Diapositiva 1

1
I sintomi non cognitivi nella demenza di Alzheimer
Giovanni Gambassi
SAGE Group Università Cattolica, Roma Brown
University, RI, USA
2
Outline - BPSD

• Introduction
• Definition and prevalence
• Aetiology and effects
• Management
• pharmacological
• non-pharmacological

3
Donne e Uomini
4
Introduction
5
Differential Diagnosis of Dementia
Other dementias Frontal lobe dementia
Creutzfeldt-Jakob disease Corticobasal
degenerationProgressive supranuclear palsy
Many others
Vascular dementiasMulti-infarct
dementiaBinswangers disease
Dementia with Lewy bodies Parkinsons disease
Diffuse Lewy body disease Lewy body variant
of AD
Vascular dementias and AD
AD and dementia with Lewy bodies
AD
5
10
65
5
7
8
Small et al, 1997 APA, 1997 Morris, 1994.
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Alzheimers Disease (AD)

• Progressive, degenerative CNS disorder
• Characterized by memory impairment plus one or
  more additional cognitive disturbances
• Gradual decline in three key symptom domains
• Activities of daily living (ADL)
• Behavior and personality
• Cognition
• Most common cause of dementia in people aged 65
  and over

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Shoghi-Jadid et al., 2002
UCLA group, J. Amer. Ger. Psych, 2002
9
67-year-old control
Alzheimer patient
PET brain images
2-(4-methylamino-phenyl)-6-hydroxybenzothiazole
(Pittsburgh Compound)
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Diagnostic Criteria For AD (DSM-IV, APA, 1994)

• Multiple Cognitive Deficits
• 1. Memory Impairment
• 2. Other Cognitive Impairment
• B. Deficits Impair Social/Occupational
• Course Shows Gradual Onset And Decline
• Deficits Are Not Due to
• 1. Other CNS Conditions
• 2. Substance Induced Conditions
• E. Do Not Occur Exclusively during Delirium
• F. Not Due to Another Psychiatric Disorder

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ALZHEIMERS DISEASE
12
ADAS-Cog Score ChangeModel-based Analysis
Improvement
6 0 6 12 18
ADAS-Cog Sscore Mean Change from Baseline
Decline in ADAS-Cog score based on the natural
history of untreated patients with moderate AD
0 6 12 14 26 38 50 62 74 85 98
Cumulative Weeks from Baseline of the
Double-blind Study
N133
Decline
Rogers and Friedhoff, 1998 Stern et al, 1994.
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Definition and prevalence
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Behavioural Psychological Symptoms of Dementia
(BPSD)

• Symptoms of disturbed perception, thought
  content, mood or behaviour that frequently occur
  in patients with dementia
• IPA consensus group (1996)

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Dementia
Dementia
BPSD
Activities of daily living
Cognitivedeficits
Behavioural and Psychological Symptoms of
Dementia A heterogeneous range of psychological
reactions, psychiatric symptoms and behaviours
resulting from the presence of dementia
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Ashford et al., 1995
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Symptom Complexes of BPSD
Anxiety
Psychosis
Agitation
Depression
Altered circadianrhythms
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Neuropsychiatric Signs and Symptoms in Dementia
Agitation
Depression
Anxiety
Aggression
Psychosis
Lifetime risk 100
Tariot 2003
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BPSD in the community

• Cache County Study, Utah, USA
• People with dementia up to 40X gt rates of BPSD
  than rest of population
• 61 any NPI disturbance Mean NPI 7
• 32 severe (NPI ? 6) disturbance
• Delusions AD gt VaD
• Depression VaD gt AD

Lyketsos et al, Am.J. Psychiatry, 2000
157708-714
22
Neuropsychiatric Symptoms in Persons with
Alzheimers Disease
with NPI Scores
(Mega et al, Neurology 1996 46 130-135)
23
BPSD in NHs
Butler et al., 1998 Colenda, 1995 Rosewarne et
al., 1996 Rovner, et al., 1986 Snowdon et al.,
1996b Zimmer et al., 1984 Rovner et al., 1991
Ames, 1993 Snowdon et al., 1996
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Multiple Behavioral Changes Occur Simultaneously
with 0,1,2,3 Symptoms (Psychosis, Agitation,
Depression)
(Levy et al, Am J Psychiatry, 1996)
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Once Present, Behavioral Symptoms Commonly Recur
of Patients
Patients Re-Examined Five times in One Year
(Levy et al, Am J Psychiatry 1996 153 1438-1443)
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Neuropsychiatric Symptoms in Persons with
Alzheimers Disease
with Sx
Lancet Neurol 20054735-42
27
Neuropsychiatric Symptoms in Persons with
Alzheimers Disease
with Sx
Lancet Neurol 20054735-42
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Relationship between type of agitation and level
of cognitive functioning
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Etiology and effects
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Syndromes

• Agitation 3 syndromes
• Psychotic symptoms delusions and hallucinations
• Depression depressed affect vs. vegetative
  symptoms

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Examples of studies of factor analyses in
agitation
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Behavioral and Psychological Symptoms

