Association between selective serotonin reuptake inhibitors and mortality following COVID-19 among patients with Alzheimer's disease

Abstract

Background:

Recent research suggests that selective serotonin reuptake inhibitors (SSRIs) may reduce mortality in COVID-19 patients; however, research into their benefits for elderly Alzheimer's disease (AD) patients remains limited.

Objective:

To investigate the relationship between SSRIs therapy and the mortality risk after COVID-19 infection in elderly patients with and without AD.

Methods:

This retrospective cohort study leveraged a large database containing over 100 million electronic health records in the US from the TriNetX platform to compare the hazard rates of mortality after COVID-19 infection in elderly AD patients prescribed SSRIs versus propensity-score matched individuals prescribed other antidepressants. This study was also conducted in separate cohorts of patients without AD to compare the findings.

Results:

When compared with non-SSRI antidepressants, SSRIs were associated with lower risk for mortality after COVID-19 infection in elderly patients without AD over early, middle, and later stages of the pandemic with HRs of 0.84 (95% CI: 0.75–0.93), 0.86 (95% CI: 0.79–0.93), and 0.77 (95% CI: 0.71–0.33), respectively. When comparing SSRIs with non-SSRI antidepressants for mortality risk following COVID-19 among patients with AD, HRs of 0.95 (95% CI: 0.71–1.27), 0.80 (95% CI: 0.61–1.06), and 0.99 (95% CI: 0.75–1.32), were found respectively.

Conclusions:

Our findings suggest that the use of SSRIs is significantly associated with reduced mortality risk following COVID-19 in elderly patients without AD compared to other antidepressants. While a lower mortality risk was also observed among AD patients, the association was not statistically significant.

Keywords

Alzheimer's disease COVID-19 mortality selective serotonin reuptake inhibitors

Introduction

The COVID-19 pandemic has significantly affected the elderly population. Older people living with Alzheimer's disease (AD) are particularly vulnerable to the direct and indirect effects of the COVID-19 pandemic due to common comorbidities and healthcare disparities, which elevate their risk of mortality if infected with SARS-CoV-2.^1,2 Depression is highly prevalent, affecting approximately 50% of patients with AD.³ The social isolation caused by lockdowns during the COVID-19 pandemic can aggravate depression and loneliness in those with AD and related dementias, leading to an increased likelihood of hospitalization and mortality.^4,5

Several studies have indicated that the use of antidepressants may be associated with improved outcomes in COVID-19 patients.⁶ Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed antidepressants.⁷ Research has observed that SSRIs have anti-inflammatory properties, potentially lowering proinflammatory cytokines, including interleukin-6 and tumor necrosis factor.^8–10 There are several findings suggesting that SSRIs could have immunomodulatory effects. Specifically, a subset of SSRIs, including fluvoxamine and, to a lesser extent, fluoxetine and citalopram/escitalopram, are recognized for their agonistic action on the sigma-1 receptor.^11,12 Based on these mechanisms, it is hypothesized that SSRIs could exert protective effects against COVID-19. Several retrospective observational studies and randomized clinical trials have explored this potential, revealing an association between SSRI usage and COVID-19 outcomes.^13–23 However, these findings are not consistent across all studies, indicating a need for further research to fully understand the impact of SSRIs on COVID-19 outcomes.

Elderly patients with AD have a high risk of death if they are infected with SARS-CoV-2.^1,2 Solid clinical evidence about the effect of SSRIs on reducing the severity of COVID-19 infection in AD patients is still limited. One recent animal model demonstrates that SSRI fluoxetine can restore novel object recognition and reverse memory impairment.²⁴ Together with recent findings of SSRIs in COVID-19 treatment,²⁵ the effect of SSRIs on vagus nerve activity might improve outcomes for AD patients affected by SARS-CoV-2.²⁴ In this study, we used a large electronic health record (EHR) database from the U.S. to conduct a nationwide retrospective cohort study to assess the association of SSRIs with the mortality risk following COVID-19 in elderly (65 years old and over) patients with AD compared with non-SSRI antidepressants. We replicated the same analyses in a separate cohort of elderly patients without AD by comparing SSRIs with non-SSRI antidepressants.

