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1 Supplementary Online Content Tiihonen J, Mittendorfer-Rutz E, Majak M, et al. Real-world effectiveness of antipsychotic treatments in a nationwide cohort of patients. JAMA Psychiatry. Published online June 7, doi: /jamapsychiatry eappendix. Methods etable 1. Covariate Definitions etable 2. The Clinical and Sociodemographic Characteristics of Prevalent and Incident Cohorts at the Cohort Entry etable 3. The Number of Users and Mean Daily Doses of All Long-Acting Antipsychotics (LAIs) and the Most Commonly Used Oral Antipsychotics etable 4. The Effect of Temporal Order of Antipsychotics for Risk of Psychiatric Rehospitalization etable 5. The Rates of Treatment Failure (Psychiatric Hospitalization, Discontinuation or Switch of Antipsychotic, or Death) During Monotherapy of Specific Antipsychotics Among Prevalent and Incident Population etable 6. The Risk of Psychiatric Rehospitalization During Any Specific Treatments Among Prevalent Population etable 7. The Risk of Treatment Failure During Any Specific Treatments Among Prevalent Population etable 8. The Number of Patients Using Combinations of Two Antipsychotics efigure 1. Restructuring of Data for Within-Individual Analyses (With Time Resetting After Each Outcome Event) efigure 2. The Adjusted Hazard Ratios and 95% CIs for Psychiatric Rehospitalization During Monotherapy Compared With no Use of Antipsychotic in Within-Individual Analyses in the Prevalent Population, With Adjustment for Concomitant Use of Antidepressants and Benzodiazepines efigure 3. The Adjusted Hazard Ratios and 95% CIs for Treatment Failure During Each Monotherapy Compared With Oral Olanzapine Use, With Adjustment for Concomitant Use of Antidepressants and Benzodiazepines efigure 4. A Secondary Head-to-Head Analysis on Treatment Failure in Monotherapy Including Only Those Patients Who Had Used Oral Olanzapine (N = 11,730) During the Follow-Up in the Prevalent Population (Adjusted HRs) efigure 5. The Adjusted Results From Within-Individual Analysis for Psychiatric Rehospitalization During Any Specific Treatment in the Prevalent Population (Including Both Monotherapy and Polytherapy) efigure 6. The Adjusted Results From Within-Individual Analyses for Treatment Failure During Any Specific Treatment Among Prevalent Population (Including Both Monotherapy and Polytherapy) efigure 7. Correlation of Adjusted Hazard Ratios (HRs) in Within-Individual Analyses of Psychiatric Rehospitalization in Any Therapy (x-axis) Versus Monotherapy (y-axis) Models Compared With no Use efigure 8. Adjusted Risk of All-Cause In- or Outpatient Visit in Within-Individual Analyses During Monotherapy Compared With no Use of Antipsychotics Among Prevalent Population efigure 9. The Adjusted Risk of Psychiatric Rehospitalization During Antipsychotic Monotherapy Compared With no Use in Between-Individual Comparisons in Prevalent Cohort efigure 10. The Adjusted Risk of Treatment Failure in Antipsychotic Monotherapy Compared With Oral Olanzapine Use in Between-Individual Comparisons in Prevalent Cohort efigure 11. The Adjusted Risk of Psychiatric Rehospitalization in Antipsychotic Monotherapy Compared With no Use Among the Incident Cohort in Within-Individual Comparisons efigure 12. The Adjusted Risk of Treatment Failure in Antipsychotic Monotherapy Compared With Oral Olanzapine Among the Incident Cohort in Within-Individual Comparisons ereferences. This supplementary material has been provided by the authors to give readers additional information about their work.

