Publications (11) View all
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Article: Connecting inflammation with glutamate agonism in suicidality.
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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.Neuropsychopharmacology advance online publication, 9 January 2013; doi:10.1038/npp.2012.248.Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 12/2012; · 6.99 Impact Factor -
Article: Altered chemokine levels in the cerebrospinal fluid and plasma of suicide attempters.
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ABSTRACT: Chemokines constitute a class of small inflammatory proteins that control the chemotaxis of leukocytes. They are also present in the central nervous system (CNS) and contribute to diverse physiological functions, such as the regulation of cell migration, axonal growth and neuronal survival. It is to date not known whether chemokines in the CNS are affected in psychiatric disorders. In this study, chemokine levels were measured in the cerebrospinal fluid (CSF) of 137 psychiatric patients in conjunction to a suicide attempt, and 43 healthy controls. A subgroup of patients (n=42) was followed up with blood samples 12 years after the initial CSF collection, when they did not show suicidal behavior. The follow-up chemokine levels were compared to those of psychiatric patients (n=17) who had never attempted suicide. Ultra-sensitive chemokine multiplex immunoassay was used to quantify eotaxin-1 (CCL11), interferon gamma-induced protein-10 (IP-10, CXCL10), macrophage inflammatory protein-1β (MIP-1β, CCL4), monocyte chemotactic protein-1 (MCP-1, CCL2), MCP-4 (CCL13) and thymus and activation regulated chemokine (TARC, CCL17). Patients were diagnosed using DSM-III-R/DSM-IV, and assessed using the Comprehensive Psychopathological Rating Scale (CPRS), including subscales, and the Suicidal Intent Scale (SIS). CSF eotaxin-1, MIP-1β, MCP-1, MCP-4 and TARC were significantly lower in suicide attempters than in healthy controls. Low chemokine levels were specifically associated with psychotic symptoms and pain. In the samples collected at follow-up, TARC was significantly lower in suicide attempters compared to psychiatric patients who had never attempted suicide. We also found a positive correlation between blood TARC and brain-derived neurotrophic factor (BDNF) levels. Our study thus provides evidence of reduced chemokine levels in suicide attempters, both in the acute suicidal setting, and at long-term, compared to non-attempters. These results warrant future studies on the detailed neurobiological functions of chemokines in psychiatric patients.Psychoneuroendocrinology 10/2012; · 5.81 Impact Factor -
Article: Taurine and glutathione levels in plasma before and after ECT treatment.
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ABSTRACT: Taurine has been shown to be elevated in plasma and lymphocytes of depressed patients, but the level normalises after successful drug therapy. During depression, levels of glutathione (GSH) are decreased in the plasma and blood. This study was performed to examine taurine and GSH levels in depressed patients before and after electroconvulsive therapy (ECT). Fasting blood samples were collected from 23 patients before the first and after the third ECT treatment. The severity of depression was estimated with the Montgomery-Åsberg Depression Rating Scale (MADRS). We analysed GSH in blood and the levels of taurine and total GSH in plasma. After three ECTs, a significant decrease in MADRS scores was found for the entire group. Simultaneously, the decrease in the plasma taurine levels was significant for the seven responders but not for the sixteen non-responders. We observed no differences in blood or plasma GSH levels after three ECT treatments when compared to values before the therapy. Plasma taurine levels decrease significantly after three ECT treatments in patients who respond to treatment. GSH levels were not affected by ECT treatment. The results indicate that taurine may play a role in the pathophysiology of depression.Psychiatry research. 03/2012; 198(1):53-7. -
Article: Elevation of cerebrospinal fluid interleukin-1ß in bipolar disorder.
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ABSTRACT: In recent years, a role for the immune system in the pathogenesis of psychiatric diseases has gained increased attention. Although bipolar disorder appears to be associated with altered serum cytokine levels, a putative immunological contribution to its pathophysiology remains to be established. Hitherto, no direct analyses of cerebrospinal fluid (CSF) cytokines in patients with bipolar disorder have been performed. We analyzed CSF cytokine concentrations in euthymic patients with diagnosed bipolar disorder type I (n = 15) or type II (n = 15) and healthy volunteers (n = 30) using an immunoassay-based protein array multiplex system. Results: The mean interleukin (IL)-1ß level (4.2 pg/mL, standard error of the mean [SEM] 0.5) was higher and the IL-6 level (1.5 pg/mL, SEM 0.2) was lower in euthymic bipolar patients than in healthy volunteers (0.8 pg/mL, SEM 0.04, and 2.6 pg/mL, SEM 0.2, respectively). Patients with 1 or more manic/hypomanic episodes during the last year showed significantly higher levels of IL-1ß (6.2 pg/mL, SEM 0.8; n = 9) than patients without a recent manic/hypomanic episode (3.1 pg/mL, SEM 1.0; n = 10). All patients were in an euthymic state at the time of sampling. Owing to the large variety of drugs prescribed to patients in the present study, influence of medication on the cytokine profile cannot be ruled out. Conclusion: Our findings show an altered brain cytokine profile associated with the manifestation of recent manic/hypomanic episodes in patients with bipolar disorder. Although the causality remains to be established, these findings may suggest a pathophysiological role for IL-1ß in bipolar disorder.Journal of psychiatry & neuroscience: JPN 03/2011; 36(2):114-8. · 5.34 Impact Factor -
Article: Increased levels of kynurenine and kynurenic acid in the CSF of patients with schizophrenia.
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ABSTRACT: 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 α7* nicotinic receptors. 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 = 16) was compared with healthy male volunteers (n = 29). KYN and KYNA concentrations were higher in patients with schizophrenia (60.7 ± 4.37 nM and 2.03 ± 0.23 nM, respectively) compared with healthy volunteers (28.6 ± 1.44 nM and 1.36 ± 0.08 nM, respectively), whereas TRP did not differ between the groups. In all subjects, KYN positively correlated to KYNA. 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.Schizophrenia Bulletin 08/2010; 38(3):426-32. · 8.80 Impact Factor
