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					   IDND Consultancy:
     Behavioral and
Psychological Symptoms of
        Dementia
           April 16, 2007
Noll Campbell, PharmD, CGP, FASCP
       Wishard Health Services
                  Discussion
   What treatment options exist for managing
    psychosis/delusions associated with BPSD?

   Based on the predominant clinical symptom, will one
    method of treatment work better than others?

   At what point does the benefit of the treatment
    exceed the potential risk?

   What information is absent that will help make a more
    significant impact in the treatment of behavioral and
    psychological symptoms of dementia?
                       Case
 Social   history:
     HH is a 92 yo AAF who presents to clinic for
      evaluation of mod/sev dementia
     Currently residing at home with a sister, who
      is also reported to have a dementia
     Niece, grand-niece provide care to patient
      from a distance
     Reports of medication non-adherence in the
      past, despite repetitive reports to the contrary
      during clinic visits
                         Case
 PMH
     Dementia – Alzheimer’s Type
     Hypertension
     Osteoarthritis
     Urinary incontinence
 PE
     Appearance:
       • Usually overdressed for clinic visit
       • Wears a wig, and quick to explain, “medications
         have made my hair fall out”
     Remaining PE WNL
                              Case
   Paranoid, Delusional history
       Patient has been pulling out her own hair
         • Evaluated at ED for sudden, nocturnal hair loss
         • Patient blames medications
       Frequent complaints of harassment from an
        insurance agent
       Causes emotional unrest in sister by suggesting the
        insurance agent will come for her also
       Few, but various other complaints of others plotting
        against her
                      Case
   Alert, oriented to person, city, and state

   ADL/IADL:
     • Other than toileting, able to manage ADL on own,
     • completely dependent in IADL
   MMSE – 17 (6th grade education)
   GDS - 1
   Medications:
     • Vitamin B12 injection monthly
     • Variable adherence to antihypertensives
                       Case
 Pertinent    labs:
     TSH: 2-3
     Vit B12: 540 (with B12 inj monthly)
     Folate: 12.6
     BMP, CBC, LFT: WNL
     Alb: 3.6
     RPR: nonreact (1997, 2004)
     FLP: WNL for CV risk, age
                 Timeline of Events

                   April –       March –       April –                   Alz.
                  Warning in    Warning in   Black Box                Research
                  Label re:     Label re:     Warning                Trust Article
                   risk of        risk of    Applied to                 in UK
                   CVAE         Diabetes        SGA



2003           2004             2005         2006             2007


       First report of       Internal            Schneider       CATIE-AD
         increased         Manufacturer          publishes          trial
       mortality risk       reviews at            SER of        suggests no
          in J Clin         request of            mortality      benefit of
        Psychiatry             FDA                  risk           SGA
                   FDA Warning

Analyses of seventeen placebo controlled trials that enrolled 5106
elderly patients with dementia related behavioral disorders revealed a
risk of death in the drug-treated-patients of between 1.6 to 1.7 times that
seen in placebo-treated patients. Clinical trials were performed with
Zyprexa (olanzapine), Abilify (aripiprazole), Risperdal (risperidone), and
Seroquel (quetiapine). Over the course of these trials averaging about 10
weeks in duration, the rate of death in drug-treated patients was about
4.5%, compared to a rate of about 2.6% in the placebo group. Although
the causes of death were varied, most of the deaths appeared to be either
cardiovascular (e.g., heart failure, sudden death) or infectious (e.g.,
pneumonia) in nature.



                               www.fda.gov
                                    Mortality Risk: SGA




                                       Schneider, L. S. et al. JAMA 2005;294:1934-1943.
                                      Schneider LS, et al. JAMA 2005;294(15):1934-1943
Copyright restrictions may apply.
Mortality Risk: FGA vs. SGA




  Trifiro, et al. Pharmacoepidemiol Drug Saf. 2006 Oct 12; [Epub ahead of print]
Mortality Risk: FGA vs. SGA




  Wang PS, et al. Risk of death in elderly users of conventional vs. atypical
  antipsychotic medications. N Engl J Med. 2005 Dec 1;353(22):2335-41.
Mortality Risk: FGA vs. SGA




  Wang PS, et al. Risk of death in elderly users of conventional vs. atypical
  antipsychotic medications. N Engl J Med. 2005 Dec 1;353(22):2335-41.
Mortality Risk: FGA vs. SGA

50

40
                                                      Atypical
30                                                    Antipsychotic
                                                      Conventional
20                                                    Antipsychotic
                                                      No
10                                                    Antipsychotic

