SAN ANTONIO – Hard evidence supporting the use of either atypical antipsychotics or antidepressants in Alzheimer’s disease patients remains scant, Dr. Daniel Weintraub reported at the annual meeting of the American Association for Geriatric Psychiatry.
Dr. Weintraub of the departments of psychiatry and neurology at the University of Pennsylvania, Philadelphia, said that although older adults with Alzheimer’s disease (AD) frequently are prescribed atypical antipsychotics to control psychosis, aggression, or agitation, the drugs also are associated with significant adverse events and a long-term increase in mortality risk in this population.
Dr. Daniel Weintraub
He noted that investigators in a 42-site, placebo-controlled trial of 421 patients with Alzheimer’s and psychosis found that the adverse effects of the agents offset possible advantages (N. Engl. J. Med. 2006;355:1525-38).
Adverse events included an increase in parkinsonism and/or extrapyramidal symptoms with olanzapine and risperidone, which occurred in 12% of patients on each drug, compared with 2% for quetiapine. All three of these agents were associated with increased sedation, compared with placebo, and olanzapine and risperidone both were associated with more confusion and changes in mental status than was placebo, said Dr. Weintraub, who is also a psychiatrist at the Philadelphia VA Medical Center.
Long-term follow-up from the DART-AD (Dementia Antipsychotic Withdrawal trial) also showed that antipsychotics were associated with an increased long-term risk of mortality in patients with AD (Lancet Neurol. 2009;8:151-7).
The picture is no rosier when it comes to the use of selective serotonin reuptake inhibitors for depression in AD, Dr. Weintraub said.
In the DIADS-2 (Depression in Alzheimer’s Disease–2) trial, no evidence of efficacy was found for the use of sertraline for the treatment of depressive symptoms in patients with AD, and an increase in adverse events was found, including a doubling of dry mouth and diarrhea vs. placebo, as well as a near trebling of dizziness. Sertraline also was associated with a significant increase in pulmonary adverse events at 24 weeks, compared with placebo (P = .006).
The cholinesterase inhibitor rivastigmine fared no better as an adjunct to usual care with haloperidol for treating delirium in a study from the Netherlands. In addition, rivastigmine did not decrease the duration of delirium, compared with placebo (median 5 vs. 3 days, respectively), and a trend was found toward higher mortality with the drug, at 22%, compared with 8% among patients treated with placebo. The actual number of patients was small, however, and the trend did not reach statistical significance. The trial was halted early (Lancet 2010;376:1829-37).
One agent that had some efficacy in AD is the N-methyl-D-aspartate (NMDA) receptor antagonist memantine, Dr. Weintraub said. He pointed to a 2008 pooled analysis of data from three large, randomized studies. The authors of the analysis found a significant benefit for memantine over placebo for the proportion of patients who showed improvement in neuropsychiatric symptom clusters at weeks 12 (P = .008) and 24 (P = .002). Memantine also proved superior to placebo for the treatment of agitation/aggression at both time points (P = .011 and .001, respectively), and the drug was well tolerated (J. Clin. Psychiatry 2008;69:341-8).
Only clozapine (Clozaril) has been shown to have efficacy at treating psychosis associated with Parkinson’s disease, but high potency antipsychotics are poorly tolerated in this population. Also, evidence suggests increased mortality risk (Am. J. Geriatr. Psych. 2010 [doi:10.1097/JGP.0b013e3182051bd6]).
For treatment of depression with Parkinson’s disease (PD), however, the news is a little better, Dr. Weintraub said. In a small trial, the tricyclic antidepressant nortriptyline was superior to placebo at change from baseline in the HAM-D (Hamilton Rating Scale for Depression; P = .002) and in the percentage of responders at 8 weeks (P = .024). In contrast, no significant difference was found in the depression scale between controlled-release paroxetine (Paxil CR) and placebo (Neurology 2009;72:886-92).
Pramipexole (Mirapex), a dopamine agonist, appears to positively affect depression in PD patients, producing significantly better mean reductions in Beck Depression Inventory scores (P = .001). About 80% of the total treatment effect was a direct effect of the drug on depression, the authors found (Lancet Neurol. 2010;9:573-80).
Finally, Dr. Weintraub said, neither antipsychotics nor antidepressants have not been formally tested in dementia with Lewy bodies. However, two studies suggest possible benefits of memantine (Lancet Neurol. 2010;9;969-77) and rivastigmine (Lancet 2000;356:2031-6) in this second most-common form of dementia.
Dr. Weintraub has received honoraria from several companies, including Novartis Pharmaceuticals, Boehringer Ingelheim, Merck Serono, and Labopharm Pharmaceuticals.