Methods

Data source

The data for this study, collected and analyzed on 1 April 2024, was sourced from the TriNetX Analytics platform within the Research US Collaborative Network. TriNetX²⁶ is a federated health research network, granting access to continuously updated and de-identified EHR data, spanning demographics, diagnoses, procedures, medications, laboratory tests, and genomic information, encompassing data from over 100 million patients across 59 healthcare organizations in the United States. Geographically, the distribution of patients within the TriNetX platform is as follows: 25% in the Northeast, 17% in the Midwest, 41% in the South, and 12% in the West, with 5% of origins unknown. Due to TriNetX's capability to provide population-level data and results without exposing protected health information, the Institutional Review Board at the MetroHealth System in Cleveland has declared research conducted using TriNetX, as described in this study, not to be human subjects research and therefore not subject to Human Subject Research Review. Previously, we utilized the TriNetX Analytics network platform to conduct extensive cohort studies, including the assessment of the potential clinical efficacy of drugs in real-world populations.^27–35

Study population

The study cohort comprised 484,633 patients aged 65 years or older, all of whom had documentation of COVID-19 infection (based on an encounter diagnosis code for COVID-19 or positive antibody test result for SARS-CoV-2) from January 2020 to December 2022. The study period was divided into three phases: March 2020 to November 2020, December 2020 to November 2021, and December 2021 to December 2022 to examine early, middle, and later stages of the pandemic respectively.

The diagnosis of COVID-19 was established using the International Classification of Diseases (ICD)-10 code for COVID-19 (ICD U07.1) or a positive RNA-based COVID-19 test (TriNetX code 9088, “SARS coronavirus 2 and related RNA”). Diagnoses for AD were determined by the ICD-10 codes for “Alzheimer's disease” (ICD G30). The death record on the TriNetX platform was documented as “decreased”. Drug exposure information is recorded as the National Drug Code (NDC, a universal product identifier for human drugs) in TriNetX. Selective serotonin reuptake inhibitors (SSRI) considered in our study include citalopram (NCD 2556), escitalopram (NCD 321988), paroxetine (NCD 32937), sertraline (NCD 36437), fluvoxamine (NCD 42355), fluoxetine (NCD 4493), vortioxetine (NCD 1455099), vilazodone (NCD 1086769). The class of antidepressants (NDC N06A) without SSRI were used as comparison drugs in our study.

Our study first evaluated the mortality risk following COVID-19 in patients with AD. The study population consisted of patients with AD, all aged 65 years or older, who had a documented prescription for antidepressants within a period of 10 days before or 7 days after their first recorded COVID-19 diagnosis to account for both individuals already on SSRIs at the time of infection and those receiving SSRIs during acute COVID-19 infection. The study population was then divided into two groups: 1) the SSRI group, consisting of patients prescribed SSRIs without any other antidepressants, and 2) the non-SSRI antidepressant group, comprising patients prescribed antidepressants other than SSRIs. Figure 1(a) lists the cohort selection during the study period from March 2020 to November 2020. Patients who died prior to receiving antidepressant prescriptions were excluded from this study.

Figure 1.

Flowchart of retrospective cohort study design: (a) SSRI group versus non-SSRI antidepressant group in AD patients; (b) SSRI group versus non-SSRI antidepressant group in non-AD patients.

Our study also examined the mortality risk following COVID-19 among patients aged 65 years or older who were never diagnosed with AD. The study population comprised individuals aged 65 years or older without AD, who were prescribed antidepressants within 10 days before or 7 days after their initial documented COVID-19 diagnosis. This study population was divided into two groups: (1) the SSRI group consisting of patients who were only prescribed SSRI without any other antidepressants, and (2) the non-SSRI antidepressant group comprising patients who were prescribed antidepressants other than SSRI. The cohort selection during the study period from March 2020 to November 2020 was listed in Figure 1(b). Patients who died before receiving antidepressant prescriptions were excluded from this study.

For each study population, the SSRI and the non-SSRI antidepressant groups were propensity score-matched (1:1 using nearest neighbor greedy matching with a caliper of 0.25 times the standard deviation) on covariates that are potential risk factors for death from COVID-19 or severity of AD, including demographics (age, sex, ethnic grouping/ethnicity), adverse socioeconomic determinants of health (including education, unemployment, social and psychosocial environment, housing), psychiatric comorbidities^36,37 (including schizophrenia, mood disorders, anxiety disorders), lifetime comorbidities^38,39 (including hypertension, diabetes, heart disease, blood cerebrovascular diseases, lung diseases, diseases of the nervous system, diseases of the circulatory system, neoplasms, kidney disease, liver disease, obesity), COVID-19 vaccine status, hospital inpatient and observation care services, and previous medication prescriptions^40,41 associated with COVID-19 and dementia (see Supplementary Table 1).

