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Dementia produces significant dependency and contributes to costly long-term care; depression contributes to high rates of suicide; and both contribute to lower quality of life and higher disability among older patients. Therefore, researchers are eager to find new ways of preventing and treating these conditions. Studies currently underway include evaluating the role of health specialists in treating depressed patients, looking at bereavement and its effects on patients, and the role of estrogen, vitamin E, NSAIDs and COX-2 inhibitors in preventing and treating Alzheimer's disease.
Older adults may soon 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., stems from the growing incidence of memory complaints and depression among older adults (U.S. Department of Health and Human Services [HHS], 1999).
"Dementia," the U.S. Surgeon General has 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" (HHS, 1999).
The importance of these conditions is mirrored by the number of medications currently in development-26 for Alzheimer's disease/dementia, including aripiprazole, galantamine (Reminyl), memantine and olanzapine (Zyprexa), and 26 for depression, including flesinoxan, reboxetine (Vestra) and substance-P antagonists (Pharmaceutical Research and Manufacturers of America, 2000).
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 interview with Psychiatric Times, P. Trey Sunderland, M.D., chief of NIMH's geriatric psychiatry branch, described the At-Risk Study, in which his staff is evaluating first-degree relatives of patients with Alzheimer's disease (AD).
These individuals, aged 50 or older, are being followed longitudinally to see whether they develop early biomarkers or symptoms of AD, Sunderland explained. The research team will look for AD-associated changes in spinal fluid proteins, genes and attention. The study currently comprises about 150 people, and Sunderland and his team are recruiting about another 100.
They are also initiating a study evaluating and treating patients who are mildly to moderately afflicted by AD but are still able to participate in cognitive testing. Patients are treated with medications, such as cholinesterase inhibitors, that are approved by the U.S. Food and Drug Administration for memory impairment.
"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 added.
To help in developing early diagnostic markers for the disease and medications that may prevent or slow the progression of AD, the branch is studying the cognitive and behavioral effects of anticholinergic agents, both alone and in combination with agonists and antagonists of other neurotransmitter systems.
Another scientifically ambitious study seeks to determine whether medical interventions in individuals with mild cognitive impairment (MCI) can help delay the onset of AD. The22 million study, funded by the NIA, Pfizer Inc., and Eisai Co. Ltd., with vitamin E donated by Roche Vitamins Inc., is being conducted at sites in the United States and Canada.
"The natural history of Alzheimer's disease tells us that 12% to 15% of people with mild cognitive impairment each year will develop AD," said Leon Thal, M.D., director of the Alzheimer's Disease Cooperative Study (ADCS), a consortium of AD clinical research centers across the country. "The goal is to test the usefulness of two medications to slow or stop the conversion from MCI to AD."
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), subjects of the double-blind, parallel-group trial are randomized to one of three treatment groups: placebo vitamin E (a-tocopherol) and placebo donepezil (Aricept) plus a multivitamin daily; vitamin E (2000 IU) and placebo donepezil plus a multivitamin daily; or donepezil (10 mg) and placebo vitamin E plus a multivitamin daily.
When vitamin E was studied in patients with AD, Thal said, it delayed important dementia milestones, such as patients' institutionalization or progression to severe dementia, by about seven months (Sano et al., 1997). (For more information on this subject, see "Moving From Treatment to Prevention in Alzheimer's Disease With Vitamin E and Estrogen," Psychiatric Times December 1999, p25-Ed.) The other agent, donepezil, is approved for treatment in Alzheimer's disease.
The primary endpoint of the three-year study is time to development of probable or possible AD. Secondary outcome measures include the Clinical Dementia Rating Scale (CDR), a pharmacoeconomics scale and a quality-of-life scale. If a study participant develops AD, they are offered open-label donepezil until the end of the study.
Thal, as ADCS director, discussed another clinical trial funded by NIA to determine whether treatment with non-steroidal 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 325 subjects in the 40-site trial will be randomly assigned to one of three treatment groups: rofecoxib (Vioxx), a new selective cyclooxygenase-2 (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. According to the NIA (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."
The NIA 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 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.
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 noted.
