Memory and Mood: Focus of Geriatric Research Efforts

By Arline Kaplan ©2001 (All Rights Reserved)

The time may soon arrive where older adults will be encouraged to have mood and memory checkups just as they are now encouraged to have physical checkups. This prediction from Michigan State University psychologist Norman Abeles, Ph.D., points to the growing incidence of memory complaints and depression among older adults (U.S. Department of Health and Human Services, 1999).

Recently, the Federal Interagency Forum on Aging-Related Statistics (2000) noted that the percentage of older adults with moderate or severe cognitive impairment in 1998 ranged from 4% among persons aged 65 to 69 to 36% among persons aged 85 and older. Similarly, the percentage of older adults with depressive symptoms climbed from 15% among those aged 65 to 79, to 21% for those aged 80 to 84 and then to 23% for those aged 85 and older.

"Dementia," the Surgeon General said, "produces significant dependency and is a leading contributor to the need for costly long-term care in the last years of life, and depression contributes to the high rates of suicide among males in this population" (U.S. Department of Health and Human Services, 1999).

"Disability due to mental illness in individuals over 65 years old will become a major public health problem in the near future," because of the rapidly growing population of older adults, the Surgeon General warned. This demographic and public health imperative has prompted several National Health Institutes, health associations and pharmaceutical companies to focus research efforts on dementia and depression. In its survey of new medicines in development for older Americans, the Pharmaceutical Research and Manufacturers of America (2000) found 26 medications in the pipeline for Alzheimer’s disease/dementia, including aripiprazole, memantine, olanzapine (Zyprexa) and galantamine (Reminyl), and 26 medications in the pipeline for depression, including reboxetine (Vestra), flesinoxan and substance P antagonists.

Cognitive Impairment

The National Institute of Mental Health (NIMH) and the National Institute on Aging (NIA) are devoting extensive resources to cognitive impairment and dementia research. In an exclusive interview, P. Trey Sunderland, M.D., chief of NIMH’s Geriatric Psychiatry Branch, described the At-Risk study where his staff is evaluating first-degree relatives of Alzheimer’s disease (AD) patients.

"They have a brother, sister, mother or father who was stricken with the illness, and they are aged 50 or older themselves and entering an age of risk. We follow them longitudinally to see whether or not they might be developing biomarkers or signs or symptoms of Alzheimer’s disease early…we are trying to look for early noncognitive signs of Alzheimer’s disease. We might look at spinal fluid and see changes of spinal fluid proteins that are associated with Alzheimer’s disease; we might look for genetic markers that might be associated with the illness; and we might look for early attention deficits or attention changes that would be harbingers of cognitive decline," Sunderland said.
While currently studying about 150 people, Sunderland and his team are recruiting another 100 or so.

"This is an ongoing study with ongoing recruitment," he said. "People come once a year, for a day or two, no more than that, and they get evaluated and then return home to their normal lives. And we accept people from all over the country. We pay their expenses when they are here in the hospital. Our coordinator for the study is Judy Friz, M.A., (301) 496-0948." (In cases of need, the branch may also help with travel expenses to the National Institutes of Health Clinical Center in Bethesda, Md.)

Individuals are also being recruited for a study in which Sunderland and his colleagues are evaluating and treating patients who are mild to moderately afflicted by Alzheimer’s disease and still able to participate in cognitive testing. Patients are treated with medications that are approved by the Food and Drug Administration for memory impairment such as cholinesterase inhibitors.

"Some other medicines are being given that are not necessarily FDA approved for Alzheimer’s disease, but may be approved for symptoms of Alzheimer’s disease like agitation or depression," Sunderland said.

He added that the Geriatric Psychiatry Branch plans to initiate a double-blind, placebo-controlled treatment trial early next year, but as yet he cannot discuss the details.

To develop a human model of memory aging and Alzheimer’s disease, the branch is studying the cognitive and behavioral effects of the anticholinergic agent scopolamine, both alone and in combination with agonists and antagonists of other neurotransmitter systems. This series of studies is meant to help in developing possible early diagnostic markers for the disease and medications that may prevent or slow the progression to Alzheimer’s disease.

Another scientifically ambitious study seeks to determine whether medical interventions in individuals with mild cognitive impairment can help delay the onset of Alzheimer’s disease. The $22 million study funded by NIA and Pfizer Inc., with vitamin E donated by Roche Vitamins Inc. is being conducted at 68 sites in the United States and Canada and involves some 750 men and women aged 55 to 90 who have mild cognitive impairment.

