Variation in the Risk of Suicide Attempts and Completed Suicides by Antidepressant Agent in Adults

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1 WEB-ONLY CONTENT Variation in the Risk of Suicide Attempts and Completed Suicides by Antidepressant Agent in Adults A Propensity Score Adjusted Analysis of 9 Years Data Sebastian Schneeweiss, MD, ScD; Amanda R. Patrick, MS; Daniel H. Solomon, MD, MPH; Jyotsna Mehta, MS; Colin Dormuth, MA, MS, ScD; Matthew Miller, MD, ScD; Jennifer C. Lee, BS; Philip S. Wang, MD, DrPH Arch Gen Psychiatry. 2010;67(5): etable 1. Inclusion Criteria Definitions for Depression a Code Depressive Illness Organic affective syndrome, depressive type 296.2x Major depressive episode, single episode 296.3x Major depressive disorder, recurrent episode Unspecified affective psychosis (eg, melancholia not otherwise specified) 298.0x Depressive-type psychoses 300.4x Neurotic depression 309.0x Brief depressive reaction 309.1x Prolonged depressive reaction Adjustment reaction with anxiety and depression 311 Depressive disorder not elsewhere classified a The codes are from the International Classification of Diseases, Ninth Revision. 24 E1

2 etable 2. Baseline Covariates and Definitions a Demographic Definition Nonpsychiatric Condition Myocardial infarction Inpatient stay with 410.xx as any diagnosis Atherosclerotic disease 440 atherosclerosis; 445 atheroembolism; cerebral atherosclerosis Breast cancer Hospital diagnosis of 174.xx, Chronic lung disease 491.xx chronic bronchitis; 492.x emphysema; 493.xx asthma; 494.x bronchiectasis; 495.xx extrinsic allergic alveolitis; 496 chronic airway obstruction not mentioned elsewhere Diabetes Diagnosis of 250.xx diabetes; polyneuropathy in diabetes; diabetic retinopathy; or diabetic macular edema; plus 1 prescription for any of the following: insulin, acarbose, miglitol, metformin hydrochloride, acetohexamide, chlorpropamide, glimepiride, glipizide, glyburide, repaglinide, tolazamide, tolbutamide, pioglitazone hydrochloride, rosiglitazone maleate, troglitazone, and nateglinide Dyslipidemia 272.xx Gastrointestinal hemorrhage 578.x gastrointestinal hemorrhage; 531.0, 531.2, 531.4, gastric ulcer with hemorrhage; 532.0, 532.2, 532.4, duodenal ulcer with hemorrhage; 533.0, 533.2, 533.4, peptic ulcer with hemorrhage; 534.0, 534.2, 534.4, gastrojejunal ulcer with hemorrhage Glaucoma 365.xx Gout 274.xx Heart failure 428.xx, , , , , , , , , , Ventricular arrhythmia 427.4x, , , 427.5x, 427.1x, Other arrhythmia 427.xx or 426.xx except for 427.4x, , , 427.5x, 427.1x, Congenital heart diseases 745.xx, 746.xx Other congenital anomalies 747.xx of circulatory system Cardiomyopathy 425.xx Rheumatic heart diseases 393.xx-398.xx except for Hypertensive heart and kidney diseases 402.xx-404.xx except for , , , , , , , , Nonrheumatic valve 424.xx Endocarditis, pericarditis, and myocarditis 420.xx, 421.xx, 422.xx Rheumatic fever 390.xx, 391.xx, 392.xx Essential hypertension 401.xx or use of thiazide Secondary hypertension 405.xx Hypothyroidism 243, 244.x Injury other than poisoning 800.xx-959.xx Lung cancer Hospital diagnosis of 162.xx, Osteoarthritis 715.xx Other malignant neoplasm Hospital diagnosis of 140.xx-208.xx excluding lung cancer, breast cancer, prostate cancer, and colorectal cancer codes Other coronary heart disease 411.xx-414.xx Pain requiring high-potency opiates Use of diacetylmorphine hydrochloride, fentanyl citrate, hydromorphone hydrochloride, hydroxyephedrine/ normethadone, meperidine hydrochloride, methadone hydrochloride, morphine sulfate Pain requiring midpotency opiates Use of codeine, hydrocodone bitartrate, oxycodone hydrochloride, pseudoephedrine hydrochloride, drocodone, propoxyphene