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Let’s say you are recovering from a recent mild COVID-19 infection, and you noticed that your thinking does not seem as sharp as it should be. You may notice difficulty finding words, or your processing speed is slower. It may take you longer to type your patient notes than it should. So-called brain fog is one of the most common and distressing symptoms described in the setting of a recent COVID-19 infection and may affect up to one-third of patients with COVID-19. Symptoms will only last for days to a couple of weeks for most patients, but for others, the symptoms can persist for months. Once patients begin to experience brain fog, is there anything that can be done to speed recovery? A recent study in the Journal of Psychosomatic Research suggests that there may be. I am Scott Beach, and this is Quick Takes for the Psychopharmacology Institute.
Perhaps surprisingly, the agent that has now shown benefit in a small study is famotidine. Famotidine is a commonly used medication for heartburn and reflux symptoms, available both over the counter and by prescription. You may have taken it after eating a particularly spicy meal. It is a traditional H2 blocker, which acts to neutralize acid in the stomach. In patients with COVID-19, it has previously been shown to reduce symptoms in nonhospitalized patients and reduce mortality in hospitalized patients. Exactly how it does so is unclear, but one leading theory is that it reduces inflammation and prevents cytokine storms by inhibiting histamine production. It may also enhance the activity of certain immune cells, including natural killer cells. Notably, there is also some evidence that famotidine has direct antiviral effects against SARS-CoV-2.
In this study, 58 patients were randomized to receive either famotidine or placebo, with 50 of them completing the study and being included in the analysis. The study was conducted in hospitalized patients at least 20 days out from infection and at least 7 days from the resolution of acute symptoms. That is interesting because it means that famotidine was not given during the acute phase of the illness or even immediately after recovery. Patients were given a cognitive screening test—either the Mini-Mental State Examination (MMSE) or the Montreal Cognitive Assessment (MoCA)—and had to score below a certain threshold to be included: 23 on the MMSE or 22 on the MoCA. That is interesting because it means that patients were already impaired before they started taking famotidine and often had been for some time. It also means they were not just subjectively impaired or with mild symptoms. Those scores are significant, especially considering patients with a known history of cognitive impairment or dementia were excluded. In the study’s main outcome, patients in the famotidine group were found to have higher MMSE and MoCA scores at weeks 6 and 12 and greater improvements in these scores. The authors also measured depression and anxiety scores using the HAM-D and HAM-A scales, respectively, and found greater improvements in patients taking famotidine, though these did not necessarily reach clinical significance.
This is not the first time that famotidine has been examined for its procognitive effects. It has been looked at in several prior studies, including a few involving patients with schizophrenia. Some studies have shown promise, though a meta-analysis failed to find any significant improvement. Studies have also examined whether longitudinal use of famotidine reduces the risk of Alzheimer’s disease, but results have again been inconclusive and mixed. This might suggest that we should interpret the results of this study with caution, given that early studies for the other conditions, also with small sample sizes, showed some promise before larger studies failed to replicate those findings.
In addition to the findings, I was struck by the fact that the authors used both the MMSE and the MoCA. Why might they use 2 cognitive scales? Well, the MMSE and the MoCA have some key differences and can be used in slightly different ways. Those who trained earlier probably were initially taught to use the MMSE. It was designed by Marshal Folstein, an expert in Alzheimer’s disease, in 1975 at Johns Hopkins. Questions on the MMSE are primarily geared towards memory, so it does a good job of detecting deficits involving short-term and working memory. The MoCA is a newer exam designed by Ziad Nasreddine in Montreal in 1995. It was specifically designed to help physicians detect mild cognitive impairment. In contrast to the MMSE, the MoCA tests a greater variety of cognitive domains and, in particular, has several tasks aimed at assessing frontal lobe functioning, making it superior at detecting executive dysfunction. Overall, the MMSE is still more widely used.
