Effectiveness of second-generation antipsychotics in dementia-related psychosis and agitation

1. Effectiveness of second-generation antipsychotics in dementia-related psychosis and agitation Evidence-Based Medicine Seminar October 26, 2006 Brian J. Mickey

2. Overview • Case presentation • Clinical question • Literature search results • CATIE-AD trial: recent results from phase 1 • Group discussion/debate/melee • special guests: Chandra Sripada and the Depression Team

3. Ms D is a 75-year-old widowed retired office clerk with a diagnosis of Alzheimer disease who was brought to the Emergency Department (PES) by her 3 daughters in January 2006 for worsening delusions. About 3 years prior to evaluation, she had presented with short-term memory decline and was diagnosed with probable Alzheimer disease. About 3 months prior to evaluation, she developed paranoid ideation about men trying to harm her, and one man in particular who rubbed noxious lotion on her back. Over the prior 2-3 days, her delusions intensified and became more distressing to her and her daughters. She perceived men outside all night shining lights into the house. She barricaded her doors and started carrying a knife for protection. She also endorsed mildly depressed mood, low energy, sleep disruption, and daytime somnolence. No manic symptoms. Case Presentation

4. Past psychiatric history mild-to-moderate depression for 30 years antidepressants prescribed by PCP for 8 years no psychosis, hospitalizations, suicidality AD diagnosis by neurologist 2003 Substance use history none General medical history probable Alzheimer disease CAD, MI and stent in July 2005 dyslipidemia hypertension asymptomatic meningioma Medications escitalopram 20 mg daily rivastigmine 6 mg qam, 3 mg qhs memantine 20 mg bid plavix 75 mg daily famotidine 20 mg daily metoprolol 20 mg bid lisinopril 20 mg daily pravachol 80 mg qhs vitamins Family history depression (daughters, mother) no dementias or psychoses Case Presentation (cont’d)

5. Social history lives alone in her own home husband died in 1990 5 children, daily contact retired office clerk daughter is DPOA Functional assessment independent in ADLs cooking less not driving unable to manage money frequently misses medication Physical examination T 97.8 HR 49 BP 171/64 no rash mild tremor, pronator drift, and satelliting on the right Mental status examination good grooming and cooperation alert and attentive to interview cannot recite days of the week in reverse oriented to year, month, and city only recalls 0/3 items at 2 minutes recalls current but not past US presidents verbal repetition intact, but word finding difficulties and paraphrasias noted extensive delusions visual, auditory, and possibly tactile hallucinations Case Presentation (cont’d)

6. Laboratory studies CBC, comprehensive panel, TSH, UA, UDS were unremarkable Neuropsychological testing (2003) verbal IQ lower than predicted deficits in memory, concentration, attention, calculation, language, visuospatial abilities MMSE: 21/30 Brain MRI (2003) 1.5-cm enhancing mass near the cribriform plate consistent with meningioma diffuse volume loss minimal periventricular FLAIR signal follow-up scan unchanged in 2004 SPECT perfusion scan (2003) hypoperfusion to medial temporal lobes bilaterally milder hypoperfusion to parietal lobes Case Presentation (cont’d)

7. Patient Intervention Comparison Outcomes In a 75-year-old patient with AD do second-generation antipsychotics ... in comparison to no treatment (placebo) ... improve symptoms of psychosis and agitation, and improve functioning? Clinical Question

8. Clinical Question • A related clinical question:What is the risk of serious adverse events when using second-generation antipsychotics in dementia-related psychosis/agitation? effectiveness adverse effects

9. Literature search results • 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 Oct 19;294(15):1934-43. • Ballard C, Waite J. The effectiveness of atypical antipsychotics for the treatment of aggression and psychosis in Alzheimer's disease. Cochrane Database Syst Rev. 2006 Jan 25;(1):CD003476. • Schneider LS, Dagerman K, Insel PS. Efficacy and adverse effects of atypical antipsychotics for dementia: meta-analysis of randomized, placebo-controlled trials. Am J Geriatr Psychiatry. 2006 Mar;14(3):191-210. • Ballard C, Howard R. Neuroleptic drugs in dementia: benefits and harm. Nat Rev Neurosci. 2006 Jun;7(6):492-500. • Schneider LS et al. for CATIE-AD Study Group. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer's disease. N Engl J Med. 2006 Oct 12;355(15):1525-38.

10. Literature search results • 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 Oct 19;294(15):1934-43. • Ballard C, Waite J. The effectiveness of atypical antipsychotics for the treatment of aggression and psychosis in Alzheimer's disease. Cochrane Database Syst Rev. 2006 Jan 25;(1):CD003476. • Schneider LS, Dagerman K, Insel PS. Efficacy and adverse effects of atypical antipsychotics for dementia: meta-analysis of randomized, placebo-controlled trials. Am J Geriatr Psychiatry. 2006 Mar;14(3):191-210. • Ballard C, Howard R. Neuroleptic drugs in dementia: benefits and harm. Nat Rev Neurosci. 2006 Jun;7(6):492-500. • Schneider LS et al. for CATIE-AD Study Group. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer's disease. N Engl J Med. 2006 Oct 12;355(15):1525-38.

11. CATIE-AD trial • Clinical Antipsychotic Trials of Intervention Effectiveness – Alzheimer Disease • NIH sponsored (minimal influence from pharmaceutical industry) • Phase 1 compares: • risperidone • olanzapine • quetiapine • placebo • Phase 2 includes a switch to a different antipsychotic or citalopram

12. Design • 421 outpatients with Alzheimer disease and psychosis, aggression, or agitation • multi-site, double-blind, placebo-controlled • randomized to risperidone, quetiapine, olanzapine, or placebo • flexible dosing • followed 36 weeks

13. Outcome measures • Primary outcome measure • time to discontinuation of treatment (TDT) for any reason • Secondary outcome measures • number of patients with at least minimal improvement in CGIC at 12 weeks • time to discontinuation of treatment due to lack of efficacy • time to discontinuation of treatment due to intolerability or adverse events • Contrasts with typical outcome measures in industry-sponsored trials • e.g., Neuropsychiatric Inventory score at pre-specified time point • outcomes not used in routine clinical practice • efficacy (pharmaceutical trial) vs effectiveness (real world)

14. Clinical characteristics • age: 78 ± 8 yr • residence • own home 73% • family’s home 10% • assisted living 10% • baseline ratings • MMSE 15 ± 6 (0-30) • ADAS 35 ± 13 (0-70) • NPI 37 ± 18 (0-144) • BPRS 28 ± 12 (0-108) delusions 82% hallucinations 49% • doses (initial / last) • olanzapine 3.2 / 5.5 mg • quetiapine 34 / 57 mg • risperidone 0.5 / 2.5 mg

15. Primary outcome • No significant differences in TDT for any reason • Medians:5.3–8.1 wk

16. Secondary outcome • TDT due to lack of efficacy • Olanzapine was superior to placebo (p<0.001) • Risperidone was superior to placebo (p=0.01) • Quetiapine did not differ from placebo (p=0.24)

17. Secondary outcome • TDT due to intolerability or adverse events • Placebo was superior to each antipsychotic medication (p<0.005)

18. Secondary outcome • Clinical Global Impression of Change (CGIC) indicating at least minimal improvement • olanzapine: 32% • risperidone: 29% • quetiapine: 26% • placebo: 21% • no significant differences between treatments (p=0.22)

19. Possible discussion points • Implications for my patient? • Interpretation of the results more generally? • Effects of population heterogeneity? • Psychosis vs agitation vs aggression? • Quetiapine underdosed? • What study should be done next?

21. Table 1

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23. Table 3