"MCI means they have memory complaints or they have some memory loss as documented by objective tests, but they have not developed Alzheimer’s disease, said Leon Thal, M.D., director of the Alzheimer’s Disease Cooperative Study, a consortium of AD clinical research centers across the country. "The natural history of Alzheimer’s disease tells us that 12% to 15% of people with mild cognitive impairment each year will develop AD. The goal is to test the usefulness of two medications to slow or stop the conversion from MCI to AD."

The clinical trial, directed by Ronald C. Petersen Ph.D., M.D., a neurologist with the Mayo Clinic, and Michael Grundman, M.D., M.P.H., an associate professor of neuroscience at the University of California, San Diego (UCSD), is a randomized, double-blind, placebo-controlled, parallel-group study of vitamin E (alpha-tocopherol) and donepezil (Aricept). Subjects are randomized to one of three treatment groups: 1) placebo vitamin E and placebo donepezil plus a multivitamin daily, 2) vitamin E (2,000 I) and placebo donepezil plus a multivitamin daily, or 3) donepezil (10 mg) and placebo vitamin E plus a multivitamin daily.

When vitamin E was studied in Alzheimer’s patients, Thal said, it delayed important dementia milestones, such as patients’ institutionalization or progression to severe dementia by about seven months (Sano et al., 1997). The other agent, donepezil, is approved for treatment in Alzheimer’s disease. Now, both pharmacotherapies are being tried in patients with MCI.

The study is being conducted over three years, with clinical evaluations every three months for the first six months and then every six months. The primary endpoint is time to development of probable or possible Alzheimer’s disease. Secondary outcome measures include the Clinical Dementia Rating Scale, a pharmacoeconomics scale and a Quality of Life scale. If a study participant develops Alzheimer’s disease, he or she is offered open-label donepezil until the end of the study.

Thal, chair of the neurosciences department at UCSD and a staff physician at the Veterans Affairs Medical Center in La Jolla, noted that there are other Alzheimer’s Disease Cooperative studies being funded by NIA grants looking at compounds that may prove beneficial for Alzheimer’s patients. For example, in Alzheimer’s patients, sleep disturbances are frequent, occurring in 45% of patients, he said. These nocturnal awakenings and agitation lead to considerable burden for caregivers and frequently lead families to the decision of nursing home placement.

Thal is principal investigator for a multicenter clinical trial of melatonin for sleep disturbances associated with AD. In this double-blind, parallel-group trial, placebo was compared with two doses of melatonin: a 2.5 mg, slow-release preparation, and a 10 mg immediate-release preparation. Subjects (n = 157) received the melatonin or placebo for 10 weeks. Actigraphs (an activity monitor worn like a wristwatch) recorded their rest/activity patterns.

"The data from the Actigraphs has been downloaded and is currently being analyzed," Thal said. The primary outcome measure is change in nocturnal sleep time from baseline to the end of the treatment phase. Other outcomes being examined are time awake after sleep onset, sleep latency, sleep efficiency, daytime agitation and changes in cognition. Adverse events and side effects are also being compared by treatment.

"Many family members are saying their relatives with Alzheimer’s disease are sleeping better, but we have to wait for the study analyses," Thal said.

Thal, as ADCS director, also discussed another clinical trial, funded by NIA, to determine whether treatment with nonsteroidal anti-inflammatory drugs (NSAIDS) will slow cognitive and clinical decline in patients with AD. Paul Aisen, M.D., professor of neurology at Georgetown University, is study project director.

"We know that inflammation in the brain contributes to AD damage," Thal said. "We hope that treatment with NSAIDS might slow this damage and its devastating effects."

The 40-site trial involves 325 subjects. Patients will be randomly assigned to one of three treatment groups: rofecoxib (Vioxx), a new selective cyclooxygenase (COX-2) inhibitor; naproxen (Anaprox), a nonselective NSAID, or placebo. This is the first clinical trial to test both classes of NSAIDs prospectively in patients with AD. Patients will be followed for 14 months.

One primary outcome measure is the 12-month change in patients’ scores on the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAScog).

"The newer COX-2 inhibitors…may have an advantage over traditional NSAIDS as potential therapeutic agents in AD," according to the National Institute on Aging (2000). "Recent studies suggest that COX-2 may play a central role in neurodegeneration supporting their use as neuroprotective agents in AD. Also, selective COX-2 inhibitors are easier for patients to tolerate than nonselective NSAIDs."

A clinical trial that Thal and colleagues are just starting encompasses comparing valproate (Depakote sprinkles) to placebo for treating agitation in nursing home patients with Alzheimer’s disease. The NIA-sponsored study will include 150 study subjects at 22 sites.

The National Institute on Aging currently funds 30 Alzheimer’s Disease Centers at major medical institutions across the nation. Thal said the center at UCSD has been involved in some 13 different trials.

