Assessing the effect of selective serotonin reuptake inhibitors in the prevention of post-acute sequelae of COVID-19, 2024, Sidky et al.

Assessing the effect of selective serotonin reuptake inhibitors in the prevention of post-acute sequelae of COVID-19
Hythem Sidky; Kristen A. Hansen; Andrew T. Girvin; Nathan Hotaling; Sam G. Michael; Ken Gersing; David K. Sahner

BACKGROUND
Post-acute sequelae of COVID-19 (PASC) produce significant morbidity, prompting evaluation of interventions that might lower risk. Selective serotonin reuptake inhibitors (SSRIs) potentially could modulate risk of PASC via their central, hypothesized immunomodulatory, and/or antiplatelet properties although clinical trial data are lacking.
Materials and

METHODS
This retrospective study was conducted leveraging real-world clinical data within the National COVID Cohort Collaborative (N3C) to evaluate whether SSRIs with agonist activity at the sigma-1 receptor (S1R) lower the risk of PASC, since agonism at this receptor may serve as a mechanism by which SSRIs attenuate an inflammatory response. Additionally, determine whether the potential benefit could be traced to S1R agonism. Presumed PASC was defined based on a computable PASC phenotype trained on the U09.9 ICD-10 diagnosis code.

RESULTS
Of the 17,908 patients identified, 1521 were exposed at baseline to a S1R agonist SSRI, 1803 to a non-S1R agonist SSRI, and 14,584 to neither. Using inverse probability weighting and Poisson regression, relative risk (RR) of PASC was assessed.

A 29% reduction in the RR of PASC (0.704 [95% CI, 0.58–0.85]; P = 4 ×10−4) was seen among patients who received an S1R agonist SSRI compared to SSRI unexposed patients and a 21% reduction in the RR of PASC was seen among those receiving an SSRI without S1R agonist activity (0.79 [95% CI, 0.67 -0.93]; P = 0.005).

Thus, SSRIs with and without reported agonist activity at the S1R were associated with a significant decrease in the risk of PASC.


Link | PDF (Computational and Structural Biotechnology Journal)

 

A significant problem with this study could be that

This algorithm is discussed here.

It's currently established that Fluvoxamine does nothing for acute Covid-19 as there have been multiple RCTs on this subject, which is probably a good thing for their study as the severity confounder of the acute infection shouldn't play an additional role (unless their ML classifier does something unexpected, which is always possible).

The Metformin study came to the conclusion that in their study the same holds for the development of LC. Apart from an overweight cohort, that study of course struggled with a very vague defintion of LC but the same would be the case here as the U09.9 ICD-10 diagnosis code doesn't require a minium duration, severity level, number of symptoms or something similar and is possibly even more vague if a possibly outdated ML classifier is making the diagnosis. The Metformin study had a very short time frame of administering Fluvoxamine (10 days as far as I can recall vs a seemingly long-term baseline prescription in this study), so might be interesting to know whether this could play a role.

If the results were to be true it would hard to see how their outlined ideas were to be the cause for it since there are other immunomodulatory treatments available that would be considered to have a far higher efficacy in modulating the immune system.

What alternative explanations could explain the S1R agonist vs non-S1R agonist data? Do some SSRIs have a higher propensity to cause withdrawal symptoms that could be wrongly attributed to something else especially if you rely on a machine learning algorithm to make a diagnosis? As they are only looking at very vague short term outcomes, does the one dampen symptoms generally better vs the other?

 

Hard to say if this study is rigorous enough to move things forward, but it would be really great if the immunological mechanisms of SSRIs were understood and medicine were able to move beyond the misleading labeling of antidepressants. IMO the acceptance of the bastardized version of depression we are seeing has been one of the most significant failures of modern medicine. It adopted a construct so generic and arbitrary that it's significantly worse than when medicine was very insistent that depression is not a thing.

They truly adopted the worst of multiple possible options. Now every-freaking-thing they can't explain is depression (or anxiety, or stress, or whatever) and the whole concept of chronic illness, or hell even any illness, has been thrown into disarray by mixing some old myths about psychosocial this and that with some other BS about "chemical imbalance".

