Müller N, Schwarz MJ. The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression. Mol Psychiatry 12: 988-1000

Department for Psychiatry and Psychotherapy, Ludwig-Maximilians-Universität München, München, Germany.
Molecular Psychiatry (Impact Factor: 14.5). 12/2007; 12(11):988-1000. DOI: 10.1038/
Source: PubMed


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-gamma, or tumor necrosis factor-alpha 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.

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Available from: Markus J Schwarz, Jul 03, 2014
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    • "In fact, kynurenic acid, an intermediate metabolic product of the TRP-KYN pathway behaves as a NMDA antagonist, displaying neuroprotective actions in the brain and inhibiting the release of the excitatory neurotransmitter glutamate and inhibiting the release of dopamine in discrete brain areas (Borland and Michael, 2004; Klein et al., 2013; Sas et al., 2007). On the other hand, quinolinic acid, one of the pathway's final products, seems to act as an NMDA agonist, promoting glutamate release and contributing to excitotoxicity and oxidative stress in the brain (McNally et al., 2008; Muller and Schwarz, 2007). Similarly , 3-hydroxykynurenine also displays neurotoxic effects by promoting the formation of oxygen species and causing neuronal apoptosis (Okuda et al., 1998; Stone, 2001). "
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    ABSTRACT: Early life experiences play a key role in brain function and behaviour. Adverse events during childhood are therefore a risk factor for psychiatric disease during adulthood, such as mood disorders. Maternal separation is a validated mouse model for maternal neglect, producing negative early life experiences that result in subsequent emotional alteration. Mood disorders have been found to be associated with neurochemical changes and neurotransmitter deficits such as reduced availability of monoamines in discrete brain areas. Emotional alterations like depression result in reduced serotonin availability and enhanced kynurenine metabolism through the action of indoleamine 2, 3-dioxygenase in response to neuroinflammatory factors. This mechanism involves regulation of the neurotransmitter system by neuroinflammatory agents, linking mood regulation to neuroinmunological reactions. In this context, the aim of this study was to investigate the effects of maternal separation with early weaning on emotional behaviour in mice. We investigated neuroinflammatory responses and the state of the tryptophan-kynurenine metabolic pathway in discrete brain areas following maternal separation. We show that adverse events during early life increase risk of long-lasting emotional alterations during adolescence and adulthood. These emotional alterations are particularly severe in females. Behavioural impairments were associated with microglia activation and disturbed tryptophan-kynurenine metabolism in brain areas related to emotional control. This finding supports the preeminent role of neuroinflammation in emotional disorders.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 09/2015; 65. DOI:10.1016/j.pnpbp.2015.09.003 · 3.69 Impact Factor
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    • "Studies have shown elevated serum levels of IL-1 β, IL-6 and tumor necrosis factor-alpha (TNF-α) in depressed patients (Young et al., 2014). Pro-inflammatory cytokines also lead to an enhanced consumption of serotonin and tryptophan via indoleamine 2,3-diox- ygenase (IDO) activation (Muller and Schwarz, 2007). "
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    ABSTRACT: The cytokine hypothesis of depression postulates that the pathophysiology of this illness incorporates an increased production of pro-inflammatory cytokines, which leads to an over-activation of the hypothalamic-pituitary-adrenal axis as well as monoaminergic disturbances. Nevertheless, it remains unclear whether the amelioration of depressive symptoms could decrease cytokine levels. Notwithstanding antidepressant drug therapy might exert anti-inflammatory effects, the effects of non-invasive neuromodulatory approaches like transcranial direct current stimulation (tDCS) on pro-inflammatory cytokine networks are largely unknown. We evaluated, in the Sertraline vs. Electric Current Therapy for Treating Depression Clinical Study (SELECT-TDCS) trial, whether the plasma levels of the soluble TNF receptors 1 and 2 (sTNFRs) changed after antidepressant treatment in a sample of 73 antidepressant-free patients with unipolar depressive disorder in an episode of at least moderate intensity. Although both tDCS and sertraline exerted antidepressant effects, the plasma levels of sTNFRs did not change over time regardless of the intervention and clinical response. Also, baseline sTNFRs levels did not predict antidepressant response. Our negative findings could be a type II error, as this trial did not use an equivalence design. To conclude, in this novel placebo-controlled trial prospectively evaluating the changes of sTNFRs in depressed patients, we found that these molecules are not surrogate biomarkers of treatment response of tDCS, whose antidepressant effects occurred regardless of normalization of immunological activity. Copyright © 2015 Elsevier B.V. All rights reserved.
    Journal of Affective Disorders 07/2015; 185:209-213. DOI:10.1016/j.jad.2015.07.006 · 3.38 Impact Factor
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    • "Furthermore , depressive episodes are often recurrent , incrementing individual and social burden ( World - Federation - for - Mental - Health , 2012 ) . Characteristic pathophysiological hallmark features include monoamine depletion , glucocorticoid receptor ( GR ) resistance , and excess of glutamate , corticotrophin - releasing hormone and cortisol levels , therefore compromising the monoaminergic and glutamatergic neurotransmission along with the hypothalamus - pituitary - adrenal ( HPA ) axis activity ( Muller and Schwarz , 2007 ) . The onset of MDD is complex and can be triggered by several different factors . "
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    ABSTRACT: Major depressive disorder (MDD) is a mood disorder of multifactorial origin affecting millions of people worldwide. The alarming estimated rates of prevalence and relapse make it a global public health concern. Moreover, the current setback of available antidepressants in the clinical setting is discouraging. Therefore, efforts to eradicate depression should be directed towards understanding the pathomechanisms involved in the hope of finding cost-effective treatment alternatives. The pathophysiology of MDD comprises the breakdown of different pathways, including the hypothalamus-pituitary-adrenal (HPA) axis, the glutamatergic system, and monoaminergic neurotransmission, affecting cognition and emotional behavior. Inflammatory cytokines have been postulated to be the possible link and culprit in the disruption of these systems. In addition, evidence from different studies suggests that impairment of glial functions appears to be a major contributor as well. Thus, the intricate role between glia, namely microglia and astrocytes, and the central nervous system's (CNSs) immune response is briefly discussed, highlighting the kynurenine pathway as a pivotal player. Moreover, evaluations of different treatment strategies targeting the inflammatory response are considered. The immuno-modulatory properties of vitamin D receptor (VDR) suggest that vitamin D is an attractive and plausible candidate in spite of controversial findings. Further research investigating the role of VDR in mood disorders is warranted.
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