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Abstract

Major depressive disorder (MDD) is associated with significant morbidity and mortality. Findings from preclinical and clinical studies suggest that psychiatric illnesses, particularly MDD, are associated with inflammatory processes. While it is unlikely that MDD is a primary 'inflammatory' disorder, there is now evidence to suggest that inflammation may play a subtle role in the pathophysiology of MDD. Most of the evidence that links inflammation to MDD comes from three observations: (a) one-third of those with major depression show elevated peripheral inflammatory biomarkers, even in the absence of a medical illness; (b) inflammatory illnesses are associated with greater rates of MDD; and (c) patients treated with cytokines are at greater risk of developing major depressive illness. We now know that the brain is not an immune privileged organ. Inflammatory mediators have been found to affect various substrates thought to be important in the aetiopathogenesis of MDD, including altered monoamine and glutamate neurotransmission, glucocorticoid receptor resistance and adult hippocampal neurogenesis. At a higher level, inflammation is thought to affect brain signalling patterns, cognition and the production of a constellation of symptoms, termed 'sickness behaviour'. Inflammation may therefore play a role in the aetiology of depression, at least in a 'cohort' of vulnerable individuals. Inflammation may not only act as a precipitating factor that pushes a person into depression but also a perpetuating factor that may pose an obstacle to recovery. More importantly, inflammatory markers may aid in the diagnosis and prediction of treatment response, leading to the possibility of tailored treatments, thereby allowing stratification of what remains a heterogenous disorder.

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... Gejala lain meliputi: (i) konsentrasi dan perhatian berkurang, (ii) harga diri dan kepercayaan diri berkurang, (iii) gagasan rasa bersalah dan tidak berguna, (iv) pandangan masa depan yang suram dan pesimistis, (v) gagasan atau perbuatan membahayakan diri atau bunuh diri, (vi) tidur terganggu, dan (vii) nafsu makan berkurang. 1 6,7 Depresi memiliki kaitan dengan disregulasi sistem imun 8 dan proses inflamasi, [8][9][10][11][12] ditunjukkan dengan peningkatan kadar C-reactive protein (CRP) 12 dan peningkatan kadar sitokin proinflamasi, meliputi: interleukin-(IL) 6, IL-1, serta tumor necrosis factor-α (TNF-α). [8][9][10][11][12] Selain itu, terapi menggunakan agen proinflamasi, misalnya interferon-α (IFN-α), yang biasa digunakan untuk terapi hepatitis C atau melanoma malignan, terbukti menimbulkan efek samping psikiatri; sekitar 80% pasien yang mendapat terapi IFN-α mengalami gejala depresi ringan atau sedang. ...
... 9 Sitokin pro-inflamasi memicu perubahan struktur dan fungsi otak. 6 Konsentrasi IL-6 dan TNF-α lebih tinggi pada pasien depresi dibandingkan kontrol. 8 Pasien yang resisten terhadap obat anti-depresan selective serotonin reuptake inhibitor (SSRI) menunjukkan peningkatan produksi sitokin pro-inflamasi IL-6 dan TNF-α dibandingkan kelompok sehat. ...
... 9 Pasien depresi yang memberikan respons terhadap terapi standar kurang dari 50%. 9,10 Peningkatan kadar sitokin pro-inflamasi plasma menjadi penanda adanya resistensi depresi terhadap terapi anti-depresan, 6 sekaligus memprediksi respons baik dengan pemberian anti-inflamasi. 13 Pasien depresi yang tidak memberi respons adekuat dengan terapi anti-depresan standar dapat diatasi dengan tiga strategi, yaitu: meningkatkan dosis obat anti-depresan, 9 mengganti jenis anti-depresan, atau menggunakan terapi augmentasi yang disebut juga terapi addon. ...
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ABSTRAK Latar Belakang: Depresi merupakan gangguan suasana perasaan yang sering ditemukan. Banyak pasien depresi tidak memberikan respons baik terhadap terapi anti-depresan standar. Celecoxib, obat golongan penghambat COX 2, dapat digunakan sebagai terapi add-on. Tujuan: Mengetahui manfaat celecoxib sebagai terapi add on pada depresi. Pembahasan: Depresi memiliki kaitan erat dengan proses inflamasi, yang ditunjukkan dengan peningkatan kadar CRP dan sitokin pro-inflamasi, khususnya IL-6, IL-1, serta TNF-α. Celecoxib bekerja menghambat sintesis PG, sehingga tidak terbentuk metabolit aktif PG, yaitu PGE 2, yang berperan dalam patofisiologi depresi. Celecoxib juga dapat meningkatkan neurotransmiter serotonin dan noradrenalin di SSP dan menekan aktivitas berlebih aksis HPA. Celecoxib sebagai terapi add on mengurangi skor HDRS, menurunkan kadar IL-6 serum, menunjukkan tingkat respons dan remisi lebih baik daripada anti-depresan tunggal atau plasebo. Dosis celecoxib yang paling sering digunakan untuk efek anti-depresan adalah 400 mg/hari selama 6 minggu. Celecoxib dapat ditoleransi dengan baik pada mayoritas pasien. Simpulan: Celecoxib efektif menurunkan gejala depresi, menurunkan konsentrasi sitokin pro-inflamasi dalam darah, menurunkan skor HDRS, dan dapat ditoleransi dengan baik. Kata kunci: Celecoxib, COX-2 inhibitor, depresi ABSTRAcT Background: Depression is the most frequent mood disorder. Many depression patients are not responsive to standard anti-depressant. Celecoxib, a COX-2 inhibitor, can be used as add-on therapy. Objective: To learn the benefits of celecoxib as add-on therapy for depression. Discussion: Depression is related to inflammatory processes, indicated by the elevated level of CRP and pro-inflammatory cytokines, such as IL-6, IL-1, and TNF-α. Celecoxib works by inhibiting the synthesis of PG, so no active metabolite PGE2 which has an important role in depression pathophysiology, is produced. Celecoxib also increases the production of serotonin and noradrenalin in the CNS and suppress the hyperactivity of HPA axis. Previous studies proved celecoxib as an add-on therapy reduced HDRS score, lowered the level of IL-6, increased the response and remission rate, better than placebo or a single anti-depressant. The most frequent dosage was 400 mg/day for 6 weeks. Celecoxib is proved to be well tolerated in the majority of patients. conclusion: Celecoxib is effective in reducing depression symptoms, blood pro-inflammatory cytokines concentration, HDRS score, and well tolerated. Rosa De Lima Renita Sanyasi, Rizaldy Taslim Pinzon. celecoxib as Add-on Therapy for Depression
... It is widely known that increased inflammatory secretion may play a significant role in etiopathogenetic of depression. Inflammatory cytokines have been suggested to alter neurotransmission (5), hippocampal neurogenesis (6), and stress-related hypothalamicpituitary-adrenal (HPA) axis (7) and sympathetic system activation (8), which can cause changes in structure and function of the brain and subsequent development of depression (9). Skeletal muscle, a major secretory organ, can secrete and produce numerous proinflammatory cytokines, such as IL-6, IL-8, and IL-15 (10). ...
... In two younger adults-based studies, weaker skeletal muscle strength has been suggested to be associated with increased serum proinflammatory cytokines (11,12). Meanwhile, increased inflammatory cytokines secretion can alter neurotransmission (5), hippocampal neurogenesis (6), and stress-related HPA axis (7) and sympathetic system activation (8), which can cause changes in structure and function of the brain, and subsequent development of depression (9). ...
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Muscle strength can be a predictor of depressive symptoms among the elderly. We conducted a prospective study aiming to examine the association between change of handgrip strength and the incidence risk of depressive symptoms among Chinese female college students. Handgrip strength was used as a representative indicator of skeletal muscle strength, and a handheld digital smedley dynamometer was applied to measure handgrip strength. We also used the 20-item Zung self-rating depression scale to evaluate depressive status, and a score of ≥50 indicated moderate-to-severe depressive symptoms. During a 1-year follow-up period, the incidence of depressive symptoms is 10.7%. Multivariate logistic regressions analysis revealed that the multivariable-adjusted ORs (95% CI) of depressive symptoms for the categories of handgrip strength change was 1.00 (reference) for group 1, 0.57 (0.28, 1.19) for group 2, 0.41 (0.19, 0.89) for group 3 and 0.33 (0.11, 0.99) for group 4 ( p = 0.018). This study indicated that change of handgrip strength level over one-year period is negatively associated with risk of depressive symptoms among Chinese female college students.
... In terms of the pathogenesis of depression, currently, there are mainly several hypotheses such as central oxidative stress, neuroinflammation damage, and neurotrophic deficiency [29][30][31]. Hippocampal brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB) is a typical neurotrophic pathway [32,33], nuclear factor E 2-related factor 2 (Nrf2)/HO-1 is a recognized transcriptional regulatory pathway for anti-oxidant defense [34,35], and cyclooxygenase-2 (COX-2) dominates the pathway of inflammatory mediators [36], all of them play key roles in the onset of depression and the efficacy of various clinical antidepressants and antidepressant active molecules. Especially, catalpol exerts antidepressant activities by regulating the gene expression levels of BDNF, TrkB, and COX-2 and the protein levels of Nrf2 and HO-1 [26][27][28]37]. ...
... Elevated inflammatory mediators and deficiency of neurotrophic factors are important triggers for the onset of depression [29,30]. In recent years, study [38] on antidepressants has shown that in addition to regulating antioxidant defense, HO-1 can also influence the levels of neuroinflammation-related molecules such as COX-2, iNOS, and NO [35,41,68] and affect the conduction of neurotrophic-related pathway BDNF/TrkB to participate in antidepressants exerting medicinal effects [42]. ...
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Catalpol is an iridoid glycoside with rich content, rich nutrition, and numerous biological activities in Rehmanniae Radix contained in classic antidepressant prescriptions in Chinese clinical medicine. Catalpol has been confirmed previously its exact antidepressant-like effect involved heme oxygenase (HO)-1, but its antidepressant molecular targets and mechanism are still unclear. Here, catalpol's antidepressant-like molecular target was diagnosed and confirmed by ZnPP intervention [the antagonist of HO-1, (10 μg/rat), intracerebroventricular] for the first time, and its molecule mechanism network was determined through HO-1 related pathway and molecules in the hippocampus. Results showed that ZnPP significantly abolished catalpol’s (10 mg/kg) reversal on depressive-like behaviors of chronic unpredictable mild stress rats, abolished catalpol’s up-regulation on the phosphorylation level of extracellular regulated protein kinases (ERK)1/2 and brain-derived neurotrophic factor (BDNF)’s receptor tropomyosin-related kinase B (TrkB), the nuclear expression level of nuclear factor E 2-related factor 2 (Nrf2), the levels of anti-oxidant factors (such as HO-1, SOD, GPX, GST, GSH) and BDNF, and abolished catalpol’s down-regulation on the levels of peroxide and neuroinflammation factors [cyclooxygenase-2 (COX-2), induced nitrogen monoxide synthase (iNOS), nitric oxide (NO)]. Thus, HO-1 could serve as an important potential molecular target for catalpol's antidepressant-like process, and the antidepressant-like mechanism of catalpol could at least involve the activation of HO-1 triggering the up-regulation of the ERK1/2/Nrf2/HO-1 pathway-related factors to enhance the anti-oxidant defense, triggering the down-regulation of the COX-2/iNOS/NO pathway-related factors to inhibit neuroinflammation, and triggering the up-regulation of the BDNF/TrkB pathway to enhance neurotrophy.
... Studies also indicate the presence of inflammatory mediators such as prostaglandin E (PGE2), a pro-inflammatory nitric oxide-NO molecule [62][63][64]. In addition, prolonged and severe depressive states may be accompanied by increased plasma levels of pro-inflammatory cytokines IL-1, IL-2, a soluble IL-2 receptor (sIL-2R), tumour necrosis factor α (TNF-α), IL-8, IL-18 and interferon-γ (IFN-γ) and a decrease in acute phase protein concentrations of albumin and transferrin as well as IL-10 and IL-12 [61,65,66]. Inflammatory cytokines have the ability to penetrate the blood-brain barrier and activate microglia, which in turn increases the activity of the enzyme indoleamine-2,3-dioxygenase (IDO), which catabolises tryptophan to kynurenine (KYN) [22,67,68]. ...
