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Effectiveness of Atypical Antipsychotic Drugs in Patients with Alzheimer’s Disease: CATIE-AD 

Effectiveness of Atypical Antipsychotic Drugs in Patients with Alzheimer’s Disease: CATIE-AD
Chapter:
Effectiveness of Atypical Antipsychotic Drugs in Patients with Alzheimer’s Disease: CATIE-AD
Author(s):

Adam P. Mecca

, and Rajesh R. Tampi

DOI:
10.1093/med/9780190625085.003.0015
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Adverse effects offset advantages in the efficacy of atypical antipsychotic drugs for the treatment of psychosis, aggression, or agitation in patients with Alzheimer’s disease.

The CATIE-AD Investigators1

Research Question:

Are atypical antipsychotics an effective treatment for psychosis, aggression, or agitation in outpatients with Alzheimer’s disease (AD)?

Funding:

The National Institute of Mental Health

Year Study Began:

2001

Year Study Published:

2006

Study Location:

42 outpatient sites in the United States

Who Was Studied:

Adults who met criteria for dementia of the Alzheimer’s type (DSM-IV) or probable AD (National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association [NINCDS-ADRDA]). In addition, participants had a Mini-Mental State Examination (MMSE) between 5 and 26, were ambulatory, and lived at home or in an assisted-living facility. Participants had delusions, hallucinations, aggression, or agitation that developed after the onset of dementia and disrupted function enough to justify treatment with medications.

Who Was Excluded:

Individuals with a primary psychotic disorder, delirium, or non-Alzheimer’s dementia, as well as those with psychosis, aggression, or agitation due to another medical condition, medication, or substance abuse

How Many Participants:

421

Study Overview:

See Figure 15.1 for a summary of the study design.

Study Intervention:

In phase 1 of this randomized, double-blind study, participants were assigned to olanzapine, quetiapine, risperidone, or placebo at starting doses determined by study physicians. After two weeks on the starting dose, adjustments were made, or the medication could be discontinued based on clinical judgment. Medications were dispensed in identical-appearing small and large capsules containing, respectively, a low and high dose of olanzapine (2.5 mg or 5.0 mg), quetiapine (25 mg or 5.0 mg), risperidone (0.5 mg or 1.0 mg), or placebo. Patients with an adequate response to study medication continued treatment for 36 weeks.

In phase 2 of the study, which is out of the scope of this chapter, participants who discontinued treatment during phase 1 were randomly assigned to receive one of the antipsychotic medications that they did not receive during phase 1, or citalopram. These results have not been reported.

In addition to increasing study medication for difficult symptoms, physicians could prescribe a benzodiazepine, oral haloperidol, or parenteral haloperidol. All patients were given equivalent access to psychoeducation.

Follow-Up:

36 weeks for phase 1

Endpoints:

Primary outcome: Time to discontinuation of treatment for any reason during phase Secondary outcomes: Minimal or greater improvement on the Clinical Global Impression of Change (CGIC) scale at week 12 of phase 1, time to discontinuation of treatment because of lack of efficacy, time to discontinuation of treatment because of adverse events, intolerability, or death.

Results

  • Median time to discontinuation for any reason was not significantly different between olanzapine, quetiapine, risperidone, and placebo.

  • Improvement on the CGIC at week 12 was not significantly different between treatment groups.

  • Median time to discontinuation because of lack of efficacy was longer with olanzapine and risperidone but not quetiapine when compared to placebo.

  • Risk of discontinuation due to adverse events, intolerance of medication, or death was significantly higher in patients on olanzapine, quetiapine, and risperidone when compared to placebo.

  • Overall 82% of patients discontinued their initially assigned medication during the 36-week follow-up period. There were no significant differences between groups for serious adverse events including stroke or death.

  • Extrapyramidal symptoms were significantly more common in the olanzapine and risperidone groups but not the quetiapine group when compared to placebo group.

  • Sedation was significantly more common in all three antipsychotic groups when compared to placebo group.

  • Cognitive disturbance and psychotic symptoms were significantly more common with olanzapine but not other antipsychotics compared to placebo (Tables 15.1 and 15.2).

