Transcript Starting Dose (mg/d)

失智症常見精神行為症狀與治療
財團法人奇美醫院柳營院區精神科
許森彥醫師
2007年10月20日
Psychosis and Agitation Associated
with Dementia
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Prevalent 10-80%
Persistent n=235, for 5 years (Devanand DP, 1997)
Contribute to caregiver suffering review (Connell CM,2001)
Accelerate functional and cognitive decline n=181, for 1.5
years (Levy ML, 1996)
• Premature institutionalization 25 pairs, for 3 years (Steele C, 1990)
Incidence of and Risk Factors for
Hallucinations and Delusions in Patients
with Probable AD
• Authors: Paulsen, J S. Salmon, D P. Thal, L J. et al.
• Source: Neurology. 54(10):1965-71, 2000 May 23.
• Methods: The authors conducted psychiatric evaluations of 329
patients with probable AD from the University of California at San
Diego Alzheimer's Disease Research Center to determine the
incidence of hallucinations and delusions. They examined data from
annual clinical and neuropsychological evaluations to determine
whether there were specific risk factors for the development of
hallucinations and delusions.
Incidence of and Risk Factors
RESULTS:
1. The cumulative incidence of hallucinations and
delusions was 20.1% at 1 year, 36.1% at 2, 49.5% at 3,
and 51.3% at 4 years.
2. Parkinsonian gait, bradyphrenia, exaggerated general
cognitive decline, and exaggerated semantic memory
decline were significant predictors.
3. Age, education, and gender were not significant
predictors.
Mental and Behavioral Disturbances in
Dementia: Findings from the Cache
County Study on Memory in Aging
• Authors: Lyketsos, C G. Steinberg, M. Tschanz, J T. et al.
• Source: AJP 157(5):708-14, 2000 May.
• METHOD: The 5,092 participants, who were 65 years old or older,
were screened for dementia. Based on the results of this screen,
1,002 participants (329 with dementia and 673 without dementia)
underwent comprehensive neuropsychiatric examinations and were
rated on the Neuropsychiatric Inventory (NPI).
Results of CCSMA Study
1. 214 (65%) had AD, 62 (19%) had VD, and 53 (16%) had another
DSM-IV dementia diagnosis.
2. 201 (61%) had exhibited one or more mental or behavioral
disturbances in the past month.
3. Apathy (27%), depression (24%), and agitation/aggression (24%)
were the most common in participants with dementia.
4. These disturbances were almost four times more common in
participants with dementia than in those without.
5. Participants with Alzheimer's disease were more likely to have
delusions and less likely to have depression.
6. Agitation/aggression and aberrant motor behavior were more
common in participants with advanced dementia.
Further Analysis of CCSMA Data
1.
2.
3.
4.
A latent class analysis revealed that these participants
could be classified into three groups (classes) based on
their neuropsychiatric symptom profile.
The largest class included cases with no neuropsychiatric
symptoms (40%) or with a mono-symptomatic
disturbance (19%).
A second class (28%) exhibited a predominantly affective
syndrome,
A third class (13%) had a psychotic syndrome.
Lyketsos CG. Sheppard JM. Steinberg M. et al. International Journal of Geriatric
Psychiatry. 16(11):1043-53, 2001 Nov.
Subtypes of Psychotic Symptoms in
Alzheimer disease
1. Factor and cluster analyses of the psychotic-symptom
items of the CERAD Behavioral Rating Scale in 188
probable and possible AD subjects who have displayed at
least one psychotic symptom.
2. Exploratory factor analysis resulted in a one-factor
solution that comprised misidentification delusions,
auditory and visual hallucinations, and the
misidentification of people.
3. Persecutory delusions were also frequently present and
were independent of the misidentification/hallucination
factor.
Cook SE. Miyahara S. Bacanu SA. et al. American Journal of Geriatric Psychiatry.
11(4):406-13, 2003 Jul-Aug.
The Relationship between
Psychiatric Symptoms and Regional
Cortical Metabolism in Alzheimer's
Disease
1.
2.
3.
Agitation/ Disinhibition factor score and metabolism in the
frontal and temporal lobes
Psychosis factor score and metabolism in the frontal lobe
Anxiety/Depression factor score and metabolism in the
parietal lobe.
Sultzer DL. Mahler ME. Mandelkern MA. et al. Journal of Neuropsychiatry & Clinical
Neurosciences. 7(4):476-84, 1995.
Delusions in AD
• Definition: A fixed false beliefs that are not attributable to
membership in a social or cultural group.
• A review of 35 studies revealed the prevalence between16
to 70 % (median 36.5 %)1
• The CCSMA study reported an incidence of delusions of
28% within 18 months.2
1. Bassiony MM. Lyketsos CG. Psychosomatics. 44(5):388-401, 2003 Sep-Oct.
2. Steinberg M. Sheppard JM. Tschanz JT. et al. Journal of Neuropsychiatry & Clinical
Neurosciences. 15(3):340-5, 2003.
