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Circadian rhythm disorder and anxiety as mental health complications in post-COVID-19

In 2020, the world gained dramatic experience of the development of the 2019 coronavirus disease pandemic (COVID-19) caused by severe acute respiratory syndrome 2 (SARS-CoV-2). Recent researches notice an increasing prevalence of anxiety and circadian rhythm disorders during COVID-19 pandemic. The aim of the study was describing clinical features of circadian rhythm disorders and the level of anxiety in persons who have had COVID-19. We have conducted a cohort retrospective study that included 278 patients who were divided into 2 study groups according to medical history: group 1 includes patients with a history of COVID-19; group 2 consists of patients who did not have clinically confirmed COVID-19 and are therefore considered not to have had this disease. To objectify circadian rhythm disorders, they were verified in accordance with the criteria of the International Classification of Sleep Disorders-3. The level of anxiety was assessed by the State-Trait Anxiety Inventory. The most common circadian rhythm disorders were sleep phase shifts. We found that COVID-19 in the anamnesis caused a greater predisposition of patients to the development of circadian rhythm disorders, in particular delayed sleep phase disorder. In addition, it was found that after COVID-19 patients have increased levels of both trait and state anxiety. In our study, it was the first time that relationships between post-COVID-19 anxiety and circadian rhythm disorders had been indicated. Circadian rhythm disorders are associated with increased trait and state anxiety, which may indicate additional ways to correct post-COVID mental disorders and their comorbidity with sleep disorders.


Introduction
In 2020, the world gained dramatic experience of the development of the 2019 coronavirus disease pandemic  caused by SARS-CoV-2. Based on previous studies, SARS-CoV-2 penetrates the blood-brain barrier and can directly affect the nervous tissue, which causes the development of neurological and psychiatric symptoms (Hossain et al. 2020) (Sharma et al. 2021) (Rahman et al. 2020). At the same time, quarantine and social distancing have a significant impact on the psychological state of the population. Separation from relatives, loss of freedom, uncertainty about disease status, and boredom can sometimes have dramatic effects. Serious socioeconomic losses can be a risk aspect for signs of mental disorders, in particular anxiety. Fear of infection, economic hardship, and stigma are important ingredients that lead to mental health problems during COVID-19 too (Akter et al. 2021) (Kaur et al. 2021). Despite the significant amount of research on various aspects of the pathogenesis and treatment of COVID-19, there are still many unresolved issues of the effectiveness of the therapy of such patients, especially the amount of psychosocial interventions and predictors of long-term prognosis (Ivanova et al. 2020).
Recently, there have been a growing number of reports of symptoms that persist in the post-COVID period. Although studies of the classification of long-term effects remain at an early stage, researchers distinguish, among others, neurocognitive, psychological, and neurological post-COVID syndromes, which are characterized by involvement of the nervous system (Alsharif and Qurashi 2021;Maltezou et al. 2021).

