Depression in Patients With Alzheimer Dementia

Alzheimer dementia (AD) represents a profound global health concern. By the year 2050, the prevalence of AD in the United States is expected to reach 15 million. At present, there are 4.5 million cases in the United States,¹ which equals an estimated cost of $100 billion each year in medical and family expenses.² Clinically, AD is characterized by the progressive deterioration of patients' cognitive and functional abilities over several years from the initial onset of symptoms.

Neuropsychiatric symptoms are highly prevalent in this patient population and often represent the greatest source of distress to both the patient and his or her caregivers. Depression is one of the most common of these symptoms and often presents differently from major depressive episodes in younger persons. Although the treatment of depression in AD remains challenging, both pharmacologic and nonpharmacologic approaches can offer relief to patients and caregivers. This article highlights the significance of depression of Alzheimer disease (dAD) as a diagnostic entity, elucidates the issues surrounding its recognition, and ultimately offers some practical treatment strategies to physicians dealing with these complex cases.

Symptoms of dAD
Neuropsychiatric symptoms in AD are a heterogeneous group, representing a spectrum of expressions including depression, agitation, hallucinations, delusions, insomnia, and others. Two recent population-based studies examined the epidemiology of these symptoms in AD. In the Cache County Study on Memory in Aging, 53% of AD patients exhibited at least one of the previously mentioned symptoms during the previous month, as defined by the Neuropsychiatric Inventory, with depression occurring in about 20%.³ Similar results were seen in the cardiovascular health study, with depression being the most prevalent symptom at 32.3%.⁴ Comparable studies in the United Kingdom reported similar findings.⁵

Additional analyses of the Cache County data found that despite the broad spectrum of neuropsychiatric symptoms, participants could be classified into 3 groups of symptom constellations: those with a monosymptomatic disturbance (19%; mostly delusions), those with a primarily psychotic syndrome (13%), and those with a primarily affective syndrome (28%).⁶ Studies from clinical settings reported that an estimated 30% to 50% of AD patients had depression. Neuropsy chiatric symptoms are reported to affect as many as 90% of AD patients over the course of their illness, with depression being among the most prevalent. These data confirm the overarching need for improved interventions in this area.

Depression can often be the first symptom in AD. Some evidence indicates that it is most common in mild to moderate illness but has a symptom constellation differing from that of depression in younger patients. For this reason, the National Institute of Mental Health (NIMH) sponsored a workgroup in 2002 to develop a set of criteria that would crystallize the cur rent consensus in the field.⁷ These criteria were predicated on the understanding that al though dAD has some similarities to major depressive disorder (MDD), it represents a unique clinical entity. Because of this qualitative distinction, existing criteria for the assessment of MDD consistently tend to underestimate the prevalence of dAD. Key differences in these criteria include: (1) dAD requires only 3 symptoms versus the 5 for MDD; (2) dAD symptoms can fluctuate more than those of MDD; (3) dAD includes symptoms of irritability and social isolation/withdrawal; and (4) dAD places greater emphasis on anhedonia (a decrease in positive affect or pleasure in response to social contact and usual activities). Generally speaking, patients with dAD tend to be more anxious, agitated, delusional, or inattentive but have less guilt and self-deprecation and are rarely suicidal. The hope among investigators is that the diagnostic criteria developed by the NIMH can more accurately capture these phenomena.

Causes of dAD
A commonly encountered belief among caregivers of patients with dementia is that receiving the diagnosis of Alz heimer disease will inevitably result in depression. This is the reason that families frequently protect their loved ones from hearing the details of their condition. However, there does not appear to be a clear association between a patient's insight into the disease and the risk of a mood disorder. In fact, many patients in whom an affective syndrome ultimately develops have little or no insight into their cognitive condition. In addition, dAD can occur at any stage in the disease process, including in advanced illness, where insight is almost universally absent.