Agitazione
Aggressività
Affacendamento Vagabondaggio Pedinamento,
Irrequietezza, Grida Disinibizione, Stereotipie,
Vestirsi/svestirsi Disturbi del sonno
Resistenza aggressiva Aggressività
fisica Aggressività verbale
Apatia
Ritiro Mancanza di interessi Demotivazione
Allucinazioni Deliri Falsi riconoscimenti
Tristezza Pianto Disperazione Bassa
autostima Ansia Colpa
Depressione
Psicosi
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Is BPSDpart of the diagnosisof dementia?
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Biological causes

• ? serotonin (depression, aggression, agitation,
  anxiety)
• ? other neurotransmitters
• imbalance between glutamate/ dopaminergic systems
  (psychosis)
• ? noradrenalin in substantia nigra (psychosis)
• ? noradrenalin in neocortex (depression)
• genetic predisposition
• causes extrinsic to dementia
• eg acute illness, pain, medications, fatigue

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Psychological causes

• Previous psychiatric illness
• links with prior and current depression1
• Premorbid personality
• - SNHS no meaningful correlations2
• Reaction of others to person with dementia
• - link between depression in persons with AD and
  GHQ in caregivers ? Causality3
• 1 Pearlson et al, 1990 2 Low et al, 2002 3
  Brodaty Luscombe, 1996

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Environmental

• Overstimulation
• Understimulation (boredom)
• Overcrowding
• Size of home - SNHS size vs BEHAVE-AD,
• Inconsistent routine
• Provocation by others
• Physical restraints

1Day et al, 2000 2Brodaty et al, 2001
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Differences in BPSD levels

• 3-4 fold difference in mean BEHAVE-AD
• Not explained by different admission policies
• Same rating methods
• Does environment or do policies matter?

1 Brodaty et al, 2001
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Conseguenze dei BPSD
Eccesso di disabilità e peggioramentodelle
prestazioni cognitive (Rapaport et al, 2001
Tekin, 2001)
Riduzione della qualità della vita dei pazientie
dei caregiver (Deimling and Bass, 1986 Burgio,
1996)
Aumento sostanziale dello stress dei
caregiver (Zanetti et al., 1997)
Aumento del rischio di precoce istituzionalizzazio
ne (Morris et al., 1990 Steele et al., 1990
ODonnell et al., 1992Bianchetti et al., 1995
Aumento significativo dei costi sociali (Murman
et al, 2002 Bianchetti et al, 2002)
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Effects of BPSD

• Residents with BPSD are more likely to1
• be physically restrained
• receive antipsychotic medication
• negatively influence care staff
• negatively influence other residents
• BPSD increase the cost of caring for a person
  with dementia in an institution2
• BPSD increase nurse stress, especially
  aggression3, calling 1Maslow K 1994 2OBrien
  JA, Shomphe LA,Caro JJ 2000 3Rodney, 2000
  4Draper et al, 2000

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Consequences
Increased morbidity Earlier nursing home
admission Increased caregiver burden Exacerbation
of existing functional and cognitive deficits
Lawlor 2004
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Clinical diagnosis
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Diagnosis and Assessment of BPSD

• Phenomenology is the basis of diagnosis
• Direct interview
• Direct observation
• Proxy report
• Measurements and scales
• Need for accurate descriptions
• Think of physical illness
• Think of sensory impairment

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Psychosis in BPSD
Psychosis in BPSD
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Diagnostic Criteria for Psychosis of AD

• Characteristic symptoms Presence of one or more
  of the following symptoms visual or auditory
  hallucinations delusions
• Primary diagnosis All the criteria for dementia
  of Alzheimer are met.

For other dementias, such as vascular dementia,
Criterion B will need to be modified
appropriately.
Jeste, Finkel 2000
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Diagnostic Criteria for Psychosis of AD

• Chronology of the onset of symptoms of psychosis
  Vs onset of symptoms of dementia
• There is evidence from the history that the
• psychotic symptoms have not been
• present continuously since prior to the onset
• of dementia.

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Diagnostic Criteria for Psychosis of AD

• Duration and severityThe psychotic symptom(s)
  have been present, at least intermittently, for 1
  month or longer. Symptoms are severe enough to
  cause some disruption in patients and/or others
  functioning.

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Diagnostic Criteria for Psychosis of AD
Exclusion of schizophrenia and related psychotic
disordersCriteria for schizophrenia,
schizoaffective disorder, delusional disorder or
mood disorder with psychotic features, have never
been met.
Relationship to deliriumThe disturbance does not
occur exclusively during the course of a delirium.
Exclusion of other causes of psychotic
symptomsThe disturbance is not better accounted
for by another general medical condition or
direct physiological effects of a substance (e.g.
drug abuse, a medication).
Jeste, Finkel 2000
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Differential Diagnosis of Psychosis of AD Vs
Psychosis of Schizophrenia in the Elderly
Psychosis of AD Schizophrenia Bizarre or
complex delusions Rare Frequent Misidentification
s of caregivers Frequent Rare Common form of
hallucinations Visual Auditory Schneiderian
first-rank symptoms Rare Frequent Active suicidal
ideation Rare Frequent Past history of
psychosis Rare Frequent
Jeste, Finkel 2000
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Depression in BPSD
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Prevalence of Depression in Dementia

