Electronic supplementary material. Drug safety

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1 Electronic supplementary material Drug safety Risk of seizures associated with antidepressant use in patients with depressive disorder: follow-up study with a nested case-control analysis using the Clinical Practice Research Datalink Marlene Bloechliger 1, MSc, Alessandro Ceschi 2,3, MD, Stephan Rueegg 4, MD, Hugo Kupferschmidt 2, MD, Stephan Kraehenbuehl 5, MD, PhD, Susan S Jick 6, DSc, Christoph R Meier 1,6,7, PhD, and Michael Bodmer 1,8, MD, MSc 1 Basel Pharmacoepidemiology Unit, Division of Clinical Pharmacy and Epidemiology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland; marlene.bloechliger@usb.ch, christoph.meier@usb.ch, michael.bodmer@zgks.ch 2 National Poisons Centre, Tox Info Suisse, Associated Institute of the University of Zurich, Zurich, Switzerland; alessandro.ceschi@usz.ch, hugo.kupferschmidt@usz.ch 3 Division of Clinical Pharmacology and Toxicology, Department of Internal Medicine, Ente Ospedaliero Cantonale Lugano, Lugano, Switzerland 4 Division of Clinical Neurophysiology, Department of Neurology, University Hospital Basel, Basel, Switzerland; stephan.rueegg@usb.ch 5 Division of Clinical Pharmacology & Toxicology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland; stephan.kraehenbuehl@usb.ch 6 Boston Collaborative Drug Surveillance Program, Boston University School of Public Health, Lexington, Massachusetts, USA; sjick@bu.edu 7 Hospital Pharmacy, University Hospital Basel, Basel, Switzerland 8 Medical Department, Zuger Kantonsspital, Zug, Switzerland 1

2 Electronic supplementary material 1. Depression Read code list Depressive episode (ICD-10 F32) Mild depressive episode (F32.0) RE Single major depressive episode, mild REu32400 [X]Mild depression REu32000 [X]Mild depressive episode REu32500 [X]Major depression mild Moderate depressive episode (F32.1) RE Single major depressive episode, moderate REu32100 [X]Moderate depressive episode REu32600 [X]Major depression moderately severe Severe depressive episode without psychotic symptoms (F32.2) RE Single major depressive episode, severe, without psychosis RE Agitated depression RE Agitated depression REu32211 [X]Single episode agitated depressn w'out psychotic symptoms REu32212 [X]Single episode major depression w'out psychotic symptoms REu32213 [X]Single episode vital depression w'out psychotic symptoms REu32200 [X]Severe depressive episode without psychotic symptoms REu33214 [X]Vital depression, recurrent without psychotic symptoms REu32700 [X]Major depression severe without psychotic symptoms RE Single major depressive episode Severe depressive episode with psychotic symptoms (F32.3) RE Single major depressive episode, severe, with psychosis REu32300 [X]Severe depressive episode with psychotic symptoms REu32311 [X]Single episode of major depression and psychotic symptoms REu32312 [X]Single episode of psychogenic depressive psychosis REu32313 [X]Single episode of psychotic depression REu32314 [X]Single episode of reactive depressive psychosis REu32800 [X]Major depression severe with psychotic symptoms Other depressive episodes (F32.8) RE11z200 Masked depression REu32y12 [X]Single episode of masked depression NOS 2

3 REu32y00 [X]Other depressive episodes REu32y11 [X]Atypical depression Depressive episode, unspecified (F32.9) RE112z00 Single major depressive episode NOS RE Single major depressive episode, unspecified REu32z00 [X]Depressive episode, unspecified REu32z11 [X]Depression NOS REu32z12 [X]Depressive disorder NOS REu33z11 [X]Monopolar depression NOS REu32z14 [X]Reactive depression NOS RE2B..00 Depressive disorder NEC RE2B1.00 Chronic depression RE Endogenous depression first episode RE Endogenous depression first episode RE Endogenous depression REu32.00 [X]Depressive episode Mild mental and behavioural disorders associated with the puerperium, not elsewhere classified (F53.0) RE Postnatal depression REu53011 [X]Postnatal depression NOS REu53012 [X]Postpartum depression NOS Mixed anxiety and depression (F41.2) REu34114 [X]Persistant anxiety depression REu41200 [X]Mixed anxiety and depressive disorder RE Anxiety with depression REu41211 [X]Mild anxiety depression Other RE11y200 Atypical depressive disorder RE02y300 Drug-induced depressive state REu33211 [X]Endogenous depression without psychotic symptoms REu33311 [X]Endogenous depression with psychotic symptoms REu32z13 [X]Prolonged single episode of reactive depression REu32.11 [X]Single episode of depressive reaction REu32.12 [X]Single episode of psychogenic depression 3