Meta-analysis of
According to the definition from the DSM-5, anxiety is the expectation of a future threat, which differs from fear in an emotional response to a real or perceived imminent threat. In addition, this term in the DSM-5 includes an additional component, namely the cognitive aspects of anxious expectation (Kupfer 2015). In the general population, anxiety disorders are usually chronic. To prevent and control chronic disease, timely treatment and management of chronic diseases are necessary, which can be achieved by identifying indicators of risk of chronicity (Ten Have et al. 2021).
Environmental factors can affect the infectivity and survival of the coronavirus. Several epidemiological and laboratory studies show that outbreaks of coronavirus disease and the rate at which it spreads depend on climate, weather conditions and population density (Doğan et al. 2020;Shahzad et al. 2021). The seasons are considered to be a significant environmental factor influencing the initiation and further dynamics of mental disorders due to a number of heliometeorological factors determining biological rhythms such as the circadian functioning of the human body. It has been established that there is a multi-vector network between medico-biological phenomena and biorhythmological features of people suffered mental disorders . Circadian rhythm disorders and sleep disorders are conditions that under normal circumstances rarely attract the attention of doctors. However, it is important to keep in mind that circadian rhythms are a factor in the optimization of the immune system. The most constitutive risk factors are genetic. The known association of affective disorders with the functioning of circadian rhythms makes it possible to study clock genes as predictors of anxiety. Although clock genes have been implicated in regulating mood, the extent to which they can influence affective disorders is not well understood. The PER3 and BMAL1 genes, which influence daytime mood, may be promising candidates (Landgraf et al. 2016;Liberman et al. 2017).
During the early period of the COVID pandemic, the attention of researchers was drawn to non-pharmacological methods of treatment of this disease   (Hussain et al., 2021). Desynchronization of circadian rhythm and immune system can lead to increased susceptibility to infectious diseases and affect their course (Bryson 2020). Circadian rhythm disorders and sleep disorders are closely related to changes in mental status and the development of affective disorders, including anxiety syndrome Difrancesco et al. 2019;Silva et al. 2020). There is evidence of an association between certain polymorphisms of 'internal clock' genes, which are associated with chronotype features and disorders of the circadian system, with the development of affective disorders, including anxiety and depression (Partonen 2012;Sipilä et al. 2010). Animal models indicate circadian changes in serotonin secretion in rats with anxiety disorders (Bacqué-Cazenave et al. 2020), which may be one of the common links in the pathogenesis between affective disorders and circadian dysfunction. In addition, circadian rhythms are reported to play a significant role in the regulation of metabolic processes and the metabolism of neurotransmitters (Tarianyk et al. 2021). Recent studies indicate a link between sleep phase shift disorders and high levels of stress and anxiety, which in combination with neurobiological components may presuppose comorbidity of these conditions (Gradisar and Crowley 2013;Kivelä et al. 2018).
However, the severity of anxiety in circadian rhythm disorders on the background of COVID-19 has not been studied yet. The aim of the study was describing the prevalence of circadian rhythm disorders and its links to the level of anxiety in persons who have had COVID-19.

Inclusion and exclusion criteria
We have conducted a cohort retrospective study that included 278 patients who consulted a family doctor for a preventive examination during 2021. This has limited a certain number of patients in study groups. Criteria for inclusion in the study were age from 18 to 59 years, complaints of sleep disorders and anxiety, 5-day work schedule with peak activity in daylight. Exclusion criteria: age from 60 years, somatic pathology in the stages of sub-and decompensation, severe mental disorders. The age was limited because younger people were children and were treated in children's hospitals. People aged more than 60 years were elderly according to the WHO classification. It means that they have more accompanying illnesses with a brain injury that can cause anxiety.

Grouping
All patients included in the study gave informed consent. The study was conducted in compliance with the basic provisions of the 'Ethical principles of scientific medical research involving human subjects,' approved by the Declaration of Helsinki  Patients were divided into 2 study groups: group 1 (n = 153)-patients with a history of COVID-19; group 2 (n = 125)-patients who did not have clinically confirmed COVID-19 and are therefore considered not to have had this disease.
During the examination of the patient, a clinical interview was conducted detailing the complaints and anamnestic data. Collection of information on the clinical course of COVID-19 was performed by analyzing both outpatient cards and extracts from inpatient cards.

Circadian rhythm disorders
To objectify circadian rhythm disorders, they were verified in accordance with the criteria of the International Classification of Sleep Disorders-3, which includes advanced sleep phase disorder, delayed sleep phase disorder, irregular sleep phase disorder, non-24-h sleep-wake disorder, jet lag, and shift work sleep disorders, others (not classified in other headings) (Berry 2012;Sateia 2014).
To assess the function of the circadian rhythm, we used a sleep diary, which was filled in by the patient for 7 days before the first visit, and data from daily thermometry, which was performed by the patient every 3 h.
The following criteria were used to confirm circadian rhythm disorders: a) persistent or recurring because of: damage to the circadian rhythm system; mismatch of internal rhythm and external factors; b) lead to insomnia and/or excessive daytime sleepiness; c) related to the disturbances in social, professional, and other spheres of activity; d) cannot be better explained by another sleep disorder, neurological or mental disorder, medication and substance use.

