Table 3.
Potential safety signals and the year in the 20 sequential analyses in which they appeared the first and last time, including the hazard ratio and the 95% confidence interval at the last appearance
| Antidepressants (years of surveillance) and serious medical event | First appearance of potential signal (years) | Last appearance of potential signal (years) | HR (95% CI), last year as a potential signal | ||||||
|---|---|---|---|---|---|---|---|---|---|
| P | S | A | P | S | A | P | S | A | |
| Duloxetine (13) | |||||||||
| Fractures | 5 | 5 | 13* | 13* | 0.68 (0.52–0.89) | 0.72 (0.55–0.94) | |||
| Hyponatremiab | 4 | 4 | 8 | 8 | 1.86 (1.07–3.24) | 1.88 (1.08–3.25) | |||
| Suicidesb | 5 | 5 | 5 | 5 | 2.06 (1.06–4.00) | 2.05 (1.06–3.97) | |||
| Escitalopram (15) | |||||||||
| Acute hepatic failurea | 5 | 5 | 5 | 6 | 6* | 5 | 2.37 (1.00–5.63) | 2.41 (1.05–5.53) | 2.25 (1.00–5.04) |
| Acute kidney injurya | 7 | 15* | 1.49 (1.02–2.16) | ||||||
| Cardiomyopathyc | 10 | 10 | 15* | 14 | 1.61 (1.02–2.51) | 1.75 (1.02–3.01) | |||
| Delusionsa | 4 | 4 | 5 | 5 | 1.59 (1.05–2.39) | 1.49 (1.01–2.21) | |||
| Epilepsy/seizures | 4 | 8 | 15* | 11 | 0.78 (0.64–0.95) | 0.81 (0.66–0.99) | |||
| Heart failure | 7 | 13 | 0.83 (0.70–1.00) | ||||||
| Hepatic failurea | 10 | 5 | 15* | 15* | 1.52 (1.04–2.21) | 2.13 (1.34–3.38) | |||
| Fractures | 8 | 15* | 0.91 (0.85–0.99) | ||||||
| Hemorrhagic strokec | 13 | 6 | 6 | 15* | 15* | 9 | 1.28 (1.02–1.62) | 1.30 (1.04–1.62) | 1.34 (1.01–1.77) |
| Hyponatremiab | 6 | 6 | 1.38 (1.07–1.78) | ||||||
| ITPa | 11 | 11 | 11 | 15* | 15* | 15* | 4.04 (1.27–12.8) | 4.97 (1.66–14.9) | 8.08 (1.55–42.2) |
| Intestinal perforationa | 15 | 15* | 4.27 (1.16–15.7) | ||||||
| Ischemic stroke | 7 | 8 | 8 | 8 | 0.86 (0.76–0.99) | 0.88 (0.77–1.00) | |||
| Renal failurea | 14 | 9 | 15* | 15* | 1.23 (1.00–1.51) | 1.42 (1.11–1.82) | |||
| Fluoxetine (20) | |||||||||
| Delusionsa | 4 | 4 | 20* | 20* | 1.61 (1.13–2.30) | 1.52 (1.09–2.14) | |||
| Epilepsy/seizures | 5 | 6 | 20* | 8 | 0.69 (0.49–0.96) | 0.69 (0.48–0.99) | |||
| Myocardial infarction | 8 | 8 | 8 | 8 | 0.70 (0.50–0.98) | 0.72 (0.52–1.00) | |||
| Ventricular arrhythmiaa | 3 | 3 | 8 | 8 | 2.11 (1.04–4.29) | 2.14 (1.08–4.23) | |||
| Paroxetine (20) | |||||||||
| Cardiomyopathyc | 2 | 14 | 1.93 (1.03–3.64) | ||||||
| Delusionsa | 9 | 11 | 20* | 15 | 1.42 (1.00–2.02) | 1.42 (1.01–1.99) | |||
| Epilepsy/seizures | 6 | 20* | 0.71 (0.52–0.98) | ||||||
| Fractures | 10 | 18 | 20* | 19 | 0.84 (0.74–0.95) | 0.88 (0.77–1.00) | |||
| Heart failure | 7 | 7 | 7 | 7 | 0.65 (0.46–0.94) | 0.67 (0.47–0.96) | |||
| Ischemic stroke | 5 | 20* | 0.78 (0.64–0.96) | ||||||