4 REu32.13 [X]Single episode of reactive depression RE Seasonal affective disorder REu33.14 [X]Seasonal depressive disorder REu33.15 [X]SAD - Seasonal affective disorder 4

5 Electronic supplementary material 2. Seizure Read code list Epilepsy (ICD-10 G 40) Localization-related (focal) (partial) idiopathic epilepsy and epileptic syndromes with seizures of localized onset (G40.0): RF25y400 BENIGN ROLANDIC EPILEPSY (=benign childhood epilepsy) RF25y200 LOCL-RLT(FOC)(PART)IDIOP EPILEP&EPILPTIC SYN SEIZ LOCL ONSET Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with simple partial seizures (G40.1): RF PARTIAL EPILEPSY WITHOUT IMPAIRMENT OF CONSCIOUSNESS RF JACKSONIAN, FOCAL OR MOTOR EPILEPSY RF255y00 PARTIAL EPILEPSY WITHOUT IMPAIRMENT OF CONSCIOUSNESS OS RF255z00 PARTIAL EPILEPSY WITHOUT IMPAIRMENT OF CONSCIOUSNESS NOS RF Simple partial epileptic seizure Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with complex partial seizures (G40.2): RF PARTIAL EPILEPSY WITH IMPAIRMENT OF CONSCIOUSNESS RF254z00 PARTIAL EPILEPSY WITH IMPAIRMENT OF CONSCIOUSNESS NOS RF Complex partial epileptic seizure Generalized idiopathic epilepsy and epileptic syndromes (G40.3): RF PROGRESSIVE MYOCLONIC EPILEPSY RF GENERALISED NONCONVULSIVE EPILEPSY RF EPILEPTIC ABSENCES RF EPILEPTIC SEIZURES - ATONIC RF JUVENILE ABSENCE EPILEPSY RF TONIC-CLONIC EPILEPSY RF EPILEPTIC SEIZURES - CLONIC RF EPILEPTIC SEIZURES - MYOCLONIC RF EPILEPTIC SEIZURES - TONIC RF TONIC-CLONIC EPILEPSY RF132z12 Myoclonic seizure RF25A.00 Juvenile myoclonic epilepsy R Absence seizure Other generalized epilepsy and epileptic syndromes (G40.4): RF250y00 OTHER SPECIFIED GENERALISED NONCONVULSIVE EPILEPSY 5

6 RF250z00 GENERALISED NONCONVULSIVE EPILEPSY NOS RF GENERALISED CONVULSIVE EPILEPSY RF251y00 OTHER SPECIFIED GENERALISED CONVULSIVE EPILEPSY RF251z00 GENERALISED CONVULSIVE EPILEPSY NOS RFyu5000 [X]OTHER GENERALIZED EPILEPSY AND EPILEPTIC SYNDROMES Special epileptic syndromes (G40.5): RF KOJEVNIKOV'S EPILEPSY RF25B.00 Alcohol-induced epilepsy RF25C.00 Drug-induced epilepsy RF25D.00 Menstrual epilepsy RF25E.00 Stress-induced epilepsy Grand mal seizures, unspecified (with or without petit mal) (G40.6): RF GRAND MAL (MAJOR) EPILEPSY RF GRAND MAL SEIZURE Petit mal, unspecified, without grand mal seizure (G40.7): RF PETIT MAL (MINOR) EPILEPSY Other epilepsy (G40.8): R667B.00 NOCTURNAL EPILEPSY RF25y.00 OTHER FORMS OF EPILEPSY RF25yz00 OTHER FORMS OF EPILEPSY NOS RFyu5100 [X]OTHER EPILEPSY Epilepsy, unspecified (G40.9): RF EPILEPSY RF25z.00 EPILEPSY NOS RF25z.11 FIT (IN KNOWN EPILEPTIC) NOS Status epilepticus (G41): Grand mal status epilepticus (G41.0): RF GRAND MAL STATUS Petit mal status epilepticus (G41.1): RF PETIT MAL STATUS Complex partial status epilepticus (G41.2): RF25y300 COMPLEX PARTIAL STATUS EPILEPTICUS 6

