The Tangled Neuron

Johnson & Johnson Risperdal Kickback Allegations

Last week, the New York Times published an article about a U.S. government complaint that Johnson & Johnson paid kickbacks to the biggest nursing home pharmacy in the U.S. to increase prescriptions of the antipsychotic Risperdal and other drugs.  On her blog ElderCareTalk, Laura Bramly has posted a great analysis of what this means for people whose family members are in memory care units.

German Institute Cites Lack of Evidence for Alzheimer's Treatments

The Institute for Quality and Efficiency in Healthcare has issued a new report on Alzheimer's treatments.  Comissioned by the German government, the report concludes:

• there is not enough proof that memantine (sold as Namenda in the U.S.) is effective in treating Alzheimer's
• cholinesterase inhibitors can "slightly delay" a decline in memory and thinking
• the evidence on ginkgo is mixed
• there's not enough proof that non-drug treatments are effective.

Axona: A Different Approach to Alzheimer's

Summary:  Axona is Accera’s new product for people with mild to moderate Alzheimer’s.  Available in the U.S. by prescription only, Axona is marketed as a medical food.  This means it was not subject to FDA pre-market review and approval.  Results of the company’s trials of Axona sound promising, but we’ll have to wait for more data to be published to get a better idea how effective the product is.

Suddenly, Axona is everywhere.  I heard people talking about it at a local Alzheimer’s educational event last week.  There’s an advertisement for it on the back cover of the latest edition of the Alzheimer’s Foundation of America’s magazine, care ADvantage.   Accera, the company that developed Axona, is also a silver sponsor of the Alzheimer’s Association’s upcoming ICAD conference.  

Axona is designed to address the “hypometabolism,” or reduced use of glucose, seen in some areas of the brains of people with Alzheimer’s.   Glucose is the brain’s source of energy.  Axona is formulated as a powder, and is mixed with water to make a once-a-day drink. 

The product is unique in its approach to Alzheimer’s and in Accera's choice to market it as a “medical food.”  I talked last week with Steve Orndorff, Ph.D., founder and CEO of Accera, to get more details.

Are You at Risk for Drug Interactions?

Summary:  A recent study suggests that some older adults are at risk for potentially dangerous drug interactions.  Make sure your doctor and your pharmacist are aware of all the supplements, prescription and over-the-counter medicines you take, and ask them to check for potential interactions.

In online forums and at meetings, I hear people with memory loss talk about the medicines and supplements they take.  It’s not unusual for them to reel off a list of several prescription drugs and twenty or more supplements.  Could the combination of some of these medicines be dangerous?

Dima Qato, PharmD, MPH

Potential drug interactions are a concern for everyone, not just for people with memory loss.  Late last year, the Journal of the American Medical Association published an article by Dr. Dima Qato and her colleagues at the University of Chicago on the medicines older Americans take.  The researchers catalogued the drug use of over 2200 people across the U.S., ages 57 through 85.

Anticholinergic Medicines and Memory Loss

Summary:  commonly-used prescription and over-the-counter drugs may contribute to memory loss in older people, particularly if taken for long periods of time.

Results of a recent study by scientists at Yale University suggest that long term use of some prescription and over-the-counter medicines contributes to memory loss in older people.  Previous studies, including one by French researchers, had also shown a connection between these medicines and memory loss.  The Yale study, which quantified the effects of using multiple anticholinergic medicines over time, confirmed this connection.  For study participants (544 men 65 and older), cumulative exposure to these medicines over a year’s time was associated with lower scores on tests of short term memory and executive function.  The study authors believe that the medicines have a similar effect on women.

Generic Razadyne: Price Decrease for Alzheimer's Drugs?

When my father started taking Aricept (a cholinesterase inhibitor) a few years ago, it cost my parents $138 per month.  When his doctor added Namenda, their monthly cost for just those two medicines was well over $200.

The price of cholinesterase inhibitors may be coming down soon, at least in the U.S.  This is because the Food and Drug Administration (FDA) has approved four companies’ applications to offer generic versions of Razadyne (galantamine).  Based on testing for “bioequivalence,” the FDA believes that these generic versions have the same therapeutic effects as branded Razadyne does.

Cholinesterase Inhibitors May Help Psychological Symptoms of Alzheimer's, At Least A Little

Researchers at Indiana University and at University of Kent and Kings College London in the U.K. recently combined the results of nine studies on whether cholinesterase inhibitors improve psychological symptoms in Alzheimer’s patients.  Cholinesterase inhibitors (Aricept, Exelon and Razadyne) are drugs prescribed to treat the cognitive symptoms of the disease.

