Treatments for Depression in Older Persons with Dementia

Author Affiliations: Dr. Gellis is Associate Professor and Director, School of Social Policy & Practice, University of Pennsylvania, Center for Mental Health & Aging, Philadelphia; Dr. McClive-Reed is Research Assistant Professor, Institute of Gerontology, School of Social Welfare, State University of New York at Albany; and Dr. Brown is Associate Professor of Nursing, College of Nursing and Health Sciences, Florida International University, Miami.
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CORRECTIONS: In the section entitled “Pharmacologic Treatment of Depression in Dementia”, subsection “Antidepressants,” buspirone is referred to as an antidepressant. Specifically, buspirone is classed as an anxiolytic with serotonergic or antidepressant activity (see Buhr & White, 2006, referenced in original article). Although buspirone has demonstrated some efficacy in trials and clinical use for both primary and augmentative treatment of depression, it is currently FDA-approved only for the treatment of anxiety disorders. In the same section, the paragraph titled “Anticholinergics” should be titled “Cholinergics.” The term “anticholinergics” is also substituted incorrectly for “cholinergics” in the final sentence of the final sentence in the section titled, “Antidepressants,” and in the first paragraph of the final “Summary” section. The authors apologize for these errors.
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Worldwide, dementia is one of the most disabling health conditions, with estimates of 24.3 million people diagnosed with dementia in 2005 and 4.6 million new cases of dementia occurring annually. This evidence-based review of the literature on depression disorders among older adults with dementia focuses on prevalence, clinical recognition, assessment, and treatment. A search of the empirical literature was undertaken to determine the extent of the problem, and the effectiveness of various pharmacological and nonpharmacological treatments. (Annals of Long-Term Care: Clinical Care and Aging 2009;17[2]:29-36)

Depression in Dementia

Dementia itself is not a disease, but a constellation of symptoms caused by diseases and disorders that affect the brain, including Alzheimer’s disease (AD), Parkinson’s disease (PD), diffuse Lewy body disease, strokes, and others. Dementia involves progressive loss of memory and other cognitive functions, such as problem-solving and emotional control. The earliest diagnosable stage of dementia, mild cognitive impairment (MCI), does not always lead to dementia; for those who do develop dementia, abilities to independently perform basic activities of daily living (ADLs) and instrumental activities of daily living (IADLs) are generally impaired as the condition progresses.

Behavioral and psychological symptoms of dementia (BPSD), also frequently referred to as neuropsychiatric symptoms of dementia, affect up to 95% of those with dementia during the course of the illness.¹ Symptoms of depression are especially common in MCI and throughout the course of dementia. Reported prevalence of depression or depressive symptoms in persons with dementia ranges from 0% to 96%,^2-5 while moderate to high rates of depression or its symptoms are consistently reported for persons with MCI (ie, 36% by Palmer and colleagues⁶; 63.3% by Solfrizzi and colleagues⁷; 39% by Hwang and colleagues8). The wide range of prevalence for depression in dementia is due to several factors, including differences in researchers’ focus on symptoms versus specifically defined depressive disorders, diverse study samples varying in causes of dementia, stage of illness, country of residence, and placement of patient, as well as variation in the instruments used to assess depressive symptoms and disorders. A recently published evidence-based practice guideline provides a feasible approach to depression assessment in persons with dementia; an overview of the guideline algorithm is provided in the Table. The guideline can be accessed at the National Guideline Clearinghouse, a public resource for evidence-based clinical practice guidelines.

Outcomes of Depression in Dementia

The occurrence of depression in people with MCI or dementia can lead to a number of negative outcomes. For example, pre-existing depression has been identified as a predictor of, or risk factor for, subsequent dementia. One meta-analysis estimated that persons experiencing depression have approximately double the risk of developing dementia as those without a prior history of depression,⁹ and more recent study findings concur.^6-10 Depression may also be a risk factor for progression from MCI to dementia. Several studies report an association between baseline depressive symptoms in participants with MCI and a later progression to dementia.^11-15

Comorbidity of cognitive impairment and depression has been associated with increased mortality,¹⁶ reduced quality of life,^17-20 and increases in caregiver burden and distress.^17,21,22 Possibly due to the negative impact on caregivers, comorbid depression and cognitive impairment are associated with higher rates of institutionalization of the care recipient with dementia.^23-25

