Long COVID, Depression, and the Immune System

A possible marker for the risk of developing long COVID.

Reviewed by Monica Vilhauer

Key points

• The risk of developing long COVID is low, but the consequences can be severe.
• Pre-existing conditions like anxiety, depression and loneliness can all increase risk.
• The role of depression and other psychological issues in long COVID is worthy of further investigation.

On January 30, 2023, the Biden Administration announced that COVID-19 is no longer a public health emergency. The Center for Disease Control (CDC) here in the US and the World Health Organization (WHO) followed suit with similar announcements, both in May of 2023. Unfortunately, those announcements do not mean that people are no longer being infected with COVID or that the disease has faded out of existence.

Outbreaks, epidemics, pandemics and endemic diseases

COVID started out as an epidemic (a regional outbreak of a disease) in China, then spread around the world becoming a pandemic. The concern is now that COVID is becoming an endemic disease, meaning that it is consistently present but that its spread and the rate at which it spreads is now predictable. Think about malaria in tropical countries, or, closer to home, chicken pox in the United States. These disease are still present, still affecting the lives of the citizens of the regions they are endemic to, but at predictable rates. Essentially, COVID has become much less of a surprise.

If you have COVID that may not be much comfort. And if you have had COVID, even if you were infected months ago, you may be concerned about the risk of what is commonly known as long COVID

Long COVID

Long COVID, also known as Post Acute Sequelae of SARS-COV-2, is defined by Monje and Iwasaki (2022) as a “collection of prolonged symptoms that develop during or following a confirmed or suspected case of COVID-19” with patients exhibiting symptoms that include “…anosmia” (loss of the sense of smell), “ageusia” (loss of the sense of taste), “cognitive impairments, depression and anxiety,” as well as “brain fog, characterized by impaired attention, concentration, memory, speed of information processing and executive function” (page 3484).

Not everyone develops long-COVID. According to a 2023 review of the research on long COVID (Davis, McCorkell, Vogel and Topol), “At least 65 million individuals around the world have long COVID, based on a conservative estimated incidence of 10% of infected people and more than 651 million documented COVID-19 cases worldwide” (page 134). These authors also point out that the number is likely much higher because of the number of undocumented cases.

A number of factors have been proposed that might help doctors predict who is at risk for long COVID. Risk factors identified so far include gender, age, severity of the initial illness and possible resulting micro-clots or organ damage, as well as people suffering from what doctors call “comorbidities” or health problems already causing difficulties when the person is infected with the COVID virus.

Depression and your immune system

One of these comorbidities that appears to increase the risk of long COVID is depression. It might seem somewhat odd that a problem associated with having long COVID is also a predictor of long COVID, but there is good reason to suspect that depression might be an important precursor. That is because clinical depression, even without the added complication of COVID, can and does impair the functioning of the immune system. It makes sense that a virus that compromises the immune system might have a more lasting effect on the body if that immune system is already weakened by depression. Lee and Giuliani (2019) reported that depression and fatigue (note, this is without the COVID virus being involved) are associated with increased activation of the immune system. In addition, antidepressant drugs that are used to treat depression have also been shown to decrease inflammation in the body and the CNS.

In a 2022 study that reviewed cases of COVID and long COVID, Wang et al., reported that “…preinfection psychological distress, including symptoms of depression, anxiety, worry about COVID-19, loneliness, and perceived stress, was strongly associated with risk of post–COVID-19 conditions among those infected with…SARS-CoV-2” (page 1084).

However, in a study done in 2023, Klein et al., compared patients suffering from long COVID and those in a control group that had had COVID but did not experience long term symptoms. These two groups did not differ in terms of their age, the severity of the initial experience of COVID (although the long COVID sufferers did report that their symptoms were more intense than were the symptoms reported by the control group), nor did they differ in pre-exposure levels of anxiety or depression. They did differ significantly in their immune system responses to the virus.

People suffering from long COVID had higher levels of circulating specialized cells that the immune system uses to identify and dispose of infectious agents in the body, as well as an “exaggerated” response by the immune system in long COVID sufferers to the COVID virus itself. Some of the levels of circulating immune system cell types were increased while others were decreased, however overall, “Circulating immune cell populations significantly changed” (page 8) in long COVID sufferers.

Long COVID patients also had lower levels of cortisol than did the control group patients. Cortisol is a hormone released by the body to help us cope with stress. Perhaps an exhausted stress coping response makes one more likely to develop long COVID? As these researchers point out, this persistent hypocortisolemia might be worth further investigation as might the role of depression and other psychological issues in the risk of long COVID and other infectious disease.