2.1 Ethics approval
The study protocol was approved by the Hospital Authority of Hong Kong ethics committee KC/KE-19-0001/ER-2.
This study aimed to characterize the association of taking antidepressants with the risk of being diagnosed with dementia, in people aged 65 years and over.
2.3 Data source
Access to comprehensive territory-wide deidentified electronic inpatient health records was provided by the Hospital Authority of Hong Kong (HKHA), a statutory body that manages all Hong Kong public hospitals and their ambulatory clinics. The HKHA services are available to all Hong Kong residents (>7.3 million), reflecting approximately 80% of all hospital admissions.15 The HKHA collects and collates public-sector inpatient, outpatient, and emergency department admissions records. The HKHA electronic health records have been validated, and previously used for investigations of medication safety.16–21 The patient-level data includes diagnosis, prescription, information on hospital admissions and discharges, payment method, and prescription and dispensing information.
2.4 Observation periods
For this study, the observation periods began on January 1, 2008, or the 65th birthday of the patient (whichever was later) and ended on December 31, 2010, or date of registered death (whichever was earlier) (a three year study period). We also imposed a five-year pre-study window as a historical period for index dementia diagnosis.
2.5 Selection criteria
2.5.1 Inclusion criteria
Eligible participants were aged 65 years or older with a first-ever (index) diagnosis of dementia, which occurred any time during the three-year study period. Dementia diagnoses were identified by the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes of Alzheimer disease (331.0), frontotemporal dementia (331.1), dementia with Lewy bodies (331.82), mild cognitive impairment (331.83),vascular dementia (290.4x), and other/nonspecific dementia (290.0, 290.1x, 290.2x, 290.3, 294.1, 294.2x, and 294.8). This method of identifying people with dementia is consistent with previous studies.22,23 We further included ICD-9-CM codes 296.x, 296.90, 300.4, 309.0, 309.28 and 311 as depression-related disorders24 for the post-hoc analysis (Refer to Table S1 for detailed names).
Because of the concerns that repeat coding of the index dementia diagnosis might be found within the database, we considered only those potentially-eligible people with no dementia diagnosis in their historical electronic medical records (five years before study entry). This assumed that the index dementia event was correctly identified as occurring during the study period. Subsequent dementia diagnoses (if any) were excluded from the analysis.
Potentially eligible participants also required at least one antidepressant medicine to be prescribed during the study period. Antidepressants were identified using British National Formulary (BNF) codes 4.3.x, specifically, tricyclic and related antidepressant drugs (4.3.1), monoamine-oxidase inhibitors (4.3.2), selective serotonin re-uptake inhibitors (4.3.3), and other antidepressant drugs (4.3.4). Refer to supplementary Table S2 for detailed drug names and their distributions within the database.
2.5.2 Exclusion criteria
Potential subjects were excluded if (a) their antidepressant drug-exposure was shorter than seven days (to eliminate the impact of potentially-ineffective exposures) and/or (b) the washout period and subsequent exposure to antidepressants overlapped (thus violating model assumptions).25
2.6 Study design
A Self-Controlled Case Series (SCCS) design was used.25 This design relies on within-person comparisons in a population of individuals who have experienced both the outcome and exposure of interest. A major advantage of this design over classic case-control and cohort study designs is that it allows for controlling for potential effects of measured and unmeasured time-invariant confounders that vary between individuals, such as underlying health status, genetic factors, hospital location, underlying frailty, socio-economic status, etc. Using this design also enabled us to adjust for time-varying factors, such as age, which is a known associate of the onset of dementia.2
2.6.1 Measurement periods and event date
The default baseline period, and four measurement periods were defined. Firstly, the drug-exposed period was defined as time receiving antidepressants, with the duration between prescription start and end dates recorded within the database for each prescription episode. Drug-exposed period was further classified as index drug-exposed period and subsequent drug-exposed period. The index drug-exposed period was defined as the first time subjects received antidepressant medication. There were two other measurement periods: pre-exposure period (50 days prior to index antidepressant prescription) and post-exposure period (washout period). The pre-exposure and post-exposure periods enabled comparison of dementia rates prior to, and after, index antidepressant episode. The washout period was applied after index drug-exposure ceased, as drugs generally require time to be excreted from body systems. We applied a washout period only after the index antidepressant administration, because subsequent washout periods (if any) might be influenced by previous drug administrations. All remaining time within the observation period constituted the baseline period, to which the measurement periods were compared. Each participant at baseline was allocated a (default) risk of dementia (risk=1).
It was possible that (presumed) continuous drug-exposed periods might have been interrupted for a range of reasons.17,26 We designed an algorithm (see pseudo-codes in the supplementary information) to obtain continuous treatment periods. We set the lengths of pre-exposure period and washout period to an arbitrary 50 days, and relevant sensitivity analyses were performed to examine the effects of the settings of the lengths of pre-exposure period and washout period. The study design and data capture periods are outlined in Figure 1.
The date of first lifetime dementia diagnosis in the HKHA Electronic Health Record (EHR) was defined as the event date. Only the first recorded dementia event for each patient during the study period was included in the analysis.
2.7.1 Main analysis
The association between antidepressant treatment and dementia diagnosis was calculated by comparing the rate of dementia diagnosed during the four measurement periods, with that during the baseline period. Specifically, the crude incidence rate per 1000 patient-days (CIR) (unadjusted by age) was calculated by dividing the number of events by the patient-days for each period.16 The age-adjusted Incident Rate Ratio (IRR) was calculated in the standard SCCS analysis by modeling dementia diagnoses within individuals as a non-homogeneous, age-dependent Poisson process and contrasting incident rates within the same individual’s person-time,25 using age in 365-day bands.
In addition to standard SCCS analysis, the nonparametric spline-based SCCS approach was applied to investigate risk changes during the observation period.27
A significance level of 5% was applied in all statistical analyses. Python (version 3.6) and R (version 3.3.2) were used for data processing and analysis. Relevant codes are publically available (https://github.com/zhongzhixu/SCCS).
2.7.2 Sensitivity analyses
Sensitivity analyses were conducted for: (a) the length of the washout period; (b) the length of the pre-exposure period; (c) the exclusion of individuals who died during the study period; (d) the exclusion of individuals whose drug duration was less than 30 days; (e) age-adjustment using 200-day age bands and 500-day age bands; and (f) the association of dementia and sub-categories of antidepressant drugs (i.e. BNF 4.3.1-4.3.4).
2.7.3 Post-hoc analysis
Post-hoc analysis was conducted to investigate whether depression-related disorders may confound the case-control study designs and cohort study designs, using the whole population within the database, to test prevalence among different subsets.