ORLANDO, FLA— Work towards the development of provisional diagnostic criteria for depression of Alzheimer’s disease began on March 9, 2000, when “an FDA [Food and Drug Administration] advisory committee meeting spoke about what the criteria were that would be acceptable to the FDA for a diagnosis that involved the psychiatric complications of Alzheimer’s disease,” said Barnett S. Meyers, MD, Professor of Psychiatry at Weill Medical College of Cornell University. One of their requirements, Dr. Meyers continued, “was that the criteria be arrived at by a consensus of experts in the field, so 20 such experts were identified and contributed. The goals were to facilitate hypothesis-driven research and provide a target for treatment studies.” At the 15th Annual Meeting of the American Association for Geriatric Psychiatry, Dr. Meyers described the criteria, which were published in the March American Journal of Geriatric Psychiatry.

“Three or more of the following symptoms must be present in the same two-week period—not all day or most of the day, but it must be during the same two-week period,” Dr. Meyers said: depressed mood, anhedonia, social withdrawal, tearfulness in less verbal patients, and decreased positive affect or pleasure in response to social contacts or usual activities, “a slight twist on anhedonia, because it allows you to capture behavioral changes.” Disruption in appetite, disturbance in sleep, and psychomotor retardation or agitation “must be distinguished from disruptive behavior, combativeness, and stereotypic behavior of Alzheimer’s disease,” he noted. Irritability, fatigue or loss of energy, feelings of worthlessness, hopelessness, or guilt, and recurrent thoughts of death, including suicide ideation or plan, were also part of the consensus criteria.

The symptoms must cause clinically significant distress or functional disruption, Dr. Meyers added, and there are exclusionary criteria: Symptoms do not occur exclusively in delirium, are not due to physiologic effects of a substance, and are not better accounted for by other conditions such as major depression. “Individuals with recurrent major depression prior to the onset of Alzheimer’s disease who now have symptoms typical of their prior episodes of major depression are presumably suffering from another episode of major depression,” he said. “But just because you have a history of major depression, you may meet criteria of depression of Alzheimer’s disease—that’s not your typical episode of major depression—and should receive the diagnosis of depression of Alzheimer’s disease.”

ASCERTAINMENT OF SYMPTOMS

George S. Alexopoulos, MD, Professor of Psychiatry and Director of the Cornell Intervention Research Center for Geriatric Mood Disorders at Weill Medical College, discussed the characteristics of depression in patients with Alzheimer’s disease, focusing on “areas of confusion in the ascertainment of symptoms of Alzheimer’s depression.” The vegetative symptoms of depression “can come from a variety of causes,” including Alzheimer’s disease proper and comorbid medical conditions, Dr. Alexopoulos said. Likewise, “loss of interest, lack of initiative, and psychomotor retardation are symptoms that are commonly found in depressive conditions because at least part of the depressive syndrome is mediated by subcortical dysfunction, which occurs early in Alzheimer’s disease and therefore might contribute to depression.”

On the cognitive side, “it’s clear that idiopathic depression is associated with cognitive impairment, and geriatric idiopathic depression that does not advance to dementia also is associated with a variety of cognitive impairments,” Dr. Alexopoulos observed. What distinguishes the two syndromes is that “the cognitive impairment in patients with Alzheimer’s disease, even in mild cases, tends to be more severe overall. As a rule, such patients have impairment in recognition memory and often some impairment in language and praxis.”

Another issue complicating the assessment of depression in Alzheimer’s disease is the change in depressive symptomatology over time. “Symptoms can fluctuate widely throughout the day, and also change as the disease progresses,” Dr. Alexopoulos added. Also, patients with Alzheimer’s disease are not immune to comorbidity. “It’s becoming clear that vascular disease superimposed on Alzheimer’s disease increases the probability of developing depressive symptoms, especially if vascular lesions occur in subcortical areas.” Finally, disability is “a distinct dimension of medical health that should be taken into consideration in all assessments” because it can complicate depression, he concluded.

DEPRESSING ASSESSING

Continuing the consideration of the assessment of Alzheimer’s depression, Ira R. Katz, MD, PhD, Director of the Geriatric Center and Professor of Psychiatry at the University of Pennsylvania, averred that “the best way of validating outcome measures or assessment techniques for depression of Alzheimer’s disease is to take a look at the randomized clinical trials that have given positive responses and ask what method for assessment they used.” Interviewer-rated scales were used, he noted, as well as general symptom and behavior instruments, self-rated instruments, and direct assessment of behavior. “The Cornell scale really has to be viewed as the gold standard in all this,” Dr. Katz said. “It’s really the best validated of all instruments. The Hamilton scale works too, but there’s a dirty secret about the Hamilton scale—you have to ‘Cornellize’ it before you can use it in demented patients. We use the Hamilton Scale with cognitively impaired patients; it really requires very detailed local conventions about who you ask for what. The patient with moderate dementia can probably tell you reliably about his current mood but not about yesterday, and you really have to ask caregivers about that and ‘operationalize’ this scale.”

