Introduction

A new coronavirus has spread globally since the first recorded human infections noted in December 2019. The virus was identified as the coronavirus of severe acute respiratory syndrome 2 (SARS-CoV-2) [1]. In early 2020, the coronavirus disease-19 (COVID-19) took on global proportions, and in March, the World Health Organization declared a state of a pandemic [2]. The mortality rate is around 2 to 3% for healthy adults. However, for the elderly, the propensity is three times higher [3]. Studies suggest that the elderly population may be more severely affected by COVID-19 infections because the virus can worsen symptoms from pre-existing conditions/diseases [4]. In addition to the risks involving frequent comorbidities in the elderly, such as diabetes and hypertension, psychiatric disorders can be precipitated and accentuated and can increase the severity of COVID-19.

Still, without palliative or preventive treatment, it is essential to isolate patients, minimize face-to-face relationships, and perform quarantine. These actions imply a drastic change in routine. Consequently, waves of anxiety and insecurity have affected the elderly, leaving them susceptible to disorders’ onset or aggravation during this period [5].

More than 20% of the world population over 60 years lives with a psychiatric disorder or neurological disease. Dementia, major depressive disorder (MDD), and anxiety are the most prevalent [6].

Some researchers argue that the lack of awareness and cognitive impairment, associated with stress, are factors that make this population more susceptible to infection [4, 5, 7] and death due to environmental impoverishment and absence of stimuli [8]. Meanwhile, there is a silent fear feeling, which affects mainly those who already have a mental vulnerability. Once infected, these people will still have to confront stigmas related to their mental state in health institutions [9].

Although social distancing is an essential preventative mechanism, it promotes feelings of loneliness, influencing the onset of or increasing the vulnerability for those who already have a psychiatric disorder(s) [3]. In particular, the elderly form one of the most vulnerable groups. Age, dementia, and MDD are risk factors for suicide [4]. Comprehensive monitoring of this population is needed because the virus, and the stressors associated with social isolation can exacerbate the symptoms of age-associated disorders [10].

This review encompasses the increased vulnerabilities of the elderly population when exposed to COVID-19. Besides, COVID-19 exposure and the relationship between psychiatric disorders and stressors inherent in the elderly population (including environmental, psychological, and social) have been examined. Relevant pathophysiological characteristics underlying the situation of psychiatric disorders, which can be aggravated or worsened by a SARS-CoV-2 infection, are also reviewed. Biological mechanisms such as changes in the immune system, inflammation, and the relationship with the hypothalamus-pituitary-adrenal (HPA) axis are discussed. Emphasis has been placed upon the involvement of mechanism(s) in conditions related to advanced age, mental disorders, stress, and infectious disease, such as COVID-19.

About COVID-19

In December 2019 were recorded the first cases of coronavirus in humans. Wuhan, a metropolitan region in the Chinese province of Hubei, was the pandemic’s initial focus. Current data account for 68,845,368 diagnosed cases and 1,570,304 deaths worldwide. The numbers continue to increase exponentially [11]. Severe acute respiratory syndrome (SARS), identified 18 years ago, was associated with coronavirus existing in animals [12]. Complete genomic sequences were performed in 5 patients in the pandemic’s initial phase, identifying that COVID-19 is 96% identical to the bat coronavirus genes. Human infection typically presents in alveolar cells. The virus uses angiotensin-converting enzyme 2 (ACE2) and replicates in the upper airways, facilitating transmission [13]. In addition to inducing viral pneumonia, SARS-CoV-2 can affect other organs. Main complications can include severe myocardial changes, arrhythmias, and shocks, especially in elderly individuals [14]. In addition to the high possibility of affecting crucial organic functions, the prevalence and risk of death increases in the elderly with chronic medical comorbidities, such as type 2 diabetes mellitus, hypertension, cerebral and vascular heart diseases, and obstructive pulmonary diseases, among others [15, 16].

