Elevated levels of kynurenic acid in the cerebrospinal fluid of patients with bipolar disorder.

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.

[1]  S. Rossell,et al.  Gender differences in prepulse inhibition (PPI) in bipolar disorder: men have reduced PPI, women have increased PPI. , 2009, The international journal of neuropsychopharmacology.

[2]  M. Thase,et al.  A history of childhood attention‐deficit hyperactivity disorder (ADHD) impacts clinical outcome in adult bipolar patients regardless of current ADHD , 2009, Acta psychiatrica Scandinavica.

[3]  K. Larsson,et al.  Elevated levels of kynurenic acid change the dopaminergic response to amphetamine: implications for schizophrenia. , 2009, The international journal of neuropsychopharmacology.

[4]  Tyrone D. Cannon,et al.  Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study , 2009, The Lancet.

[5]  S. Erhardt,et al.  Clozapine interacts with the glycine site of the NMDA receptor: electrophysiological studies of dopamine neurons in the rat ventral tegmental area. , 2008, Life sciences.

[6]  S. Erhardt,et al.  Activation of rat ventral tegmental area dopamine neurons by endogenous kynurenic acid: A pharmacological analysis , 2007, Neuropharmacology.

[7]  M. Bourin,et al.  Dopamine dysregulation syndrome: implications for a dopamine hypothesis of bipolar disorder , 2007, Acta psychiatrica Scandinavica. Supplementum.

[8]  D. Bucci,et al.  Elevations of endogenous kynurenic acid produce spatial working memory deficits. , 2007, Schizophrenia bulletin.

[9]  M. Gisslén,et al.  Acute psychotic symptoms in HIV-1 infected patients are associated with increased levels of kynurenic acid in cerebrospinal fluid , 2007, Brain, Behavior, and Immunity.

[10]  W. Turski,et al.  Enhancement of brain kynurenic acid production by anticonvulsants--novel mechanism of antiepileptic activity? , 2006, European journal of pharmacology.

[11]  D. Bucci,et al.  Increased concentration of cerebral kynurenic acid alters stimulus processing and conditioned responding , 2006, Behavioural Brain Research.

[12]  S. Erhardt,et al.  Subchronic treatment with kynurenine and probenecid: effects on prepulse inhibition and firing of midbrain dopamine neurons , 2006, Journal of Neural Transmission.

[13]  S. Erhardt,et al.  Effects of COX‐1 and COX‐2 inhibitors on the firing of rat midbrain dopaminergic neurons—Possible involvement of endogenous kynurenic acid , 2006, Synapse.

[14]  Sheri L. Johnson,et al.  The psychopathology and treatment of bipolar disorder. , 2006, Annual review of clinical psychology.

[15]  T. Robbins,et al.  Behavioural pharmacology: 40+ years of progress, with a focus on glutamate receptors and cognition , 2006, Trends in pharmacological sciences.

[16]  F. Joseph McClernon,et al.  Nicotinic effects on cognitive function: behavioral characterization, pharmacological specification, and anatomic localization , 2006, Psychopharmacology.

[17]  S. Weis,et al.  Upregulation of the initiating step of the kynurenine pathway in postmortem anterior cingulate cortex from individuals with schizophrenia and bipolar disorder , 2006, Brain Research.

[18]  R. Schwarcz,et al.  Chronic neuroleptic treatment reduces endogenous kynurenic acid levels in rat brain , 2006, Journal of Neural Transmission.

[19]  K. Blennow,et al.  Elevated levels of kynurenic acid in the cerebrospinal fluid of male patients with schizophrenia , 2005, Schizophrenia Research.

[20]  M. Geyer,et al.  Endogenous kynurenic acid disrupts prepulse inhibition , 2004, Biological Psychiatry.

[21]  Eduard Vieta,et al.  Cognitive function across manic or hypomanic, depressed, and euthymic states in bipolar disorder. , 2004, The American journal of psychiatry.

[22]  D. Kupfer,et al.  Rationale, design, and methods of the systematic treatment enhancement program for bipolar disorder (STEP-BD) , 2003, Biological Psychiatry.

