Background: The COVID-19 pandemic forced social distancing to decelerate the virus spread. This study evaluated the impact of social distancing imposed by COVID-19 on Brazilians’ mental health and quality of life (QoL). Methods: In this cross-sectional community-based online survey, data from 1,156 volunteers were gathered between May 11 and June 3, 2020. We considered independent variables the sociodemographic and clinical characteristics, the LOT-R for Optimism/Pessimism constructs, and the Brief Scale for Spiritual/Religious Coping. Dependent variables were the PHQ-9 for depressive symptoms; the GAD-7 for anxiety disorder; and the WHOQOL-BREF. The presence of depressive and anxiety disorder was estimated with logistic regression. Multivariate GLM assessed the effects of independent variables on the WHOQOL-BREF domains. Outcomes: There was a high prevalence of depressive symptoms (41.9%) and anxiety disorder (29.0%). Negative spiritual/religious coping was positively correlated with depressive symptoms (OR, 2.14; 95%CI, 1.63-2.80; p<0.001) and anxiety (OR, 2.46; 95%CI, 1.90-3.18; p<0.001), and associated with worse social and environmental QoL (p<0.001). Healthcare professionals showed a lower risk of depressive symptoms (OR, 0.71; 95%CI, 0.55-0.93; p<0.001). Participants with friend/family with COVID-19 scored lower on psychological and environmental QoL (p<0.05). Longer social isolation duration decreased risk of anxiety disorder (OR, 0.99; 95%CI, 0.98-0.99; p=0.004). Interpretation: We found a higher risk of impaired mental health and QoL in Brazil, which has become the pandemic epicenter. Several factors seem to affect the Brazilian population in a particular way, and this knowledge may contribute to local health policies in dealing with COVID-19 consequences. Funding Statement: Not applied. Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: The Research Ethics Committee of the Faculty of Medicine of Itajuba, Brazil approved this study (#4,010,466). All participants gave informed consent online. All procedures were carried out under Brazilian ethical regulations and the 1964 Helsinki Declaration
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