Depression and suicidality: A link to premature T helper cell aging and increased Th17 cells

Schiweck, Carmen; Valles‐Colomer, Mireia; Arolt, Volker; Müller, Norbert; Raes, Jeroen; Wijkhuijs, Annemarie J.M.; Claes, Stephan; Drexhage, Hemmo A.; Vrieze, Elske

doi:10.1016/j.bbi.2020.02.005

Cited by 70 publications

(47 citation statements)

References 52 publications

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“…Moreover, a principal component analysis of 20 CSF biomarkers among a heterogenous group of 124 psychiatric patients with suicide attempt suggested that suicidal behaviors may be clustered into different combinations of biomarkers within the immune system, monoamine neurotransmitter system and HPA axis ( Lindqvist et al., 2011 ). Recently, memory T helper cells were shown distinguishably higher in depressed patients with high risk for suicide ( Schiweck et al., 2020 ). Such innovative studies will help to identify neuroimmune-based biomarker candidates of SSB exclusive of other conditions.…”

Section: Neuroimmune Dysregulation In Suicide Suicidal Behavior and Associated Conditionsmentioning

confidence: 99%

Psychoneuroimmunology: The new frontier in suicide research

Neupane

2021

Brain, Behavior, & Immunity - Health

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Elucidating complex, multifactorial phenomena like suicide and suicidal behaviors (SSB) require multidisciplinary fields such as Psychoneuroimmunology (PNI). Indeed, our appreciation of the bidirectional communication channels between the brain and the rest of the body with its immune arsenal as the key player has positioned PNI as a promising field of research. We now know that major psychiatric, behavioral, and somatic disorders related to SSB accompany neuroimmune dysregulation. These disorders range from depression, emotional dysregulation, atopy, and epilepsy to certain viral and parasitic infections. By utilizing epidemiological, genetic, microbial, and molecular approaches, the PNI research community has excogitated novel biomarker candidates and pathways in support of SSB risk stratification at individual level. This remarkable progress in just two previous decades shall, if successful, help implement personalized prevention and treatment strategies, using PNI-assisted tools. The aims of this narrative review and opinion piece are to summarize important discoveries concerning the role of neuroimmune activation in SSB and to highlight important future directions for the field. Major caveats of the findings concerning methodological approaches, clinical reality of frequent comorbid psychopathology, and novel molecular targets are presented. Finally, this review calls on the PNI research community for increased attention towards factors that promote resilience to suicide, while accepting “consciousness” under its wing. Thus, PNI represents the new frontier in suicide research. Future breakthroughs in this discipline shall bring us closer to understanding the biological substrates of qualia i.e., subjective, and experiential meanings of life and death.

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Section: Neuroimmune Dysregulation In Suicide Suicidal Behavior and Associated Conditionsmentioning

confidence: 99%

Psychoneuroimmunology: The new frontier in suicide research

Neupane

2021

Brain, Behavior, & Immunity - Health

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“…Interestingly, it has been postulated by Chen and colleagues [ 125 ], who found increased Th17 frequencies and decreased Treg concentrations in the blood of MDD patients, that very low concentrations of TGF-β may give rise to Th17 cells, whereas high concentrations of TGF-β may favor the production of Tregs. This inverse relationship is supported by additional clinical and preclinical studies that have shown an increased Th17:Treg ratio in MDD [ 124 , 125 , 126 ] and a downregulation of Th17 with a corresponding increase in Tregs in response to antidepressant administration in mice [ 130 , 131 ]. Additionally, the promotion of depressive-like behavior via the upregulation of Th1 and Th17 in a GSK-3 knockin mouse model has been shown, demonstrating the persistent activation of both GSK-3 isoforms [ 132 ].…”

Section: Gsk-3 Inflammation and Mddmentioning

confidence: 79%

“…In MDD, there is a tendency for T cell differentiation to elevate inflammatory Th1 and Th17 proliferation in tandem with Th2 and Treg cell downregulation [ 119 , 120 , 124 , 125 , 126 ]. The T cell modulatory cytokine, TGF-β, has had mixed reports, demonstrating both reduced [ 120 , 127 , 128 ] and increased [ 129 ] activity in patients with MDD.…”

Section: Gsk-3 Inflammation and Mddmentioning

confidence: 99%

Glycogen Synthase Kinase-3: A Focal Point for Advancing Pathogenic Inflammation in Depression

McCallum

Perreault

2021

Cells

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Increasing evidence indicates that the host immune response has a monumental role in the etiology of major depressive disorder (MDD), motivating the development of the inflammatory hypothesis of depression. Central to the involvement of chronic inflammation in MDD is a wide range of signaling deficits induced by the excessive secretion of pro-inflammatory cytokines and imbalanced T cell differentiation. Such signaling deficits include the glutamatergic, cholinergic, insulin, and neurotrophin systems, which work in concert to initiate and advance the neuropathology. Fundamental to the communication between such systems is the protein kinase glycogen synthase kinase-3 (GSK-3), a multifaceted protein critically linked to the etiology of MDD and an emerging target to treat pathogenic inflammation. Here, a consolidated overview of the widespread multi-system involvement of GSK-3 in contributing to the neuropathology of MDD will be discussed, with the feed-forward mechanistic links between all major neuronal signaling pathways highlighted.

