Connecting inflammation with glutamate agonism in suicidality

Sophie Erhardt, Chai K Lim, Klas R Linderholm, Shorena Janelidze, Daniel Lindqvist, Martin Samuelsson, Kristina Lundberg, Teodor T Postolache, Lil Träskman-Bendz, Gilles J Guillemin, Lena Brundin, Sophie Erhardt, Chai K Lim, Klas R Linderholm, Shorena Janelidze, Daniel Lindqvist, Martin Samuelsson, Kristina Lundberg, Teodor T Postolache, Lil Träskman-Bendz, Gilles J Guillemin, Lena Brundin

Abstract

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.

Figures

Figure 1
Figure 1
Simplified diagram of the kynurenine pathway.
Figure 2
Figure 2
Quinolinic acid and kynurenic acid in cerebrospinal fluid of suicide attempters and healthy controls. (a) Cerebrospinal fluid quinolinic acid. (b) Cerebrospinal fluid kynurenic acid. (c) The quinolinic acid/kynurenic acid quotient. (d) Cerebrospinal fluid quinolinic acid in violent and nonviolent suicide attempters. (e) Cerebrospinal fluid quinolinic acid in suicide attempters with primary mood disorder (Major Depressive Disorder and Depression NOS), with other diagnoses and in controls. (f) Cerebrospinal fluid quinolinic acid in suicide attempters in the follow-up study. The lines connect measures of cerebrospinal fluid quinolinic acid from the same patients, between the suicide attempt and at 6 months after the attempt. The mean values+s.e.m. are shown for patients and controls, respectively, in figures (a–e) *P⩽0.05; **P⩽0.01; ***P⩽0.001.
Figure 3
Figure 3
Associations of quinolinic acid with IL-6, age, sample storage time and suicidality; and kynurenic acid with age. Associations between ln-quinolinic acid and (a) ln-IL-6 (n=87, Pearson's R=0.23, P=0.033), data from patients and controls; (b) age (n=100, Pearson's R=0.21, P<0.0038) data from patients and controls; (d) sample storage time (linear regression model, β=−0.41, P=0.075); (e) total scores on the Suicide Intent Scale (SIS) (n=53, Spearman ρ=0.30, P=0.028), data from patients only; and (f) scores on the subscale on the SIS rating objective circumstances of the suicide attempt (n=53, Spearman ρ=0.34, P=0.012), data from patients only. (c) Association between kynurenic acid and age (n=97, Pearson's R=0.043, P=0.68).

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