In Italy, 9 out of 10 deaths occur in individuals aged 70 and over [4]. The mortality rate reached 29.6% for people over 80 years old [17]. In the USA, the elderly represent 80% of deaths due to COVID-19 [2]. Studies carried out in Wuhan, the pandemic’s initial focus, showed higher mortality in those who had diabetes and cardiovascular diseases [30, 32]. The stressors that occur throughout life alter homeostasis in various physiological processes, such as oxidative stress, inflammation, and metabolic disorders, and culminate in an increase of allostatic load. This overload seems to be inherent in psychiatric disorders that frequently occur in comorbidities with frequent chronic diseases in old age [33].

Individuals with MDD and other disorders are prone to develop autoimmune and inflammatory diseases [33, 34]. Chronic inflammation can contribute to relevant neurotransmitter dysfunctions related to MDD and other psychiatric disorders [35], as well as impaired neurogenesis [36]. The increase in inflammation, which occurs with age and in psychiatric disorders, may be associated with other factors inherent to both conditions. This state of hyper inflammation can culminate in some degree of blood-brain barrier rupture. In these conditions, chronic microglial activation and neuroinflammation may occur [37]. Persistent microglial activation can lead to neuronal death and reduced neurogenesis [38].

Several studies have observed the involvement of inflammation in the beginning and in the maintenance of depression. Thus, researchers postulate the inflammatory hypothesis of depression [39]. The inflammation hypothesis considers that the inflammatory challenges in the CNS activate the microglia. The activated microglia releases several inflammatory cytokines, such as IL-1β, IL-6, TNF-α, IL-2, IL-18, and INF-γ. The cytokines activate the HPA axis and induce an increase in the indoleamine-2,3-dioxygenase (IDO) activity. In turn, IDO deviates tryptophan metabolism, reducing the synthesis of serotonin and liberating toxic metabolites. These metabolites alter the integrity of the blood-brain barrier and cause neurodegeneration and depression [39].

The routes by which inflammation can reach the CNS and contribute to trigger or worsen MDD include the following: cytokine trafficking through leaks in the blood-brain barrier; active transport through saturable molecules; activation of endothelial cells and perivascular macrophages, which secrete cytokines and other inflammatory mediators; binding to cytokine receptors present in afferent fibers of the vagus nerve; and allowing the sending of signals to specific regions, such as the nucleus of the solitary tract and hypothalamus. An important question concerning age is whether vascular insults at the end of life may have an essential role in bringing inflammatory cytokines to the CNS [40]. The nuclear factor kappa beta (NF-κB) appears to have a relevant role in communicating peripheral inflammation with the CNS [40].

Researchers point out that the mammalian target of rapamycin (mTOR) pathway is an important mechanism involved in MDD. The reduction of mTOR activity can lead to MDD, while drugs that increase the activity, such as ketamine, are considered potent antidepressants [41]. Some studies show that ketamine induces an anti-inflammatory profile through mTOR in parallel to antidepressant effects in humans’ severe depression [42]. Notwithstanding, animal studies have shown that ketamine increased TNF-α in serum, and rapamycin did not reverse the effect of ketamine. Also, ketamine did not alter the levels of IL-1β and IL-6. Therefore, although the evidence is still controversial, it appears that the pro-inflammatory effect of ketamine in the study in question did not occur through the mTOR pathway [43]. Howsoever, some researches highlight the activity of the mTOR pathway on viruses because it is a target mechanism used by the virus, which triggers the rapid activation of machinery for the synthesis of the viral proteins, thus leading to an increased load and infection by SARS-CoV-2, among other viruses. mTOR activity also acts in the pro-inflammatory process, as it induces inflammatory stimulation by IL-6 [23]. Besides, mTOR pathway activation seems to reduce the p53 protein, which is involved in apoptosis and reduction of viral replication [44]. Thus, the inhibition of the mTOR pathway could be a pharmacological strategy for reducing viral load and hyper inflammation [44, 45].