Based on their “meta-analysis” of the combined results, the researchers concluded that these medicines appeared to reduce psychological symptoms in people with mild to moderate Alzheimer’s.  However, the positive effects were small enough that they might not make a difference for patients or caregivers.

The analysis did not show a positive effect for people with severe Alzheimer’s. 

Who Should Get Alzheimer's Drugs?

If you live in the U.K. and have been diagnosed with early stage Alzheimer’s, you might not be able to get Alzheimer’s drugs, at least not through the country’s National Health Service.  Based on cost-benefit analyses, the government agency NICE (National Institute for Health and Clinical Excellence) recommended in 2006 that cholinesterase inhibitors (Aricept, Reminyl, Exelon) should be offered only to people in the moderate stages of Alzheimer’s.  The agency also recommended against prescribing these drugs for the cognitive symptoms of people with vascular dementia, and against prescribing memantine (Namenda, Ebixa) outside of clinical trials.  These recommendations are still being appealed.

NICE considers the cost/benefit ratio for all new drugs (not just Alzheimer’s drugs) in deciding what will be covered by the National Health Service.  The New York Times reports that other countries, including the U.S., are looking at NICE’s methods.

With this as background, a recent commentary in the journal Nature seems ironic.  In the commentary, seven co-authors say the use of Alzheimer’s medicines and other cognition-enhancing drugs by cognitively “normal” people could benefit both individuals and society.  They call for more research to understand the potential benefits and harm that could result.

Beyond Drugs: Other Ways To Treat Alzheimer's and Dementia (Part 2 - The Problems with Drug Treatments for Psychological Symptoms)

In a previous post on the "Psychosocial Issues and Neuropsychology" session at ICAD, I wrote about Dr. Alistair Burns' presentation on  how caregiver interventions and nondrug therapies can help reduce dementia-related psychological symptoms like agitation and anxiety.  During the same session, Dr. Clive Ballard, Director of Research for the Alzheimer's Society and a Professor at Kings College London Institute of Psychiatry, made the case for why we need nondrug interventions.  Dr. Ballard focused on reviewing the evidence that drug treatments are often sub-optimal.

The Alzheimer's Action Plan: Book Review

Summary: The Alzheimer's Action Plan is a comprehensive resource for patients and families. It's not likely that most people with memory loss will get the standard of care the authors would want for their own parents, but the guidelines in the book will help patients and families get as close to that standard as possible.

The scenario at the beginning of The Alzheimer's Action Plan will be familiar to many adult children whose elderly parents have memory problems:  warning signs, denial of problems by both your parent and his doctor, increasing problems, seemingly sudden diagnosis of Alzheimer's, no advice or support.  While this scenario doesn't exactly reflect my family's situation, I wish we had had this book when my father was alive.

Lisa Gwyther, M.S.W.

I met the authors at ICAD last week.  Dr. Murali Doraiswamy is Chief of Biological Psychiatry and past Director of Psychiatry Clinical Trials at Duke University Medical Center.  Lisa Gwyther is Director of the Alzheimer's Family Support Program at Duke's Center for Aging and current President of the Gerontological Society of America.  The combination of the viewpoint of a doctor involved in clinical trials and that of a social worker who has worked with thousands of families makes The Alzheimer's Action Plan a comprehensive resource.

Dr. Doraiswamy and Ms. Gwyther wrote the book to answer the question they often hear:  "what would you do if your mother was starting to have memory problems?"  To get a flavor for how the book is structured around real-world concerns, read the last chapter, "Our Top 40 Questions and Answers," first.  You'll find thoughtful answers to other questions they hear, including:

• "How do I get my father to go to the doctor when he thinks nothing is wrong?"

Flurizan, Lipitor and Alzhemed: Negative Study Results

On Monday, Myriad Genetics Inc. announced the failure of Flurizan in Phase III trials.  This news follows the results from the LEADe study showing the cholesterol drug Lipitor did not benefit Alzheimer's patients, and the failure of Alzhemed in Phase III trials last year.

With all this disappointing news, it seems more important than ever for professionals, with input from patients and their families, to talk about new approaches to Alzheimer's research and care.  Maybe implementing some of the ideas discussed at the National Institute on Aging 2006 conference would help.  I'll be at ICAD (the International Conference on Alzheimer's disease) in late July - it will be interesting to see whether new approaches are widely discussed.

