Abstract
Patients with major psychiatric disorders (MPD) that include schizophrenia (SCH), bipolar disorder (BP), and major depressive disorder (MDD) are at increased risk for coronavirus disease 2019 (COVID-19). However, the safety and efficacy of COVID-19 vaccines in MPD patients have not been fully evaluated. This study aimed to investigate adverse events (AEs)/side effects and efficacy of COVID-19 vaccines in MPD patients. This retrospective study included 2034 patients with SCH, BP, or MDD who voluntarily received either BBIBP-CorV or Sinovac COVID-19 vaccines, and 2034 matched healthy controls. The incidence of AEs/side effects and the efficacy of COIVD-19 vaccinations among the two groups were compared. The risk ratio (RR) of side effects in patients with MPD was 0.60 (95% confidence interval [CI]: 0.53-0.68) after the first dose and 0.80 (95% CI: 0.65-0.99) following the second dose, suggesting a significantly lower risk in the MPD group versus healthy controls. The RRs of AEs did not differ between patients and controls. Notably, fully vaccinated patients exhibited a decreased risk of influenza with or without fever compared with controls (RR=0.38, 95% CI: 0.31-0.46; RR=0.23, 95% CI: 0.17-0.30; respectively). Further subgroup comparisons revealed a significantly lower risk of influenza with fever in MDD (RR=0.13, 95% CI: 0.08-0.21) and SCH (RR=0.24, 95% CI: 0.17-0.34) than BP (RR=0.85, 95% CI: 0.69-1.06) compared to controls. We conclude that the benefit-risk ratio of COVID-19 vaccination was more favorable in SCH or MDD versus BP when compared with controls. These data indicate that COVID-19 vaccines are safe and protective in patients with MPD from COVID-19.
Keywords: COVID-19 vaccine, SARS-CoV-2, safety, effectiveness, schizophrenia, bipolar disorder, major depressive disorder
Introduction
Major psychiatric disorders (MPD) cause serious functional impairments that disrupt cognition, mood, and the performance of major life activities [1,2]. Schizophrenia (SCH), bipolar disorder (BP), and major depressive disorder (MDD) are the most prevalent MPD [1,2]. SCH is characterized by hallucinations, delusions, disturbances of thoughts, speech, and behavior, social inattentiveness, and cognitive impairment [3]. BD causes characteristic extreme mood swings that include both manic/hypomanic and depressive episodes [4]. MDD presents with persistent sadness‚ hopelessness‚ loss of interest in daily activities, and psychomotor retardation [5]. Patients with MPD are highly susceptible to coronavirus disease 2019 (COVID-19) and are also at increased risk for poor clinical outcomes [6,7], primarily due to MPD-associated disorders of immune function [8-12], kynurenine pathway activity [13], C-reactive protein levels [14], endocrine homeostasis, and host microbiosis [15]. Consequently, COVID-19 immunization is essential to protect patients with MDP [16-21]. The World Health Organization, the US National Academies of Sciences, the American Psychological Association, the World Psychiatric Association, and other psychiatric and public health authorities urge that individuals with MDP be given priority for COVID-19 vaccination [16-21].
Certain antidepressants may inhibit severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) cellular entry and propagation and may also exert anti-inflammatory effects, thereby holding promise as COVID-19 therapeutics [22]. These observations raise the hypothesis that a subset of psychotropic medications could inhibit the uptake of SARS-CoV-2 inactivated or recombinant vaccine antigens by immune effector cells and attenuate vaccine response. These findings have indeed ignited interest in elucidating the interactions between MPD, therapeutic agents, and COVID-19 vaccines. An assessment of the safety and effectiveness of COVID-19 vaccination in patients with MDP is imperative. However, studies of the safety and efficacy of COVID-19 vaccine in patients with MPD are lacking, with the exception of one pilot study that examined the interaction between a COVID-19 vaccine and three therapeutic modalities (including electroconvulsive therapy) in a Chinese psychiatrist who subjected himself to a self-study [21].
During the past twenty years, the Chinese government has made concerted efforts to destigmatize mental illness [15,23,24]. President-Xi Jinping has repeatedly expressed his empathy to patients with MPD. However, an ingrained stigmatization of individuals with MPD and their guardians persists [25,26]. Consequently, many patients and their guardians are inclined to conceal their psychiatric diagnoses. Although the Chinese government has emphasized that individuals with any disease should be carefully assessed for the risk-benefit ratio of COVID-19 immunization to assure safety, many patients with MPD deny their condition when presenting for COVID-19 vaccination.