Table 15.1 Summary of NINCDS-ADRDA Criteria for Probable AD Dementia

  • Dementia established by clinical exam, cognitive screening, or neuropsychological testing

  • Deficits in two or more cognitive domains

  • Progressive worsening of cognitive function

  • No disturbance of consciousness

  • Onset between age 40 and 90

  • Absence of another disease that could account for the progressive deficits

Notes: NINCDS-ADRDA = National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association. AD = Alzheimer’s disease.

Source: McKhann et al.11

Table 15.2 Summary of CATIE-AD Phase 1 Key Findings

Outcome

Olanzapine

Quetiapine

Risperidone

Placebo

P Value

Mean initial/final dose (mg/day)

3.2/5.5

34.1/56.5

0.7/1.0

Time to discontinuation – all cause (weeks)

8.1

5.3

7.4

8.0

0.52

Treatment response based on CGIC (% patients)

32%

26%

29%

21%

0.22

Time to discontinuation – lack of efficacy (weeks)

22.1

9.1

26.7

9.0

0.002

Risk of discontinuation due to adverse events (HR)

4.32

3.58

3.62

1.0

0.009

Notes: CATIE-AD = Clinical Antipsychotic Trials of Intervention Effectiveness–Alzheimer’s Disease study. CGIC = Clinical Global Impression of Change. HR = hazard ratio compared to placebo group.

Criticisms and Limitations:

The trial included patients with probable AD dementia but excluded those with other causes of dementia included mixed etiology. Therefore, the results may only be applicable to patients with AD.

Patients in this study had a large range of disease stages (MMSE range between 5 and 26 for inclusion). This likely adds variability to the results since medications may have differential effectiveness depending on disease severity.

The study did not detect an increased risk of serious adverse events with antipsychotic use, but the sample size may be too small to detect a difference for these outcomes since the event rates are relatively low.

Other Relevant Studies and Information:

  • Antipsychotic use is associated with increased risk of death in patients with dementia2 (see Chapter 16).

  • A population based cohort study in nursing homes suggests that quetiapine may carry slightly less risk of mortality and cerebrovascular events when compared to olanzapine, aripiprazole, ziprasidone, and risperidone. Haloperidol appears to have twice the risk of mortality and cerebrovascular events when compared to risperidone.3

  • One discontinuation study showed that patients with AD who responded to treatment with risperidone for agitation or psychosis are at increased risk of relapse when medication is stopped.4

  • This is contrasted by evidence from another study that reports no detriment to cognition or neuropsychiatric symptoms with antipsychotic discontinuation.5

  • Citalopram has been shown to significantly improve symptoms of agitation in AD in a randomized control trial, but its use may be limited by QTc prolongation and increased cardiovascular risk at higher doses.6

  • The effect of citalopram is thought to extend to escitalopram and this is being studied in an ongoing randomized controlled trial.7

  • After ruling out an otherwise treatable cause for behavioral or perceptual disturbances and patients are not responsive to redirection, the American Psychiatric Association (APA) clinical guidelines,8 American Association for Geriatric Psychiatry (AAGP),9 and American Geriatric Society (AGS)10 recommend the judicious use of antipsychotics to treat psychosis, agitation, and other behavioral symptoms in those with dementia.

Summary and Implications:

The CATIE-AD trial showed that among patients with psychosis, agitation, or aggression due to AD, the efficacy of atypical antipsychotics is questionable, and their use comes with considerable risks of side effects and adverse events. The trial did suggest that the efficacy of olanzapine and risperidone may be slightly greater than quetiapine. The use of atypical antipsychotics to manage behavioral symptoms among patients with AD should be reserved for patients who have not adequately responded to nonpharmacological methods or lower risk medications and are in danger of harm due to continued neuropsychiatric symptoms.

Clinical Case: Atypical Antipsychotic Use for Agitation in Dementia Due to Alzheimer’s Disease

Case History

A 75-year-old woman with diabetes, hypertension, and dementia due to AD (recent MMSE was 21) comes to clinic for an urgent appointment. Her husband explains that despite a trial on escitalopram to 10 mg daily for agitation that was initiated 8 weeks ago, his wife is getting increasingly upset in the late afternoon. She became aggressive toward him, swinging her arms, and then fell backwards but luckily onto her bed and did not sustain any injuries. She is still sleeping well at night, and her gait is otherwise stable. He is worried that she may get hurt during one of these episodes and asks if there is a stronger medication to help calm her down.