AAFP-ACP Guidelines for Drug Treatment of Dementia: What Do You Think Of The AAFP's Photo?

When my father was struggling with memory loss, his doctors prescribed both Aricept and Namenda. If they helped his memory and thinking, I couldn’t tell. For Dad, the side effects of these medicines didn’t seem to be worth any benefit.

Dad and my nephew Chris play the piano

But for other people with memory loss, these drugs seem to be very helpful, and the side effects are generally tolerable. This wide variety in benefits and side effects may be what the American Academy of Family Practitioners (AAFP) and the American College of Physicians (ACP) were trying to address when they published new guidelines about drug treatment of dementia last month.

Amyloid Inhibitors for Alzheimer's: Less Promising Than Thought?

Summary: Amyloid inhibitors, a type of Alzheimer’s drug under development, may not be as promising as once thought. A cheap and easy test early in the drug development process should help researchers focus on the most promising compounds. This finding does not apply to the vaccines being developed to clear amyloid.

If you’re one of the millions waiting for Alzheimer’s drugs now under development, you’ll want to know that researchers at the University of California, San Franciso (UCSF) have come to some interesting conclusions about one type of potential treatment. Which do you want first - the good news or the bad?

UCSF researchers Brian Shoichet, Ph. D. (left) and Robert Fletterick, Ph.D

Let’s start with the bad news. It looks like “amyloid inhibitors” may not be as promising as once thought. Some Alzheimer’s researchers are focused on developing these compounds to prevent beta amyloid proteins from clumping together to form the fibrils and plaques thought to be harmful to your brain. But as with other diseases, the trick is to find compounds that will affect only the beta amyloid “target,” without affecting other proteins your body and brain might need.

Research conducted in the lab of Brian Shoichet, a professor in the Department of Pharmaceutical Chemistry at UCSF, suggests that amyloid inhibitors often affect too many other proteins to be safe and effective Alzheimer’s treatments. The results of his work on this topic were published in late January in Nature Chemical Biology online.

Enbrel – an Alzheimer’s “Miracle” and Irresponsible Reporting

When I started blogging about Alzheimer’s and dementia, people began sending me links to information about miracle cures for memory loss. I’ve received entire books about “hidden discoveries” and Alzheimer’s conspiracies in the mail. So far, none of the information (including an analysis I received a few weeks ago explaining how oral sex causes Alzheimer’s!) has been backed up by careful research. So when I saw excerpts of a press release about a new “miracle” cure for Alzheimer’s early this month in the Alzheimer’s Daily News (“Alzheimer’s Treatment Shows Promise”), I didn’t pay much attention.

But it turns out other media outlets were repeating the words of the press release, and attaching sensational headlines. ScienceDaily’s headline read “Reversal of Alzheimer’s Symptoms Within Minutes In Human Study” and FOXNews.com said “Study: Arthritis Drug Shows Promise in Reversing Symptoms of Alzheimer’s.”

It’s no surprise that Alzheimer’s message boards are full of emails about this “study,” which is really a case report published in The Journal Of Neuroinflammation. The case report tells about a man with probable Alzheimer’s who appeared to show immediate improvement (“within minutes”) when the arthritis drug Enbrel was injected into his spine. This “study” is not a clinical trial, and involved only one patient. The journal also published a link to a video [look under Additional Material - requires Apple QuickTime to view] “depicting family’s description of change in patient.”

Articles about this report were published with little or no investigative journalism or analysis. Many appear to simply repeat, word for word, a press release from the University of Arkansas. [This was weird in and of itself - why would we rely on a University of Arkansas press release about research supposedly conducted at UCLA and USC?] Most of us still harbor hopes for a cure for memory loss, and we want to believe Alzheimer’s headlines. Irresponsible reporting may drive advertising revenues, but it doesn’t help us sort through what might be helpful and what’s simply hype.

Gabrielle Strobel has published a careful analysis of this case and the circumstances surrounding the report on the Alzheimer Research Forum site. I also like Dr. Peter Whitehouse’s comments during an ABC interview, published on his Beyond The Myth blog.

Cholesterol, Statins and Alzheimer’s, Part 2 of 3

Summary: In a small pilot trial, Lipitor (a statin), seemed to improve scores on neuropsychological tests, especially for patients with mild Alzheimer’s, high cholesterol and the APOE4 genetic variation. The results of two large trials of statins for treatment of Alzheimer’s should be published in 2008. Whether or not statins prove to be effective against Alzheimer’s, this research adds to the evidence of a connection between heart disease and some dementias.