Pharmacologic Treatment of Depression in Dementia

Both pharmacologic and nonpharmacologic treatment approaches have been found to be helpful in reducing depression in cognitive impairment and dementia. Pharmacologic treatment of depression in patients with dementia, although common, presents some unusual difficulties. Patients with dementia have more comorbid illnesses than those without dementia, with approximately 60% of those with AD having three or more medical conditions. This heightened level of comorbidity results in the use of multiple medications. Therefore, drug interactions and polypharmacy may help provoke BPSD in some patients with dementia, or may play a part in driving these patients’ sometimes atypical responses to the drugs used to treat BPSD.²⁶ Given their physical and cognitive frailty, persons with dementia may also be particularly susceptible to adverse effects. Since individuals with dementia may be less able to communicate, clinicians and caretakers must carefully observe their behavior for evidence of adverse events when new medications are introduced. Prescribing new medications intended to treat depression or other BPSD in these patients should always be made using the familiar adage originated for dosing the elderly, “Start low, and go slow.”²⁷

Antidepressants
Antidepressants are frequently prescribed for treatment of depression in dementia. A recent meta-analysis examined treatment of depression with tricylic antidepressants (TCAs; imipramine and clomipramine), and selective serotonin reuptake inhibitors (SSRIs; sertraline and fluoxetine) in five studies on patients with dementia.²⁷ Treatment response and remission was superior to placebo in the combined sample, but significant declines in cognitive scores occurred during the use of TCAs in both studies employing them. Reviews of research on the pharmacologic treatment of BPSD in general^28-30 indicate positive effects of various antidepressants (eg, sertraline, fluoxetine, citalopram, trazodone) on depression in dementia, with citalopram and sertraline being the most commonly prescribed.^31-33 Case reports and small pilot studies indicate that other antidepressants, including buspirone and mirtazapine, may improve depression in patients with dementia,^28,29,34 but no large trials have been performed in this population to date. The practice guideline issued in 2007 by the Work Group on Alzheimer’s Disease and Other Dementias of the American Psychiatric Association³⁵ currently supports SSRIs as the first pharmacologic treatment of choice for depression in dementia, as SSRIs tend to be better tolerated than other antidepressants. However, the Work Group suggests that if patients with dementia cannot tolerate higher dosages when needed for remission of depression, trials of alternative antidepressants such as bupropion, venlafaxine, and mirtazapine may be considered.

Newer medications that show potential promise in the treatment of depression in dementia include anticholinergics, anticonvulsants, and memantine.

Anticholinergics
Decreased cholinergic activity, primarily resulting from decreased acetylcholine concentrations caused by dementia-related neurological changes, has been associated with decreased cognitive ability in dementia, as well as increases in BPSD, including anxiety and depression.³⁶ Cholinesterase inhibitors have been used to successfully target these problems by increasing levels of acetylcholine in patients with mild-to-moderate dementia.³⁷ In particular, a recent randomized controlled trial demonstrated improvement in depression scores of patients with dementia, as measured by the Hamilton Depression Scale, for patients given rivastigmine or a combined regimen of rivastigmine and fluoxetine, as compared to placebo.³⁸

Anticonvulsants
Anticonvulsants, through their modulation of gamma-aminobutyric acid (GABA), may be another class of agents for treating BPSD. GABA concentrations are often decreased in cortical regions of the brain of patients with dementia, and medications that increase GABA levels have been shown to improve mood disorders.²⁸ However, trials of the anticonvulsant carbamazepine to treat BPSD have yielded contradictory results,³⁹ or have not reported data on depression. At least one clinical trial of valproate, another anticonvulsant, resulted in significant improvement in melancholic, sorrowful, and anxious behaviors,⁴⁰ but the results of other small trials of valproate are contradictory.³⁰ Preliminary trials of the anticonvulsant lamotrigine in elderly patients with dementia also noted improvement in symptoms of agitation and depression.⁴¹

Memantine
Memantine, a drug that reduces excessive glutamate receptor signaling, has also been studied in patients with dementia. Glutamate signaling is important for learning and memory, but in some patients with dementia it may increase to “oversignaling” levels that destroy neurons. A recent review and meta-analysis of the research on memantine for the treatment of psychological symptoms of dementia showed small but significant improvements as measured by the Neuropsychiatric Inventory, with limited adverse effects.⁴²

In summary, a variety of pharmacologic treatments have some efficacy in the treatment of depression in dementia, but care must be exercised in their use with this population of generally frail older persons to avoid adverse effects. Alexopoulos and colleagues⁴³ constructed an expert consensus response after surveying 50 experts in dementia from North America on preferred, alternate, and unacceptable treatment choices for BPSD. The general consensus was that SSRIs were the preferred pharmacologic treatment for depression in patients with dementia. Further research appears to be needed to establish the effects of both older and newer pharmacologic options on depression in persons with dementia.

