Experimental Drugs on Alzheimer's patients

• FDA "black box" not associated with changes in atypical antipsychotic prescribing rates
  
  
• Non-drug therapy improves brain blood flow
  
• Homocysteine may predict decline in Alzheimer's

Large scale, systematic reviews of published research show that the currently approved Alzheimer's drugs are effective in providing modest but noticeable improvements to people in the mild to moderate stage of the disease, and also found mixed results regarding safety in some of these products, according to new research reported today in Madrid at the 10th International Conference on Alzheimer's Disease and Related Disorders (ICAD), presented by the Alzheimer's Association.

Also among the "Late Submissions" presentations on the last day of ICAD 2006 were:

• A review of atypical antipsychotic prescribing in Alzheimer's in a large managed care database found that an FDA "black box" warning was not associated with a substantial change in prescribing patterns for up to 10 months after the warning was issued.
  
• In people 65 and older, a nondrug therapy for mild cognitive impairment (MCI) including occupational therapy and aerobic exercise improved blood flow in areas of the brain normally affected in Alzheimer's, and also improved memory test scores.
  
• Homocysteine levels in the blood may predict the rate of cognitive decline in Alzheimer's.

"The diversity of research in this session is a wonderful indicator of the vigor of Alzheimer's research," said Ralph Nixon, MD, PhD, a member of the Alzheimer's Association's Medical & Scientific Advisory Council. "And we will continue to move the field forward as fast as we are given money to move it with. While the current drugs provide some noticeable benefits for a period of time, with the aging of the Baby Boomers, we desperately need better therapies that slow, stop and even prevent Alzheimer's disease."

Nixon is Professor of Psychiatry and Cell Biology at NYU School of Medicine, and Director of the Center for Dementia Research at NYU's Nathan Kline Institute.

Systematic Review of the Evidence for Cholinesterase Inhibitors for Alzheimer's

Since the introduction of the first cholinesterase inhibitor (ChEI) as treatment for Alzheimer's, many clinicians have used the approved cholinergic drugs - donepezil, galantamine and rivastigmine - as first line therapies for mild to moderate Alzheimer's. (Tacrine, the first FDA approved ChEI for Alzheimer's, is no longer recommended because of side effects.) Yet, a debate on whether ChEIs are effective continues. For example, in 2005, the National Institute for Health and Clinical Excellence (NICE), which is the independent treatment advisory agency of the United Kingdom's government-funded National Health Service, reviewed its previous recommendation that the ChEIs be used for mild to moderate Alzheimer's. The draft revision indicated that the ChEIs would no longer be recommended as they were not cost effective.

"Due to widespread protests from the public and the medical profession, NICE is reconsidering and will recommend the ChEIs for moderate Alzheimer's only," said Jacqueline Birks, MA, MSc, CStat, of the Cochrane Dementia and Cognitive Improvement Group, Division of Geratology, Department of Clinical Medicine, University of Oxford.

To help inform this debate, Birks conducted a systematic review for the Cochrane Library of all blinded, randomized trials in which treatment for five months or longer with a ChEI was compared with placebo or another ChEI. The main outcomes were cognitive function, global function assessed by a clinician, mood and behavior, activities of daily living and reports of adverse events. She sought to evaluate the efficacy, tolerability and cost effectiveness of the three drugs at the recommended optimal doses in people with Alzheimer's of any severity.

The review included 9,200 patients from 18 trials. The results showed that treatment for periods of six months and one year with donepezil, galantamine or rivastigmine produced modest improvements in cognitive function (on average 2.5 points of the 70 point ADAS-Cog scale), activities of daily living and behavior compared to placebo. The Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-Cog) is the most generally accepted scale for measuring cognitive function in Alzheimer's. In addition, clinicians rated overall performance more positively in ChEI treated patients than the placebo group. According to Birks, none of the treatment effects are large.

The review also found that more patients in ChEI treatment groups (29 percent) drop out of research studies because of side effects than those who received placebo (18 percent). There also was evidence of more adverse events in patients treated with a ChEI than with placebo. Nausea, vomiting and diarrhea, were significantly more frequent in the ChEI groups than in placebo. There was some evidence that the use of donepezil is neither more nor less expensive that placebo when assessing total health care costs.

"We conclude that the cholinesterase inhibitors, donepezil, galantamine and rivastigmine, are efficacious for mild to moderate Alzheimer's, and that they show similar treatment effects," Birks said. "There is some evidence that the results are similar for severe dementia. It would be inappropriate to base a decision regarding the availability of ChEIs on their cost effectiveness, for which there is no good evidence."

