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If you practice in a region where the risk of hospitalization and death from COVID-19 is still high, and if you and your patient decide to start an antidepressant, citalopram and venlafaxine are less preferred. Why? Of course, there are the usual reasons. Citalopram carries more QT risk compared with other SSRIs, and venlafaxine is hard to discontinue. But here’s the region-specific reason: Neither citalopram nor venlafaxine is a FIASMA. What’s a FIASMA? The acronym stands for functional inhibitors of acid sphingomyelinase activity. In this Quick Take, we’ll look at some amazingly rapid advances in understanding why multiple antidepressants and even some antipsychotics offer some protection against severe COVID-19 infection.
Hi! Jim Phelps here for the Psychopharmacology Institute. Only a few months ago, we posted a Quick Take on early data suggesting that fluvoxamine offers some protection against COVID. Then came an astonishing randomized trial from Brazil testing fluvoxamine for just this purpose and showing a 30% reduction in emergency care and hospitalizations. Then came data showing that this benefit was not restricted to fluvoxamine alone. Several other antidepressants, including fluoxetine, appeared to lower the risk of severe illness among patients who get COVID-19 infections. Now comes the recognition of an entire broad class of medications, of which these antidepressants along with several antipsychotics are members—namely FIASMAs.
Since these are our medications, we in psychiatry should understand a bit more about FIASMAs. A new study from France’s National Institute of Health and Medical Research provides evidence for benefit from many of our psychiatric medications but not all of them. You might remember acid sphingomyelinase. When this enzyme is not working properly, sphingomyelin accumulates in cells and eventually kills them, causing Niemann-Pick disease—a lysosomal storage disorder. But since you last studied basic science in medical school, cellular biologists have discovered another role for acid sphingomyelinase. It regulates generation of ceramides, a lipid that has multiple intracellular signaling properties. That finally brings us back to COVID-19 because COVID activates the acid sphingomyelinase-ceramide system to promote its own entry into cells.
Which brings us back to our psychiatric medications. Many of them happen to be FIASMAs, functional inhibitors of acid sphingomyelinase activity. Patients who are taking a FIASMA and then get COVID may be at lower risk of severe illness, according to multiple indirect studies and a few randomized trials of individual agents, including that Brazilian study. But now the French study asks, is the benefit from psychiatric medications really based on their FIASMA effects, their effects on acid sphingomyelinase? If so, then one would expect to see a more benign course among patients taking any FIASMA, not just specific psychiatric medications that had previously been shown to be of benefit, like fluoxetine and fluvoxamine. So, how many psychotropics are we talking about here? It’s a lot. Basically, all SRIs are FIASMAs except for citalopram. Duloxetine is a FIASMA but not venlafaxine, mirtazapine, or mianserin. Several first-generation antipsychotics are FIASMAs, including chlorpromazine and perphenazine, but none of the routine second-generation agents are except, interestingly, aripiprazole. None of the benzodiazepines, Z drugs, or mood stabilizers are FIASMAs.
To investigate if this protection against severe COVID is truly a class benefit common to all the FIASMAs, Nicolas Hoertel and a large research consortium from France looked at rates of very severe illness, intubation, and death among people hospitalized with COVID-19 in Paris. They compared rates for patients who at admission were taking a psychotropic with FIASMA effects vs rates for those not taking such medications. The results are given as a hazard ratio, which is the rate in the exposed group as a percentage of the rate in the unexposed group. After adjusting for covariates, such as age, gender, obesity and other medical conditions, that hazard ratio was 0.50. Patients who were taking a FIASMA medication were half as likely to be intubated or die. Isn’t that amazing?
Of course, this is just 1 study, and I just read a press release regarding another study of 1700 patients showing that those who were taking antipsychotics or mood stabilizers had double the rate of dementia after COVID infection. That’s a new finding that warrants replication, like the FIASMA understanding has already undergone, before we start thinking about changing our prescribing behavior. Even there, Hoertel and colleagues remind us that their data are correlational and do not firmly establish causality. For now, they suggest 2 clinical conclusions. First, if a patient hospitalized with COVID-19 is taking a FIASMA psychotropic, don’t stop it. And second, they note that for resource-poor, unvaccinated countries, investigation should continue regarding the deliberate use of FIASMA psychotropics as prophylaxis against severe illness from COVID-19, starting with widely available medications that have the highest in vitro acid sphingomyelinase inhibition.
This paper by Hoertel and colleagues is a follow-up on their previous observational study, which was cited as a basis for launching the amazing Brazilian randomized trial in the first place. So, this new paper of theirs might seem less crucial after all that, but it was done to generalize the effect from select antidepressants to all FIASMA psychotropics. For the full list of medications that they investigated in this study, see Figure 1, their cohort diagram. The study is linked here at the Psychopharmacology Institute.
Abstract
The acid sphingomyelinase (ASM)/ceramide system may provide a useful framework for better understanding SARS-CoV-2 infection and the repurposing of psychotropic medications functionally inhibiting the acid sphingomyelinase/ceramide system (named FIASMA psychotropic medications) against COVID-19. We examined the potential usefulness of FIASMA psychotropic medications in patients with psychiatric disorders hospitalized for severe COVID-19, in an observational multicenter study conducted at Greater Paris University hospitals. Of 545 adult inpatients, 164 (30.1%) received a FIASMA psychotropic medication upon hospital admission for COVID-19. We compared the composite endpoint of intubation or death between patients who received a psychotropic FIASMA medication at baseline and those who did not in time-to-event analyses adjusted for sociodemographic characteristics, psychiatric and other medical comorbidity, and other medications. FIASMA psychotropic medication use at baseline was significantly associated with reduced risk of intubation or death in both crude (HR = 0.42; 95%CI = 0.31-0.57; p < 0.01) and primary inverse probability weighting (IPW) (HR = 0.50; 95%CI = 0.37-0.67; p < 0.01) analyses. This association was not specific to one FIASMA psychotropic class or medication. Patients taking a FIASMA antidepressant at baseline had a significantly reduced risk of intubation or death compared with those taking a non-FIASMA antidepressant at baseline in both crude (HR = 0.57; 95%CI = 0.38-0.86; p < 0.01) and primary IPW (HR = 0.57; 95%CI = 0.37-0.87; p < 0.01) analyses. These associations remained significant in multiple sensitivity analyses. Our results show the potential importance of the ASM/ceramide system framework in COVID-19 and support the continuation of FIASMA psychotropic medications in these patients and the need of large- scale clinical trials evaluating FIASMA medications, and particularly FIASMA antidepressants, against COVID-19.
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Reference
Hoertel, N., Sánchez-Rico, M., Gulbins, E., Kornhuber, J., Carpinteiro, A., Abellán, M., … & Limosin, F. (2022). Association between FIASMA psychotropic medications and reduced risk of intubation or death in individuals with psychiatric disorders hospitalized for severe COVID-19: an observational multicenter study. Translational Psychiatry, 12(1), 1-11.
