Population‐Based Signals of Antidepressant Drug Interactions Associated With Unintentional Traumatic Injury

Abstract

Antidepressants are very widely used and associated with traumatic injury, yet little is known about their potential for harmful drug interactions. We aimed to identify potential drug interaction signals by assessing concomitant medications (precipitant drugs) taken with individual antidepressants (object drugs) that were associated with unintentional traumatic injury. We conducted pharmacoepidemiologic screening of 2000-2015 Optum Clinformatics data, identifying drug interaction signals by performing self-controlled case series studies for antidepressant + precipitant pairs and injury. We included persons aged 16-90 years codispensed an antidepressant and ≥ 1 precipitant drug(s), with an injury during antidepressant therapy. We classified antidepressant persondays as either precipitant-exposed or precipitant-unexposed. The outcome was an emergency department or inpatient discharge diagnosis for unintentional traumatic injury. We used conditional Poisson regression to calculate confounder adjusted rate ratios (RRs) and accounted for multiple estimation via semi-Bayes shrinkage. We identified 330,884 new users of antidepressants who experienced an injury. Among such persons, we studied concomitant use of 7,953 antidepressant + precipitant pairs. Two hundred fifty-six (3.2%) pairs were positively associated with injury and deemed potential drug interaction signals; 22 of these signals had adjusted RRs > 2.00. Adjusted RRs ranged from 1.06 (95% confidence interval: 1.00-1.12, P = 0.04) for citalopram + gabapentin to 3.06 (1.42-6.60) for nefazodone + levonorgestrel. Sixty-five (25.4%) signals are currently reported in a seminal drug interaction knowledgebase. We identified numerous new population-based signals of antidepressant drug interactions associated with unintentional traumatic injury. Future studies, intended to test hypotheses, should confirm or refute these potential interactions.

Antidepressant drug–drug–drug interactions associated with unintentional traumatic injury: Screening for signals in real‐world data

“…We also noticed that among the antidepressants screened, sertraline, citalopram, and escitalopram had the largest number and proportion of drug triads signaled for increased injury rates. This pattern aligns with the findings of our previous screening on pairwise drug–drug interactions (DDIs), in which sertraline, citalopram, and escitalopram were the three antidepressants with the most DDI signals for injury 10 . The reasons behind their higher number 3DI signals are unclear, as their pharmacokinetics are unlikely to differ from other antidepressants in a way that may contribute to more drug interactions.…”

“…Within each individual, the outcome rate during exposed person‐days was compared with unexposed person‐days, and an increased outcome rate signaled for potential 3DIs. This study design is well‐suited for 3DI screening as it controls for the effects of confounding variables that do not change over time, is highly computationally efficient, and has previously been used in high‐throughput pharmacoepidemiologic screening to identify drug interaction signals associated with injury 10,17–20 …”

“…This study design is well‐suited for 3DI screening as it controls for the effects of confounding variables that do not change over time, is highly computationally efficient, and has previously been used in high‐throughput pharmacoepidemiologic screening to identify drug interaction signals associated with injury. 10 , 17 , 18 , 19 , 20 …”

“…As other medications may have pharmacokinetic (e.g., by inhibiting antidepressants’ hepatic metabolism) or pharmacodynamic (e.g., by contributing to antidepressants’ central nervous system [CNS] effects) interactions with antidepressants, 8,9 they may heighten potential injury risks associated with antidepressants. In a recent pharmacoepidemiologic screening study, 256 antidepressant + co‐dispensed drug pairs had 1.1‐ to 3.1‐fold increased rates of unintentional traumatic injury, compared with antidepressant use alone 10 ; this study did not examine drug triads. Unintentional injury is a public health problem as it often causes morbidity and mortality and incurs substantial economic costs 11 .…”

Skeletal muscle relaxant drug–drug–drug interactions and unintentional traumatic injury: Screening to detect three‐way drug interaction signals

“…First, it automatically controls for measured and unmeasured confounders that are stable over the observation period, such as sex, race and chronic conditions; second, measured confounders that change over time can be addressed via statistical adjustment; third, restricting the study sample to persons experiencing an outcome and the lack of needing to identify control series is highly computationally efficient and suitable for high-throughput screening; and fourth, it is not prone to exposure-trend bias. 12 We have used this epidemiologic method to study opioid and antidepressant DDIs leading to injury, 13,14 insulin secretagogue DDIs leading to hypoglycaemia, [15][16][17] anticoagulant DDIs leading to thromboembolism, 18,19 and anticoagulant and antiplatelet DDIs leading to bleeding. [20][21][22]…”