... Studies of convalescents one month and 3 months after discharge from the hospital indicate an increase in the incidence of psychiatric disorders, including depressive disorders and a deterioration of cognitive functions [28,30,105,217]. In addition, stress during a pandemic, associated with a change in life in almost every aspect, fear of illness, death and other psychosocial factors [7,49,165], can activate the stress axis [46], affect the severity of inflammation in the brain and, consequently, its structural and functional changes [55,65,71,218]. Research confirms that females, the healthcare professionals, elderly individuals, children, college students and psychiatric patients are in the group at increased risk of developing depressive disorders during the COVID-19 pandemic [151,[219][220][221][222][223]. ...
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The dysfunctional effects of the coronavirus disease 2019 (COVID-19) infection on the nervous system are established. The manifestation of neuropsychiatric symptoms during and after infection is influenced by the neuroinvasive and neurotrophic properties of SARS-CoV-2 as well as strong inflammation characterised by a specific “cytokine storm”. Research suggests that a strong immune response to a SARS-CoV-2 infection and psychological stressors related to the pandemic may cause chronic inflammatory processes in the body with elevated levels of inflammatory markers contributing to the intensification of neurodegenerative processes. It is suggested that neuroinflammation and associated central nervous system changes may significantly contribute to the etiopathogenesis of depressive disorders. In addition, symptoms after a COVID-19 infection may persist for up to several weeks after an acute infection as a post-COVID-19 syndrome. Moreover, previous knowledge indicates that among SSRI (selective serotonin reuptake inhibitor) group antidepressants, fluoxetine is a promising drug against COVID-19. In conclusion, further research, observation and broadening of the knowledge of the pathomechanism of a SARS-CoV-2 infection and the impact on potential complications are necessary. It is essential to continue research in order to assess the long-term neuropsychiatric effects in COVID-19 patients and to find new therapeutic strategies.
... It is known that inflammation has been implicated in the pathophysiology and maintenance of MDD. In studies related to MDD and inflammation, changes in the levels of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α as well as CRP have been previously reported (Raison et al., 2006;Brietzke et al., 2009;Howren et al., 2009;Krishnadas and Cavanagh, 2012;Mota et al., 2013;Serafini et al., 2013;Cubała and Landowski, 2014;Money et al., 2016;Kappelmann et al., 2018;Leighto et al., S.P. 2018;Milenkovic et al., 2019;Slavich and Sacher, 2019). These inflammatory markers have also been examined in associated to the severity of depression or suicidality severity in MDD and other mood disorders (O'Donovan et al., 2013;Serafini et al., 2013;Black and Miller, 2015;Ducasse et al., 2015) Other inflammatory markers that have been determined in MDD are complete blood inflammatory ratios such as the NLR, PLR, and MLR (Demir et al., 2015;Demircan et al., 2016;Ekinci and Ekinci, 2017;Gündüz et al., 2017; Fig. 1. ...
Article
We determined whether an elevated neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR) were associated with depression in major depressive disorder (MDD), or suicide risk in MDD patients. A total of 137 adolescents with MDD who were antidepressant-naïve and 56 healthy controls (HC) were included. Recent suicidal behaviors were assessed. The NLR, PLR, and MLR were calculated from parameters obtained from a routine complete blood cell count parameters and compared between the MDD subgroups and HC. Cohen's d was calculated as a measure of effect size. The linear relationship between biomarkers with depression severity or suicidality severity was also analysed. Changes in CBC parameters and inflammatory ratios appeared to be more closely related to the suicidality severity than depressive severity. As compared with HC, the WBC count, neutrophil percentage, platelet count, NLR, and PLR were higher in MDD, whereas the lymphocyte percentage was lower. As compared to non-suicidal ideation (non-SI) MDD and HC, the lymphocyte percentage was decreased in MDD with suicidal attempts (SA), whereas monocyte count and MLR were increased. Suicidal attempts in MDD patients were associated with the lower lymphocytes percentage, as well as the elevated monocyte count and MLR.
... The rise in pro-inflammatory cytokines is generally adaptive, transient, and regulated by anti-inflammatory mechanisms. The neuroinflammatory hypothesis suggests that proinflammatory cytokines or the immune system may play a role in the etiopathogenesis of depression [3,5]. COVID-19 has caused the Chinese pandemic process in Wuhan, and around the world, and it affects older people the most because their immune systems are weakened.It is not known exactly if it was symptomatic in humans [6]. ...
... The inflammatory pathway is thought to play a vital role in the development of epilepsy. 31 Furthermore, increasing evidence suggests that inflammatory pathways might be related to several other neuropsychiatric comorbidities, including cognitive dysfunction, 32,33 depression, 34,35 autism spectrum disease, 36 anxiety, 37 and schizophrenia. 38 The investigation of protein-protein networks can be used for drug target discovery, drug discovery, and drug design. ...
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Objective An association between the rs10496964 polymorphism and the ZEB2 gene has not yet been reported, and the role of ZEB2 in epilepsy therapy is also unclear. The aims of this research were to evaluate the role of ZEB2 in the therapy of epilepsy and to explore the association between rs10496964 and ZEB2 expression. Methods We used the expression quantitative trait loci (eQTL) dataset resource from the Brain eQTL Almanac to evaluate the association between rs10496964 and ZEB2 expression in human brain tissue. Pathway and process enrichment analysis, protein–protein interaction analysis, and PhosphoSitePlus® analysis were then performed to further evaluate the role of ZEB2 in the therapy of epilepsy. Results The rs10496964 polymorphism was found to regulate the expression of ZEB2 in human brain tissue. The ZEB2 protein interacts with the targets of approved antiepileptic drugs, and a post-translational acetylation modification of ZEB2 was associated with an epilepsy drug therapy. Conclusion Our findings suggest that ZEB2 may be involved in the therapy of epilepsy, and rs10496964 regulates ZEB2 expression in human brain tissue.
... Thus, studies in veterans with GWI and animal prototypes of GWI imply that multiple factors, including incessant oxidative stress, neuroinflammation, and alterations in signaling pathways mediating pro-cognitive effects underlie cognitive and mood dysfunction in GWI. Such a conclusion is supported by findings that incessant oxidative stress and neuroinflammation could induce cognitive problems and depression [70][71][72]. ...
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Persistent cognitive and mood dysfunction is the primary CNS symptom in veterans afflicted with Gulf War Illness (GWI). This study investigated the efficacy of melatonin (MEL) for improving cognitive and mood function with antioxidant, antiinflammatory, and pro-cognitive effects in a rat model of chronic GWI. Six months after exposure to GWI-related chemicals and stress, rats were treated with vehicle or MEL (5, 10, 20, 40, and 80 mg/kg) for eight weeks. Behavioral tests revealed cognitive and mood dysfunction in GWI rats receiving vehicle, which were associated with elevated oxidative stress, reduced NRF2, catalase and mitochondrial complex proteins, astrocyte hypertrophy, activated microglia with NLRP3 inflammasomes, elevated proinflammatory cytokines, waned neurogenesis, and synapse loss in the hippocampus. MEL at 10 mg/kg alleviated simple and associative recognition memory dysfunction and anhedonia, along with reduced oxidative stress, enhanced glutathione and complex III, and reduced NLRP3 inflammasomes, IL-18, TNF-α, and IFN-γ. MEL at 20 mg/kg also normalized NRF2 and catalase and increased microglial ramification. MEL at 40 mg/kg, in addition, reduced astrocyte hypertrophy, activated microglia, NF-kB-NLRP3-caspase-1 signaling, IL-1β, MCP-1, and MIP-1α. Moreover, MEL at 80 mg/kg activated the BDNF-ERK-CREB signaling pathway, enhanced neurogenesis and diminished synapse loss in the hippocampus, and improved a more complex hippocampus-dependent cognitive function. Thus, MEL therapy is efficacious for improving cognitive and mood function in a rat model of chronic GWI, and MEL's effect was dose-dependent. The study provides the first evidence of MEL's promise for alleviating neuroinflammation and cognitive and mood impairments in veterans with chronic GWI.
... These studies showed alterations in the inflammatory process like increased production of interleukin-1 (IL-1),interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-alpha) [4]. So,alteration in immune system may play a role in the etiopathogenesis of depression [5][6][7]. Also,Antidepressants have been shown to decrease and normalize high pre-therapeutic serum proinflammatory cytokine levels [6,8]. Stress and depression may result in an increased number of leukocytes and neutrophils, as well as decreased lymphocytes [4]. ...
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Background: Depression is one of the most common disorders. It has 5% prevalence worldwide and 2.8% in India. One of the etiological hypotheses for depression is inflammatory mechanism. Neutrophil lymphocyte ratio (NLR), cortisol, and vitamin D are the marker of systemic inflammation. This study assessed the association and correlation between Neutrophil lymphocyte ratio, cortisol, and vitamin D with depression and its severity.Aim: To see the association between Neutrophil lymphocyte ratio,cortisol, Vitamin D with depression and their correlation with the severity of Depression.Methodology: This study included 120 patients with depression and 120 healthy controls. Severity of depression was assessed by Hamilton Depression Rating Scale (HAM-D). N/L ratio, cortisol, and vitamin D were measured in both groups. Comparison of socio-demographic profile by independent T-test and Pearson correlation was applied to see correlation between variables. ANOVA test was applied to compare both the groups in terms of biomarkers.Results: N/L ratio, cortisol, and vitamin D were significantly deranged in cases compared to controls. A positive correlation was observed between severity of depression and N/L ratio and cortisol and an inverse correlation with vitamin D. Conclusion: There is association between N/L ratio, serum cortisol and vitamin D with depression and it also has correlation with severity of depression.
... Overall, numerous studies, reviewed by Willkinson and Goodyer, suggest that a continuous dysregulation of the HPA axis with a central deficit of the feedback mechanisms is predominant in depressive disorders [108]. For example, the increased activity of the HPA system in humans has been associated with glucocorticoid receptor (GR) resistance, which could be the result of either a decreased expression or a reduced functionality of GR [109]. Therefore, ineffective cortisol-mediated negative feedback does not reduce the excessive activity of the HPA axis during chronic stress. ...
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Major depressive disorder (MDD) is a heterogeneous disease affecting one out of five individuals and is the leading cause of disability worldwide. Presently, MDD is considered a multifactorial disease with various causes such as genetic susceptibility, stress, and other pathological processes. Multiple studies allowed the formulation of several theories attempting to describe the development of MDD. However, none of these hypotheses are comprehensive because none of them can explain all cases, mechanisms, and symptoms of MDD. Nevertheless, all of these theories share some common pathways, which lead us to believe that these hypotheses depict several pieces of the same big puzzle. Therefore, in this review, we provide a brief description of these theories and their strengths and weaknesses in an attempt to highlight the common mechanisms and relationships of all major theories of depression and combine them together to present the current overall picture. The analysis of all hypotheses suggests that there is interdependence between all the brain structures and various substances involved in the pathogenesis of MDD, which could be not entirely universal, but can affect all of the brain regions, to one degree or another, depending on the triggering factor, which, in turn, could explain the different subtypes of MDD.
... COPD represents a type of chronic inflammation that is characterized by neutrophil infiltration [44]. Another study found that the excessive or prolonged production of proinflammatory cytokines could cause anxiety and chronic inflammation [45]. Bratek et al. found that anxiety test scores were positively correlated with the relative number of neutrophils in induced sputum. ...