Research is beginning to shed light on some of the proposed biologic foundations of dAD. Several pathologic studies^8-10 consistently showed a relationship between depression in dementia and a loss of noradrenergic neurons in the locus caeruleus. A fluorodeoxy glucose positron emission tomography (PET) study found hypometabolism in the right superior frontal gyrus in patients with dAD as opposed to those without.¹¹ A previous PET study also demonstrated frontal lobe hypometabolism that was most prominent on the left side in depressed patients with dementia.¹² In addition, a recent autopsy study dem onstrated the consistent finding of Lewy bodies in the amygdala of dAD patients.¹³ The further elucidation of these underlying mechanisms may help to guide future treatment efforts.

Diagnosis of dAD
One major challenge for clinicians is the limited capacity of AD patients to accurately convey their mood state. Both impaired language and executive functioning may contribute to a patient's inability to fully integrate and convey the subjective experience of depression despite profound sadness. In that regard, much of the diagnosis relies on the caregivers' observations, since they have frequent contact with the patient.

Experience teaches that it is best to interview informants separately to allow for the greatest opportunity to be candid. A careful history must accurately assess the time course and pattern of any symptoms, and the use of rating scales can aid the clinician in assessing symptom severity. The Cornell Scale for Depression in Dementia (CSDD) is particularly useful because it integrates the patient and caregiver interviews to reach a composite rating.¹⁴Careful at tention in this often medically complex population to comorbid physical factors that may mimic or complicate the diagnosis of dAD is of equal importance (Table 1). Delirium should be considered when the changes are acute. Issues such as medication toxicity (especially from anticholinergic agents), infections, metabolic abnormalities, pain, con stipation, and other primary medical problems are common.

Treatment of dAD
Once an accurate diagnosis is made, treatment requires a pragmatic ap proach. In all cases, specific nonbiologic interventions should be made first. Nonpharmacologic treatment approaches offer an advantage over medication therapies because of their safety and are often a first-line treatment in more mildly depressed patients or in cases in which the caregiver is depressed.¹⁵ In more severe cases, or in situations in which patients fail to respond to these efforts, biologic treatments take precedence. Unfortunately, many good treatment plans fail or yield only partial benefit. These cases require a persistent effort that continually con siders alternative approaches.

Caregiver support
Several fundamental principles guide effective caregiver interventions; these are briefly outlined in Table 2. An es sential first step in interventions is to focus on education about dementia and depression. In many circumstances, this includes helping caregivers make needed changes in the patient's environment (providing adequate structure, increasing physical comfort, and reducing overstimulation) or their own ap proach (having reasonable expectations, remaining calm and reassuring, not rushing the patient). The importance of developing a predictable daily rou tine that incorporates pleasur able activities for the patient should be paramount. In addition, caregivers vary in their aptitude to problem-solve when difficult situations arise. Working with them systematically as problems pre sent can help them cultivate this skill. It is essential to convey a sense of hope, allow an opportunity to "vent,&334; and praise their successes. It is also important to help caregivers recognize when the level of care a patient requires ex ceeds their abilities and may necessitate a change in living arrangements. Another key support is the clinician's 24-hour availability in case of crisis.

Additional resources, such as a local Alzheimer Association support group (go to www.alz.org for listings) and reading material, including The 36-Hour Day¹⁶ can provide added support.

Behavioral approaches
There are few studies of behavioral interventions in AD. One controlled study examined 2 interventions-one targeted to the patient, which focused on the provision of pleasant activities, and one that was caregiver-oriented and taught problem-solving skills.¹⁷ Both were more effective than usual care or a "wait list" control group in reducing depression in AD patients. In another controlled trial, an exercise training program combined with caregiver training also demonstrated an improvement in depression ratings.¹⁸ Often, interventions such as these are best implemented in the context of adult day treatment or in a senior citizens' center. Helping caregivers acquire information about local programs through a local chapter of the Alzheimer Association or the local department of aging can go a long way in establishing the most appropriate setting for clinical benefit.

The role of medications
When depression is severe or a CSDD score is above 12,19 when the patient is suicidal or violent, or when the patient is not eating or drinking, antidepressant therapy is likely required.¹⁵ Currently, there is no FDA-approved treatment for dAD; however, Table 3 summarizes the results of existing controlled trials of antidepressant medications in AD. It should be noted that most of these studies used DSM-IV diagnostic criteria, because the NIMH criteria for dAD were not in existence at the time.

