Serum levels of excitatory amino acids, serine, glycine, histidine, threonine, taurine, alanine and arginine in treatment‐resistant depression: modulation by treatment with antidepressants and prediction of clinical responsivity

Maes, Michaël; Verkerk, Robert; Vandoolaeghe, Eric; Lin, Aihua; Scharpé, Simon

doi:10.1111/j.1600-0447.1998.tb10004.x

Cited by 157 publications

(99 citation statements)

References 27 publications

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“…Increased activity of the glutamatergic system in the peripheral blood of depressive patients has been repeatedly shown [69,70,71], although this result could not be replicated by all groups [72]. The inconsistency of the findings, however, might be due to methodological problems [73].…”

Section: Inflammation Influences the Metabolism Of Serotonin And Noramentioning

confidence: 91%

Immunology of Major Depression

Müller¹

2014

Neuroimmunomodulation

148

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High levels of several proinflammatory components of the immune system, such as interleukin-6, C-reactive protein, tumor necrosis factor (TNF)-α, or neopterin in patients suffering from major depression (MD) point to the involvement of an inflammatory process in the pathophysiology of MD. The direct and indirect effects of cytokines on neurotransmitter storage and release - mediated by microglia cells and astrocytes - are discussed. The tryptophan/kynurenine metabolism is one of the indirect mechanisms because the enzyme indoleamine 2,3-dioxygenase - a key enzyme of this metabolism in the central nervous system - is driven by pro- and anti-inflammatory cytokines and degrades serotonin. Moreover, neuroactive kynurenines such as kynurenic acid and quinolinic acid act on the glutamatergic neurotransmission as N-methyl-D-aspartate antagonists and agonists, respectively. Alterations of the serotonergic, noradrenergic and glutamatergic neurotransmission have been shown with low-level neuroinflammation and may be involved in symptom generation. Epidemiological and clinical studies show a role for inflammation as a risk factor for MD. A large-scale epidemiological study in MD clearly demonstrates that severe infections and autoimmune disorders are lifetime risk factors for MD. The vulnerability-stress-inflammation model matches with this view as stress may increase proinflammatory cytokines and even contribute to a lasting proinflammatory state. Further support comes from the therapeutic benefit of anti-inflammatory medications such as the cyclo-oxygenase-2 inhibitors, TNF-α antagonists and others, and the anti-inflammatory and immunomodulatory intrinsic effects of antidepressants.

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Section: Inflammation Influences the Metabolism Of Serotonin And Noramentioning

confidence: 91%

Immunology of Major Depression

Müller¹

2014

Neuroimmunomodulation

148

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“…20,21 Several studies showed an increased activity of the glutamatergic system in the peripheral blood of depressive patients, [22][23][24] although this result could not be replicated by all authors. 25 The inconsistency of the findings, however, might be due to medication effects, low statistical power and a lack of appropriate control of diagnosis. 9 Support for increased glutamatergic activity in depression comes from magnetic resonance spectroscopy: elevated glutamate levels were found in the occipital cortex of unmedicated subjects with MD.…”