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Abstract Background: Anxiety is a common comorbidity associated with chronic obstructive pulmonary disease (COPD), but no well-recognized method can provide effective relief. Liuzijue Qigong (LQG) is a traditional Chinese fitness method, based on breath pronunciation. This study aimed to examine the efficacy of LQG to relieve anxiety in COPD patients and to explore the factors that influence anxiety, including whether LQG is effective during the coronavirus disease 2019 (COVID-19) outbreak. Methods: We conducted an open-label, randomized, controlled, clinical trial. A total of 60 patients with stable COPD were randomly assigned to two groups. Both groups were given routine medical treatment, and the patients in the pulmonary rehabilitation (PR) group were given an extra intervention in the form of LQG, performed for 30 minutes each day for 12 weeks. Data collection was performed at baseline and 12 weeks (during the COVID-19 epidemic). The primary outcomes were the self-rating anxiety scale (SAS) scores, and the secondary outcomes were relevant information during the epidemic and analyses of the related factors that influenced SAS scores during the COVID-19 outbreak. Results: Compared with baseline, patients in both groups demonstrated varying degrees of improvements in their SAS scores (all P < 0.01). An analysis of covariance, adjusted for baseline scores, indicated that the SAS scores improved more dramatically in the PR group than in the control group (F = 9.539, P = 0.004). During the outbreak, the SAS scores for sleep disorder were higher than all other factors, reaching 1.38 ± 0.67, and the scores for “I can breathe in and out easily” for the PR group were lower than the scores for the control group (Z = -2.108, P = 0.035). Significant differences were identified between the two groups for the categories “How much has the outbreak affected your life”, “Do you practice LQG during the epidemic” and “Do you practice other exercises during the epidemic” (all P < 0.05). Compared with current reports, LQG had a relatively high adherence rate (80.95%). A multiple linear regression analysis revealed multiple predictors for SAS scores during the outbreak: group (b = -3.907, t = -3.824, P < 0.001), COPD assessment test score (b = 0.309, t = 2.876, P = 0.006), SAS score at baseline (b = 0.189, t = 3.074, P = 0.004), and living in a village (b = 4.886, t = 2.085, P = 0.043). Conclusion: LQG could effectively reduce the risks of anxiety among COPD patients, even during the COVID-19 outbreak. For those COPD patients with high COPD assessment test and high baseline SAS scores or who live in villages, we should reinforce the management and intervention of psychological factors during the epidemic.
... There is increasing evidence to suggest that the immune and inflammatory system plays a role in the pathophysiology of depression (4)(5)(6). Individuals with MDD have been shown to have increased numbers of circulating granulocytes and monocytes, elevated levels of circulating pro-inflammatory cytokines and acute phase proteins (7)(8)(9). Furthermore, a previous study suggested that elevated levels of peripheral inflammatory markers in patients with MDD were associated with increased anhedonia (10). ...
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Background Research on neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR) in depression is still emerging and has increased 3-fold since the first meta-analysis. An updated meta-analysis with sufficient studies can provide more evidence for a potential relationship between NLR, PLR, MLR, and depression. Methods We identified 18 studies from the PubMed, EMBASE, Cochrane library, and Web of Science databases. Meta-analyses were performed to generate pooled standardized mean differences (SMDs) and 95% confidence intervals (CIs) between patients with depression and controls. Sensitivity analysis, subgroup analysis, meta-regression, and publication bias were conducted. Results A total of 18 studies including 2,264 depressed patients and 2,415 controls were included. Depressed patients had significantly higher NLR and PLR compared with controls (SMD = 0.33, 95% CI: 0.15–0.52, p < 0.001 and SMD = 0.24, 95% CI: 0.02–0.46, p < 0.05, respectively). MLR was slightly higher in depressed individuals compared to controls (SMD = 0.15, 95% CI: −0.26 to 0.55, p > 0.05), despite the absence of significance. Sensitivity analysis removing one study responsible for heterogeneity showed a higher and significant effect (SMD = 0.32, 95% CI: 0.20–0.44) of MLR. Three subgroup analyses of NLR, PLR, MLR, and depression revealed obvious differences in the inflammatory ratios between depressed patients and controls in China and the matched age and gender subgroup. Individuals with post-stroke depression (PSD) had higher NLR and MLR values as compared to non-PSD patients (SMD = 0.51, 95% CI: 0.36–0.67, p < 0.001 and SMD = 0.46, 95% CI: 0.12–0.79, p < 0.01, respectively). Meta-regression analyses showed that male proportion in the case group influenced the heterogeneity among studies that measured NLR values ( p < 0.05). Conclusions Higher inflammatory ratios, especially NLR, were significantly associated with an increased risk of depression. In the subgroup of China and matched age and gender, NLR, PLR, and MLR were all elevated in depressed patients vs. controls. Individuals with PSD had higher NLR and MLR values as compared to non-PSD patients. Gender differences may have an effect on NLR values in patients with depression.
... Neurotransmitters can directly or indirectly affect the activity of the basal nerve node, thus inducing repetitive behavior (Langen et al., 2011). In addition, these neurotransmitters have been linked with many mood disorders and contribute to the development of stress-related mood disorders (Schiepers et al., 2005;Krishnadas and Cavanagh, 2012;Bortolato et al., 2015), which are accompanied by the performance of anxiety-like behavior or depressive-like behavior. Further studies are necessary to validate the role of these genes in MSB, such as gene overexpression and gene knock-out. ...
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Motor stereotypic behaviors (MSBs) are common in captive rhesus macaques (Macaca mulatta) and human with psychiatric diseases. However, large gaps remain in our understanding of the molecular mechanisms that mediate this behavior and whether there are similarities between human and non-human primates that exhibit this behavior, especially at gene expression and gut microbiota levels. The present study combined behavior, blood transcriptome, and gut microbiota data of two groups of captive macaques to explore this issue (i.e., MSB macaques with high MSB exhibition and those with low: control macaques). Observation data showed that MSB macaques spent the most time on MSB (33.95%), while the CONTROL macaques allocated more time to active (30.99%) and general behavior (30.0%), and only 0.97% of their time for MSB. Blood transcriptome analysis revealed 382 differentially expressed genes between the two groups, with 339 upregulated genes significantly enriched in inflammation/immune response-related pathway. We also identified upregulated pro-inflammatory genes TNFRSF1A, IL1R1, and IL6R. Protein–protein interaction network analysis screened nine hub genes that were all related to innate immune response, and our transcriptomic results were highly similar to findings in human psychiatric disorders. We found that there were significant differences in the beta-diversity of gut microbiota between MSB and CONTROL macaques. Of which Phascolarctobacterium, the producer of short chain fatty acids (SCFAs), was less abundant in MSB macaques. Meanwhile, PICRUSTs predicted that SCFAs intermediates biosynthesis and metabolic pathways were significantly downregulated in MSB macaques. Together, our study revealed that the behavioral, gene expression levels, and gut microbiota composition in MSB macaques was different to controls, and MSB was closely linked with inflammation and immune response. This work provides valuable information for future in-depth investigation of MSB and human psychiatric diseases.
... Increased systemic inflammation is another physiological alteration observed in some patients with depression (Krishnadas and Cavanagh, 2012;Lopresti et al., 2014;Zou et al., 2018). It is proposed that cortisol changes disrupt homeostasis of the immune system, stimulating proinflammatory cytokines, such as interleukin 6 (IL-6), and tumor necrosis factor-α (Zunszain et al., 2011;Sousa et al., 2015). ...
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The comprehension of the pathophysiology of the major depressive disorder (MDD) is essential to the strengthening of precision psychiatry. In order to determine the relationship between the pathophysiology of the MDD and its clinical progression, analyzed by severity of the depressive symptoms and sleep quality, we conducted a study assessing different peripheral molecular biomarkers, including the levels of plasma C-reactive protein (CRP), serum mature brain-derived neurotrophic factor (mBDNF), serum cortisol (SC), and salivary cortisol awakening response (CAR), of patients with MDD ( n = 58) and a control group of healthy volunteers ( n = 62). Patients with the first episode of MDD ( n = 30) had significantly higher levels of CAR and SC than controls ( n = 32) and similar levels of mBDNF of controls. Patients with treatment-resistant depression (TRD, n = 28) presented significantly lower levels of SC and CAR, and higher levels of mBDNF and CRP than controls ( n = 30). An increased severity of depressive symptoms and worse sleep quality were correlated with levels low of SC and CAR, and with high levels of mBDNF. These results point out a strong relationship between the stages clinical of MDD and changes in a range of relevant biological markers. This can assist in the development of precision psychiatry and future research on the biological tests for depression.
... Another hallmark of high-income countries is the high prevalence of inflammation-associated neuropsychiatric disorders. For example, >1% of US women are affected by chronic fatigue syndrome [41,42] and as many as 20% of US adults may be affected by major depressive disorder [43][44][45]. Neuropsychiatric Box 1. Clearing the cloud of confusion surrounding hygiene: two types of hygiene with different effects on COVID-19 and on our immune system 1. The term hygiene can refer to either one of two very different ways of avoiding infection. ...
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Suboptimal understanding of concepts related to hygiene by the general public, clinicians, and researchers is a persistent problem in health and medicine. Although hygiene is necessary to slow or prevent deadly pandemics of infectious disease such as COVID-19, hygiene can have unwanted effects. In particular, some aspects of hygiene cause a loss of biodiversity from the human body, characterized by the almost complete removal of intestinal worms (helminths) and protists. Research spanning more than half a century documents that this loss of biodiversity results in an increased propensity for autoimmune disease, allergic disorders, probably neuropsychiatric problems, and adverse reactions to infectious agents. The differences in immune function between communities with and communities without helminths have become so pronounced that the reduced lethality of SARS-CoV-2 in low-income countries compared to high-income countries was predicted early in the COVID-19 pandemic. This prediction, based on the maladaptive immune responses observed in many cases of COVID-19 in high-income countries, is now supported by emerging data from low-income countries. Herein, hygiene is subdivided into components involving personal choice versus components instituted by community wide systems such as sewage treatment facilities and water treatment plants. The different effects of personal hygiene and systems hygiene are described, and appropriate measures to alleviate the adverse effects of hygiene without losing the benefits of hygiene are discussed. Finally, text boxes summarizing this information are provided to function as stand-alone, public-domain handouts with the goal of informing the public about hygiene and suggesting solutions for biomedical researchers and policy makers.
... When it binds to those receptors, TNF-a activates several signaling pathways that mediate different intracellular effects (43). It is reported that this cytokine could underlie the mechanism of depression through the activation of the hypothalamo-pituitary-adrenocortical (HPA) axis, the activation of neuronal serotonin transporters, and the stimulation of the indoleamine 2,3-dioxygenase which leads to tryptophan depletion by converting tryptophan in kynurenine (44). Several studies performed on animal models have linked TNF-a to the pathophysiology of major depression disorder (45), and the administration of TNF-a antagonists have been demonstrated to exert antidepressant and pro-cognitive effects in these models (46,47). ...
Article
Background: Rosmarinus officinalis L.is traditionally used as an infusion in the treatment of several diseases and in particular against neuropsychiatric disorders, such as anxiety and depression. It was established that rosemary extracts show an antidepressant effect on animal models. However, to the best of our knowledge, there is no scientific data that highlights the therapeutic effects of rosemary intake on human mental health. Aim:This study investigated whether rosemary tea consumption affects the plasma levels of anxiety and depression biomarkers in healthy volunteers. Methods:Twenty-two healthy volunteers aged between 20 and 50 years old consumed rosemary tea prepared from 5 g of dried rosemary in 100 mL boiled water once a day for 10 days. Plasma concentrations of Brain-Derived Neurotrophic Factor (BDNF), Interleukine-6 (IL-6), Interleukine-4 (IL-4), Tumor Necrosis Factor- alpha (TNF-α), Interferon-gamma (IFNϒ), and cortisol were measured by enzyme-linked immunosorbent assay using commercial ELISA kits (R&D systems) before rosemary consumption and at the end of the experiment. Results:Rosemary tea consumption significantly increased the concentration of BDNF([BDNF]D0 = 22363.86 ± 12987.66 pg/mL, [BDNF]D10 = 41803.64 ± 28109.19, p = 0.006) and TNF-α([TNF-α] D0 = 39.49 ± 14.44 pg/mL, [TNF-α] D10 = 56.24 ± 39.01, p = 0.016). However, a slight variation that was statistically non-significant in INFϒ, cortisol, IL-4, IL-6 levels and in the ratio IL-4/INFϒ was observed (p > 0.05). Conclusion:Our findings highlight the promising anxiolytic and/or antidepressant effects of rosemary tea consumption in healthy volunteers since it increases the level of the most reliable depression biomarker BDNF. However, more powerful studies with larger sample size, carefully-chosen target population and, an extended intervention period are required. Keywords: Rosemary teaBDNFanxietydepressioncytokinecortisol
... When addressing a TBI, one must be cognizant that structural, functional, and metabolic changes may have occurred (29)(30)(31)(32)(33)(34)(35)(36)(37)(38). Mechanistically, there can be substantial overlap between MDD and TBI in terms of neural disruption (6,7), with both linked with an inflammatory response within the brain that negatively influences neural pathways, neurotransmitter release, growth factors, and neurogenesis (39)(40)(41)(42). Glutamate and GABA are two of the neurotransmitters directly altered after a TBI (43) linked with MDD (44). ...
