Curr Psychiatry Rep (2015) 17: 53 DOI 10.1007/s11920-015-0595-8

GERIATRIC DISORDERS (W MCDONALD, SECTION EDITOR)

New Research on Anxiety Disorders in the Elderly and an Update on Evidence-Based Treatments Carmen Andreescu 1 & Daniel Varon 1

Published online: 16 May 2015 # Springer Science+Business Media New York 2015

Abstract Anxiety disorders are frequently encountered in the elderly, but they are largely undetected and untreated. Epidemiological studies indicate a prevalence ranging from 1.2 to 15 %. With the exception of generalized anxiety disorder and agoraphobia, which can often start in late life, most anxiety disorders in older patients are chronic and have their onset earlier in life. Anxiety disorders are an often unrecognized cause of distress, disability, and mortality risk in older adults, and they have been associated with cardiovascular disease, stroke, and cognitive decline. The mechanisms of anxiety in older adults differ from that in younger adults due to agerelated neuropathology, as well as the loss and isolation so prominent in late life. Our review intends to provide a comprehensive summary of the most recent research done in the field of anxiety disorders in the elderly. Recent findings in clinical research, neuroimaging, neuroendocrinology, and neuropsychology are covered. An update on treatment options is discussed, including pharmacological and nonpharmacological alternatives.

Keywords Anxiety disorders . Elderly . Neurobiological research . Evidence-based treatment

Introduction One in four adults in the USA will have at least one episode of an anxiety disorder in their lifetime [1]. Epidemiological studies showed that most anxiety disorders in the elderly are chronic and usually occur earlier in life [2], except for generalized anxiety disorder (GAD) and agoraphobia, which often may have onset later in life [3]. However, late-life GAD is largely undetected and untreated in primary care. A study from 2001 estimates the rates of GAD in primary care at about 8 %, while primary care physicians make this diagnosis in about 0.1 % of cases [4]. Overall, the epidemiological studies that assessed anxiety in late life [5–8, 9•] give a rather large range of prevalence for all anxiety disorders in the elderly, from 1.2 to 15 % (community samples) [10]. The most recent epidemiological study reports a lifetime prevalence of 11 % for GAD with 24.6 % of these being late-onset (first episode after age 50) and only 36.3 % receiving treatment [9•]. Anxiety disorders in the elderly are an often unrecognized cause of distress, disability, and mortality risk. More recently, late-life GAD has been linked to increased risk of stroke and other cardiovascular events, after controlling for other risk factors [11•, 12], and have also been linked with increased risk of conversion from mild cognitive impairment to Alzheimer’s disease [13•].

This article is part of the Topical Collection on Geriatric Disorders

New Research in Anxiety Disorders in the Elderly

* Carmen Andreescu [email protected]

Clinical Research

1

Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School Of Medicine, 3811 O’Hara Street, Pittsburgh, PA, USA

A recent study from 2015 looked at risk factors for GAD onset in the elderly in a sample of 1711 individuals 65 and older (the ESPRIT study) [14]. The authors followed anxiety-free, nondemented participants for 12 years and reported that the

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principal predictors of late-onset GAD were gender (female), recent adverse life events, chronic medical illness (respiratory disorders, cardiac illness, cognitive impairment), and chronic mental illness (depression, phobia, and a history of GAD) [14]. Additionally, poverty, parental loss or separation, a history of mental illness in the parents, and poor psychological support during childhood were also independently associated with incident GAD [14]. Neurobiological Neuroimaging With very few exceptions [15–18], most of the evidence regarding the neurobiology of late-life anxiety is extrapolated from midlife studies. Some of the neurobiological findings implicate structures involved in heightened fear response, especially hyperactivation in the amygdala and insula in specific phobia, PTSD, and social anxiety [19]. PTSD has been additionally linked to hypoactivity in the thalamus, the dorsal and rostral cingulate, as well as the ventro- and dorsomedial prefrontal cortex [19]. GAD has been associated with a more polymorphic pattern, including heightened amygdala response to anticipatory threat [20], increased amygdaladorsolateral prefrontal connectivity [21], and greater insulaorbitofrontal connectivity during induction of worry [22]. However, the neural network abnormalities described in younger adults might not be entirely translatable into the elderly, given the various anatomical and pathophysiological changes observed in the aging brain [23]. The few available studies have focused mainly on the neurobiology of late-life GAD. Structural Neuroimaging Studies The only study that explored the structural neuroanatomy of late-life GAD described a positive correlation between orbitofrontal cortex volume correlated and worry severity (as measured by PSWQ) [16], a finding the authors interpret as pointing toward the role of OFC in emotional decision-making under uncertain conditions (which is a function of worry). Information regarding the architecture of the white matter, including the role macro- or microlesions in the white matter is not explored with regard to late-life anxiety disorders, a significant literature gap given the prevalence of disorders such as GAD in the elderly. Functional Neuroimaging Studies The few available studies have reported differences in functional connectivity at rest between middle age and elderly participants with GAD, with younger subjects presenting a more robust long-range connectivity in the default mode network than older GAD subjects [24]. A study that explored the neural basis of emotion regulation in elderly GAD reported that, compared with nonanxious subjects, the GAD participants failed to engage the

