Anti-psychotics prescribed to patients with Alzheimer's disease may indeed have a sedating effect, but at a large cost, according to Yale researcher Dr. Bob Rosenheck. In a study published in the November 2007 issue of the Archives of General Psychiatry, Rosenheck found that there was no overall difference in the actual quality of life for patients prescribed anti-psychotic drugs and patients given placebo pills.

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Rosenheck spoke with CBC investigative reporter David McKie about his comprehensive cost-benefit analysis and the need to rethink regulatory policies. Here is an excerpt of the interview.

David McKie: Tell me a bit about your study on the cost-benefit analysis of these second-generation anti-psychotics.

Dr. Bob Rosenheck: The most recent study involved the cost-benefit of atypical anti-psychotics as compared to placebo, which is essentially no drug at all, in the treatment of agitation and psychotic symptoms in Alzheimer's disease.

McKie: What did you find?

Rosenheck: Essentially we found, not surprisingly, the patients assigned to the sugar pill, their drug costs and overall health care costs were cheaper by $40 or so a month, which adds up to a couple of hundred dollars a year. But in an overall measure of quality of life and in several other measures, there really were no benefits for the drugs.

McKie: How can that be?

Rosenheck: Well, these were drugs that were originally developed to treat schizophrenia and have also been used in bipolar disorder, and so they really were not designed to treat Alzheimer's disease. The hope has been that if you have symptoms in Alzheimer's disease that are similar to the symptoms in schizophrenia, perhaps these drugs would be effective. The drugs are quite commonly used as a tranquillizer, but the studies have not been very strong in showing they're effective. Actually, the studies show that they do have a sedating effect — they do calm people down, but they also have serious side-effects. People — at least in this study — didn't stay on the medications for very long.

McKie: When you say they sedate people, what do you mean there?

Rosenheck: They make them a little less agitated in their behaviour.

McKie: Could that not be what the physician wants? I'm thinking particularly of troublesome Alzheimer's patients in nursing homes, where you want to prevent someone from being agitated, someone from wandering?

Rosenheck: Well, it might be, but then you also may restrict their levels of activities, reduce the quality of their life, and so they're tradeoffs. In this study … we didn't just look at how long people stayed on the medications and why, we looked at each time point — three months, six months, nine months. We looked at measures of quality of life, overall quality of life — how well do they socialize, how active are they — and we found that in fact there was overall no difference in the actual quality of life between the medications at somewhat greater costs.

McKie: Other than drowsiness, what other kind of side-effects are we talking about?

Rosenheck: Well you can experience neurological side-effects where people can get Parkinsonian symptoms. You can have dry mouth, some of the medicines can give you the shaking syndrome. You can get stiff from muscular problems.

McKie: And what about the risk of death?

Rosenheck: This study didn't focus on that … the sample size was too small, there were a very small number of deaths in this study. But there have been larger studies which suggest that when patients are on either the newer medicines or older anti-psychotic medicines there is a small, increased risk of death.

McKie: So, could that be one of the reasons why the Food and Drug Administration in April of 2005 and Health Canada in June of 2005 put out a black box warning and health advisory respectively about being cautious in giving these drugs to the frail elderly?

Rosenheck: Yes, that's precisely why those warnings were issued.

McKie: The analysis that we've done has shown that the prescription of these drugs — particularly the atypical anti-psychotics — have if anything increased, even if you adjust for population increase, after the FDA black box warning and the Health Canada advisory. You expressed some surprise by that.

Rosenheck: Well, first of all, the black box warnings had to do with the use of these drugs in nursing home patients and people with Alzheimer's disease or other dementias. There was no expression of concern about the general use of these drugs, which are predominantly used in younger people with schizophrenia or other mental illnesses. So from that point of view, I wouldn't have expected those warnings to reduce overall use of these medicines, unless you have some data particular on the use of elderly people or people with Alzheimer's disease or other dementias.

