Opinion Long COVID-19 and Peripheral Serotonin: A Commentary and Reconsideration, 2024, Anderson et al.

[SNT Gatchaman]

Long COVID-19 and Peripheral Serotonin: A Commentary and Reconsideration
George M Anderson; Edwin H Cook; Randy D Blakely; James S Sutcliffe; Jeremy Veenstra-VanderWeele

We believe there are serious problems with a recently published and highly publicized paper entitled “Serotonin reduction in post-acute sequelae of viral infection.” The blood centrifugation procedure reportedly used by Wong et al would produce plasma that is substantially (over 95%) depleted of platelets. Given this, their published mean plasma serotonin values of 1.2 uM and 2.4 uM for the control/contrast groups appear to be at least 30 to 60 times too high and should be disregarded. The plasma serotonin values reported for the long COVID and viremia patients also should be disregarded, as should any comparisons to the control/contrast groups. We also note that the plasma serotonin means for the two control/contrast groups are not in good agreement.

In the “Discussion” section, Wong et al state that their results tend to support the use of selective serotonin reuptake inhibitors (SSRIs) for the treatment of COVID-19, and they encourage further clinical trials of SSRIs. While they state that, “Our animal models demonstrate that serotonin levels can be restored and memory impairment reversed by precursor supplementation or SSRI treatment”, it should be noted that no data are presented showing an increase or restoration in circulating serotonin with SSRI administration. In fact, one would expect a marked decline in platelet serotonin due to SSRIs’ effective inhibition of the platelet serotonin transporter.

Wong et al hypothesize that problems of long COVID arise from too little peripheral serotonin. However, given the frequent presence of a hyperaggregation state in long COVID, and the known augmenting effects of platelet serotonin on platelet aggregation, it is plausible to suggest that reductions in platelet serotonin might be associated with a lessening of the cardiovascular sequelae of COVID-19.

Link | PDF (Journal of Inflammation Research) [Open Access]

 

[SNT Gatchaman]

Commentary on Serotonin reduction in post-acute sequelae of viral infection (2023, Cell)

@Janna Moen PhD in case you haven't already seen this.

 

[SNT Gatchaman]

My first question is - are the levels of serotonin really different in LC? It would be a bit surprising, as, if it were that simple, you would think we would know that already. So, my set point is skepticism.

This is Figure 1J of serotonin levels, sorry it came out blurry. The columns are moderate Covid, severe Covid, recovered, PASC. The y axis markers are 0, 1000, 2000, 3000.

Therefore, that chart is interesting. The recovered people do seem to have slightly high serotonin versus normal ranges but the data points are in the ball park. And the people with Covid and with PASC do, on average, have low levels, with many having levels below the normal range.

I wonder if there was anything different about the sampling procedure, length of time before analysis...

In Figure 1J, the mean plasma 5-HT value for recovered COVID patients of ~1200 nM (1.2 uM, ~210 ng/mL) is contrasted to a substantially lower mean value in long COVID patients. While in Figure 2B the mean plasma 5-HT value for healthy controls of ~2400 nM (2.4 uM, ~420 ng/mL) is contrasted to the lower values obtained for viremia patients.

Unfortunately, the means and distributions of the plasma 5-HT data presented for the contrast/control groups are clearly in error. According to one of the authors of Wong et al, the plasma samples used for the 5-HT determinations were prepared by centrifuging blood at 1500 xg for 10 minutes. This crucial information regarding the centrifugation conditions was not provided in the paper, but rather obtained through personal communication with a corresponding author (M. Levy, November 12, 2023). This force and time of centrifugation typically leads to plasma platelet counts of <10,000 platelets/uL, about 4% or less of those seen in the typical whole blood specimen (250,000 platelets/uL). In fact, similar spins are recommended and used to prepare plasma largely depleted of platelets for use in coagulation assays. Given that (1) a marked depletion (4% or less remaining) in platelets is expected for the plasma samples employed, (2) over 99% of blood 5-HT is found in the platelet, and (3) typically reported means for whole blood 5-HT are about 1 uM, one would expect to see mean 5-HT values for plasma so prepared to be about 0.04 uM or less.

Thus, the reported mean plasma 5-HT values of 1.2 uM and 2.4 uM for the control/contrast groups appear to be at least 30 to 60 times too high and should be disregarded. The plasma 5-HT values reported for the long COVID and viremia patients also should be disregarded, as should any comparisons to the control/contrast groups. It is further noted that the plasma 5-HT means for the two control/contrast groups are not in good agreement.

 

[SNT Gatchaman]

the role (or roles) of 5-HT in acute and long COVID remains very much an open question. Wong et al hypothesize that problems arise from too little peripheral 5-HT. However, given the frequent presence of a hyperaggregation state in long COVID, and the known augmenting effects of platelet 5-HT on platelet aggregation, it is also plausible to suggest that reductions in platelet 5-HT could be beneficial.

In summary, we reach the following conclusions: (1) the crucial plasma 5-HT data reported in Figures 1J and 2B of Wong et al should be disregarded as clearly and markedly erroneous; (2) reports of circulating 5-HT levels should clearly define how the sample is prepared; (3) platelet counts should be obtained when measuring circulating 5-HT and will significantly improve interpretation of the measurements; and (4) though the role of peripheral 5-HT in long COVID remains unclear, it can be suggested that reduced platelet 5-HT might actually be associated with a lessening of cardiovascular sequelae of COVID-19.

 

[Grigor]

Very critical commentary, but it did seem quite surprising to see serotonin pop up as such a significant finding when it hadn't been before.

 

[EndME]

Interesting comment by a much smaller team than the original study team and largely consisting of psychiatrists.

Will be interesting to see if and how Wong et al reply to this, especially since the list of authors is ridiculously long and consists of names and teams that have gone very viral in the LC field (Peluso, Wherry, Henrich, Deeks, Cherry, Levy).