Covid, mental health, and inflammation

6 October 2022

Michael Eriksen Benros is professor of immuno-psychiatry in the Department of Immunology and Microbiology at the University of Copenhagen, head of biological and precision psychiatry at the Mental Health Centre Copenhagen, Copenhagen University Hospital, and co-chair of the ECNP Immuno-NeuroPsychiatry Network. A specialist in immuno-psychiatry, biological psychiatry, epidemiology and precision psychiatry, at the ECNP Congress in Vienna he will speak on ‘Covid-19 and consequences for mental health and cognition’ (S16.03). Here he speaks to ECNP press officer Tom Parkhill.

TP: Michael, what’s your background and why are you interested in Covid?
MEB: I’m a professor, medical doctor and chief consultant in psychiatry. Since the very start of my research career, I have been investigating the link between the immune system and mental disorders. Immuno-psychiatry has always been at the core of my interest field, so when the Covid-19 pandemic arose, it was a natural step for me to be involved. The Danish nationwide registers and biobanks allow us to look at data from the entire Danish population – we can see whenever someone is treated for an infection or has hospital contacts with an infection or auto-immune disorders, and we can adjust the data for relevant confounders as social or familial factors and longitudinally follow the risk for brain disorders. One of my research programmes is on the link between the immune system and mental disorders, both regarding large-scale epidemiological and immunogenetic associations. We also perform clinical studies where we sample cerebrospinal fluid (CSF), blood and microbiome, from patients with new-onset psychosis and depression, in addition to placebo-controlled RCTs with immune-modulating treatments. So Covid was an obvious part of my research track.

I see that you have several recent papers on Covid.
Early on in the pandemic we published the first systematic review on the mental health consequences of the pandemic. Much has happened since then, and we have just published a novel article in Nature Medicine reviewing the current state of the art, providing an overview of how the Covid pandemic affected mental health. This looks at indirect effects – people who have not had Covid but who are nevertheless touched by the societal effects – and direct effects, which means Covid sufferers.

So what have you found?
Our clinical Covid studies looked at all patients hospitalised with Covid-19 here in the major hospital of Copenhagen. Every patient admitted with Covid was screened daily for psychiatric and neurological conditions and symptoms. During the acute phase the most prominent mental health issue was delirium – around a third of patients suffered delirium, but the rate went up in patients who were in intensive care. However, these numbers looked rather similar to that of many other patients in the hospital, so we early on realised that we needed to recruit controls to match these individuals. The individuals admitted due to Covid-19 and the matched control individuals with similar non-Covid disease were then re-investigated six months after discharge from the hospital, and screened for psychiatric and neurological symptoms and new onset diagnoses.

This study was published in JAMA Psychiatry in the spring. It was the first Covid study with matched controls with similar disease severity but not due to Covid-19, which is needed to determine the specificity of the affection of the brain by Covid-19. And this showed that both groups were affected. The ones with Covid-19 had a high occurrence of mental disorders, but when we compared this with the matched patients – hospitalised for the same amount of time, showing the same inflammatory levels as the Covid group – there was very little difference, although there was a small but significant effect on cognition in the Covid group. We also screened the Covid-19 patients when they were discharged from the hospitals, showing a large improvement in cognition at follow-up: at discharge they had average levels of 19.2 on the Montreal Cognitive Assessment (MoCA) scale, but after six months this had improved by itself to 26.1 points on the MoCA scale. This was a large improvement from the point of discharge, but compared to the other matched patients the difference at follow-up was small. Also, looking at the mental disorder diagnosis, it was around 19-20% in both groups, which is roughly double the levels you see in the general population, so both groups were affected. And looking at symptoms, these were similarly prevalent in both groups, at around 81-93%.

We are currently expanding the cohort and with longer follow-up points, but we have also taken cerebrospinal fluid from patients with Covid-19. When Covid started, there were worries raised early on in the pandemic due to the neurotropic potential of SARS-CoV-2 about how often it enters the brain and whether it directly causes mental health symptoms. Here we show that the infection itself was not present in the CSF fluid of the patients. Worldwide active infection with SARS-CoV-1 in the brain has only been shown in case reports, but some of the individuals with severe Covid-19 infection in our cohort had antibodies to the infection in the CSF. However, there was no clear indication of intrathecal antibody production. Thus, this is likely due to inflammation in the periphery increasing permeability of the blood-brain barrier and then antibodies (like many other components) entering the brain. So the current evidence indicates that the most common way Covid-19 can cause a brain effect is to induce a peripheral immune response which can then increase the permeability of the blood-brain barrier, as you would also see in many other types of severe infections. For me, the current question with Covid is ‘How does it differ from other infections of similar severity?’ To answer this on a large scale we are looking into the Danish national registers, where we have records of all Covid-19 tests performed in the whole of Denmark, including individuals hospitalised for Covid-19. We can link these to the risks of mental and neurological disorders, and we can also compare these to other types of infection for the whole population.

