COVID-19 and immune effects on mental health
The COVID-19 pandemic is a promoter of anxiety, depression, and other mental health disorders that is supercharged through a self-amplifying loop of anxiety » increased stress chemistry driving brain inflammation » anxiety, depression, and other neuropsychiatric disorders. This is magnified by a dysregulated immune inflammatory response to the SARS-CoV-2 virus.
Is COVID-19 Leading to a Mental Illness Pandemic?
That's the title of a commentary published recently in Medscape Psychiatry. The author, a practicing psychiatrist, states:
As I see this period in time, my first thoughts are that we are witnessing a national epidemic of trauma. Specifically, what we have here is a clinical picture of PTSD.
On top of the fear of contagion, uncertainty, financial worry, social distancing, and disruption of everyday routines, there is also the stoking of anxiety by some of the media outlets.
I spoke with Juliana Tseng, PsyD, a clinical psychologist based in New York, and she said that the hype, half-truths, and false information from some outlets in the popular media are making things worse. Dr. Tseng added that the lack of coordination among local, state, and federal governments also is increasing fear and alienation.
This perspective was echoed in a viewpoint published in JAMA Internal Medicine about the mental health consequences of COVID-19 and the effects of physical distancing.
In the context of the COVID-19 pandemic, it appears likely that there will be substantial increases in anxiety and depression, substance use, loneliness, and domestic violence; and with schools closed, there is a very real possibility of an epidemic of child abuse. This concern is so significant that the UK has issued psychological first aid guidance from Mental Health UK.7
The worldwide COVID-19 pandemic, and efforts to contain it, represent a unique threat, and we must recognize the pandemic that will quickly follow it—that of mental and behavioral illness—and implement the steps needed to mitigate it.
Immunology and neuropsychiatric symptoms
In addition to the fear of illness and anxiety about the future that can precipitate anxiety- and stress-related disorders that themselves feed the fires of inflammation, the immune inflammatory response to viral infection can drive a variety of neurologic and neuropsychiatric conditions in mutual reinforcement. In a paper just published in Brain, Behavior, and Immunity, the authors list these highlights:
Are we facing a crashing wave of neuropsychiatric sequelae of COVID-19? Neuropsychiatric symptoms and potential immunologic mechanisms
The COVID-19 pandemic is a significant source of psychological distress globally.
The novel coronavirus and host immunologic response may also directly affect brain and behavior.
Acute and delayed neuropsychiatric sequelae have been associated with past viral pandemics.
Prospective monitoring of COVID-19 patients is needed to determine neuropsychiatric outcomes.
A psychoneuroimmunology perspective will aid in promoting post-pandemic public mental health.
The authors note that past viral pandemics have produced in their wake a variety of neuropsychiatric conditions due to individual's immune response which is often not sufficiently recognized.
...less attention has been given to the role of the virus itself (several acute respiratory syndrome coronavirus; SARS-CoV-2), and the host immunologic response to infection, on the human central nervous system (CNS) and related neuropsychiatric outcomes...Past pandemics have demonstrated that diverse types of neuropsychiatric symptoms, such as encephalopathy, mood changes, psychosis, neuromuscular dysfunction, or demyelinating processes, may accompany acute viral infection, or may follow infection by weeks, months, or longer in recovered patients.
Acute neuropsychiatric manifestations have already been recognized in earlier reports, but there is the potential for chronic conditions to emerge that would vastly outnumber the acute cases. Many of these may take years to recognize.
However, beyond acute infection, the delayed or chronic effects of this pandemic, particularly on public mental health, will not be fully appreciated for several years.
Documented conditions include depression, anxiety, and trauma-related disorders; encephalopathies; loss of smell and/or taste; psychotic disorders; demyelinating and neuromuscular complications; and neurodegenerative disorders.
Mechanisms of neuropsychiatric manifestations related to COVID-19
The same authors review mechanisms including viral infiltration into the central nervous system, cytokine network dysregulation...
Even in the absence of CoV-2 infiltration into the CNS, peripheral cytokines involved in the host anti-viral response (see Section 2.1) may elicit neuropsychiatric symptoms by precipitating neuroinflammatory responses and/or compromised blood-brain-interface (BBI) integrity, leading to peripheral immune cell transmigration into the CNS, and disruption of neurotransmission.
...peripheral immune cell transmigration (into the brain)...
In the CNS, virus-infected monocytes can propagate neuroinflammation, and therefore neuropsychiatric symptoms, by releasing inflammatory cytokines, and by promoting microglial activation...
And, most importantly considering the marked increase in autoimmune disordersin general (see forthcoming post), is post-infectious autoimmunity--a phenomenon that is far more common than often recognized...