One of those trials (Mulnard et al., 2000) sought to determine whether estrogen replacement therapy would slow the progression of Alzheimer’s disease in postmenopausal, hysterectomized women.

A total of 120 women with mild to moderate AD participated in the study. They were randomized to estrogen, 0.625 mg/d or 1.25 mg/d or placebo. Cognitive, global and other outcome measures were evaluated at screening, baseline and two, six, 12 and 15 months.

At the end of the trial, researchers concluded that the women taking high- or low-dose estrogen showed no improvement in their cognition and no slowing of the disease progression, Thal said.
However, several studies are looking at the potential role of estrogen in preventing AD, he said. For example, Mary Sano, M.D., at Columbia University’s College of Physicians and Surgeons, is the principal investigator in the multicenter, randomized, double-blind placebo-control trial of estrogen (Premarin) and estrogen and progesterone combination (Prempro) in the possible prevention of memory loss and Alzheimer’s disease in women. An estimated 900 healthy women aged 65 or older with a positive family history of memory problems are being recruited for the study. So far, about 10% of that number has been enrolled, said Thal.

Thal also mentioned other prevention trials, including a randomized trial of Gingko biloba versus placebo that will involve some 3,000 healthy men and women, aged 75 or older (principal investigator: Steven DeKosky, M.D., from the University of Pittsburgh Alzheimer’s Disease Research Center), and a comparative trial of the common nonsteroidal anti-inflammatory drug naproxen (Naprox) and the selective COX-2 inhibitor celecoxib (Celebrex) (principal investigator: John Breitner, professor and chair of the department of mental hygiene at Johns Hopkins University).

Depression and Older Adults

Depression is a major risk factor for suicide in older adults.

"Elderly white men have six to seven times greater suicide rate than the general population," said George Alexopoulos, M.D., professor of psychiatry at Weill Medical College of Cornell University. "There is enormous literature all agreeing that physicians in internal medicine and primary care frequently do not recognize depression in elderly patients, he said, and even when they do, they under treat it."

To promote better recognition and treatment, NIMH is sponsoring the Prevention of Suicide in the Elderly Project (PROSPECT) being conducted by the three NIMH-supported Intervention Research Centers: Cornell University, University of Pennsylvania and University of Pittsburgh, said Alexopoulos who is the principal investigator of the Coordinating Center (Cornell). The principal investigator of the University of Pennsylvania site is Ira Katz, M.D., Ph.D., professor of psychiatry, and of the University of Pittsburgh, Charles "Chip" Reynolds III, M.D., professor of psychiatry and neuroscience. Drs. Alexopoulos, Katz and Reynolds are directors of the Intervention Research Centers of their respective universities.

The study is seeking to address various obstacles, Alexopoulos said. One such obstacle is the limited time that primary care physicians have. Depressed, elderly, primary care patients may either perceive depression as a natural consequence of old age or even be insulted if they are told that they are depressed. Internists need to have either the time to address these feelings or staff their office appropriately so that a non-physician can help the elderly depressed patient cope with feelings related to the diagnosis and treatment of depression.

"Another important obstacle originates from the chronic and relapsing nature of depression," Alexopoulos said. Not only do primary care physicians need to initiate treatment of the acute episode, he explained, but they also need to make sure patients respond to treatment and adhere to treatment so that they can avoid relapses and recurrences. It is a rare primary care office that has the resources to provide the long-term care required by depressed elderly patients.

To address those obstacles, Alexopoulos and colleagues are training "health specialists" to collaborate with primary care physicians and help them increase recognition of depressed patients, offer timely and appropriately targeted treatment recommendations and encourage patients’ adherence to treatment. As part of their specialized training, the health specialists—nurses and social workers—must attend lectures on geriatric depression, participate in clinical case conferences, review relevant medical literature, and learn how to recognize and treat depression according to the Agency for Health Care Policy and Research (AHCPR) depression guidelines which were modified for geriatric patients by the investigators (Depression Guideline Panel, 1993 a, b). Research psychiatrists supervise the training of health specialists and credential them in the diagnosis and treatment of geriatric depression.

The PROSPECT Study will investigate 1,200 subjects aged 60 and older (920 with depressive symptoms and signs and 280 without significant depressive symptomatology). Half of the depressed patients are treated at six primary care practices providing the intervention services of the health specialist. The other half are treated at six comparable practices offering "enhanced care."

"Enhanced care is usual care, enhanced by diagnostic information on depression offered to the physicians by the research team. After diagnostic information is offered, primary care physicians are free to offer any treatment they elect or even ask for a clinical consultation," said Alexopoulos. "In the intervention practices, the physician has the benefit of the health specialist. The health specialist essentially takes over the patient, follows the guideline and informs the physician of the step-by-step recommendations offered AHCPR Guidelines."