Nonetheless, he said, several studies are looking at the potential role of estrogen in preventing AD. 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-controlled trial of estrogen (Premarin) and an estrogen and progesterone combination (Prempro) in the possible prevention of memory loss and AD in women.
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., University of Pittsburgh Alzheimer's Disease Research Center) and a comparative trial of the common NSAID naproxen and the selective COX-2 inhibitor celecoxib (Celebrex) (principal investigator: John C. Breitner, M.D., M.P.H., Johns Hopkins University).
Depression and Older Adults
To promote better recognition and treatment of depression, the NIMH is sponsoring the Prevention of Suicide in the Elderly Project (PROSPECT), conducted by three NIMH-supported intervention research centers: Cornell University, University of Pennsylvania and University of Pittsburgh, according to George Alexopoulos, M.D., professor of psychiatry at Weill Medical College of Cornell University. Alexopoulos is the principal investigator of the coordinating center at Cornell; the principal investigator at the University of Pennsylvania site is Ira Katz, M.D., Ph.D., professor of geriatric psychiatry, and at the University of Pittsburgh site, it is Charles Reynolds III, M.D., professor of psychiatry and neuroscience and director of the Mental Health Clinical Research Center for Late-Life Mood Disorders. The three men are directors of the intervention research centers at their respective universities.
The study, which was originally designed to reduce suicidal ideation in the older population, is seeking to address various obstacles to care, Alexopoulos explained. When patients perceive depression as a natural consequence of old age or take the diagnosis as an insult, for example, internists need appropriate time with patients or staff to help patients cope with related feelings.
"Another important obstacle originates from the chronic and relapsing nature of depression," Alexopoulos said. Physicians need to initiate treatment and ensure that patients are responding and compliant. "It is a rare primary care office that has the resources to provide the long-term care required by depressed elderly patients," he noted.
To address these concerns, Alexopoulos and colleagues are training nurses and social workers as health specialists who will collaborate with primary care physicians. As part of their training, these specialists 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 Agency for Health Care Policy and Research (AHCPR) depression guidelines, which the PROSPECT investigators modified for geriatric patients. Research psychiatrists supervise the health specialists and ensure they are experts in depression diagnosis and treatment.
The PROSPECT study will investigate 1,200 subjects aged 60 and older (920 with depressive symptoms and 280 without). Half the depressed patients will be treated at six primary care practices providing the intervention services of the health specialist. The other half will be treated at six comparable practices that offer "enhanced care."
Care is "enhanced by the fact that we offer diagnostic information on the patient to the physician, and then the physician does what he or she wants with regard to treatment," said Alexopoulos. "In the intervention practices, the physician has the benefit of the health specialist, [who] essentially takes over the patient, follows the guideline and guides the physician as to what to do step-by-step."The health specialist also does the patient follow-up and advises the physician of new clinical events. Thus, the primary care provider "in a very time-efficient way remains on top of the case because of the health specialist's care," Alexopoulos explained.
Depressed patients will be given the selective serotonin reuptake inhibitor citalopram (Celexa) as first-line treatment. If they 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 and so forth), psychiatric consultations are conducted.
"We are measuring not only depressive symptomatology, but outcomes related to function, medical morbidity and suicidality," Alexopoulos said.
Another NIMH depression-related study centers on bereavement in older adults. "Depression occurs in up to 40% of people who have lost their spouse at some point during that first year," NIMH's Sunderland told PT. His team is also looking at older patients' immune system response associated with depression and bereavement.
For 13 months, the study is following people who have lost their spouses of 20 or 30 years and a comparison group who have not lost a spouse. "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 supports the findings of Reynolds et al. (1999) that individuals who are bereaved are more likely to become depressed than is the general population. The risk of depression is quite high not just in 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 depression, which can feel and look normal, because everyone gets sad when they have lost someone close to them, but [depression] can significantly impair their lives," said Sunderland.
He added that Reynolds and colleagues found that medications, such as nortriptyline (Pamelor), combined with interpersonal psychotherapy are helpful in reversing the depression.
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. Available at www.nih.gov/nia/news/pr/2000/02-07.htm. Accessed Nov. 2.
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.