2 eappendix. Methods Study population Unique personal identification numbers enable the linking of various health care registers with other types of data sources, allowing the creation of longitudinal cohorts. Persons with a diagnosis of schizophrenia were identified based on four register sources: inpatient care from the National Patient Register (maintained by the National Board of Health and Welfare) since 1988, specialized outpatient care from the National Patient Register (PR) since 2001, disability pension from the MiDAS register (maintained by the Social Insurance Agency of Sweden) since 1994, and sickness absence data from the MIDAS register since Drug use data was gathered from the Prescribed Drug Register (maintained by the National Board of Health and Welfare) since July Dates of death were obtained from the Causes of Death Register (maintained by the National Board of Health and Welfare), and demographic characteristics for the cohort were obtained from the LISA register (maintained by Statistics Sweden). All working aged persons are included in all registers and linkable with personal identification numbers. The source population for this study consisted of all persons with a diagnosis of schizophrenia, schizotypal and delusional disorders [(F20-F29) (according to the International Classification of Diseases version 10 (ICD-10) classification)]. The inclusion criteria for this study was diagnosis of schizophrenia (F20 or F25) as main diagnoses in the registers on inpatient, specialized outpatient, sickness absence or disability pension for residents in Sweden during July 1, 2006 until December 31, The number of persons fulfilling the inclusion criteria was 33,940 (Figure 1). Individuals were excluded from the cohort if they were aged less than 16 at cohort entry or over age 64 at Persons entered the cohort when the first diagnosis was recorded in any of the four databases. After applying the age criteria, 4,117 persons were excluded, resulting in 29,823 persons included in the prevalent study population. Further exclusion criteria were utilized to identify persons with newly diagnosed disease within the prevalent population. The incident cohort (N = 4,603) was formed by excluding persons with a previous main or contributory diagnosis of F20-29 (ICD-10) or 295 (ICD-9) before July 1, 2006 in the four databases, or those who were using antipsychotics between July 1, 2005 and July 1, 2006 according to the Prescribed Drug Register (N=25,220). The cohort entry date was defined as the first diagnosis fulfilling the inclusion criteria, and the follow-up time was through December 31, 2013.

3 Patient involvement No patients were involved in setting the research question or the outcome measures, nor were they involved in developing plans for design or implementation of the study. No patients were asked to advise on interpretation or writing up of results. There are plans to disseminate the results of the research to study participants and the relevant patient community. Exposure Drug use was modelled using the PRE2DUP method. 1 The method is based on mathematical modelling of drug purchasing behavior for each person and for each drug substance (ATC code). The sliding averages of daily dose are calculated from the dispensing data and restricted with parameters defining the minimum and maximum daily dose for each drug package (Nordic product number, vnr). The method takes into account the stockpiling of drugs, dose changes, and periods of hospital care when drugs are provided by the caring unit but not recorded in the register. For the modelling of antipsychotics, each drug substance was coded according to drug formulation as oral or LAI, and drug use periods were constructed separately for oral and LAI use. The PRE2DUP method has been validated in both expert-opinion based validation 1 and also by comparing it with interview-based medication use data. 2 The method has been utilized in previous studies on antipsychotics and safety endpoints. 3,4,5

4 etable 1. Covariate Definitions Variable Definition Models utilizing the variable Order of treatments Order of treatment continuously updated in the WI, TC models, categorized as no treatment, 1st, 2nd, 3rd, >3 rd Time since cohort entry Time since cohort entry continuously updated in WI the models, categorized as 0-1, 1-3, >3 years Antipsychotic polypharmacy Concomitant use of two or more antipsychotics WI, TC (yes/ no), only in models not analyzing specifically polypharmacy but adjusting for it Age Age at cohort entry, categorized as 16-24, 25-34, TC 35-44, 45-54, 55-64, 65 Gender Male or female TC Year of cohort entry Categorized as , , TC 2013 Time since diagnosis at cohort Categorized as 0-1, 1-3, >3 years TC entry Number of previous Continuously updated in the models, categorized TC psychiatric inpatient visits as 0, 1, >1 Non-adherence Defined at the cohort entry: TC Prevalent patients excluding incident cases: No on-going antipsychotic treatment within 4 months prior to the first inpatient hospitalization during the study period. Incident patient: no filled antipsychotic prescription within one month after the first schizophrenia (ICD-10 codes: F20 or F25) inpatient hospitalization during the study period. Exposure to other medications Continuously updated variables, each having WI, TC status never until the first purchase of a specific drug occurred. After the first purchase, exposure was current use if prior purchases determined that exposure was still on-going and past use otherwise (prior purchases too far away in the past). Corresponding ATC codes listed below. Antidepressants N06AA, N06AB, N06AC, N06AD, N06AE, N06AF, WI, TC N06AG, N06AX Benzodiazepines and N05BA 01-22, N05CD, N05CF, N03AE01 WI, TC related drugs Analgesics N02A, N02B, N02C, M01A TC Anti-parkinsonian N04AA, N04AB, N04AC TC drugs/anticholinergics Lipid-modifying agents C10AA, AB, AC, AD, AX, C10BA01, C10BA02, C10BA03, C10BA06, C1BX01-05 TC