Level of anxiety measurement
The level of anxiety was assessed by the State-Trait Anxiety Inventory (STAI). It consists of 40 questions divided into two blocks, the first of which is responsible for trait anxiety, and the second-for state. The scale of trait anxiety describes anxiety as a characteristic permanent behavioral trait, due to which a person perceives objectively safe things as a source of danger. At the same time, the state scale characterizes the emotional reaction to the current situation. Each of the 40 questions contains a Likert-scale answer in the form of a statement from 1 point (never) to 4 points (very often). A separate sum of points is calculated for each block, which can vary from 20 to 80 points, whereby a larger amount corresponds to a higher intensity of anxiety. It is considered that < 30 points are a low level of anxiety, 31-45 points-moderate, > 45 points-high (Julian 2011).

Statistical analysis
Statistical analysis was performed using EZR Statistics v.1.13 and Microsoft Office Excel 2019. Qualitative variables were presented in the form of absolute values (abs.) and relative value (P) with the calculation of relative error (p). To compare qualitative data, χ2-Pearson with Yates correction was used. To analyze the risk of comorbidity of nosologies, the calculation of the risk ratio with a 95% confidence interval was used. The results were considered statistically significant at p < 0.05.
Among patients who have had COVID-19, only 44 (28.8 ± 3.7%) patients considered themselves to be in contact with carriers and assumed the possibility of the disease development, another 48 (31.4 ± 3.7%) patients considered having had no prior contact with infected persons, however, admitted the possibility of COVID onset, and 61 (39.9 ± 3.9%) patients were sure that they would not get sick.
We found that the history of COVID-19 was not associated with the risk of developing advanced sleep phase disorder (RR = 0.84, 95% CI 0.51-1.38), irregular sleep phase disorders (RR = 0.61, 95% CI 0.33-1.09) and non-24-h circadian rhythm (RR = 1.51, 95% CI 0.42-5.52). At the same time, the presence of a history of COVID-19 increased the risk of developing delayed sleep phase disorders by 1.5 times (RR = 1.44, 95% CI 1.01-2.08). Other circadian rhythm disorders were relatively isolated, so they are not subject to statistical analysis due to the lack of data.
In group 1, low levels of trait anxiety were found in 64 patients, moderate-in 65, and high-in 24, while in group 2, low levels were found in 72 people, moderate-in 34, and high-in 19, which is presented in Fig. 1. It was found that in the group of patients with COVID-19 in the anamnesis, a moderate level of trait anxiety prevailed, compared to the group 2, where a low level prevailed (χ 2 = 8.02, p = 0.019).
The level of state anxiety in group 1 was low in 46 people, moderate-in 48, and high-in 59, and in group 2 54 people had low levels, 47-moderate and in 24-high, which is presented in Fig. 2.
It was determined that in patients who have had COVID-19, there is statistically significant higher intensity of state anxiety and its high level prevails, while in patients haven't had COVID-19 low and moderate levels of anxiety were the most common (χ 2 = 12, 72, p = 0.002).
The levels of trait anxiety in patients with various forms of circadian rhythm disorders, taking into account the presence of COVID-19 in the anamnesis, are presented in Table 1.
In group 1, the increase in the level of trait anxiety was associated with the presence of a delayed sleep phase disorder (χ 2 = 32.67, p < 0.001), non-24-h rhythm (χ 2 = 7.21, p = 0.021) and a disorder of the irregular phase of sleep (χ 2 = 22.46, p < 0.001). At the same time, patients in group 1 who were diagnosed with advanced sleep phase disorder, no significant differences (χ 2 = 5.87, p = 0.0542) in the severity of personal anxiety compared with those who did not have this disorder.
The distribution of levels of state anxiety in patients with various forms of circadian rhythm disorders, taking into account the presence of COVID-19 in the anamnesis, is presented in Table 2.
An increase in state anxiety in group 1 and group 2 was found in patients with delayed sleep phase disorder (χ 2 = 34.46, p < 0.001 and χ 2 = 66.53, p < 0.001, respectively), irregular sleep phase disorders (χ 2 = 31,89, p < 0.001 and χ2 = 18.71, p < 0.001, respectively) and non-24-h rhythm (χ 2 = 31.85, p < 0.001 and χ 2 = 20.79, p < 0.001, respectively). The presence of advanced sleep phase disorder was not associated with more pronounced state anxiety in both group 1 (χ 2 = 0.72, p = 0.712) and group 2 (χ 2 = 0.26, p = 0.881). It was not possible to estimate the differences in the intensity of trait and state anxiety in patients with jet lag and shift work disorder due to the small number of observations.