Section: Glutamate In Depressionmentioning

confidence: 99%

The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression

2007

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Beside the well-known deficiency in serotonergic neurotransmission as pathophysiological correlate of major depression (MD), recent evidence points to a pivotal role of increased glutamate receptor activation as well. However, cause and interaction of these neurotransmitter alterations are not understood. In this review, we present a hypothesis integrating current concepts of neurotransmission and hypothalamus-pituitary-adrenal (HPA) axis dysregulation with findings on immunological alterations and alterations in brain morphology in MD. An immune activation including increased production of proinflammatory cytokines has repeatedly been described in MD. Proinflammatory cytokines such as interleukin-2, interferon-c, or tumor necrosis factor-a activate the tryptophan-and serotonin-degrading enzyme indoleamine 2,3-dioxygenase (IDO). Depressive states during inflammatory somatic disorders are also associated with increased proinflammatory cytokines and increased consumption of tryptophan via activation of IDO. An enhanced consumption of serotonin and its precursor tryptophan through IDO activation could well explain the reduced availability of serotonergic neurotransmission in MD. An increased activation of IDO and its subsequent enzyme kynurenine monooxygenase by proinflammatory cytokines, moreover, leads to an enhanced production of quinolinic acid, a strong agonist of the glutamatergic N-methyl-D-aspartate receptor. In inflammatory states of the central nervous system, IDO is mainly activated in microglial cells, which preferentially metabolize tryptophan to the NMDA receptor agonist quinolinic acid, whereas astrocytes -counteracting this metabolism due to the lack of an enzyme of this metabolism -have been observed to be reduced in MD. Therefore the type 1/type 2 immune response imbalance, associated with an astrocyte/microglia imbalance, leads to serotonergic deficiency and glutamatergic overproduction. Astrocytes are further strongly involved in re-uptake and metabolic conversion of glutamate. The reduced number of astrocytes could contribute to both, a diminished counterregulation of IDO activity in microglia and an altered glutamatergic neurotransmission. Further search for antidepressant agents should take into account anti-inflammatory drugs, for example, cyclooxygenase-2 inhibitors, might exert antidepressant effects by acting on serotonergic deficiency, glutamatergic hyperfunction and antagonizing neurotoxic effects of quinolinic acid. Molecular Psychiatry (2007) 12, 988-1000; doi:10.1038/sj.mp.4002006; published online 24 April 2007 Keywords: major depression; psychoneuroimmunology; IDO; glutamate; immune system; serotonin Glutamate in depressionGlutamatergic neurotransmission is involved in depression and interacts with the serotonergic and noradrenergic systems The common therapeutic mechanism of antidepressant drugs is the enhancement of serotonergic and/or noradrenergic neurotransmission. On the basis of this pharmacological profile of antidepressant drugs, neurochemical research on major depression ...

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“…Specifically, it has been shown that glutamate metabolism differs significantly between depressed patients and controls when assessing glutamate and/ or glutamine levels in plasma or cerebrospinal fluid and when examining platelet intracellular Ca 2+ release in response to glutamate stimulation (66 -70). Furthermore, some of these differences have been resolved by chronic antidepressant treatments (71,72). Magnetic resonance imaging methods have shown reduced glutamate levels in the anterior cingulate cortex (73,74), which were returned to normal levels following successful antidepressant treatments (74,75).…”

Section: Glutamate and Depressionmentioning

confidence: 99%

The Role of Sigma Receptors in Depression

2005

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Abstract. Behavioral models used to test potential antidepressants have shown that ligands that bind to sigma receptors possess "antidepressant-like" properties. The focus of this review is to discuss the literature concerning sigma receptors and their ligands, with respect to their antidepressants properties. In addition to the behavioral data, we discuss electrophysiological and biochemical models demonstrating sigma receptors' ability to modulate important factors in the pathophysiology of depression and / or the mechanisms of action of antidepressants such as the serotonergic neurotransmission in the dorsal raphe nucleus (DRN) and the glutamatergic transmission in the hippocampus. We also discuss the significance of these two systems in the mechanism of action of antidepressants. Sigma ligands have potential as antidepressant medications with a fast onset of action as they produce a rapid modulation of the serotonergic system in the DRN and the glutamatergic transmission in the hippocampus. As these effects of sigma ligands may produce antidepressant properties by completely novel mechanisms of action, they may provide an alternative to the antidepressants currently available and may prove to be beneficial for treatment-resistant depressed patients.

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Serum levels of excitatory amino acids, serine, glycine, histidine, threonine, taurine, alanine and arginine in treatment‐resistant depression: modulation by treatment with antidepressants and prediction of clinical responsivity

Cited by 157 publications

References 27 publications

Immunology of Major Depression

Immunology of Major Depression

The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression

The Role of Sigma Receptors in Depression

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