Cholinesterase Inhibitors and Risk of Death in Vascular Dementia

Some concerns have been raised about the safety of drugs for Alzheimer's and dementia. Galantamine has been associated with an unexpected increased risk for death in trials of patients with mild cognitive impairment (MCI) but not in Alzheimer's. Galantamine is not currently approved for treatment of MCI. Also, a study of donepezil in vascular dementia resulted in increased deaths among patients taking the drug compared with placebo. Though donepezil is not approved in North America and Europe for treating vascular dementia, it is commonly used for this purpose and is approved in several other countries, mainly in Asia.

In light of these concerns, Lon S. Schneider, MD, professor of psychiatry, neurology, and gerontology at the University of Southern California, Keck School of Medicine, and colleagues from the Cochrane Dementia and Cognitive Improvement Group systematically reviewed the available double-blind placebo- controlled trials of cholinesterase inhibitors (ChEls) and memantine, a drug that is approved in the U.S. and E.U. for treatment of moderate to severe Alzheimer's, and statistically analyzed the studies to assess the risk of death. They identified 42 published and unpublished trials of ChEIs and 12 memantine trials. Most were of 6 months duration, totaling more than 20,000 patients in ChEI trials and about 3,600 in memantine trials. Ten trials were not included because the sponsors declined to provide required data.

Overall, when all the cholinesterase inhibitor studies were analyzed together or when the memantine trials were analyzed, the researchers found no evidence for increased risk of death with these drugs. Looking more carefully, they also found no evidence for increased risks in patients with mild to moderate Alzheimer's, the level of illness for with the ChEIs drugs are approved.

Unexpectedly, the researchers found decreased risk of death for those taking donepezil in four trials in moderate to severe Alzheimer's. They found approximately a 50 percent decrease in risk - a drop from about five percent in the placebo group to 2.5 percent in the donepezil group.

"This effect implies a substantial potential public health impact," Schneider said, "in that, for every 41 patients with moderate to severe Alzheimer's treated with donepezil, statistically one death could be prevented over the course of about six months." Donepezil is not approved for treatment of severe Alzheimer's, and only recently have trials of cholinesterase inhibitors in severe Alzheimer's been done.

With respect to risks for donepezil in vascular dementia, the researchers found only three studies, which had great statistical variability among them - two showing increased risk and one showing decreased risk.

"This is concerning," Schneider said. "More studies are needed as a potential increased risk for death could be as high as three times that of people who are not treated. Our study shows why careful examination of all clinical trials together is required to better assess medications' efficacy and safety implications, and also why results from all clinical trials with drugs for Alzheimer's should be made public."

FDA Warning Not Associated with Substantial Decline in Use of Atypical Antipsychotics in Alzheimer's Population

In April 2005, the U.S. Food and Drug Administration (FDA) requested that drug manufacturers add a "black box" warning to prescribing information for atypical antipsychotic drugs because they were determined to be associated with increased mortality in elderly people with dementia with a rate of death estimated at 1.6 to 1.7 times greater than that of placebo. Most deaths were either heart-related or from infections.

Atypical antipsychotics are regularly prescribed to treat a group of very common and very debilitating symptoms often referred to as "behavioral and psychiatric symptoms of dementia," though they are not approved for that purpose. These symptoms include anxiety, depressed mood, hallucinations, delusions, aggression, agitation, wandering, culturally inappropriate behaviors, and sleep disturbances. According to the International Psychogeriatric Association, approximately 83 percent of patients with dementia demonstrate some type of behavioral disturbance.

According to the Alzheimer's Association, people with Alzheimer's and their families often report that these behavioral and psychiatric symptoms are more difficult to manage and cause greater distress than the more well known cognitive symptoms of memory loss, language problems, and reasoning impairment. Behavioral symptoms are often a determining factor in a family's decision to place a loved one in residential care. After placement, these symptoms can have an enormous impact on care and quality of life for individuals living in long-term care facilities.

To examine the number and types of prescriptions being used by clinicians to treat these symptoms in patients with dementia, Henry J. Riordan, Ph.D., of i3 Research, Basking Ridge, NJ, and colleagues examined prescribing trends of atypical antipsychotic agents in the elderly demented patient population by examining the claims database of a large U.S. health plan for a 10-month time period both before and after the FDA warnings were issued. Keeping patient identity anonymous, they included data for all those over 65 years of age with a diagnosis of dementia of any type, including Alzheimer's, who received a prescription for an atypical antipsychotic during this time period.

There were approximately 900,000 people aged 65 and over included in the database. The researchers found that of these, 4,715 had a diagnosis of dementia and were taking an atypical antipsychotic before the black-box warning was issued. Following the warning, 4,545 people with dementia had a prescription claim for an antipsychotic medication, a 3.6 percent decrease.

Data indicate that the FDA black-box warning was not associated with a substantial decrease in the use of atypical antipsychotics in this elderly population with dementia. One interpretation suggested by Riordan is that the benefits of these atypical antipsychotic agents are perceived by prescribers to outweigh their associated risks or the risks associated with no treatment at all.