Article
Rehabilitation of cognitive and psychosocial deficits resulting from traumatic brain injury (TBI) continues to be an area of concern in health care. Commonly co-occurring psychiatric disorders, such as major depressive disorder and posttraumatic stress disorder, create additional hurdles when attempting to remediate cognitive sequelae. There is increased need for procedures that will yield consistent gains indicative of recovery of function. Intermittent theta-burst stimulation (iTBS), a form of repetitive transcranial magnetic stimulation, has potential as an instrument that can be tailored to aid cognitive processes and support functional gains. The use of iTBS enables direct stimulation of desired neural systems. iTBS, performed in conjunction with behavioral interventions (e.g., cognitive rehabilitation, psychotherapy), may result in additive success in facilitating cognitive restoration and adaptation. The purpose of this theoretical review is to illustrate how the technical and physiological aspects of iTBS may enhance other forms of neurorehabilitation for individuals with TBI. Future research on combinatorial iTBS interventions has the potential to translate to other complex neuropsychiatric conditions.
... Previous studies have however suggested a link between inflammation and depressive illness. Available data suggested that depression is associated with a higher concentration of some inflammatory cytokines [38][39][40]. Krishnadas and Cavanagh [39] however reported that in some predisposed individuals, stress could induce proinflammatory cytokine release which in-turn stimulates the release of extrahepatic enzyme Indoleamine 2, 3 dioxygenase (IDO). Thus enhanced IDO pathways possibly lead to a reduction in serotonin availability and increase in glutamate receptor activation as a result of metabolism of kynurenine into quinolinic acid. ...
Article
Background: A link between major depressive disorder (MDD) and haematological as well as co-agulation disorders has been postulated. This study aims to evaluate haematological and haemostatic changes among Nigerians with major depressive disorder Methods: Two hundred volunteers consisting of an equal number of individuals diagnosed with major depressive disorder (MDD) based on DMS-IV criteria and apparently healthy control participated in this study. The blood sample was collected into tri-sodium citrate K2EDTA bottles respectively and was evaluated for some haemostatic parameters , using ELISA, Clauss, Quick’s One Stage, Proctor and Rapaport’s methods. Results: The mean WBC, hemoglobin and differential lymphocyte were significantly higher among MDD total volunteers (p < 0.001). The red cell indices and platelet count were lower among MDD (p <0.001). Also the prothrombin time (PT), fibrinogen, protein-C and erythrocytes sedimentation rate (ESR) were all raised (p <0.001) among volunteers with MDD. Positive associations existed be-tween MCV and RBC (r: 0.364; p<0.001), PT and APTT (r: 0.319 p <0.001), APTT and fibrinogen (r: 0.239, p = 0.017) as well as PT and fibrinogen (r: 0.275 p = 0.006) at 95% confidence interval. Conclusion: Changes in total leucocytes count, lymphocytes values and haemostatic parameters among volunteers with depression may impacts deleterious effects on the immune response as well as haemostatic homeostasis, while decreased red cell indices may suggest occult nutritional anaemia.
... Growing evidence supports a link between depression and inflammatory processes (Miller and Raison, 2016;Pfau et al., 2018). It has been estimated that $1/3 of MDD patients have increased levels of circulating proinflammatory biomarkers, even in the absence of other co-existing inflammatory pathology (Raison and Miller, 2011;Krishnadas and Cavanagh, 2012) and that patients suffering from underlying inflammatory conditions such as autoimmune disorders tend to develop depressive symptoms more often than general population or healthy controls (Benros et al., 2013). This linkage is supported by a recent meta-analysis study that found a number of inflammatory markers are increased in depressed subjects compared to controls, suggestive of a proinflammatory state (Osimo et al., 2020). ...
Article
Despite the high prevalence of major depressive disorder (MDD), understanding of the biological underpinnings remains limited. Rodent models suggest that changes in activity and output of dopamine (DA) neurons in the ventral tegmental area (VTA) are important for depressive-like phenotypes. Additionally, brain inflammatory processes are thought to contribute to MDD pathology and inflammation in the VTA has been linked to changes in VTA DA neuronal activity. Thus, we sought to determine whether there is increased inflammatory signaling in the VTA following forms of chronic stress that induce depressive-like symptoms. First, we subjected male mice to either physical or vicarious chronic social defeat stress (CSDS), paradigms known to induce long-term depressive-like behavior and changes in VTA signaling. Second, we subjected male and female mice to subchronic variable stress (SCVS), a paradigm that induces depressive-like behavior only in female mice. We then isolated mRNA from the VTA and assessed proinflammatory gene regulation via RT-PCR. Our results show that physical, but not vicarious, CSDS increases interleukin 1β (IL-1β) mRNA expression and this inversely correlates with social interaction score. In contrast, IL-1β expression was unchanged in male or female mice following SCVS. No significant increases in VTA ionized calcium binding adapter molecule 1 (Iba1) and glial fibrillary acidic protein (GFAP) immunochemistry were detected following CSDS that would be indicative of a robust inflammatory response. In conclusion, we show that chronic stressors distinctively alter expression of proinflammatory genes in the VTA and changes may depend on the severity and time-course of the stress exposure.
... Major depressive disorder affects approximately 16% of the world's population (3), continues to be a major cause of disability worldwide, and is the number one cause of suicide (4). Excessive inflammation and neurodegenerative changes have been reported in MDD, both of which have been associated with cognitive impairment (5). However, the underlying pathology of MDD remains poorly understood, in part due to the heterogeneity of genetic and environmental factors related to proposed mechanisms of action (6). ...
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Alterations in the peripheral (e.g., serum, plasma, platelet) concentrations of arginine and its related catabolic products (i.e., ornithine, citrulline) in the urea and nitric oxide cycles have been reported to be associated with major depressive disorder (MDD). The meta-analysis herein aimed to explore the association between the concentration of peripheral arginine, its catabolic products and MDD, as well as to discuss the possible role of arginine catabolism in the onset and progression of MDD. PubMed, EMBASE, PsycINFO and Web of Science were searched from inception to June 2020. The protocol for the meta-analysis herein has been registered at the Open Science Framework [https://doi.org/10.17605/osf.io/7fn59]. In total, 745 (47.5%) subjects with MDD and 823 (52.5%) healthy controls (HCs) from 13 articles with 16 studies were included. Fifteen of the included studies assessed concentrations of peripheral arginine, eight assessed concentrations of ornithine, and six assessed concentrations of citrulline. Results indicated that: (1) the concentrations of arginine, ornithine, and citrulline were not significantly different between individuals with MDD and HCs when serum, plasma and platelet are analyzed together, (2) in the subgroups of serum samples, the concentrations of arginine were lower in individuals with MDD than HCs, and (3) concurrent administration of psychotropic medications may be a confounding variable affecting the concentrations of arginine, ornithine, and citrulline. Our findings herein do not support the hypothesis that arginine catabolism between individuals with MDD and HCs are significantly different. The medication status and sample types should be considered as a key future research avenue for assessing arginine catabolism in MDD.
... Это означает, что разбалансировка метаболизма аденозина, как основной триггерной молекулы запускающий секрецию глутамата через аденозин-связывающие рецепторы (например, ADORA2A, ген Adora2A +114) будет приводить или к депрессии, связанной с длительным потенциированием возбуждения (гиперфункция NMDA-системы), или к депрессии, связанной с отсутствием активации трансмиттерных сигнальных систем (гипофункция NMDA-системы) при нарушении секреции глутамата при дефиците аденозина и избытке АТФ. При этом избыток АТФ будет усиливать воспаление микроглии, что усугубит способность микроглиальных макрофагов синтезировать экто 5 нукелеотидгидролазу, и что приведет к акселеративному усилению деструктивного процесса [31,32]. Также этот означает, что действие факторов каннабиноидной системы (например, ADHD12b, ген Adhd12b +78), может изменить сложившуюся разбалансировку активирующего влияния глутамата, что будет способствовать восстановлению нейронных связей и купированию депрессивного синдрома. ...
Article
In the current report, the effect of bioactive compounds of the M2 macrophage secretome on transcription of hippocampal genes in mice with a depression-like condition caused by social stress has been investigated. Surgically resected hippocampus was used for mRNA isolation with following RNA sequencing procedures. Comparative analysis of transcriptomes from the control depressive mice treated with physiological saline solution and mice after intranasal administration of M2 macrophages-conditioned medium revealed that remission of the depressive-like state is associated with a significant up- and downregulation of a number of genes, which were found to participate in restoration/regulation of ATP/Adenosine balance. Among the events associated with positive changes in behavioral pattern of depressive mice, the switch of microglial environment from a pro-inflammatory phenotype to an anti-inflammatory one, and subsequent restoration of compromised cannabinoid and glutamatergic transmitter pathways has been predicted.
... COPD represents a type of chronic inflammation that is characterized by neutrophil infiltration [44]. Another study found that the excessive or prolonged production of proinflammatory cytokines could cause anxiety and chronic inflammation [45]. Bratek et al. found that anxiety test scores were positively correlated with the relative number of neutrophils in induced sputum. ...
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Abstract Background: Anxiety is a common comorbidity associated with chronic obstructive pulmonary disease (COPD), but no well-recognized method can provide effective relief. Liuzijue Qigong (LQG) is a traditional Chinese fitness method, based on breath pronunciation. This study aimed to examine the efficacy of LQG to relieve anxiety in COPD patients and to explore the factors that influence anxiety, including whether LQG is effective during the coronavirus disease 2019 (COVID-19) outbreak. Methods: We conducted an open-label, randomized, controlled, clinical trial. A total of 60 patients with stable COPD were randomly assigned to two groups. Both groups were given routine medical treatment, and the patients in the pulmonary rehabilitation (PR) group were given an extra intervention in the form of LQG, performed for 30 minutes each day for 12 weeks. Data collection was performed at baseline and 12 weeks (during the COVID-19 epidemic). The primary outcomes were the self-rating anxiety scale (SAS) scores, and the secondary outcomes were relevant information during the epidemic and analyses of the related factors that influenced SAS scores during the COVID-19 outbreak. Results: Compared with baseline, patients in both groups demonstrated varying degrees of improvements in their SAS scores (all P < 0.01). An analysis of covariance, adjusted for baseline scores, indicated that the SAS scores improved more dramatically in the PR group than in the control group (F = 9.539, P = 0.004). During the outbreak, the SAS scores for sleep disorder were higher than all other factors, reaching 1.38 ± 0.67, and the scores for “I can breathe in and out easily” for the PR group were lower than the scores for the control group (Z = -2.108, P = 0.035). Significant differences were identified between the two groups for the categories “How much has the outbreak affected your life”, “Do you practice LQG during the epidemic” and “Do you practice other exercises during the epidemic” (all P < 0.05). Compared with current reports, LQG had a relatively high adherence rate (80.95%). A multiple linear regression analysis revealed multiple predictors for SAS scores during the outbreak: group (b = -3.907, t = -3.824, P < 0.001), COPD assessment test score (b = 0.309, t = 2.876, P = 0.006), SAS score at baseline (b = 0.189, t = 3.074, P = 0.004), and living in a village (b = 4.886, t = 2.085, P = 0.043). Conclusion: LQG could effectively reduce the risks of anxiety among COPD patients, even during the COVID-19 outbreak. For those COPD patients with high COPD assessment test and high baseline SAS scores or who live in villages, we should reinforce the management and intervention of psychological factors during the epidemic.