Earlier on in the pandemic, our ECNP Immuno-NeuroPsychiatry Network performed a meta-analysis of all studies published on Covid-19 patients with mental disorders – asking questions such as do they have a different risk of being hospitalised, of going into an ICU, and also about mortality. We have been able to show that people with severe mental disorders, in particular Covid patients with psychotic disorders, had increased risk of hospitalisation and being admitted to ICU units. Mortality is also increased in this group.

Can you give us any figures on this?
Individuals with psychotic disorders suffering from Covid-19 had a roughly 77% increased mortality risk after adjustments. That led us, early in the pandemic (around January 2021), to publish a paper in Lancet Psychiatry advocating that patients with severe mental disorders should be included in the priority vaccination programme. At that time it was only people with severe general medical conditions who were included in the priority programme.

Yes, I remember the paper. I worked with Livia De Picker and Marion Leboyer on a press release from the ECNP Immuno-NeuroPsychiatry Network to help publicise the call. Of course, you are co-chair of this group. What was the effect of the Lancet Psychiatry paper?
Well it’s always difficult to understand the effect of a single paper. Denmark was one of the first countries to have people with severe mental disorders included in the priority group, even before the paper. However, shortly afterwards patients with severe mental disorders were included in the priority list in most Western countries. Although this may have happened anyway, the paper helped to put the focus on equality in health care for people with severe mental disorders, which is much needed and was informative for the health authorities. The paper has also just been shortlisted for the UK Royal College of Psychiatrists’ Award for Psychiatric Global Contributor of the Year, which highlights the importance of the paper’s contribution to public health.

This brings us to the societal effect on mental health, as you mentioned earlier. There are lots of existing mental health patients who have not been seen or treated because of the pandemic, but at the same time there are lots of people who didn’t have mental health problems but who have become more stressed, more anxious, because of Covid. Social anxiety, for example, may be on the increase.
In our review we looked at both the direct effects and the indirect effects. In one of our own studies on indirect effects of the pandemic we looked at all psychiatric admissions and mental health referrals in a population-based study utilising electronic health record data from half of the Danish population. We looked at different periods, and also at different lockdown periods. In Denmark we found that there was no increase in the number of adults admitted to mental health hospitals, and there was no increase in the number of mental health referrals, nor in suicides or suicide attempts. In fact, during lockdowns the number of admissions went down. The only increase we saw was in children and young adults below 18 years of age. But in fact this was a continuation of the trend which we had seen before the onset of the pandemic. Of course these studies are only on mental disorders requiring hospital contact, so there are some limitations regarding generalisability to less severe mental health symptoms. But we see some of the same patterns in controlled studies in the general population; in some you see a small decrease in mental health levels during the lockdown period, but this then returns to normal afterwards. We also have conducted a population-based Danish study on a group of 2,190 individuals, where interviews were performed both before and during the pandemic. We interviewed them during the first lockdown and found a significant decrease in mental and physical health, but the absolute overall decrease was rather small. So, luckily, the effects on society have not been as big as we feared at the beginning of the pandemic.

This is recent data, looking at effect after two and a bit years of the pandemic. So after this time we feel that it could have been worse.
The pandemic has had effects on mental health, but overall they have been smaller than feared in the beginning of the pandemic. Some people with prior mental disorders or challenges actually feel better during the pandemic, because there are fewer stresses. And of course there are other people who have not had any big issues and suddenly get health anxieties. It seems that this may somewhat even out. But of course this is in the Western world, where we are able to look at effects differently. We also have had several initiatives to help us through this; for example in Denmark we have had helplines and other initiatives for the general public, and the mental health services increased the use of telepsychiatry. But less privileged countries may be different – we also lack high quality research studies from these countries.

Is there anything we should be wary of, is there anything we should pay close attention to in the future? I’m asking you to speculate, of course.
It’s something we need to continue to follow and monitor closely, both regarding the direct and the indirect effects. Even when the brain effects of SARS-CoV-2 infection might not be so different from that after other infections with similar severity relatively speaking, if many more than before the pandemic develop severe disease, it would of course have an impact on the individual and societal level regarding the long-term effects. Regarding the indirect effects of the pandemic, the population may show good resilience, but maybe that will not always be so, if the waves keep coming. Other events, such as the war in Ukraine, also cause stresses, and these events may reinforce a larger effect on society. Of course if the Covid pandemic and the war in Ukraine end up causing a financial crisis, then there will surely be larger effects on mental health. In the financial crisis of 2007 we saw that things were okay for around a year and a half, then there was a general worsening in mental health. So it’s important that we keep monitoring the situation and learning from it for future pandemics. From my own point of view as a researcher, I think that it is really important that we use the resources which have gone into Covid-19 to dig deeper, to pull out some of the biological underpinnings of why we see this association between inflammation and mental health, not just with Covid-19 patients, but with other patients with infections and inflammatory conditions, looking at what happens molecularly in the brain and how can we prevent such things as cognitive decline and mental disorders. We need to use this current investment to find out what causes this relationship, which might also provide biological underpinnings for mental disorders more broadly, and help identify treatment targets to develop better treatments.


Michael Eriksen Benros will speak on Tuesday 18 October 2022:
S16.03 – Covid-19 and consequences for mental health and cognition

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