In my last post, I wrote how recent research has dampened hopes that the cholesterol-lowering drugs called statins can reduce the risk of dementia. But what about people who’ve already been diagnosed with dementia?

Two large trials of statins to treat Alzheimer’s are underway. Dr. Larry Sparks, Head of the Ralph & Muriel Roberts Laboratory For Neurodegenerative Research at the Sun Health Research Institute in Arizona, is a lead investigator for one of these trials. He’s enthusiastic about exploring the connection between cholesterol and Alzheimer’s.

“Think about it,” Dr. Sparks says. “APOE4 [the genetic variation linked to increased risk of Alzheimer’s] leads to elevated cholesterol. I don’t think cholesterol causes Alzheimer’s, but I believe it negatively influences it, or causes it to progress faster. There’s definitely a vascular influence.”

Earlier in his career, Dr. Sparks was a Medical Examiner in Kentucky. While performing autopsies of non-demented people with coronary artery disease, he noticed they had amyloid plaques similar to those in people who had been diagnosed with Alzheimer’s. Later, working at the Sun Health Research Institute, he found that rabbits fed high cholesterol diets developed amyloid plaques in their brains. This plaque build-up was reversed when the cholesterol was removed from the rabbits’ diet.

Now, in a small pilot trial, Dr. Sparks and his colleagues have shown that a statin called Lipitor may actually improve scores on neuropsychological tests for some people with Alzheimer’s. In an article published last year, they wrote that Lipitor seemed to help the most in patients with mild Alzheimer’s, high cholesterol and the APOE4 genetic variation.

So reducing cholesterol to treat Alzheimer’s seems logical, right? Nothing is that simple with Alzheimer’s and dementia.

First, some scientists think statins might work by reducing inflammation in the brain, rather than by reducing cholesterol. Second, brain cells produce cholesterol because they need it to function. While bringing down cholesterol levels in the blood might prove helpful for Alzheimer’s, decreasing cholesterol in the brain may harm neurons. Three statins, Mevacor (Lovastatin), Zocor (Simvastatin) and Baycol (Cerivastatin – now off the market in the US) appear to work in the brain as well as in the blood. Two trials at the University of Pittsburgh testing the effects of Mevacor and Zocor on cognitive functioning in people with high cholesterol showed the drugs may have caused a small decrease in performance on some neuropsychological tests. While the effect of these statins on the brain is unknown, Dr. Sparks thinks a safer approach is to influence the brain indirectly by using statins that reduce cholesterol in the blood rather than in the brain.

Finally, a new study shows a late-life drop in cholesterol may actually be associated with an increased risk of Alzheimer’s. I’ll talk about that in my next post.

The results of the two large trials of statins for treatment of Alzheimer’s [CLASP (testing simvastatin or Zocor) and LEADe (testing atorvastatin or Lipitor)] should be published in 2008. Whether or not statins prove to be effective against Alzheimer’s, this research adds to the evidence of a connection between heart disease and some dementias. Dr. Sparks puts it this way: “if you’re sufficiently resilient that you don’t succumb to cardiovascular disease, then you’re looking down the barrel of dementia.”

Cholesterol, Statins and Alzheimer's: Part 1 of 3

Summary: Cholesterol is the Anna Nicole Smith of the Alzheimer’s world – it’s always in the news, and its relationships are hard to understand. High cholesterol in mid-life may be a risk factor for developing dementia. Studies on whether cholesterol-lowering drugs called statins can reduce that risk have had mixed results, with more recent research finding no effect. As with the men claiming to be the father of Ms. Smith’s baby, further tests will determine the role cholesterol-lowering drugs will play.

Going through my father’s medical records, I found a 2004 notation from his first neurologist: The recent total cholesterol (on Mevacor) was only 139 (LDL 81). Therefore, the Mevacor will be decreased to 10 mg. daily beginning today.

Mevacor is a statin, prescribed to lower cholesterol levels. But as far as I know, Dad’s cholesterol was always low – why was he taking Mevacor?

In the last few years, headlines on the use of statins to prevent dementia have swung from wild optimism to flat-out skepticism, and it seems Dad was dragged along for the ride.

