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Table 1 Systematic reviews reporting a quantitative synthesis of the evidence for the outcomes selected by the working group

From: Safety of psychotropic medications in people with COVID-19: evidence review and practical recommendations

Review Type of study Population Intervention Comparison Outcome Summary AMSTAR-2
Clegg et al. 2011 [23] Systematic review of observational studies and RCTs (no meta-analysis) Patients from medicine and surgery settings, mostly elderly Antidepressants
Antipsychotics Benzodiazepines
No exposure or placebo Risk of delirium Increased risk for benzodiazepines as a class (1 case–control study; n = 1341; OR 3.0, 95% CI 1.3 to 6.8), with higher risk for longer-acting agents and higher doses; antipsychotics as a class (1 prospective cohort study; n = 325; OR 4.5; 95% CI 1.8 to 10.5), but not for haloperidol (1 RCT; n = 430; OR 0.9, 95% CI 0.6 to 1.3); and tricyclic antidepressants (1 RCT; n = 111; RR 1.7, 95% CI 1.4 to 2.1). Critically low
Dragioti et al. 2019 [30] Umbrella review (meta-analyses of observational studies) Mixed (general population; people with depression) Antidepressants No exposure Cardiovascular risk Increased risk of coronary heart disease for TCAs (N = 14; n = 347,750; OR 1.51, 95% CI 1.07 to 2.12; CE IV). Critically low
Risk of acute heart disease not increased for SSRIs (N = 14; n = 818,337; RR 1; 95% CI 0.83 to 1.22). Critically low
Risk of myocardial infarction not increased for antidepressants as a class (N = 21; n = 1,793,877; RR 1.03, 95% CI 0.88 to 1.22). Critically low
Increased risk of cerebrovascular disease for SSRIs (N = 6; n = 280,784; RR 1.26, 95% CI 1.14 to 1.39; CE III). Critically low
Risk of cerebrovascular disease not increased for TCAs (N = 4; n = 278,749; RR 1.06, 95% CI 0.96 to 1.17). Critically low
Coagulation risk Increase risk of severe bleeding at any site for SSRIs and SNRIs taken together (N = 44; n = 1,443,029; OR 1.41, 95% CI 1.27–1.57; CE II). Critically low
Dzahini et al. 2018 [32] Systematic review and meta-analysis of observational studies Mixed (general population; people with schizophrenia, bipolar disorder, depression), mostly elderly Antipsychotics No exposure Risk of infections Risk of pneumonia is increased by FGAs (N = 5; n = 29,510, RR 1.69, 95% CI 1.34 to 2.15), SGAs (N = 6; n = 30,656; RR 1.93, 95% CI 1.55 to 2.41) and antipsychotics as a class (N = 7; n = 30,760; RR 1.83, 95% CI 1.60 to 2.10). No differences emerged between FGAs and SGAs. Critically low
Huhn et al. 2019 [48] Systematic review and network meta-analysis of RCTs Adults with multi-episode schizophrenia Antipsychotics Placebo Cardiovascular risk Significantly increased risk of QTc prolongation (N = 51; n = 15,467): quetiapine (OR 3.43, 95% CI 0.94 to 6.0); olanzapine (OR 4.29, 95% CI 1.91 to 6.68); risperidone (OR 4.77, 95% CI 2.68 to 6.87); iloperidone (OR 6.93, 95% CI 4.49 to 9.36); ziprasidone (OR 9.7, 95% CI 7.43 to 12.04); amisulpride (OR 14.1, 95% CI 7.71 to 20.45); serenditole (OR 23.9, 95% CI 20.56 to 27.33). Low
Kunutsor et al. 2018 [55] Systematic review and meta-analysis of observational studies General population Antidepressants No exposure Coagulation risk Increased risk of venous thromboembolism for antidepressants as a class (N = 6; n = 828,327; OR 1.27; 95% CI 1.06 to 1.51), TCAs (N = 4; n = 59,161; OR 1.16; 95% CI 1.06 to 1.27), SSRIs (N = 4; n = 58,088; OR 1.12; 95% CI 1.02 to 1.23), and other antidepressants (N = 3; n = 3198; OR 1.59, 95% CI 1.21 to 2.09). Critically low
Lu et al. 2016 [59] Systematic review and meta-analysis of RCTs Adults with insomnia and COPD Benzodiazepines Placebo Respiratory risk No differences between benzodiazepines (i.e., triazolam and temazepam) and placebo in terms of percentage of time below 90% arterial oxygen saturation during sleep (N = 3; n = 94; weighted MD 1.32; 95% CI − 7.33 to 9.97) and other respiratory outcomes during sleep (sleep apnea, Apnea–Hypopnea Index, arterial oxygen saturation). Critically low