The health specialist does the patient follow-up and advises the physician if a new clinical event happens.

So the primary care physician "in a very time-efficient way remains on top of the case because of the health specialist’s care," Alexopoulos said.

The AHCPR Guidelines recommend the use of an antidepressant in patients with clinically significant depression. In this study, the selective serotonin reuptake inhibitor (SSRI) citalopram is used as the first treatment step. If the patients refuse the SSRI or fail to respond to it, they are offered interpersonal psychotherapy. For patients with complicated depression (e.g., concomitant dementia, bipolar disorder, substance use disorder), psychiatric consultations are conducted.

To document the impact of the intervention on patient care and on physician knowledge and attitudes, the researchers are gathering data from the clinical assessment of patients, on health services utilization from practice-based medical records and on cause of death from death certificates.

"We are measuring not only depressive symptomatology, but outcomes related to function, medical morbidity and suicidality," Alexopoulos said.

Even though the study will not be completed until 2003, Alexopoulos said "our impression is that there are more patients getting treatment and having better outcomes in the intervention practices than the enhanced care practices."

Another NIMH depression-related study centers on bereavement in older adults. Each year, an estimated 800,000 men and women in the United States are widowed.

"Depression occurs in up to 40% of people who have lost their spouse at some point during that first year," said NIMH’s Sunderland, "But we are also looking at biologic changes that are associated with depression and bereavement…There is a long-standing theory that people get sick more frequently in the year after they have lost their spouse, and we are trying to see if that is true, and if [bereavement] is associated with particular immune dysfunctions."

The study is following a group of people who lost their spouses of 20 or 30 years and a comparison group who have not lost a spouse. Both groups are being followed for 13 months after entering the study.

"We are seeing some evidence that 25% to 40% [of the bereaved individuals] become clinically depressed, and we are seeing a slight increase in the number of physical illnesses in those people who are clinically depressed versus those who are not depressed," Sunderland said.

The bereavement study, he added, supports the findings of Reynolds et al. (1999) that
more people get depressed who have been bereaved than the average population. The risk of depression is quite high not just the first two or three months of mourning, but during the entire year following a spouse’s death.

"Clinicians, psychiatrists and general practitioners alike, should be on the lookout for that depression, which can feel and look normal, because everyone gets sad when they have lost someone close to them, but [that depression] can significantly impair their lives," said Sunderland.

He added that Reynolds and colleagues found that medications, such as nortriptyline (Pamelor), and interpersonal psychotherapy are helpful in reversing the depression.

References

Depression Guideline Panel (1993a), Depression in Primary Care: Volume 1. Detection and Diagnosis. Clinical Practice Guideline, Number 5. Rockville, Md.: U.S. Department of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research.

Depression Guideline Panel (1993b), Depression in Primary Care: Volume 2. Treatment of Major Depression. Clinical Practice Guideline, Number 5. Rockville, Md.: U.S. Department of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research.

Federal Interagency Forum on Aging-Related Statistics (2000), Older Americans 2000: Key Indicators of Well-Being. Available at www.nih.gov/nia/news/pr/2000/0810.htm. Accessed on Nov. 2, 2000.

Mulnard RA, Cotman CW, Kawas C et al. (2000), Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease—a randomized controlled trial. JAMA 283(3): 1007-1015.

National Institute on Aging (2000), NIA to study COX-2 inhibitor, other NSAID as new treatment for Alzheimer’s disease. NIH news release. Feb. 7. Available at www.nih.gov/nia/news/pr/2000/02-07.htm. Accessed on Nov. 2, 2000.

Pharmaceutical Research and Manufacturers of America (2000), New Medicines in Development for Older Americans. Washington, D.C.: PhRMA.

Reynolds CF, Miller MD, Pasternak RE et al. (1999), Treatment of bereavement-related major depressive episodes in later life: a controlled study of acute and continuation treatment with nortriptyline and interpersonal psychotherapy. Am J Psychiatry 156(2):202-208.

Sano M, Ernesto C, Thomas RG et al. (1997), A controlled trial of selegiline, alpha-tocopherol, or both as treatment of Alzheimer’s disease. The Alzheimer’s Disease Cooperative Study. N Engl J Med 336(17):1216-1222.

U.S. Department of Health and Human Services (1999), Mental Health: A Report of the Surgeon General. Rockville, Md.: U.S. Department of Health and Human Services, Substance Abuse and Mental Health Services Administration, Center for Mental Health Services, National Institutes of Health, National Institute of Mental Health.

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