I think the important thing about the Alzheimer's study is that this is an off-label use. When medicines are approved they're approved for use in a specific illness. The FDA has determined that this medicine is better than placebo of a sugar pill in the treatment of particular illnesses. But doctors then can use their own judgment to try these medicines for other illnesses. More than half the people who get [atypical anti-psychotics] actually don't have the illnesses for which the FDA has approved their use, they're used off-label, and the off-label uses have been very little studied.

McKie: Knowing what you know now and knowing that a lot more research needs to be done, does it concern you that when you take a look at their use in the elderly, at least in the Canadian context, that there is an increase in prescriptions?

Rosenheck: I think we don't have enough information on who and why these drugs are being used to really know. It could be that there are older people with real schizophrenia who are for some reason being identified now and that this is an appropriate use. Without knowing more information, particularly about the diagnoses, it's just hard to tell.

McKie: So, what are physicians, if they read this study, to take from this, and how does this inform their practice?

Rosenheck: Well the main thing is they need to be cautious and follow patients very closely to see if they're having unpleasant side-effects. [They should] see if they are getting the benefit, which is modest in scale, and to know that at least in the research context it's hard to discern substantial benefit. If they have an agitated patient, it may be more important to think of psycho-social interventions, providing them with more attention with more social restraints than chemical restraints.

McKie: What is the Canadian government to take from this study?

Rosenheck: Off-label use, while it's allowed, should be done very cautiously, and the credo of the physician is first, do no harm. And so, in the off-label use there should be real caution. In the use for the indications where there is evidence of benefit, clearly the doctor [must] weigh the benefits of the drug versus the side-effects, versus the health hazards.

The issue for the health-care system is to use its resources prudently, where they can get the biggest gain in health care for dollar expended. I think that does mean there should be more use of intermediate potency anti-psychotics and not the extremely side-effect prone drugs … I think the public good would be served by greater use of these [mid-range] drugs, which can be as effective with few side-effects at much lower cost, but how to encourage such use is a big challenge.

McKie: There are four drugs mentioned in the Health Canada advisory to which I alluded at the beginning of the interview: Risperdal, Seroquel, Clozaril and Zyprexa. Of those four, which ones, if you had to rank them, which ones are the most problematic?

Rosenheck: Now I don't have data on this. But one would think, given the thinking about how these are problematic in elderly people, would be the most sedating and that would probably be Clozaril and Zyprexa, and then to a certain extent, Seroquel. And I think it's clear the clozapine [Clozaril] and Zyprexa are the most sedating, and I think there was some evidence in the paper I recently reported that Zyprexa increased dependence somewhat more than the other treatments.

David McKie:Where do we go from here?

Rosenheck: It's important to differentiate the Canadian situation from the American situation, because Canada does have a system for evaluating drug prices. It has the patent medicines review board, which reviews treatments for which high costs are being charged and decides whether they merit it.

The other thing we need in both Canada and the United States is an independent institution that compares treatments to each other. So the regulatory framework of the FDA and the similar institution in Canada is just to decide whether one treatment is better than nothing. Many studies show that when companies study their own products they're more likely to find them superior, and what we really do need is an independent body.

Once a drug is established as a blockbuster, you know selling say a billion dollars a year or so, then the public really needs to know is this really better than other less expensive alternatives? I think that's a lacuna in our institutional framework that could be filled without great public expense. If the public is going to spend a great deal of money on a treatment, it ought to demand there really be expenditure on really determining how much better it is than other less expensive, available products.

David McKie: It seems as though we're at a crossroads aren't we?

Rosenheck: This is a continuing evolution of health-care policy and regulatory policy as there are new technologies that weren't even conceived of 20 years ago, the world has to change and the way we organize society has to change. I don't see this as a particularly pivotal moment in health-care regulation. I suppose with these recent studies it's a specific moment for rethinking atypical anti-psychotic policies, but I think this is the ongoing process of public decision-making, and thank God for it.

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