| Polyneuropathyc | 15 | 15 | 20* | 20* | 2.74 (1.30–5.79) | 2.63 (1.30–5.33) | |||
| Renal failure | 9 | 9 | 20* | 13 | 0.61 (0.38–1.00) | 0.50 (0.28–0.92) | |||
| Sertraline (20) | |||||||||
| Cardiomyopathy | 10 | 18 | 0.50 (0.26–0.95) | ||||||
| Epilepsy/seizures | 19 | 20* | 0.78 (0.66–0.93) | ||||||
| Fractures | 5 | 5 | 20* | 20* | 0.84 (0.78–0.90) | 0.86 (0.81–0.93) | |||
| Heart failurec | 11 | 11 | 14 | 14 | 1.20 (1.03–1.40) | 1.22 (1.05–1.42) | |||
| Hepatotoxicityb | 2 | 2 | 4 | 3 | 1.90 (1.04–3.45) | 1.79 (1.02–3.13) | |||
| Hepatic necrosisa | 19 | 20* | 2.66 (1.12–6.30) | ||||||
| Renal failure | 6 | 6 | 15 | 15 | 0.80 (0.64–1.00) | 0.75 (0.57–0.99) | |||
| Toxic liver diseasea | 2 | 3 | 1.73 (1.01–2.97) | ||||||
| Venlafaxine (20) | |||||||||
| Arrhythmiaa | 13 | 13 | 20* | 20* | 1.43 (1.17–1.75) | 1.41 (1.16–1.73) | |||
| Epilepsy/seizures | 4 | 9 | 0.70 (0.51–0.97) | ||||||
| Hyponatremiab | 4 | 4 | 20* | 20* | 1.40 (1.05–1.87) | 1.38 (1.04–1.83) | |||
| Pulmonary fibrosisa | 18 | 20* | 2.30 (1.11–4.79) | ||||||
| Suicidesb | 18 | 9 | 20* | 20* | 1.31 (1.00–1.71) | 1.33 (1.03–1.71) | |||
| Citalopram (20) | |||||||||
| Cardiac arresta | 10 | 10 | 12 | 10 | 1.46 (1.02–2.09) | 1.73 (1.11–2.71) | |||
| Delusions | 10 | 12 | 0.79 (0.63–0.98) | ||||||
| Epilepsy/seizuresb | 5 | 5 | 20* | 20* | 1.33 (1.18–1.51) | 1.35 (1.18–1.56) | |||
| Fracturesb | 5 | 5 | 20* | 20* | 1.13 (1.08–1.19) | 1.16 (1.09–1.22) | |||
| Hepatic failurea | 20 | 20* | 1.49 (1.06–2.11) | ||||||
| Hyponatremia | 6 | 6 | 18 | 7 | 0.88 (0.78–0.99) | 0.84 (0.72–0.98) | |||
| Ischemic strokec | 16 | 20 | 20* | 20* | 1.11 (1.03–1.19) | 1.11 (1.02–1.20) | |||
| Renal failurea | 6 | 6 | 8 | 20 | 1.35 (1.05–1.75) | 1.27 (1.06–1.52) | |||
| Self-harm | 4 | 4 | 4 | 4 | 0.49 (0.28–0.87) | 0.65 (0.42–0.99) | |||
Bold medical events and HRs (95% CI) indicate signals selected for further assessment. Blank fields illustrate analysis not relevant or that no potential safety signal was detected
A additional secondary analysis for citalopram and escitalopram excluding both in the comparator group, CI confidence interval, DME designated medical event, EMA European Medicines Agency, HR hazard ratio, ITP immune thrombocytopenic purpura, S secondary comparing each drug with all others excluding drug of interest, SmPC summary of product characteristics, SNRI serotonin-norepinephrine reuptake inhibitor, SSRI selective serotonin reuptake inhibitor, P primary comparing each drug with citalopram
*Significant signal (p < 0.05) the last year of surveillance
aFrom the EMA DME list
bFound in SmPCs for some SSRIs or SNRIs
cMedical events missing from the EMA DME list and the SmPCs added because of importance