Atypical Antipsychotics May Hasten Cognitive Decline in Alzheimer's

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August 18, 2011 -- Use of atypical antipsychotics to treat agitation or psychosis in patients with Alzheimer's disease (AD) may lead to severe cognitive impairment, according to new findings from the Clinical Antipsychotic Trials of Intervention Effectiveness - Alzheimer's Disease (CATIE-AD) study.

In the analysis, investigators found that patients with AD randomly assigned to olanzapine, quetiapine, or risperidone showed a significant decrement in neuropsychological functioning, as seen on several cognition measurements, compared with those receiving placebo.

"We found that the atypical antipsychotics used in this study were as a group associated with worsening cognitive function and that the magnitude of this impairment was, on average, the rough equivalent of 1 year's progression of illness," principal investigator of the CATIE-AD studies Lon S. Schneider, MD, professor of psychiatry, neurology, and gerontology at the University of California (USC) Keck School of Medicine in Los Angeles, told Medscape Medical News.

"It really comes down to the fact that the current medications aren't very effective in treating agitation, aggression, or psychosis in dementia. So maybe we should be trying to address these problems in different ways than merely prescribing the medications that have been licensed for treating patients with schizophrenia or major depression."

The study is published in the August issue of the American Journal of Psychiatry.
http://ajp.psychiatryonline.org/cgi/content/abstract/168/8/831

Efficacy Offset by Adverse Effects

"Delusions or hallucinations appear in 30% to 50% of patients with AD, and up to 70% demonstrate agitated or aggressive behaviors," report the researchers.

In findings published in 2006 in the New England Journal of Medicine(2), atypical antipsychotics showed "modest efficacy" in decreasing behavioral symptoms in the CATIE-AD patients after 12 weeks compared with placebo. However, they also showed more treatment-related adverse events.

In a meta-analysis conducted the same year (3), Dr. Schneider's team found small effect sizes on symptom rating scales for aripiprazole and risperidone along with significant adverse events, including cerebrovascular events and worsening cognitive test scores, in older patients with AD.

"Any advantages of efficacy found for these drugs were offset in general by lack of tolerability and by adverse effects. So they should be used with a great deal of care," said Dr. Schneider.

He added that the meta-analysis(4) showing a link between atypical antipsychotics and increased mortality risk in an elderly population with dementia helped support the Food and Drug Administration's (FDA's) subsequent black box warning in 2005.

A recent study(5) published in the Archives of General Psychiatry and reported by Medscape Medical News at that time showed use of atypicals to treat behavioral symptoms has decreased significantly since the FDA warning was issued. However, other studies(6,7) have shown that the overall prescription rate has not decreased ( Arch Intern Med. 2010;170:89-95 and CMAJ. 2008;179:438-446).

In the current study, investigators evaluated data on the 421 outpatients with AD and psychosis or aggressive behavior from CATIE-AD, which was conducted at 45 sites in the United States between April 2001 and November 2004.

Significant Decline

During the first phase of the trial all participants were randomized to receive flexible doses of either olanzapine (n = 100; mean dose, 5.5 mg/day), quetiapine (n = 94; mean dose, 56.5 mg/day), risperidone (n = 85; mean dose, 1.0 mg/day), or placebo (n = 142).

After 2 weeks, they could discontinue their allocated treatment and switch to another randomly assigned medication, on their clinicians' request. If they discontinued use of that medication, patients could move into phase 3 of the study, which consisted of open-label treatment with one of the other randomly assigned study drugs.

"At any time, the clinician could choose to enter the patient into phase 4, where data collection continued but the physician prescribed medication," explain the researchers.

The subjects were followed up for 9 months and scheduled to undergo cognitive assessments at the 12-, 24-, and 36-week timepoints. This new analysis assessed the 357 patients (54% male; mean age, 77.6 years) who participated in at least 1 baseline and 1 follow-up cognitive measure.

Measurements included the Mini-Mental State Examination (MMSE), the cognitive subscales of the AD Assessment Scale (ADAS-Cog) and of the Brief Psychiatric Rating Scale (BPRS), a cognitive summary score that combined changes on 18 cognitive tests, and the Clinical Global Impression of Change (CGIC).

Results showed that at 36-week follow-up all of the patients had declined significantly in most cognitive areas, including worsening scores on the MMSE (−2.4 points) and ADAS-Cog (−4.4 points).

The only statistically significant difference between individual antipsychotic groups and the placebo group were greater cognitive decline in the following:

* the cognition summary for those taking olanzapine or risperidone (P = .04 and P = .001, respectively);
* the MMSE for those taking olanzapine (P = .05); and
* BPRS for those taking quetiapine (P = .05).

When all 3 atypical groups were combined, participants' cognitive function decreased significantly more than their counterparts who were taking placebo on the MMSE (P = .004), BPRS (P = .05), and cognitive summary (P = .004).

"Over the 36-week trial period, patients receiving any antipsychotic had an average decline 2.46 points greater on the MMSE than placebo patients, a difference both statistically significant and clinically relevant," write the researchers.

The average CGIC scores for all 4 groups indicated minimal improvement and did not differ significantly (placebo, 3.13; olanzapine, 3.11; quetiapine, 2.83; risperidone, 2.81).

Permanent Effect?

"Because we did not measure differences in the rates of cognitive decline over longer exposure periods, we cannot address the question of whether these drugs would accelerate [the] decline permanently or merely impair cognition during acute administration," the investigators write.

They note that they also do not know whether the decrease in cognition was due to a worsening of Alzheimer's pathology or if it was an independent effect.