hydrochloride Parkinson disease 332.0, 332.1, Peptic ulcer disease and related conditions (without hemorrhage) 531.1, 531.3, 531.5, 531.7, gastric ulcer without hemorrhage; 532.1, 532.3, 532.5, 532.7, duodenal ulcer without hemorrhage; 533.1, 533.3, 533.5, 533.7, peptic ulcer without hemorrhage; 534.1, 534.3, 534.5, 534.7, gastrojejunal ulcer without hemorrhage Pneumonia 480.x, 481, 482.xx, 483.x, 484.x, 485, 486 Poisoning or drug toxic effects 960.xx-979.xx poisoning by medicinal and biological substances; 980.xx-989.xx toxic effects of substances chiefly nonmedical as to source Prostate cancer Hospital diagnosis of 185.xx, Colorectal cancer Hospital diagnosis of 153.xx, 230.3x, 154.xx (except 154.2, 154.3, and 154.4), Rheumatoid arthritis 714.x plus disease-modifying antirheumatic drug or steroid use Seizure disorder 345 epilepsy; 345.xx epilepsy; 780.3x convulsion Sepsis 0.38.xx septicemia; systemic inflammatory response syndrome due to infectious process without organ dysfunction Stroke or transient ischemic attack Inpatient diagnosis of 433.x1 occlusion and stenosis of precerebral arteries with infarction; 434.x1 occlusionof cerebral arteries with infarction; 435.x transient cerebral ischemia; 436 acute but ill-defined cerebrovascular disease; 437.1x other generalized ischemic cerebrovascular disease; 437.9x unspecified cerebrovascular disease; 438.x late effects of cerebrovascular disease Urinary incontinence 788.3x (continued) E2

3 etable 2. Baseline Covariates and Definitions (continued) a Demographic Depression c Anxiety or sleep disorder Anxiety disorder Sleep disorder Mania Manic-depressive illness Attention-deficit/hyperactivity disorder Substance abuse Alcohol abuse or dependence Drug abuse or dependence Psychiatric Disorders b Definition 300.0x anxiety states; 300.2x phobic disorders; 300.3x obsessive-compulsive disorders 307.4x specific disorders of sleep of nonorganic origin; 347 cataplexy and narcolepsy; 347.xx cataplexy and narcolepsy; 780.5x sleep disturbances 296.0x manic disorder, single episode; 296.1x manic disorder, recurrent episode; 296.4x bipolar affective disorder, manic; 296.5x bipolar affective disorder, depressed; 296.6x bipolar affective disorder, mixed; 296.7x bipolar affective disorder, unspecified; 296.8x bipolar affective disorder, other and unspecified; other specified affective psychoses (eg, mood swings) 312.xx; 314.xx 291 alcoholic psychoses; 291.0x alcohol withdrawal delirium; 291.1x alcohol amnestic syndrome; 291.2x other alcoholic dementia; 291.3x alcohol withdrawal hallucinosis; 291.4x idiosyncratic alcohol intoxication; 291.5x alcoholic jealousy; 291.8x other specified alcoholic psychosis; 291.9x unspecified alcoholic psychosis; 303 alcohol dependence syndrome; 303.xx alcohol dependence syndrome; 305.0x alcohol abuse 292 drug psychoses; 292.0x drug withdrawal syndrome; 292.1x paranoid and/or hallucinatory state induced by drugs; 292.2x pathological drug intoxication; 292.8x other specified drug-induced mental disorders; 292.9x unspecified drug-induced mental disorder; 304 drug dependence; 304.xx drug dependence; 305.2x-305.9x nondependent abuse of drugs Psychotic disorder 290.8x other specified senile psychotic conditions; 290.9x unspecified senile psychotic condition; 295 schizophrenic disorders; 295.xx schizophrenia; 297 paranoid states; 297.xx paranoid states; 298 other nonorganic psychoses; 298.1x-298.9x other nonorganic psychoses; 299 psychoses with origin specific to childhood; 299.xx psychoses with origin specific to childhood; 780.1x hallucinations Dementia ICD-9 code of 290.0x senile dementia; 290.1x presenile dementia; 290.2x senile dementia with delusional or depressive features; 