Riordan further noted that, "As other therapies may not be considered as effective in treating these symptoms, or cause undesirable side effects, clinicians are left with few choices. This suggests an unmet need for new, safe and effective therapies for the behavioral and psychiatric symptoms in Alzheimer's."

Non-Drug Treatment (Exercise & Occupational Therapy) Improves Brain Blood Flow in MCI

A team led by Seigo Nakano, MD, PhD, at the Fifth Department of Internal Medicine, School of Medicine, Fukuoka University, Fukuoka, Japan evaluated the effects of a non-drug therapy on regional cerebral blood flow in amnestic MCI (MCI with memory loss only) among seniors living in the community.

"I was particularly motivated to examine nondrug therapy to prevent further increases in medical expenses as Japanese society is aging at an extremely rapid pace," Nakano said.

The scientists evaluated 32 amnestic MCI subjects aged 65 years or above in Ajimu, Japan. Eighteen participants received nonpharmacological interventions, and 14 control subjects did not. The intervention included occupational therapy, which was planning and doing simple tasks, and aerobic exercise of climbing up and down a step. Specifically, those in the intervention group helped with the renovation of an old building. During the course of the project, they did planning and were assigned to simple tasks. They also decided the menu for lunch, did shopping and cooked the meal. The seniors in the intervention group did these tasks once a week from November 2004 to November 2005.

All participants were given tests of memory, attention, verbal fluency, and other measures of mental functioning before and after the intervention; regional cerebral blood flow was measured using SPECT. On the baseline SPECT study, there was no significance between intervention and control groups. After one year of follow-up, the cognitive functions and regional cerebral blood flow were revaluated.

The researchers found that in the participants with MCI who received the therapy, the memory score and verbal fluency score after the therapy were significantly better compared to those who did not receive the therapy. According to the researchers, the cerebral blood flow of all participants before the intervention showed a pattern typically seen in early Alzheimer's; the blood flow in areas called the posterior cingulate gyri, precuneus and parietal lobules was low. One year later, the researchers observed that, in those who received the therapy, the overall area with low blood flow became smaller and the blood flow in areas usually low in Alzheimer's was improved.

"In people with amnestic MCI, our nondrug therapy may improve cerebral blood flow in areas that usually decrease in Alzheimer's," Nakano said. "This suggests possible effectiveness in preventing them from progressing to Alzheimer's, which deserves further study."

Homocysteine Levels May Predict Rate of Decline in Alzheimer's

In Alzheimer's, the decline in memory and other cognitive skills over time occurs at different rates in different people. For some, the decline is rapid so that in a few years they cannot cope with living on their own, no longer recognize friends or family and require full-time care. In others, the decline is slower and it may be 10 years or more before the final stage is reached. Little is known about why these rates of decline differ so much between individuals.

A team from the University of Oxford led by Professor David Smith, using statistical methods devised by Dr. Abderrahim Oulhaj, believes that the level of homocysteine in the blood may be one factor that predicts the rate of decline. Homocysteine is an amino acid that is involved in metabolism in cells of the body and which passes out into the blood. Elevated blood levels of homocysteine have been linked to increased risk of premature coronary artery disease, stroke, and venous blood clots, even among people with normal cholesterol levels.

In this new study, the researchers examined the association between the level of homocysteine measured when a person with Alzheimer's first visited the clinic and the subsequent rate of decline in cognitive skills. 102 people with a clinical diagnosis of Alzheimer's were evaluated every six months using CAMCOG (the cognitive and self-contained part of the Cambridge Examination for Mental Disorders of the Elderly) for a minimum of 18 months (three bi-annual visits) up to a maximum of 11 years. The CAMCOG is a brief neuropsychological battery designed to assess cognitive functions, and to detect mild degrees of cognitive impairment.

The scientists found that the higher the homocysteine level at the first measurement, the more rapid the subsequent decline.

"A model that best fitted the results was not a straight line but a curved rate of decline," Smith said. "The decline starts slowly, accelerates and then occurs rapidly, finally slowing again."

The researchers also observed a strong relationship between the concentration of homocysteine and the rate of decline; patients with twice as much homocysteine as other study participants declined twice as rapidly and reached the mid-point of their decline two years earlier. The relationship varied according to the age of the patient, and was strongest in patients younger than 75 at the start of the study.

"Because homocysteine can be lowered by taking high doses of folic acid and vitamin B12, the next step is to see whether B vitamin treatment will slow the rate of decline in Alzheimer's, giving people with the disease more time with higher levels of functioning," Smith said.

Mary Joseph Foundation a non-profit international organization.

Helping people who have Alzheimer's disease and children who are hungry especially in the third world countries,