In early 2000, when Dad started calling himself “stupid,” Loyola University researchers announced their analysis of hospital records showed patients taking statin drugs had a lower prevalence of probable Alzheimer’s. A paper by Boston University scientists that same year showed that British patients taking statins seemed to have a reduced risk of developing dementia. Dad probably saw the headlines: “Cholesterol drug may prevent Alzheimer’s” and “Statins Take On the Brain: Cholesterol-lowering drugs may also treat or prevent Alzheimer's disease.”

By 2001, he was combing through newsletters from Mayo Clinic and Harvard Medical School looking for ways to improve his memory. That year, Finnish researchers at the University of Kuopio published an article in BMJ that seemed to confirm the Alzheimer’s/cholesterol link. In their study of 1449 Finns followed over 21 years, high cholesterol levels at midlife were a risk factor for Alzheimer’s disease later in life. Shortly after that, studies in several labs showed a relationship between cholesterol and beta amyloid plaques and suggested that, at least in a test tube, high cholesterol leads to increased beta amyloid production. Surely the newsletters Dad subscribed to carried stories about these studies.

In 2003 or 2004, his family doctor must have prescribed Mevacor, but none of us know why. Maybe both Dad and his doctor had read about these studies, and agreed to give a statin a try.

By early 2005, Dad wasn’t reading much at all. But when I called to say hi one day, he was exasperated by a headline he’d seen in the local paper. “Did you see that?” he asked. “Now they say those drugs don’t help your brain.” The story was about a study by Johns Hopkins University researchers. After following approximately 5000 people over a period of five years, they found “no association between statin use and subsequent onset of dementia or AD”. Later that year, University of Washington scientists said that their analysis of statin use and dementia prevalence among 2798 participants in the Cardiovascular Health Study showed the use of statins was not associated with decreased risk of dementia. They wrote that the results of their investigation and similar studies depended on how they looked at the data, and that more research is needed.

After these negative results were published, the excitement about using statins to prevent Alzheimer’s had died down. Dad had stopped taking Mevacor anyway, and had definitely developed dementia.

Although statins may not prevent Alzheimer’s, studies are underway to see if they can be used to treat the disease after onset. I’ll write more about that in my next post.

Alzheimer's, Ulcerative Colitis and the Poetry of Donald Rumsfeld

My brother James called from his hospital bed in New Mexico to ask me to research cyclosporine, a potential treatment for his ulcerative colitis. He is weak and has lost more than thirty pounds. The beeping in the background means his IV system needs attention. I hold on while the nurses add steroids, morphine and the solution he gets his nourishment from.

James at Dripping Springs, Las Cruces, New Mexico

As with Alzheimer’s, no one is sure what triggers ulcerative colitis. And although medicines for ulcerative colitis are more effective than those for Alzheimer’s, there are not a lot of studies about treating an acute case like my brother’s. This is probably due to the fact that most people in the midst of painful, severe, life-threatening ulcerative colitis attacks don’t volunteer for clinical trials.

I pulled up the prescribing information for cyclosporine, and sorted through the few articles I could find. I looked up terms I didn’t understand (“parathesia” is a tingling or numbness, “renal insufficiency” is a fancy term for kidney failure). I checked the size of the studies on cyclosporine for ulcerative colitis (small, with around 50 participants). I marked some pages, and made some notes.

Then I called my brother back. “Did I wake you up?”

“That’s OK.”

“Cyclosporine is an immunosuppressant.” I was looking at Mayo Clinic’s site.

“Mmmmm,” he said. I think he already knew this.

“This potent drug is normally reserved for people who don't respond well to other medications or who face surgery because of severe ulcerative colitis,” I read to him. I flipped to a list of side effects I found in a study published in 2003. “Irreversible liver damage, kidney damage in 23% of patients, infections in 20%, seizures in 3%.”

“I don’t want that drug.” By then, he was wide awake. His doctor planned to start the cyclosporine within a couple of days if James didn’t get better.

The rush to research is a reflex action for me. But I don’t think all my compulsive research helped my father deal with his dementia, and I worry it won’t help my brother. I can only evaluate information from a layperson’s point of view. Am I influencing James and his wife Katya to refuse a treatment he needs? I’m getting an uncomfortable sense of déjà vu.

This is the way it goes when doctors and patients have to deal with a lot of unknowns. I was still thinking about this when the Alzheimer’s Research Forum posted a table called “What We Know, What We Don’t Know” for discussion and comment. Under the What We Know column, the editors listed research findings and achievements. There are 41 entries in the What We Know Column. But for every entry in the What We Know column, there is a corresponding entry in the What We Don’t Know column.

