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 More on Seroquel, etc (from 10/12/06 NEJM article authors) 
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Joined: Fri Aug 11, 2006 1:46 pm
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Post More on Seroquel, etc (from 10/12/06 NEJM article authors)
An interesting study was published in the 10/12/06 issue of the New England Journal of Medicine on the use of antipsychotics in those with Alzheimer's Disease:

Effectiveness of atypical antipsychotic drugs in patients with Alzheimer's disease.
Schneider LS, Tariot PN, Dagerman KS, Davis SM, Hsiao JK, Ismail MS, Lebowitz BD, Lyketsos CG, Ryan JM, Stroup TS, Sultzer DL, Weintraub D, Lieberman JA; CATIE-AD Study Group.
Keck School of Medicine, University of Southern California, Los Angeles, CA
N Engl J Med. 2006 Oct 12;355(15):1525-38.
PubMed ID: 17035647

The study looked at use of Zyprexa (olanzapine), Seroquel (quetiapine), and Risperdal (risperidone) to deal with psychosis, agression, and agitation in AD patients.

Some letters to the editor were published in the 1/25/07 issue of the NEJM that deal with the original article from 10/12/06. One letter says basically if antipsychotics are so bad let's try antidepressants, antiepileptic drugs, and Namenda to deal with psychosis, aggression, and agitation. The study's authors respond that adequate evidence of the efficacy of these others drugs is lacking and they may not be any safer that antipsychotics.

Another letter asked why the study didn't use a higher dose of Seroquel (which they say is particularly important for patients at risk of parkinsonism) and why they didn't try Clozaril. The study's authors respond that Seroquel "was associated with adverse events and discontinuation owing to intolerability — and at rates similar to those of olanzapine and risperidone and to those in randomized nursing-home trials, in which higher doses of the drug were administered."

They go on to say: "Considering the alternatives, we agree that quetiapine is a preferred antipsychotic drug for patients with extrapyramidal signs and symptoms caused by other antipsychotic agents, dementia with Lewy bodies, and Parkinson’s disease."

They note that phase 2 of the study "will assess empirically whether patients with extrapyramidal signs who have discontinued their first antipsychotic drug may preferentially benefit from quetiapine. However, despite clinical and anecdotal experience and advocacy by experts, two small, placebo-controlled, randomized trials of quetiapine for psychosis in Parkinson’s disease have not demonstrated its efficacy."

Finally, they "cannot endorse the use of clozapine in elderly patients with dementia because of the dose-independent, age-related high risk of agranulocytosis, which is often irreversible; high rates of orthostatic hypotension; and strong anticholinergic effects. Although clozapine may be tolerable and effective in very low doses, we cannot consider the risk of agranulocytosis as being manageable."

So....the debate continues...


Sun Feb 11, 2007 4:02 pm
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Funny, I had the opportunity recently to (briefly) discuss this exact same paper with a geropsychiatrist. His clinical experience, albeit anecdotal, mirrors many of the observations in Schneider, et al.

Our wacky shared hypothesis is that genetic differences, possibly in neurotransmitter uptake or drug metabolism, account for the wide variability in safety and response across the atypical class. Less geekily, if you look at the entire pool of people with LBD, some are really efficient at picking up a given neurotransmitter or breaking down a particular drug (or class of drugs), others lack as much capacity to do so. The various combinations and permutations of these genetic differences combine with the LBD disease process to create a range of response/adverse drug event combos that make the averages look bad, but individual cases look pretty good.

The tricky part is putting this knowledge into clinical practice. Take, for example, the well-known phenomenon of SSRI failure, when the most common treatments for depression just don't work in a given person. There's relatively good evidence that a certain portion of these failures are due to having the "long" version of the 5HTT-LPR allele. In these patients, you can pump them full of Prozac and it's not going to make them any less depressed. Now, consider the metabolism side; people who carry genetic differences for p450 2C9 metabolism could find that they clear Prozac at, say, 40% the rate of the normal population. The combo of these genes could easily result in someone starting on a normal dose of Prozac, getting no relief, and having their dosage increased, still to no relief, and then getting it increased again.... you see how this might add up to a person with acute Prozac toxicity.