7 Other status epilepticus (G41.8): RFyu5200 [X]OTHER STATUS EPILEPTICUS Status epilepticus, unspecified (G41.9): RFyu5900 [X]Status epilepticus, unspecified RF STATUS EPILEPTICUS RF25X.00 STATUS EPILEPTICUS, UNSPECIFIED Seizure (convulsive) NOS (R56.8): RR [D]CONVULSIONS RR003z11 [D]Seizure NOS RR003y00 [D]Other specified convulsion RR003z00 [D]Convulsion NOS RRyu7100 [X]Other and unspecified convulsions R1B64.11 Convulsion - symptom RR [D]Fit R1B64.11 Convulsion symptom Others: R1O30.00 EPILEPSY CONFIRMED RF EPILEPTIC SEIZURES - AKINETIC RF PSYCHOMOTOR EPILEPSY RF PSYCHOSENSORY EPILEPSY RF LIMBIC SYSTEM EPILEPSY RF EPILEPTIC AUTOMATISM RF FOCAL EPILEPSY RF MOTOR EPILEPSY RF SENSORY INDUCED EPILEPSY RF SOMATOSENSORY EPILEPSY RF25F.00 Photosensitive epilepsy RF VISCERAL REFLEX EPILEPSY RF PARTIAL EPILEPSY WITH AUTONOMIC SYMPTOMS RF VISUAL REFLEX EPILEPSY RF UNILATERAL EPILEPSY RF POST-ICTAL STATE (altered state of consciousness after a seizure) RF25y000 CURSIVE (RUNNING) EPILEPSY 7

8 RF25y100 GELASTIC EPILEPSY RSC20000 TRAUMATIC EPILEPSY REu05y11 [X]Epileptic psychosis NOS R1B27.00 Seizures in response to acute event 8

9 Electronic supplementary material 3. Person-time assessment No antidepressant treatment: Start date: depression diagnosis First-time antidepressant prescription no antidepressant treatment Mono- or mixed use: Prescription antidepressant 1 (no other antidepressant prescriptions) Prescription antidepressant 2 End of mixed-use, start of mono use +90 days Past use Mono-use antidepressant 1 End of exposure antidepressant 1 Mono-use antidepressant 2 +7 days Mixed-use (concomitant use of antidepressants 1 and 2 End of exposure antidepressant 2 Past use: Prescription of antidepressant 1 (no other antidepressant prescriptions) Start past-use Either new prescription of antidepressant or past use until end of follow-up +7 days Mono-use antidepressant 1 Past-use End of exposure to antidepressant 1 9 Either new prescription of antidepressant or past use until end of follow-up

10 Prescription of >1 antidepressants Start past-use +90 days Past-use End of exposure to all antidepressants Mixed use (concomitant use of >1 antidepressants) 10

11 Electronic supplementary material 4. Odds ratios for seizures in users of different antidepressant drug classes compared to non-users of antidepressants, by current or past use, and by dementia Analysis restricted to patients with dementia Antidepressant drug class No. Cases (n=51) (%) a No. Controls (n=38) (%) a OR crude 95% CI OR adj. b 95% CI SSRIs No use 7 (1.1) 9 (0.4) 1 reference 1 reference Current use (last presc. 90 days ago) 29 (4.7) 11 (0.4) Past use (last presc. >90 days ago) 15 (2.4) 18 (0.7) SNRIs No use 44 (7.1) 34 (1.4) 1 reference 1 reference Current use (last presc. 90 days ago) X X NA NA NA NA Past use (last presc. >90 days ago) 5 (0.8) X NA NA NA NA TCAs No use 43 (7.0) 29 (1.2) 1 reference 1 reference Current use (last presc. 90 days ago) X X NA NA NA NA Past use (last presc. >90 days ago) 8 (1.3) 5 (0.2) Other antidepressants c No use 39 (6.3) 31 (1.3) 1 reference 1 reference Current use (last presc. 90 days ago) 9 (1.5) 6 (0.2) Past use (last presc. >90 days ago) X X NA NA NA NA Analysis restricted to patients without dementia Antidepressant drug class No. Cases (n=568) (%) a No. Controls (n=2,438) (%) a OR crude 95% CI OR adj. b 95% CI SSRIs No use 98 (15.8) 548 (22.1) 1 reference 1 reference Current use (last presc. 90 days ago) 214 (34.6) 618 (25.0) Past use (last presc. >90 days ago) 256 (41.4) 1,272 (51.4) SNRIs No use 507 (81.9) 2,256 (91.1) 1 reference 1 reference Current use (last presc. 90 days ago) 29 (4.7) 61 (2.5) Past use (last presc. >90 days ago) 32 (5.2) 121 (4.9)