This makes me wonder if I should keep blogging about Alzheimer’s research, when there is so much “unknown.” But I think many of us want to understand what’s in the What We Know and What We Don’t Know columns when we’re weighing treatment options for various diseases. And who knows what we’ll find out about Alzheimer’s in the next few years? Maybe there will be a “breakthrough” discovery that really improves prevention or treatment.

Maybe this is what Donald Rumsfeld meant during a February 12, 2002 news briefing when he said:

As we know,
There are known knowns.
There are things we know we know.
We also know
There are known unknowns.
That is to say
We know there are some things
We do not know.
But there are also unknown unknowns,
The ones we don't know
We don't know.

I’ll update you on my brother’s progress. In the meantime, maybe we need to add a third column to our tables: What We Don’t Know We Don’t Know. It’s that Rumsfeld column that keeps me blogging about Alzheimer’s.

Diabetes and Alzheimer's

I was sorry to hear that Paula Martinac’s father died last month. As she writes in Dementia Blues, he had both diabetes and dementia. Gail Rae Hudson’s (The Mom and Me Journals) mom is a Type 2 diabetic, and has had what Gail refers to as “dementia-lite” since suffering a mini-stroke. “I think that her diabetes is definitely linked to her mental acuity,” Gail emailed me. “The better control we have of her blood glucose levels, the better her mental acuity.”

Bad for your memory?

These connections between insulin problems and dementia in real life are reflected in recent scientific theories and study results:

- Diabetes may increase the risk of Alzheimer’s

- Diet-induced insulin resistance [a condition in which the body fails to properly use insulin] increases beta amyloid production in mice, and is associated with increased memory problems and increased levels of plaque in the brains of these mice

- Alzheimer’s might be a “type 3 diabetes”

- Mutations in the IDE (insulin degrading enzyme) gene are associated with a higher risk of both diabetes and Alzheimer’s

- IDE degrades or decreases both insulin and beta amyloid [the protein thought to cause Alzheimer’s].

Diabetes and insulin resistance are clearly linked to dementia, but no one knows exactly how. Theories about the mechanism by which insulin problems may cause dementia include:

- Insulin affects glucose utilization in the brain [glucose provides the brain’s energy]

- Insulin modulates acetylcholine [a neurotransmitter involved in learning and memory] levels in the brain

- Insulin increases abnormal changes in tau, the protein that makes up the tangles found in neurons in Alzheimer’s brains

- Insulin makes cortisol [a stress hormone, chronically high levels of which are sometimes linked to cognitive impairment] more toxic to neurons

- Insulin increases inflammation in the brain, damaging cells and increasing production of beta-amyloid, which further increases inflammation

- Insulin problems may increase vascular disease, clogging blood vessels, and reducing blood flow to the brain

- Increased insulin uses more IDE, so less IDE is available to degrade the beta amyloid thought to cause Alzheimer’s.

Even before they can understand how insulin problems contribute to dementia, researchers are studying whether diabetes medicines can help treat or prevent Alzheimer’s and dementia. Scientists at the Veterans Affairs Puget Sound Health Care System and the University of Washington found that raising insulin levels in some patients [those without the APOE4 genetic mutation associated with Alzheimer’s] improved their memories. These researchers are also testing nasal insulin in people diagnosed with early Alzheimer’s or Mild Cognitive Impairment. In a small trial, “nasal insulin improved the ability to retain story details about 25 percent,” says Dr. Suzanne Craft, one of the researchers and Professor of Psychiatry and Behavioral Sciences at the University of Washington.

The idea of increasing insulin levels to improve memory seems counterintuitive, since high insulin levels may damage the brain. “In a healthy physiology, optimal levels of insulin that are secreted and cleared quickly are likely beneficial,” Dr. Craft explains. “But excessive or prolonged elevations are likely detrimental because of induction of insulin resistance and inflammation.” So we may need just the right level of insulin to keep our brains humming along.

Scientists are also studying drugs that increase sensitivity to insulin, instead of increasing insulin levels. “It’s too early to tell about the comparative benefits of the two approaches,” says Dr. Craft. Results of one study using this approach were disappointing. A twenty-four week trial of Rosaglitazone, a drug that increases sensitivity to insulin, in people diagnosed with mild to moderate Alzheimer’s disease showed no benefit over placebo. (Trial results did show that the drug may have helped participants who did not have the APOE gene mutation, but this needs further study.)