There's commercially-available testing for 2C9 and 5HTT-LPR genetic variations. The catch is, they're relatively unknown in the community setting, and somewhat expensive. Even in research protocols, it's not yet common to gather genetic information to see if the difference in response to drugs is responsible for the differences in efficacy. It may well be that people with a particular combo of genes do really well on Zyprexa but won't respond to Seroquel. It may be that Geodon is the second coming for some people, but is associated with more mortality in others. Until we can drive this testing out into clinical practice, we are stumbling around blindly and some people are going to get injured or killed as a result.

On a happy note, Mayo Clinic's _Center for Personalized Medicine_ is possibly a decade ahead of the majority of the medical community in terms of evaluating these genetic differences and their impacts on clinical practice. While I'm not aware of there being any LBD-specific research in that group, their push to get pharmacogenetic testing recognized as a valuable tool for clinicians, not just researchers, is going to benefit a lot of people. Right now, they're partnered with a major pharmaceutical benefit manager to study pharmacogenetic optimizations in blood thinner dosing, which has the potential to virtually eliminate the third-most-common reason for hospitalization in adverse drug events.

Eric

_________________
Cal is not the real name of a real 84 year old with DLB. I don't speak for LBDA, nor do I have clever initials behind my name, so information is provided without warranty. Caveat everybody. I blog at http://PragmaticCaregiver.blogspot.com


Sun Feb 11, 2007 4:52 pm
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Post More on Seroquel+all antipsychotics (Ann Intern Med 6/5/07)
Last week PubMed made available an abstract* of a new study on the dangers of using antipsychotics in older adults with dementia. The study was done in Canada. The medical journal article was published in the 6/5/07 issue of the Annals of Internal Medicine. (See the bottom of this post for the abstract.)

The UPI had a news story on Monday about this research. The story mentions an '05 FDA warning on antipsychotics. You can find the April '05 FDA warning on fda.gov at:
http://www.fda.gov/cder/drug/advisory/a ... hotics.htm

The UPI news story quotes the researchers as saying that they think the FDA should consider extending the warning on antipsychotics to point out that the risk with conventionals is even greater.

Here's a link to the UPI story as well as the full text:

http://www.upi.com/Health_Business/Anal ... eath/6137/

Analysis: Antipsychotics linked to death
Published: June 4, 2007 at 6:16 PM
By Steve Mitchell, UPI Senior Medical Correspondent

WASHINGTON, June 4 (UPI) -- Both newer atypical antipsychotics and older conventional drugs in this class increase the risk of death when used in older adults with dementia, according to a study released Monday.

The Food and Drug Administration added a warning about the death risk to the labeling of atypical antipsychotics in 2005, but the researchers of the new study say the agency may want to consider a similar warning for conventional antipsychotics because the risk may be even greater with these medications.

"I hope there would be some consideration of extending the warning," Sudeep Gill, a geriatric medicine specialist at Providence Care-St. Mary's of the Lake Hospital and the study's lead author, told United Press International.

Conventional antipsychotics include chlorpromazine and haloperidol. Atypicals include Eli Lilly's Zyprexa, Johnson & Johnson's Risperdal and AstraZeneca's Seroquel.

One reason for adding the warning is to inform physicians who may be considering putting their patients on conventional antipsychotics in an attempt to avoid the life-threatening risk associated with the atypicals.

"Physicians may want to switch back to conventionals, but that may be the wrong thing to do because, if anything, the risk may be higher," Gill said.

He said part of the reason the FDA and other regulatory bodies may not have applied the warning to conventional antipsychotics is the paucity of clinical data on these drugs made it difficult to draw any definitive conclusions about their risk. But his study may help shed some light on the issue.

The findings, which are published in the June 5 issue of Annals of Internal Medicine, also suggest the death risk associated with atypicals persists for up to six months.

In the study, Gill and colleagues analyzed data from healthcare databases in Canada of more than 27,000 people 66 years of age or older with dementia between 1997 and 2002. Atypical antipsychotics increased the risk of death within the first month of use and the risk may last as long as six months into treatment. Conventional antipsychotics were associated with a greater risk of death than atypicals at both one month and six months.

The risk/benefit ratio of these drugs "is a very delicate balance," Gill said. "There are patients that need these drugs but probably more patients are getting them than need them."

