In this study, we described the main socio-demographic and clinical characteristics of individuals with SARS-CoV-2 infection and mental disorders and analysed the effect of the latter on the risk of death and hospitalization in men and women.
In our cohort of confirmed COVID-19 cases, mental illness was more frequent in women than in men, as shown in previous studies 17,19. Anxiety was the most frequent mental condition, followed by depression and mood disorders, and cognitive disorders, although some gender-differences in the distribution of mental illnesses were shown. Wang et al. observed that patients with a recent mental disorder diagnosis had significantly higher odds of COVID-19 than those free of mental illness, with depression and schizophrenia as the strongest predictors after adjusting by age, gender, and ethnicity 17. However, another study showed that patients with a previous diagnosis of a mental disorder had the same risk for testing positive for SARS-CoV-2 infection than people without mental illness 8.
Most of the patients in our cohort were natives; however, the higher proportion of migrants observed in the population without mental illness may be due to the “healthy migrant effect”, which suggests that migrants are initially healthier than natives, and that their health worsens as the duration of their stay increases 20–24. We found no association between deprivation index and residence area and COVID-19 infection. In contrast, in a previous study conducted in Aragon, COVID-19 incidence was slightly higher in patients belonging to the more deprived areas 19, probably due to inequalities in their living conditions such as precarious housings, overcrowded accommodations and limited access to outdoor spaces, increasing the risk of exposure to the virus and infection susceptibility19,25.
In general, patients with mental illness showed a higher number of chronic diseases and multimorbidity and polypharmacy rates. These factors have already been associated to lower income and educational levels 12, and a higher burden of cardiometabolic and respiratory comorbidities such as diabetes and chronic obstructive pulmonary disease (COPD) that reduce life expectancy 16.
One of the major findings of this cohort study was that mental disorders were associated to an increase in the risk of mortality and hospitalization in COVID-19 patients, and that these effects were influenced by sex. Though not an objective of our work, other studies have determined that hospitalizations and deaths are more frequent in men 17.
Recent studies confirmed that pre-existing mental disorders were associated with COVID-19 mortality and an increased risk of hospitalisation7,14 due to their high morbidity burden 17, and that poorer outcomes were more frequent in patients with psychotic disorders like schizophrenia and schizotypal disorders, compared with patients with mood disorders 13,14,26. The fact that patients with cognitive disorders had the highest mortality and hospitalization prevalence rates has been observed in other studies 2,27. It could be explained by the fact that patients with dementia may have less capacity to communicate their medical concerns 27, the atypical symptoms that may impede the early recognition of the disease, and their association with age and comorbid conditions 2. Schizophrenia spectrum disorders have been associated with an increased risk of death3,6,9,10,12,18 and hospitalization, and this risk was not only limited to psychiatric diagnoses in hospitals 12,16. In another study, schizophrenia also increased mortality; however, it did not associate an increase in admissions to the Intensive Care Unit compared with non- schizophrenia patients 10,18. In yet another study, schizophrenia spectrum disorders were associated to mortality, while mood and anxiety disorders were not 3.
The fact that mental illness increased the risk of negative outcomes of COVID-19 patients has been linked to the relationship between severe mental illness (SMI), unhealthy lifestyles (e.g., physical inactivity, poor diets, sleep disturbances, social isolation and high alcohol and tobacco use) and a higher burden of somatic disease 12,26. Furthermore, SMI has been associated with dysregulation of biological processes such as immune-inflammatory alterations, which may predispose these patients to more severe infections or to secondary bacterial infections 12,26. Even before COVID-19, the incidence of pneumonia was higher in SMI, and was associated with antipsychotic medications, tobacco use, and other factors. Furthermore, clozapine, which is the antipsychotic reserved for treatment-resistant schizophrenia patients, can suppress immune functions, and increase susceptibility to infections like pneumonia 28. Toubasi and Lee et al. observed that patients who were diagnosed with mental disorders needed more mechanical ventilation, were more frequently admitted to the Intensive Care Unit, and had higher mortality 8,14. Fond et al. described an increased risk of mortality and poor COVID-19 outcomes in patients with mental disorders irrespective of the main clinical risk factors for severe COVID-19 7. This suggests that there are other factors that can lead to these health inequities, like a lack of communication skills, cognitive impairment 8,18, limited comprehension of medical advice, poor self-awareness 18, lack of caregivers or family support 8 and the stigmatization of mental disorders. All of these conditions can aggravate social isolation of patients with mental disorders and hinder or delay COVID-19 infection diagnosis 12. Thus, it is possible that patients with SMI may have a harder time complying with protective hygiene measures, stay-at-home advice, and other recommendations 10,28, while they are also more likely to reside in congregate facilities, such as psychiatric inpatient units, homeless shelters, community housings, and prisons, where the inability to effectively maintain social distance and/or quarantine increases the risk of COVID-19 transmission13. Long-term use of alcohol, tobacco and other drugs is associated with pulmonary (COPD, pulmonary hypertension), cardiovascular (myocardial infarction, arrhythmias and cardiac insufficiency), and metabolic (hypertension and diabetes) diseases, all of which are risk factors for COVID-19 and its negative outcomes 7. In addition, tobacco, the use of which is much more common in SMI patients 10,17,28, is associated with poorer COVID-19 prognoses, mostly due to its effects on the respiratory system and immune responsiveness 10,13, and the higher ACE-2 expression levels in respiratory tissue cells28. All these factors could result in a delay in the access to hospital care and a worsening of the respiratory condition, which are important indicators of severe illness 18.