• Depression has long been recognized as a major
  co-morbidity of dementia syndromes.
• Prevalence of depression in DAT 0-20, but
  lacking diagnostic criteria specific for
  depression in dementia, most studies report
  prevalence of depressive symptoms
• Prevalence rates in Vascular Dementia 19 - 43

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Depression as the First Sign of Dementia

• Patients initially diagnosed with depressive
  pseudodementia or "reversible dementia" may not
  achieve complete cognitive recovery following
  remission of depression.
• An average of 11-23 of patients with initially
  reversible dementia become irreversibly demented
  every year
• Irreversible dementia begins to be diagnosed
  about two years after the initial recovery from
  depression

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Clinical Characteristics of Depression in BPSD

• Depressive symptoms in dementia patients often
  fluctuate
• Depressed patients with DAT exhibited more
  self-pity, rejection sensitivity, anhedonia and
  psychomotor disturbance than depressed older
  patients without dementia.
• Major depression in DAT is associated with an
  increased mortality rate, but no acceleration of
  cognitive decline.

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Etiology of Depression in Dementia

• Major depression in AD has been associated with
• increased degeneration of brainstem aminergic
  nuclei, particularly the locus coeruleus
• Relative preservation of the cholinergic nucleus
  basalis of Meynert
• No increase in the numbers of senile plaques or
  neurofibrillary tangles in the neocortex or
  allocortex
• Modest decreases in the levels of serotonin and
  5-HIAA
• Environmental and psychosocial factors

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Agitation in BPSD
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Agitation

• Some patients have symptoms that do not neatly
  fit into the better defined symptom complexes of
  BPSD (e.g. psychosis, depression or anxiety).
• These symptoms are consigned to the grab-bag
  category of agitation
• Agitation can be defined as inappropriate verbal,
  vocal or motor activity that is not judged by an
  outside observer to result directly from the
  needs or confusion of the person

Koss, Weiner, et al. 1997
Cohen-Mansfield and Billig, 1986
58
Agitation Symptoms - I

• Physically Non-Aggressive
• General Restlessness
• Repetitive Mannerisms
• Pacing
• Hiding Objects
• Inappropriate Handling
• Shadowing
• Escaping protected environment
• Inappropriate Dressing/Undressing

Cohen-Mansfield, 1989
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Agitation Symptoms - II

• Physically Aggressive
• Hitting
• Pushing
• Scratching
• Grabbing
• Kicking
• Biting
• Spitting

Cohen-Mansfield, 1989
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Agitation Symptoms - III

• Verbally Non-Aggressive
• Negativism
• Chanting
• Repetitive Sentences
• Constant Interruptions
• Constant Requests for Attention

Cohen-Mansfield, 1989
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Agitation Symptoms - IV

• Verbally Aggressive
• Screaming
• Cursing
• Temper Outbursts
• Socially Inappropriate Commentary

Cohen-Mansfield, 1989
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Aggression

• 12 of patients showed aggressive episodes (5
  with verbal aggression, 7 with physical
  aggression) during the preceding 4 weeks
• Physical aggression is significantly associated
  with more frequent delusions and more severe
  irritability

Chemerinski E et.al. , 1998
63
Catastrophic Reactions

• Sudden, excessive emotional response or physical
  behavior
• Occur in approximately 40 of mild-moderately
  impaired dementia patients
• During neuropsychological evaluation, 16 of
  dementia patients demonstrated catastrophic
  reactions
• Can be precipitated by other BPSD such as
  misperception, hallucinations or delusions

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Anxiety Symptoms in BPSD
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Clinical Characteristics of Anxiety Symptoms in
BPSD

• No specific definition of anxiety in BPSD is
  available
• The most common clinical forms are
• Generalized Anxiety Disorder type symptoms
• Godot syndrome repeatedly asking questions on a
  forthcoming event
• Fear of being left alone
• Pacing
• Wringing of hands, fidgeting
• Chanting

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Ham-A Items that Differentiate Between AD-GAD
and AD-Controls

• Somatic Symptoms
• Cardiovascular Symptoms
• Respiratory Symptoms
• Gastrointestinal Symptoms
• Autonomic Symptoms

• Anxious Mood
• Tension
• Fears
• Insomnia
• Muscular Symptoms

Chemerinsky E, Petraca G, Manes F et al, 1998
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Variation With Type of Dementia

• Visual hallucinations are more common in Diffuse
  Lewy Body Dementia
• Disinhibition symptoms occur early in the some of
  the Frontotemporal Dementias
• Earlier onset of behavioral symptoms has been
  described in Huntingtons chorea,
  Creutzfeldt-Jacob disease and Picks disease

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Management

• Non pharmacologicalPharmacological

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Gestione dei BPSD

• valutare deficit sensoriali
• es. sordità
• escludere una causa medica
• es. dolore, tireotossicosi
• escludere una causa iatrogena
• es. BDZ, anticolinergici

