One of the most unusual patterns in the pandemic has been the high association between anxiety and fear-related disorders and death in severe COVID-19. It seems to be primarily linked to the USA (Gundlapalli 2021) and is not a pattern observed in other parts of the world. This risk is separate from depression which does not have an increased mortality risk for severe COVID-19
Why would there be increased mortality associated with anxiety and fear-related disorders in the United States? This was not noted in China early in the pandemic (Guan 2020) or the United Kingdom when studying the data of over 17 million patients (Williamson 2020).
This pattern is not associated with an increased risk of getting COVID-19 but only to the severity of the disease once an individual has been infected. It suggests that underlying pathological changes in anxiety and fear-related disorders can predispose to severe disease.
Part of my research is the look at outlying conditions and try and make sense of COVID-19 mortality. Anxiety and depression being a risk factor is one of those patterns that needs to be clarified.
In the context of COVID-19 autoimmunity, how could this association between anxiety/depression be explained?
In our research we have associated severe COVID-19 to elevated levels of serum ACE2 (McMillan 2021). Any condition that is associated with high levels (Sukrit 2020), increases the risk of severe disease. This is because the viral spike protein binds tightly to the free serum ACE2. In the context of severe COVID-19, the serum ACE2 can get caught up in the immune activation.
Watch 3 minute Doodly video explaining autoimmunity here >
This means any factor which increases serum ACE-2 levels could increase the risk for severe COVID-19.
Why would anxiety and fear-related disorders be a risk factor primarily in the United States?
If this was a pattern that was consistent across the whole world it would suggest that there may be a direct association between anxiety and fear-related disorders and severe disease. The fact that it seems to be primarily concentrated in the USA is likely to indicate that it is more related to treatment as possibly the most likely explanation .
One of the unusual patterns with regards to therapy in the United States is the high use of antidepressant prescriptions. This means the majority of patients will be placed on treatment once there is the possibility for a diagnosis for depression. Additionally, the levels of stress seems to be higher overall in the society. Recent data shows a 6% increase in antidepressant use at the end of 2020!
The pattern for prescribing is also likely to be mirrored in other aspects of mental health disorders.
Luo, Yan, et al. "National prescription patterns of antidepressants in the treatment of adults with major depression in the US between 1996 and 2015: a population representative survey based analysis." Frontiers in psychiatry 11 (2020): 35.
There is a known association between use of some antidepressants and heart disease, however not all antidepressants are a risk for cardiovascular complications (Seung-Won 2014). Looking at the data in the USA, depression is not directly associated with increased risk of death in COVID-19.
Under the heading of anxiety and fear-related disorders would be psychiatric diseases. There is a known association between cardiovascular mortality and antipsychotic medication. In fact, the work by Correll 2010, also highlighted the impact of antipsychotics on weight gain which could also increase levels of serum ACE2.
Based on the principle of autoimmunity in COVID-19, this increase in serum ACE2 could lead to higher risk of severe disease. The answer to the unusual association in the United States could eventually be related to medication.
The limitations to having a full understanding includes no access to data to clarify if those patients who died with anxiety and fear-related disorders were currently on antipsychotic medication at the time of admission to hospital. It would make a really interesting area of study.
References
Williamson, Elizabeth J., et al. "Factors associated with COVID-19-related death using OpenSAFELY." Nature 584.7821 (2020): 430-436.
Guan, Wei-jie, et al. "Clinical characteristics of coronavirus disease 2019 in China." New England journal of medicine 382.18 (2020): 1708-1720.
Luo, Yan, et al. "National prescription patterns of antidepressants in the treatment of adults with major depression in the US between 1996 and 2015: a population representative survey based analysis." Frontiers in psychiatry 11 (2020): 35.
Oh, Seung‐Won, et al. "Antidepressant use and risk of coronary heart disease: meta‐analysis of observational studies." British Journal of Clinical Pharmacology 78.4 (2014): 727-737.
McMillan, Philip, et al. "COVID-19—A theory of autoimmunity against ACE-2 explained." Frontiers in Immunology 12 (2021): 582166.
Narula, Sukrit, et al. "Plasma ACE2 and risk of death or cardiometabolic diseases: a case-cohort analysis." The Lancet 396.10256 (2020): 968-976.
Correll, Christoph U., John M. Kane, and Peter Manu. "Obesity and coronary risk in patients treated with second-generation antipsychotics." European archives of psychiatry and clinical neuroscience 261.6 (2011): 417-423.
Patients with depression usually use selective serotonin reuptake inhibitors which stimulate cholinergic anti-inflammatory pathway that is potent activator of regulatory and effector T cells to prevent hypersensitivity, hyper-inflammation and coagulopathy during infection with SC2.
I would argue that anxiety and fear-related disorders are caused by dysregulation of endocrine system. A good strategy for prevention of severe Covid-19 for such patients is diet change: from carbohydrates to protein diet. Carnivore diet for instance. I lack data to explain the molecular mechanism of that, but cortisol, B0AT1, GABA, glutamine have roles in all that.
I noticed anecdotal case when patient with adrenaline rush had asymptomatic C19, while surrounding individuals had mild to severe C19. Therefore, overactive adrenal glands are not always predisposition to severe C19.
There are many factors that contribute to weakening of the immune system, and increasing vulnerability to myriad diseases. They also contribute to synergistic interactions, as discussed in the following.
An OpEd titled "Have we entered a self-sustaining modus operandi for COVID-19?" has been posted recently on Trial Site News (https://trialsitenews.com/have-we-entered-a-self-sustaining-modus-operandi-for-covid-19/#comments). It addresses potential consequences of COVID-19 "vaccinations" followed by repeated boosters. Because most of the critical infrastructure personnel in the USA (doctors, nurses, military, law enforcement, teachers, pilots, etc.) were required to receive the initial COVID-19 "vaccinations" in order to remain employed, and are being required to get the boosters to remain employed, the consequences for the USA could be catastrophic if the scenario posited in the OpEd comes to pass. Recent events suggest we have entered the initial phases of this scenario.