5 Antidiabetic drugs Drugs used to treat addictive disorders Substance abuse A10A, A10BA, BB, BC, BD, BF, BG, BH, BX, A10XA N07BB01, N07BB02, N07BB03, N07BB04, N07BB05, N07BC01, N07BC02, N07BC0, N07BC04, N07BC51 A continuously updated variable with status no until the first substance abuse indication occurred and yes thereafter. Corresponding ICD-10/ ATC codes listed below. Alcohol F10.1 / N07BB01-05 Cannabis F12.1 Drugs psychoactive F19.1 Drugs others F55 Cocaine F14.1 Drugs opioids F11.1 / N07BC01-04, N07BC51 Tobacco F17.1 Drugs anxiolytics F13.1 Drugs hallucinogens F16.1 Solvent F18.1 Education level Time-varying, yearly updated variable. TC Categorized as low (<9 years), medium (9-12 years), high (>12 years) or missing Family situation Time-varying, yearly updated variable. Patient is a TC child under 20 years of age living at home, married/ in a relationship living with children, married/in a relationship living without children, single without children, single with children or missing. Prior suicide attempt Continuously updated variable, defined as X60- TC X84 or Z91.5 Prior sickness absence due to Continuously updated variable, schizophrenia TC schizophrenia (F20, F25) as main diagnosis Prior disability pension due to Continuously updated variable, schizophrenia TC schizophrenia (F20, F25) as main diagnosis Prior use of LAI Continuously updated variable, yes vs. no? TC Recent switches in antipsychotic treatment Time-varying, continuously updated variable, whether person has 3 or more switches within the previous 3 months. TC= traditional Cox model, WI= within-individual Cox model, LAI = long-acting injection; ICD = International Classification of Diseases; ATC = Anatomical Therapeutic Chemical classification TC TC TC TC

6 etable 2. The Clinical and Sociodemographic Characteristics of Prevalent and Incident Cohorts at the Cohort Entry Age Prevalent cohort N=29,823 Incident cohort N=4,603 N (%) N (%) , , , , , , , Mean (min. max) 44.9 (16, 72) 36.5 (17, 69) Median (IQR) 46 (36 54) 34 (25 46) Female gender 12, , Median time since documented diagnosis (IQR) Education 3.8 ( ) 0.0 ( ) Low 9, , Medium 14, , High 5, , Missing Comorbidities Substance abuse Antidiabetic drug use (current) Lipid modifying drug use (current) Analgesic use (current) IQR indicates interquartile range.