... Επίσης, στο πλαίσιο της κατάθλιψης υπάρχει αύξηση βιοδεικτών φλεγμονής (περιφερικοί δείκτες φλεγμονής -όπως IL-6, IL-1β, CRP και TNFα -είναι αυξημένοι σε κατά τα άλλα υγιή άτομα με ΜΚΔ, ενώ μετα-ανάλυση 24 μελετών προσδιορισμού κυτταροκινών σε ασθενείς με κατάθλιψη έδειξε σημαντικά υψηλότερες τιμές TNFa και IL6 σε σύγκριση με μάρτυρες). 68 Επιπλέον, έχει φανεί ότι έκθεση σε ανοσοτροποποιητικούς παράγοντες αυξάνει τον κίνδυνο για κατάθλιψη (χορήγηση ιντερφερόνης α για ηπατίτιδα C, μελάνωμα, CA νεφρών, αιματολογικές κακοήθειες ή κονδυλώματα: το 16-58% των ασθενών αναπτύσσουν κατάθλιψη), 69 ενώ το στρες κινητοποιεί προφλεγμονώδεις οδούς (το οξύ και το χρόνιο στρες συνοδεύεται από αύξηση των προφλεγμονωδών κυτταροκινών και ελάττωση των αντιφλεγμονωδών). Οι προφλεγμονώδεις κυτταροκίνες ενεργοποιούν την IDO (indoleamine 2,3-dioxygenase, εξωηπατικό ένζυμο), η οποία αποδομεί την τρυπτοφάνη προς την πλευρά της παραγωγής κυνουρενίνης (και όχι, όπως η υδροξυλάση της τρυπτοφάνης, προς την παραγωγή σεροτονίνης). ...
Article
Treatment resistant depression is associated with serious and persistent symptomatology, chronic course, reduced quality of life, high rates of comorbidity with medical conditions or other mental disorders, increased indirect health care cost, increased suicidality and risk for hospitalization, negative impact to patients' functioning and occupation and poor treatment outcomes in general. The concept of treatment resistant depression emerged in the 1970s to describe a group of patients suffering from major depressive disorder who failed to reach remission of symptoms after at least two trials with antidepressant (efficient regarding dosage, compliance, and duration). Despite the introduction of many antidepressants over the following years, a large proportion of depressed patients fail to respond to available treatments, and this constitutes a continuing therapeutic challenge.
... Depression probably represents a maladaptive version of cytokine-induced sickness, which might occur in the presence of an exacerbation in intensity and/or duration of the innate immune response, or in the case of increased vulnerability to depression [59]. Moreover, depression occurs at a substantially higher rate in patients with inflammatory disorders such as multiple sclerosis, psoriasis, rheumatoid arthritis, inflammatory bowel disease [70,71], myocardial infarction [72]. ...
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According to the World Health Organization, the major psychiatric and neurodevelopmental disorders include major depression, bipolar disorder, schizophrenia, and autism spectrum disorder. The potential role of inflammation in the onset and progression of these disorders is increasingly being studied. The use of non-steroidal anti-inflammatory drugs (NSAIDs), well-known cyclooxygenase (COX) inhibitors, combined with first-choice specific drugs have been long investigated. The adjunctive administration of COX inhibitors to classic clinical treatments seems to improve the prognosis of people who suffer from psychiatric disorders. In this review, a broad overview of the use of COX inhibitors in the treatment of inflammation-based psychiatric disorders is provided. For this purpose, a critical analysis of the use of COX inhibitors in the last ten years of clinical trials of the major psychiatric disorders was carried out.
... Indeed, the mechanism by which inflammatory markers affect behavioral and emotional outcomes has been extensively discussed (Amodeo et al., 2017;Dantzer et al., 2008). Evidence suggests that inflammatory cytokines in the brain can change the structure and function of the brain by altering neurotransmission, hippocampal neurogenesis, and stress-related hypothalamic-pituitary-adrenal axis and sympathetic system activation (Krishnadas and Cavanagh, 2012). These alterations may lead to changes in cognition and can produce depressive symptoms. ...
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Background Increasing evidence suggests that youth with Major Depressive Disorder (MDD) exhibit early indicators of cardiovascular disease. A leading hypothesized mechanism of this association is via inflammatory pathways, however, results examining this direct association are mixed. Our objective was to synthesize and quantify observational studies examining the association of depression and inflammation among children and adolescents. Methods Electronic searches were conducted in MEDLINE, Embase, PsycINFO, and Scopus, yielding 2,757 non-duplicate records from 1946 to 2019. The included studies measured depression or depressive symptoms and examined its association with inflammation in participants younger than 18 years. All relevant articles were reviewed and data extracted by two independent coders. Estimates were examined by using random-effects meta-analysis. Results Twenty-two studies (20,791 participants) were included. Significant associations were observed between concurrent depression and CRP (n = 7; r = 0.12; 95% confidence interval [CI] = 0.04 to 0.19), and IL-6 (n = 7; r = 0.17; 95% CI= 0.10 to 0.24). Longitudinal analyses revealed that depression is a significant predictor of IL-6 (n = 3; r = 0.29; 95% CI= 0.04 to 0.50) and conversely, that inflammation (measured by CRP or IL-6) predicts future depression (n = 4; r = 0.04; 95% CI= 0.00 to 0.08). Limitations Results are limited by the small number of studies preventing examination of some moderator variables. Findings are correlational, not causal. Conclusion Depression is positively associated with concurrent and future inflammation among children and adolescents. Results suggest that bidirectional associations may exist between depression and a pro-inflammatory state.
... The occurrence of systemic inflammation in mouse models was ostensible from the activation of the peripheral adaptive immune response through haptenated metabolite of PER (Joshi et al., 2018), the altered microbiome in the gut causing portal endotoxemia and activation of TLR4 signaling in the small intestine (Alhasson et From multiple studies in rat and mouse models of GWI, it appears that cognitive and mood dysfunction in GW veterans is likely due to a combination of factors. First, the persistent oxidative stress and inflammation in the brain could considerably interfere with the cognitive and mood function (Krishnadas & Cavanagh, 2012;Navakkode, Liu, & Soong, 2018;McGrattan et al., 2019;Carlessi, Borba, Zugno, Quevedo, & Reus, 2019). While the inflammatory response of an organism is a defense mechanism in a state of redox balance, dysregulation of the immune response occurs with increased oxidative stress (Solleiro-Villavicencio & Rivas-Arancibia, 2018). ...
Article
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Gulf War Illness (GWI), a chronic multisymptom health problem, afflicts~30% of veterans served in the first GW. Impaired brain function is among the most significant symptoms of GWI, which is typified by persistent cognitive and mood impairments, concentration problems, headaches, chronic fatigue, and musculoskeletal pain. This review aims to discuss findings from animal prototypes and veterans with GWI on mechanisms underlying its pathophysiology and emerging therapeutic strategies for alleviating brain dysfunction in GWI. Animal model studies have linked brain impairments to incessantly elevated oxidative stress, chronic inflammation, inhibitory interneuron loss, altered lipid metabolism and peroxisomes, mitochondrial dysfunction, modified expression of genes relevant to cognitive function, and waned hippocampal neurogenesis. Furthermore, the involvement of systemic alterations such as the increased intensity of reactive oxygen species and proinflammatory cytokines in the blood, transformed gut microbiome, and activation of the adaptive immune response have received consideration. Investigations in veterans have suggested that brain dysfunction in GWI is linked to chronic activation of the executive control network, impaired functional connectivity, altered blood flow, persistent inflammation, and changes in miRNA levels. Lack of protective alleles from Class II HLA genes, the altered concentration of phos-pholipid species and proinflammatory factors in the circulating blood have also been suggested as other aiding factors. While some drugs or combination therapies have shown promise for alleviating symptoms in clinical trials , larger double-blind, placebo-controlled trials are needed to validate such findings. Based on improvements seen in animal models of GWI, several antioxidants and anti-inflammatory compounds are currently being tested in clinical trials. However, reliable blood biomarkers that facilitate an appropriate screening of veterans for brain pathology need to be discovered. A liquid biopsy approach involving analysis of brain-derived extracellular ves-icles in the blood appears efficient for discerning the extent of neuropathology both before and during clinical trials. Published by Elsevier Inc.
... For example, immune system dysregulation, characterized by chronic activation of pro-inflammatory mechanisms, is associated with both poor physical performance and depressive symptoms. Inflammatory cytokines, such as C-reactive protein (CRP) and interleukin (IL) are able to cross the blood-brain barrier and disrupt amygdala and anterior cingulate cortex function (Krishnadas and Cavanagh, 2012), and have been linked with subsequent depressive symptoms (Smith et al., 2018). In addition, higher circulating levels of CRP and IL-6 have been shown to be related to poorer walking performance in a cross-sectional study (Taaffe et al., 2000). ...
Article
Impaired mobility often co-occurs with depression. However, there is no systematic review evidence as to whether mobility impairments precede the onset of depression. The objective of this systematic review and meta-analysis was to evaluate whether mobility impairment could predict incident depression. A systematic search of cohort studies were performed in MEDLINE, EMBASE, CINAHL and PsycINFO. The target population was people with no depressive symptoms at baseline and follow-up for depression or depressive symptoms of at least three months. Of 1061 identified abstracts, 13 studies met the review eligibility criteria. The majority of included studies (8 out of 13) were of high methodological quality. Follow-up periods ranged from 12 months to 16 years. Gait speed was the most consistently reported mobility measure. Participants with slow gait speed were at higher risk of developing depressive symptoms (pooled OR = 1.93, 95%CI: 1.54 to 2.42, 11 studies). This review shows that slow gait speed is predictive of the onset of depressive symptoms. Systematic review registration number: CRD42020153791
... 36 Numerous studies have shown that patients with depression have significantly increased levels of inflammatory markers in the central and peripheral tissues. 37 In particular, IL-6 is one of the inflammatory markers increasing most discernably in blood samples of patients with depression. Imaging studies have found that ECT may reduce IL-6 levels, reversing the changes in brain structure caused by increased IL-6 levels, thereby relieving symptoms of depression. ...
Article
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Background: The occurrence of depression was related with a state of mild hypoxia for a long time. Hypoxia-inducible factor-2α (HIF-2α) modulates the process from acute to chronic hypoxia, consequently regulating changes in inducible nitric oxide synthase (iNOS). Increasing levels of iNOS combined with major depressive disorder (MDD) have been associated with the concentration of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), which increase the severity of depression. Objective: The aim was to investigate whether depressive symptoms might be improved by regulating HIF-2α levels to decrease the degree of oxidative stress and inflammation using electroconvulsive therapy (ECT). Methods: In this observational study, 49 MDD patients were divided into the ECT group (n=32) and control group (n=17). The Hamilton Depression Rating Scale (HAMD) was used to evaluate depressive symptoms of patients at enrollment and after 2 weeks of treatment. The levels of HIF-2α, NOS, IL-6, and TNF-α in plasma were analyzed accordingly. Results: The total score in each dimension of HAMD decreased more efficiently in the ECT group than in the control group (p < 0.05). The plasma levels of IL-6 in the ECT group were notably decreased after the 2-week treatment (t = 3.596, p = 0.001). The decreased trend to statistical significance of HIF-2α was observed after treatment in the ECT group (p = 0.091). Conclusion: The present study demonstrated that the therapeutic effects of long-term ECT therapy for MDD may further benefit from and contribute to the improvement of MDD-associated chronic hypoxia.