• approccio ambientale e comportamentale
• ottimizzare stimolazione, sostenere
  caregiver
• approccio farmacologico sui sintomi bersaglio
• gtgtanche in funzione di gravità e acuzieltlt

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• Which BPSD need to be treated?
• Many BPSDs do not have to be treated.
• Some BPSDs should not be treated with
  psychotropic drugs.
• Etiology of the symptom needs to be determined
  and addressed. For a small proportion of
  patients whose behavior is dangerous or grossly
  disturbing, and no nonpharmacologic approach is
  effective, a pharmacologic approach is appropriate

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Brodaty et al, MJA, in press (2003178(4))
Brodaty et al, MJA, 2003 178231-234
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• Nonpharmacologic therapies

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Treatment Options
Antipsychotics
Antidepressants
Anticonvulsants
Cholinesterase inhibitors
Anxiolytics / Sedatives
Antipsychotics are the only agents to show
consistent benefit
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30s 40s 50s 60s 70s
80s 90s 00 02
Haloperidol Fluphenazine Thioridazine Loxapine Per
phenazine
ClozapineRisperidone OlanzapineQuetiapineZipr
asidone
ECT
Aripiprazole Next-generation
Chlorpromazine
First-generationantipsychotics
Second-generationantipsychotics
ECT electroconvulsive therapy. Kapur and
Remington. Ann Rev Med. 200152503. Worrel et
al. Am J Health Syst Pharm. 200057238.
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Conventional Antipsychotics

• Mechanisms of action
• ? Block synaptic actions of dopamine
• ?The antagonism of dopamine in the mesolimbic
• mesocortical system is thought to be the basis
• of the therapeutic actions, while antagonism of
• the nigrostriatal system is the major factor in
• the extrapyramidal side effects

78
Aloperidolo vs. Placebo nel BPSDin corso di
Malattia di Alzheimer
2-3 mg/die
N71 DB cross- over 6 6 settimane
Responders - BPRS
0.50-0.75 mg/die
20 EPS moderati o gravi
Devanand et al, 1998
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AP tradizionali nei Behavioral and Psychological
Symptoms of Dementia
Metaanalisi degli Studi Controllati
7 studi in doppio cieco vs. PBO 4-8 sett.
252 pazienti AD/VaD con psicosi/agitazione

• Rating scale CGI ( p.ti migliorati)
• differenza farmaco/PBOgtgteffetto netto 16

Equivalenza terapeutica interclasse
EPS, iperprolattinemia, deficit cognitivi,
ipotensione ortostatica, effetti anticolinergici
Schneider et al, 1996
80
Modest Efficacy of Conventional Antipsychotics
for Agitation/Psychosis
Placebo
Active treatment
Efficacytreatment estimate 25
Tolerabilityexcess adverse events 25
-25
25
75
0
difference 95 CI (active minus placebo)
Meta-analysis of 16 randomized, double-blind
trialsCI, confidence interval Lanctôt et al 1998
81
Conventional Antipsychotics

• Side effects
• Sedation commonly seen with all antipsychotics
• Extrapyramidal reactions- Acute dystonia-
  Akathisia- Tardive dyskinesia late occurring,
  usually irreversible
• Neuroleptic malignant syndromeFever, rigidity,
  severe EPS, autonomic dysfunction
• Autonomic dysfunction alpha adrenergic
  antagonists
• Cholinergic antagonism
• Postural hypotension
• Hyperprolactinemia

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Antipsicotici Tradizionali
Alta Potenza
ALO
D2
Bassa Potenza
POTENZA ANTIPSICOTICA
BLOCCO dei recettori dopaminergici D2
Stahl, Ess. Psychopharmacol, 2000
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Effetti del Blocco Recettoriale da AP
Tipo di recettore Effetto terapeutico Effetto indesiderato
Colinergico M-1 Riduzione EPS Effetti anticolinergici Disturbi cognitivi
Istaminergico H-1 Sedazione Aumento peso Sonnolenza
Adrenergico a-1 Sedazione Ipotensione ortostatica Tachicardia riflessa
Adrenergico a-2 Modulazione DA nella PFC Miglioramento funzione cognitiva e sintomi depressivi Blocco attività antiipertensiva della clonidina
84
Nuovi Antipsicotici
H1
M1
a1
CLZ OLZ
SDA
D2
MARTA
Stahl, Ess. Psychopharmacol, 2000
85
Nuovi AntipsicoticiVantaggi sul piano della
tollerabilità

• Minore incidenza di EPS e DT
• Scarsa induzione di
• Prolattina

86
Atypical antipsychoticsadvantages in the elderly

• Lower incidence of EPS and less TD
• Lower incidence of central and peripheral
  anticholinergic adverse effect
• Favorable safety profile
• Lower potential for drug interactions
• Lower risk of liver dysfunction
• Less or no induction of prolactin
• Better compliance, less relapse

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Prevalence of use
88
Atypical antipsychotics