Symptoms of respiratory and nervous system damage predominated in patients who had COVID-19. Among the latter, there were disturbances of smell and taste, ataxia and damage to peripheral nerves, which, in turn, may indicate the neurotoxicity of the SARS-CoV-2 virus.
On the other hand, the fact of coronavirus infection itself could act as a psycho-traumatic factor that caused changes in the mental state of patients, as most of them considered themselves protected and insensitive to the disease, i.e., did not expect the onset of COVID. In addition, the long-term quarantine measures that have been introduced due to the pandemic have affected both the mental and physical conditions of people. A high prevalence of anxiety disorders has been reported both in the acute period of COVID-19 and within 6-7 months after it.
There are a variety of data on the frequency of their occurrence, which ranges from 16 to 45% (Chen et al. 2021;Fernández-de-las-Peñas et al. 2021a).
The most common circadian rhythm disorders were sleep phase shifts. We found that COVID-19 in the anamnesis caused a greater predisposition of patients to the development of circadian rhythm disorders, in particular delayed sleep phase disorder. In addition, it was found that after COVID-19 patients have increased levels of both trait and state anxiety. The prevalence of delayed sleep phase disorder may be due to both the neurotropic nature of the SARS-CoV-2 and the quarantine associated with COVID-19 pandemic. Thus, the effect of a change in light exposure under lockdown conditions on daily functioning was observed, namely a shift of the rhythm by 3 or more hours ahead. This has led to a decrease in exposure to natural light, which affects the central circadian oscillator, which can also affect physical and nutritional activity (Bertrand et al. 2021;Leone et al. 2020). It was also noted that the delay in sleep during a pandemic is associated with a worse quality of sleep and the psychological state of the respondents, and as a result, reduces the quality of their life and the degree of disability (Robillard et al. 2021).
Some limitations of our study should be considered. In particular, it was conducted within one hospital. It will be useful to conduct similar studies in different countries in order to accumulate sufficient data. In addition, we were limited by clinical interviews without neurophysiological study of sleep structure or analysis of circadian biomarkers. The study of these features may play an important role in establishing a link between post-COVID-19 anxiety and circadian rhythm disorders. Furthermore, investigating of the chronotype of patients may be useful, which is usually considered as the middle of a sleep time on the free day. It is intriguing in further research to study the role of chronotype in the formation of circadian rhythm disorders and increased post-COVID-19 anxiety. The relationship between the severity of anxiety syndrome and circadian rhythm disorders in the post-COVID period has been established. Delayed sleep phase disorder, irregular sleep phase disorder, and non-24-h rhythm had the most pronounced link to the increased levels of anxiety. These conditions are accompanied by a process of maladaptation due to an imbalance between the socially acceptable work schedule and the daily functioning of the patient.

Concluding Remarks
The post-COVID period is characterized by complications in the form of mental disorders, in particular anxiety disorders. An equally important symptoms of the post-COVID period are circadian rhythm disorders, which can enhance the level of affective disorders. Among the circadian rhythm disorders, delayed sleep phase disorder occurs most frequently in the post-COVID period, which is associated with a higher level of anxiety in these patients. These links may indicate possible ways to optimize approaches to the treatment of post-COVID syndrome, for example, reducing affective symptoms by correcting circadian dysfunction. It was the first time that links between post-COVID anxiety and circadian rhythm disorders, which should be taken into account when planning the rehabilitation after COVID-19 and may even change the approach to the organization of the working time and schedule of such employees in the first six months after the disease. A significant innovation could be the implementation of psychological care services for those who have suffered from COVID-19 whose approach will include psychotherapeutic methods taking into account the biological rhythms.