In contrast to the denial of MPD at the time of COVID-19 vaccination, patients often reported vaccine adverse events (AEs) and side effects to their psychiatrists. These symptoms suggested potential interactions between vaccines and therapeutic agents, which inspired us to study the safety and effectiveness of COVID-19 vaccines in patients with MPD.
Faced with the threat posed by pandemic COVID-19 to this group of vulnerable patients, we conducted this retrospective study of patients with SCH, BP, or MDD who denied their psychiatric diagnoses when receiving COVID-19 vaccines. We aimed to determine the incidence and severity of AEs/side effects and the efficacy of the BBIBP-CorV [27] and Sinovac COVID-19 vaccines [28] in patients with MPD.
Materials and methods
Study population
We conducted a retrospective study covering a 16-month period from August 1, 2020 to November 30, 2021 to evaluate COVID-19 vaccination and clinical outcomes of patients with MPD (SCH, BP, or MDD) receiving outpatient psychiatric treatment and who denied their psychiatric diagnoses at the time of COVID-19 vaccination. We matched healthy individuals recommended by the patients or their guardians in a control group. This retrospective cohort study population comprised 2210 patients with MPD and 2210 well-matched healthy individuals who were fully vaccinated against COVID-19.
Patients and healthy individuals came from 7 provinces/municipalities of China, representing diverse geographic regions across the nation that included the East (Wenzhou city), North (Harbin city), Central (Tianjin, Jining, Zhengzhou, and Xinxiang cities), and West (Taiyuan, Chongqing cities). Inclusion and exclusion criteria for patients with MPD and criteria for matched healthy controls are provided in Supplementary Materials.
The Ethics Committee of Tianjin Four Center Hospital of Tianjin Medical University approved this study (Approval No. 2020-K01). Signed informed consent was provided by patients and their guardians.
COVID-19 vaccines
All subjects received either BBIBP-CorV (Sinopharm COVID-19 Vaccine, Beijing Institute of Biological Products Co., Ltd.) (Beijing, China) [27] or Sinovac COVID-19 vaccine (Sinovac Biotech Ltd., Beijing, China) [28]. BBIBP-CorV and Sinovac are inactivated SARS-CoV-2 vaccines produced in Vero cells and administered in two 0.5 ml doses injected intramuscularly into the deltoid muscle at a dosing interval of 2-4 weeks.
Outcomes
The outcome measures of COVID-19 vaccine safety were the incidence of AEs and side effects, which are defined in Supplementary Materials. The outcome measure of COVID-19 vaccine efficacy was the incidence of COVID-19 and/or influenza within the 31 days after being fully vaccinated. Case definitions of COVID-19 and influenza are provided in Supplementary Materials.
Statistical analysis
Statistical analyses were conducted by using SAS statistical software (version 9.3, SAS Institute, Cary, NC, USA). Continuous variables were expressed as mean ± standard deviation (SD) (normally distributed data) or median ± interquartile range (non-normal data). Categorical variables were presented as numbers and percentages. Demographic and clinical characteristics and AEs of MPD patients and healthy controls were compared using the t-test (or Wilcoxon rank sum test) and chi-square test/Fisher’s exact test as appropriate. A two-sided level of P<0.05 was considered significant.
Generalized estimating equation (GEE) with log-linked binomial model was used to assess the relative risk of AEs and side effects between patients with MPD and healthy controls. Multivariate GEE modes were used to adjust for age, sex, education level, exposure risk of working condition, economic status, and the type of vaccination [29].
Results
Study population
A total of 2034 patients and 2034 healthy controls were included. The subject qualification rate was 92.04%. Demographic, socioeconomic, and clinical characteristics of the study subjects are listed in Table 1. There were no significant differences in age and sex between the MPD and control groups (P>0.05).
Table 1.