For this reason, there should be a very careful discussion between the physician and the patient when considering using these drugs in older patients, and there should be more of an emphasis on non-drug treatments, Gill said.

The FDA gave only general comments that shed no light on how the agency may be viewing this class of drugs.

"As part of our commitment to drug safety, we continuously analyze products throughout their life cycle to better understand and quantify potential or real risks," FDA spokeswoman Sandy Walsh told UPI. "FDA remains committed to working to advance the scientific understanding and regulatory approaches needed for safe use of marketed drug products."

Some experts in this area thought the data was not enough to warrant adding a warning to conventional antipsychotics.

"This is not enough to change the warning on the labeling of conventional antipsychotics," Lon Schneider, a professor of psychiatry, neurology and gerontology at the University of Southern California's Keck school of medicine, told UPI.

Schneider, who led a 2005 study published in the Journal of the American Medical Association that found atypical antipsychotics could increase the risk of death in dementia patients, said because the current study was observational and not a clinical trial, there could be confounders that might erase or diminish the increased risk of death. As it was the risk was "really very, very small," he said.

Another factor that may be influencing the findings is inappropriate use of these medications by physicians.

"Physicians shouldn't be using some of these drugs the way they're using them," Schneider said, noting that they may not be carefully monitoring patients while they're taking the drugs and they may keep them on the medications longer than appropriate.

However, Harold Sox, editor of Annals of Internal Medicine, thought the methodology of the study was sound enough that the FDA should take a close look at the medications.

"If I were the FDA I would have to think hard about these findings and whether to add a warning for conventional antipsychotics," Sox told UPI. "It's really a wake up call for the FDA to look at this issue carefully."



* Here's the abstract published this week on PubMed (see pubmed.gov):

Annals of Internal Medicine. 2007 Jun 5;146(11):775-86.

Antipsychotic drug use and mortality in older adults with dementia.

Gill SS, Bronskill SE, Normand SL, Anderson GM, Sykora K, Lam K, Bell CM, Lee PE, Fischer HD, Herrmann N, Gurwitz JH, Rochon PA.
Queen's University, Kingston, Ontario, Canada.

BACKGROUND: Antipsychotic drugs are widely used to manage behavioral and psychological symptoms in dementia despite concerns about their safety.

OBJECTIVE: To examine the association between treatment with antipsychotics (both conventional and atypical) and all-cause mortality.

DESIGN: Population-based, retrospective cohort study.

SETTING: Ontario, Canada.

PATIENTS: Older adults with dementia who were followed between 1 April 1997 and 31 March 2003.

MEASUREMENTS: The risk for death was determined at 30, 60, 120, and 180 days after the initial dispensing of antipsychotic medication. Two pairwise comparisons were made: atypical versus no antipsychotic use and conventional versus atypical antipsychotic use. Groups were stratified by place of residence (community or long-term care). Propensity score matching was used to adjust for differences in baseline health status.

RESULTS: A total of 27,259 matched pairs were identified. New use of atypical antipsychotics was associated with a statistically significant increase in the risk for death at 30 days compared with nonuse in both the community-dwelling cohort (adjusted hazard ratio, 1.31 [95% CI, 1.02 to 1.70]; absolute risk difference, 0.2 percentage point) and the long-term care cohort (adjusted hazard ratio, 1.55 [CI, 1.15 to 2.07]; absolute risk difference, 1.2 percentage points). Excess risk seemed to persist to 180 days, but unequal rates of censoring over time may have affected these results. Relative to atypical antipsychotic use, conventional antipsychotic use was associated with a higher risk for death at all time points. Sensitivity analysis revealed that unmeasured confounders that increase the risk for death could diminish or eliminate the observed associations.

LIMITATIONS: Information on causes of death was not available. Many patients did not continue their initial treatments after 1 month of therapy. Unmeasured confounders could affect associations.

CONCLUSIONS: Atypical antipsychotic use is associated with an increased risk for death compared with nonuse among older adults with dementia. The risk for death may be greater with conventional antipsychotics than with atypical antipsychotics.

PubMed ID#: 17548409


Sun Jun 10, 2007 5:10 pm
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