Nonpharmacologic Treatments for Depression in Dementia

Clinical guidelines specify the use of nonpharmacologic treatments for BPSD before pharmacologic treatments are tried.^28,44 Nonpharmacologic therapies that specifically target depression or its symptoms fall roughly into three categories: emotion-oriented therapies, brief psychotherapies, and sensory stimulation therapies.

Emotion-Oriented Therapies
The primary aim of emotion-oriented therapies is to fit the therapy to emotional needs of people with dementia, and by doing so, improve their quality of life, social functioning, and ability to cope with the cognitive, emotional, and social consequences of the disease as they subjectively experience them.⁴⁵ Examples of emotion-oriented approaches include reminiscence, reality, validation, and simulated presence therapy.

Reminiscence therapy encourages persons with dementia to talk about their pasts, generally using memory aids such as old family photos and personal objects.⁴⁶ Reality orientation therapy is based on the theory that inability to orient themselves reduces the ability of those with dementia to function, and that confusion can be reduced by giving repeated orientation clues, such as the time of day, date, season, or names. Validation therapy assumes that the person with dementia may choose to retreat to an inner reality based on emotions, rather than trying to wrestle with failing intellectual powers. The therapist accepts the resulting disorientation of a person with dementia and validates his or her presumed feelings, providing a background for meaningful conversations addressing their emotions.⁴⁷ Simulated presence therapy involves exposing an individual with dementia to audio or videotaped recordings of loved ones.⁴⁸

Unfortunately, the limited literature available on emotion-oriented therapies in patients with dementia includes few studies with depression as a measured outcome. Even when these outcomes are reported, findings on the effects of emotion-oriented therapies on these and other BPSD are inconsistent and are based on limited or methodologically questionable studies.^49-55 Despite several positive clinical reports of efficacy for these interventions, there is currently insufficient evidence for their effectiveness in reducing any BPSD, and almost no research providing data on their effects on depression. However, numerous anecdotal and research reports of clinical effectiveness, and the client-centered nature of these individualized therapies, suggest that they might yet prove to be of value. More methodologically sound, larger, and well-controlled randomized trials are urged by their supporters (eg, Finnema and colleagues⁴⁵).

Brief Psychotherapies
Brief psychotherapies that have been used with some success in persons with depression in dementia include behavior therapy and cognitive-behavioral therapies (CBTs). Behavioral therapies are more commonly applied in the later stages of dementia, while modified CBTs appear to be more successful with those in the earlier stages of cognitive decline.

Behavior therapy requires a period of detailed assessment in which the triggers, behaviors, and reinforcers (also known as the ABC: Antecedents, Behaviors and Consequences) are identified, and their relationships made clear to the patient. Interventions are then based on an analysis of these findings. There are several interventions for patients with dementia based on behavior theory, including token economy, progressive muscle relaxation, imaging, and social skills training, to name a few.⁵⁴ However, most trials of such therapies do not focus on depression as an outcome. An exception is behavioral programming based on Lewinsohn’s Pleasant Events model.⁵⁶ The model has three core components: (1) explaining the approach to the patient, emphasizing that a person’s behavior is related to how he or she feels; (2) identifying pleasant and negative events in the patient’s daily life, and assisting patients to work on increasing the first and decreasing the second; and (3) explaining that relaxation and mood monitoring are tools to assist the patient in improving. Logsdon and Teri⁵⁷ constructed and validated a Pleasant Events Schedule—Alzheimer’s Disease (PES-AD) to assist caregivers in implementing an intervention for patients with dementia. Teri and colleagues⁵⁸ applied this model to people with dementia, and found that depression scores improved in those who participated in a home-based program combining exercise with behavioral management training for caregivers; however, the effects of the behavioral management component alone were not studied. Lichtenberg and colleagues⁵⁹ also examined the effect of a program based on this model on depression in nursing home residents with dementia. They found no differences on depression scores on either of two standard scales used, although statistically significant positive mood increases were noted.