Demographic, socioeconomic, and clinical characteristics
| Demographic, socioeconomic, and clinical characteristics | Patients with severe mental illness (n=2034) | Healthy controls (n=2034) | p value | |
|---|---|---|---|---|
| Sex | Female | 1117 (54.9) | 1118 (55.0) | 0.9749 |
| Male | 917 (45.1) | 916 (45.0) | ||
| Education level (Years) | ≤12 | 1257 (61.8) | 1246 (61.3) | 0.7230 |
| >12 | 777 (38.2) | 788 (38.7) | ||
| Job | No | 197 (9.7) | 196 (9.6) | 0.9577 |
| Yes | 1837 (90.3) | 1838 (90.4) | ||
| Exposure risk | 1 | 489 (24.0) | 457 (22.5) | 0.0346 |
| 2 | 336 (16.5) | 407 (20.0) | ||
| 3 | 1017 (50.0) | 978 (48.1) | ||
| 4 | 192 (9.4) | 192 (9.4) | ||
| High-risk occupation | 1 | 415 (20.4) | 416 (20.5) | 0.9970 |
| 2 | 1267 (62.3) | 1261 (62.0) | ||
| 3 | 350 (17.2) | 355 (17.5) | ||
| 4 | 2 (0.1) | 2 (0.1) | ||
| Family economic status | 1 | 203 (10.0) | 205 (10.1) | 0.9469 |
| 2 | 1495 (73.5) | 1486 (73.1) | ||
| 3 | 336 (16.5) | 343 (16.9) | ||
| Personal income | 1 | 468 (23.0) | 450 (22.1) | 0.7944 |
| 2 | 1186 (58.3) | 1198 (58.9) | ||
| 3 | 380 (18.7) | 386 (19.0) | ||
| Type of mental illness | BP | 581 (28.6) | N/A | N/A |
| MDD | 640 (31.5) | N/A | N/A | |
| SCH | 813 (40.0) | N/A | N/A | |
| Therapeutic drug dose in past 16 months (mg) | Chlorpromazine equivalent | 178884.2±205715.9 | N/A | N/A |
| Fluoxetine equivalent | 18302.3±22498.4 | N/A | N/A | |
| Valproate equivalent | 265592.9±264622.3 | N/A | N/A | |
| Diazepam equivalent | 3361.6±1813.7 | N/A | N/A | |
| Trihexyphenidyl | 407.8±994.8 | N/A | N/A | |
| Promethazine | 2259.3±12372.0 | N/A | N/A | |
Note: BP, bipolar disorder; MDD, major depressive disorder; SCH, schizophrenia.
Vaccine safety
The number and proportion of participants experiencing vaccine-related AEs/side effects are summarized in Table 2. The incidence of AEs after the first dose was 8.8% (179/2034) in patients and 7.5% (153/2034) in controls, which was similar between the two groups (P=0.1365). The most common AE was hypertensive crisis, accounting for 46.9% (84/179) and 39.9% (61/153) of AEs reported in patients with MPD and healthy controls experiencing AEs, respectively. Notably, the types of AEs differed significantly between patients with MPD and controls (P<0.0001, Table 2). None of the participants experiencing AEs after the first dose received a second dose.
Table 2.
COVID-19 vaccine adverse events/side effects and efficacy
| Patients with severe mental illness (n=2034) | Healthy controls (n=2034) | p value | ||
|---|---|---|---|---|
| COVID-19 vaccine | BBIBP-CorV | 1540 (75.7) | 1530 (75.2) | 0.7156 |
| Sinovac | 494 (24.3) | 504 (24.8) | ||
| AEs after 1st dose | No | 1855 (91.2) | 1881 (92.5) | 0.1365 |
| Yes | 179 (8.8) | 153 (7.5) | ||
| Types of AEs after 1st dose | Acute myocardial infarction | 0 (0.0) | 1 (0.7) | <0.0001 |
| Allergic purpura | 0 (0.0) | 1 (0.7) | ||
| Anaphylactic shock | 27 (15.1) | 11 (7.2) | ||
| Encephalitis | 0 (0.0) | 1 (0.7) | ||
| Hypertensive crisis | 84 (46.9) | 61 (39.9) | ||
| Hypochondriasis | 0 (0.0) | 14 (9.2) | ||
| Hypotension shock | 29 (16.2) | 7 (4.6) | ||
| Leukemia | 1 (0.6) | 0 (0.0) | ||
| Persistent high fever | 16 (9.0) | 48 (31.4) | ||
| Seizure | 4 (2.2) | 1 (0.7) | ||
| Unexplained severe malaise | 18 (10.1) | 3 (2.0) | ||
| Severe panic episode | 0 (0.0) | 5 (3.3) | ||
| AE onset after 1st dose (hours) | 0.5±0.0 | 0.5±11.5 | <0.0001 | |
| AE resolution (hours) | 12.0±21.0 | 24.0±376.0 | <0.0001 | |
