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 (P<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.

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 a7* 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 5 16) was compared with healthy male volunteers (n 5 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.

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Acute elevation of the endogenous NMDA-receptor antagonist kynurenic acid (KYNA) is associated with an increased neuronal activity of rat ventral tegmental area (VTA) dopamine (DA) neurons and disruption in prepulse inhibition (PPI). In the present study, the effects of subchronic exposure to kynurenine and probenecid (20 mg/kg/day and 10 mg/kg/day, respectively for 14 days), aiming at increasing brain KYNA turnover, on rat VTA dopaminergic firing and on PPI were investigated. This treatment increased neuronal firing of VTA DA neurons, changed the response of these neurons to systemically administered nicotine (3-400 microg/kg, i.v.) and tended to disrupt PPI. Present results show that the effect on firing of VTA DA neurons by acutely elevated levels of brain KYNA also persists following subchronic exposure. In addition, no adaptive changes seem to occur with regard to the electrophysiological effects of KYNA on VTA DA neurons following subchronic treatment with kynurenine and probenecid.