Based on the results of the Clinical Antipsychotic Trials of Intervention Effectiveness–Alzheimer’s Disease (CATIE-AD), how should this patient be treated?

Suggested Answer

CATIE-AD showed that there is substantial rate of discontinuation with the use of atypical antipsychotics used to treat psychotic symptoms, aggression, or agitation due to AD. This was largely due to adverse events and side effects. The secondary outcomes of time to discontinuation due to lack of efficacy favored olanzapine and risperidone over quetiapine and placebo.

The patient in this vignette is typical of patients included in CATIE-AD and has the additional history of trialing a selective serotonin reuptake inhibitor (SSRI) for agitation that was unsuccessful. There are considerable risks of side effects with atypical antipsychotics, but there is also significant risk to the patient’s well-being due to continued agitation. Published guidelines by the APA, AAGP, and AGS suggest that if education about behavioral interventions and non-antipsychotic medications like SSRIs are not effective, the use of atypical antipsychotics like aripiprazole, olanzapine, quetiapine, or risperidone may be warranted despite the risks. This treatment decision should be undertaken in collaboration with the patient and the caregivers so that the risks and benefits of treatment can be further evaluated.

References

1. Schneider, L. S., Tariot, P. N., Dagerman, K. S., Davis, S. M., Hsiao, J. K., Ismail, M. S., . . . Lieberman, J. A. (2006). Effectiveness of atypical antipsychotic drugs in patients with Alzheimer’s disease. New England Journal of Medicine, 355, 1525–1538.Find this resource:

2. Schneider, L.S., Dagerman, K.S., & Insel, P. (2005). Risk of death with atypical antipsychotic drug treatment for dementia: Meta-analysis of randomized placebo-controlled trials. JAMA, 294(15), 1934–1943.Find this resource:

3. Huybrechts, K. F., Gerhard, T., Crystal, S., Olfson, M., Avorn, J., Levin, R., . . . Schneeweiss, S. (2012). Differential risk of death in older residents in nursing homes prescribed specific antipsychotic drugs: Population based cohort study. BMJ, 344, e977.Find this resource:

4. Devanand, D. P., Mintzer, J., Schultz, S. K., Andrews, H. F., Sultzer, D. L., de la Pena, D., . . . Levin, B. (2012). Relapse risk after discontinuation of risperidone in Alzheimer’s disease. New England Journal of Medicine, 367(16), 1497–1507.Find this resource:

5. Ballard, C., Lana, M. M., Theodoulou, M., Douglas, S., McShane, R., Kossakowski, K., . . . Juszczak, E. (2009). A randomized, blinded, placebo-controlled trial in Dementia Patients Continuing or Stopping Neuroleptics (The DART-AD Trial). Lancet Neurology, 8(2), 151–157.Find this resource:

6. Porsteinsson, A. P., Drye, L. T., Pollock, B. G., Devanand, D. P., Frangakis, C, Ismail, Z., . . . Lyketsos, C. G. (2014). Effect of citalopram on agitation in Alzheimer disease: The CitAD randomized clinical trial. JAMA, 311(7), 682–691.Find this resource:

7. Leibovici, A. (2012). Escitalopram treatment of patients with agitated dementia. Retrieved from https://clinicaltrials.gov/ct2/show/NCT00260624.

8. Reus, V. I., Fochtmann, L. J., Eyler, A. E., Hilty, D. M., Horvitz-Lennon, M., Jibson, M. D., . . . Yager, J. (2016). The American Psychiatric Association practice guideline on the use of antipsychotics to treat agitation or psychosis in patients with dementia. American Journal of Psychiatry, 173(5), 543–546.Find this resource:

9. Lyketsos, C. G., Colenda, C. C., Beck, C., Blank, K., Doraiswamy, M. P., Kalunian, D. A., & Yaffe, K. (2006). Position statement of the American Association for Geriatric Psychiatry regarding principles of care for patients with dementia resulting from Alzheimer disease. American Journal of Geriatric Psychiatry, 14(7), 561–572.Find this resource:

10. Reuben, D. B., Herr, K. A., Pacala, J. T., Potter, J. F., Semla, T. P., & American Geriatrics Society. (2016). Dementia. In idem, Geriatrics at your fingertip (18th ed.). New York: American Geriatrics Society.Find this resource:

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