| Side effects after 1st dose | No | 1726 (84.9) | 1517 (74.6) | <0.0001 |
| Yes | 308 (15.1) | 517 (25.4) | ||
| Types of side effects after 1st dose | Fatigue | 11 (3.6) | 10 (1.9) | <.00001 |
| Influenza-like symptoms without fever | 73 (23.7) | 294 (56.9) | ||
| Muscle and joint pain | 104 (33.8) | 73 (14.1) | ||
| Nausea and vomiting | 71 (23.1) | 39 (7.5) | ||
| Pain, itch, or swelling | 49 (15.9) | 101 (19.5) | ||
| Side effect onset after 1st dose (hours) | 12.0±21.5 | 24.0±21.0 | <0.0001 | |
| Side effect resolution (hours) | 72.0±60.0 | 72.0±72.0 | 0.0001 | |
| Vaccinated 2nd dose | Yes | 1849 (90.9) | 1812 (89.1) | 0.0532 |
| No | 185 (9.1) | 222 (10.9) | ||
| AEs after 2nd dose | No | 1844 (99.41) | 1874 (99.63) | 0.3670 |
| Yes | 11 (0.59) | 7 (0.37) | ||
| Types of AEs after 2nd dose | Severe panic attack | 0 (0.0) | 5 (71.4) | 0.0012 |
| Anaphylactic shock | 1 (9.1) | 0 (0.0) | ||
| Hypertensive crisis | 8 (72.7) | 0 (0.0) | ||
| Hypochondriasis | 0 (0.0) | 2 (28.6) | ||
| Hypotensive shock | 2 (18.2) | 0 (0.0) | ||
| AE management | Antidepressant therapy | 0 (0.0) | 5 (71.4) | 0.0001 |
| Symptomatic treatment | 11 (100.0) | 0 (0.0) | ||
| Antipsychotic agent treatment | 0 (0.0) | 2 (28.6) | ||
| AE onset after 2nd dose (hours) | 0.5±0.0 | 480.0±240.0 | <0.0001 | |
| AE resolution (hours) | 9.0±4.0 | 2160.0±696.0 | 0.0005 | |
| Side effects after 2nd dose | No | 1717 (92.6) | 1717 (91.3) | 0.0809 |
| Yes | 138 (7.4) | 164 (8.7) | ||
| Type of side effects after 2nd dose | Fatigue | 6 (4.3) | 6 (3.7) | 0.0003 |
| Influenza-like symptoms without fever | 0 (0.0) | 18 (11.0) | ||
| Pain, itch, or swelling | 132 (95.7) | 140 (85.4) | ||
| Side effect onset after 2nd dose (hours) | 7.0±2.5 | 12.5±5.0 | 0.0071 | |
| Side effects resolution (hours) | 5.0±6.0 | 6.0±1.0 | 0.0025 | |
| SARS-CoV-2 infection | 0 | 0 | n/a | |
| Influenza without fever after 2nd dose | No | 1794 (96.7) | 1622 (86.2) | <0.0001 |
| Yes | 61 (3.3) | 259 (13.8) | ||
| Influenza with fever after 2nd dose | No | 1719 (92.8) | 1536 (81.7) | <0.0001 |
| Yes | 136 (7.3) | 345 (18.3) | ||
| COVID-19 antibody status | Negative | 123 (90.4) | 195 (56.5) | <.00001 |
| Positive | 13 (9.6) | 150 (43.5) | ||
| Time between 2nd vaccine dose and antibody test (days) | 35.0±6.0 | 34.0±14.0 | 0.8829 | |
COVID-19, coronavirus disease 2019; AE, adverse event.
The incidence rates of AEs following the second dose were similar between the patient and control groups (0.59%, 11/1849; and 0.37%, 7/1812; respectively; P=0.3670). Notably, the types of AEs after the second dose were significantly different between the patient and control groups (P=0.0012, Table 2). Specific AEs are described in Supplementary Materials.
Vaccine side effects are summarized in Table 2. Patients and controls experienced significantly different side effect rates after the first dose (15.1%, 308/2034; and 25.4%, 517/2034 respectively; P<0.0001). Influenza-like symptoms without fever were the most common side effects in controls reporting side effects (56.9%, 294/517). Myalgia and arthralgia were the most frequent symptoms in patients reporting side effects (33.8%, 104/308). After the second dose, pain, itching, or swelling were observed in 85.4% (140/164) of controls and 97.7% (132/138) of patients reporting side effects. Influenza-like symptoms without fever occurred in 11.0% (18/164) of controls reporting side effects.