Even if it’s not clearly effective in treating Alzheimer’s, perhaps this approach will work to prevent mild memory problems from progressing to full-blown dementia. A preliminary study of Rosiglitazone in 30 people diagnosed with Mild Cognitive Impairment showed improvements in memory and attention. Researchers are now recruiting for a larger trial of the drug in people with Mild Cognitive Impairment. The study will measure the drug’s effects on attention and memory in 120 people 55 and older.

Whether or not diabetes drugs are useful in preventing or treating Alzheimer’s, this research shows how important it is to prevent insulin resistance and diabetes. “Our work strongly suggests that preventing insulin resistance by increasing physical activity, optimizing diet and preventing obesity will ameliorate the risk of Alzheimer’s disease, or at least delay onset,” Dr. Craft says.

Antipsychotic Medicines and Alzheimer's, continued

I wrote in an earlier post about a new study concluding that the side effects of antipsychotic medicines often outweigh the advantages for Alzheimer’s patients. In some situations, modifying the dementia patient’s environment may reduce agitation or other behavioral symptoms without medications. “In many treatment contexts (home, nursing home, group living situations), behavioral management techniques are probably under-utilized and medications are probably over-utilized,” says Dr. Ray Ownby, Professor of Psychiatry at the University of Miami Miller School of Medicine.

Patty Doherty of The Unforgettable Fund commented on the problems her family had when her father became agitated by “that guy,” who was his own reflection in the mirror. The dose of Risperdal needed to stop her father’s hallucinations made him sleep day and night. Instead, Patty’s family simply covered all the reflective surfaces in her dad’s environment.

Several web sites offer high level descriptions of environmental changes and behavioral management techniques for agitation, aggression, hallucinations and delusions in Alzheimer’s patients:

- Alzheimer’s Foundation of America
- U.S. National Institute on Aging
- The Alzheimer’s Association.

When environmental changes and behavioral management techniques aren’t enough, and antipsychotics aren’t well tolerated or effective, doctors may try medications approved for other uses. Several clinical trials are underway to determine how effective these drugs already on the market are in reducing agitation in dementia patients. These medications include:

-Cholinesterase inhibitors such as donepezil (Aricept – currently used for treatment of Alzheimer’s disease)
-Memantine (currently used for treatment of Alzheimer’s disease)
-Anticonvulsants such as Valproate and Depakote
-Antidepressants such as Citalopram (Celexa).

Tegretol, another anticonvulsant, is also sometimes prescribed for agitation.

In the meantime, research is underway to find new antipsychotic medications with fewer side effects. One such effort at The Fisher Center for Alzheimer’s Research at the Rockefeller University focuses on Fisher Center scientists’ discovery that some of the adverse effects of the current antipsychotic medicines stem from the fact that they block dopamine receptors. Dopamine is a neurotransmitter, or chemical messenger in the brain, and too little of it has been associated with Parkinson’s disease and some of the Parkinson’s-like side effects of antipsychotic medicines.

“Much of this research deals with a protein called DARPP-32, which is located inside brain cells involved in dopamine signaling,” explains Dr. William Netzer, a researcher at The Fisher Center and scientific liaison to the Fisher Center for Alzheimer's Research Foundation and the Michel Stern Parkinson's Disease Research Foundation. “DARPP-32 is a master regulator protein, integrating numerous signals from its cellular environment and orchestrating the cell's responses. [Fisher Center Director] Dr. Greengard and colleagues found that DARPP-32 connects several major signaling systems in the brain. They are the dopamine, serotonin and glutamate systems, and each is involved at various levels in agitation and other behaviors. It may be possible to fine-tune the way DARPP-32 regulates these systems so that certain side effects of antipsychotic and anti-agitation drugs may be avoided, either by directly or indirectly affecting the functions of DARPP-32.”

I hope some of these existing drugs or new antipsychotic medicines will be prove to be more effective than current antipsychotics and environmental changes. In the meantime, Alzheimer’s patients, their caregivers and doctors are left with a trial and error process for managing psychiatric symptoms.

Antipsychotic Medications and Alzheimer's

Throughout his life, my father laughed away any worries. He never locked doors; he trusted everyone. When lightening struck a transformer ten feet from where he stood, he brushed it off. Nothing kept him awake at night.

