Do Acetylcholinesterase Inhibitors Increase Anxiety and Depression in Elderly Adults with Dementia?

To the Editor: The Cache County Study showed that the prevalence of anxiety and depression is four times as high in U.S. elderly adults with dementia than in those without.1 Dementia disorders may increase anxiety and depression through neurodegenerative changes in regions of the brain involved in behavioral regulation. Despite the reported association between severity of cognitive impairment and symptoms of anxiety and depression in individuals with dementia,2 drugs known to have cognitive effects in dementia generally show only modest benefit in decreasing the comorbid anxiety or depression.3 It has recently been suggested that acetylcholinesterase (AChE) inhibitors (AChE-Is), a class of drugs routinely used for treatment in individuals with Alzheimer's disease (AD) and dementia with Lewy bodies, may lead to increases in anxiety and depression. Pharmacological and molecular inhibition of AChE increased anxiety-like and pro-depressive behaviors in a mouse study.4 Furthermore, bisphenol A, an organic solvent, was shown to increase anxiety-like behavior in mice through a decrease in the activity of brain AChE.5 Anxiolytic and antidepressant medications also alter AChE activity, supporting a role for brain cholinergic signaling in the regulation of anxiety and depressive behaviors.6 It may therefore be that AChE inhibitors, such as donepezil and rivastigmine, contribute to symptoms of anxiety and depression in elderly adults with dementia. To investigate whether the use of AChE-Is is associated with symptoms of anxiety and depression in elderly adults with dementia, symptoms of anxiety and depression were prospectively studied in a clinical cohort of elderly adults with dementia. Subjects were 63 consecutive individuals aged 65 and older with a diagnosis of dementia treated at the memory disorders clinic of the Michael DeBakey Veteran Affairs Medical Center (Houston, TX). Symptoms of anxiety were assessed using the Geriatric Anxiety Inventory and Penn State Worry Questionnaire administrated by medical students blinded to study design. Similarly, the prevalence of depression was examined using the Beck Depression Inventory. Information was also collected on demographic characteristics, dementia subtypes, dementia severity based in part on the Montreal Cognitive Assessment, and medications. For analysis, participants were divided into two groups based on whether they had used cholinergic medications within the past year. The two groups did not differ in demographic characteristics of dementia severity (Table 1). The prevalence of anxiety and depression did not differ between the two groups (Table 1). Because AChE-I use is more common in individuals with AD, the prevalence of anxiety and depression of participants with AD (n = 23) was compared with that of participants with non-AD dementias (n = 40). The two groups had a comparable prevalence of anxiety (Geriatric Anxiety Inventory score ≥9: AD, 17.4% vs non-AD, 20%, Fisher exact test P > .99) and depression (Beck Depression Inventory ≥10%: AD, 13% vs non-AD, 17.5%, Fisher exact test P = .73) The prevalence of subclinical anxiety of the three cholinergic medication groups was further compared using a lower cutoff for the Penn State Worry Questionnaire. The prevalence of anxiety did not differ between the two groups (AChE-I = 33.3%, no AChE-I = 41.1%, Fisher exact test P = .43). In summary, this study did not find an association between AChE-Is and symptoms of anxiety and depression in elderly adults with dementia. This finding is contrary to the observation from a recent study in mice that showed that greater hippocampal cholinergic stimulation was associated with anxiety and prodepressive behaviors.4 There could be a number of reasons for the disparity between these two contrasting observations. First, greater cholinergic stimulation in the brain could have age-dependent effects.7 Hence, it is possible that greater cholinergic stimulation leads to greater anxiety in younger individuals but not in elderly adults. Second, it is possible that greater cholinergic stimulation has brain region–specific effects; thus, perhaps only selective hippocampal cholinergic stimulation increases anxiety, but this does not explain why pharmacological increase in global cholinergic activity leads to prodepressive and anxiety-like behavior in mice.4 Third, it is possible that their positive effect on cognition balances the anxiety-like and prodepressive effects of AChE-Is. Finally, it is important to consider a possible ceiling effect in this analysis; that is, a higher prevalence of anxiety and depression in elderly adults with dementia might curtail small but clinically relevant differences in anxiety and depression between different medication groups. In conclusion, this prospective study showed that the use of AChE-Is did not increase the symptoms of anxiety and depression in elderly adults. Larger prospective trials are needed to more fully ascertain the influence of cholinergic stimulation on anxiety and depression in elderly adults with dementia. We would like to thank the clinical assistants and medical students working at the Veterans Affairs Medical Center Neurology Clinic for their assistance with data collection. Conflict of Interest: The editor in chief has reviewed the conflict of interest checklist provided by the authors and has determined that the authors have no financial or any other kind of personal conflicts with this paper. Author Contributions: Jawaid: study concept, data mining, statistical analysis, writing the manuscript. Pawlowicz: data mining, manuscript writing. Schulz: organization of study subjects, revision of draft for intellectual content. Sponsor's Role: None.

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