9 January 2009. Antipsychotics are getting pushback as a treatment for behavioral symptoms in AD patients. While at first blush it may seem reasonable to use these drugs to control psychiatric symptoms in moderate and advanced dementia, prior studies have warned of serious side effects (see ARF related news story), limited efficacy (see ARF related news story), and in short-term (8-12 week) trials even increased mortality in AD patients taking second-generation antipsychotics (see ARF related news story). That deadly risk is now confirmed by results from the much longer dementia antipsychotic withdrawal trial (DART-AD), published in today’s Lancet Neurology online. Led by Clive Ballard at King’s College London, DART-AD investigators found that over a period of 12 months, patients continuing on drug instead of placebo had a significantly increased rate of mortality. The authors write that “...the accumulating safety concerns, including the substantial increase in long-term mortality, emphasise the urgent need to put an end to unnecessary and prolonged prescribing.”
Ballard and colleagues randomized 165 AD patients living in care facilities in the U.K. to either continue their use of antipsychotic treatment (at enrollment patients had to have been taking such a drug for three months) or to take a placebo for 12 months. At the end of the randomized period, the probability of survival in the drug group was 90 percent, compared to 97 percent in the placebo group. The researchers also followed patients for up to three and a half years after the trial, finding even more pronounced differences in mortality. At 24 months, survival was 46 and 71 percent in drug and placebo groups, respectively, and the differences were even greater at 36 and 54 months. The authors write that it is not clear why the biggest differences in mortality occur after the 12-month trial. One plausible explanation is that the frailest patients are most likely to die within the first 12 months regardless of medication status. Another possibility is that the close monitoring of patients during the trial helped prevent fatalities. Whatever the reason, the hazard ratio for survival over the full study (54 months) was 0.58 in the drug group compared to placebo, meaning people were a little over half as likely to still be alive if they had been on antipsychotic drugs than if they had been on placebo.
“This work further emphasises the clinical imperative to review antipsychotic medication that is regularly prescribed, and to avoid a protracted period of treatment with antipsychotic drugs in people with dementia,” write the authors. In fact, the U.S. Food and Drug Administration is aware of the increased mortality in AD patients treated with antipsychotics and has issued a black box warning to that effect, also noting that the drugs are not approved for AD (see FDA public health advisory). Nevertheless, some clinicians see antipsychotics as an important part and parcel of AD management and are not convinced that the clinical trial data capture the full story. John (Wes) Ashford, a psychiatrist at Stanford University, California, has reported that AD patients are the most violent of all psychiatric patients (see Paveza et al., 1992) and he wrote ARF via e-mail, “the most agitated patients need to be managed acutely and cannot participate in such trials.” For this reason he believes that real-life, placebo-controlled trials of antipsychotic medications cannot be conducted (see full comment below). In fact, Ballard and colleagues concede that this is a limitation of their study. Enrollment required a Mini-Mental State Exam score of 6 or more and a Severe Impairment Battery score of 30 or more, effectively eliminating the most severely affected patients.
And even if there is increased risk of mortality, might these drugs offer some relief for this terminal illness over the short term if managed properly? As Ashford wrote, “…isn't there the issue of allowing patients to die with dignity? These drugs, just like morphine for cancer patients, will provide some measure of better end-of-life care.” A better scenario might be to have drugs that relieve psychotic symptoms without dangerous side effects. Both Ballard and colleagues and Ashford note that other drugs, such as memantine, antidepressants, selective serotonin reuptake inhibitors, and even low doses of certain antipsychotics may fit the bill, but more research is needed.—Tom Fagan.
Ballard C, Hanney ML, Theodoulou M, Douglas S, McShane R, Kossakowski K, Gill R, Juszczak E, Yu L-M, Jacoby R, for the DART-AD investigators. Lancet. 2009, January 9; online publication.