Some research also notes that severe treatment-resistant depression (TRD) is associated with an increase in several inflammatory proteins, such as IL-6, IL-8, and IL-12, among others [46]. The researchers also observed that older patients with a higher load of medication had higher inflammatory markers levels [46]. Previous studies have also noted that the increase in inflammatory molecules is also positively related to increasing age, among other situations of stress during life [47]. Considering that increasing age seems to be associated with immunosenescence, with a low-grade chronic inflammatory state [25], stress and psychiatric disorders can exacerbate inflammation, making the elderly more vulnerable to diseases that challenge the immune system, increasing inflammatory processes.

From another angle, the elevated release of glucocorticoids during chronic stress increases microglial activation and neuroinflammation [48]. Recent research also postulates that microglia’s function is one of the critical mechanisms constituting the pathophysiology of depression, among other psychiatric disorders [49, 50]. Repeated microglia activation can cause systemic inflammation and tissue damage. Besides, persistent inflammation can culminate in glucocorticoid resistance [51]. Thus, the relationship between the HPA axis and the immune system, considering stress and age, can trigger a vicious cycle, hyperactivating the endocrine and inflammatory mechanisms (Fig. 1), which make the elderly more susceptible, both to the worsening of COVID-19 symptoms and an increase in the severity of psychiatric disorders.

Other Disorders—Predisposing Factors During COVID-19

Other psychiatric and neurodegenerative disorders may predispose greater severity to the infectious condition of COVID-19. In 11.9% of elderly Italian patients who died from Covid-19, dementia was comorbidity [7]. Social exclusion due to isolation is one of the most considerable risks of cognitive impairment, increasing the risk of Alzheimer’s disease [52]. Psychotic disorders [53] and obsessive and somatic symptoms related to the pandemic are also documented [54]. It is essential to consider that these diseases and post-traumatic stress disorder (PTSD) even present the deregulation of circulating pro-inflammatory cytokines. This event can aggravate the infectious condition [55,56,57].

Noteworthy are the studies on neuropsychiatric diseases before SARS-CoV-2 infection. In a series of case studies, the authors observed that older adults with a history of neuropsychiatric disease had delirium as a severe manifestation of COVID-19. Subsequently, these individuals manifested motor and cognitive changes, such as agitation, rigidity, abulia, and alogia. Parallel to neurological and cognitive changes, patients showed an increase in systemic C-reactive protein (CRP). The authors suggest that these patients should be monitored in order to promote mental health and diagnose forehand the development or increase neuropsychiatric and cognitive damages [58].

Can Disorders Increase the Severity of COVID-19 Symptoms?

Before the pandemic, some populations already lived with the effects of psychiatric disorders on their daily lives, directly impacting their quality of life. Severe depressive conditions are estimated to reduce life expectative from 13 to 30 years due to inflammatory and neurological complications associated with the disease [8, 59]. Neuroinflammation is a biological factor present in the pathology of the MDD [60] and a relevant aggravating factor of the COVID-19 [21]. IL-1β is one of the critical pro-inflammatory mediators in trauma, abuse, childhood maltreatment, and anxiety disorder. Besides, IL-1β expression tends to change according to the severity of anxiety and depressive symptoms [61]. IL-1β is also associated as a pathway of inflammation induced by caspases’ activation during COVID-19 infection [62]. According to clinical findings, individuals who already have pathologies that increase inflammatory cytokines expression, including IL-1β, may experience worsening of COVID-19 inflammatory symptoms [62].

An important mediator of inflammatory cytokines and the immune system is the HPA axis, often deregulated in individuals with stress-related psychiatric disorders [51, 63]. Studies with rodents show that corticosterone levels are positively related to vulnerability to stress [64, 65]. MDD is one of the pathologies associated with chronic stress, and, therefore, in many patients, the HPA axis is unregulated, also involving the dysregulation of the inflammatory process. In addition to activating the inflammatory pathways, cytokines act as regulators of the HPA axis [60, 66] and can induce glucocorticoid resistance [60]. This condition harms the negative feedback of the axis, which triggers a vicious cycle, leading to a chronic process involved in inflammation and organic dysfunctions [56].