As we saw, in some cases, multimorbidity9,12,26 and having an additional chronic disease was associated with COVID-19 complications, especially in diabetes, obesity, cardiovascular disease, COPD, immunodeficiency, cancer and hypertension 28–30, all of which are more common in patients with SMI 10. It is believed that certain comorbidities increase the inflammatory response, a biological factor common to severe COVID-19 pathophysiology (cytokine storm), and the chronic low-grade inflammation caused by mental illnesses. This response could lead to acute respiratory distress syndrome and death in patients with COVID-19 6,9,12,17. The reasons why underlying medical conditions cause more severe COVID-19 cases are not yet fully understood, but ACE-2, the receptor to which SARS-CoV-2 binds to cause infection, is highly expressed in the heart and lungs. Whatever the mechanism, the higher rate of smoking and comorbid medical conditions in SMI, in combination with the medications routinely used in its treatment, may create the perfect storm for COVID-19 complications 28. In addition, polypharmacy has been associated with a higher risk of developing severe COVID-19 6. Other studies have reported that exposure to anxiolytic and antipsychotic drug treatments was associated with higher risk of pneumonia13 and severe COVID-19 outcomes 6,26. Although the cause is unclear 6, it is thought that antipsychotics can aggravate cardiovascular and thromboembolic risk, interfering with the immune response, and can cause pharmacokinetic and pharmacodynamic interactions with drugs used to treat COVID-19 26.
Although further research is required to determine the underlying mechanisms of these associations, our findings highlight the need for targeted approaches to manage and prevent COVID-19 in the at-risk groups that were identified in this study 26, as well as the need for the development of new clinical decision-making guidelines, including improvements in follow-up and targeted interventions 3. Other recommendations would be to maintain active surveillance, facilitate the access to prompt and timely treatments when needed 8,12 and prioritize specific risk groups during vaccination campaigns 12,14. Hence, an important step towards the prevention of unfavourable COVID-19 outcomes in these patients would be to optimize the management of their pulmonary, metabolic and cardiovascular diseases, and to improve their adherence to treatment 12.
Strengths and limitations
The main strength of this study lies in the fact that we analysed all the individuals of the reference population with a laboratory-confirmed COVID-19 infection, including nearly 150,000 patients. From the beginning of the pandemic, numerous studies have been published analysing the consequences of COVID-19 in terms of hospitalization and severity, but few have focused on mental illnesses. Our work is one of the first to study the negative consequences of COVID-19 on seven different mental pathologies.
In addition, we exhaustively analysed all the chronic diagnoses registered by physicians in their electronic health records (EHRs). Furthermore, a free software with an open algorithm was used to manage chronic conditions in the analyses, facilitating reproducibility and comparability of results. One of the main limitations lies on the observational, cross-sectional nature of the study, which prevents the establishment of causal relationships between the explanatory variables and infection severity; nonetheless, our results call attention to certain factors that should be further investigated to confirm their influence. Another limitation of our study was related to the lack of relevant variables 12 such as tobacco use, body mass index, and social determinants that could influence the severity of COVID-19 and that were not available in our cohort. Given that smoking, alcohol use and being overweight are especially common among patients with psychiatric disorders, we cannot rule out the possibility that our results could be influenced by some of these confounding factors. Moreover, we collected data on the use of oral psychotropic drugs but the information on intravenously administered psychotropic drugs was not recorded. Finally, the COVID-19 pandemic occurred in a series of waves that, as other studies have pointed out 19, has led to differences in infection diagnosis due to the availability of diagnostic tests and the updates in diagnostic protocols, resulting in a potential misclassification of cases.