7 etable 3. The Number of Users and Mean Daily Doses of All Long-Acting Antipsychotics (LAIs) and the Most Commonly Used Oral Antipsychotics Prevalent Incident N Median dose mg (IQR) N Median dose mg (IQR) DDD mg/day First generation LAIs Fluphenazine LAI ( ) ( ) 1.0 Flupentixol LAI ( ) ( ) 4.0 Haloperidol LAI 1, ( ) ( ) 3.3 Perphenazine LAI 3, ( ) ( ) 7.0 Zuclopenthixol LAI 4, ( ) ( ) 15.0 First generation orals Chlorprothixene ( ) ( ) 300 Flupentixol oral 1, ( ) ( ) 6.0 Haloperidol oral 3, ( ) ( ) 8.0 Levomepromazine oral 5, ( ) ( ) 300 Melperone ( ) ( ) 300 Perphenazine oral 2, ( ) ( ) 30.0 Zuclopenthixol oral 3, ( ) ( ) 30.0 Second generation LAIs Olanzapine LAI ( ) ( ) 10.0 Paliperidone LAI 1, ( ) ( ) 2.5 Risperidone LAI 3, ( ) ( ) 2.7 Second generation orals Aripiprazole oral 7, ( ) 1, ( ) 15.0 Clozapine oral 5, ( ) ( ) 300 Olanzapine oral 11, ( ) 1, ( ) 10.0 Paliperidone oral 1, ( ) ( ) 6.0 Quetiapine oral 6, ( ) 1, ( ) 400 Risperidone oral 7, ( ) 1, ( ) 5.0 Sertindole oral ( ) ( ) 16.0 Ziprasidone oral 1, ( ) ( ) 80.0 IQR indicates interquartile range. DDD indicates define daily dose by World Health Organization. Paliperidone LAI refers to once-monthly injection. (

8 etable 4. The Effect of Temporal Order of Antipsychotics for Risk of Psychiatric Rehospitalization HR p-value events PY IR Order of antipsychotics 0 reference reference ( , ) (0.87, 1.13) ( , ) (0.89, 1.17) ( , ) (0.87, 1.17) ( , ) > (0.80, 1.14) ( , ) Time (years) since CED 0 1 reference reference ( , ) (0.88, 0.95) < ( , ) > (0.82, 0.89) < ( , ) 0 indicates no antipsychotic used yet, 1 indicates the first antipsychotic exposure, and so on. PY indicates person years and IR indicates incidence rate.

9 etable 5. The Rates of Treatment Failure (Psychiatric Hospitalization, Discontinuation or Switch of Antipsychotic, or Death) During Monotherapy of Specific Antipsychotics Among Prevalent and Incident Population Prevalent Incident Person years Events Incidence rate/ 10 person years Person years Events Incidence rate/ 10 person years First generation LAIs Fluphenazine LAI ( ) 3 0 na Flupentixol LAI 1, ( ) ( ) Haloperidol LAI 2,656 1, ( ) ( ) Perphenazine LAI 4,937 3, ( ) ( ) Zuclopenthixol LAI 6,149 3, ( ) ( ) First generation orals Flupentixol oral 2, ( ) ( ) Haloperidol oral 3,334 1, ( ) ( ) Levomepromazine oral 1,120 1, ( ) ( ) Perphenazine oral 3,374 2, ( ) ( ) Zuclopenthixol oral 3,381 1, ( ) ( ) Second generation LAIs Olanzapine LAI ( ) ( ) Paliperidone LAI ( ) ( ) Risperidone LAI 4,359 2, ( ) ( ) Second generation orals Aripiprazole oral 5,661 4, ( ) ( ) Clozapine oral 14,198 3, ( ) ( ) Olanzapine oral 19,486 9, ( ) 1,665 1, ( ) Quetiapine oral 4,342 3, ( ) ( ) Risperidone oral 11,184 4, ( ) ( ) Other 2,889 1, ( ) ( ) Polytherapy 43,605 21, ( ) 2,107 1, ( ) Paliperidone LAI refers to once-monthly injection.

10 etable 6. The Risk of Psychiatric Rehospitalization During Any Specific Treatments Among Prevalent Population Person years Events Incidence rate/10 person years First generation LAIs Fluphenazine LAI ( ) Flupentixol LAI 2, ( ) Haloperidol LAI 5,088 1, ( ) Perphenazine LAI 8,788 3, ( ) Zuclopenthixol LAI 12,656 4, ( ) First generation orals Chlorprothixene ( ) Flupentixol oral 3, ( ) Haloperidol oral 7,931 2, ( ) Levomepromazine oral 14,818 5, ( ) Melperone ( ) Perphenazine oral 5,943 1, ( ) Zuclopenthixol oral 8,025 2, ( ) Second generation LAIs Olanzapine LAI ( ) Paliperidone LAI ( ) Risperidone LAI 7,640 2, ( ) Second generation orals Aripiprazole oral 14,971 5, ( ) Clozapine oral 23,736 6, ( ) Olanzapine oral 33,789 8, ( ) Paliperidone oral 1, ( ) Quetiapine oral 12,299 5, ( ) Risperidone oral 17,699 3, ( ) Sertindole oral ( ) Ziprasidone oral 3, ( )

11 Other treatment periods in addition to monotherapy are included in the analysis, compared with no use of that drug. Paliperidone LAI refers to once-monthly injection.