As discussed, routine diagnostic criteria do not likely capture an accurate picture of the condition and could overlook aspects of treatment response. Other challenges in the interpretation of this literature are inconsistencies in efficacy findings, limited replication studies, and several negative studies that indicated no superiority of the drug over placebo. As a function of these limitations, these data cumulatively serve as a general guide to the treatment of dAD, but do not yet offer any definitive man agement recommendations.

At this point, the initial approach is to begin with an SSRI. The evidence seems to indicate a similar efficacy be tween tricyclic antidepressants (TCAs) and SSRIs, with the latter being better tolerated with fewer cognitive side ef fects. Common side effects of SSRIs are largely related to their serotonergic activity and include GI distress, tremor, headache, restlessness, and insomnia. No controlled studies exist that examine the effects of newer antidepressant categories (serotonin-norepinephrine reuptake inhibitors, bupropion, or mirtazapine) in dAD. The best safety and efficacy data exist for sertraline and citalopram (with the latter arguably extrapolated to escitalopram based on their pharmacologic similarity), which make them a reasonable starting point in treatment.

These clinical trials seem to indicate that antidepressant dosing in dementia should be similar to that in younger patients. This is a key distinction from the standard lower dosing of other neuroleptic agents in this population. Titration to the maximal target dose over 4 weeks is ideal; however, slower schedules are appropriate as clinically indicated. If no response is seen after that time, a change is likely warranted or consideration may be given to augmentation with an antipsychotic or anticonvulsant. If partial benefit is seen after 4 weeks, full benefit may require up to 12 weeks of treatment. Scales such as the CSDD can be useful in monitoring this response.

If there is still inadequate response at 12 weeks, consider a medication change following a 2-week taper. Reasonable second-line agents include nor adrenergic drugs such as venlafaxine, mirtazapine, secondary amine TCAs, or a monoamine oxidase inhibitor. This choice theoretically relates to the previously described finding of the loss of noradrenergic neurons in the locus cae ruleus. If mood is im proved but agitation remains, a subsequent step can include adding an anticonvulsant such as divalproex. In our experience, initial dosages of 250 mg bid or 500 mg qhs are often required, with a titration to a serum level of 50 to 100 µg/mL; how ever, clinical re sponse is often seen at lower levels. This initial dosing may be somewhat higher then standard geriatric dosing.

For treatment-refractory patients, consideration should be given to electroconvulsive therapy, especially when patient safety is at risk because of suicidality, violence, or poor self-care. The concern for increased postictal delirium can be minimized by careful patient selection and in many cases, treatment has also been demonstrated to result in improved cognitive functioning in dementia.²⁰

Conclusion
Depression is a very frequent neuropsychiatric symptom in AD and is responsible for significant morbidity and caregiver burden. The symptom constellation of dAD differs from that of major depressive episodes, frequently including irritability, agitation, delusions, anxiety, and anhedonia. This syndrome has only recently been identified and provisional diagnostic criteria for dAD should help in understanding causes and treatments. Successful management requires the thoughtful integration of pharmacologic and non pharmacologic treatment strategies. The desire to maximize the quality of life for those dealing with this devastating disease fuels this effort.

Dr Kozauer is a neuropsychiatry postdoctoral fellow in the division of geriatric and neuropsychiatry, Dr Rosenberg is assistant professor of psychiatry and behavioral sciences in the division of geriatric and neuropsychiatry, and Dr Lyketsos is professor and chair of the department of psychiatry at The Johns Hopkins Hospital in Baltimore, Md. Dr Kozauer and Dr Rosenberg report that they have no conflicts of interest concerning the subject matter of this article. Dr Lyketsos receives grant support from NIMH, NIA, Associated Jewish Federation of Baltimore, Forest Labora tor ies, GlaxoSmithKline, Eisai, Pfizer, Astra-Zeneca, Eli Lilly, Ortho-McNeil, Bristol-Myers Squibb, and Novartis. He is a consultant/advisor for Astra-Zeneca, GlaxoSmithKline, Eisai, Novartis, Forest Laboratories, and Supernus Pharmaceuticals. He has received speaking honoraria from Pfizer, Forest Laboratories, and GlaxoSmithKline.

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