But when I visited my parents for Dad’s 73rd birthday last year, he was confused and seemed to be hallucinating. “Where are the others?” he asked over and over. “They were here a little while ago – I’m sure I saw them.” I had flown up by myself, and no one was with us in the house.

Later that week, he told Mom he couldn’t sleep because he thought the vibrating box fan in the doorway of the bedroom was going to attack him. He was upset, and it was hard for my mother to reassure him.

Symptoms like Dad’s are common in Alzheimer’s patients, and add to caregivers’ burdens. According to the U.S. National Institute for Mental Health (NIMH), antipsychotic drugs are widely used to treat psychiatric symptoms in people with Alzheimer’s. More than 27% of patients in American nursing homes receive these drugs, which were initially developed for schizophrenia. But, at least in the U.S., these drugs carry “black-box” warnings that they are not approved for the treatment of patients with dementia-related psychosis.

Results of a five year study of antipsychotic medicines in Alzheimer’s patients were published earlier this month in the New England Journal of Medicine. The “Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Alzheimer’s Disease” study tested three antipsychotic medications against a placebo in 421 Alzheimer’s patients living in their own homes, in family members’ homes, or in assisted living. The medications tested were:

- olanzapine (Zyprexa)
- quetiapine (Seroquel) and
- risperidone (Risperdal).

Input from caregivers was used to help with doctors’ assessments of any improvements or side effects. Although these drugs showed some benefit for some patients, the researchers concluded that “adverse effects offset advantages in the efficacy of atypical antipsychotic drugs for the treatment of psychosis, aggression, or agitation in patients with Alzheimer’s disease.”
Side effects seen in some patients included problems with coordination of movement, sedation, confusion and psychotic symptoms. Antipsychotic medicines have also been shown to increase the risk of developing diabetes and stroke.

Despite recent headlines about this research (“Little Benefit Seen in Antipsychotics Used in Alzheimer's,” etc.), it’s hard to say what the study results mean for each individual patient. Dr. Constantine Lyketsos, Chair of Psychiatry at Johns Hopkins Bayview and Vice Chair of Psychiatry at Johns Hopkins Medicine, co-authored the study. “Neither the CATIE study nor other studies suggest that these medicines shouldn’t be used,” he says. “If you look at the CATIE study, it’s not that the medicines weren’t effective, but the risk/benefit ratio has changed. For the sub-groups of trial participants for whom the medications weren’t discontinued because of side effects, they were more effective than placebo. If a patient’s symptoms are high-risk, then doctors can try antipsychotics with careful safety monitoring. If one of these drugs is well-tolerated, then I can tell you from clinical practice that it’s often effective.”

Constantine (Kostas) G. Lyketsos, M.D., MPH

“I think it would be unfortunate if everyone stopped prescribing any medication solely on the basis of one study,” agrees Dr. Ray Ownby, Professor of Psychiatry at the University of Miami Miller School of Medicine. “Contrary to what many people believe about the study results (and I'll agree that the presentation is confusing), I would not argue that it shows that antipsychotics don't work. It simply shows that antipsychotics aren't enormously effective and that they have lots of side effects. Physicians should prescribe what's appropriate for their individual patients while being aware of the risks and benefits of any given treatment.”

In a “Question and Answer” page on this study, the NIMH recommends caution in prescribing these drugs:

Although some patients may benefit greatly from these medications, the evidence from this study suggests these medications hold limited value for the majority of patients. These results further emphasize the challenge of managing behavioral problems in Alzheimer's patients. Prior to prescribing these medications, clinicians must ensure that agitation or aggression in their Alzheimer's patients are not related to medical, social, or environmental factors (e.g., fever from an infection, side effects from another medication) which might be mitigated without resorting to psychotropic medications.

In a future post, I’ll write about potential alternatives to these drugs, and efforts to develop antipsychotic medications with fewer side effects. But right now, there are no easy answers for doctors or for caregivers.

In the weeks after Dad’s birthday, things got better. Although he was still confused sometimes, he didn’t seem to be hallucinating, and wasn’t as agitated. His doctor thought maybe his symptoms were the result of heat exhaustion (he had mowed the lawn in the summer heat just before these incidents). I now wonder if he’d had a small hemorrhagic stroke that day. If my father had lived longer, he might have gone through more periods when he was anxious, agitated and confused. As the anniversary of his death approaches, we all miss him terribly. But I’m glad we didn’t have to agonize over whether antipsychotic medicines would help him or hurt him.