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prefrontal structures during worry reappraisal [17, 18], while engaging subcortical structures such as the paraventricular nucleus and the amygdala [18]. These findings suggest that elderly GAD subjects actually become more anxious when they attempt to reappraise worry, a finding salient for the psychotherapeutic interventions available for late-life anxiety (e.g., cognitive reappraisal, a chore part of cognitivebehavioral therapy, may actually be counterproductive in elderly with GAD) [18]. Older GAD also appears to have reduced recruitment of the prefrontal attentional control regions, consistent with a model of top-down deficits in late-life GAD [15]. These findings suggest treatment strategies such as attentional retraining [25, 26]. Neuropsychological Findings In older adults, anxiety impairs working memory, attention, and problem-solving ability [27–30]. Recent investigations have extended these observations to clinical samples, describing poorer short-term memory in geriatric GAD [31] and poorer working memory with greater GAD symptoms [27, 32]. Higher rates of anxiety in participants with mild cognitive impairment (MCI) have been reported in both population and clinical samples [33–35]. Longitudinal studies have reported that anxiety is an independent predictive factor of progression from MCI to AD [36]. In a 3-year longitudinal study, Palmer et al. showed that worrying alone was associated with a fivefold increased risk of AD in elders with MCI compared to elders with MCI without persistent worrying [37]. A more recent multicenter, prospective study on 333 healthy older adults showed that elevated anxiety symptoms moderated the effect of beta-amyloid on cognitive decline in preclinical AD, resulting in a more rapid decline [38•]. The relationship between anxiety and cognitive impairment is probably bidirectional as there is evidence that impaired cognitive performance increases anxiety [39]. Thus, some authors have argued that increased anxiety represents not a risk factor but a consequence of the individual’s self-awareness of cognitive decline and consequent worry about further degradation in cognitive status [39]. Neuroendocrinology Apprehensive anticipations appear to induce limbic and paralimbic hyperactivation, leading to autonomic hyperactivity and subsequent higher cortisol levels [40]. Chronically increased cortisol level has been associated in GAD with increased serotonin uptake [41], with decrease hypothalamus [42] and hippocampal volume [43] and decreased activation of the prefrontal cortex [44] (which may contribute to the deficits in emotion regulation reported in anxiety disorders). Aging increases the vulnerability to adverse effects of stress because the homeostatic mechanisms preventing an excessive

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biological stress response are diminished [27, 45, 46]. Latelife GAD has been associated with increased cortisol levels by some [47], but not all [48] studies. A double-blind controlled study has showed that SSRI-treated patients with increased baseline cortisol had a significantly greater reduction in cortisol when compared with placebo-treated elderly GAD [49]. Similar findings were reported after CBT (in younger GAD) [50]. Recent research shows increases in ß-amyloid-42 peptide (Aß42) production and tau hyperphosphorylation attributable to excessive HPA activation (mediated via corticotropin releasing factor-1 [CRF1]) suggesting a direct link between chronic stress, increased CRF production, and the putative pathogenic steps in Alzheimer’s disease [27, 51–53].

Update on Treatment Options Current Pharmacological Options Recommendations for pharmacotherapy in elderly anxious subjects are usually based on extrapolation of findings from middle-age adults. However, elderly patients are more susceptible to drug-induced side effects, including anticholinergic effects (urinary retention, delirium, cognitive impairment), antiadrenergic effects (orthostatic hypotension), and antihistaminergic effects (mainly sedation) [54]. Elderly patients have changes in both pharmacokinetics and pharmacodynamics due to diminished glomerular filtration, reduced hepatic metabolization, decreased cardiac output, and changes in the density and activity of target receptors [55]. The evidence base for pharmacotherapy in older adults is limited and consists mainly of several small clinical trials, many quite old and in mixed populations [27]. The need for treatment is assessed based on the severity and duration of the illness, the impact of quality of life, the presence of comorbid depression or cognitive impairment, as well as the concomitant use of other medications [56•]. SSRIs and serotonin norepinephrine reuptake inhibitors (SNRIs) remain the first-line medications for both short-term and long-term treatment. Two small RCTs [57, 58] and a fullscale RCT [46] demonstrated the efficacy of SSRIs in the acute treatment of older adults with anxiety disorders, predominantly GAD. In the latter study, which randomized 177 older adults with GAD, escitalopram was superior to placebo in cumulative response (69 vs. 51 %). A more recent study (2010) compared in a randomized, single blind trial the efficacy of sertraline and buspirone for late-life GAD (N=46) [59]. The authors conclude that both sertraline and buspirone were efficacious and well tolerated for the treatment of GAD in the elderly [59]. The SNRIs have proven efficacious in the treatment of GAD and panic disorder in midlife [56•], but they appear to be less well tolerated than SSRIs. A retrospective examination of phase 3 venlafaxine XR and duloxetine data

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found both medications to be efficacious in older adults, with a side effect profile similar to younger adults [60, 61]. However, venlafaxine is associated with dose-dependent increase in blood pressure, while others have reported orthostatic hypotension [92]. Monitoring BP is recommended with higher doses, especially in the elderly [56•]. Overall, both SSRIs and SNRIs are relatively well tolerated, but clinicians should assess the potential risks of SSRIs in the elderly population, including gait impairment increasing risk for falls [62], GI bleeding [63], bone loss [64], and hyponatremia [65]. Such reports suggest that the risk-benefit ratio for acute and longterm SSRI/SNRI use is not the same as in younger adults [27]. Other antidepressant drugs, such as tricyclic antidepressants (TCA) and irreversible monoamine oxidase inhibitors (MAOI) have proven to be efficacious in some anxiety disorders, but their use in the elderly should be limited to cases resistant to other treatment options due to their side effect profile. The evidence for the efficacy of mirtazapine (Remeron) is limited and inconsistent [66], but elderly patients may benefit from its effects on sleep and appetite. Benzodiazepines are still the most commonly used pharmacological treatment for geriatric anxiety [67], despite the association of these medications with falls [68], disability [69], and cognitive impairment and decline [27, 70]. A recent survey done in Japan on 796 elderly with anxiety disorders, showed a very high rate of use of benzodiazepine anxiolytics in the elderly 71.6 % (mean dose of diazepam 10.3±9.1 mg/ day) [71]. Compared with younger subjects (