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“…Active immune processes appear to be relevant for the development of major psychiatric disorders in a subgroup of patients as suggested by evidence from recent studies [e.g., [13][14][15][16][17]]. For example, inflammation appears to contribute to the development of depression [18][19][20][21][22], several antidepressants and antipsychotics show anti-inflammatory effects [e.g., [23][24][25][26]], and several studies demonstrated microglia activation and progressive brain changes in recent-onset schizophrenia [27,28]. Therefore, the abnormalities of CNS metabolism observed with depressive or schizophrenic disorders might arise, at least to some extent, because genetically modulated inflammatory reactions damage the microvascular system of the brain.…”

Section: Etiopathology: Active Immune Processes (Non-genetic Component)mentioning

confidence: 99%

Inflammatory processes linked to major depression and schizophrenic disorders and the effects of polypharmacy in psychiatry: evidence from a longitudinal study of 279 patients under therapy

Stassen

Bachmann²,

Bridler

et al. 2020

Eur Arch Psychiatry Clin Neurosci

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Over the past 2 decades, polypharmacy has become the de-facto standard of acute treatment in psychiatry where patients with psychiatric disorders receive a multiple medication regimen. There is growing evidence for a potential link between major psychiatric disorders and inflammatory processes. Combining these two aspects aims at avoiding polypharmacy attempts among patients with inflammatory activation through alternative treatment strategies. In this study, we addressed the following questions: (1) to what extent can polypharmacy be explained through the factors "diagnosis", "previous history", "severity at baseline", "age", "gender", and "psychiatrist in charge"; (2) what are the differences between polypharmacy and monotherapy regarding efficacy and side effect profiles; and (3) what amount of between-patient variance is explainable by the natural antibody immunoglobulin M (IgM) within each diagnostic group. This naturalistic longitudinal study was comprised of 279 patients under therapy with a clinical diagnosis of depressive (ICD-10: "F3x.x"; n = 195) or schizophrenic disorders (ICD-10: "F2x.x"; n = 84). The study protocol included (1) assessment of previous history by the SADS Syndrome Check List SSCL-16 (lifetime version); (2) repeated measurements over 5 weeks assessing the time course of improvement by the Hamilton Depression Scale HAM-D and the Positive and Negative Syndrome Scale PANSS, along with medication and unwanted side effects through the Medication and Side Effects Inventory MEDIS; and (3) the collection of blood samples from which DNA and serum were extracted. The association between inflammatory response system and psychiatric disorders was detailed by fitting multi-layer Neural Net (NN) models to the observed data ("supervised learning"). The same approach was used to set up prediction models of side effects. Our data showed that polypharmacy was omnipresent. Yet the various polypharmacy regimens had no advantage over monotherapy: we even found slightly larger baseline score reductions under monotherapy, independent of primary diagnoses and for comparable baseline severities. Most patients experienced unwanted side effects. The close link between side effects and treatment regimen was revealed by a linear model in which the mere number of drugs explained a significant (p < 0.001) proportion of the observed variance. As to the inflammatory response system: For the F2 patients, our NN model identified a 22.5% subgroup exhibiting a significant correlation of r = 0.746 (p = 0.0004) between global schizophrenia scores and IgM levels, along with a correct prediction of response of 94.4%, thus explaining 55.7% of the observed between-patient variance. For the F3 patients, our NN model identified a 19.6% subgroup exhibiting a significant correlation of r = 0.644 (p = 0.00003) between global depression scores and IgM levels, along a correct prediction of response of 89.6%, thus explaining 41.4% of the observed between-patient variance. Polypharmacy is omnipresent in today's acute treatment of psychi...

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Depression and suicidality: A link to premature T helper cell aging and increased Th17 cells

Cited by 70 publications

References 52 publications

Psychoneuroimmunology: The new frontier in suicide research

Psychoneuroimmunology: The new frontier in suicide research

Glycogen Synthase Kinase-3: A Focal Point for Advancing Pathogenic Inflammation in Depression

Inflammatory processes linked to major depression and schizophrenic disorders and the effects of polypharmacy in psychiatry: evidence from a longitudinal study of 279 patients under therapy

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