Patients with MPD had a similar risk of AEs compared to controls after the first dose (adjusted risk ratio [RR]=1.19, 95% confidence interval [CI] 0.97-1.46), and second dose (adjusted RR=1.55, 95% CI 0.60-3.99) in multivariate analysis. Interestingly, the adjusted RR of side effects after the first dose (RR=0.60, 95% CI 0.53-0.68) and the second dose (RR=0.80, 95% CI 0.65-0.99) suggested a lower risk of side effects in the MPD group compared to controls (Table 3).
Table 3.
COVID-19 vaccine adverse event/side effect incidence and efficacy in MPD and control groups
| Univariate analysis RR (95% CI) (Patients vs. controls) | p value | Multivariate analysis RR (95% CI) (Patients vs. controls) | p value | |
|---|---|---|---|---|
| AEs after 1st dose | 1.17 (0.95-1.44) | 0.6890 | 1.19 (0.97-1.46) | 0.5894 |
| Side effects after 1st dose | 0.60 (0.52-0.68) | 0.0357 | 0.60 (0.53-0.68) | 0.0023 |
| AEs after 2nd dose | 1.54 (0.60-3.96) | 0.3182 | 1.55 (0.60-3.99) | 0.2157 |
| Side effects after 2nd dose | 0.82 (0.66-1.02) | 0.0493 | 0.80 (0.65-0.99) | 0.0120 |
| Influenza without fever after 2nd dose | 0.23 (0.18-0.30) | 0.0001 | 0.23 (0.17-0.30) | <0.0001 |
| Influenza with fever after 2nd dose | 0.38 (0.32-0.46) | <0.0001 | 0.38 (0.31-0.46) | <0.0001 |
COVID-19, coronavirus disease 2019; AE, adverse event. Results of multivariate analysis were adjusted for age, sex, education level, workplace exposures, economic status, and type of vaccine.
Vaccine efficacy
No cases of COVID-19 occurred in patients with MPD or in controls. None of the fully vaccinated participants developed persistent high fever (≥ 39.5°C, ≥ 72 h) and severe pneumonia. In contrast to fully vaccinated controls, fully vaccinated patients with MPD exhibited decreased risks of influenza with or without fever (adjusted RR=0.38, 95% CI 0.31-0.46; adjusted RR=0.23, 95% CI 0.17-0.30, respectively) (Table 3). Post-vaccination SARS-CoV-2 seroprevalence in controls who developed febrile influenza was 43.5% (150/345), higher than that in patients with MPD (9.6%, 13/136) (P<0.0001) (Table 2).
Differences in COVID-19 vaccine safety and efficacy between MPD subgroups
Patients with MPD were stratified into BP, MDD, and SCH subgroups. The number and proportion of patients experiencing AEs/side effects in each subgroup are summarized in Table 4. There were no significant differences in AE incidence among the three subgroups, whereas rates of side effects from the first and second doses were significantly different (P=0.0054, P<0.0001). Information regarding AEs/side effects in the subgroups is provided in Supplementary Materials.
Table 4.
COVID-19 vaccine adverse events/side effects and efficacy in MPD subgroups
| BP (n=581) | MDD (n=640) | SCH (n=813) | p value | ||
|---|---|---|---|---|---|
| COVID-19 Vaccine | BBIBP-CorV | 421 (72.5) | 638 (99.7) | 481 (59.2) | <0.0001 |
| Sinovac | 160 (27.5) | 2 (0.3) | 332 (40.8) | ||
| AE after 1st dose | No | 538 (92.6) | 588 (91.9) | 729 (89.7) | 0.1251 |
| Yes | 43 (7.4) | 52 (8.1) | 84 (10.3) | ||
| Side effects after 1st dose | No | 485 (83.5) | 526 (82.2) | 715 (87.9) | 0.0054 |
| Yes | 96 (16.5) | 114 (17.8) | 98 (12.1) | ||
| Vaccinated 2nd dose | Yes | 540 (92.9) | 588 (91.9) | 727 (89.4) | 0.1652 |
| No | 41 (7.1) | 52 (8.1) | 86 (10.6) | ||
| AE after 2nd dose | No | 539 (99.8) | 582 (99.0) | 723 (99.4) | 0.1881 |
| Yes | 1 (0.2) | 6 (1.0) | 4 (0.6) | ||
| Side effects after 2nd dose | No | 539 (99.8) | 582 (99) | 723 (99.4) | <0.0001 |
| Yes | 1 (0.2) | 6 (1.0) | 4 (0.6) | ||
| Influenza without fever after 2nd dose | No | 532 (98.5) | 573 (97.4) | 689 (94.8) | 0.0006 |
| Yes | 8 (1.5) | 15 (2.6) | 38 (5.2) | ||
| Influenza with fever after 2nd dose | No | 453 (83.9) | 572 (97.3) | 696 (95.7) | <0.0001 |
| Yes | 87 (16.1) | 16 (2.7) | 31 (4.3) | ||
| COVID-19 antibody status | Negative | 79 (90.8) | 14 (87.5) | 28 (90.3) | 0.9464 |
| Positive | 8 (9.2) | 2 (12.5) | 3 (9.7) | ||
COVID-19, coronavirus disease 2019; MPD, major psychiatric disorders; BP, bipolar disorder; MDD, major depressive disorder; SCH, schizophrenia; AE, adverse event.