[23]  S. Erhardt,et al.  Increased phasic activity of dopaminergic neurones in the rat ventral tegmental area following pharmacologically elevated levels of endogenous kynurenic acid. , 2002, Acta physiologica Scandinavica.

[24]  Luke Clark,et al.  Sustained attention deficit in bipolar disorder. , 2002, The British journal of psychiatry : the journal of mental science.

[25]  D. Blackwood,et al.  Case-control study of neurocognitive function in euthymic patients with bipolar disorder: an association with mania. , 2002, The British journal of psychiatry : the journal of mental science.

[26]  K. Blennow,et al.  Kynurenic acid levels are elevated in the cerebrospinal fluid of patients with schizophrenia , 2001, Neuroscience Letters.

[27]  R. Schwarcz,et al.  Increased cortical kynurenate content in schizophrenia , 2001, Biological Psychiatry.

[28]  R. Schwarcz,et al.  The Brain Metabolite Kynurenic Acid Inhibits α7 Nicotinic Receptor Activity and Increases Non-α7 Nicotinic Receptor Expression: Physiopathological Implications , 2001, The Journal of Neuroscience.

[29]  William Perry,et al.  Sensorimotor gating deficits in bipolar disorder patients with acute psychotic mania , 2001, Biological Psychiatry.

[30]  Tyrone D. Cannon,et al.  The neuropsychology and neuroanatomy of bipolar affective disorder: a critical review. , 2001, Bipolar disorders.

[31]  C. Parsons,et al.  Novel systemically active antagonists of the glycine site of the N-methyl-D-aspartate receptor: electrophysiological, biochemical and behavioral characterization. , 1997, The Journal of pharmacology and experimental therapeutics.

[32]  R. Schwarcz,et al.  Brain‐Specific Modulation of Kynurenic Acid Synthesis in the Rat , 1997, Journal of neurochemistry.

[33]  M. Demitrack,et al.  Quinolinic acid and kynurenine pathway metabolism in inflammatory and non-inflammatory neurological disease. , 1992, Brain : a journal of neurology.

[34]  R. Schwarcz,et al.  Age-related changes in kynurenic acid production in rat brain , 1992, Brain Research.

[35]  M. Beal,et al.  Cerebral synthesis and release of kynurenic acid: an endogenous antagonist of excitatory amino acid receptors , 1990, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[36]  M. Beal,et al.  Measurement of kynurenic acid in mammalian brain extracts and cerebrospinal fluid by high-performance liquid chromatography with fluorometric and coulometric electrode array detection. , 1990, Analytical biochemistry.

[37]  G. Lombardi,et al.  Kynurenic acid is present in the rat brain and its content increases during development and aging processes , 1988, Neuroscience Letters.

[38]  C. Grossman,et al.  Kynurenic acid antagonises responses to NMDA via an action at the strychnine-insensitive glycine receptor. , 1988, European journal of pharmacology.

[39]  S. Erhardt,et al.  Pharmacological Manipulation of Kynurenic Acid , 2009, CNS drugs.

[40]  E. Jönsson,et al.  Cerebrospinal fluid kynurenic acid in male and female controls - correlation with monoamine metabolites and influences of confounding factors. , 2007, Journal of psychiatric research.

[41]  R. Schwarcz,et al.  The brain metabolite kynurenic acid inhibits alpha7 nicotinic receptor activity and increases non-alpha7 nicotinic receptor expression: physiopathological implications. , 2001, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[42]  S. Erhardt,et al.  Pharmacological elevation of endogenous kynurenic acid levels activates nigral dopamine neurons , 2001, Amino Acids.

[43]  L. Altshuler,et al.  Cognitive impairment in euthymic bipolar patients with and without prior alcohol dependence. A preliminary study. , 1998, Archives of general psychiatry.

[44]  M. First,et al.  Structured clinical interview for DSM-IV axis II personality disorders : SCID-II , 1997 .

[45]  M. Geyer,et al.  Startle habituation and sensorimotor gating in schizophrenia and related animal models. , 1987, Schizophrenia bulletin.