12 TCAs No use 432 (69.8) 1,867 (75.4) 1 reference 1 reference Current use (last presc. 90 days ago) 35 (5.7) 143 (5.8) Past use (last presc. >90 days ago) 101 (16.3) 428 (17.3) Other antidepressants c No use 513 (82.9) 2,268 (91.6) 1 reference 1 reference Current use (last presc. 90 days ago) 25 (4.0) 45 (1.8) Past use (last presc. >90 days ago) 30 (4.9) 125 (5.1) Abbreviations: OR, odds ratio; CI, confidence interval; adj., adjusted; X, cell contains <5 observations (due to ethics regulations to preserve confidentiality, the exact count is not displayed); NA, not applicable; presc., prescription; SSRIs, selective serotonin reuptake inhibitors; SNRIs, serotonin-norepinephrine reuptake inhibitors; TCAs, tricyclic antidepressants. a Due to rounding, percentages may not total 100. b Adjusted for alcohol consumption, other antidepressant drug classes, benzodiazepines, antipsychotics, opioids, schizophrenia, affective disorders other than depression, compulsive disorders, suicide attempt or suicidal ideation, Parkinson s disease, TIA, and stroke. c This group consisted of the drugs mirtazapine, bupropion, reboxetine, and trazodone. 12

13 Electronic supplementary material 5. Odds ratios for seizures in users of different antidepressant drug classes compared to non-users of antidepressants, by current or past use, and by a history of stroke/tia Analysis restricted to patients with a history of stroke/tia Antidepressant drug class No. Cases (n=90) (%) a No. Controls (n=103) (%) a OR crude 95% CI OR adj. b 95% CI SSRIs No use 15 (2.4) 24 (1.0) 1 reference 1 reference Current use (last presc. 90 days ago) 50 (8.1) 31 (1.3) Past use (last presc. >90 days ago) 25 (4.0) 48 (1.9) SNRIs No use 85 (13.7) 96 (3.9) 1 reference 1 reference Current use (last presc. 90 days ago) X 5 (0.2) NA NA NA NA Past use (last presc. >90 days ago) X X NA NA NA NA TCAs No use 65 (10.5) 70 (2.8) 1 reference 1 reference Current use (last presc. 90 days ago) 8 (1.3) 16 (0.7) Past use (last presc. >90 days ago) 17 (2.8) 17 (0.7) Other antidepressants c No use 77 (12.4) 98 (4.0) 1 reference 1 reference Current use (last presc. 90 days ago) 6 (1.0) X NA NA NA NA Past use (last presc. >90 days ago) 7 (1.1) X NA NA NA NA Analysis restricted to patients without a history of stroke/tia Antidepressant drug class No. Cases (n=529) (%) a No. Controls (n=2,373) (%) a OR crude 95% CI OR adj. b 95% CI SSRIs No use 90 (14.5) 533 (21.5) 1 reference 1 reference Current use (last presc. 90 days ago) 193 (31.2) 598 (24.2) Past use (last presc. >90 days ago) 246 (39.7) 1,242 (50.2) SNRIs No use 466 (75.3) 2,194 (88.6) 1 reference 1 reference Current use (last presc. 90 days ago) 27 (4.4) 59 (2.4) Past use (last presc. >90 days ago) 36 (5.8) 120 (4.9)

14 TCAs No use 410 (66.2) 1,826 (73.8) 1 reference 1 reference Current use (last presc. 90 days ago) 27 (4.4) 131 (5.3) Past use (last presc. >90 days ago) 92 (14.9) 416 (16.8) Other antidepressants c No use 475 (76.7) 2,201 (88.9) 1 reference 1 reference Current use (last presc. 90 days ago) 28 (4.5) 49 (2.0) Past use (last presc. >90 days ago) 26 (4.2) 123 (5.0) Abbreviations: OR, odds ratio; CI, confidence interval; adj., adjusted; X, cell contains <5 observations (due to ethics regulations to preserve confidentiality, the exact count is not displayed); NA, not applicable; presc., prescription; SSRIs, selective serotonin reuptake inhibitors; SNRIs, serotonin-norepinephrine reuptake inhibitors; TCAs, tricyclic antidepressants. a Due to rounding, percentages may not total 100. b Adjusted for alcohol consumption, other antidepressant drug classes, benzodiazepines, antipsychotics, opioids, schizophrenia, affective disorders other than depression, compulsive disorders, suicide attempt or suicidal ideation, dementia, and Parkinson s disease. c This group consisted of the drugs mirtazapine, bupropion, reboxetine, and trazodone. 14

