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The psychiatric syndromes caused by COVID infection may look like commonplace DSM-5 disorders, but the cause and treatment may be different.

Reference: Boldrini M, Canoll PD, Klein RS. How COVID-19 Affects the Brain. JAMA Psychiatry. 2021 Mar 26.

Published On: 5/24/2021

Duration: 16 minutes, 11 seconds

Transcript: 

Kellie Newsome: Today we explore 3 ways that the coronavirus can affect the brain, causing syndromes that resemble traditional psychiatric disorders but may differ in their causes and treatments.

Dr. Aiken: Welcome to The Carlat Psychiatry Podcast, keeping psychiatry honest since 2003. I’m Chris Aiken, the editor in chief of The Carlat Psychiatry Report.

Kellie Newsome: And I’m Kellie Newsome, a psychiatric NP and a dedicated reader of every issue.

From Vitamin D to COVID

Kellie Newsome: Last year Paul Riordan joined our writing staff. Paul is a psychiatrist at Duke Medical Center who is also boarded in internal medicine and hospice and palliative care, and he’s been using his triple-boarded knowledge to clarify areas on the med-psych interface. This month, he took on vitamin D in psychiatric disorders. Vitamin D has been touted as a cure all for everything from cancer to depression, so Dr. Riordan went into this with a bit of skepticism, doubtful that one vitamin could cure all or that more was necessarily better. But he did identify a positive signal in the mixed results of the clinical research: Patients with depression and vitamin D deficiency, and his article in the May edition gives specifics on how to order the labs, cut off levels to treat – as well as cut offs for when vitamin D goes too high – and dosing strategies. 

As Dr. Riordan prepared the article, new research on vitamin D and COVID came out. Dr. Riordan’s article addresses whether vitamin D supplementation can prevent COVID, and in this companion podcast we’re going to brief update you on how COVID affects the brain.

The official name of this virus is severe acute respiratory syndrome coronavirus 2, or SARS-CoV-2. The disease it causes is COVID; just like HIV is a virus and AIDS is the illness. COVID is a respiratory illness, but there is also evidence that the virus affects the brain.

It’s likely that all of us have come in contact with the SARS-2 coronavirus, but not everyone who is exposed to the virus develops the COVID syndrome. And not everyone who has COVID has neuropsychiatric manifestations – but many do – around 20-70%. The neuropsychiatric symptoms are many. The most common is anosmia, or loss of smell. There can also be cognitive problems, which patients often describe as “brain fog,” and new-onset anxiety, depression, psychosis, delirium, seizures, and even suicidal behavior.

These neuropsychiatric symptoms are somewhat independent of the respiratory symptoms. They can occur before, during or after them. Often they endure for months after the respiratory symptoms resolve.

3 Ways that COVID Affects the Brain

How does a respiratory virus affect the brain? We don’t have precise answers yet, but there are at least 3 possibilities.

Dr. Aiken:

1. The SARS-2 coronovirus might directly enter the brain just as other viruses like HIV and herpes do. It could get in through the nose and olfactory nerves, or through the blood brain barrier. The traditionally tight blood brain barrier becomes more porous during inflammation, which might let the virus pass in.
2. Alternatively, it could damage the brain indirectly through inflammatory pathways. Systemic inflammation lowers monoamines like serotonin, dopamine and norepinephrine as well as brain trophic factors like BDNS, and these undesirable effects might unleash psychiatric illness.
3. Finally, the COVID could injury the brain through stroke. The virus damages vascular endothelial cells, causing thrombi to pass into the brain or other organs. The risk of stroke is 3-7 fold higher during COVID.

Inflammation and Depression

Another word for inflammation is the cytokine storm, which means the armies that fight infection are set loose with guns blazing throughout the brain and body. Examples of these cytokines are interleukins and tumor necrosis factor, quinolinic acid, and the excitatory neurotransmitter glutamate – which is an inflammatory mediator and is also neurotoxic, as in killing brain cells. We know a lot about inflammatory depression already – see our January 2020 issue for more on that – and there’s a good chance that these concepts apply to post-COVID depression as well. 

Inflammatory depression is marked by anhedonia. Inflammation wears down serotonin and norepinephrine, but it particularly blunts dopamine in the CNS, leading to low motivation and absence of pleasure. Cognitive problems, motor slowing, and neurovegetative symptoms are also common during inflammatory depression. Inflammatory depressions are less likely to respond to antidepressants, particularly serotonergic ones. 

Lessons from Earlier Coronoavirus’

Kellie Newsome: If this sounds a little speculative, you’re right. Much of the research we have comes from earlier coronavirus outbreaks the first SARS epidemic of 2003 or the Middle East respiratory syndrome coronavirus outbreak of 2012. Each of those coronavirus outbreaks caused about 700-900 deaths worldwide, a pale comparison to the 3.5 million deaths that the 2019 strain has caused. Ironically though the 2019 coronavirus is less deadly than the earlier strains. Only about 1 in 100 infected persons die from it. So why is it causing so many more deaths? The reason is that it is more transmissible – jumping to 6 more people for every 1 person it infects. Transmission happens exponentially, while death rates hold steady, so a high transmission rate can easily bump the fatality rates up on a global scale.

Getting back to the brain effects, we do have evidence that inflammation is contributing to the post-COVID psychiatric syndromes. Last October a group from Milan, Italy measured markers of inflammation in 402 survivors of COVID-19 and then followed them up for a month. The more inflammatory markers they had, the more likely they were to develop depression and anxiety at follow-up.

Coronavirus and Ischemic Brain Injury

Another model that might help us understand post-COVID depression is traumatic brain injury or TBI. In TBI, inflammation comingles with vascular injury to cause neuronal loss in the brain, and these two pathways are part of COVID infection as well. The damage that ischemia and inflammatory forces bring to the brain has been linked to violence and suicidal behavior in TBI, and suicide is elevated during inflammatory states like COVID as well.