Autoimmune disorders of the nervous system, such as BBE and GBS, have been described following SARS-CoV-1 and MERS-CoV (Kim et al., 2017, Tsai et al., 2004). Viral infections may precede development of autoimmunity in vulnerable individuals. The underlying mechanisms may include viral infection creating an inflammatory milieu which favors aberrant immune responses and promoting expansion of host antibodies or lymphocytes, which are cross-reactive both with viral antigen and self-antigen (i.e. “molecular mimicry”) (Fairweather et al., 2005, Rose, 2017). In animal models of MS, auto-reactive lymphocytes have been identified which cross-react with both CoV epitopes and human myelin (Desforges et al., 2019), suggesting that molecular mimicry might be a potential mechanism by which CoV infection could potentiate development of autoimmune neuropsychiatric sequelae.
Additionally, they note that gut microbial translocation may alter the gut microbiome in a way that would favor neuropsychiatric pathogenesis...
Viral shedding in feces of COVID-19 patients is known to occur for at least five weeks post-infection (Yongjian Wu et al., 2020). Although the extent and mechanisms of viral infiltration of gut epithelium by SARS-CoV-2 are currently unknown, ACE2 is expressed by gut epithelial cells, and almost 40% of COVID-19 patients present with gastrointestinal (GI) symptoms (Zhang et al., 2020)...It may be the case that SARS-CoV-2 infection precipitates changes in gut microbial composition, which could be involved in the pathogenesis of neuropsychiatric symptoms via the gut-brain axis...
The authors conclude with an call to arms of great significance to public health:
We urge the biomedical community’s attention to the needs of longitudinal monitoring of neuropsychiatric symptoms and neuroimmune status in individuals exposed to SARS-CoV-2 at different time points across the life course, including in utero, throughout childhood development, in adulthood, and in advanced age, to fully appreciate and mitigate the long-term deleterious impacts of COVID-19 on brain and behavior. Thus, a psychoneuroimmunology perspective will be invaluable in tackling this rapidly developing public health crisis.
Anxiety and chronic inflammation
The bi-directional relationship between mental health conditions such as anxiety, PTSD, and OCD and chronic inflammation (including post-infectious chronic inflammation due to immune dysregulation) has been observed in research like this study published in the journal Depression and Anxiety.
The association between inflammatory dysregulation and diagnoses associated with chronic, impactful, and severe anxiety
Anxiety is characterized by prolonged preparation for real or perceived threat. This may manifest both as psychological and physiological activation, ultimately leading to greater risk for poor health. Chronic inflammation may play an integral role in this relationship, given the influential role that it has in chronic illness.
When authors examined levels of inflammatory cytokines and C‐reactive protein, biomarkers of chronic inflammation, in people with anxiety disorders, PTSD, or OCD compared to healthy controls that were documented in 41 studies a striking pattern emerged.
Results demonstrated a significant overall difference between healthy controls (HCs) and people with anxiety disorders in pro‐inflammatory cytokines (P = 0.013, Hedge's g = –0.39), which appears to be largely driven by interleukin‐1β (IL‐1β; P = 0.009, Hedge's g = –0.50), IL‐6 (P < 0.001, Hedge's g = –0.93), and tumor necrosis factor‐α (P = 0.030, Hedge's g = –0.56).
These data demonstrate the association between inflammatory dysregulation and diagnoses associated with chronic, impactful, and severe anxiety and provides insight into the way that anxiety, and in particular PTSD, is related to certain inflammatory markers.
And Medscape Medical Newsreported on findings that were to be presented at the annual conference of the Anxiety and Depression Association of America (ADAA) 2020 in March that further emphasize the connection that worry and anxiety have with increased inflammation.
Worry and anxiety are strongly linked to fluctuations in levels of inflammatory markers, which can compromise the immune system, potentially leaving individuals at increased risk for physical illness, new research suggests.
The researchers' intent was to investigate the specific mechanisms that underlie the relationship between prolonged worrying and poor health outcomes by examining inflammatory biomarkers of 85 healthy adults subjected to an experimental worry condition.https://adaa.org/conference/2020-San-Antonio
Results showed that blood samples taken in three consecutive draws displayed significant changes in levels of the inflammatory cytokines IL-6...FN-γ significantly increased during the worry condition compared with baseline. Levels then decreased during relaxation, highlighting that IFN-γ may particularly be influenced by worry.
Medscape quotes lead author Megan Elizabeth Renna, PhD:
"Basically, high levels of inflammatory markers like IFN over time can be related to numerous chronic health conditions," she said. In addition, "high levels of IL-6 are generally not good and may be a marker of disease/poor health," she added.