Article
Depression is a serious disease that has considerable impact on lipid metabolism and inflammatory responses. Recent studies have shown that leptin, which is well known as a mediator of energy homeostasis and is a cytokine in inflammatory response, plays an important role in depression. Acupuncture is widely used to treat depression; however, the underlying mechanisms and the effect of acupuncture on depression remain poorly understood. In this study, we utilized the chronic restraint stress (CRS) induced depression model and acupuncture treatment was performed at KI10, LR8, LU8, LR4 (AP) or non-acupoint (NP). Then, lipidomics was applied to investigate the effects of acupuncture on lipid metabolism and analyze leptin signals in the brain and changes of immune markers. Acupuncture treatment at AP improved depression-like behavior in an open-field test, forced swimming test, and marble burying test. Concurrently, CRS mice treated with AP acupuncture (CRS+AP) had significantly lower levels of aspartate aminotransaminase (AST, liver injury markers) and exhibited different lipid patterns in liver lipidomic profiles. In particular, triglycerides (TGs) contributed the change of lipid patterns. Compared to CRS mice, TG with relatively high degrees of unsaturated fatty acids increased in CRS+AP mice, but did not change in CRS+NP mice. The levels of leptin in plasma and leptin receptor positive cells in the brain (hypothalamus and hippocampus) decreased and increased, respectively, in CRS+AP mice, while opposite patterns were exhibited in CRS and CRS+NP mice. These results indicated that acupuncture treatment at AP attenuated leptin insensitivity in CRS mice. Additionally, expression of pro-inflammatory cytokines such as interleukin-1 beta and tumor necrosis factor-alpha were decreased in the spleen, plasma, and liver of CRS+AP mice, which was one of results of alleviation of leptin resistance. In conclusion, these results show that AP acupuncture treatment effectively alleviated the depression-like behavior, affected immune responses, and altered hepatic lipid metabolism through the attenuation of leptin insensitivity.
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Inflammation has been reliably associated with depression. However, the directionality of this association is poorly understood, with evidence that elevated inflammation may promote and precede the development of depression, as well as arise following its expression. Using data from older adults (N = 1,072, ages 60-73) who participated in the ongoing longitudinal St. Louis Personality and Aging Network (SPAN) study, we examined whether inflammatory markers (interleukin-6: IL-6, C-reactive protein: CRP, and tumor necrosis factor α: TNFα) and depression were prospectively predictive of one another. Fasting serum samples and self-reports of depressive symptoms (Beck Depression Inventory-II) were obtained from participants at 2 sessions approximately 2 years apart. Structural equation models as well as regressions that accounted for a host of potentially confounding covariates as well as depression at baseline revealed that baseline IL-6 and CRP, but not baseline TNFα were associated with elevated depressive symptoms at the follow-up session (IL-6: β = 0.080, p = 0.036; CRP: β = 0.083, p = 0.03; TNFα: β = 0.039, p = 0.314). However, there was no association between baseline depressive symptoms and follow-up inflammatory markers (βs = -0.12 - -0.006, all ps > 0.05). Collectively, these data suggest that inflammation prospectively predicts depression, but depression does not predict inflammation in older age. These data add to a growing literature suggesting that inflammatory signaling may plausibly promote the development of depression.
Article
Objectives Vitamin E has various functions in humans, including antioxidant, anti-inflammatory, anti-cancer, and anti-atherogenic actions, as well as direct effects on enzymatic activities and modulation of gene transcription. In addition to these functions, vitamin E is also important for the central nervous system, and its role in the prevention and/or treatment of some neurological diseases has been suggested. In particular, the role of vitamin E in the modulation of major depressive disorder (MDD) is an issue that has emerged in recent studies. Many factors have been implicated in the pathophysiology of this disorder, including inflammation, oxidative, and nitrosative stress. Methods This narrative review discusses the involvement of inflammation, oxidative, and nitrosative stress in the pathophysiology of MDD and presents clinical and preclinical studies that correlate vitamin E with this psychiatric disorder. Results We gathered evidence from clinical studies that demonstrated the relationship between low vitamin E status and MDD symptoms. Vitamin E has been reported to exert a beneficial influence on the oxidative and inflammatory status of individuals, factors that may account for the attenuation of depressive symptoms. Preclinical studies have reinforced the antidepressant-like response of vitamin E, and the mechanisms underlying its effect seem to be related to the modulation of oxidative stress and neuroinflammation. Conclusion We suggest that vitamin E has potential to be used as an adjuvant for the management of MDD, but more studies are clearly needed to ascertain the efficacy of vitamin E for alleviating depressive symptoms.
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Major Depressive Disorder (MDD) is a leading cause of disability worldwide, creating a high medical and socioeconomic burden. There is a growing interest in the biological underpinnings of depression, which are reflected by altered levels of biological markers. Among others, enhanced inflammation has been reported in MDD, as reflected by increased concentrations of inflammatory markers—C-reactive protein, interleukin-6, tumor necrosis factor-α and soluble interleukin-2 receptor. Oxidative and nitrosative stress also plays a role in the pathophysiology of MDD. Notably, increased levels of lipid peroxidation markers are characteristic of MDD. Dysregulation of the stress axis, along with increased cortisol levels, have also been reported in MDD. Alterations in growth factors, with a significant decrease in brain-derived neurotrophic factor and an increase in fibroblast growth factor-2 and insulin-like growth factor-1 concentrations have also been found in MDD. Finally, kynurenine metabolites, increased glutamate and decreased total cholesterol also hold promise as reliable biomarkers for MDD. Research in the field of MDD biomarkers is hindered by insufficient understanding of MDD etiopathogenesis, substantial heterogeneity of the disorder, common co-morbidities and low specificity of biomarkers. The construction of biomarker panels and their evaluation with use of new technologies may have the potential to overcome the above mentioned obstacles.
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Neuropsychiatric aspects of chronic hepatitis C virus infection in the absence of liver cirrhosis.
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Macrophages can acquire a plethora of effector functions in response to the surrounding cytokines and tissue environment. Depending on their ontogeny and the prevailing extracellular stimuli, macrophages become specialized (“polarized”) for pathogen elimination and immune response promotion, or for tissue repair, wound healing and immunosuppression. This “polarization” versatility underlies the macrophage ability to maintain tissue homeostasis, as well as to initiate and resolve inflammatory responses. Recent findings indicate that macrophage functional polarization can be modulated through engagement of serotonin (5-HT) receptors on the macrophage cell surface. In the present chapter, we summarize the current knowledge on the physio-pathological relevance of the expression of serotonin receptor 5-HT2B on macrophages and other myeloid cells, and discuss its value as a functionally-relevant polarization marker and a potential therapeutic target in inflammatory responses.
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Psychiatric illnesses, including depression and anxiety, are highly comorbid with epilepsy (for review see Josephson and Jetté (Int Rev Psychiatry 29:409–424, 2017), Salpekar and Mula (Epilepsy Behav 98:293–297, 2019)). Psychiatric comorbidities negatively impact the quality of life of patients (Johnson et al., Epilepsia 45:544–550, 2004; Cramer et al., Epilepsy Behav 4:515–521, 2003) and present a significant challenge to treating patients with epilepsy (Hitiris et al., Epilepsy Res 75:192–196, 2007; Petrovski et al., Neurology 75:1015–1021, 2010; Fazel et al., Lancet 382:1646–1654, 2013) (for review see Kanner (Seizure 49:79–82, 2017)). It has long been acknowledged that there is an association between psychiatric illnesses and epilepsy. Hippocrates, in the fourth–fifth century B.C., considered epilepsy and melancholia to be closely related in which he writes that “melancholics ordinarily become epileptics, and epileptics, melancholics” (Lewis, J Ment Sci 80:1–42, 1934). The Babylonians also recognized the frequency of psychosis in patients with epilepsy (Reynolds and Kinnier Wilson, Epilepsia 49:1488–1490, 2008). Despite the fact that the relationship between psychiatric comorbidities and epilepsy has been recognized for thousands of years, psychiatric illnesses in people with epilepsy still commonly go undiagnosed and untreated (Hermann et al., Epilepsia 41(Suppl 2):S31–S41, 2000) and systematic research in this area is still lacking (Devinsky, Epilepsy Behav 4(Suppl 4):S2–S10, 2003). Thus, although it is clear that these are not new issues, there is a need for improvements in the screening and management of patients with psychiatric comorbidities in epilepsy (Lopez et al., Epilepsy Behav 98:302–305, 2019) and progress is needed to understand the underlying neurobiology contributing to these comorbid conditions. To that end, this chapter will raise awareness regarding the scope of the problem as it relates to comorbid psychiatric illnesses and epilepsy and review our current understanding of the potential mechanisms contributing to these comorbidities, focusing on both basic science and clinical research findings.
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The relationship between temperament as a manifestation of personality and mood disorders comes from Greek antiquity. Throughout history, the relationship between personality and depression has been conceptualized in at least four ways: (1) Personality is a predisposing or vulnerability factor for the development of depression. (2) Personality changes are a consequence of mood alteration resulting from depression. (3) Personality is a subclinical manifestation of depression (affective temperaments). And (4) personality characteristics influence the manner in which depression clinically manifests. Currently, there is a tendency to recover the concept of affective temperaments (depressive, hypertensive, cyclothymic, irritable, and anxious), considering them as subclinical manifestations of some disorder within the affective spectrum. These temperaments have been shown to be universal, with distinctive characteristics and without gender differences. Although in depressive illness there is important evidence regarding both functional and structural neurobiological alterations, much less is known about the biological findings of personality dysfunction in depression. One reason, in part, is that explanatory models are required that integrate various levels of analysis, including the different types of gene-environment relationships. In this chapter, we will review the relationship between personality and depression, then we will describe the main neurobiological findings underlying personality dysfunction in depression, and finally we will analyze the relationship between genes and environment in depression, taking into account the approach of differential sensitivity to environmental stimuli. We will conclude with some recommendations for future research.
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Background: The aim of this study is to investigate whether symptoms of anxiety and depression disorders in women during the perinatal period predict the occurrence of lactation mastitis. Methods: This is a retrospective longitudinal study of 622 Greek women who were monitored from pregnancy until the first year postpartum (during the period January 2015-May 2018). The Edinburgh Postnatal Depression Scale (EPDS) and the Perinatal Anxiety Screening Scale (PASS) were administered at four time points: (a) 24th-28th gestation week, (b) 34th-38th gestation week, (c) 6 weeks postpartum, and (d) 12 months postpartum. Multivariate binary logistic regression analyses were performed. Results: Results showed that (a) increased EPDS (p < 0.02) and PASS (p < 0.05) scores during the last period before birth, (b) increased EPDS score at 6 weeks postpartum (p < 0.02), (c) PMS symptoms (p < 0.03), (d) traumatic life events during the last year (p < 0.03), and (e) the existence of a history of psychotherapy (before pregnancy) (p = 0.050) appear to be the psycho-emotional factors that can predict the possible occurrence of lactation mastitis in a breastfeeding mother. Conclusions: The association between women's poor mental health and the occurrence of a physical health problem, such as lactation mastitis, is recognized. This study highlights the important role of early and timely detection of perinatal mental health disorders.
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The high prevalence and variability of neurological and psychiatric symptoms in systemic lupus erythematosus has become the basis for emphasizing the special neuropsychiatric form of the disorder. Affective disorders (pathological changes in mood and anxiety) are the second most common neuropsychiatric manifestations in patients with systemic lupus erythematosus. However, the current nomenclature primarily focuses on the general clinical manifestations of affective disorders in neuropsychiatric form systemic lupus erythematosus, without evaluating the problems of their etiopathogenesis. Thereby, the aim of this review is the integration of information on the pathological mechanisms of depression and anxiety in patients with systemic lupus erythematosus. The available data on the biological aspects of the anxiety and depression in systemic lupus erythematosus indicate that the complex pathological models may be the best approach for studying, diagnosing, and treating comorbid pathology. The latter can be based on expanding the existing clinical categories, supplementing them with data on pathological mechanisms specific to particular sub-cohorts of patients. Such an approach can provide the specific and most effective preventive, diagnostic and therapeutic measures for each category of patients.
