Research Article: Trazodone use and risk of dementia: A population-based cohort study

Date Published: February 5, 2019

Publisher: Public Library of Science

Author(s): Ruth Brauer, Wallis C. Y. Lau, Joseph F. Hayes, Kenneth K. C. Man, David P. J. Osborn, Robert Howard, Joseph Kim, Ian C. K. Wong, Carol Brayne

Abstract: BackgroundIn vitro and animal studies have suggested that trazodone, a licensed antidepressant, may protect against dementia. However, no studies have been conducted to assess the effect of trazodone on dementia in humans. This electronic health records study assessed the association between trazodone use and the risk of developing dementia in clinical practice.Methods and findingsThe Health Improvement Network (THIN), an archive of anonymised medical and prescribing records from primary care practices in the United Kingdom, contains records of over 15 million patients. We assessed patients from THIN aged ≥50 years who received at least two consecutive prescriptions for an antidepressant between January 2000 and January 2017. We compared the risk of dementia among patients who were prescribed trazodone to that of patients with similar baseline characteristics prescribed other antidepressants, using a Cox regression model with 1:5 propensity score matching. Patients prescribed trazodone who met the inclusion criteria (n = 4,716; 59.2% female) were older (mean age 70.9 ± 13.1 versus 65.6 ± 11.4 years) and were more likely than those prescribed other antidepressants (n = 420,280; 59.7% female) to have cerebrovascular disease and use anxiolytic or antipsychotic drugs. After propensity score matching, 4,596 users of trazadone and 22,980 users of other antidepressants were analysed. The median time to dementia diagnosis for people prescribed trazodone was 1.8 years (interquartile range [IQR] = 0.5–5.0 years). Incidence of dementia among patients taking trazodone was higher than in matched users of other antidepressants (1.8 versus 1.1 per 100 person-years), with a hazard ratio (HR) of 1.80 (95% confidence interval [CI] 1.56–2.09; p < 0.001). However, our results do not suggest a causal association. When we restricted the control group to users of mirtazapine only in a sensitivity analysis, the findings were very similar to the results of the main analysis. The main limitation of our study is the possibility of indication bias, because people in the prodromal stage of dementia might be preferentially prescribed trazodone. Due to the observational nature of this study, we cannot rule out residual confounding.ConclusionsIn this study of UK population-based electronic health records, we found no association between trazodone use and a reduced risk of dementia compared with other antidepressants. These results suggest that the clinical use of trazodone is not associated with a reduced risk of dementia.

Partial Text: Dementia affects more than 47 million people worldwide [1]. Global estimates suggest that the total economic costs caused by dementia increased from US$279.6 billion in 2000 to $948 billion in 2016, with an annual growth rate of 15.94%. This included costs of informal care at $95.1 billion in 2000 and $401.9 billion in 2016, with an annual growth rate of 21.50% [2]. Dementia is characterised by a decline in cognitive functioning which impacts on activities of daily living [1]. Dementia not only affects patients but also has a significant negative effect on caregivers. Caregivers of patients with dementia are significantly more stressed than caregivers for people without dementia, and suffer more serious depressive symptoms and physical problems [3]. Effective interventions in the prevention and management of dementia are urgently needed. Alzheimer dementia (AD) and vascular dementia (VD) are the most common forms, and it can be challenging to differentiate the two clinically [4]. AD is characterised by the presence of extracellular amyloid plaques and intraneuronal neurofibrillary tangles, which are accompanied by nerve cell death and tissue loss [5]. The pathophysiological causes of AD are complex but are thought to involve overactivation of the unfolded protein response (UPR) [6]. Healthy activation of the UPR usually occurs in response to an accumulation of unfolded or misfolded proteins in the endoplasmic reticulum—e.g., in an attempt to restrict a viral infection [7].

The study protocol and analysis plan was approved by the Scientific Review Committee for The Health Improvement Network (THIN) database research (Reference Number: 17THIN048, June 2017; see S1 Protocol). Further ethics approval was not required for this secondary analysis of routinely collected data.

In this large, population-based study of electronic health records from the UK, we found no association between trazodone use and a reduced risk of dementia compared with other antidepressants. The results were consistent across different patient subgroups, definitions of dementia outcomes, and treatment durations as well as when comparing specific antidepressants to trazodone. The proportion of patients with dementia observed in both trazodone-treated individuals and those treated with other antidepressants were consistent with other UK population-based incidence studies [25].

Using electronic health records from UK primary care, we showed that trazodone use was not associated with a reduced risk of dementia compared with other antidepressants. These results refute the suggestions from animal studies that trazodone might stop or delay the onset of dementia in patients at the prodromal stage of dementia.



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