The adjusted RR of AEs after the first dose in MDD (RR=1.15, 95% CI 0.85-1.57), SCH (RR=1.35, 95% CI 1.05-1.75), and BP (RR=1.00, 95% CI 0.72-1.38) suggested that the risk of AEs was not significantly increased in either subgroup compared to controls (Table 5). Notably, the risk of side effects after the first dose was significantly decreased in MDD (RR=0.65, 95% CI 0.54-0.79), BP (RR=0.66, 95% CI 0.54-0.80), and SCH (RR=0.50, 95% CI 0.41-0.61) compared to controls. The adjusted RR of AEs after the second dose was 2.63 (95% CI 0.88-7.82) in MDD, 1.42 (95% CI 0.42-4.84) in SCH, and 0.49 (95% CI 0.06-3.94) in BP patients, suggesting a lower risk of AEs compared to controls (Table 5).
Table 5.
Comparison of AEs/side effects and efficacy of COVID-19 vaccine among MPD subgroups and controls
| Comparison subgroups | Univariate analysis RR (95% CI) | p value | Multivariate analysis RR (95% CI) | p value | |
|---|---|---|---|---|---|
| AE after 1st dose | BP vs. Control | 0.98 (0.71-1.36) | 0.2541 | 1.00 (0.72-1.38) | 0.1890 |
| MDD vs. Control | 1.08 (0.80-1.46) | 0.1369 | 1.15 (0.85-1.57) | 0.1483 | |
| SCH vs. Control | 1.37 (1.07-1.77) | 0.0007 | 1.35 (1.05-1.75) | 0.0179 | |
| Side effects after 1st dose | BP vs. Control | 0.65 (0.53-0.79) | <0.0001 | 0.66 (0.54-0.80) | 0.0010 |
| MDD vs. Control | 0.70 (0.58-0.84) | <0.0001 | 0.65 (0.54-0.79) | <0.0001 | |
| SCH vs. Control | 0.47 (0.39-0.58) | <0.0001 | 0.50 (0.41-0.61) | <0.0001 | |
| AEs after 2nd dose | BP vs. Control | 0.48 (0.06-3.93) | 0.0563 | 0.49 (0.06-3.94) | 0.8571 |
| MDD vs. Control | 2.64 (0.89-7.83) | 0.9833 | 2.63 (0.88-7.82) | 0.7469 | |
| SCH vs. Control | 1.42 (0.42-4.85) | 0.5630 | 1.42 (0.42-4.84) | 0.4260 | |
| Side effects after 2nd dose | BP vs. Control | 1.57 (1.22-2.03) | <0.0001 | 1.57 (1.22-2.02) | 0.0001 |
| MDD vs. Control | 0.32 (0.20-0.52) | <0.0001 | 0.26 (0.16-0.43) | <0.0001 | |
| SCH vs. Control | 0.68 (0.50-0.94) | <0.0001 | 0.77 (0.56-1.05) | 0.0500 | |
| Influenza without fever after 2nd dose | BP vs. Control | 0.10 (0.05-0.21) | <0.0001 | 0.10 (0.05-0.21) | <0.0001 |
| MDD vs. Control | 0.18 (0.11-0.3) | <0.0001 | 0.18 (0.11-0.30) | <0.0001 | |
| SCH vs. Control | 0.37 (0.26-0.51) | <0.0001 | 0.37 (0.26-0.51) | <0.0001 | |
| Influenza with fever after 2nd dose | BP vs. Control | 0.86 (0.69-1.06) | 0.3690 | 0.85 (0.69-1.06) | 0.4579 |
| MDD vs. Control | 0.14 (0.09-0.23) | 0.0023 | 0.13 (0.08-0.21) | <0.0001 | |
| SCH vs. Control | 0.22 (0.16-0.32) | 0.0001 | 0.24 (0.17-0.34) | 0.0177 | |
