Author ORCID Identifier

https://orcid.org/0000-0002-5973-934X

Year of Publication

2019

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Public Health

Department

Epidemiology and Biostatistics

First Advisor

Dr. Erin L. Abner

Abstract

Dementia is a clinical syndrome caused by neurodegeneration or cerebrovascular injury. Patients with dementia suffer from deterioration in memory, thinking, behavior and the ability to perform everyday activities. Since there are no cures or disease-modifying therapies for dementia, there is much interest in identifying modifiable risk factors that may help prevent or slow the progression of cognitive decline. Medications are a common focus of this type of research.

Importantly, according to a report from the Centers for Disease Control and Prevention (CDC), 19.1% of the population aged 60 and over report taking antidepressants during 2011-2014, and this number tends to increase. However, antidepressant use among the elderly may be concerning because of the potentially harmful effects on cognition. To assess the impacts of antidepressants on the risk of dementia, we conducted three consecutive projects.

In the first project, a retrospective cohort study using Marginal Structural Cox Proportional Hazards regression model with Inverse Probability Weighting (IPW) was conducted to evaluate the average causal effects of different classes of antidepressant on the risk of dementia. Potential causal effects of selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), atypical anti-depressants (AAs) and tri-cyclic antidepressants (TCAs) on the risk of dementia were observed at the 0.05 significance level. Multiple sensitivity analyses supported these findings.

Unmeasured confounding is a threat to the validity of causal inference methods. In evaluating the effects of antidepressants, it is important to consider how common comorbidities of depression, such as sleep disorders, may affect both the exposure to anti-depressants and the onset of cognitive impairment. In this dissertation, sleep apnea and rapid-eye-movement behavior disorder (RBD) were unmeasured and thus uncontrolled confounders for the association between antidepressant use and the risk of dementia. In the second project, a bias factor formula for two binary unmeasured confounders was derived in order to account for these variables. Monte Carlo analysis was implemented to estimate the distribution of the bias factor for each class of antidepressant. The effects of antidepressants on the risk of dementia adjusted for both measured and unmeasured confounders were estimated. Sleep apnea and RBD attenuated the effect estimates for SSRI, SNRI and AA on the risk of dementia.

In the third project, to account for potential time-varying confounding and observed time-varying treatment, a multi-state Markov chain with three transient states (normal cognition, mild cognitive impairment (MCI), and impaired but not MCI) and two absorbing states (dementia and death) was performed to estimate the probabilities of moving between finite and mutually exclusive cognitive state. This analysis also allowed participants to recover from mild impairments (i.e., mild cognitive impairment, impaired but not MCI) to normal cognition, and accounted for the competing risk of death prior to dementia. These findings supported the results of the main analysis in the first project.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2019.123

Available for download on Monday, May 03, 2021

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