Prolonged stress situations cause an overload of corticosteroids [60] and increase the susceptibility to contracting viral infections. Long-lasting changes in the HPA axis and the immune system can trigger epigenetic changes in the innate immune system’s stem cells and adaptive immunity from a viral infection. This situation can culminate in prolonged neuropsychiatric changes after the disease. On the other hand, the effects of prolonged stress on the HPA axis can induce epigenetic changes that make the individual more susceptible to the worsening of viral infections and greater susceptibility to activation of latent viruses [56, 67]. Immunosenescence naturally causes dysregulation in the immune system, and, when associated with stress, this vulnerability is amplified [68]. The significant decrease in circulating B cells and antibodies [69] as well as an increase in IL-6 and CRP [70] are factors that contribute to impaired immune responses in the elderly [68, 71, 72]. These conditions increase the risk of mortality associated with infections [68]. IL-6 and CRP levels systematically increase in an age-dependent manner [70]. CRP is also high in older people with depression and dementia [73]. The biological mechanisms involved in depression and anxiety disorders, associated with advanced age, become important aggravating factors for the progression of COVID-19.

CRH elevates circulating pro-inflammatory cytokines through monocytic activation, beyond its function on the HPA axis. Animals subjected to stress express high levels of circulating IL-1β, IL-17, and TNF-α [63]. Individuals who contracted COVID-19 have a higher rate of platelet-derived growth factor (PDGF), TNF-α, and vascular endothelial growth factor (VEGF), when compared with uninfected people [21]. These events suggest a greater severity and fatality of COVID-19 in people who have comorbidities induced by stressful events, mainly dementia and psychiatric disorders [74].

Renin-angiotensin-aldosterone system (RAAS) also is a mechanism involved in COVID-19 infection. This system is responsible for regulating the variation of extracellular fluid and blood pressure. Researches indicate that RAAS is directly affected by SARS-CoV-2 because the angiotensin-converting enzyme 2 (ACE2), a regulator of the vasopressor axis, is the molecule that allows the communication, entry, and replication of the virus into the cell [56, 75].

ACE2 is expressed in all districts of the human body, including brain tissue, comprising a possible explanation for the central nervous system (CNS) involvement, although studies are still speculative. It is suggested that therapies that involve a decrease in the expression of ACE2 may lead to hyperactivation of the renin-angiotensin system and the HPA axis and, in the long term, culminate in MDD, anxiety, and post-traumatic stress [56]. Studies with mice revealed that overexpression of ACE2 in CRH target cells decreased anxiety in plus-maze and open field tests [76].

Some populations may be more prone to develop neurological problems as a result of COVID-19. Brain aging is the leading risk factor for neurodegenerative diseases and cognitive decline. Such clinical conditions increase the risk of complications associated with COVID-19. Felice et al. [77] observed different types of coronavirus (CoV-OC43 and CoV-229E) in brain tissue and cerebrospinal fluid in patients with Parkinson’s disease (PD). PD mainly affects the elderly and induces a decrease in movement. Thus, repercussions of their pathophysiology can compromise the respiratory system, worsening the infectious condition of Covid-19 [78].

Hypertension and diabetes are other documented aggravations regarding COVID-19 [53].

Can COVID-19 Worsen the Symptoms of Psychiatric Disorders in the Elderly?

Considering the unfavorable consequences of a pandemic, the first signs of psychic shock appear. Excess of information can intensify emotional instability and lead to paranoia [3]. The situation worsens when someone relative is affected, triggering periods of extreme sadness and depression [4]. The apprehension about their vulnerability and the maintenance of security contribute to panic episodes. Those who already have a mental disorder are more conducive to suffering from stress and may be more susceptible to relapse or worsening of pre-existing mental health situations [80].

