Genetic and nongenetic factors associated with an increased inflammatory response may mediate a link between severe coronavirus disease 2019 (COVID-19) and serious mental illness (SMI). However, systematic assessment of inflammatory response-related factors associated with SMI that could influence COVID-19 outcomes is lacking. In the present review, dietary patterns, smoking and the use of psychotropic medications are discussed as potential extrinsic risk factors and angiotensin-converting enzyme (ACE) insertion/deletion (I/D) gene polymorphisms are considered as potential intrinsic risk factors. A genetics-based prediction model for SMI using ACE-I/D genotyping is also proposed for use in patients experiencing severe COVID-19. Furthermore, the literature suggests that ACE inhibitors may have protective effects against SMI or severe COVID-19, which is often linked to hypertension and other cardiovascular comorbidities. For this reason, we hypothesize that using these medications to treat patients with severe COVID-19 might yield improved outcomes, including in the context of SMI associated with COVID-19.
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), was initially viewed as a primarily respiratory disease, leading to viral pneumonia in some cases. However, it is now recognized as a complex disease affecting various body systems (
The data on whether mental illness affects the severity of COVID-19 are mixed. Studies indicate that the prevalence of COVID-19 among patients with serious mental illness (SMI) is either lower than (
Severe COVID-19 comprises the presence of pneumonia, severe acute respiratory distress syndrome, microvascular thrombosis and/or cytokine storms, all of which involve underlying inflammation (
In the present review, some of these candidate factors are critically discussed (
Previous studies have suggested that psychotropic medications could affect inflammatory processes. Various antipsychotics, antidepressants and antiepileptics have been shown to favor the anti-inflammatory state by increasing levels of anti-inflammatory cytokines and decreasing those of proinflammatory cytokines (
Clinical trials have shown that aspirin, estrogens, N-acetylcysteine, minocycline, pregnenolone, celecoxib and n-3 polyunsaturated fatty acids (PUFAs) have antipsychotic effects (
The use of antipsychotics has also been reported to be associated with reduced physical activity, possibly because of the side effects of antipsychotics, which include extrapyramidal symptoms and fatigue (
Nonsteroidal anti-inflammatory medications, various pro-inflammatory cytokine inhibitors, statins, n-3 PUFAs, pioglitazone, minocyclin and modafinil have been indicated to exert antidepressant effects (
Antiepileptics are regularly used to treat bipolar affective disorder, and are also prescribed to patients with schizophrenia at a lower rate, estimated at 20% (
Several studies have convincingly shown an association between vitamin D deficiency and COVID-19 severity (
Dietary intake represents another important modulator of the inflammatory response (
A number of PUFAs act as natural ligands of peroxisome proliferator-activated receptors (PPARs) and sterol regulatory element-binding protein (SREBP) transcription factors, which regulate lipid and glucose metabolism, and overall energy homeostasis (
A dietary deficiency of n-3 PUFAs can lead to changes in the phospholipid fatty acid composition of membranes, and thereby induce changes in the collective physicochemical properties of the bilayer, such as flexibility and fluidity (
Notably, an article by Bousquet
Recently, Abdulah and Hassan (
The estimated prevalence of smoking among people with SMI is 50–80% worldwide, which is significantly higher than that in the general population, and people with SMI are also more likely to smoke heavily, considered as ≥30 cigarettes or 1.5 packs daily (
Studies of patients with COVID-19 have identified cigarette smoking as an important risk factor for severe outcomes (
Among people with SMI, smoking is likely to interact with factors modulating vulnerability to COVID-19, such as the use of psychotropic medications and maintenance of an unhealthy dietary pattern (
Certain studies have indicated a link between smoking and an unhealthy or proinflammatory dietary pattern among patients with SMI (
Smoking has been identified as an important factor contributing to vitamin D deficiency (
Genetic variations have been proposed to play a role in vulnerability to SMIs (
Results of a meta-analysis that included a large number of participants (n=10,223) in case-control studies indicated that the ACE-DD homozygous genotype was associated with an elevated risk of depression in a Caucasian and mixed ethnic group consisting of several European populations (German, British, Belgian, Finish and Israeli) and Asian populations (Japanese and Chinese) (
A number of studies have assessed the relevance of the ACE-I/D polymorphism in COVID-19-associated deaths. During the first wave of the pandemic, Delanghe
Given the association of ACE-DD with the highest ACE activity and consequently high production levels of proinflammatory and profibrotic Ang II, Bellone and Calvisi (
The disadvantageous effects in COVID-19 of the ACE-DD homozygous genotype and, by implication, high ACE activity (
As aforementioned, ACE-I/D polymorphisms have potential relevance in SMI (
SMI and severe COVID-19 appear to have an increased inflammatory response in common. Numerous extrinsic and intrinsic factors may act as modulators of inflammatory processes among patients with SMI. Extrinsic factors, such as an unhealthy dietary pattern and excessive smoking, could contribute to the etiology of severe COVID-19 in people with SMI, as in the general population, but are potentially modifiable through lifestyle changes. In addition, physical activity, which has been reduced during COVID-19 quarantine, is relevant to the ability of the immune system to defend against viral infection, as well as to psychological health and well-being. However, the etiopathogenesis of severe COVID-19 may be heterogeneous among patients with SMI because of interactions among these factors, antipsychotic medications and genetic polymorphisms, such as ACE-I/D. Within the RAS, ACE simultaneously promotes the inflammatory reponse and counteracts the activity of ACE2, the host receptor that mediates SARS-CoV-2 cell entry. Several studies support the relevance of the functional ACE-I/D polymorphism in both SMI and severe COVID-19. For this reason, genotyping individuals with severe COVID-19 for the ACE-I/D polymorphism might offer predictive utility for COVID-19 outcomes and the risk of new-onset, COVID-19-associated SMI. Furthermore, ACE inhibitors exhibit promise for the mitigation of psychotic symptomatology and cognitive deficits, and their positive effects in severe COVID-19 accompanied by hypertension and other cardiovascular comorbidities have been reported. Thus, the administration of ACE inhibitors to patients with severe COVID-19 might be of benefit in the mitigation of severe disease and prevention of new-onset SMI secondary to COVID-19 disease.
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This study was supported by grants from the University of Rijeka, Croatia (grant nos. 17.07.2.1.10 and uniri-biomed-18-251). The university had no further role in the study design; data collection, analysis or interpretation; or the decision to submit this paper for publication.
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SN and HJ designed the study and wrote the manuscript. VP, DK and ABT wrote and drafted the manuscript. Data authentication is not applicable. All authors read and approved the final manuscript.
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The authors declare that they have no competing interests.
Proposed factors leading to more severe COVID-19 in patients with SMI. COVID-19, coronavirus disease 2019; SMI, serious mental illness; ACE, angiotensin-converting enzyme; PUFA, polyunsaturated fatty acids.