290.3x senile dementia with delirium; 290.4x arteriosclerotic dementia; 291.1x alcoholic amnestic syndrome; 291.2x other alcoholic dementia; drug-induced dementia; 294 other organic psychotic conditions (chronic); 294.0x amnestic syndrome (nonalcoholic Korsakoff psychosis or syndrome); 294.1x dementia in conditions classified elsewhere; 294.8x other specified organic brain syndromes (chronic); 294.9x unspecified organic brain syndrome (chronic); 330 cerebral degenerations usually manifested in childhood; 330.xx cerebral degenerations usually manifested in childhood; 331.0x Alzheimer disease; 331.1x Pick disease; 331.2x senile degeneration of brain; 331.7x cerebral degeneration in diseases classified elsewhere; 331.8x other cerebral degeneration; 331.9x cerebral degeneration, unspecified Other psychiatric disorder Delirium Personality disorders Other mental disorders Electroconvulsive therapy Concurrent lithium use Concurrent use of anticonvulsants or bipolar disorder medications presenile dementia with delirium; 290.3x senile dementia with delirium; arteriosclerotic dementia with delirium; 291.0x alcoholic delirium; drug-induced delirium; 293 transient organic psychotic conditions; 293.0x acute delirium; 293.1x subacute delirium; 293.8x other specified transient organic mental disorder; 293.9x unspecified transient organic mental disorder; 348.3x encephalopathy, unspecified; toxic encephalopathy 301 personality disorders; 301.xx personality disorders 300.1x hysteria; 300.5x-300.9x other neurotic disorder; 302 sexual deviations and disorders; 302.xx sexual deviations and disorders; 306 physiological malfunction arising from mental factors; 306.xx physiological malfunction arising from mental factors; 307.0x-307.3x special symptoms or syndromes not elsewhere classified; 307.5x-307.9x special symptoms or syndromes not elsewhere classified; 308 acute reaction to stress; 308.xx acute reaction to stress; 309.2x-309.9x adjustment reaction with disturbance other than depressed mood; 310 specific nonpsychotic mental disorders due to organic brain damage; 310.xx specific nonpsychotic mental disorders due to organic brain damage; 313 disturbance of emotions specific to childhood or adolescence; 313.xx disturbance of emotions specific to childhood or adolescence; 315 specific delays in development; 315.xx specific delays in development; 316 psychic factors associated with diseases classified elsewhere; 316.xx psychic factors associated with diseases classified elsewhere Psychiatric Treatment Physician billing code for electroconvulsive therapy in 6 months prior to treatment initiation Prescription for lithium during the 6 months prior to antidepressant initiation with adequate days supply to cover the antidepressant initiation date Prescription for valproate sodium/divalproex sodium, carbamazepine, lamotrigine, olanzapine, quetiapine fumarate, aripiprazole, ziprasidone hydrochloride, or risperidone during the 6 months prior to antidepressant initiation with adequate days supply to cover the antidepressant initiation date Abbreviation: ICD-9, International Classification of Diseases, Ninth Revision. 24 a The codes are from the ICD b Defined as having 1 or more hospitalizations with the condition recorded or 2 or more physician claims with the condition recorded. c Because all patients have qualified via one of these codes, this variable does not act as a confounder but is listed here only for completeness. 