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A new series of enkephalin-like tetrapeptide analogs modified at the C-terminus by an N-(3,4-dichlorophenyl)-N-(piperidin-4-yl)propionamide (DPP) moiety were designed, synthesized, and tested for their binding affinities at opioid receptors and monoamine transporters to evaluate their potential multifunctional activity for the treatment of chronic pain. Most ligands exhibited high binding affinities in the nanomolar range at the opioid receptors with a slight delta-opioid receptor (DOR) selectivity over mu-opioid receptor (MOR) and kappa-opioid receptor (KOR) and low binding affinities in the micromolar range at the monoamine transporters, SERT and NET. Ligands of which the positions 1 and 4 were substituted by Dmt and Phe(p-X) residues, respectively, showed the excellent binding affinities at three opioid receptors. Among them, Dmt-D-Tic-Gly-Phe(4-F)-DPP was the most promising considering its excellent opioid affinities, particularly unexpected high binding affinity (Ki = 0.13 nM) at the KOR, and moderate interactions with serotonin/norepinephrine reuptake inhibitors (SNRIs). Docking studies revealed that the ligand was a good fit for the KOR binding pocket (binding score = 8,750).
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Several traits related to positive and negative affect show a high genetic as well as phenotypic correlation with well-being in humans, and are therefore collectively termed as “Well-being spectrum”. Genome-Wide Association studies (GWA studies) on “well-being measurement” have led to identification of several genomic variants (Single Nucleotide Variants - SNVs), but very little has been explained with respect to their functionality and mode of alteration of well-being. Utilizing a pool of 1258 GWA studies based SNVs on “well-being measurement”, we prioritized the SNVs and tried to annotate well-being related functionality through several bioinformatic tools to predict whether a protein sequence variation affects protein function, as well as experimentally validated datasets available in ENCODE based web-tools namely rSNPBase, RegulomeDB, Haploreg, along with GTEx Portal and STRING based protein interaction networks. Prioritization yielded three key SNVs; rs3781627-A, rs13072536-T and 5877-C potentially regulating three genes, PSMC3, ITIH4 and SERPINC1, respectively. Interestingly, the genes showed well clustered protein-protein interaction (maximum combined confidence score >0.4) with other well-being candidate genes, namely TNF and CRP genes suggesting their important role in modulation of well-being. PSMC3 and ITIH4 genes are also involved in driving acute phase responses signifying a probable cross-talk between well-being and psychoneuroimmunological system. To best of our knowledge this study is the first of its kind where the well-being associated GWA studies-SNVs were prioritized and functionally annotated, majorly based on functional data available in public domain, which revealed PSMC3, ITIH4 and SERPINC1 genes as probable candidates in regulation of well-being spectrum.
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Depression induced by unpredictable chronic stress (UCS) has been widely studied using animal models. However, its underlying pathological mechanisms remain unclear. Increased inflammatory cytokines (ICs) in the central nervous system (CNS) are closely related to depressive disorder. UCS was used as an animal model in this study to investigate how UCS-induced changes in cytokine signaling lead to depression. We found that UCS could increase ICs in the CNS, especially in the habenular nucleus (Hb). UCS resulted in decreased expression of Menin in Hb and increased the activation of the NF-κB signaling pathway. Local administration of tumor necrosis factor-α in the lateral Hb (LHb) could induce depressive-like behavior in rats. The anti-inflammatory drug aspirin and the NF-κB inhibitor pyrrolidine dithiocarbamate could alleviate depressive-like behavior. This phenomenon was not observed for local administration in the dorsal raphe nucleus and paraventricular nucleus. These results indicate that LHb is the main central target for ICs to regulate depressive-like behaviors. We also found that LHb lesions could improve the inflammatory response in the hippocampus, reduce the activation of the NF-κB signaling pathway and the expression of ICs, and increase the expression of brain-derived neurotrophic factor and its receptor tropomyosin receptor kinase B, collectively improving the neuroinflammation caused by UCS. Moreover, LHb lesions improve not only hippocampal neurogenesis damage caused by UCS by activating the PI3K/mTOR signaling pathway but also hippocampal function by reducing the expression of apoptosis-related proteins, including phosphorylated p53, Bax, Bcl2, and cleaved-caspase3. In conclusion, our study sheds light on the pathogenesis of ICs-induced depression. Anti-inflammation in the CNS could be a new strategy in the treatment of depression.
Article
Objective To determine associations between dietary intake and well-being in pregnancy. Methods This retrospective cohort analysis combined three studies; The ROLO Study (a Randomised cOntrol trial of a LOw glycemic index diet in pregnancy), the PEARS study (Pregnancy Exercise And nutrition Research Study with smartphone app support) and a probiotic Randomised control trial. All data were collected prior to study interventions (16 weeks). Dietary intakes during pregnancy were determined using 3-day food diaries. The WHO-5 item Well-Being Index was used to assess mental well-being. Initial associations were evaluated using Pearson correlations, and further defined with multiple regression analysis adjusted for age, BMI, HP deprivation index and MET scores. Results 1,521 women were included in the analysis; mean age 32±4 years and BMI 27kg/m² (IQR 17-56kg/m²). The mean well-being score was 59%. Regression analysis showed that fibre (B = 0.07, p=0.02), magnesium (B=0.08, p<0.01), niacin (B=0.09, p<0.01), thiamine (B=0.07, p=0.01) and folate (b=0.08, p=0.02) were all positively and significantly associated with well-being in a pregnant population. Benjamini-Hochberg procedure to correct for multiple testing was applied; and significance remained. Conclusion Maternal nutrition and well-being are related during early pregnancy. Our findings suggest that fibre, magnesium, and particular B vitamins may be of importance for promoting positive mental well-being during pregnancy.
Article
Background: Patients wtih type 2 diabetes mellitus (DM) have an increased risk of depressive symptoms. Whether serum neutrophil gelatinase-associated lipocalin (NGAL) is associated with depressive symptoms in old patients with type 2 DM is still uncertain. Objective: We aim to investigate whether serum NGAL levels were associated with elevated risk of depressive symptoms in patients with type 2 DM in an old population. Methods: Blood samples from 1012 hospitalized patients were measured for serum NGAL within the first 24 hours after admission. The Center for Epidemiological Studies Depression (CES-D) scale was performed to calculate depressive score. Cox analyses were used to examine the prognostic value of serum NGAL on detecting depressive symptoms during a median period of 5 years (range = 0.3-6.2 years). Results: 136 (36.6)% of all subjects have depressive symptoms during the follow-up period. Linear analysis showed that serum NGAL levels at baseline were associated with CES-D score after adjusting for clinically relevant variables in type 2 DM patients (Sβ = 0.118, 95% CI 0.106-0.171, P < .001) but not in non-DM patients (Sβ = 0.025, 95% CI, -0.047-0.083; P = .205). Cox analysis revealed that serum NGAL did have an independent prognostic value on predicting depressive symptoms (HR = 2.247, 95% CI 1.415-3.811, P-trend<0.001, Model 2) in type 2 DM patients but not in non-DM patients (HR = 1.811, 95% CI 1.209-3.292, P-trend = 0.189, Model 2) during follow-up period. Conclusions: We found the first evidence that serum NGAL were strongly associated with depressive symptoms in patients with type 2 DM but not in non-DM patients. Further studies are needed to prove the underlying mechanism for the impact of type 2 DM on the association.
Article
The neutrophil to lymphocyte ratio (N:L) is an emergent transdiagnostic biomarker shown to predict peripheral inflammation as well as neuropsychiatric impairment. The afferent signaling of inflammation to the central nervous system has been implicated in the pathophysiology of sickness behavior and depression. Here, the N:L was compared to structural and functional limbic alterations found concomitant with depression within a geriatric cohort. Venous blood was collected for a complete blood count, and magnetic resonance imaging as well as phenotypic data were collected from the 66 older adults (aged 65–86 years) from the [MASKED FOR REVIEW]. The N:L was regressed on gray matter volume and resting-state functional connectivity (rsFC) of the subgenual anterior cingulate (sgACC). Thresholded parameter estimates were extracted from structural and functional brain scans and bivariate associations tested with scores on the geriatric depression scale. Greater N:L predicted lower volume of hypothalamus and rsFC of sgACC with ventromedial prefrontal cortex. Both parameters were correlated (p < 0.05) with greater symptomology in those reporting moderate to severe levels of depression. These findings support the N:L as a transdiagnostic biomarker of limbic alteration underpinning mood disturbance in non-treated older adults.
Article
The association between pro-inflammatory cytokines and depression is widely acknowledged. However, longitudinal data that show they lead to depression are few. In a community-based sample of older individuals (n = 2761, ages = 55–98 y) in the Singapore Longitudinal Ageing Study (SLAS), we analyzed the associations between inflammatory markers (CRP, IL6, TNFα, and inflammation risk score) and depression (defined as the presence of depressive symptoms, depression history or treatment). Cross-sectional analysis showed that CRP, IL-6 and TNFα were significantly associated with depression at baseline. Longitudinal analysis controlling for a host of potentially confounding risk factors and initial depression revealed that IL-6, TNFα, and inflammation risk score were associated with elevated risk of depression at follow-ups. However, there was no significant association between CRP and subsequent depression after adjusting for sociodemographic, lifestyles and inflammatory medical condition variables. In summary, this prospective study shows that inflammation predicts depression in older adults, and suggests that the heterogeneous findings among studies may be due to differences in study population characteristics, depression, inflammatory markers, and the extent of adjusting for confounders.
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The cytokine tumor necrosis factor-(TNF), well-known for its roles in cellular responses to tissue injury, has recently been shown to be produced in response to physiological activity in neuronal circuits. TNF stimulates receptors in neurons linked to the activation of the transcription factor NF-B, and recent findings suggest that this signaling pathway can modulate neuronal excitability and vulnerability of neurons to excitotoxicity. Because data indicate that TNF is produced, and NF-B activated, under conditions associated with learning and memory, we performed experiments in the hippocampal slice preparation aimed at elucidating roles for TNF and NF-B in modulating synaptic plasticity. Whereas stimulation of Schaffer collateral axons at a frequency of 1 Hz induced long-term depression (LTD) of synaptic transmission in region CA1 of wild-type mice, LTD did not occur in slices from TNF receptor knockout mice. Stimulation at 100 Hz induced long-term potentiation (LTP) in slices from both wild-type mice and mice lacking TNF receptors. Basal transmission was unaltered in mice lacking TNF receptors. Pretreatment of slices from wild-type mice with B decoy DNA prevented induction of LTD and significantly reduced the magnitude of LTP. Collectively, these data suggest important roles for TNF and signaling pathways that modulate NF-B activity in regulation of hippocampal synaptic plasticity. Synapse 35:151–159, 2000.
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Depression and fatigue are frequent side effects of interferon-α (IFN-α) treatment, and there is compelling evidence that the inflammatory response system (including interleukin-6, IL-6) and the serotonergic system is important in the pathophysiology of such symptoms. Functional polymorphisms in the promoter region of the IL-6 gene (rs1800795) and serotonin transporter gene (5-HTTLPR) have been identified as regulating these systems. The present study aimed to determine if these polymorphisms were associated with the development of depression and fatigue during IFN-α and ribavirin treatment. Ninety-eight Caucasian patients receiving pegylated IFN-α and ribavirin treatment for chronic hepatitis C virus at King's College Hospital, London, and Emory University Hospital, Atlanta, participated in this prospective cohort study. Symptoms of depression and fatigue were measured before treatment and at weeks 4, 8, 12 and 24 during treatment. The ‘low IL-6’ synthesizing genotype (CC) was associated with significantly fewer symptoms of depression (effect size=0.7 at week 24; F=9.4, d.f.=436, P=0.002). The ‘high transcription’ serotonin transporter (5-HTT) genotype (LL) was also associated with significantly fewer symptoms of depression, but with a much smaller effect (effect size=0.2 at week 24; F=4.5, d.f.=436, P=0.03). Neither polymorphisms were associated with symptoms of fatigue (IL-6: F=1.2, d.f.=430, P=0.2; 5-HTT: F=0.5, d.f.=430, P=0.5). The smaller effects of the 5-HTT polymorphism on depression may be explained by an interaction between the genes (F=5.0, d.f.=434, P=0.02): the ‘protective’ effect of the 5-HTTLPR polymorphism was evident only in the presence of the ‘low IL-6’ genotype (F=5.4, d.f.=64, P=0.02), not in the presence of the ‘high IL-6’ genotype (F=2.2, d.f.=369, P=0.1). The association between the IL-6 polymorphism and reduced risk of depressive symptoms confirms the role of the inflammatory response system in the pathophysiology of IFN-α-induced depression; in contrast, the effect of the 5-HTT gene was small and perhaps dependent on the status of the inflammatory response.Keywords: interleukin-6, serotonin transporter, depressive symptoms, fatigue, cytokine, immunotherapy
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Studies consistently report that groups of individuals with major depressive disorder (MDD) demonstrate increased levels of a variety of peripheral inflammatory biomarkers when compared with groups of nondepressed individuals. These findings are often interpreted as meaning that MDD, even in medically healthy individuals, may be an inflammatory condition. In this article, we examine evidence for and against this idea by looking more closely into what the actual patterns of inflammatory findings indicate in terms of the relationship between MDD and the immune system. Data are presented in support of the idea that inflammation only contributes to depression in a subset of patients versus the possibility that the depressogenic effect of inflammatory activation is more widespread and varies depending on the degree of vulnerability any given individual evinces in interconnected physiologic systems known to be implicated in the etiology of MDD. Finally, the treatment implications of these various possibilities are discussed.