15 Electronic supplementary material 6. Odds ratios for seizures in users of different antidepressant drug classes compared to non-users of antidepressants, by current or past use Antidepressant drug class No. Cases (n=619) (%) a No. Controls (n=2,476) (%) a OR crude 95% CI OR adj. b 95% CI No use of antidepressants 34 (5.5) 228 (9.2) 1 reference 1 reference SSRIs Current use (last presc. 90 days ago) 243 (39.3) 629 (25.4) Past use (last presc. >90 days ago) 271 (43.8) 1,290 (52.1) SNRIs Current use (last presc. 90 days ago) 31 (5.0) 64 (2.6) Past use (last presc. >90 days ago) 37 (6.0) 122 (4.9) TCAs Current use (last presc. 90 days ago) 35 (5.7) 147 (5.9) Past use (last presc. >90 days ago) 109 (17.6) 433 (17.5) Other antidepressants c Current use (last presc. 90 days ago) 34 (5.5) 51 (2.1) Past use (last presc. >90 days ago) 33 (5.3) 126 (5.1) Abbreviations: OR, odds ratio; CI, confidence interval; adj., adjusted; NA. not applicable; presc., prescription; SSRIs, selective serotonin reuptake inhibitors; SNRIs, serotonin-norepinephrine reuptake inhibitors; TCAs, tricyclic antidepressants. a Cases and controls could be users of more than one antidepressant group and thus be listed more than once in the table (thus percentages do not total 100%). b Adjusted for alcohol consumption, other antidepressant drug classes, benzodiazepines, antipsychotics, opioids, schizophrenia, affective disorders other than depression, compulsive disorders, suicide attempt or suicidal ideation, dementia, Parkinson s disease, TIA, and stroke. c This group consisted of the drugs mirtazapine, bupropion, reboxetine, and trazodone. 15

16 Electronic supplementary material 7. Odds ratios for seizures in users of different antidepressant drug classes compared to non-users of antidepressants, by current or past use, and by switching of antidepressants during follow-up, compared to non-users of antidepressants Antidepressant drug class No. Cases (n=619) (%) a No. Controls (n=2,476) (%) a OR crude 95% CI OR adj. b 95% CI No use 34 (5.5) 228 (9.2) 1 reference 1 reference Analyses restricted to patients who did not switch antidepressants SSRIs Current use (last presc. 90 days ago) 150 (24.2) 396 (16.0) Past use (last presc. >90 days ago) 148 (23.9) 800 (32.3) SNRIs Current use (last presc. 90 days ago) 6 (1.0) 16 (0.7) Past use (last presc. >90 days ago) X 26 (1.1) NA NA NA NA TCAs Current use (last presc. 90 days ago) 15 (2.4) 63 (2.5) Past use (last presc. >90 days ago) 27 (4.4) 157 (6.3) Other antidepressants c Current use (last presc. 90 days ago) 9 (1.5) 13 (0.5) Past use (last presc. >90 days ago) X 18 (0.7) NA NA NA NA Analyses restricted to patients who switched antidepressants SSRIs Current use (last presc. 90 days ago) 93 (15.0) 233 (9.4) Past use (last presc. >90 days ago) 123 (19.9) 490 (19.8) SNRIs Current use (last presc. 90 days ago) 25 (4.0) 48 (1.9) Past use (last presc. >90 days ago) 34 (5.5) 96 (3.9) TCAs Current use (last presc. 90 days ago) 20 (3.2) 84 (3.4) Past use (last presc. >90 days ago) 82 (13.3) 276 (11.2) Other antidepressants c Current use (last presc. 90 days ago) 25 (4.0) 38 (1.5) Past use (last presc. >90 days ago) 31 (5.0) 108 (4.4) Abbreviations: OR, odds ratio; CI, confidence interval; adj., adjusted; NA, not applicable; presc., prescription; SSRIs, selective serotonin reuptake inhibitors; SNRIs, serotonin-norepinephrine reuptake inhibitors; TCAs, tricyclic antidepressants; X, cell contains <5 observations (due to ethics regulations to preserve confidentiality, the exact count is not displayed). a Cases and controls could be users of more than one antidepressant group and thus be listed more than once in the table (thus percentages do not total 100%). b Adjusted for alcohol consumption, other antidepressant drug classes, benzodiazepines, antipsychotics, opioids, schizophrenia, affective disorders other than depression, compulsive disorders, suicide attempt or suicidal ideation, dementia, Parkinson s disease, TIA, and stroke. 16

17 c This group consisted of the drugs mirtazapine, bupropion, reboxetine, and trazodone. 17