Statistical analyses

Kaplan-Meier analysis with hazard ratios (HRs) and 95% CIs was used to compare the risk of mortality between two groups: patients prescribed SSRIs and patients prescribed non-SSRI antidepressants. The follow-up period for the outcomes ranged from 1 to 12 months after the index event, which was defined as the date of the first COVID-19 documentation (Figure 1). All statistical tests were conducted in April 2024 within the TriNetX Analytics platform with significance set at p-value <0.05 (two-sided).

Results

Mortality risk after COVID-19 infection in AD patients aged 65 and over

For the analysis of the mortality risk of COVID-19 in patients with AD, the study population included 444 patients prescribed SSRI and 434 patients prescribed non-SSRI antidepressants during the study period from March 2020 to November 2020 (Table 1). The SSRI group compared with the non-SSRI antidepressant group included more females and had a higher prevalence of depression, mental health disorders, heart disease, hypertension, and obesity. After propensity-score matching, the two cohorts (207 patients in each) did not significantly differ in demographics, comorbidities, or adverse socioeconomical determinants. As shown in Figure 2, consistent reductions in mortality risk after COVID-19 infection were observed in AD patients prescribed medication during the early, middle, or later stages of the pandemic. However, the results did not reach statistical significance.

Figure 2.

Association of SSRI use with the mortality risk after COVID-19 infection in patients with AD using Cox proportional hazards regression.

Table 1.

The characteristics of AD patients who were prescribed SSRI or other antidepressants during the study period from March 2020 to November 2020 before and after propensity-score matching for covariates.

