Effects of adjunctive N-acetylcysteine on depressive symptoms: Modulation by baseline high-sensitivity C-reactive protein

Porcu, Mauro; Urbano, Mariana Ragassi; Verri, Waldiceu A.; Barbosa, Décio Sabbatini; Baracat, Marcela M.; Vargas, Heber Odebrecht; Machado, Regina Célia Bueno Rezende; Pescim, Rodrigo R.; Nunes, Sandra Odebrecht Vargas

doi:10.1016/j.psychres.2018.02.056

Cited by 29 publications

(28 citation statements)

References 30 publications

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“…The literature search yielded 1545 results, out of which 37 studies met the inclusion criteria for meta-analysis (Legros et al ., 1985; Penninx et al ., 2003; Ladwig et al ., 2005; Liukkonen et al ., 2006; O'brien et al ., 2006; Almeida et al ., 2007; Kling et al ., 2007; Danese et al ., 2008; Nilsson et al ., 2008; Cizza et al ., 2009; Harley et al ., 2010; Ma et al ., 2011; Naghashpour et al ., 2011; Hannestad et al ., 2013; Raison et al ., 2013; Shanahan et al ., 2013; Park et al ., 2014; Uher et al ., 2014; Wium-Andersen et al ., 2014; Courtet et al ., 2015; Wysokiński et al ., 2015; Cepeda et al ., 2016; Haroon et al ., 2016; Rapaport et al ., 2016; Shin et al ., 2016; Ekinci and Ekinci, 2017; Euteneuer et al ., 2017; Gallagher et al ., 2017; Horsdal et al ., 2017; Jha et al ., 2017; Cáceda et al ., 2018; Chamberlain et al ., 2018; Felger et al ., 2018; Osimo et al ., 2018 b ; Porcu et al ., 2018; Shibata et al ., 2018; Wei et al ., 2018). Please see Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Prevalence of low-grade inflammation in depression: a systematic review and meta-analysis of CRP levels

et al. 2019

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BackgroundPeripheral low-grade inflammation in depression is increasingly seen as a therapeutic target. We aimed to establish the prevalence of low-grade inflammation in depression, using different C-reactive protein (CRP) levels, through a systematic literature review and meta-analysis.MethodsWe searched the PubMed database from its inception to July 2018, and selected studies that assessed depression using a validated tool/scale, and allowed the calculation of the proportion of patients with low-grade inflammation (CRP >3 mg/L) or elevated CRP (>1 mg/L).ResultsAfter quality assessment, 37 studies comprising 13 541 depressed patients and 155 728 controls were included. Based on the meta-analysis of 30 studies, the prevalence of low-grade inflammation (CRP >3 mg/L) in depression was 27% (95% CI 21–34%); this prevalence was not associated with sample source (inpatient, outpatient or population-based), antidepressant treatment, participant age, BMI or ethnicity. Based on the meta-analysis of 17 studies of depression and matched healthy controls, the odds ratio for low-grade inflammation in depression was 1.46 (95% CI 1.22–1.75). The prevalence of elevated CRP (>1 mg/L) in depression was 58% (95% CI 47–69%), and the meta-analytic odds ratio for elevated CRP in depression compared with controls was 1.47 (95% CI 1.18–1.82).ConclusionsAbout a quarter of patients with depression show evidence of low-grade inflammation, and over half of patients show mildly elevated CRP levels. There are significant differences in the prevalence of low-grade inflammation between patients and matched healthy controls. These findings suggest that inflammation could be relevant to a large number of patients with depression.

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Section: Resultsmentioning

confidence: 99%

Prevalence of low-grade inflammation in depression: a systematic review and meta-analysis of CRP levels

et al. 2019

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“…Similar beneficial effects existed for combinations of antidepressant drugs with anti-inflammatory agents. Table 1C shows that five out of seven studies (52–56) found a significant improvement of an (add-on) anti-inflammatory therapy, when patients with high signs were compared to patients with low signs of inflammation. The anti-inflammatory agents used in these studies were infliximab, minocycline, n -acetylcysteine, and fish oil (the latter as monotherapy, and compared to placebo).…”

Section: Resultsmentioning

confidence: 99%

“…These varying neuro-modulating actions of anti-inflammatory drugs make complex interactions in the neuro-immune network possible, inducing varying outcomes of combinations of antidepressants and anti-inflammatory agents. Of note also is that three of the reviewed studies of add-on anti-inflammatory agents had included bipolar depressed patients (54, 56, 58). This applies in particular to the study on aspirin (54), in which a reducing effect was found in “inflammatory” versus “non-inflammatory” patients.…”

Section: Discussionmentioning

confidence: 99%

Low-Grade Inflammation as a Predictor of Antidepressant and Anti-Inflammatory Therapy Response in MDD Patients: A Systematic Review of the Literature in Combination With an Analysis of Experimental Data Collected in the EU-MOODINFLAME Consortium