Although CBT is more commonly used with caregivers of patients with dementia than with the patients themselves, a few studies have tested the effects of individual or group CBT on BPSD, and on depression in particular. Teri and colleagues^60,61 reported clinical improvements in depression scores on standardized measures following CBT, using two strategies for treating persons with AD. Cognitive therapy was used with adults with mild dementia to challenge the person’s negative cognitions in order to reduce distortions, and enable the person to generate more adaptive ways of viewing specific situations and events. Behavioral intervention (based on the Lewinsohn’s Pleasant Events model described above) was used with adults with more moderate or severe dementia. Koder⁶² also addressed the use of CBT techniques to treat anxiety in two cases of older patients with cognitive impairment, and reported positive results.

Other modifications to CBT, besides targeting cognitive strategies to early-stage dementia and behavioral strategies to later stages, involve reducing the cognitive load on the person with dementia by increasing repetition, utilizing concrete examples, and providing memory aids, such as cue cards. Implementing CBT with persons with dementia also requires a highly structured format and continuous monitoring of the individual’s understanding of the therapeutic material. Also, most CBT programs for persons with dementia involve their caregivers, both as CBT “coaches” for the care recipient, and as treatment partners who often benefit from the intervention as well.^53,60,62

Early efforts also have been made to examine the efficacy of a related strategy, problem-solving therapy (PST),⁶³ in treating depression in persons with cognitive deficits. Specifically, Alexopoulos and colleagues⁶⁴ observed improvements in depression following PST in persons with executive dysfunction, although those with Mini-Mental State Examination scores indicating MCI or dementia were screened out of the sample. A single case study found that PST significantly improved the depression scores and clinical profile of an older patient with PD and MCI, both short- and long-term (6 mo post-treatment).⁶⁵ However, further research on the implementation of PST in persons with depression with diagnosed MCI or dementia is needed.

Although there have been no methodologically rigorous trials of CBT or PST to treat depression in persons with dementia, interest in this topic has been revived.⁶⁶ Stanley and McNeese⁶⁷ have recently received funding from the National Institutes of Mental Health (NIMH) to conduct a randomized controlled trial of the impact of CBT on anxiety in persons with mild-to-moderate dementia, and they plan to measure depression using the Geriatric Depression Scale⁶⁸ as a secondary outcome, with results expected in 2010. In addition, Kiosses⁶⁹ is currently conducting an NIMH-funded trial of PST to treat older adults with depression and cognitive impairment, with results anticipated in 2011.

Sensory Stimulation Therapies
Sensory stimulation therapies that have been used to treat BPSD include art/music therapy, aromatherapy, animal-assisted/pet therapy, activity therapies, massage/touch therapies, and multisensory approaches (eg, Snoezelen, described below). The goals of these therapies range from improvement of mood to increased health to improvement in memory. Similar to the emotion-oriented therapies, few rigorous studies have been performed, and results of efficacy are mixed, although reports from clinical observers are generally very positive. The impact of sensory stimulation therapies on depression in dementia has received limited attention, but their potential for efficacy appears positive.

Art therapy is theorized to provide people with dementia with meaningful stimulation, improved social interaction, and a chance to exercise personal choice.⁵² Clinical observation of persons with dementia engaging in art therapy has indicated that it can provide pleasure and improve mood. However, participants in an art therapy program studied by Rusted and colleagues⁷⁰ actually exhibited increased depression scores on two standardized measures over the course of a 40-week program, possibly due to feelings of failure in achieving a pleasing work of art. Reviews on art therapy in dementia suggest that further and more rigorous research is needed to assess its potential benefits on depression in this population.⁷¹

Several clinical reports have described benefits gained by people with dementia from music therapy involving either listening or performing, although most involve listening.⁷² Lord and Garner⁷³ found that a group of nursing home residents who regularly had music played to them, as compared to a comparison group who did not, experienced higher levels of well-being, better social interaction, and improvements in autobiographical memory. More recently, Holmes and colleagues⁷⁴ randomized patients with moderate-to-severe dementia and diagnosed apathy to conditions of silent periods, prerecorded music, or live interactive music, and found much higher levels of positive engagement in the live music condition than in the silence or recorded condition. Other studies support the beneficial effects of music therapy on various BPSD other than depression,^75-81 indicating that this mode of intervention deserves further attention.

Aromatherapy is one of the fastest growing of all the complementary therapies.⁸² It appears to have several advantages over the pharmacologic treatments widely used for dementia, especially limitation of adverse effects from traditional pharmacotherapy. There have been some positive results from three controlled trials that have shown statistically significant reductions in agitation, with excellent compliance and tolerability.^83-85 However, the type of aromatherapy oils tested, method of administration, and outcome measures used varied widely across the few available studies, and depression has not been studied as an outcome. Further trials are needed before conclusions can be drawn on the effectiveness of aromatherapy for depression or other BPSD.