Characteristics	Before Matching			After Matching
Characteristics	Exposure Cohort	Control Cohort	SMD	Exposure Cohort	Control Cohort	SMD
Total No.	444	434		207	207
Age	81.6 (8.3)	80.5 (8.5)	0.12^a	81.1 (8.4)	81.1 (8)	0.001
Sex, %
Female	56.8	62.9	0.12^a	58.4	57.9	0.009
Male	40.3	34.5	0.12^a	38.1	39.1	0.01
Ethnicity, %
Hispanic/Latinx	5.6	5.5	0.004	5.8	6.2	0.02
Not Hispanic/Latinx	76.5	71.2	0.12^a	74.4	72.4	0.04
Race, %
African American/Black	9.1	20.7	0.33^a	13.5	14.9	0.04
White	75.6	62.6	0.28^a	66.1	67.6	0.03
Asian	2.2	2.3	0.003	4.8	4.8	0
Medical History, %
Mental disorders due to known Physiological conditions	79.5	77.1	0.05	67.6	71.9	0.09
Mental and behavioral disorders due to psychoactive substance use	12.8	13.5	0.02	12.5	12.1	0.01
Schizophrenia	11.1	13.5	0.07	11.5	12.5	0.02
Mood disorders	53.6	47.9	0.11^a	44.4	45.8	0.02
Anxiety	40.3	35.7	0.09	32.8	31.4	0.03
Behavioral syndromes associated with physiological disturbances and physical factors	3.1	5.5	0.11^a	4.8	4.8	0
Depressive episode	47.5	41.4	0.12^a	40.1	40.5	0.009
Major depressive disorder, recurrent	12.3	12.2	0.005	9.6	11.1	0.04
Hypertensive diseases	74.3	71.8	0.05	63.2	68.1	0.1
Diabetes mellitus	31.1	33.8	0.05	27.1	30.4	0.07
Ischemic heart diseases	37.3	37.5	0.003	32.3	37.2	0.1
Other forms of heart disease	57.6	52.3	0.11^a	47.8	49.7	0.03
Cerebrovascular diseases	30.6	31.3	0.01	25.6	28.1	0.05
Kidney disease	40.3	41.7	0.02	38.1	39.6	0.02
Diseases of liver	7.4	7.3	0.002	8.2	6.2	0.07
Diseases of the respiratory system	58.3	57.8	0.01	51.2	50.7	0.009
Diseases of the nervous system	82.8	82.9	0.001	70.1	73.9	0.08
Diseases of the circulatory system	82.6	81.5	0.02	71.9	75.8	0.08
Neoplasms	35.1	32.4	0.05	30.9	32.8	0.04
Endocrine, nutritional and metabolic diseases	77.4	80.1	0.06	70.5	72.9	0.05
Diseases of the blood and blood-forming organs and certain disorders involving the immune mechanism	48.2	52.3	0.08	44.9	47.3	0.04
Symptoms involving cognition, perception, emotional state and behavior	64.6	60.6	0.08	57.1	58.9	0.03
Abnormal results of function studies	33.3	30.1	0.06	30.9	32.8	0.04
Heart failure	23.6	24.6	0.02	20.7	21.7	0.02
Asthma	8.7	9.4	0.02	8.2	8.7	0.01
Atrial fibrillation and flutter	23.6	22.8	0.01	19.3	21.7	0.05
Acute myocardial infarction	10.1	11.9	0.05	10.6	13.5	0.08
Cardiac arrhythmias	26.8	22.5	0.09	20.2	22.2	0.04
Chronic obstructive pulmonary disease	18.1	17.2	0.01	14.9	11.5	0.09
Overweight and obesity	20.9	14.7	0.16^a	16.9	19.3	0.06
Alzheimer's disease	75.4	74.8	0.01	63.7	66.1	0.05
Dementia	60.3	53.6	0.13^a	48.7	51.2	0.04
Mild cognitive impairment of uncertain or unknown etiology	13.1	11.7	0.03	12.5	11.5	0.02
SARS-CoV-2 (COVID-19) vaccine	0	2.3	0.21^a	0	0
Adverse socioeconomical determinants of health, %	5.4	6.2	0.03	4.8	5.8	0.043
Hospital inpatient and observation care services, %	51.1	48.6	0.05	44.9	47.3	0.04
Antidepressants, %
Non-selective monoamine reuptake inhibitors	4.2	8.3	0.16^a	8.7	6.2	0.09
Monoamine oxidase inhibitors, non-selective	0	0		0	0
Monoamine oxidase A inhibitors	0	0		0	0
Other antidepressants	21.4	68.6	1.07^a	41.5	43.4	0.03
Drugs used for dementia, %
Anti-dementia drugs	56.9	45.8	0.22^a	43.01	44.4	0.02
Other Drugs, %
Antipsychotics	44.6	40.3	0.08	35.7	35.7	0
Antivirals	13.2	11.5	0.05	11.1	11.1	0
Tocilizumab	0	2.3	0.21^a	0	0
Ritonavir	0	0		0	0
Nirmatrelvir	0	0		0	0
Remdesivir	0	2.3	0.21^a	0	0
Baricitinib	0	0		0	0

SMD, standardized mean difference. ^aSMD > 0.1, a threshold for declaring imbalance.

Mortality risk after COVID-19 infection in non-AD patients aged 65 and over

In examining the COVID-19 mortality risk among patients not suffering from AD, the study population included 4365 patients prescribed SSRIs and 6369 prescribed other types of antidepressants during the study period from March 2020 to November 2020 (Table 2). To ensure a balanced comparison of the two patient groups, we applied the same methods of propensity-score matching and Cox proportional hazards analysis as we did in the previously described analysis. In Figure 3, we observed that patients prescribed SSRIs have a consistently lower mortality risk after COVID-19 infection in elderly patients without AD compared to those prescribed non-SSRI antidepressants during different stages of the pandemic.

Figure 3.

Association of SSRI use with the mortality risk after COVID-19 infection in patients without AD using Cox proportional hazards regression.

Table 2.

The characteristics of non-AD patients who were prescribed SSRI or other antidepressants during the study period from March 2020 to November 2020 before and after propensity-score matching for covariates.