| AEs after 1st dose | MDD vs. BP | 1.10 (0.74-1.62) | 0.6974 | 1.27 (0.88-1.83) | 0.6582 |
| SCH vs. BP | 1.40 (0.98-1.98) | 0.5821 | 1.26 (0.92-1.73) | 0.6030 | |
| Side effects after 1st dose | MDD vs. BP | 1.08 (0.84-1.38) | 0.6317 | 0.88 (0.69-1.13) | 0.7000 |
| SCH vs. BP | 0.73 (0.56-0.95) | 0.0211 | 0.82 (0.63-1.06) | 0.0290 | |
| AEs after 2nd dose | MDD vs. BP | 5.45 (0.66-45.11) | 0.9851 | 5.38 (0.65-44.63) | 0.8090 |
| SCH vs. BP | 2.94 (0.33-26.21) | 0.6938 | 2.95 (0.33-26.28) | 0.9600 | |
| Side effects after 2nd dose | MDD vs. BP | 0.20 (0.12-0.34) | 0.0004 | 0.16 (0.10-0.28) | <0.0001 |
| SCH vs. BP | 0.43 (0.31-0.62) | 0.0026 | 0.50 (0.35-0.70) | 0.0039 | |
| Influenza without fever after 2nd dose | MDD vs. BP | 1.70 (0.73-3.98) | 0.4820 | 1.62 (0.69-3.80) | 0.6044 |
| SCH vs. BP | 3.49 (1.64-7.42) | 0.0495 | 3.42 (1.61-7.26) | 0.0288 | |
| Influenza with fever after 2nd dose | MDD vs. BP | 0.17 (0.10-0.28) | 0.0001 | 0.14 (0.08-0.24) | <0.0001 |
| SCH vs. BP | 0.26 (0.18-0.39) | <0.0001 | 0.30 (0.20-0.44) | <0.0001 |
COVID-19, coronavirus disease 2019; AE, adverse event; BP, bipolar disorder; MDD, major depressive disorder; SCH, schizophrenia; RR, risk ratio; CI, confidence interval. Results of multivariate analysis were adjusted for age, sex, education level, exposure to working environment, economic status, and type of vaccine.
Compared to controls, patients with MDD or SCH demonstrated a decreased risk of influenza with or without fever (adjusted RR of influenza with fever in MDD=0.13, 95% CI 0.08-0.21; adjusted RR of influenza without fever in MDD=0.18, 95% CI 0.11-0.30; adjusted RR of influenza with fever in SCH=0.24, 95% CI 0.17-0.34; adjusted RR of influenza without fever in SCH=0.37, 95% CI 0.26-0.51) (Table 5). However, the risk of influenza with fever was similar in patients with BP and controls (adjusted RR=0.85, 95% CI 0.69-1.06), whereas the risk of influenza without fever was significantly lower in BP compared with healthy controls (adjusted RR=0.10, 95% CI 0.05-0.21) (Table 5). Moreover, the risk of influenza with fever in patients with SCH or MDD was decreased in comparison with the BP subgroup (adjusted RR=0.30, 95% CI 0.20-0.44 in SCH versus BP; adjusted RR=0.14, 95% CI 0.08-0.24 in MDD versus BP) (Table 5). However, compared to patients with BP, patients with SCH demonstrated an increased risk of influenza without fever (adjusted RR=3.42, 95% CI 1.61-7.26), whereas compared to patients with BP, the risk of influenza without fever was similar in patients with MDD (adjusted RR=1.62, 95% CI 0.69-3.80) (Table 5).