 

A related preprint yesterday, with similar use of U09.9 coding as noted above by EndME —

SSRI Use During Acute COVID-19 Infection Associated with Lower Risk of Long COVID Among Patients with Depression (MedRxiv)
Zachary Butzin-Dozier; Yunwen Ji; Sarang Deshpande; Eric Hurwitz; Jeremy Coyle; Junming (Seraphina) Shi; Andrew N. Mertens; Mark van der Laan; John M. Colford; Rena C. Patel; Alan Hubbard; on behalf of the National COVID Cohort Collaborative

BACKGROUND
Long COVID, also known as post-acute sequelae of COVID-19 (PASC), is a poorly understood condition with symptoms across a range of biological domains that often have debilitating consequences. Some have recently suggested that lingering SARS-CoV-2 virus in the gut may impede serotonin production and that low serotonin may drive many Long COVID symptoms across a range of biological systems. Therefore, selective serotonin reuptake inhibitors (SSRIs), which increase synaptic serotonin availability, may prevent or treat Long COVID. SSRIs are commonly prescribed for depression, therefore restricting a study sample to only include patients with depression can reduce the concern of confounding by indication.

METHODS
In an observational sample of electronic health records from patients in the National COVID Cohort Collaborative (N3C) with a COVID-19 diagnosis between September 1, 2021, and December 1, 2022, and pre-existing major depressive disorder, the leading indication for SSRI use, we evaluated the relationship between SSRI use at the time of COVID-19 infection and subsequent 12-month risk of Long COVID (defined by ICD-10 code U09.9). We defined SSRI use as a prescription for SSRI medication beginning at least 30 days before COVID-19 infection and not ending before COVID-19 infection. To minimize bias, we estimated the causal associations of interest using a nonparametric approach, targeted maximum likelihood estimation, to aggressively adjust for high-dimensional covariates.

RESULTS
We analyzed a sample (n = 506,903) of patients with a diagnosis of major depressive disorder before COVID-19 diagnosis, where 124,928 (25%) were using an SSRI. We found that SSRI users had a significantly lower risk of Long COVID compared to nonusers (adjusted causal relative risk 0.90, 95% CI (0.86, 0.94)).

CONCLUSIONS
These findings suggest that SSRI use during COVID-19 infection may be protective against Long COVID, supporting the hypothesis that serotonin may be a key mechanistic biomarker of Long COVID.


Link | PDF (Preprint: MedRxiv)

 

It may have nothing to do with serotonin.

Effects of agonism on the sigma-1 receptor.

Modulation of the Blood–Brain Barrier by Sigma-1R Activation 2024
Brailoiu, Eugen; Barr, Jeffrey L.; Wittorf, Hailey N.; Inan, Saadet; Unterwald, Ellen M.; Brailoiu, Gabriela Cristina

Sigma non-opioid intracellular receptor 1 (Sigma-1R) is an intracellular chaperone protein residing on the endoplasmic reticulum at the mitochondrial-associated membrane (MAM) region. Sigma-1R is abundant in the brain and is involved in several physiological processes as well as in various disease states. The role of Sigma-1R at the blood–brain barrier (BBB) is incompletely characterized.

In this study, the effect of Sigma-1R activation was investigated in vitro on rat brain microvascular endothelial cells (RBMVEC), an important component of the blood–brain barrier (BBB), and in vivo on BBB permeability in rats.

The Sigma-1R agonist PRE-084 produced a dose-dependent increase in mitochondrial calcium, and mitochondrial and cytosolic reactive oxygen species (ROS) in RBMVEC. PRE-084 decreased the electrical resistance of the RBMVEC monolayer, measured with the electric cell-substrate impedance sensing (ECIS) method, indicating barrier disruption. These effects were reduced by pretreatment with Sigma-1R antagonists, BD 1047 and NE 100. In vivo assessment of BBB permeability in rats indicates that PRE-084 produced a dose-dependent increase in brain extravasation of Evans Blue and sodium fluorescein brain; the effect was reduced by the Sigma-1R antagonists. Immunocytochemistry studies indicate that PRE-084 produced a disruption of tight and adherens junctions and actin cytoskeleton. The brain microcirculation was directly visualized in vivo in the prefrontal cortex of awake rats with a miniature integrated fluorescence microscope (aka, miniscope; Doric Lenses Inc.). Miniscope studies indicate that PRE-084 increased sodium fluorescein extravasation in vivo.

Taken together, these results indicate that Sigma-1R activation promoted oxidative stress and increased BBB permeability.

Link | PDF (International Journal of Molecular Sciences) [Open Access]

Also note BiP is aka GRP78 / HSPA5, and regulates WASF3 as noted in Paul Hwang's NIH study, which referenced Mitochondrial ATAD3A combines with GRP78 to regulate the WASF3 metastasis-promoting protein (2015, Nature Oncogene) —

See also Sigma-1 Receptor Chaperones at the ER-Mitochondrion Interface Regulate Ca2+ Signaling and Cell Survival (2007, Cell)