Arteaga-Henríquez

Simon

Burger³

et al. 2019

Front. Psychiatry

118

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Low-grade inflammation plays a role not only in the pathogenesis of major depressive disorder (MDD) but probably also in the poor responsiveness to regular antidepressants. There are also indications that anti-inflammatory agents improve the outcomes of antidepressants. Aim: To study whether the presence of low-grade inflammation predicts the outcome of antidepressants, anti-inflammatory agents, or combinations thereof. Methods: We carried out a systematic review of the literature on the prediction capability of the serum levels of inflammatory compounds and/or the inflammatory state of circulating leukocytes for the outcome of antidepressant/anti-inflammatory treatment in MDD. We compared outcomes of the review with original data (collected in two limited trials carried out in the EU project MOODINFLAME) on the prediction capability of the inflammatory state of monocytes (as measured by inflammatory gene expression) for the outcome of venlafaxine, imipramine, or sertraline treatment, the latter with and without celecoxib added. Results: Collectively, the literature and original data showed that: 1) raised serum levels of pro-inflammatory compounds (in particular of CRP/IL-6) characterize an inflammatory form of MDD with poor responsiveness to predominately serotonergic agents, but a better responsiveness to antidepressant regimens with a) (add-on) noradrenergic, dopaminergic, or glutamatergic action or b) (add-on) anti-inflammatory agents such as infliximab, minocycline, or eicosapentaenoic acid, showing—next to anti-inflammatory—dopaminergic or lipid corrective action; 2) these successful anti-inflammatory (add-on) agents, when used in patients with low serum levels of CRP/IL-6, decreased response rates in comparison to placebo. Add-on aspirin, in contrast, improved responsiveness in such “non-inflammatory” patients; 3) patients with increased inflammatory gene expression in circulating leukocytes had a poor responsiveness to serotonergic/noradrenergic agents. Conclusions: The presence of inflammation in patients with MDD heralds a poor outcome of first-line antidepressant therapies. Immediate step-ups to dopaminergic or glutamatergic regimens or to (add-on) anti-inflammatory agents are most likely indicated. However, at present, insufficient data exist to design protocols with reliable inflammation parameter cutoff points to guide such therapies, the more since detrimental outcomes are possible of anti-inflammatory agents in “non-inflamed” patients.

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“…The CRP and ferritin responses to IV NAC were favorable in our patient, and we observed similar benefit in nine additional patients without G6PD deficiency. Anti-viral [ 7 , 8 ] and anti-inflammatory properties of NAC have been well documented [ [9] , [10] , [11] ]. The morbidity and mortality of human coronaviruses causing lower respiratory tract infections appears to stem from the exuberant immune response of the host.…”

Section: Discussionmentioning

confidence: 99%

“…IV NAC has long been used to safely treat patients with acetaminophen overdose [ 58 , 59 ], or ARDS [ 60 , 61 ]. NAC was also found to reduce CRP levels in several controlled clinical trials [ 10 , 11 ]. CRP elevation is a prominent risk factor for disease progression in patients infected with COVID-19 [ 62 , 63 ].…”

Section: Discussionmentioning

confidence: 99%

Therapeutic blockade of inflammation in severe COVID-19 infection with intravenous N-acetylcysteine

Ibrahim

Perl

Smith

et al. 2020

Clinical Immunology

119

110

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Glucose 6-phosphate dehydrogenase (G6PD) deficiency facilitates human coronavirus infection due to glutathione depletion. G6PD deficiency may especially predispose to hemolysis upon coronavirus disease-2019 (COVID-19) infection when employing pro-oxidant therapy. However, glutathione depletion is reversible by Nacetylcysteine (NAC) administration. We describe a severe case of COVID-19 infection in a G6PD-deficient patient treated with hydroxychloroquine who benefited from intravenous (IV) NAC beyond reversal of hemolysis. NAC blocked hemolysis and elevation of liver enzymes, C-reactive protein (CRP), and ferritin and allowed removal from respirator and veno-venous extracorporeal membrane oxygenator and full recovery of the G6PDdeficient patient. NAC was also administered to 9 additional respirator-dependent COVID-19-infected patients without G6PD deficiency. NAC elicited clinical improvement and markedly reduced CRP in all patients and ferritin in 9/10 patients. NAC mechanism of action may involve the blockade of viral infection and the ensuing cytokine storm that warrant follow-up confirmatory studies in the setting of controlled clinical trials.

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Effects of adjunctive N-acetylcysteine on depressive symptoms: Modulation by baseline high-sensitivity C-reactive protein

Cited by 29 publications

References 30 publications

Prevalence of low-grade inflammation in depression: a systematic review and meta-analysis of CRP levels

Prevalence of low-grade inflammation in depression: a systematic review and meta-analysis of CRP levels

Low-Grade Inflammation as a Predictor of Antidepressant and Anti-Inflammatory Therapy Response in MDD Patients: A Systematic Review of the Literature in Combination With an Analysis of Experimental Data Collected in the EU-MOODINFLAME Consortium

Therapeutic blockade of inflammation in severe COVID-19 infection with intravenous N-acetylcysteine

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