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The Coming Epidemic of COVID-19-Associated Depression

It will be a crashing wave.

Acute infection with SARS-CoV-2 has been shown to result in persistent symptoms involving mood, sleep, anxiety, and fatigue associated with major depression.

In a recent study of U.S. adults with prior COVID-19 illness, for example, more than 52 percent met the criteria for moderate or severe major depressive disorder (Perlis, 2021). Similarly, a study conducted by British researchers reported substantial psychiatric comorbidity in the six months following COVID-19 infection, with the highest incidence occurring among those who had been hospitalized (Taquet, 2021).

These findings comport with those of studies conducted in connection with other coronavirus epidemics, including the SARS-CoV (Severe Acute Respiratory Syndrome) outbreak of 2003 and the MERS-CoV (Middle East Respiratory Syndrome) outbreak of 2012 and 2013, which also found high rates of depression among survivors for months to years following infection (Mazza, 2020).

As of this writing, roughly 130 million people have survived COVID-19 worldwide, with the United States ranking first among nations in the number of cases. The extraordinary scope of the pandemic, in combination with the pervasiveness of major depressive disorder among recovered individuals, means we will soon be facing a secondary epidemic of mental illness that could affect survivors and their families for years to come.

The role of stressors, such as stigma, social isolation, economic anxiety, and uncertainty about the future, in the high rates of depression among COVID-19 survivors has received a lot of attention. Less attention has been paid to the role of systemic immune-mediated inflammatory responses triggered by the infection itself, which have been demonstrated in many studies to set the stage for major depressive disorder.

In order to deal with the expected wave of COVID-19-related psychiatric comorbidities, the development of new interventions to mitigate the elevated risk of immune-mediated depression following acute infection is imperative.

Zeroing in on cytokines

Over the past two decades, a substantial body of evidence has accumulated identifying an association between inflammation and depression (Alpert, 2020). In the case of COVID-19, depression is believed to be associated with inflammatory cytokines, or cell signaling proteins, such as tumor necrosis factor-alpha (TNF-α) and Interleukin-6 (IL-6), that induce and maintain immune-mediated systemic inflammation.

In COVID-19 inflammation associated with “cytokine storm syndrome,” or an overreaction of the immune system can cause the body to attack its own tissues and organs. Many of the deaths

from COVID-19 are associated with the occurrence of cytokine storm syndrome in patients who have been admitted to the hospital with symptoms of COVID-19 pneumonia.

Patients with major depressive disorder (MDD) display features of a significant remodeling of their cytokine profiles. A 2018 study comparing MDD patients with no previous history of treatment with healthy controls found, for instance, that a stunning 66 to 100 percent of the untreated MDD patients displayed elevated levels for six of the seven measured pro-inflammatory cytokines, with levels that were 2 to 13 times those of the controls (Syed, 2018).

Though the mechanisms by which an out-of-control immune response promotes depression are complex and multifold – culprits include neuroinflammation, disruption of the blood-brain barrier, impairment of neurotransmission, peripheral immune cell invasion of the central nervous system, and more – it is clear is that therapies to curb cytokine activity can potentially be used to treat COVID-19-associated depression (Alpert, 2020; Benedetti, 2020, Holmes, 2020).

One such therapy is MYMD-1, an immunometabolic modulator that is the subject of an upcoming Phase 2 trial to treat immune-mediated depression in COVID-19 patients. The trial is expected to be launched in the last quarter of 2021.

The importance of the trial can’t be overstated. Despite the prevalence of COVID-19-related mental illness, the trial is the first and only clinical trial of a pharmaceutical intervention to treat COVID-19-related immune-mediated depression.

Like many of the most effective drugs in the medical arsenal, this is a synthetic alkaloid originally derived from a plant. It addresses immunometabolic dysregulation by modulating numerous pro-inflammatory cytokines, including, IL-6, IL-17A, and most importantly, TNF-α. Because TNF-α is located at the head of the cascade of molecular signals that induce inflammation, it, therefore, cuts off inflammation at its source.