Discussion
This study of the safety and efficacy of COVID-19 vaccines provides vital information to assist psychiatrists and other physicians in the care of patients with MPD. First, the incidence of COVID-19 vaccine-related AEs in patients with MPD was not significantly increased, while the risk of side effects was significantly reduced compared to controls; this evidence affirms the practice of providing COVID-19 vaccinations to patients with MDP. Second, COVID-19 vaccination was associated with a significantly lower incidence of influenza with and without fever in MDD or SCH patients compared to BP patients. Third, compared to controls, patients with BP did not show decreased risk of influenza with fever although the risk of influenza without fever was significantly reduced. Fourth, the risk of influenza without fever was increased in SCH compared to BP patients, whereas the risk of influenza with fever was significantly decreased in SCH or MDD.
Our findings affirm the prioritization of patients with MPD for COVID-19 vaccination [16]. Our data may also suggest that fully vaccinated BP patients, especially those in the hypo-manic phase, should receive specific measures to prevent influenza, as patients often neglect influenza-like illnesses, thus facilitating disease progression and pneumonia [30,31].
Because none of the participants contracted COVID-19, we conclude that all fully-vaccinated patients and controls acquired protective immunity. This outcome is attributed to the implementation of strict infection prevention and control strategies introduced by our government that include free COVID-19 vaccination, social distancing, mask-wearing, and timely disinfection of public transport. Our data also demonstrated a higher post-vaccination SARS-CoV-2 seroprevalence among controls compared to MPD patients tested in the context of febrile influenza. Due to the absence of previous information regarding COVID-19 vaccine-induced seroconversion in patients with MPD, we cannot make further comparisons to explain this difference. Certain antidepressants that include selective serotonin reuptake inhibitors may reduce SARS-CoV2 cellular entry and exert immunomodulatory effects [22], and have shown promise as COVID-19 therapies in three clinical trials [32,33]. Based on these findings, we hypothesize that antipsychotics that exert serotonin re-uptake inhibition similar to antidepressants (e.g. olanzapine, clozapine, ziprasidone, risperidone, aripiprazole) [34-36], may inhibit the cellular entry and propagation of SARS-CoV-2 virus and attenuate pro-inflammatory cytokine cascades, potentially offering novel therapeutic options for COVID-19. Furthermore, we hypothesize that drugs that inhibit SARS-CoV-2 entry may inhibit uptake and processing of inactivated or recombinant vaccine antigens by immune effector cells, thereby reducing post-vaccine seroconversion. This hypothesis is supported by the lower post-vaccination SARS-CoV-2 seroprevalence in MPD patients vs. controls tested in the context of febrile influenza-like illness and by the lower rate of side effects in MPD patients vs. controls. However, the clinical relevance of postvaccination seronegativity is unclear, because laboratory correlates of clinical protection are undefined [37-40] and because no cases of COVID-19 were observed in either group. This hypothesis may be worthy of future research.
Several limitations of our study should be mentioned. The first is its retrospective observational design. Outcome data were retrieved from outpatients. The strength of evidence of retrospective studies may be inferior to that of prospective studies, although we made every effort to ensure the accuracy of information regarding AEs and efficacy. Second, the potential effect of psychotropic agents on COVID-19 vaccine efficacy are difficult to determine. This potential interaction should be studied further. Third, patients with MPD were not stratified into subsets of first-episode or relapsed cases. There might be a link between initial or recurrent disease and the safety and efficacy of COVID-19 vaccines. Fourth, although we used a detailed questionnaire, our study may have been confounded by recall bias. Fifth, post-vaccination seroconversion was evaluated only in participants presenting with influenza, which may have introduced selection bias. The lower SARS-CoV-2 seroprevalence in patients of MPD with influenza and fever versus controls cannot be used as an index to evaluate the clinical efficacy of COVID-19 vaccines. Sixth, although study participants had normal memory function to assure accuracy in recalling their medical regimens and COVID-19 vaccine-related information, sample bias could not be avoided. Hence, prospective studies should be conducted to fully clarify the safety and efficacy of COVID-19 vaccines.
In conclusion, patients with MPD did not experience an increased risk of AEs after COVID-19 vaccination compared to well-matched healthy controls. Vaccination protected all participants from COVID-19. Furthermore, fully vaccinated patients with SCH or MDD showed lower risks of influenza with and without fever than those with BP. These findings suggest that COVID-19 vaccines are safe and protective in patients with severe MPD, especially those with SCH or MDD.
Acknowledgements
This study was supported by the Key Projects of the Natural Science Foundation of Tianjin, China (17JCZDJC35700 to CJZ), the Tianjin Health Bureau Foundation (2014KR02 to CJZ), and the Talent Fund of Tianjin Anding (to CJZ).
Disclosure of conflict of interest
None.
Supporting Information
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