Both scales offer a total of 30 possible points. For the MMSE, a score of 18–23 out of 30 generally indicates mild cognitive impairment, whereas a score of 17 or less suggests major impairment or dementia. For the MoCA, a cutoff score of 25 or 26 is generally used to distinguish patients at risk for having mild cognitive impairment from healthy controls, and a score of 19 to distinguish those at risk for having dementia. Some studies have suggested that optimal cutoffs may differ by race and ethnicity, and a point is generally added for patients with less than 12 years of formal education. One thing for clinicians to know about both exams is that they can be insensitive in detecting early cognitive changes in highly intelligent, high-functioning adults because those individuals have a longer rate of fall, so to speak, before demonstrating deficits. The cutoffs used in this study that we’re examining today fall into the mild cognitive impairment range for both the MMSE and the MoCA. So, importantly again, the deficits demonstrated by patients in the study are certainly not negligible.
So, here is the big question: Based on these results, would I recommend patients reporting brain fog after COVID-19 take famotidine? Would I take famotidine myself if I were experiencing symptoms? The answer to both questions is yes. Right now, there are not many other great options: SSRIs, stimulants, and stimulant-like medications all have anecdotal evidence but no clear benefit in studies. The current recommendation is for cognitive pacing. Essentially, do not force your brain to take on too much at once, and listen to it when you start to feel fatigued or notice errors. Take a break and return to the task later. For many people, that’s easier said than done and a frustrating proposition. Famotidine is safe and well-tolerated, with few adverse effects. Brain fog symptoms can be extremely distressing to patients and impactful on quality of life. If there is a readily available medication that might mitigate symptoms and speed recovery, that is a very reasonable recommendation, even if the sample size in this study is small. I hope we can get a replication of these data in a larger sample, but until then, I recommend that patients with brain fog at least try famotidine.
Abstract
Effect of Famotidine on Cognitive and Behavioral Dysfunctions Induced in Post-COVID-19 Infection: A Randomized, Double-Blind, and Placebo-Controlled Study
Sara Momtazmanesh, Sahar Ansari, Zahra Izadi, Parnian Shobeiri, Venus Vatankhah, Arash Seifi, Fereshteh Ghiasvand, Mahboobeh Bahrami, Mohammdreza Salehi, Ahmad Ali Noorbala, Shahin Akhondzadeh
Objectives: This is an investigation of the efficacy and safety of famotidine, a selective histamine H2 receptor antagonist, on improvement of cognitive impairment, depression and anxiety symptoms developing post-COVID-19, in a 12-week, randomized controlled trial.
Methods: A total of 50 patients with a confirmed diagnosis of COVID-19 and a score ≤ 23 on the Mini-Mental State Examination (MMSE) test or a score ≤ 22 on the Montreal Cognitive Assessment (MoCA) were randomly assigned to either the famotidine (40 mg twice daily) or the placebo group. Changes in MMSE scores at weeks 6 and 12 were the primary outcome, while changes in other scales were the secondary outcomes. Participants and evaluators were blinded.
Results: At weeks 6 and 12, patients in the famotidine group had significantly higher MMSE scores (p = 0.014, p < 0.001, respectively). Regarding the MoCA scale, the famotidine group had a significantly higher score at weeks 6 and 12 (p = 0.001, p < 0.001, respectively). Considering the HAM-D scale (Hamilton Depression Rating Scale), at weeks 6 and 12, the famotidine group experienced a larger reduction (p = 0.009, p = 0.02, respectively). Additionally, comparison of the HAM-A scale scores (Hamilton Anxiety Rating Scale) at weeks 6 and 12 showed a statistically significant larger reduction in the famotidine group (p = 0.04, p = 0.02, respectively). The two groups did not differ in the frequency of adverse effects.
Conclusion: Our study supports safety and efficacy of famotidine in treating cognitive impairment, depression and anxiety symptoms induced by COVID-19.
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Reference
Momtazmanesh, S., Ansari, S., Izadi, Z., Shobeiri, P., Vatankhah, V., Seifi, A., Ghiasvand, F., Bahrami, M., Salehi, M., Noorbala, A. A., & Akhondzadeh, S. (2023).
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Journal of Psychosomatic Research, 172
, 111389.