J Clin Psychiatry, 2004
89
Predictors of atypicals use
Adj OR 95 CI
Female 1.12 1.04-1.21
Alzheimers disease 1.21 1.12-1.32
Other Dementia 1.15 1.06-1.24
Parkinsons disease 1.57 1.34-1.84
Depression 1.35 1.25-1.47
Hypertension 1.09 1.02-1.17
Antidepressants 1.38 1.28-1.49
Cholinesterase inhibitors 1.74 1.53-1.98
Self-pay 1.21 1.11-1.31
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Significance vs placebo
Atypical
Primary endpoint
Reference
Katz et al 1999 De Deyn et al 1999 Brodaty et al
2003 Mintzer et al 2004 Satterlee et al
1995 Street et al 2000 De Deyn et al 2004 De Deyn
et al 2003 Breder et al 2004 Streim et al 2004
BEHAVE-AD total score gt30 reduction in
BEHAVE-ADtotal score CMAI total aggression
score BEHAVE-AD psychosis score Not stated NPI/NH
core total score NPI/NH hallucinations and
delusions NPI/NH psychosis NPI/NH psychosis Not
stated
? O ? O O ? O O ? ?
Risperidone Olanzapine
Aripiprazole
BEHAVE-AD, Behavioural Pathology in Alzheimers
Disease scale CMAI, Cohen-Mansfield agitation
inventory NPI/NH, Neuropsychiatric Inventory
Nursing Home version
92
Clinical trials

• Risperidone

93
Reduction of Psychosis in Persons with AD

Percent of Patients Whose Delusions Resolved With
Treatment

(Sx at baseline not at end of study)
(Katz et al, J Clin Psychiatry 1999 60 107)
94
Reduction of Agitation in Persons with AD
(p0.02)
(p0.06)
Percent of Symptomatic Patients With Scores Of 0
or 1 At Study End
(Katz et al, J Clin Psychiatry 1999 60 107)
95
Risperidone Improved Response Rates in Patients
with Dementia
12-week, double-blind study in 625 nursing-home
patients with agitation /or psychosis


Response ratea ()
Placebo
1.0
2.0
Risperidone (mg/day)
p0.02 p0.002 vs placebo agt50 decrease in
BEHAVE-AD total score Katz et al 1999
96
Aggression in Dementia 12-week, double-blind
study in 345 patients with aggression mean dose
about 1 mg/d
63
70
60
50
37
40
Responders ()
30
20
10
0
Risperidone
Placebo
P lt 0.001 Brodaty H, et al. J Clin Psychiatry.
200364134-143.
97
Multicenter Double-Blind Trial of Risperidone vs
Haloperidol 12-week, double-blind study in 344
nursing-home patients with agitation/or
psychosis mean dose about 1 mg/d each
70
60
50
PatientsResponding ()
40
30
20
10
0
Placebo
Risperidone
Haloperidol

• ? 30 ? in BEHAVE-AD total score.
• De Deyn PP, et al. Neurology. 199953946-955.

98
Comparative Effects of Risperidone and
Haloperidol on MMSE Scores in Persons with AD

Change In MMSE Score
Plac
Risperidone
Haloperidol
(DeDeyn et al, Neurology 1999 53 946)
99
Clinical trials

• Olanzapine

100
Reduction of Psychosis in Persons with AD
Plac
5 mg
10 mg
15 mg
Change in NPI Psychosis Score (Del Hall)


(Street et al, Arch Gen Psychiatry 2000 57 968)
101
Reduction of Agitation in Persons with AD
Placebo
5 mg
10 mg
Reductions On NPI Agitation Score


(Street et al, Arch Gen Psychiatry, 2000)
102
Response Rates in Patients with Dementia
6-week, double-blind study in 206 nursing-home
patients with agitation /or psychosis
80


60
Response ratea ()
40
20
0
Placebo
5
10
15
Olanzapine (mg/day)
p0.05 p0.01 vs placebo agt50 decrease in
NPI/NH core total scores Street et al 2000
103
Difference versus Placebo on CGI-C10-week,
double-blind study in 652 nursing-home patients
w/ psychosis
5
4
3.1
3.2

3.0
CGI-C mean changefrom baseline (LOCF)
2.9
2.8
3
2
4.8a
4.7a
4.8a
4.8a
4.9a
1
Olanzapine dose
2.5 mg (n134)
5 mg (n124)
7.5 mg (n128)
1 mg (n128)
Placebo (n129)
p0.03 aBaseline score CGI-C, Clinical Global
Impression of Change LOCF, last observation
carried forward De Deyn et al 2004
104
Reduction of Occupational Disruptiveness Reported
by Caregivers of Persons with AD
Placebo
5 mg
10 mg
Reductions On NPI/NH Occupational Disruptiveness S
cale Score

(Street et al, Arch Gen Psychiatry, 2000)
105
Clinical trials

• Quetiapine

106
Psychosis in DementiaChange From Baseline to
Week 10 LOCF
Various Efficacy Outcome Measures
Quetiapine Haloperidol Placebo
4
2
0
-2
Change From Baseline
-4