0
     2-Year Mortality

        Raivio MM, et al. Am J Geriatr Psychiatry. 2007 Feb 9
          Data with SGA in BPSD
   OLZ vs. Haloperidol                            Quetiapine vs.
    in 58 pts. with DAT1                            Haloperidol in 30 pts.2
       OLZ (4.71 mg) vs.                                Quetiapine (125mg)
        Haloperidol (1.75 mg)                             vs. Haloperidol
       Treatment duration of                             (1.9mg)
        3 weeks                                          Similar effect on NPI
   Similar efficacy for                                 Suggestion of
                                                          improved recall with
    aggression on CMAI
                                                          quetiapine


            1Verhey   RR, et al. Dement Geriatr Cogn Disord. 2006;21(1):1-8
            2Savaskan   E. et al. Int J Neuropsychopharmacol. 2006 Oct;9(5):507-16
  Symptom-Driven Treatment

     Trazodone                                         Haloperidol

Depressive symptoms                                     Delusions

Repetitive behaviors                      Excessive motor activity

                                                     Unwarranted
 Verbal aggression
                                                     accusations

Oppositional behavior
      Sultzer DL, et al. Am J Geriatr Psychiatry. 1997 Winter;5(1):60-9
    Neuropsychiatric Inventory (NPI)
   Developed in 1994 to evaluate BPSD
   15-30 minutes to administer
   Evaluates the following domains:
        Delusions                        Euphoria
        Hallucinations                   Dysinhibition
        Dysphoria                        Irritability/lability
        Anxiety                          Apathy
        Agitation/Aggression             Aberrant      Motor Behavior
        Sleep                            Appetite



                 Cummings JL, et al. Neurology 1994;44(12):2308-14.
                    Case
 92   yo AAF with history of DAT

         episodes of paranoia, delusions,
 Frequent
 and occasional violence

 Hashistory of ED visit for paranoia in
 recent past

 Otherwise   medically stable
                  Discussion
   What treatment options exist for managing
    psychosis/delusions associated with BPSD?

   Based on the predominant clinical symptom, will one
    method of treatment work better than others?

   At what point does the benefit of the treatment
    exceed the potential risk?
     • Who is the most appropriate person to make this
       decision?
   What information is absent that will help make a more
    significant impact in the treatment of behavioral and
    psychological symptoms of dementia?
                 Case
            of atypical antipsychotics
 Risk/benefit
 discussed and family agreed to treatment
        prescribed risperidone 0.5mg po
 Patient
 BID with good clinical effect
 Adherence became a problem, pt.
 switched to aripiprazole 10mg po daily
           all medication withdrawn,
 Eventually
 pending pursuit of guardianship and
 placement in AL
Changes in NPI with Memantine




          Cummings, J. L. et al. Neurology 2006;67:57-63
                                    Studies of Typical and Atypical Antipsychotics: Outcomes




Copyright restrictions may apply.
                                                Sink, K. M. et al. JAMA 2005;293:596-608.
 Unable   to obtain


     Frenchman IB. Clinical experience with risperidone,
     haloperidol, and thioridazine for dementia-associated
     behavioral disturbances.
     Int Psychogeriatr. 1997 Dec;9(4):431-5.


     Suggests rates of EPS at 7%, 22%, and 18%, respectively.
     Improvement in agitation by 94%, 65%, and 67%.
 No increased risk of CVAE in users of
 FGA or SGA based on retrospective,
 case-control data from 6 US nursing
 homes. – SAGE database. Liperoti, et al. J
 Clin Psychiatry 2005.
 Comparison of olanzapine and risperidone in the
  treatment of psychosis and associated
  behavioral disturbances in patients with
  dementia.
  Am J Geriatr Psychiatry. 2005 Aug;13(8):722-30.
 5-HT2A receptor polymorphism may
  modulate antipsychotic treatment response
  in Alzheimer's disease
  Sebastiaan Engelborghs, Clive Holmes, Michelle
  McCulley, Peter P. De Deyn
  International Journal of Geriatric Psychiatry
  Volume 19, Issue 11, 2004. Pages 1108-1109
 Suh GH, et al. A randomized, double-blind,
  crossover comparison of risperidone and
  haloperidol in Korean dementia patients with
  behavioral disturbances.
  Am J Geriatr Psychiatry. 2004 Sep-
  Oct;12(5):509-16.
 Gareri P. Comparison of the efficacy of new and
  conventional antipsychotic drugs in the
  treatment of behavioral and psychological
  symptoms of dementia (BPSD).
  Arch Gerontol Geriatr Suppl. 2004;(9):207-15.
 Sommer    BR, Finn HH, et al. Safety and
  efficacy of anticonvulsants in elderly
  patients with psychiatric disorders:
  oxcarbazepine, topiramate and
  gabapentin.
  Expert Opin Drug Saf. 2007 Mar;6(2):133-
  45.
 Lanctot, et al. 1998; SER of 13 RCT
  comprising 295 patients
www.apana.org.uk/risp-icon.jpg
http://www.ep.org.au/images/ozp.gif
www.ep.org.au/images/quet.gif
www.ep.org.au/images/quet.gif