key: cord-0801889-bgcmz6tm authors: Serrano García, Antonio; Montánchez Mateo, Judith; Franch Pato, Clara Margarita; Gómez Martínez, Rocío; García Vázquez, Paula; González Rodríguez, Isabel title: Interleukin 6 and depression in patients affected by Covid-19 date: 2021-03-04 journal: Med Clin (Engl Ed) DOI: 10.1016/j.medcle.2020.11.013 sha: ee222d290e3a485076781dd32da3c03aceb35733 doc_id: 801889 cord_uid: bgcmz6tm Introduction Rise of central cytokines resulting from infections produces neuronal changes. Covid-19 allows the study of depressive symptoms in sustained stress and its relationship with molecular mechanisms. Objectives To assess correlation between IL-6, IL-1β and TNF-α and depressive symptoms. Characterize the depressive symptoms present. Methods Observational study. Patients admitted for Covid-19 older than 60 years with a interleukin determination were included. The Yesavage Geriatric Depression Scale was used, associating each item with a neurotransmitter. Results 27 patients included. We did not find correlation between IL-6 levels and the GDS scale score (rho = 0.204; 95% CI -0.192 to 0.543); with IL-1β levels (rho = -0.126; 95% CI -0.490 to 0.276); nor of TNF-α (rho = -0.033; 95% CI -0.416 to 0.360). 3 patients (11.1%) presented score compatible with depressive disorder. It was associated with a deficiency of Noradrenaline and Serotonin. Conclusions We found no correlation between the levels of IL-6, IL-1β, and TNF-α with the GDS score. Depressive symptomatology is similar to vascular depressions. Brief original article Interleukin 6 and depression in patients affected by AUTORES: Serrano García A*, Montánchez Mateo J**, Franch Pato CM*, Gómez Martínez R*, García Vázquez P*, González Rodríguez I* *Servicio de Psiquiatría. Complejo Asistencial Universitario de León **Servicio de Inmunología Clínica. Complejo Asistencial Universitario de León. Introducción: El incremento de citocinas centrales resultante de infecciones produce cambios neuronales. La Covid-19 permite estudiar los síntomas depresivos en un estrés sostenido y su relación con mecanismos moleculares. Objetivos: Valorar la correlación entre niveles de IL-6, IL-1β y TNF-α y sintomatología depresiva. Caracterizar los cuadros depresivos presentes. Métodos: Estudio observacional. Se incluyeron pacientes ingresados por Covid-19 mayores de 60 años con una determinación de interleucinas. Se utilizó la Escala de depresión geriátrica de Yesavage, asociándose cada ítem con un neurotransmisor. Resultados: 27 pacientes incluidos. No encontramos correlación entre los niveles de IL-6 y la puntuación de la escala GDS (rho=0,204; IC95% -0.192 a 0.543); con los niveles de IL-1β (rho=-0,126; IC95% -0.490 a 0.276); ni de TNF-α (rho=-0,033; IC95% -0.416 a 0.360). 3 pacientes (11,1%) presentaron una puntuación compatible con cuadro depresivo. Se asoció a déficit de Noradrenalina y Serotonina. Conclusiones: No hallamos correlación entre los niveles de IL-6, IL-1β y TNF-α con la puntuación en la GDS. La sintomatología depresiva presenta características similares a las depresiones vasculares. Objectives: To assess correlation between IL-6, IL-1β and TNF-α and depressive symptoms. Characterize the depressive symptoms present. Methods: Observational study. Patients admitted for Covid-19 older than 60 years with a interleukin determination were included. The Yesavage Geriatric Depression Scale was used, associating each item with a neurotransmitter. Results: 27 patients included. We did not find correlation between IL-6 levels and the GDS scale score (rho = 0.204; 95% CI -0.192 to 0.543); with IL-1β levels (rho = -0.126; 95% CI -0.490 to 0.276); nor of TNF-α (rho = -0.033; 95% CI -0.416 to 0.360). 3 patients (11.1%) presented score compatible with depressive disorder. It was associated with a deficiency of Noradrenaline and Serotonin. Conclusions: We found no correlation between the levels of IL-6, IL-1β, and TNF-α with the GDS score. Depressive symptomatology is similar to vascular depressions. Psychological stress or the stress caused by an infection activates toll-like receptors which, once the NF-kB transcription factor or NLRP3 inflammasome and other inflammatory cytokines have been activated, increase the levels of interleukin 1 beta (IL-1) and interleukin 6 (IL-6), leading to general disease symptoms as well as symptoms characteristic of depression such as dysphoria and anhedonia 1 . Increased IL-1, IL-6 and TNF- as a result of infections or stress leads to stimulation of the glutamatergic NMDA and -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, as well as a decrease in the expression of neuronal GABA-A receptors, causing an increase in reversible excitability 2 . The NF-kB pathway complex is present in a wide variety of cells such as lymphocytes and endothelial cells. Activation of the NF-kB pathway and subsequent production of cytokines may be related to the deterioration of endothelial cells. In vitro and animal depression models have shown that TNF- modifies the endothelial cells of the bloodbrain barrier by increasing permeability and reducing tight junction protein expression associated with extracellular spaces. The NF-Kb-IKK signalling pathway has been associated with the regulation of neuronal morphology, necessary and sufficient to induce anxiety-and depression-like behaviours in mice 3 . Benros et al. conclude that the increased risk of suffering from a mood disorder after hospitalization for infections and autoimmune diseases was 62% (RRI, 1.62; 95% CI 1.60-1.64) and 45% (RRI, 1.45 ; 95% CI 1.39-1.52) respectively. When they had both, the risk increased further (RRI, 2.35; 95% CI 2.25-2.46) 4 . Covid-19 provides a model for studying depression in the context of sustained stress and its correlation with molecular mechanisms. The main objective of this study is to assess the correlation between IL-6 levels and depressive symptoms. Secondary objectives were to assess the same correlation between depressive symptoms and IL-1 and TNF- levels, as well to characterise psychopathologically the depressive symptoms present during hospitalization. Laboratory and sociodemographic data were obtained from the medical records of the patients that were included. The