12 etable 7. The Risk of Treatment Failure During Any Specific Treatments Among Prevalent Population Person years Events Incidence rate/10 person years First generation LAIs Fluphenazine LAI ( ) Flupentixol LAI 2,640 1, ( ) Haloperidol LAI 5,088 2, ( ) Perphenazine LAI 8,788 5, ( ) Zuclopenthixol LAI 12,660 7, ( ) First generation orals Chlorprothixene ( ) Flupentixol oral 3,839 1, ( ) Haloperidol oral 7,931 3, ( ) Levomepromazine oral 14,818 7, ( ) Melperone ( ) Perphenazine oral 5,943 3, ( ) Zuclopenthixol oral 8,025 4, ( ) Second generation LAIs Olanzapine LAI ( ) Paliperidone LAI ( ) Risperidone LAI 7,640 4, ( ) Second generation orals Aripiprazole oral 14,971 9, ( ) Clozapine oral 23,736 8, ( ) Olanzapine oral 33,789 16, ( ) Paliperidone oral 1,283 1, ( ) Quetiapine oral 12,299 7, ( ) Risperidone oral 17,699 7, ( ) Sertindole oral ( ) Ziprasidone oral 3,383 1, ( ) Treatment periods in addition to monotherapy are included in the analysis, compared with no use of that drug. Paliperidone LAI refers to once-monthly injection.

13 etable 8. The Number of Patients Using Combinations of Two Antipsychotics _SO_ri _SO_ol _SO_p _SO_zi _SO_ar _SO_s _SO_q _SO_cl _SD_ri _SD_ol _SD_p _SD_a _FO_pe _FO_h _FO_fl _FO_zu _FO_levo _FO_m _FO_chl _FD_h _FD_fl _FD_pe _FD_fl _FD_zu sper anza aliperi pra ipi erti ueti ozap sper anza aliperi ripi rph alo upx clo mep elp orp alo uph rph upx clo total _SO_risper _SO_olanza _SO_paliperi _SO_zipra _SO_aripi _SO_serti _SO_queti _SO_clozap _SD_risper _SD_olanza _SD_paliperi _SD_aripi _FO_perph _FO_halo _FO_flupx _FO_zuclo _FO_levomep _FO_melp _FO_chlorp _FD_halo _FD_fluph _FD_perph _FD_flupx _FD_zuclo total FO indicates first generation oral, FD first generation long-acting injection (LAI), SO second generation oral, and SD second generation LAI. The most common combinations used were oral olanzapine plus oral aripiprazole (2191 patients) and oral olanzapine plus levomepromazine (1878 patients).

14 efigure 1. Restructuring of Data for Within-Individual Analyses (With Time Resetting After Each Outcome Event)