Animal-assisted therapy (AAT) has been reported to lessen agitation and improve socialization in persons with dementia in small, uncontrolled trials.^86,87 Two small studies reported reductions of apathy and withdrawal in persons with dementia who were exposed to therapy dogs in a nursing home setting.^88,89 However, in the only study that employed a measurement of depression, no significant changes in depression occurred.⁸⁸ Further studies with larger samples and expanded measurement are needed. In their review of the limited literature available on AAT and dementia, Filan and Llewellyn-Jones⁹⁰ concluded that AAT may have positive effects on BPSD, but the duration of these effects is unknown, and studies are needed to disentangle the relative benefits gained from “visiting” animals versus “resident” animals. Possible interaction effects from dual exposure of patient and staff/caregivers to the animals during therapy also require further exploration.

Activity therapies include structured physical and recreational activities. A review of 27 studies by Eggermont and Scherder⁹¹ concluded that physical activity programs can improve mood in patients with dementia, with a recent study⁹² indicating that whole-body movement programs have a greater positive impact than walking alone. One study found that depression scores improved in people with dementia who participated in a home-based program combining exercise with behavioral management training for caregivers⁵⁸; unfortunately, it is not possible to disentangle the effects of one intervention from the other. Another study with depression as an outcome found that a biweekly exercise program improved ADL function in persons with AD as compared to controls over a 1-year period, but had no impact on depression scale scores.⁹³ These mixed results indicated that activity therapy may be beneficial for depression in dementia, but studies need to focus closely on the effects of specific types of activities.

A review of massage and touch interventions for dementia found that the very limited amount of reliable evidence available supported massage and touch interventions for anxiety associated with dementia, especially hand massage for the immediate or short-term reduction of agitated behavior.⁹⁴ Cohen-Mansfield95 reported decreases in anxiety in two small trials, one involving daily hand massage and therapeutic touch, and the other a hand massage with essential oils. Unfortunately, no massage trials appear to have considered depression as an outcome variable. Massage therapy, like other complementary and alternative medicine options for dementia, requires further research to establish its efficacy in BPSD, including depression.

Multisensory approaches usually involve using a room designed to provide several types of sensory stimulation such as light (frequently in the form of moving flexible-fiber optics), texture (cushions and vibrating pads), smell, or sound. The use of these resources is tailored to the individual, and therefore not all of the available forms of stimulation may be used in one session. One such approach, called Snoezelen, provides sensory stimuli to stimulate the primary senses of sight, hearing, touch, taste, and smell, through the use of lighting effects, tactile surfaces, meditative music, and the odor of relaxing essential oils. A review by Verkaik and colleagues⁹⁶ provides some evidence that Snoezelen/Multisensory stimulation in a multisensory room is effective in reducing apathy in persons with late-stage dementia. A recent randomized controlled trial by Staal and colleagues⁹⁷ also found that patients on a geriatric psychiatric unit receiving Snoezelen and standard psychiatric care had reduced apathy and agitation scores, as well as increased ADLs, as compared to patients receiving standard care alone. Although multisensory approaches to treatment of BPSD appear quite promising, there is a need for more research-based evidence to inform and justify the use of Snoezelen and similar multisensory approaches in dementia care.⁹⁸

Summary

A wide range of pharmacologic and nonpharmacologic treatments have been used to relieve depression in persons with cognitive impairment and dementia. Clinical consensus and research appear to support SSRIs as a first choice for the treatment of depression in dementia. In patients who are nonresponsive or those with special needs, other medications have been used, including antipsychotics, anticholinergics, anticonvulsants, memantine, and complementary/alternative medications. Extra care is required in prescribing to this population, due to the generally high level of medical and psychiatric comorbidity and potential difficulty in assessing the responses of cognitively impaired individuals.

Nonpharmacologic interventions including emotion-oriented therapies, behavioral and cognitive-behavioral modification programs, and structured activity programs demonstrate initial support for treating depression, anxiety, and other BPSD. Sensory stimulation therapies such as art/music therapy, aromatherapy, animal-assisted/pet therapy, activity therapies, massage/touch therapies, and multisensory approaches show some promise for successful treatment of depression in dementia, but further and more rigorous research is needed to establish their validity.

Dr. Gellis has received funding support from National Institutes of Mental Health grant K01 MH071253 and the John A. Hartford Foundation. Dr. Brown has received funding support from National Institutes of Mental Health K01 MH0669421.

The authors report no relevant financial relationships.