-46. DOI: 10.1111/j.1600-0447.2009.01399.x. View

18.

Nilsson L, Linderholm K, Engberg G, Paulson L, Blennow K, Lindstrom L . Elevated levels of kynurenic acid in the cerebrospinal fluid of male patients with schizophrenia. Schizophr Res. 2005; 80(2-3):315-22. DOI: 10.1016/j.schres.2005.07.013. View

19.

Schwieler L, Linderholm K, Nilsson-Todd L, Erhardt S, Engberg G . Clozapine interacts with the glycine site of the NMDA receptor: electrophysiological studies of dopamine neurons in the rat ventral tegmental area. Life Sci. 2008; 83(5-6):170-5. DOI: 10.1016/j.lfs.2008.05.014. View

20.

Nilsson L, Nordin C, Jonsson E, Engberg G, Linderholm K, Erhardt S . Cerebrospinal fluid kynurenic acid in male and female controls - correlation with monoamine metabolites and influences of confounding factors. J Psychiatr Res. 2006; 41(1-2):144-51. DOI: 10.1016/j.jpsychires.2005.12.001. View