Research Article: Risk of head and traumatic brain injuries associated with antidepressant use among community-dwelling persons with Alzheimer’s disease: a nationwide matched cohort study

Date Published: August 1, 2017

Publisher: BioMed Central

Author(s): Heidi Taipale, Marjaana Koponen, Antti Tanskanen, Piia Lavikainen, Reijo Sund, Jari Tiihonen, Sirpa Hartikainen, Anna-Maija Tolppanen.


Antidepressant use has been associated with an increased risk of falling, but no studies have been conducted on whether antidepressant use is associated with an increased risk of head injuries which often result from falling among older persons. The objective of this study was to investigate the risk of head and brain injuries associated with antidepressant use among community-dwelling persons with Alzheimer’s disease.

A matched cohort study was conducted by comparing new antidepressant users (n = 10,910) with two matched nonusers (n = 21,820) in the MEDALZ study cohort. The MEDALZ cohort includes all community-dwelling persons newly diagnosed with Alzheimer’s disease between 2005 and 2011 in Finland. Incident antidepressant users were identified based on register-based dispensing data from the Prescription register with a 1-year washout period for antidepressant use. Nonusers were matched with users based on age, gender, and time since Alzheimer’s disease diagnosis. The outcome events were defined as any head injuries and traumatic brain injuries based on diagnoses in Hospital Discharge and Causes of Death registers. Propensity score adjusted Cox proportional hazard models were utilized. Sensitivity analyses with case-crossover design were conducted. All registers are linkable with unique personal identification numbers assigned for each resident.

Antidepressant use was associated with an increased risk of head injuries (age-adjusted event rate per 100 person-years 2.98 (95% confidence interval (CI) 2.49–3.06) during use and 2.43 (95% CI 2.06–2.35) during nonuse, adjusted hazard ratio (HR) 1.35, 95% CI 1.20–1.52) and traumatic brain injuries (age-adjusted event rate per 100 person-years 1.33 (95% CI 1.13–1.53) during use and 1.10 (95% CI 1.00–1.20) during nonuse, adjusted HR 1.26, 95% CI 1.06–1.50). The risk was highest during the first 30 days of use (HR 1.71, 95% CI 1.10–2.66 for head injuries; HR 2.06, 95% CI 1.12–3.82 for traumatic brain injuries) and remained at an elevated level for head injuries for over 2 years of use. In case-crossover analyses, antidepressant use was consistently associated with a higher risk of head injuries.

Antidepressant use was associated with an increased risk of the most severe outcomes, head and brain injuries, in persons with Alzheimer’s disease. Antidepressant use should be carefully considered and the association confirmed in future studies.

The online version of this article (doi:10.1186/s13195-017-0285-3) contains supplementary material, which is available to authorized users.

Partial Text

Alzheimer’s disease (AD), the most common form of dementia, is a major public health challenge due to population aging [1]. Age is the most important risk factor for AD. As AD leads to dependency on other people it is associated with significant health care and societal costs. For these reasons, optimal care of this vulnerable patient group is a key challenge for the future.

In this study, 10,910 antidepressant users and 21,820 matched nonusers were included; the majority of these were women in both groups (69.0%). The mean age of antidepressant users was 79.5 (standard deviation (SD) 6.8) years and 79.6 (SD 6.7) years for nonusers. Table 1 shows the comparison between users and nonusers in terms of baseline characteristics. Antidepressant users were more likely to use other psychotropic drugs (antipsychotics and benzodiazepines and related drugs) and opioids and to have history of hospital-treated bipolar disorder or depression. None of the factors were associated with antidepressant use after adjusting for propensity score.

To our knowledge, this is the first study to assess the risk of head and brain injuries associated with antidepressant use. Antidepressant users had an increased risk of head injuries and TBIs among persons with Alzheimer’s disease in the exposure-matched cohort design while adjusting for propensity score. The risk was highest at the beginning of antidepressant use and, for head injuries, lasted for over 2 years of use and, for traumatic brain injury, the risk was evident only at the beginning of use although the risk estimates were also suggestive of increased risk after that. As-treated and intention-to-treat analyses for the first 180 days resulted in similar results as for the main analyses. Sensitivity analyses with within-individual case-crossover design indicated that antidepressant use is associated with an increased risk of head injuries but not consistently with TBIs. In general, the associations between antidepressant use and TBIs were less consistent and some analyses lacked statistical significance although the risk estimates indicated an increased risk, possibly due to small number of events for users.

We investigated antidepressant use and the associated risk of head and brain injuries in a large, nationwide cohort including community-dwelling persons with Alzheimer’s disease. The results are generalizable to community-dwelling persons with AD. The analyses were restricted to the first head or brain injury to avoid multiple hospitalizations due to the same event. The new user design, with exclusion of prevalent users, controls for survival and selection biases associated with prevalent use. As aging and the progression of AD increases the risk of head and brain injuries, we formed an exposure-matched cohort design by matching nonusers to every antidepressant initiator. With this design, we were able to control for time since AD diagnosis which is a proxy for progression of the disease. We also matched comparison persons in terms of age since age is a major risk factor for falling [31]. Besides having age, gender, and time since AD diagnosis utilized in the matching, the analyses were adjusted for propensity score predicting antidepressant treatment and propensity score adjusted analyses confirmed the increased risk. Intention-to-treat analyses controlled for informative censoring and led to similar results. As in all observational studies, residual confounding may still exist. It is possible that the indications of antidepressant use may partially explain the observed association. In the observational study setting we lacked precise knowledge on indications for drug use, and the severity, frequency, and duration of symptoms for which antidepressants were used. However, sensitivity analyses with a case-crossover design were conducted to further assess unmeasured confounding at an individual level, such as problems with balance or mobility, and capabilities for activities of daily functioning. The sensitivity analyses confirmed results for head injuries and partly for TBIs.

Antidepressant use has been previously associated with an increased risk of falls, but our novel findings indicate that they are associated with severe injurious falls, i.e., those resulting in head or brain injuries among persons with Alzheimer’s disease. The association between antidepressant use and head and brain injuries should be confirmed in further studies. As antidepressant use has also been associated with an increased risk of falling in previous studies, clinicians should keep on carefully considering indications and use of antidepressants for the safety of vulnerable patients.




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