Characteristics	Before Matching			After Matching
Characteristics	Exposure Cohort	Control Cohort	SMD	Exposure Cohort	Control Cohort	SMD
Total No.	4365	6369		2713	2713
Age	74.4 (8.6)	73.4 (8.5)	0.11^a	74 (8.6)	74 (8.7)	0.001
Sex, %
Female	57.9	54.7	0.06	56.2	54.9	0.02
Male	38.3	42.9	0.09	40.6	42.1	0.02
Ethnicity, %
Hispanic/Latinx	6.7	7.2	0.01	7.1	7.6	0.01
Not Hispanic/Latinx	67.7	68.4	0.01	66.3	66.6	0.004
Race, %
African American/Black	12.6	17.2	0.12^a	14.6	13.9	0.01
White	70.4	65.1	0.11^a	66.9	67.9	0.02
Asian	1.3	2.1	0.06	1.6	1.5	0.005
Medical History, %
Mental disorders due to known Physiological conditions	14.8	13.4	0.03	11.6	11.3	0.01
Mental and behavioral disorders due to psychoactive substance use	14.4	18.6	0.11^a	12.6	13.4	0.02
Schizophrenia	5.1	4.9	0.005	4.2	4.1	0.003
Mood disorders	43.4	35.1	0.17^a	26.8	27.3	0.01
Anxiety	35.7	30.1	0.11^a	24.8	24.4	0.009
Behavioral syndromes associated with physiological disturbances and physical factors	3.8	7.2	0.14^a	3.4	3.7	0.01
Depressive episode	39.4	31.1	0.17^a	24.1	24.8	0.01
Major depressive disorder, recurrent	8.6	8.7	0.001	6.8	6.9	0.002
Hypertensive diseases	64.1	63.6	0.009	50.9	52.7	0.03
Diabetes mellitus	34.3	35.8	0.03	28.1	28.7	0.01
Ischemic heart diseases	32.6	31.2	0.03	24.8	26.1	0.02
Other forms of heart disease	46.3	45.1	0.02	35.6	36.2	0.01
Cerebrovascular diseases	23.1	20.6	0.05	16.9	16.9	0.0009
Kidney disease	32.1	31.9	0.001	24.7	25.4	0.01
Diseases of liver	10.7	12.2	0.04	9.1	9.3	0.007
Diseases of the respiratory system	56.3	57.2	0.01	44.4	45.4	0.02
Diseases of the nervous system	55.7	58.5	0.05	44.6	44.6	0.0007
Diseases of the circulatory system	72.4	71.9	0.01	59.3	60.9	0.03
Neoplasms	34.4	34.8	0.008	27.4	27.4	0
Endocrine, nutritional and metabolic diseases	71.1	70.4	0.01	57.2	58.5	0.02
Diseases of the blood and blood-forming organs and certain disorders involving the immune mechanism	41.5	42.3	0.01	32.7	32.8	0.003
Symptoms involving cognition, perception, emotional state and behavior	38.7	37.1	0.03	28.7	30.6	0.04
Abnormal results of function studies	25.8	26.4	0.01	19.5	19.7	0.004
Heart failure	23.1	21.8	0.02	17.1	16.8	0.009
Asthma	12.2	13.8	0.04	9.3	9.9	0.02
Atrial fibrillation and flutter	19.5	17.4	0.05	14.1	15.1	0.02
Acute myocardial infarction	8.8	8.2	0.02	6.2	6.3	0.006
Cardiac arrhythmias	18.2	18.5	0.008	14.3	14.7	0.01
Chronic obstructive pulmonary disease	18.7	20.5	0.04	15.4	15.8	0.01
Overweight and obesity	27.1	26.6	0.009	20.6	20.9	0.008
Dementia	9.3	7.9	0.05	7.2	6.7	0.02
Mild cognitive impairment of uncertain or unknown etiology	3.2	3.1	0.01	2.4	2.5	0.009
SARS-CoV-2 (COVID-19) vaccine, %	0.2	0.2	0.01	0.3	0.3	0
Adverse socioeconomical determinants of health, %	4.1	4.9	0.04	3.4	3.2	0.008
Hospital inpatient and observation cares services, %	37.1	36.2	0.01	27.4	27.6	0.004
Antidepressants, %
Non-selective monoamine reuptake inhibitors	4.4	14.1	0.33^a	5.3	6.1	0.03
Monoamine oxidase inhibitors, non-selective	0.2	0.1	0.01	0.3	0.3	0
Monoamine oxidase a inhibitors	0	0		0	0
Other antidepressants	14.5	58.1	1.01^a	23.4	23.5	0.003
Drugs used for dementia, %
Anti-dementia drugs	6.2	5.1	0.04	4.2	4.4	0.01
Other Drugs, %
Antipsychotics	22.3	24.7	0.05	19.1	18.8	0.007
Antivirals	14.5	15.5	0.02	11.5	11.7	0.004
Baricitinib	0	0.1	0.05	0	0
Tocilizumab	0.2	0.1	0.008	0.3	0	0.08
Ritonavir	0.2	0.3	0.02	0.3	0.3	0
Nirmatrelvir	0.2	0.1	0.01	0.3	0.3	0
Remdesivir	0.4	0.3	0.01	0.3	0.3	0

SMD, standardized mean difference. ^aSMD > 0.1, a threshold for declaring imbalance.