Although the investigators write that the declines found in this study reached "at least as great a magnitude as the effect of cholinesterase inhibitors but in the negative direction," they add that use of atypicals may still be warranted in individual cases.

"The relative adverse effects on cognitive function within the class of medication need to be addressed in further studies that include assessment of attention, psychomotor function, and executive function," they write.

Dr. Schneider noted that nonpharmacologic treatments should also be investigated.

"Much of medication use is due to the lack of interest, willingness, funding, or ability to provide psychosocial or environmental interventions to patients with agitation, aggression, and psychosis who have dementia."

He explained that much agitation can be redirected and that aggression often comes about due to cognitive impairment -- and can be mitigated by the way caregivers react to or communicate with patients.

"These approaches have limits too, but certainly they are not applied enough because they involve significant amounts of time and training," said Dr. Schneider.

Few Alternative Treatments

"Risk-benefit analysis is always part of the decision to use psychotropic medication. The aged are a particularly vulnerable group, and this study strongly underscores that vulnerability," write D. P. Devanand, MD, from the Division of Geriatric Psychiatry at the College of Physicians and Surgeons at Columbia University in New York City, and Susan K. Schultz, MD, from the Department of Psychiatry at the University of Iowa College of Medicine in Iowa City, in an accompanying editorial.

"Neuropsychological testing across a range of domains in this study offers a powerful look at the progression of AD in the context of treating neuropsychiatric symptoms," they add.

However, they caution that several caveats should be considered "when interpreting the findings and their potential impact on clinical practice," including that the investigators had to combine the 3 treatment groups to find statistical differences from placebo on the MMSE and the summary scores.

"It is likely that individual vulnerabilities to specific antipsychotics are mediated by a variety of factors, including concomitant medications, medical comorbidity, and underlying frailty, that are beyond the scope of this analysis."

In addition, the editorialists note that "while dose effects were not addressed in this analysis, adverse events in this population are dose related, and treatment dropouts occur more frequently with risperidone doses above 2 mg and olanzapine doses above 5 mg."

Other concerns cited include that data for any patient receiving an antipsychotic for at least 2 weeks was included, whether they had switched medications or not, which may result in short-term harmful effects that may not continue with longer treatment exposure.

Dr. Devanand and Dr. Schultz note that alternative pharmacologic treatments, such as benzodiazepines, also provide risky cognitive liabilities.

"Despite the widespread awareness of adverse consequences, we can only infer that atypical antipsychotics continue to be prescribed for dementia treatment because there is a lack of alternatives and there is a perceived clinical benefit by care providers," they write.

"These complex issues will require a thoughtful and balanced evaluation with an appreciation of the care setting, individual patient vulnerabilities, and goals of care."

The study was supported by the National Institute of Mental Health, the USC Alzheimer's Disease Research Center, and the Department of Veterans Affairs. Medications were provided by AstraZeneca, Forest, Janssen, and Eli Lilly. The study authors report several disclosures, which are listed in the original article. The editorialists report having received research support from Eli Lilly and Novartis and are currently consultants for Bristol-Myers Squibb and Sanofi-Aventis.

Am J Psychiatry. 2011;168:831-839, 767-769. Abstract Editorial


1. Vigen CL, Mack WJ, Keefe RS, Sano M, Sultzer DL, Stroup TS, Dagerman KS, Hsiao JK, Lebowitz BD, Lyketsos CG, Tariot PN, Zheng L, Schneider LS.. Cognitive Effects of Atypical Antipsychotic Medications in Patients With Alzheimer's Disease: Outcomes From CATIE-AD. Am J Psychiatry 2011; 168:831-839.
http://ajp.psychiatryonline.org/cgi/content/abstract/168/8/831

2. Schneider LS, Tariot PN, Dagerman KS, Davis SM, Hsiao JK, Ismail MS, et al. Effectiveness of Atypical Antipsychotic Drugs in Patients with Alzheimer's Disease. N Engl J Med 2006; 355:1525-1538.
http://www.nejm.org/doi/full/10.1056/NEJMoa061240#t=abstract

3. Schneider LS, Dagerman MS, Insel KMS, Philip SMS. Efficacy and Adverse Effects of Atypical Antipsychotics for Dementia: Meta-analysis of Randomized, Placebo-Controlled Trials. Am J Geriatric Psychiatry 2006; 14(3):191-210.
http://www.geertswalaszek.com/geropsych/docs/schneider-ajgp-2006.pdf

4. Schneider LS, Dagerman KS, Insel P. Risk of Death With Atypical Antipsychotic Drug Treatment for Dementia
Meta-analysis of Randomized Placebo-Controlled Trials. JAMA 2005;294(15):1934-1943.
http://jama.ama-assn.org/content/294/15/1934.full

5. Brauser D. Use of Atypicals for Dementia Takes Sharp Downturn After FDA Warning.
http://www.medscape.com/viewarticle/737208

6. Che Y, Briesacher BA, Field TS, Tjia J, Lau DT, Gurwitz JH. Unexplained Variation Across US Nursing Homes in Antipsychotic Prescribing Rates. Arch Intern Med. 2010;170(1):89-95.
http://archinte.ama-assn.org/cgi/content/full/170/1/89

7. Valiyeva E, Herrmann N, Rochon PA, Gill SS, Anderson GM. Effect of regulatory warnings on antipsychotic prescription rates among elderly patients with dementia: a population-based time-series analysis. CMAJ 2008; 179(5): 438-446.
http://www.cmaj.ca/content/179/5/438.full