ORLANDO—The risk of mortality associated with the prescription of antipsychotics or valproic acid for behavioral disturbances in patients with dementia is considerably greater than was estimated previously, according to a large national study described at the 2014 Annual Meeting of the American Association for Geriatric Psychiatry.
The retrospective study included 45,669 matched pairs of Veterans Affairs (VA) patients older than 65 with dementia diagnosed between 1998 and 2009. One member of each pair was taking haloperidol, olanzapine, quetiapine, risperidone, valproic acid, or a nontricyclic antidepressant. The other member of each pair was not taking any of these medications and had not been taking any of them for at least the previous six months. Investigators defined the number needed to harm (NNH) as the number of dementia patients who would need to be on one of the medications for 180 days to result in one additional death, compared with matched controls. The NNH ranged from a worst-case scenario of 15 for haloperidol to 50 for quetiapine, said Donovan T. Maust, MD, Professor of Geriatric Psychiatry at the University of Michigan in Ann Arbor.
The patient pairs were matched according to demographics; comorbid medical and psychiatric diagnoses, including delirium within the previous 12 months; and a history of psychiatric hospitalization, noted Dr. Maust.
| Donovan T. Maust, MD |
Study Had a Longer Duration Than Previous Trials The NNHs found in this large study are considerably lower than in the two earlier meta-analyses conducted by other investigators. In the first meta-analysis, the estimated NNH for second-generation antipsychotics versus placebo was 100. More recently, a 2011 Agency for Healthcare Research Quality comparative effectiveness review found an NNH of 87 for second-generation antipsychotics when used to treat behavioral disturbances in elderly patients with dementia. The meta-analyses may have found more favorable NNHs because they relied mainly on studies that lasted for eight to 12 weeks and therefore failed to capture the additional drug-related deaths that occurred during the 180-day study in VA patients, said Dr. Maust.
The advantages of the VA study are that it provides a truer picture of the mortality risks of antipsychotics and valproic acid and that it delineates the mortality risks for individual medications, compared with no treatment. Earlier studies considered antipsychotics together as a class, noted Dr. Maust.
“You can see that the risk is basically doubled with risperidone, compared to quetiapine. I would use quetiapine as my first-line agent if I had to use anything. And I’ve stopped using haloperidol altogether,” said Dr. Maust.
Inpatient Treatment With Antipsychotics Continues
After the FDA issued its black box warning in 2005 about the increased mortality risk of atypical antipsychotics in elderly patients with dementia, those drugs began to be prescribed less frequently for the treatment of agitation and other behavioral symptoms in patients with dementia. At the same time, the use of conventional antipsychotics increased. After the 2008 black box warning regarding conventional antipsychotics, outpatient prescriptions for these agents decreased, but the use of valproic acid increased. The new study calculated an NNH of 29 for valproic acid, however, which suggests that this drug is problematic, too.
“It’s a bit like Whac-a-Mole, where once one drug goes off the list, then people try something else. They’re such frustrating behaviors, and it’s such a distressing situation for the patient, the family, and the providers that it makes sense that people are trying alternatives,” said Dr. Maust.
The study identified an NNH of 158 for patients on antidepressant therapy, but this result probably is not clinically meaningful because it is similar to the background mortality risk in this elderly, sick population, he added.
Although the use of antipsychotics to treat behavioral disturbances in patients with dementia may have decreased in outpatient settings since the black box warnings, it has not decreased in the inpatient setting. At the meeting, Jung In “Kristin” Lee, MD, Geriatric Psychiatrist at the Mayo Clinic in Rochester, Minnesota, presented a retrospective study of all patients hospitalized in her unit with a discharge diagnosis of dementia during 2002 and 2012. In 2002, well before the black box warnings, 58% of 52 patients with dementia were discharged on an antipsychotic agent. Quetiapine was the most commonly prescribed agent. Similarly, 65% of the 43 patients with dementia discharged in 2012 were on an antipsychotic, and quetiapine was the most common medicine. In both years, only one dementia patient was discharged on a conventional antipsychotic, said Dr. Lee.
—Bruce Jancin