Post-COVID Psychiatric Syndromes: First Steps

If your patient has COVID, ask them if they had neuropsychiatric symptoms during or after the infection – loss of smell, headaches, cognitive problems or new psychiatric symptoms. Neurologists recommend 3 lifestyle interventions for the neuropsychiatric symptoms of COVID:

1. Aerobic exercise. We don’t have an exact dose, but some studies suggest that patients with inflammatory depression may need more intensive exercise than those with regular depression. For example, 30-60 minutes a day of vigorous exercise like running and weight lifting as opposed to 30-60 minutes a day of brisk walking. But brisk walking is usually the place to start if depression is what your patient is dealing with. 
2. Mediterranean diet. This diet has anti-inflammatory effects and improved depression and cognition in several trials, including a recent one last month where it improved ADHD in children. Tell your patient to eat more vegetables, fruit, beans, nuts, and a moderate amount of lean meats and fish. They should swap all their butters and oils for extra virgin olive oil – including for frying – and all their carbs for 100% whole grains, like brown rice, oatmeal, quinoa, and 100% whole grain breads and pastas.
3. Sleep. The brain repairs itself during sleep, which is part of the reason that sleep enhances learning. Deep sleep is not only essential to recovery from COVID, but it may also protect against the infection to begin with. Sleep is necessary to a healthy immune system. Poor sleep raises the risk of viral infections 3-4 fold, and it even interferes with immunization – vaccines don’t work as well if people have insomnia around the time they were vaccinated.

Beyond that, anything that lowers stress is likely to have anti-inflammatory effects – specific benefits have been found with tai chi, yoga, mindfulness, and CBT for insomnia.

Medications for Inflammatory Depression

In terms of psychiatric medications for post-COVID symptoms, we don’t have research to guide us, but we do have an idea from earlier studies on inflammatory depression. 

Inflammation is measured with the high sensitivity C reactive protein or CRP. When depressed patients have a high CRP, serotonergic antidepressants do not work as well. High means a CRP above 1 or above 3 depending on the study. Instead tricyclic antidepressants – specifically nortriptyline – and dopaminergic medications – specifically bupropion – have better evidence to work.  Pramipexole – which is purely dopaminergic through D3 in the nucleus accumbens – may also work, and it has good studies in bipolar and unipolar depression. A few episodes ago we discussed new research on minocycline 200mg/day in depression, and mentioned a new study showing this glutamateric medication works better when the CRP is elevated. 

Other medications that may – at least in theory – work better during inflammation include ketamine and lithium. Lithium has broad neuroprotective effects, and it also has direct antiviral effects, killing viruses and preventing them from replicating. Most of that research has been done on herpes virus, but it has also gone against a dozen other DNA and RNA viruses including other coronaviruses, though not the one behind COVID-19. On the other hand, patients with active viral infections are more at risk for lithium toxicity, whether from dehydration or NSAID use.

Curcumin – a bioactive ingredient in turmeric – also has half a dozen small controlled trials in depression, including one where it compared well to against fluoxetine. This may prove useful as curcumin is also being used experimentally to reduce the COVID cytokine – so far the studies are small but positive.

There are 3 other supplements with antidepressant effects that may be useful for inflammatory depression – each of these has at least one study where it worked better in pateints with elevated CRPs. 

• N-acetylcysteine (NAC) is the main antioxidant in the brain and dosed 2000 mg a day. 
• L-methylfolate is the brain-active form of folate and involved in production of monoamines like dopamine and serotonin; it is FDA cleared in depression at a dose of 15 mg a day. 
• And Omega-3 fatty acids – these healthy fats make up 30% of the brain where they coat brain cells and are involved in brain repair and neuroprotection. There are two types of omega 3’s – EPA and DHA – and to treat depression you need a product with at least 1,000 mg EPA and a higher ratio of EPA to DHA – the ratio should be at least 1.5 times more EPA than DHA. I keep a list of good products like this that have been tested by independent labs on my website at moodtreatmentcenter.com/products.

Psychological Causes

This is not to suggest that inflammation, ischemia, and CNS infection are the only pathways through which COVID causes depression. Fear, isolation, and the numerous stressors that infection and quarantine bring are also at play. Not to mention physical activity and diet quality – both of which have been on the decline during quarantine. Those psychosocial factors are unique to each patient, and best discerned from a psychiatric interview. While you do that, listen out for signs of severe physical illness, or neuropsychiatric symptoms that are not typical for depression and anxiety, like loss of smell, seizures, marked headache or cognitive problems, and recent delirium. Those signs suggest suggest that the COVID infection may have injured the brain through one of these other pathways.

Divergent Thinking

And now for the word of the day…. Divergent thinking

Kellie Newsome: “Before the problem of the creative artist psychoanalysis must, alas, lay down its arms,” wrote Sigmund Freud in 1927, and we haven’t made much headway on the subject since then. In fact, we are still struggling to define creativity, much less explain it. Divergent thinking is the most widely accepted measure of creativity. It tests a person’s ability to generate unique and diverse solutions to a problem. Here’s an example. In the Alternative Uses Test, subjects are asked to think of as many diverse uses for a common object – like a brick – as possible in a few minutes. Well, it could be used as a paperweight, a computer stand, a weapon, a seed starter, meat tenderizer, a fishing rod holder. The more answers the better. 

Dr. Aiken: Creativity is hard to define, and bipolar is difficult to diagnose, but we’ll look at some ways that the two overlap in next week’s podcast: Bipolar, Barbiturates, and Punk Rock.

Follow us on twitter where we feature a new research paper every day. Today’s study looks at risk factors for dissociation during ketamine and esketamine therapy.

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