Discussion

In this study, we conducted a retrospective observational study to investigate the potential effectiveness of SSRIs in decreasing the risk of death among AD patients infected with COVID-19 utilizing a nationwide database of patient EHR data from TriNetX. Elderly patients without AD who were prescribed SSRIs exhibited a significantly lower mortality risk after COVID-19 infection compared to matched patients prescribed non-SSRI antidepressants. A similar lower mortality risk after COVID-19 infection was observed in patients with AD, although it was not statistically significant in patients without AD.

Several clinical studies have indicated the potential of SSRIs in reducing mortality risk after COVID-19 infection. A clinical trial involving 152 outpatients with COVID-19 showed a lower likelihood of clinical deterioration over 15 days in patients treated with fluvoxamine compared with placebo.¹⁵ The multicenter, randomized, placebo-controlled TOGETHER trial has provided evidence supporting the efficacy of fluvoxamine as an early treatment option for COVID-19 patients, showing its potential to prevent disease progression, serious health complications, and reduce mortality rates.¹⁶ An open-label trial among 51 patients in the ICU showed lower mortality in the fluvoxamine compared to a control group.¹⁷ Conversely, another clinical trial involving 1208 patients with mild to moderate COVID-19 found that treatment with fluvoxamine did not reduce the duration of COVID-19 symptoms. Notably, no deaths were reported in this study.¹⁸ The results of several retrospective cohort studies examining the use of SSRIs in the treatment of COVID-19 show mixed outcomes. A large retrospective cohort study conducted by the University of California, San Francisco, and Stanford University indicates a potential association between the use of SSRIs and reduced death rates from COVID-19.¹³ An observational multicenter retrospective cohort study conducted at AP-HP Greater Paris University hospitals suggests that the use of SSRI and non-SSRI antidepressants could be associated with a lower risk of death or intubation in patients hospitalized for COVID-19.¹⁴ In contrast, one study indicated that SSRI use in COVID-19 patients might not be safe and suggested that adverse outcomes associated with SSRI use could be enhanced when used with remdesivir.¹⁹ Another study reported higher mortality rates among SSRI users compared to non-SSRI users within 60 days following a positive SARS-CoV-2 polymerase chain reaction (PCR) test.²⁰ Meanwhile, a different study found no significant difference in effects between the antidepressant group and two non-antidepressant groups.²¹ Additionally, several studies have indicated that SSRI use has no significant impact on COVID-19 outcomes.^22,23 Different from these studies, we investigated the possible effects of SSRIs on reducing the risk of mortality after COVID-19 infection in elderly patients with or without AD. The results indicated significant associations of SSRIs with a lower risk of mortality after COVID-19 infection compared to non-SSRI antidepressants.

The pure mechanism underlying the association between SSRIs and a reduced risk of COVID-19 mortality has not been fully elucidated, however, various potential explanations have been suggested. First, SSRIs are hypothesized to have antiviral effects against COVID-19, primarily through the high affinity with sigma-1 receptors (S1Rs).¹⁰ This mechanism suggests possible modulation of the immune activity of macrophages, which are cells integral to the body's inflammatory response.¹¹ Additionally, SSRIs have been shown to downregulate the expression of HIV-related coreceptors on macrophages and peripheral blood mononuclear cells within individuals infected with HIV.⁴² Given the emerging view of depression as an inflammatory disease, the role of SSRIs may extend beyond mood regulation to influencing immune response.¹¹ Second, acid sphingomyelinase (ASM) is known to play a significant role in viral infections by affecting endosomal function. SSRIs such as fluoxetine and fluvoxamine, which are lysosomotropic agents, can modulate endolysosomal pH, potentially impairing the formation of viral replication complexes, in addition to impeding viral trafficking and budding.⁴³ Therefore, the pH-altering properties of these SSRIs might be beneficial in treating COVID-19 by impairing the virus's ability to replicate and spread within the host cells.⁴⁴ Among individuals with post-COVID-19 syndrome, the metabolic and immune-related kynurenine pathway was found to be overactive, consuming excessive tryptophan, the precursor to serotonin.⁴⁵ As SSRIs increase serotonin availability and may alleviate the lack of endogenous serotonin from tryptophan overconsumption, this therapeutic mechanism remains plausible. In an animal study examining septic shock, administration of intracerebroventricular serotonin prevented the induction of hypotension and hypothermia while decreasing the production of immune-related cytokines TNF (tumor necrosis factor)-α, IL-1B, IL-6, and IL-10,⁴⁶ supporting serotonins immune-modulating effects. As hypercoagulability leading to venous thrombus or embolism remains a main cause of mortality from COVID-19 infection, the known anti-platelet properties of SSRIs⁴⁷ may also contribute to lower rates of mortality. Finally, other potential mechanisms by which SSRIs may exert beneficial effects in the context of COVID-19 include their ability to decrease platelet aggregation, reduce mast cell degranulation, elevate melatonin levels, and provide antioxidant activities.⁴⁸