Yesavage Geriatric Depression Scale (GDS) 5 was used for the evaluation of depressive symptoms (study variable) because it is easy to apply and has a study population-adapted profile. The dichotomous structure of the GDS allows, in a hypothetical way, to correlate each item with a depressive symptom and, in turn, with the theoretical regulatory neurotransmitter (table 1 table 1) . A consensus was reached between 3 psychiatrists with more than 10 years of experience for this correlation. Although there may be discrepancies on its utility and accuracy, it allows for an approach that views depressive symptomatology as a continuum with normality, from a non-dualistic theoretical model, considering psychopathology as a symptom of a systemic disease. Data collection was carried out at the León University Healthcare Complex (CAULE) between 17th April and 7th May 2020, when it was interrupted because requests for IL-6 levels ceased. We do not know the reason for this cessation, although it coincides with the end of the most intense phase of the pandemic. Spearman's rho test was used to estimate the correlations. The determination of IL-6 levels was requested in the case of 48 admitted patients over the age of 60░; 3 of them did not have Covid-19, 5 were admitted to the ICU, 2 died, 4 had cognitive abnormalities and 7 had been discharged or transferred. Finally, 27 patients J o u r n a l P r e -p r o o f were included in the study. Patients were detected through the Immunology laboratory, which reported the IL-6 determinations requested, regardless of the reason. The sociodemographic and laboratory variables are shown in table 2 table 2. The profile of the patient over 60░ years of age, admitted to the ward for Covid-19 whose IL-6 levels are requested is a male (70.4%), from rural areas (51.9%), and interleukin levels are requested around the eighth day of admission. We found a mean elevation of IL-6 levels, strongly influenced by extreme values (median 11░pg/ml). Increased levels of CRP, ferritin, D-dimer and heart rate, and decreased oxygen saturation and lymphocytes were observed. The rest of the parameters remained at normal levels. Psychopathologically, 3 of the 27 patients (11.1%) had a score on the GDS scale compatible with the presence of a depressive disorder. We found no correlation between IL-6 levels and the score obtained on the GDS scale (Spearman's rho░=░0.204; 95% CI from −0.192 to 0.543). We also found no correlation between the GDS scale and IL-1 levels (Spearman's rho░=░-0.126; 95%CI from -0.490 to 0.276); nor with TNF- levels (Spearman's rho░=░-0.033; 95%CI from -0.416 to 0.360). For the psychopathological characterization we performed a weighting between different neurotransmitters. According to Table 1 , 17 items were assigned to serotonin, 6 to norepinephrine and 7 to dopamine. We divided the score obtained for each neurotransmitter by the number of items assigned. We found that the psychopathological condition shows symptoms associated with deficits in noradrenaline (mainly) and serotonin, and very little in dopamine. Figure 1 shows the neurotransmitter abnormalities found. The sample was limited to patients admitted to hospital. Therefore, it cannot be extrapolated to the most severe conditions (patients admitted to the ICU have not been included), nor to mild conditions. The scarcity of patients with GDS scale scores compatible with depressive symptoms stands out (only 3). Patients were in a situation of hospitalization for a little-known, potentially lethal disease, isolated and without visits. The mean stay at the time of assessment was higher than 8 days. We consider that the patients were subjected to a situation of intense stress, but the responses to the GDS scale hardly reflect the presence of depressive symptoms. It would be necessary to consider other factors with an effect on mood, such as the euphoric effect of corticosteroids or a direct effect of Covid-19 that could cause moria and even hyperthymia. As the prescribed treatment has not been collected and possible brain damage has not been examined, these factors cannot be determined, and research will need to be expanded in future studies. The lack of correlation between interleukin levels and GDS scores could be influenced by the low sample size or because there is no correlation, although this would go against what is described in other conditions 6 . The non-correlation would reinforce the claim that the disease or its treatment had an effect on mood. We observe that the condition is characterized by a noradrenergic deficit, followed by a serotonergic deficit. This suggests that it shares characteristics with vascular depression 7 . The fact that mood disorders in Covid-19 share a psychopathological profile with vascular depression is compatible with a process in which cardiovascular 8, 9 and neurological disorders are evident 10 . There was hardly any dopaminergic deficitdependent symptomatology, which could be related to a euphoric effect of Covid-19 or its treatment. There is no correlation between the levels of IL-6, IL-1 and TNF- with the score obtained in the GDS in patients above 60░years of age with moderate Covid-19 symptoms. Depressive symptoms in patients over 60░years of age with moderate Covid-19 symptoms shares characteristics with vascular depression, showing noradrenergic and serotonergic deficits. Nueva teoría sobre la depresión: un equilibrio del ánimo entre el sistema nervioso y el inmunológico, con regulación de la serotonina-quinurenina y el eje hipotálamo-hipófisosuprarrenal Perspectives on neuroinflammation and excitotoxicity: A neurotoxic conspiracy? Pathogenesis of depression: Insights from human and rodent studies Autoimmune diseases and severe infections as risk factors for mood disorders: a nationwide study Geriatric Depression Rating scale: Comparison with self-report and psychiatric rating scales Niveles séricos de il-6 y depresión en varones con cáncer de pulmón no microcítico avanzado Opciones Terapéuticas en depresiones vasculares COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options Symmetric cutaneous vasculitis in COVID-19 pneumonia Neurobiology of COVID-19 None of the authors has a conflict of interest.