The remodeling of relationships puts at risk the elderly who are already prone to depression and anxiety and increase the possibilities of “amplifying pre-existing conditions” [81]. Mehra et al. [5] report the case of an older adult who has been with depression for more than 50 years. For 3 weeks, he was too anxious about COVID-19. On physical examination, no abnormalities were identified. The mental status exam pointed to “excessive concern about becoming infected with COVID-19.” It was necessary to increase the dose of antidepressant and psychotherapy sessions to control the manifestations. The same author brings the case of an older woman diagnosed with recurrent depression for 7 years, without medication and symptom control. After the outbreak of COVID-19, she showed anxiety about her health. The patient needed emergency care due to depressive and psychotic symptoms and treatment with antidepressants and antipsychotics.

Both cases exemplify that the pandemic’s social changes cause emotional suffering and frustration in older people with mental disorders [31].

Given the context of worsening psychiatric symptoms driven by the pandemic, it is crucial to focus on the necessary care to maintain the mental health of the elderly, considering the characteristics of people who already lived with suffering, as well as those who developed emotional damage. Among the most vulnerable groups are those who live in nursing homes or recovery clinics. Because their assistance requires several professionals, they are unable to perform isolation [4]. In general, measures to prevent the risks of mental illness must offer the necessary support thanks to family and social support networks, in addition to the care provided by health professionals and services. In this sense, it is imperative to convey information to prevent psychiatric effects, considering that this information can be understandable and straightforward to reduce barriers and facilitate understanding.

The elderly and their family members must manage their daily needs, such as the continuous use of medications and guidance from health professionals regarding pharmacological and non-pharmacological treatments. It is beneficial in this period that the elderly can perform physical activity at home and that they seek ways to communicate with family and friends during this period. It is convenient for those who have technological tools to use them to maintain safe distance contact [92].

Cellular devices and computers can compose crucial mental health care tools during this period. Its use facilitates communication with the family and social circle, counseling sessions, and information on medical and psychological needs [93]. Direct contact, based on calls to mental health centers, can screen the symptoms of anxiety and depression and reduce the impact of pandemic context in the mental health of the elderly [94].

It is well suited to maintain the daily activities performed by the elderly. It is also essential to create other practices that enrich their daily lives, create leisure moments at home, and use painting, music, literature, and other options that they have easier access. These recommendations provide an opportunity for the elderly to remain active and healthy when contemplating the biopsychosocial dimensions. Such actions must be integrated and carried out as long as they are adequately supported by health professionals and public policies [95].

On the other hand, it should be in mind that not all older people can ease the pandemic moment’s tension. For some, even exercise is challenging due to confinement [4]. There are several situations of social and individual vulnerability. The low capacity for resilience can impair mental health. Looking for the different demands is necessary to integrate the health services that provide care at that time and palliative actions and to insert mental health at the epicenter of the care provided [3].

It is also essential to observe simple guidelines that can help maintain mental health in the elderly, reduce stress and anxiety, and promote self-care for the elderly and those around them during the COVID-19 period. Among the guidelines is to remain physically healthy, including physical exercises, among other attitudes [96].

Physical exercises can be a strategy for controlling MDD and other psychiatric disorders and other chronic diseases, which, besides being associated with the conditions, can predispose greater severity to the symptoms of COVID-19. With the regular practice of physical activities, many physiological mechanisms involved in the endocrine axis and immune function can be improved, reducing both the severity of psychiatric disorders and the possible severity of SARS-CoV-2 infection. Among the critical mechanisms affected by regular physical exercise are the reduction of oxidative stress and pro-inflammatory cytokines, with consequent beneficial changes in the biological processes of degradation of tryptophan. The increased availability of tryptophan and, consequently, serotonin levels are important factors for reducing symptoms related to depression and other disorders. Furthermore, the reduction of peripheral inflammation and neuroinflammation improves brain dynamics in the limbic circuit and may be achieved through regular physical exercises [60].