15 Illustration of data-analysis after time resetting by using each individual as his/her own control (continued) In the within-individual analyses stratified Cox model is used. Each individual forms his/her own stratum. Within each stratum, time periods from the same individual resulting after time resetting are used in comparisons as different individuals are compared in a traditional Cox model. The figure below illustrates how the likelihood contribution of one individual is calculated in the within-individual model. The full likelihood is a product over all individual contributions. The method is also illustrated in Supplement to: Lichtenstein P, Halldner L, Zetterqvist J, et al. Medication for attention deficit hyperactivity disorder and criminality. N Engl J Med 2012;367: DOI: /NEJMoa In this illustration it is assumed that at any given time t an individual may have either of two possible statuses (0 or 1), denoted X(t). The status is X(t) = 0 when the individual is not treated with any antipsychotic and X(t) = 1 when treated. The individual is also assumed to have his/her own baseline hazard that is proportional to exp(x(t)*b). In general, at the time of an event, the risk set consists of all ongoing sub-periods, i.e., of those that (after time resetting) began before the event and ended after it. The illustrated individual has two events from which his/her likelihood contribution arises. At the time of the first event (t = 100), the risk set consists also of (sub)period B. At the time of the second event (t = 170) there are no other ongoing sub-periods. Individual contributions of each of the two events are given in the figure and yield a total contribution of [1/(1 + exp(b))] x 1. Start of follow-up (t = 0) First outcome event at the end of period A (t=100) when treatment is not on: likelihood contribution exp(b x 0)/(exp(b x 0) + exp(b)) = 1/(1+exp(b)). Period B serves as a control with contribution exp(b) in the denominator. Antipsychotic treatment A: Period between the start of followup and the first outcome event Second outcome event at the end of period B (t=170) when treatment is on: likelihood contribution exp(b)/exp(b) = 1. None of the other periods serve as a control by contributing to the denominator. B: Period between the first and second outcome events End of followup 30 days after the second outcome event (t = 30) C: Period between the second outcome event and the end of follow-up t = 0 t = 30 t = 100 t = 170

16 efigure 2. The Adjusted Hazard Ratios and 95% CIs for Psychiatric Rehospitalization During Monotherapy Compared With no Use of Antipsychotic in Within-Individual Analyses in the Prevalent Population, With Adjustment for Concomitant Use of Antidepressants and Benzodiazepines Paliperidone LAI refers to once-monthly injection.

17 efigure 3. The Adjusted Hazard Ratios And 95% CIs for Treatment Failure During Each Monotherapy Compared With Oral Olanzapine Use, With Adjustment for Concomitant Use of Antidepressants and Benzodiazepines Paliperidone LAI refers to once-monthly injection.

18 efigure 4. A Secondary Head-to-Head Analysis on Treatment Failure in Monotherapy Including Only Those Patients Who Had Used Oral Olanzapine (N = 11,730) During the Follow-Up in the Prevalent Population (Adjusted HRs) Paliperidone LAI refers to once-monthly injection.

19 efigure 5. The Adjusted Results From Within-Individual Analysis for Psychiatric Rehospitalization During Any Specific Treatment in the Prevalent Population (Including Both Monotherapy and Polytherapy) Paliperidone LAI refers to once-monthly injection.

20 efigure 6. The Adjusted Results From Within-Individual Analyses for Treatment Failure During Any Specific Treatment Among Prevalent Population (Including Both Monotherapy and Polytherapy) Paliperidone LAI refers to once-monthly injection.

21 efigure 7. Correlation of Adjusted Hazard Ratios (HRs) in Within-Individual Analyses of Psychiatric Rehospitalization in Any Therapy (x-axis) Versus Monotherapy (y-axis) Models Compared With no Use Paliperidone LAI refers to once-monthly injection.

22 efigure 8. Adjusted Risk of All-Cause In- or Outpatient Visit in Within-Individual Analyses During Monotherapy Compared With no Use of Antipsychotics Among Prevalent Population Paliperidone LAI refers to once-monthly injection.

23 efigure 9. The Adjusted Risk of Psychiatric Rehospitalization During Antipsychotic Monotherapy Compared With no Use in Between-Individual Comparisons in Prevalent Cohort Paliperidone LAI refers to once-monthly injection.

24 efigure 10. The Adjusted Risk of Treatment Failure in Antipsychotic Monotherapy Compared With Oral Olanzapine Use in Between-Individual Comparisons in Prevalent Cohort Paliperidone LAI refers to once-monthly injection.

25 efigure 11. The Adjusted Risk of Psychiatric Rehospitalization in Antipsychotic Monotherapy Compared With no Use Among the Incident Cohort in Within-Individual Comparisons Paliperidone LAI refers to once-monthly injection.

26 efigure 12. The Adjusted Risk of Treatment Failure in Antipsychotic Monotherapy Compared With Oral Olanzapine Among the Incident Cohort in Within-Individual Comparisons Paliperidone LAI refers to once-monthly injection.

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