Other domains of assessment are depressive items in general dimensional behavioral or functional scales, Dr. Katz said. “The Neuropsychiatric Inventory deservedly has very wide use, and the Behave AD also has a couple of very well-constructed depressive items that have been proven to be quite useful.

“Those are the most widely used approaches. All of the measures key on either what people tell you or what you observe from watching their behavior,” Dr. Katz commented. The best studies of whether demented people can tell you when they’re depressed come from use of the Geriatric Depression Scale (GDS) in cognitively impaired patients, he explained. “When administered in an interview format, the GDS remains reliable and valid in patients with mild to moderate dementia. Problems include missing data and nonsense responses, but the ‘missense’ responses aren’t bad: If people can answer yes or no, you can probably believe what they say.”

Dr. Katz then discussed the utility of direct observation of behavior in assessing depression in Alzheimer’s disease. “There’s a real tradition of this in gerontology and geriatrics, beginning with borrowing from the Eckman and Freesien facial action coding system,” he noted. “Hurly developed a discomfort scale for affects and emotions in patients with Alzheimer’s disease, and Powell Lawton developed an observed emotion rating scale.”

Based on these various tools, “the conclusion has to be that we really do have reliable and valid methods for assessing depression in Alzheimer’s disease,” Dr. Katz said.

TOWARDS TREATMENT

“This whole exercise eventually goes to treatment, and our effort to see how we should be treating this disturbance of depression that we see in patients with Alzheimer’s disease,” said Costas Lyketsos, MD, MHS, from Johns Hopkins University Hospital. “An important point I think needs emphasis is that we’re studying depression because in and of itself it produces a lot of suffering, but we know in the Alzheimer’s setting that it has additional or excess disability in several domains. If you’re going to do treatment research, in addition to looking at outcomes that relate to depression itself, it’s really important to have outcomes that look at all these other domains as well to see what happens in them.”

Dr. Lyketsos testified that “there’s very little research that has actually tested the efficacy of most of these treatment options, but antidepressants are the treatment modalities that have been studied the most. There have been seven studies between 1989 and 2001—three positive and, interestingly, four negative studies—showing that certain antidepressants might not have efficacy for the treatment of depression,” he said. “Also, these have been short-term intervention studies. Given that this may be a transient symptom, one might think that you need a longer-term outcome to be able to draw any firm conclusions.”

Linda Terry “has led the way in looking at efficacy of other treatments, particularly caregiver and patient-related interventions,” Dr. Lyketsos added. “One was where the caregivers are taught how to problem solve, another where the caregiver is taught how to give patients pleasant-event-type activities. These were compared to usual care, and both had efficacy, but these were pretty much milder depressions, and we’re not sure where they would fall within the range of depression with Alzheimer’s disease.”

There are no other efficacy studies, “only open studies with electroconvulsive therapy, typically showing efficacy even in very demented patients with Alzheimer’s disease, and two comparative efficacy studies showing what we tend to see in this realm, that SSRIs [selective serotonin reuptake inhibitors] and tricyclics actually have comparable efficacy, but SSRIs are better tolerated,” Dr. Lyketsos noted. “We don’t have multi-modality or cross-modality comparison studies yet, and really very little is known of the effects on excess disability. Probably the most consistent finding is that cognition may improve when depression is alleviated.”

Dr. Lyketsos was hopeful that treatment research with depression of Alzheimer’s disease as the new entry point would “allow us to look over time, perhaps in longer time frames, at what happens to mood outcomes and other outcomes that are important to our patients. There clearly are issues about the disturbance itself. I think we all agree that depression of Alzheimer’s disease is a starting point in the consensus panel that needs to be further assessed longitudinally and in relation to the particular disturbances that we see in Alzheimer’s disease, the disability and so forth. We need to appreciate the possibility that this is a distinct syndrome, or part of it is a distinct syndrome, that might have its own cause. And then we need to perhaps do this in the context of treatment research that is going to be looking more broadly and in the longer term at what happens over time to these various outcomes.”

—C. Justin Romano

Suggested Reading
Olin JT, Schneider LS, Katz IR, et al. Provisional diagnostic criteria for depression of Alzheimer disease. Am J Geriatr Psychiatry. 2002;10:125-128.

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