Ostuzzi et al. 2019 [105] Systematic review and meta-analysis of RCTs Adults with depression and ischemic heart disease Antidepressants Placebo Cardiovascular risk No differences emerged for antidepressants as a class (SSRIs the most represented) in terms of mortality because of cardiovascular events (N = 14; n = 2674; RD 0.0, 95% CI − 0.01 to 0.01) and nonfatal cardiac events (N = 9; n = 1869; RD − 0.01, 95% CI − 0.04 to 0.02). High
Papola et al. 2019 [70] Umbrella review (meta-analysis of observational studies) Mixed (general population; people with dementia, schizophrenia, or other psychiatric conditions), mostly elderly Antipsychotics No exposure Cardiovascular risk For antipsychotics as a class, there was an increased risk of sudden cardiac death (N = 6; n = 677,488; OR 2.24; 95% CI 1.45 to 3.46; CE III), myocardial infarction (N = 9; n = 399,868; OR 2.21; 95% CI 1.41 to 3.46; CE III), and stroke (N = 9; n = 65,700; OR 1.45, 95% CI 1.24 to 1.7; CE III). Meta-regression showed that the risk of myocardial infarction and stroke was higher in the elderly. Moderate
Coagulation risk For antipsychotics as a class, there was an increased risk of venous thromboembolism (N = 14; n = 31,417,175; OR 1.55, 95% CI 1.31 to 1.83; CE II). Low
Pollok et al. 2018 [72] Systematic review and meta-analysis of RCTs Adults with depression and COPD Antidepressants Placebo Respiratory risk No increased risk of respiratory impairment for TCAs (change in dyspnea during walk according to the Pulmonary Functional Status Instrument: N = 1; n = 30; MD 0.50; 95% CI − 1.34 to 2.34) and SSRIs (change in FEV1: N = 2; n = 148; MD 0.01; 95% CI − 0.03 to 0.05). High
Schneider-Thoma et al. 2019 [78] Systematic review and meta-analysis of RCTs Mixed (83% adults; 8% elderly; 42% schizophrenia; 30% bipolar disorder; 11% depression; 6% dementia) Antipsychotics (mostly second-generation) Placebo Respiratory risk Increased risk of respiratory, thoracic, and mediastinal serious adverse events in studies with at least one serious adverse event according to a maximum estimate (worst-case scenario) (N = 38; n = 13,007; OR 1.72; 95% CI 1.02 to 2.89). Low
Cardiovascular risk Risk of cardiac (N = 54; n = 19,642; OR 1.22; 95% CI 0.85 to 1.75) and vascular serious adverse events (N = 33; n = 12,842; OR 1.82; 95% CI 0.97 to 3.41) were not increased in studies with at least one serious adverse event according to a maximum estimate (worst-case scenario). Low
Risk of infections Increased risk of infections in studies with at least one serious adverse event according to a maximum estimate (worst-case scenario) (N = 88; n = 28,479; OR 1.43; 95% CI 1.06 to 1.92). Low
Sun et al. 2018 [83] Systematic review and meta-analysis of observational
studies
General population, mostly elderly Benzodiazepines No exposure Risk of infections Increased risk of pneumonia for benzodiazepines and related medications (e.g., zolpidem) (N = 10; n = 1,520,285; OR 1.25; 95% CI 1.09 to 1.44). The risk was confirmed for current and recent exposure (not for past exposure); for long-acting, intermediate-acting and short-acting agents; and for younger and older patients. Critically low
Wu et al. 2019 [95] Systematic review and network meta-analysis of RCTs Medical and surgical patients at risk of delirium Antipsychotics Benzodiazepines
Mood stabilizers
Placebo/treatment as usual Risk of delirium Decreased incidence of delirium as compared to placebo or treatment as usual (N = 38; n = 8168) emerged for olanzapine (OR 0.25; 95% CI 0.09 to 0.69) and risperidone (OR 0.27; 95% 0.07 to 0.99), while no differences emerged for lorazepam, haloperidol, and gabapentin. A higher incidence emerged for midazolam hydrochloride (OR 2.98; 95% CI 1.30 to 6.80). Low
  1. AD antidepressant, AP antipsychotic, CE credibility-of-evidence classification (I = convincing evidence; II = highly suggestive evidence; III = suggestive evidence; IV = weak evidence), CI confidence interval, FEV forced expiratory volume, FGA first-generation antipsychotic, ICU intensive care unit, MA meta-analysis, MD mean difference, N number of studies included in the analysis, n number of participants included in the analysis, OR odds ratio, RCT randomized controlled trial, SGA second-generation antipsychotic, SR systematic review, RR risk ratio, SNRI serotonin–norepinephrine reuptake inhibitors, SSRI selective serotonin reuptake inhibitor, TCA tricyclic antidepressant, VTE venous thromboembolism