Depression is a debilitating condition with a profound impact on quality of life for millions of people worldwide. Physical exercise is used as a treatment strategy for many patients, but the mechanisms that underlie its beneficial effects remain unknown. Here, we describe a mechanism by which skeletal muscle PGC-1α1 induced by exercise training changes kynurenine metabolism and protects from stress-induced depression. Activation of the PGC-1α1-PPARα/δ pathway increases skeletal muscle expression of kynurenine aminotransferases, thus enhancing the conversion of kynurenine into kynurenic acid, a metabolite unable to cross the blood-brain barrier. Reducing plasma kynurenine protects the brain from stress-induced changes associated with depression and renders skeletal muscle-specific PGC-1α1 transgenic mice resistant to depression induced by chronic mild stress or direct kynurenine administration. This study opens therapeutic avenues for the treatment of depression by targeting the PGC-1α1-PPAR axis in skeletal muscle, without the need to cross the blood-brain barrier.

No 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.

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.

No abstract

No abstract

No abstract

Background: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. Methods: We analyzed CSF cytokine concentrations in euthymic patients with diagnosed bipolar dis order 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)-1β 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, respect ively). Patients with 1 or more manic/hypomanic episodes during the last year showed significantly higher levels of IL-1β (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). Limitations: 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-1β in bipolar disorder. In recent years, a role of the immune system in the pathogenesis of psychiatric diseases has gained increased attention. In this regard, many investigators have focused on cytokines, proteins that directly initiate and control immunological responses. We recently demonstrated a selective activation of brain interleukin (IL)-1β in schizophrenia, 2 a disease that appears similar to bipolar disorder with regard to symptomatology, treatment and risk genes. 3,4 Interestingly, a polymorphism in the promoter region of the IL1B gene has been suggested to comprise a shared genetic susceptibility for bipolar disorder and schizophrenia. 5 Indeed, bipolar disorder appears to be linked to inflammation, as indicated by genetic polymorphisms, gene expression and cytokine activation, 6 although direct evidence for a pathophysiological involvement of the immune system of the brain is still sparse. This may be 115 related to the fact that evaluation of cytokine levels in patients with bipolar disorder has been restricted to serum analyses. The bidirectional communication between the immune system of the brain and that of peripheral organs is complex, 7 and serum cytokines do not predict brain cytokine activation in healthy volunteers. 8 Hence, the immune system of the brain, including local cytokine release from microglia and astrocytes, may be independent of the immune sys...