The Risk of Hip Fracture Due to Mirtazapine Exposure When Switching Antidepressants or Using Other Antidepressants as Add-On Therapy

Abstract

BackgroundAntidepressants are associated with adverse effects such as sedation and hypotension, which can result in falls and fractures. Few studies have assessed the risk of hip fracture due to mirtazapine, and no known studies have assessed whether the risk of hip fracture is higher in patients taking other antidepressant medicines in combination with mirtazapine.ObjectivesThis study aimed to examine the risk of hip fracture in older people due to mirtazapine use as well as switching between or concurrently using mirtazapine and other antidepressants.MethodA matched case–control study was conducted. Cases were people aged over 65 years who were eligible for Australian Government Department of Veterans’ Affairs (DVA) benefits and who sustained a hip fracture between 2009 and 2012. Each case was matched with up to four randomly selected controls of the same gender and age (± 2 years). Multivariable conditional logistic regression was used to estimate associations between antidepressant use and hip fracture. In order to assess whether combined antidepressant effects differed from the sum of individual effects, the relative excess risk due to interaction (RERI) was calculated.ResultsThe study population comprised 8828 cases and 35,310 controls. The median age of these participants was 88 years and 63% were women. The risk of hip fracture was increased for mirtazapine (continuous use: odds ratio [OR] 1.27, 95% confidence interval [CI] 1.12–1.44). The combinations associated with increased odds of hip fracture were addition of selective serotonin reuptake inhibitors (SSRIs) to mirtazapine (OR 11, 95% CI 2.2–51; RERI 7.7, 95% CI −9.0 to 24), addition of tricyclic antidepressants (TCAs) to mirtazapine (OR 14, 95% CI 1.4–132; RERI 12, 95% CI −19 to 43) and continuous use of both SSRIs and mirtazapine (OR 2.4, 95% CI 1.4–4.2; RERI 0.4, 95% CI −0.9 to 1.7). RERIs indicated that the effect of each antidepressant pair equalled the sum of the effects of individual antidepressant use. There was no evidence of dispensing of lower strength mirtazapine upon introducing TCAs and SSRIs.ConclusionsOur results show elevated risk of hip fracture following use of mirtazapine alone and in combination with other antidepressants. The overlapping use of antidepressants may reflect the treatment of comorbidities (e.g. anxiety), switching from mirtazapine to other antidepressants, or add-on therapy. Our results highlight the risks of employing add-on therapy or switching antidepressants in older people, providing further evidence to support cautious cross-tapering where switching between antidepressants is required.Electronic supplementary materialThe online version of this article (doi:10.1007/s40801-017-0120-y) contains supplementary material, which is available to authorized users.

Association rules method and big data: Evaluating frequent medication combinations associated with fractures in older adults

“…Particularly, the results showed that zopiclone was frequently co‐prescribed with other drugs prior to a fracture event. Several studies have shown that z hypnotics significantly increase the risk of fracture in older adults, and our results are biologically plausible …”

“…Several studies have shown that z hypnotics significantly increase the risk of fracture in older adults, and our results are biologically plausible. [30][31][32][33][34] The sensitivity analyses repeated with weekly (7-day) and monthly (30-day) time windows did not change the overall results. These time windows were chosen to align with the best practice recommendations for conducting a case-crossover study.…”

A data visualisation method for assessing exposure misclassification in case-crossover studies: the example of tricyclic antidepressants and the risk of hip fracture in older people

“…While a meta-analysis of case-control and cohort studies suggests an association between TCAs and hip fracture, this relationship has not been previously assessed in any other case-crossover study controlling for patient-specific, time-invariant confounders [ 15 ]. In line with Maclure and Mittleman’s recommendation [ 6 ] to conduct a case-control study as a type of validation for a case-crossover study, our case-control study conducted in the same setting found that new use of TCAs was not independently associated with hip fracture [ 16 ]. The conservative use of TCAs at low doses to treat neuropathic pain or depression in older people could partly explain the lack of association in our case-crossover and case-control studies [ 7 ].…”

<p>Individual Antidepressants and the Risk of Fractures in Older Adults: A New User Active Comparator Study</p>

“…We applied an active comparator new user design, 34 comparing the risk of persons initiating a certain AD to the risk of persons initiating mirtazapine (active comparator) which is frequently used and has been associated with a low risk of hip fractures. 35 To be eligible, persons had to be older than 65 years and have at least 12 months of continuous enrollment before cohort entry. Patients entered the cohort at the date of the first AD dispensation after 365 days without such a dispensation ("initiation").…”