A new study, not yet peer-reviewed and available as a preprint, found a strong association between the use of non-cardiovascular drugs and severe COVID-19—defined as the need for intensive care or fatal outcome. The most significant effect was for antipsychotic drugs, pointing to a potential causal relationship between this class of drugs and severe COVID-19.
“The strongest association was with antipsychotic drugs. As the recognized indications for these drugs are not known to be associated with susceptibility to severe COVID-19, there is no obvious explanation for this association other than causality.”
A previous study by Laporte and Healy had postulated a series of drugs that might be associated with severe COVID-19. Paul M. McKeigue from the University of Edinburgh and colleagues used this list to investigate whether polypharmacy—that is, the prescription of multiple drugs—was associated with severe COVID-19. This is the first systematic study to investigate this relationship.
Here is how the study was designed: first authors ascertained all COVID-19 infections in Scotland through an electronic system. Then, McKeigue and colleagues found all admissions to intensive care in the country and obtained death certificates. Severe COVID-19 was defined by a positive COVID-19 test followed by admission to intensive care within 28 days or a death certificate with COVID-19 as the cause of death.
After determining all COVID-19 cases, authors selected up to ten controls for each case matching for sex, age, and primary care practice. With these criteria, the authors included 4272 cases and 36948 controls.
For all cases and controls, McKeigue and colleagues extracted ICD-10 diagnoses – this is a medical code system for diagnosis – in the past five years and included all drugs dispensed in the past 240 days until 15 days before COVID-19 infection. The authors started by testing associations between all non-cardiovascular drugs prescribed and severe COVID-19.
Researchers used the Laporte-Healy list of drug classes that were thought to increase the risk of severe COVID-19 because they were knowingly associated with increased pneumonia risk. They also accounted for socioeconomic status and known risk factors in their analysis.
The authors estimated rate ratios for severe COVID-19 and used several approaches to distinguish between causality and confounding. Rate ratios tell you how more or less common a particular event was in an exposed group. For example, a rate ratio of five means that a certain incident occurred five times more in one group than in the other.
In this study, the authors aimed to determine if persons who were prescribed certain medications had higher or lower rates of severe COVID-19 than the controls.
The authors employed measures to distinguish causality from confounding to make sure that the relationship they found was indeed between the two variables they were testing and not influenced by other factors. That is important because a statistical association may not mean causality. For example, you may find an association between certain drugs and specific outcomes, but if your sample has other risk factors that are not accounted for, the relationship may not be relevant.
First, the authors found that rates of severe COVID-19 increased with the number of non-cardiovascular drugs dispensed, and this association was not restricted to persons living in resident care homes. Second, the authors found that:
“The drug classes associated with severe COVID-19 include proton pump inhibitors, laxatives, multiple classes of drugs acting on the central nervous system, nutritional supplements, and non-steroidal anti-inflammatory drugs.”
An increased risk for severe COVID-19 was found for H1 antihistamines (e.g., Claritin), antidepressants (e.g., Prozac, Zoloft), urinary antispasmodics, gastrointestinal antispasmodics, drugs for vertigo, antimuscarinic drugs used in the treatment of parkinsonism, and antiepileptic drugs. The researchers also found that:
“In both univariate and multivariable analyses, the highest rate ratio was associated with antipsychotic drugs.”
For antipsychotic drugs, the rate ratio was 4.14, and for opioids 3.62. McKeguei and colleagues also found a dose-dependent association between severe COVID-19 and opioids (such as morphine) and proton pump inhibitors (drugs used to treat peptic ulcers, like omeprazole). To summarize the results:
“We have shown that severe COVID-19 is associated with polypharmacy, defined by the number of drugs classes dispensed during the period of observation, in individuals without conditions designated as conferring high risk.”
The researchers provide evidence that the association between antipsychotics and severe COVID-19 is likely to be causal in nature. That is further supported by the associations found with chemically similar drugs – such as drugs for nausea, and because the reason why these drugs are prescribed is not related to higher susceptibility to COVID-19.
The rate ratio of people taking antipsychotics who had severe COVID-19 cases suggests a connection, but the absolute number of cases is relatively small. Also, the study included people who were prescribed antipsychotics in the past 240 days, but the effects may be different for those taking the drugs for different periods of time. While the study has some limitations and was not yet peer-reviewed, it provides crucial evidence suggesting a causal relationship between the prescription of antipsychotic drugs and severe COVID-19.
Combining these findings with the current evidence about shorter life expectancy related to long-term use of antipsychotics, metabolic effects caused by these drugs, and severe side-effects, this seems to be an opportune moment to avoid over-prescription of this class of drugs and attempt to taper, reduce, or discontinue whenever possible.
This study provides compelling evidence of the risks of serious disease and fatal outcomes for COVID-19 and antipsychotics. Guidelines for the prescription of these drugs should be reviewed in light of this evidence, and targeted strategies should be put in place to track polypharmacy and antipsychotic use aiming to reduce these practices and protect individuals.
McKeigue, P. M., Kennedy, S., Weir, A., Bishop, J., McGurnaghan, S. J., McAllister, D., … & Caparrotta, T. M. (2020). Associations of severe COVID-19 with polypharmacy in the REACT-SCOT case-control study. medRxiv. [pre-print] (Link)