The lack of statistical significance for mortality reduction among AD patients prescribed SSRIs may be due to the smaller sample size lacking the power to pick up an effect (n = 201, 267, 400), as the non-AD analysis included over ten times the number of patients (n = 2661, 5420, 7388) in each time period. Alternatively, other uncontrolled factors may differ between AD and non-AD patients such as SSRI use practices, clinical setting, or true physiologic response to SSRI medication. Additionally, both SSRI and non-SSRI antidepressants have been shown to attenuate COVID-19 infection severity in some studies.^13,49 As the results of this study solely describe the difference in mortality between SSRIs and non-SSRI antidepressants, it remains possible that AD patients may have less of an observable difference in the reduction of COVID-19 mortality between classes of antidepressants than patients without AD.

Our study has several limitations. First, information on drug usage duration, dosage, and patient adherence is limited in the EHR database; for instance, prescriptions filled by external providers and not recorded in TriNetX cannot be accounted for, making it challenging to assess the effects of drug use duration, dosage, and compliance on COVID-19 mortality reduction. Second, patients prescribed SSRIs may differ from those prescribed other antidepressants due to side effects and the severity of their mood disorders. To address this, we used propensity-score matching to account for confounding factors, including depression severity. However, inherent limitations of EHR studies, such as misclassification bias and residual confounding, could not be entirely eliminated. While we matched for adverse socioeconomic determinants of health (including physical, social, and psychosocial environment, housing) and hospital inpatient and observation care services, certain variables such as living arrangements (e.g., living alone, with families, or in long-term care facilities) were not captured by patient EHRs. These uncaptured risk factors could represent unmeasured confounders. Third, patients in the TriNetX database represented those who had medical encounters with healthcare systems contributing to the TriNetX platform. Although this database encompasses data from over 100 million patients in the United States, it may not be representative of the entire US population. Therefore, results from the TriNetX platform need to be validated in other populations.

In conclusion, the results from this study suggest that SSRIs may have the potential to decrease mortality risk following COVID-19 in patients with or without AD compared to other antidepressants, highlighting the necessity for further research and clinical trials to understand its potential effect of SSRIs on the severity of COVID-19 outcomes.

Supplemental Material

sj-docx-1-alz-10.1177_13872877241283820 - Supplemental material for Association between selective serotonin reuptake inhibitors and mortality following COVID-19 among patients with Alzheimer's disease

Supplemental material, sj-docx-1-alz-10.1177_13872877241283820 for Association between selective serotonin reuptake inhibitors and mortality following COVID-19 among patients with Alzheimer's disease by Zhenxiang Gao, Ian Dorney, Pamela B Davis, David C Kaelber and Rong Xu in Journal of Alzheimer's Disease

Footnotes

Acknowledgments

The authors have no acknowledgments to report.

Author contributions

Zhenxiang Gao (Methodology; Validation; Visualization; Writing – original draft; Writing – review & editing); Ian Dorney (Writing – original draft; Writing – review & editing); Pamela B Davis (Writing – review & editing); David C Kaelber (Data curation); Rong Xu (Supervision; Writing – review & editing).

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: We acknowledge support from the National Institute on Aging (AG07664, AG057557, AG061388, and AG062272), and the National Institute on Alcohol Abuse and Alcoholism (AA029831).

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data availability

The data that support the findings of this study are openly available in “”.

Supplemental material

Supplemental material for this article is available online.

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Supplementary Material

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