New Diagnostic Tool Validates Alzheimer’s-Syndrome Depression

By developing a new diagnostic tool, a consortium of researchers has collected some of the strongest evidence to date validating the diagnosis of major depressive syndrome of Alzheimer’s disease.

For more than 20 years, a number of geriatric psychiatrists and neurologists have suspected that depression that occurs in the context of dementia in elderly people is not the same as depression that occurs in elderly people who are cognitively normal. Now, a landmark study from researchers who first proposed a distinct diagnosis provides solid empirical data based on a standardized, systematic assessment tool.

“All of the patients at each of the sites—which included four National Institute on Aging–funded Alzheimer’s disease research centers at the University of California, Los Angeles, the Mayo Clinic, Indiana University, and Mt. Sinai School of Medicine, along with the geriatric psychiatry branch at the National Institute of Mental Health—were given a semi-structured, clinical assessment that we had developed for the diagnosis called the Clinical Assessment of Depression in Dementia [CADD],” said George Zubenko, M.D., Ph.D., a professor of psychiatry at the University of Pittsburgh.

Zubenko told Psychiatric News that the development of CADD was a significant step forward in research methodology. Previous reports of depression in the context of Alzheimer’s had varied widely as far as prevalence and symptomatology, simply because each used different assessments and variable methodologies.

Zubenko said, “We used common, reliable methodology so that we were all collecting the same information in the same way, using the same sources of both direct and ancillary information from both informants and medical records. Then, having gone through that common methodology for assessment, we applied a common set of diagnostic criteria so that we could establish a diagnosis.”

The development of CADD and its validation in 243 patients with Alzheimer’s disease and 151 nondemented elderly comparison subjects at the five research centers is reported in the May issue of the American Journal of Psychiatry.

Incorporates Existing Scales

CADD is a diagnostic interview that incorporates a structured, anchored version of the 17-item Hamilton Depression Rating Scale that has previously been validated for use in a geriatric population. In addition, CADD includes the subsection of the Neuropsychiatric Inventory that assesses the presence or absence, frequency, and severity of a list of hallucinations and delusions commonly experienced by patients with dementia.

A portion of the Structured Clinical Interview for DSM-III-R that scores signs and symptoms required for the diagnosis of major depression is also included, with the end result of CADD being a single, coherent clinical interview that can be completed in approximately 30 minutes. Responses to each item are elicited from each patient, as well as a best informant or caregiver, and includes a final judgment by the trained clinician who conducts the interview and has reviewed available medical records.

CADD also records sociodemographic information, current medications, age at onset of cognitive decline, and the patient’s score on the Mini-Mental State Exam, as well as the Clinical Dementia Rating at the time of assessment. Finally, the instrument includes a narrative summary describing the evaluator’s diagnostic assessment.

Validating Instrument and Diagnosis

Zubenko and his colleagues report that nearly half (44.9 percent) of the patients with Alzheimer’s disease had experienced at least one major depressive episode during their lifetimes, and a third (34.6 percent) developed major depressive episodes at or after the onset of cognitive decline.

In comparison, 28.5 percent of the nondemented patients had experienced at least one major depressive episode, which allowed the researchers to look for differences in the presentation of depression between the two groups of patients.

Significantly, the team found that the largest portion of patients with Alzheimer’s disease most likely to develop a major depressive episode were those with the mildest cognitive impairment. Compared with nondemented patients, patients with Alzheimer’s disease were significantly more likely to report diminished ability to concentrate or indecisiveness and significantly less likely to report sleep disturbances (either insomnia or hypersomnia) and feelings of worthlessness or excessive guilt. Interestingly, no significant changes were seen in depressive features between mildly, moderately, and severely demented patients.

Zubenko and his colleagues believe that CADD reliably diagnosed and characterized the number and course of major depressive episodes occurring in patients with Alzheimer’s disease. The next step, Zubenko said, is to confirm that the CADD methodology is generalizable across patient populations. The underlying question then, he added, is to find out what anatomical or physiological changes are responsible for the unique nature of depression in the context of dementia as differentiated from depression in cognitively normal seniors.

There is evidence, Zubenko noted (including studies he did as far back as the 1980s), that “the major depressive syndrome of Alzheimer’s disease is associated with accelerated degeneration of aminergic neurons in the brain stem—the collection of cells that synthesize the majority of the aminergic neurotransmitters—serotonin, norepinephrine, and dopamine.”

Those studies, he added, are some of the only evidence that supports the aminergic hypothesis of depression, work that needs to be advanced and expanded.

“Having [validated CADD], we are now across our sites characterizing a large number patients from [other investigators’] longitudiinal cohorts of clinically diagnosed Alzheimer’s and their control groups, with the goal being to use our common reliable methodology in a prospective longitudinal way to characterize the emergence of major depressive episodes in these patients,” Zubenko said. “The expectation then is, that as patients die, we will be getting their brains and be able to move ahead with neurochemical and pathological studies of the correlates of change that mark this disease.”

The study, “A Collaborative Study of the Emergence and Clinical Features of the Major Depressive Syndrome of Alzheimer’s Disease,” is posted on the Web at http://ajp.psychiatryonline.org. ▪

Am J Psychiatry 2003 160 857