key: cord-0992491-yyuvghy5
authors: Benedetti, Francesco; Mazza, Mario; Cavalli, Giulio; Ciceri, Fabio; Dagna, Lorenzo; Rovere-Querini, Patrizia
title: Can Cytokine Blocking Prevent Depression in COVID-19 Survivors?
date: 2020-10-26
journal: J Neuroimmune Pharmacol
DOI: 10.1007/s11481-020-09966-z
sha: 6f37d2c78a819f27f847abae757f1965f1bc7ec0
doc_id: 992491
cord_uid: yyuvghy5

nan

role of IL-1 and IL-6 in depression, we hypothesize that depressive symptoms should be lower in COVID-19 survivors treated with cytokine-blocking agents.

We now prospectively evaluated the severity of depressive symptoms (Zung Self-rating Depression Scale, ZSDS) and PTSD (revised Impact of Event Scale, IES-R), one and three months after discharge, in 84 male COVID-19 survivors who during hospitalization had received the best available medical treatment at the time, including hydroxychloroquine, lopinavir/ritonavir, and respiratory support, alone or combined with anakinra (5 mg/Kg/day twice daily until clinical benefit, defined as sustained improvement of respiratory parameters and 75% reduction of serum C-reactive protein, CRP), or tocilizumab (single i.v. dose of 400 mg, followed by a second dose 24-hour apart in the event of further worsening in respiratory function). We also extracted from available charts levels of inflammatory markers during acute COVID-19, at hospital admission and before discharge: CRP, neutrophil/lymphocyte ratio (NLR), and SII. The protocol was approved by the local ethical committee. At discharge, all patients fulfilled grade 1 of the 7-point WHO Clinical severity scale (Discharge from hospital with resumption of normal activities).

We tested the effect of treatment (standard management vs. standard management plus cytokine-blocking agents) and of inflammatory markers on the psychopathological status (selfreport scores) by modelling the influences of the predictors on the outcomes in the context of the General Linear Model (GLM) or Generalized Linear Model (GZLM) as appropriate, and calculating the statistical significance of the effect of the single independent factors on the dependent variables by least squares parametric estimates of predictor variables in the GLM, or by the likelihood ratio iterative estimation procedure, providing the most asymptotically efficient test in the GLZM. Analyses of multivariate and univariate effects were performed with a commercially available software (StatSoft Statistica 12, Tulsa, OK, USA) and following standard computational procedures.

Patients treated with cytokine-blocking agents stayed longer in the hospital and had significantly lower SII and NLR at discharge, but not at admission. There were no group differences in age, oxygen saturation at one month follow-up, CRP at admission and at discharge. There were no differences between patients treated with Anakinra vs. Tocilizumab (Table 1) .

A GLM repeated measure ANOVA showed a significant protective effects of cytokine-blocking agents on depressive symptoms over time (Time x treatment interaction: F = 3.96, df 2,81, p = 0.0228), with better ZSDS index scores for treated patients at three months (F = 3.67, p = 0.0298) (Fig. 1) ; and no effect on PTSD symptoms, with IES-R scores decreasing in all groups (effect of time: F = 11.82, p < 0.001), thus suggesting specific protective effects against depression.

When entering the delta change of SII (hospital admissiondischarge) in the GLM model, with length of hospital stay as nuisance covariate, delta SII showed a significant effect (higher reduction of SII, lower depression; F = 4.24, p = 0.0438) and the time x treatment interaction remained highly significant (F = 7.07, p = 0.0018).

Finally, considering a categorical measure of current depression (with cutoff at ZSDS index score = 50), 9/55 (16.4%) patients treated without, and 1/28 (3.6%) treated with cytokine blockers, scored in the pathological range for depression at three months after discharge. A GLZM ANOVA with either SII at discharge, or delta SII, as covariates, showed a significant effect of cytokine-blocking agents in reducing the risk of clinical depression at three months follow-up (χ 2 = 6.872, p = 0.0088).

Our observation suggests protective effects of treatment with cytokine-blocking agents in early phases of COVID-19 against the later onset of depressive symptoms, but not of PTSD, in survivors. Clearly, the naturalistic setting of this first study does not allow to disentangle effects on systemic inflammation in preventing depression, from other possible mechanisms concurring, but it warrants interest for further study. We suggest that, adding up to our ongoing prospective cohort study (Mazza et al. 2020) , studies addressing neuropsychiatric complications of COVID-19 should carefully assess the possible therapeutic effect of cytokine-blocking agents in survivors. The interplay between inflammatory mediators and neurotransmitters emerged as a mechanism underpinning depression (Miller and Raison 2016) , and, beyond COVID-19 pandemic, studying the possible antidepressant 

Conflicts of Interest/Competing Interests The authors have no relevant financial or non-financial interests to disclose.

The study protocol was approved by the local ethical committee in accordance with the principles in the Declaration of Helsinki. Written informed consent was obtained from all participants.

Consent to Participate Informed consent was obtained from all individual participants included in the study.

The authors affirm that human research participants provided informed consent for publication of the study.

Code Availability Not applicable.

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