Psychiatric and behavioral symptoms associated with Alzheimer's disease-such as anger, agitation, aggression, and paranoid thoughts and ideas-may improve with the use of second-generation antipsychotic medications, a new federally funded study has found.
Improvements were seen both in global measures and in measures of specific symptoms. In addition, the analysis indicates that particular symptoms may respond better to different second-generation antipsychotic medications.
The new analysis of data from the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease (CATIE-AD), funded by the National Institute of Mental Health, will be published online ahead of print by The American Journal of Psychiatry (AJP), the official journal of the American Psychiatric Association. The report will appear online1 under AJP in Advance on June 2, and will appear in print in the July issue of AJP.
David L. Sultzer, M.D., and his colleagues in the CATIE-AD Study Group, followed 421 outpatients with Alzheimer's disease with associated symptoms of psychosis or agitation/aggression. Patients were randomly assigned to masked treatment with one of three second-generation antipsychotic medications (olanzapine, quetiapine, risperidone) or placebo, for up to 36 weeks.
The treating physician could adjust a patient's dose or, after the first two weeks of treatment, discontinue the initially assigned medication due to insufficient efficacy, intolerable adverse effects, or other reasons. Once a patient discontinued their initially assigned medication, they were said to have completed phase one of the CATIE-AD research protocol.
The primary CATIE-AD results, reported previously2, found that there were no significant differences overall among medications with regard to the time to discontinuation of the medication. Only 19 percent of patients took their initially assigned medication for the entire 36 weeks of the study. However, using the median time to medication discontinuation as the outcome measure, olanzapine and risperidone were found to be more effective. Placebo, on the other hand, was found to be the most tolerable treatment, associated with the fewest adverse effects.
In the current analysis of patient symptoms at the end of phase one treatment, improvements were seen in both global and specific symptoms. Beneficial effects of olanzapine and risperidone were apparent in patients' total scores on the Neuro-psychiatric Inventory, which measures 12 psychiatric symptoms. Risperidone also showed a significant effect as measured with the Clinician's Assessment of Overall Change.
Specific symptoms were tracked with the Brief Psychiatric Rating Scale (BPRS). Patients taking olanzapine and risperidone showed significantly greater improvement compared to patients taking placebo on the BPRS item measuring hostility, suspiciousness, and uncooperativeness. Risperidone was also associated with a decrease in the rating of psychosis.
The improved symptom ratings, however, frequently occurred very close to the time when the clinician was changing the medication, often due to his or her assessment of insufficient efficacy. The authors note that clinicians may have been seeking even greater improvement, or were balancing benefit with other considerations, such as adverse effects or intolerance. Clinicians' treatment expectations and patients' circumstances probably contributed to the perception of effectiveness.
Among the 150 patients who took the initially assigned medication for at least 12 weeks, benefits were also apparent, including more improvement in agitation ratings for patients taking quetiapine compared with patients taking placebo. On the other hand, when compared to placebo, olanzapine was associated with worsened ratings of emotional withdrawal and depressed mood.
For the patients who completed 12 weeks of treatment with medication, more patients who took risperidone (61 percent) were rated by clinicians as "much improved" or "very much improved," followed by patients taking quetiapine (52 percent), olanzapine (45 percent) and placebo (40 percent).
"The CATIE results indicate that hostility, aggression, and paranoia may improve with antipsychotic treatment, " said lead author David Sultzer, M.D., a professor of psychiatry and biobehavioral sciences at the UCLA School of Medicine, and director of the Gero/Neuropsychiatry Division for the VA Greater Los Angeles Healthcare System.
"Although the benefits are modest on average, they don't seem to improve function, and we also need to consider possible side effects. Some 'agitated' symptoms may respond better than others, and this kind of information can help clinicians choose among treatment options. The best choices are based on individual patient's circumstances."
CATIE-AD studied patients living at home or in assisted living facilities; patients in skilled nursing homes were not included. Each met criteria for Alzheimer's disease and had experienced delusions, hallucinations, agitation, or aggression nearly every day over the previous week or intermittently over 4 weeks.
Two sets of analyses were conducted: one analysis included all patients who took at least one dose of medication and utilized the last observation carried forward as the final measurement. The second analysis included only the 150 patients who continued their initially assigned medication for at least 12 weeks.
"Families and patients with Alzheimer's disease are severely affected by the hostility, agitation, and paranoia that often accompany the illness's signature memory loss," noted AJP editor-in-chief Robert Freedman, M.D. "It is clear that antipsychotic medications have helpful yet modest effects for some of these troubling behaviors. But this study also outlines the significant negative effects associated with treatment. We are publishing this study to give doctors new information for their patients about both the possible upside and downside of treatment with these medications."
The authors note that the average improvement on the rating scales was limited and was not apparent for all symptoms. Anger, aggression, and paranoid ideas showed the greatest improvement, as reflected by a more than 50 percent decrease in scores on the "hostile suspiciousness" factor of the BPRS among patients who completed 12 weeks of treatment with risperidone.
Antipsychotic medications did not improve cognition, functional skills, caregivers' needs, or quality of life. In addition, patients taking olanzapine experienced a greater decline in functional skills, compared with those who took placebo.
This study was supported by the National Institute of Mental Health and by the U.S. Department of Veterans Affairs. Medications for the study were provided by AstraZeneca Pharmaceuticals, Forest Pharmaceuticals, Janssen Pharmaceutica, and Eli Lilly and Co. Other funding received by the authors is disclosed in the article itself.
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References
1. Sultzer DL, Davis SM, Tariot PN, Dagerman KS, Lebowitz BD, Lyketsos CG, Rosenheck RA, Hsiao JK, Lieberman JA, Schneider LS, CATIE-AD Study Group: Clinical Symptom Responses to Atypical Antipsychotic Medications in Alzheimer's Disease: Phase 1 Outcomes From the CATIE-AD Effectiveness Trial. Am J Psychiatry (published online June 2, 2008; doi: 10.1176/appi.ajp.2007.07111779)
2. Schneider LS, Tariot PN, Dagerman KS, Davis SM, Hsiao JK, Ismail S, Lebowitz BD, Lyketsos CG, Ryan JM, Stroup TS, Sultzer DL, Weintraub D, Lieberman JA: Effectiveness of Atypical Antipsychotic Drugs in Patients With Alzheimer's Disease. N Engl J Med 2006; 355:1525-1538
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