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Major depressive disorder (MDD) is a heterogeneous illness for which there are currently no effective methods to objectively assess severity, endophenotypes, or response to treatment. Increasing evidence suggests that circulating levels of peripheral/serum growth factors and cytokines are altered in patients with MDD, and that antidepressant treatments reverse or normalize these effects. Furthermore, there is a large body of literature demonstrating that MDD is associated with changes in endocrine and metabolic factors. Here we provide a brief overview of the evidence that peripheral growth factors, pro-inflammatory cytokines, endocrine factors, and metabolic markers contribute to the pathophysiology of MDD and antidepressant response. Recent preclinical studies demonstrating that peripheral growth factors and cytokines influence brain function and behavior are also discussed along with their implications for diagnosing and treating patients with MDD. Together, these studies highlight the need to develop a biomarker panel for depression that aims to profile diverse peripheral factors that together provide a biological signature of MDD subtypes as well as treatment response.
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Serum levels of inflammatory cytokines, for example, tumor necrosis factor alpha (TNFα), interleukin-6 (IL-6), and IL-1 beta (IL-1β), are elevated in subjects with major depressive disorder (MDD). The reason why this occurs is unclear. Elevated levels of inflammatory cytokines could be a result of brain dysfunction in MDD. It is also possible that inflammatory cytokines contribute to depressive symptoms in MDD. If the first assumption is correct, one would expect levels to normalize with resolution of the depressive episode after treatment. Several studies have measured changes in cytokine levels during antidepressant treatment; however, the results vary. The purpose of this study was to pool all available data on changes in serum levels of TNFα, IL-6, and IL-1β during antidepressant treatment to determine whether these levels change. Studies were included if they used an approved pharmacological treatment for depression, patients had a diagnosis of MDD, and serum levels of TNFα, IL-6, and/or IL-1β were measured before and after treatment. Twenty-two studies fulfilled these criteria. Meta-analysis of these studies showed that, overall, while pharmacological antidepressant treatment reduced depressive symptoms, it did not reduce serum levels of TNFα. On the other hand, antidepressant treatment did reduce levels of IL-1β and possibly those of IL-6. Stratified subgroup analysis by class of antidepressant indicated that serotonin reuptake inhibitors may reduce levels of IL-6 and TNFα. Other antidepressants, while efficacious for depressive symptoms, did not appear to reduce cytokine levels. These results argue against the notion that resolution of a depressive episode is associated with normalization of levels of circulating inflammatory cytokines; however, the results are consistent with the possibility that inflammatory cytokines contribute to depressive symptoms and that antidepressants block the effects of inflammatory cytokines on the brain.
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This article highlights the evidence linking depression to increased inflammatory drive and explores putative mechanisms for the association by reviewing both preclinical and clinical literature. The enzyme indoleamine 2,3-dioxygenase is induced by proinflammatory cytokines and may form a link between immune functioning and altered neurotransmission, which results in depression. Increased indoleamine 2,3-dioxygenase activity may cause both tryptophan depletion and increased neurotoxic metabolites of the kynurenine pathway, two alterations which have been hypothesized to cause depression. The tryptophan-kynurenine pathway is comprehensively described with a focus on the evidence linking metabolite alterations to depression. The use of immune-activated groups at high risk of depression have been used to explore these hypotheses; we focus on the studies involving chronic hepatitis C patients receiving interferon-alpha, an immune activating cytokine. Findings from this work have led to novel strategies for the future development of antidepressants including inhibition of indoleamine 2,3-dioxygenase, moderating the cytokines which activate it, or addressing other targets in the kynurenine pathway.
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A consortium of researchers, advocates and clinicians announces here research priorities for improving the lives of people with mental illness around the world, and calls for urgent action and investment.
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Omega-3 fatty acids play a critical role in the development and function of the central nervous system. Emerging research is establishing an association between omega-3 fatty acids (alpha-linolenic, eicosapentaenoic, docosahexaenoic) and major depressive disorder. Evidence from epidemiological, laboratory and clinical studies suggest that dietary lipids and other associated nutritional factors may influence vulnerability and outcome in depressive disorders. Research in this area is growing at a rapid pace. The goal of this report is to integrate various branches of research in order to update mental health professionals.
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Antidepressants increase adult hippocampal neurogenesis in animal models, but the underlying molecular mechanisms are unknown. In this study, we used human hippocampal progenitor cells to investigate the molecular pathways involved in the antidepressant-induced modulation of neurogenesis. Because our previous studies have shown that antidepressants regulate glucocorticoid receptor (GR) function, we specifically tested whether the GR may be involved in the effects of these drugs on neurogenesis. We found that treatment (for 3-10 days) with the antidepressant, sertraline, increased neuronal differentiation via a GR-dependent mechanism. Specifically, sertraline increased both immature, doublecortin (Dcx)-positive neuroblasts (+16%) and mature, microtubulin-associated protein-2 (MAP2)-positive neurons (+26%). This effect was abolished by the GR-antagonist, RU486. Interestingly, progenitor cell proliferation, as investigated by 5'-bromodeoxyuridine (BrdU) incorporation, was only increased when cells were co-treated with sertraline and the GR-agonist, dexamethasone, (+14%) an effect which was also abolished by RU486. Furthermore, the phosphodiesterase type 4 (PDE4)-inhibitor, rolipram, enhanced the effects of sertraline, whereas the protein kinase A (PKA)-inhibitor, H89, suppressed the effects of sertraline. Indeed, sertraline increased GR transactivation, modified GR phosphorylation and increased expression of the GR-regulated cyclin-dependent kinase-2 (CDK2) inhibitors, p27(Kip1) and p57(Kip2). In conclusion, our data suggest that the antidepressant, sertraline, increases human hippocampal neurogenesis via a GR-dependent mechanism that requires PKA signaling, GR phosphorylation and activation of a specific set of genes. Our data point toward an important role for the GR in the antidepressant-induced modulation of neurogenesis in humans.
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The mainstay of pharmacologic therapy for rheumatoid arthritis includes the use of disease-modifying agents like sulfasalazine and methothrexate, and more recently, anti-tumor necrosis factor-α agents. Depression remains a major co-morbidity in patients with rheumatoid arthritis and is thought to contribute to disability and mortality in these patients. Evidence now suggests that a biologic link exists between substrates responsible for inflammatory conditions and mood disorders. Most of this evidence comes from preclinical studies. Nevertheless, more research into this area is helping us to understand the possible mechanisms through which these conditions interact with each other. We describe a 60-year-old Indian man with rheumatoid arthritis diagnosed 15 years ago who had minimal response to multiple therapies with disease-modifying agents and whose arthritis symptoms surprisingly remitted when he was started on a specific serotonin reuptake inhibitor antidepressant, three years ago, for co-morbid major depression. This remission has been maintained with this medication, and the patient is currently not taking any antirheumatoid medications. Possible mechanisms linking substrates of mood disorders and inflammation are reviewed in this case report, particularly the serotonergic system. Evidence seems to suggest a significant interaction between the serotonergic systems and inflammation. This interaction seems to be bidirectional. An understanding of this relation is most important to gain insight not only into pathophysiological mechanisms underlying this condition, but also into how treatments for these conditions may complement each other and possibly provide greater therapeutic options in both of these disabling conditions.
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There has been an explosion in our knowledge of the pathways and mechanisms by which the immune system can influence the brain and behavior. In the context of inflammation, pro-inflammatory cytokines can access the central nervous system and interact with a cytokine network in the brain to influence virtually every aspect of brain function relevant to behavior including neurotransmitter metabolism, neuroendocrine function, synaptic plasticity, and neurocircuits that regulate mood, motor activity, motivation, anxiety and alarm. Behavioral consequences of these effects of the immune system on the brain include depression, anxiety, fatigue, psychomotor slowing, anorexia, cognitive dysfunction and sleep impairment; symptoms that overlap with those which characterize neuropsychiatric disorders, especially depression. Pathways that appear to be especially important in immune system effects on the brain include the cytokine signaling molecules, p38 mitogen-activated protein kinase and nuclear factor kappa B; indoleamine 2,3 dioxygenase and its downstream metabolites, kynurenine, quinolinic acid and kynurenic acid; the neurotransmitters, serotonin, dopamine and glutamate; and neurocircuits involving the basal ganglia and anterior cingulate cortex. A series of vulnerability factors including aging and obesity as well as chronic stress also appears to interact with immune to brain signaling to exacerbate immunologic contributions to neuropsychiatric disease. The elucidation of the mechanisms by which the immune system influences behavior yields a host of targets for potential therapeutic development as well as informing strategies for the prevention of neuropsychiatric disease in at risk populations.
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The cytokine tumor necrosis factor-alpha (TNF), well-known for its roles in cellular responses to tissue injury, has recently been shown to be produced in response to physiological activity in neuronal circuits. TNF stimulates receptors in neurons linked to the activation of the transcription factor NF-kappaB, and recent findings suggest that this signaling pathway can modulate neuronal excitability and vulnerability of neurons to excitotoxicity. Because data indicate that TNF is produced, and NF-kappaB activated, under conditions associated with learning and memory, we performed experiments in the hippocampal slice preparation aimed at elucidating roles for TNF and NF-kappaB in modulating synaptic plasticity. Whereas stimulation of Schaffer collateral axons at a frequency of 1 Hz induced long-term depression (LTD) of synaptic transmission in region CA1 of wild-type mice, LTD did not occur in slices from TNF receptor knockout mice. Stimulation at 100 Hz induced long-term potentiation (LTP) in slices from both wild-type mice and mice lacking TNF receptors. Basal transmission was unaltered in mice lacking TNF receptors. Pretreatment of slices from wild-type mice with kappaB decoy DNA prevented induction of LTD and significantly reduced the magnitude of LTP. Collectively, these data suggest important roles for TNF and signaling pathways that modulate NF-kappaB activity in regulation of hippocampal synaptic plasticity.
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Schizophrenia is associated with immune system dysfunction, including aberrant cytokine levels. We performed a meta-analysis of these associations, considering effects of clinical status and antipsychotic treatment following an acute illness exacerbation. We identified articles by searching PubMed, PsychInfo, and Institute for Scientific Information and the reference lists of identified studies. Forty studies met the inclusion criteria. Effect sizes were similar for studies of acutely relapsed inpatients (AR) and first-episode psychosis (FEP). Interleukin (IL)-1β, IL-6, and transforming growth factor-β (TGF-β) appeared to be state markers, as they were increased in AR and FEP (p < .001 for each) and normalized with antipsychotic treatment (p < .001, p = .008, and p = .005, respectively). In contrast, IL-12, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and soluble IL-2 receptor (sIL-2R) appeared to be trait markers, as levels remained elevated in acute exacerbations and following antipsychotic treatment. There was no difference in IL-6 levels between stable medicated outpatients and control subjects (p = .69). In the cerebrospinal fluid, IL-1β was significantly decreased in schizophrenia versus controls (p = .01). Similar effect sizes in AR and FEP suggest that the a