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4 etable 3. Event Hazard Ratios for Composite and Violent Composite Outcomes During 6-Month Follow-up Comparing Other Selective Serotonin Reuptake Inhibitors vs Fluoxetine and Comparing Other Antidepressant Classes vs Selective Serotonin Reuptake Inhibitors a HR (95% CI) Composite Outcome Violent Suicide Completed Suicide Adjusted for Age, Sex, and Calendar Year Adjusted for Propensity Score Decile c Adjusted for Propensity Score Decile c Adjusted for Propensity Score Decile c Antidepressant b Unadjusted All Adults Citalopram 0.62 ( ) 0.92 ( ) 0.69 ( ) 0.25 ( ) 0.78 ( ) Fluvoxamine 1.26 ( ) 1.33 ( ) 1.09 ( ) 0.99 ( ) 0.78 ( ) Paroxetine 0.95 ( ) 1.12 ( ) 0.94 ( ) 0.62 ( ) 0.48 ( ) Sertraline 0.72 ( ) 0.83 ( ) 0.69 ( ) 0.48 ( ) 0.63 ( ) Class SNRIs 1.09 ( ) 1.18 ( ) 1.20 ( ) 0.81 ( ) 0.68 ( ) MAOIs 0.71 ( ) 0.62 ( ) 0.63 ( ) No events No events Other newer and atypical agents 0.90 ( ) 0.93 ( ) 0.91 ( ) 0.93 ( ) 1.03 ( ) TCAs 0.96 ( ) 1.04 ( ) 1.05 ( ) 0.48 ( ) 0.34 ( ) Treatment-Naive Adults d Citalopram 0.78 ( ) 0.95 ( ) 0.97 ( ) 0.26 ( ) 0.53 ( ) Fluvoxamine 1.12 ( ) 1.25 ( ) 1.01 ( ) 0.63 ( ) 0.66 ( ) Paroxetine 1.02 ( ) 1.11 ( ) 1.01 ( ) 0.52 ( ) 0.63 ( ) Sertraline 0.83 ( ) 0.95 ( ) 0.77 ( ) 0.32 ( ) 0.62 ( ) Class SNRIs 1.13 ( ) 1.14 ( ) 1.17 ( ) 0.61 ( ) 0.53 ( ) MAOIs 1.02 ( ) 1.12 ( ) 1.05 ( ) No events No events Other newer and atypical agents 0.91 ( ) 0.97 ( ) 0.98 ( ) 0.93 ( ) 1.04 ( ) TCAs 1.10 ( ) 1.26 ( ) 1.31 ( ) 0.47 ( ) 0.33 ( ) Adults With No Prior Suicide Attempt Citalopram 0.63 ( ) 0.91 ( ) 0.76 ( ) 0.25 ( ) 0.41 ( ) Fluvoxamine 1.29 ( ) 1.36 ( ) 1.14 ( ) 0.99 ( ) 0.78 ( ) Paroxetine 0.93 ( ) 1.08 ( ) 0.92 ( ) 0.52 ( ) 0.39 ( ) Sertraline 0.75 ( ) 0.87 ( ) 0.72 ( ) 0.48 ( ) 0.63 ( ) Class SNRIs 1.10 ( ) 1.18 ( ) 1.21 ( ) 0.82 ( ) 0.75 ( ) MAOIs 0.74 ( ) 0.65 ( ) 0.67 ( ) No events No events Other newer and atypical agents 0.91 ( ) 0.95 ( ) 0.92 ( ) 0.98 ( ) 1.11 ( ) TCAs 1.00 ( ) 1.08 ( ) 1.09 ( ) 0.50 ( ) 0.36 ( ) Abbreviations: CI, confidence interval; HR, hazard ratio; MAOIs, monoamine oxidase inhibitors; SNRIs, serotonin-norepinephrine reuptake inhibitors;, selective serotonin reuptake inhibitors; TCAs, tricyclic agents. a Outcomes indicate attempted and completed suicide. The reference group for the SSRI comparisons is fluoxetine hydrochloride (Prozac); the reference group for the antidepressant drug class comparisons is. The MAOIs were not investigated owing to the small numbers of exposed subjects. b Citalopram indicates citalopram hydrobromide (Celexa); fluvoxamine, fluvoxamine maleate (Luvox); paroxetine, paroxetine hydrochloride (Paxil); sertraline, sertraline hydrochloride (Zoloft); and SNRIs, venlafaxine hydrochloride. c The propensity score includes demographic, psychiatric, and general clinical covariates listed in etable 2. d No antidepressant use in the past 3 years. E4

5 Composite Event-Free Probability DComposite Event-Free Probability CComposite Event-Free Probability BComposite Event-Free Probability A Citalopram hydrobromide Fluvoxamine maleate Paroxetine hydrochloride Sertraline hydrochloride efigure 1. Attempted suicide free and completed suicide free survival in pairwise comparisons of selective serotonin reuptake inhibitors citalopram hydrobromide (A), fluvoxamine maleate (B), paroxetine hydrochloride (C), and sertraline hydrochloride (D) with fluoxetine hydrochloride, multivariate adjusted by the inverse probability of treatment. E5

6 AComposite Event-Free Probability BComposite Event-Free Probability CComposite Event-Free Probability MAOIs Other newer and atypical agents TCAs efigure 2. Attempted suicide free and completed suicide free survival in pairwise comparisons of monoamine oxidase inhibitors (MAOIs) (A), other newer and atypical agents (B), and tricyclic agents (TCAs) (C) with selective serotonin reuptake inhibitors (), multivariate adjusted by the inverse probability of treatment. E6