Olanzapine

Medication use was ascertained from GH computerized pharmacy dispensing data that included drug name, strength, route of administration, date dispensed, and amount dispensed for each drug. Anticholinergic use was defined as those medications deemed to have strong anticholinergic activity as per consensus by an expert panel of health care professionals.^{8 (link),13 (link)} Since we were drawing on medication data from as early as 1984 (e.g. extending back 10 years prior to study entry), it was necessary to enhance this contemporary list with medications no longer on the market. Therefore, two clinician/investigators (SLG, JTH) reviewed previously published standard pharmacology/pharmacotherapy reference books to identify additional anticholinergic medications.^{25 ,26} eTable 1 lists the strong anticholinergic medications according to medication class (e.g., first generation antihistamines, tertiary tricyclic antidepressants, bladder antimuscarinics).
To create our exposure measures, we first calculated the total medication dose for each prescription fill by multiplying the tablet strength by the number of tablets dispensed. This product was then converted to a standardized daily dose (SDD) by dividing by the minimum effective dose per day recommended for use in older adults according to a well-respected geriatric pharmacy reference (eTable 1).²⁷ For each participant, we summed the SDD for all anticholinergic pharmacy fills during the exposure period to create a cumulative total standardized daily dose (TSDD) (see example calculation in eFigure 1). This previously published method allows for standardized conversion of doses of different anticholinergic medications into a single exposure measure so that we are able to capture overall anticholinergic burden.^{28 (link),29 (link)}The primary measure of anticholinergic use was 10-year cumulative exposure (eFigure 2). Prescription fills in the most recent 1 year period were excluded because of concern about protopathic bias.^{30 (link)} Our exposure was time-varying; we assessed 10-year cumulative exposure at study entry and updated the exposure as participants were followed forward in time. We categorized cumulative exposure as no use, 1-90 days, 91-365 days, 366-1095 days, or >1095 days (i.e. >3 years), with cut-points based on clinical interpretability and the exposure distribution observed in our sample. As an example, a person would reach the heaviest level of exposure if they took any of the following medications daily for more than 3 years: oxybutynin 5 mg, chlorpheniramine 4 mg, olanzapine 2.5 mg, meclizine 25 mg or doxepin 10 mg.

We evaluated four different algorithms to identify delirium: 1) ICD diagnosis codes alone, 2) antipsychotics use alone, 3) either ICD diagnosis codes OR antipsychotics use, and 4) both ICD diagnosis codes AND antipsychotics use. For algorithms based on ICD diagnosis codes, delirium was considered present if any of the following 32 explicit (i.e., including the term “delirium”) or implicit ICD-9 diagnosis codes (e.g., “encephalopathy”) was used among the in-hospital discharge codes (see Supplementary Table S1).¹⁴ In claims data from October 1, 2015, the corresponding 52 ICD-10 diagnosis codes were used.¹⁴ For algorithms based on antipsychotics use, delirium was considered present if any antipsychotic drugs were used; in our study, we found that only haloperidol, olanzapine, and quetiapine had been prescribed. We did not examine other drugs that could influence the risk of delirium (e.g., benzodiazepine or dexmedetomidine).