-6
-8
-10
BPRS BPRS BPRS
NPI-NH2 NPI- CGI-STotal
Agitation Anergia
Agitation
P 0.023 QTP vs placebo P 0.005 QTP vs
HAL NPI-NH2 sum of hallucinations and
delusions Tariot PN, et al. Presented at the
15th Annual American Association for Geriatric
Psychiatry (AAGP) Meeting. Orlando, FL February
24-27, 2002. Manuscript under review, Tariot et
al.
107
Agitation in Residents with Dementia (STAR)
Final visit (LOCF)
Week
0
1
2
4
6
8
10
0
Quetiapine 200 mg/day
Quetiapine 100 mg/day
-2
Placebo
-4
LSM change in PANSS-EC score
-6
Improvement


-8


-10
plt0.05 plt0.01 vs placebo n260 Zhong et al
2004
108
Clinical trials

• Aripiprazole

109
Psychosis in Alzheimers Disease
Aripiprazole(mg/day)
Comparator
Duration(Week)
Patient Population
N
Psychosis associated with AD outpatient
208
Trial 1
10
215
Placebo
Psychosis associated with AD nursing home
2, 5, 10
Placebo
480
10
Trial 2
Psychosis associated with AD nursing home
190
215
Placebo
10
Trial 3
Bristol-Myers Squibb Company and Otsuka America
Pharmaceutical, Inc. (data on file).
110
Aripiprazole in Psychosis of AD
Response Rate
P 0.175
75
50
Responders ()
25
0
Placebo
Aripiprazole
Response defined as 50 decrease from baseline in
NPI-psychosis subscale score De Deyn PP, et al.
16th Annual American Association for Geriatric
Psychiatry (AAGP) Meeting. Honolulu, Hawaii
March 2003 (poster presentation).
111
Clinical Trials Summary

• Most patients in trials had severe dementia
• Most studies were for agitation
• Few studies in psychosis per se
• Effect size about 20 for drugs that "work "
• Few comparative studies
• Role of guidelines
• Risk/benefit is a moving target

112
Atypicals Summary

• Atypicals are effective in the management of
  agitation alone or in association with psychosis
  in the elderly
• Datasets vary in quality and magnitude most
  trials done in patients with advanced dementia
• Atypicals probably offer improved tolerability
  compared with conventional agents
• New safety concerns serve as reminder to only use
  when non-pharmacologic efforts fail
• Differences exist among atypicals in their
  tolerability profiles that impact upon
  individualized treatment selection

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116
Risperidone Adverse Events
Risperidone 2.0 mg (n165)
Risperidone 1.0 mg (n148)
40
Risperidone 0.5 mg (n149)
35
Placebo (n163)
30
25

Patients ()
20
15
10
5
0
Injury
Peripheral edema
Pain
Somnolence
Agitation
EPS
Fall
Multicenter, fixed-dose, double-blind trial
plt0.05 vs placebo Katz et al 1999
117
Olanzapine Adverse Events
Olanzapine 15 mg (n53)
40
Olanzapine 10 mg (n50)

35
Olanzapine 5 mg (n56)
30
Placebo (n47)


25

Patients ()
20

15
10
5
0
Accidental injury
Somnolence
Pain
Abnormal Gait
Anorexia
Ecchymosis
Agitation
plt0.05 vs placebo plt0.01 vs placebo plt0.001
vs placeboStreet et al 2000 In De Deyn 2004,
48 AEs rate
118
Quetiapine Adverse Events
Quetiapine 200 mg/day (n117)
Quetiapine 100 mg/day (n124)
Placebo (n92)
Patients ()
EPS
Cardio-vascular
Cerebro-vascular
Postural hypotension
Sedation
Somnolence
Falls
EPS, Extrapyramidal symptoms safety and
tolerability analyses were conducted using total
patient population (N333) Zhong et al 2004
119
Aripiprazole Adverse Events (1 trial)
25
Aripiprazole (n 105)
Placebo (n 102)
20
15
Patients ()
10
5
0
Somnolence
Accidental
Urinary Tract
Bronchitis
Hypertension
Injury
Infection
Accidental injuries were not associated with
somnolence, light-headedness or EPS De Deyn PP,
et al. 16th Annual American Association for
Geriatric Psychiatry (AAGP) Meeting. Honolulu,
Hawaii March 2003 (poster presentation).
120
Weight Change After 10 Weeks on Standard Drug
Doses, Estimated From a Random Effects Model
6
5
4
Nonpharmacologic controls
3
2
95 confidence interval for weight change (kg)
1
0
1
2
3
thioridazine/mezoridazine
placebo
molindone
ziprasidone
fluphenazine
haloperidol
polypharmacy
risperidone
chlorpromazine
sertindole
olanzapine
clozapine
nonpharmacologic control
Allison et al. Am J Psychiatry 1561686-1696, 1999
121
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122
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123
Cerebrovascular Adverse Events (CVAEs) Associated
with Risperidone and Olanzapine
2002-2004 dopo re-analisi retrospettiva,
segnalata dalle ditte produttrici agli organi
regolatori canadese e americano unincidenza
significativamente maggiore, rispetto al placebo,
di CVAEs (es. stroke, TIA) in RCT con risperidone
() e olanzapina () condotti su pazienti anziani
con psicosi correlata a demenza
FDA- EMEA warning su scheda informativa
http//www.fda.gov/medwatch/ Racoosin JA, AAGP
Meeting, 2004 FDA, Division of
Neuropharmacological Drug Products
124
(No Transcript)
125
CNS Drugs 200519(2)91-103
126
Risperidone placebo-controlled trials
127
Olanzapine placebo-controlled trials
128
February 26
129
(No Transcript)
130
Modification of antipsychotic effect by a prior
history of cerebrovascular disease on the risk of
new cerebrovascular events (CVEs)
J Clin Psychiatry, 2005
131
Nuovi AP e CVAEs
CRITICA METODOLOGICA non stratificazione dei
campioni per fattori di rischio cardiovascolare
gtgt significative differenze nei tassi di
comorbilità medica tra i bracci degli studi