Here, in addition to not intending to exhaust the possibilities of improving the quality of life, it is also important to highlight that any initiative and care is impossible for a large percentage of the elderly population. Therefore, these are issues that will still demand public health concerns and future research needs.

Considerations and Conclusions

Researches conducted during the initial phase of COVID-19 indicate that the impact on mental health was already moderate to severe, and many people had manifestations of anxiety and depression [97]. During pandemics, it is common for government efforts to be directed towards physical signs. However, it is also important that both health institutions and science are aware of the consequences related to the mental health of the elderly [81]. Although social isolation is the most critical measure in co** with SARS-CoV-2, attention to mental health is extremely necessary because suicide risks are also high [92].

Several studies on the biological processes that emerge with age, stress, psychiatric disorders, and the SARS-CoV-2 infection suggest that there may be a synergism in these situations, leading to an increase in severity, both for COVID-19 and for damage mental health of the elderly. The stress involved in the psychosocial environment and the condition inherent to the disease triggers the HPA axis and the immune system’s inflammatory processes. Advanced age can bring immunosenescence, which is also related to a chronic inflammatory degree. These associated conditions alone can culminate in a higher degree of chronic inflammation, predisposing the elderly to psychiatric disorders, such as anxiety and MDD, among others. Studies report that social isolation has been linked to increased depression and suicide, increased inflammation, and reduced immune response to viral infections. These conditions also predispose the elderly to more severe conditions when they contract SARS-CoV-2 [94].

It is essential to pay attention to the mental damage resulting from the synergism between a possible unfavorable biological condition related to aging and a SARS-CoV-2 infection. This combination can converge to a state of hyper inflammation, a more significant change in the function of the HPA axis, and the onset or worsening of psychiatric disorders. (Fig. 2).

Fig. 2
figure 2

Immunosenescence in aging is accompanied by a chronic inflammatory state. Simultaneously, chronic stress during a pandemic may deregulate negative feedback from the hypothalamic-pituitary-adrenal (HPA) axis. The chronic increase in glucocorticoids (cortisol) is accompanied by an increase in cytokines and other pro-inflammatory molecules. In turn, pro-inflammatory cytokines contribute to the imbalance of the HPA axis, which can culminate in resistance to glucocorticoids, contributing to an increase or maintenance of a chronic pro-inflammatory state. These associated conditions predispose the elderly to trigger or worsen major depressive disorder (MDD) and other psychiatric disorders, as well as make them more vulnerable to the severity of COVID-19 symptoms. On the other hand, the pro-inflammatory cytokine storm, a condition of the severity of SARS-CoV-2 infection, can trigger or worsen psychiatric disorders in the elderly. CRH ➔ corticotropin-releasing hormone; ACTH ➔ adrenocorticotropic hormone; IL ➔ interleukin; TNF-α ➔ tumor-necrosis factor-α; CRP ➔ C-reactive protein. Images were extracted from Biorender app

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For the inadequate care provided to the mentally vulnerable population during the pandemic, health policymakers’ collaboration is necessary to create and implement quality and accessible services during the crisis, especially for the elderly [87], a group especially fragile about their mental state. For maintenance, some actions can be implemented based on the Active Aging Policy, adopted by several countries, which focuses on health promotion and protection [98]. Each country must have public policies geared to its needs to attend different specificities. In addition to social measures, there is an urgent need to strengthen geriatric technical and professional training, due to the imminent risk of worsening psychopathological and neurodegenerative conditions [81].

In addition to the suggestions for attention and care for the elderly during the pandemic, it is essential to note that both health organizations worldwide and science should consider an increase in mental impairment in the elderly population worldwide from the conditions listed in this and other studies. Paying attention to these issues is essential for studies and ways to understand and alleviate mental suffering and further damage to the elderly’s health.