Moreover, those with high depressive symptom scores showed higher levels of inflammation.
Medscape includes comments by Jeanette Bennett, PhD, Department of Psychological Science, the University of North Carolina Charlotte in regard to the mental stress effects of enduring adaptations to the COVID-19 pandemic:
..."the relationship between stress and inflammation is cyclical...The association between anxiety/stress and inflammation is strong, and reducing one often leads to improvement of the other," she added. "Furthermore, once–psychologically healthy individuals may find themselves having more negative thoughts and potentially developing their first depressive or anxious episode," she said.
Shared mechanisms of mental and physical illness
In an excellent paper published in the Journal of Evaluation in Clinical Practice, Dr. Bennett and co-author examine the clinical significance of the core association of autoimmunity and immune dysregulation with depression, psychosis, and other neuropsychiatric disorders. They state:
Converging and accumulating evidence for the cross-communication among the nervous, immune, and endocrine systems, a field of study known as psychoneuroimmunology, implicates immunological dysfunction as a shared and common mechanism of both mental and physical illness. For example, psychiatric disorders likeschizophrenia, bipolar disorder, major depression, and anxiety disorders have higher prevalence rates across a spectrum of autoimmune conditions compared to the general population. Additionally, subclinical immunological abnormalitiesare observed in a variety of psychiatric conditions, with chronic inflammation most extensively studied in the pathophysiology of depression.
They review shared biological mechanisms underlying the neuroinflammation of autoimmunity and mental disorders including psychosis, depression, and bipolar disorder. For example...
...elevated inflammatory markers predict onset of depressive symptoms in longitudinal studies. Additional immune alterations observed in major depressive disorder include reduction of natural killer (NK) cell activity and decreased number of lymphocytes such as B cells...
Bipolar disorder...appears linked to changes in immune functioning. One meta-analysis of 30 studies investigating inflammation in 1351 patients with bipolar disorder reported higher concentrations of cytokines IL-6 and tumour necrosis factor-alpha (TNFα) as well as IL-2 soluble receptors during manic phases. Furthermore, acute psychosis and mania may be accompanied with changes in cell-mediated immune responses, including reductions in NK cell count and increased number of macrophages. First-episode psychosis as well as psychotic relapse are associated with a proinflammatory shift in systemic inflammation, indexed by increased pro-inflammatory IL-6 and TNFα and decreased anti-inflammatory IL-10.These findings highlight the relevance of subclinical immune dysregulation and inflammation in mental disorders.
Besides reviewing biomarkers for inflammation, they acknowledge the role of the gut, gut barrier, and gut microbiome in mental health; and comment that remediation requires an individualized approach.
...altered composition and reduced diversity of gut microflora are found in autism, depression, anxiety disorders, bipolar disorder, and schizophrenia. Clinical depression as well as other psychiatric conditions also display evidence of disruption in the mucus and endothelial cell barrier that line the GI tract. This increased permeability of the intestines can allow bacteria in the gut to enter the bloodstream, resulting in an inflammatory response. Microbiome and gut health are therefore critical and interrelated components of both immune and mental health.
As diet, microbiome composition, and potential dietary sensitivities are highly variable between individuals and thus more difficult to empirically study in group analyses, this case-by-case approach to treating psychiatric symptoms with dietary modifications may be viewed as a form of personalized medicine...Notably, therapeutically targeting inflammation is likely not a one-size-fits-all approach.
This points to the profound importance of the vagus nerve in both regulation of the immune system and the primary driver of GI function and barrier maintenance.
The authors also comment on the sorry fragmentation of the dominant model of clinical practice that maintains a kind of tunnel vision for differentially treating individual symptoms; and conclude by asserting that...
The cross-communication among the nervous, immune, and endocrine systems suggests that chronic inflammation may be a common response mechanism underlying both psychological and physiological chronic illness. This framework blurs existing distinctions between mental and physical disorders, implicating new and integrative treatment targets for preventing and treating chronic disease. In contrast to traditional treatment approaches and their focus on individual symptom management, targeting inflammation offers a plausible mechanistic framework to integrate mental and physical healthcare.
Conceptualizing mental and physical health through the lens of psychoneuroimmunology implicates inflammation as a common mechanism of chronic illness, reinforcing the notion that “mental health is the health of the whole body”.
The hallmark of the serious cases of COVID-19 is a dysregulated immune response. Clinicians should anticipate the need to evaluate the underlying contributing causes of chronic inflammation and its immune polarization in a personalized manner; and be familiar with sustainable therapies that regulate both the immune and nervous systems for the surge of mental health conditions that may occur in the wake of the COVID-19 pandemic.