Little Benefit Seen in Antipsychotics Used in Alzheimer's
Thursday, October 12, 2006
Antipsychotic drugs that are widely used to calm agitated patients with Alzheimer's disease help very few of them, and those modest benefits are canceled out by the frequent side effects, a comprehensive government-funded study has found.
The surprising finding is expected to trigger a broad reevaluation of the widespread use of the drugs in patients with Alzheimer's and other forms of dementia. As many as a quarter of the Alzheimer's patients in nursing homes are prescribed the powerful drugs, even though they have never been formally approved for this purpose.
"I wish I could say the odds are better," said Thomas R. Insel, director of the National Institute of Mental Health, which funded the $17 million study. "This paper says most people are not going to be any different on these drugs than they would on placebo."
The researchers did not conclude that the drugs should never be used, and a minority of patients do benefit. But the study suggests that doctors would be well advised to prescribe the drugs sparingly and as a last resort, experts said.
The study is the latest to produce sobering data on the newer, expensive antipsychotics such as Zyprexa, Risperdal and Seroquel, which are among the most widely prescribed drugs in the United States at an annual cost of about $10 billion. Another government-funded study recently showed that the drugs were no better than an older and much cheaper drug called perphenazine in the treatment of schizophrenia.
Taken together, the government-sponsored clinical trials have highlighted two troublesome issues in the regulation and use of psychiatric medications in the United States.
The schizophrenia study showed that the short-term trials that pharmaceutical companies sponsor to gain Food and Drug Administration approval have limited value in telling doctors how patients will fare overall, or whether newer drugs are worth their higher cost.
The Alzheimer's study has revealed a different problem -- the extent to which physicians are prescribing and using medications in the absence of empirical data to guide them. None of the antipsychotic drugs is currently approved for Alzheimer's disease, and several short-term industry-sponsored clinical trials have failed to show a benefit. The FDA has required prominent "black box" warnings on the drugs' labels about side effects in elderly people following cases where the drugs were associated with strokes and death.
"Clearly the drugs cannot be cost-effective, because there is nothing to choose between drugs and placebo," said Lon Schneider, the lead author of the new study published today in the New England Journal of Medicine. "Most patients are not benefiting."
Insel, Schneider and Jason H.T. Karlawish, an Alzheimer's expert at the University of Pennsylvania who wrote a commentary about the new study, said it also underscores the desperate need to develop better treatments for Alzheimer's patients who are agitated or psychotic.
About 5 million Americans suffer from dementias, including Alzheimer's, and large numbers of them experience periods of agitation and psychotic symptoms that are extremely debilitating for them, their caregivers and medical facilities.
"You can't respond to agitation by saying 'Here is some olanzapine,' " said Karlawish, referring to the drug sold under the brand name Zyprexa. "The question is, why is there agitation?"
Such symptoms could be the result of overstimulation, sleep deprivation, untreated pain, moving to a new environment or dehydration, the experts said.
Like young children, patients with dementia can also be set off by a conversation that normal adults brush off or find routine. Karlawish suggested that this could be because dementias affect the frontal lobe of the brain, which plays an important role in judgment and self-control.
"Any good parent knows there are effective and ineffective ways to respond to their 4-year-old," Karlawish said. Similarly, he said, "there are effective and non-effective ways to respond to someone with frontal-lobe damage."
Clinicians and caregivers would do well to deal with such potential triggers of agitation before considering antipsychotic medication, Schneider agreed. The drugs might be useful in patients who continue to have agitation and breaks with reality despite such efforts, but Schneider cautioned that the drugs ought to be prescribed for limited periods and stopped if side effects emerge. Those effects include uncontrolled muscle movements, excessive sedation, worsened mental functioning and confusion.
The manufacturers of the three drugs used in the study all said they do not recommend their products for Alzheimer's patients. Eli Lilly and Co. makes Zyprexa, AstraZeneca makes Seroquel, and Janssen Pharmaceutica makes Risperdal.
The new study found that Risperdal and Zyprexa seemed to help Alzheimer's patients more than Seroquel, but those two medications also had more serious side effects.