• Effetti non correlati alla dose o al tempo

• Meccanismi patogenetici ipotizzabili
• Ipotensione ortostatica
• Iperprolattinemia gtgt aterosclerosi
• Dislipidemia gtgt aterosclerosi
• Diabete gtgt aterosclerosi
• Eccessiva sedazione gtgt disdratazione
• Tromboembolismo venoso

Smith Beier, Am Med Dir Association, 2004,
129-131
132
Antipsychotics and heart failure
Gambassi et al. Arch Intern Med, March 28, 2005
133
Arch Intern Med, Dec 12, 2005
Likelihood of being hospitalized for VTE among
antipsychotic users vs non users
Crude HR Adj. HR 95 CI
Risperidone 1.60 1.94 1.48-2.56
Olanzapine 1.81 2.01 1.31-3.08
Clozapine/Quetiapine 1.85 2.19 1.09-4.37
Phenothiazines 1.02 1.10 0.71-1.69
Other Conventionals 1.59 1.78 1.20-2.64
Multiple antipsychotics 3.32 4.18 2.22-7.86
134
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135
Alexopoulos et al, J Clin Psych, 2004 65 (suppl
2)
136
(No Transcript)
137
(No Transcript)
138
(No Transcript)
139
First-line agents sertraline 25 - 150 mg/die or
citalopram 10 - 40 mg/die (escitalopram is a
reasonable alternative for the latter)
Full response may take as long as 9-12 weeks
Absence of a
partial response after 6 weeks indicates that any
improvement may be unlikely with further treatment
Preferred second line agents mirtazapine,
venlafaxine, secondary amine TCAs or MAOI/RIMA
Lyketsos Lee, 2004, Dement Ger Cogn Disord, 17,
55-64
140
Effects of Donepezil in Nursing Home NPI-NH
Individual Item Analysis
Placebo (n 105) Donepezil (n 103)
Improvement
-3
-2
-1
Baseline
0
Mean change from baseline NPI-NH individual item
score at Week 24
Anxiety
1
Disinhibition
Delusions
Hallucinations
Elation/euphoria
Irritability/lability
Apathy/indifference
Agitation/aggression
Night-time behavior
Depression/dysphoria
Aberrant motor behavior
2
Appetite/eating
3

Decline
4
Tariot et al, 2001. P ?.05 for second analysis
no significant difference on overall analysis.
141
Effects of Galantamine on Behavioral Symptoms
NPI Total Scores
Placebo Galantamine 8 mg/d
Galantamine 16 mg/d Galantamine 24 mg/d
-3
Improvement
-2
-1
Mean ( SEM) change in NPI score from baseline
0

1
2
3
Deterioration
4
Baseline 1 2 3 4 5
n978.P lt .05 vs placebo.Am J Psychiatry
2004161532-538
Time (months)
142
Effects of Rivastigmine on Behavior Following 52
Weeks of Therapy
Improve