The researchers of the trial expect to follow the COVID-19 trial with other studies of the therapeutic potential of the synthetic alkaloid, including for multiple sclerosis (MS), an autoimmune disease, and MS-related depression. A study in a mouse model of MS found that the synthetic alkaloid improves the course of the disease and regulates immune response without causing toxicity or immunosuppression, suggesting potential for the treatment of autoimmune disease (Glenn, 2020).

Infection and autoimmune disease have both been found to increase the permeability of the blood-brain barrier, which in turn increases the vulnerability of the brain to pathogens, inflammatory cytokines, and other harmful agents in the blood that can promote depression (Alpert, 2020; Benros, 2013; Holmes, 2020).

Addressing the ‘crashing wave’

Medicine has been focused for more than a year on the immediate impact of the pandemic. But it has yet to come to terms with its aftermath. In addition to the lingering symptoms experienced by COVID “long-haulers” and the permanent organ damage that is a consequence for some, medicine may be facing “a crashing wave” of COVID-19-related neuropsychiatric sequelae, in the words of one researcher (Troyer, 2020).

In addition to the need to collect high-quality data on the impact of the pandemic on mental health, an immediate priority is the urgent need for research to address how the mental health consequences of the pandemic can be mitigated. The upcoming clinical trial is a big step in that direction.


Alpert, Orna, et al. “Cytokine Storm Induced New Onset Depression in Patients with COVID-19. A New Look at the Association Between Depression and Cytokines – Two Case Reports” Brain, Behavior, and Immunity 9 (December 2020). DOI: 10.1016/j.bbih.2020.100173.

Benedetti, Francesco, et al. “Can Cytokine Blocking Prevent Depression in COVID-19 Survivors?” Journal of Neuroimmune Pharmacology (October 26, 2020). DOI: 10.1007/s11481-020-09966-z.

Benros, Michael E, et al. “Automimmune Disease and Severe Infections As Risk Factors for

Mood Disorders: A Nationwide Study,” JAMA Psychiatry 70 (8) (August 2013). DOI: 10.1001/jamapsychiatry.2013.1111.

Glenn, Justin D, et al. “MYMD-1, a Novel Alkaloid Compound, Ameliorates the Course of Experimental Autoimmune Encephalomyelitis,” Journal of Neuroimmunology (February 15, 2020). DOI: 10.1016/j.jneuroim.2019.577115.

Holmes, Emily A, et al. “Multidisciplinary Research Priorities foe the COVID-19 Pandemic: A Call to Action for Mental Health Science,” The Lancet 7 (June 1, 2020). DOI: 10.1016/S2215-0366(20)30168-1.

Mazza, Mario Gennaro, et al. “Anxiety and Depression in COVID-19 Survivors: Role of Inflammatory and Clinical Predictors.” Brain, Behavior, and Immunity 89 (October 2020). DOI: 10.1016/j.bbi.2020.07.037.

Perlis, Roy H, et al. “Association of Acute Symptoms of COVID-19 and Symptoms of Depression in Adults,” JAMA Network Open 4 (March 12, 2021). DOI: 10.1001/jamanetworkopen.2021.3223.

Syed, Shariful, et al. “Defective Inflammatory Pathways in Never Treated Depressed Patients Is Associated with Poor Treatment Response,” Neuron 99 (September 5, 2018). DOI: 10.1016/j.neuron.2018.08.001.

Taquet, Marie, et al. “6-month Neurological and Psychiatric Outcomes in 236379 Survivors of COVID-19: A Retrospective Cohort Study Using Electronic Health Records.” The Lancet 8 (May 1, 2021). DOI: 10.1016/S2215-0366(21)00084-5.

Troyer, Emily A, Jordan N. Kohn, and Suzi Hong. “Are We Facing a Crashing Wave of Neuropsychiatric Sequelae of COVID-19? Neuropsychiatric Symptoms and Potential Immunologic Mechanisms.” Brain, Behavior, and Immunity (July 2020). DOI: 10.1016/j.bbi.2020.04.027.

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