-3.5


-3


-2.5


-2
Mean Change from Baseline

-1.5
-1
-0.5
0
Apathy
Anxiety
Appetite
behavior
Delusion
Agitation
Euphoria
Irritability
Depression
Aberr. motor
Disinhibition
Hallucinations
Night-time behavior
Curr Med Res Opin 2004201605-12
In patients with symptoms at baseline. Plt0.05
vs baseline. Plt0.001 vs baseline.
143
Inibitori delle Colinesterasi nel BPSD
Metaanalisi di 29 Studi
6 studi con valutazione al
Neuropsychiatric Inventory (NPI)
lieve, significativo
miglioramento
10 studi con valutazione Alzheimer Disease
Assessment Scale (ADAS)
miglioramento non significativo
Nessuna differenza tra i vari composti
Effetto primario o secondario ? Conseguenze
sulloutcome a lungo termine ?
Trinh et al, Jama, 2003
144
The Cochrane Database of Systematic Reviews 2005
Issue 4
1. Moderate to severe AD. Two out of three six
month studies show a small beneficial effect of
memantine. Pooled data indicate a beneficial
effect at six months on cognition (4.12 points on
the 100 point SIB , 95 CI 2.14 to 5.74, P lt
0.00001), activities of daily living (1.27 points
on the 54 point ADCS-ADLsev, 95 CI 0.44 to 2.09,
P 0.003) and behaviour (2.76 points on the 144
NPI, 95 CI 0.88 to 4.63, P 0.004), supported
by clinical impression of change (0.28 points on
the 7 point CIBIC, 95 CI 0.15 to 0.41, P lt
0.0001).2. Mild to moderate AD. In a single six
month trial, memantine had a beneficial effect on
ITT analysis of cognition, (1.9 ADAS-Cog points,
95 CI 0.35 to 3.45, P 0.02) and behaviour
(3.50 NPI points 95 CI 0.15 to 6.85, P 0.04)
supported by clinical global impression of change
(0.30 CIBIC points, 95 CI 0.09 to 0.51, P
0.005), but no effect on activities of daily
living or OC analysis of cognition. The
statistical significance of these benefits could
be overturned by data from two unpublished
studies known to show no significant effect. 3.
Mild to moderate vascular dementia. In two six
month studies, memantine improved cognition (1.85
ADAS-Cog points, 95 CI 0.88 to 2.83, P
0.0002), and behaviour (0.84 95 CI 0.06 to 0.91,
P 0.03) but this was not supported by clinical
global measures.4. Patients taking memantine
appeared to be less likely to develop agitation
(93/1167 8 versus 134/1141 12 (Peto odds
ratio (OR) 0.65, 95 CI 0.49 to 0.86, P
0.002). This was consistently seen in moderate to
severe dementia. There were no data which
suggested an effect on agitation which is already
present.
145
Valproic acid for agitation in dementia (Cochrane
Review). In The Cochrane Library, Issue 3,
2004. Chichester, UK John Wiley Sons, Ltd.
Name Country Population Mean Age Female Intervention Diagnoses Mean MMSE
Porsteinsson 2001  United States  Multicentric, Institutionalised Alzheimer's dementia, vascular dementia and other dementias  85.0  61.0  Valproic acid (N28) placebo (N28). divalproex sodium titrated to mean dose of 826mg/d 6 wk course.  Dementia MMSE DSM IV NICDS-ADRDA. Agitation CMAI Aggression CMAI sub scale. Global CGI.  6.8 
Sival 2002  The Netherlands  Institutionalised, Alzheimer's dementia, vascular dementia, and other dementias.  80.4  59.5  Valproic acid (N42) placebo (N42) Sodium valproate 480mg/d 3 wk course.  Dementia MMSE DSM IV NINCDS-ADRDA,Clinical Dementia Rating Scale. Agitation BPRS subset. Aggression Patel's method SDAS-9 sub scale CGI GIP. Global CGI   
Tariot 2001  United States  Multicentric, Institutionalised Alzheimer's dementia, vascular dementia, and other dementias.  83.3  64.0  Valproic acid (N87) placebo (N85) Divalproex sodium (delayed release) patients titrated to target dose of 20mg/kg/d median dose 1000mg/d 6 wk course.  Dementia MMSE DSM IV. Agitation CMAI. Aggression CMAI sub scale. Global CGI  7.4 
146
Valproic acid for agitation in dementia (Cochrane
Review). In The Cochrane Library, Issue 3,
2004. Chichester, UK John Wiley Sons, Ltd.

• No evidence of efficacy of valproic acid for
  agitation in people with dementia.
• Three randomized controlled studies were
  identified, but because of problems
  (metodologici)it was not possible to pool
  results in a meta-analysis.
• A limited meta-analysis of adverse effects
  showed drowsiness occurred more commonly in the
  treated than in the control group as did urinary
  tract infection.
• Examination of individual trials showed that
  low dose (480 mg/day) sodium valproate was
  ineffective in controlling agitation in people
  with dementia, and high dose (1000 mg/day)
  divalproex sodium was associated with
  unacceptable adverse effects.
• While further research on the value of
  valproate preparations is indicated, current
  evidence does not support use of this drug to
  control agitation of people with dementia.

147
Conclusion

• BPSD is not a diagnosis, nor can BPSD be
  considered symptoms which occur across diagnoses.
• A way to address BPSD is as a secondary
  diagnosis, such as dementia with aggressive
  features
• Several syndromes have been described
  consistently and reliably, and there is no
  shortage of assessment instruments to identify
  and quantify them.
• A reliable characterization is a necessary but
  not a sufficient condition for drug trials.

148
Conclusion

• There is a need to
• Investigate the possible etiologies of behaviors
  or psychological symptoms. Therefore
• differentiate between psychiatric symptoms and
  natural sequelae of memory problems
• address probable etiologies via nonpharmacologic
  interventions prior to pharmacological ones.
• Document need for pharmacological treatment
  beyond the presence of symptoms
• Pharmacologic studies design needs to assure
  that
• Studies are conducted with the same population
  for which the drug is to be prescribed
• Studies examine impact on nontarget behaviors

149
giovanni_gambassi_at_rm.unicatt.itgiovanni_gambassi_at_
brown.edu