Delusions in AD
• Delusion of stealing is the most prevalent, followed by
persecutory delusions, delusion of reference, infidelity,
grandiosity, and somatic delusions.1
• The presence of delusions in AD was associated with
greater cognitive impairment, especially frontal/temporal
dysfunction, and possibly with a more rapidly progressive
dementia.2
1. Bassiony MM. Lyketsos CG. Psychosomatics. 44(5):388-401, 2003 Sep-Oct.
2. Jeste DV. Wragg RE. Salmon DP. Harris MJ. Thal LJ. American Journal of Psychiatry.
149(2):184-9, 1992 Feb.
Hallucinations in AD
• Definition: False sensory perceptions.
• A review of 35 studies revealed the prevalence between 4
to 76 % (median 23 %)1
• The CCSMA study reported an incidence of hallucinations
of 16% within 18 months.2
1. Bassiony MM. Lyketsos CG. Psychosomatics. 44(5):388-401, 2003 Sep-Oct.
2. Steinberg M. Sheppard JM. Tschanz JT. et al. Journal of Neuropsychiatry & Clinical
Neurosciences. 15(3):340-5, 2003.
Hallucinations in AD
• Visual (4-59 %, median 23 %) and auditory (1-29 %,
median 12 %) hallucinations are far more prevalent than
tactile, olfactory and somatic hallucinations.1
• The presence of hallucinations may be more common in
the later stage of AD.2
1. Bassiony MM. Lyketsos CG. Psychosomatics. 44(5):388-401, 2003 Sep-Oct.
2. Devanand DP. Brockington CD. Moody BJ. et al. International Psychogeriatrics. 4 Suppl
2:161-84, 1992. .
Misidentification Phenomenon
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A prevalence of 23% to 50% has been reported.1,2
Common manifestations:3
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The failure to recognize one’s home (“this is not my
home” phenomenon)
Belief that strangers are living in the house (phantom
boarder syndrome)
Belief that loved ones are impostors (Capgras
phenomenon)
1. Rubin E, Drevets W, Burke A. J Geriatr Psychiatry Neurol. 1:16-20, 1988.
2. Merriam A, Aronson N, Gaston P, et al. J Am Geriatr Soc. 26:7-12, 1988.
3. Leroi I. Voulgari A. Breitner JC. Lyketsos CG. American Journal of Geriatric Psychiatry.
11(1):83-91, 2003 Jan-Feb.
Agitation of Dementia
• Problem behaviors or disruptive behaviors
• Definition:
– Inappropriate verbal, vocal, or motoric activity that is not
judged by an outside observer to result directly from the
needs or confusion of the agitated individual. (CohenMansfield J, 1986)
– Behaviors that is disruptive, unsafe or interferes with
care in a given environment. (Rosen J, 1994)
Behavioral and Psychological
Symptoms of Dementia (BPSD)
• A heterogeneous range of psychological reactions,
psychiatric symptoms, and behaviors occurring in
people with dementia of any etiology.
• Defined by International Psychogeriatric Association
in 1996.
Classification of Agitated Behaviors
• Aggressive behaviors
• Physically non-aggressive behaviors
• Verbal/vocal agitated behaviors
Aggressive Behaviors
• Hitting, biting, kicking, spitting, pushing, grabbing,
scratching, tearing things, hurting self or others,
physical sexual advances
• Correlated with male gender, severe cognitive
impairment, premorbid aggressive personality,
psychosis, feeling of been intruded
Physically Non-aggressive
Behaviors
• Hiding objects, hoarding objects, general restlessness,
intentional falling, pacing, aimless wandering, trying to get
to a difference place, handling things inappropriately, eating
inappropriate substances, inappropriate dressing and
disrobing, performing repetitious mannerisms
• More active throughout their lives and less medical
conditions
• Akathisia should be considered under antipsychotics
exposure.
Verbal/vocal Agitated Behaviors
• Most frequently
• Repetitive sentences or questions, unwarranted
requests for attention or help, complaining,
negativism, making strange noises, screaming,
verbal sexual advances, cursing and verbal
aggression
• Correlated with female gender, poor health, pain,
depression
Management of agitation and psychosis
Assessment of Psychosis and
Agitation
•
The ABCs of dementia management
1. Antecedents
2. Behavior
3. Consequences
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The strategy of identifying stimuli
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Stimulus-Response
Antecedents
• Medical
– Urinary tract infection, pain, …
• Environmental
– Noise, ambient temperature, …
• Psychiatric
– New onset delusion, …
• Social
– Recent housing relocation, …
• Related to caregiver’s approach
Characterizing Behavioral
Disturbance
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Verbal or physical ?
Aggressive or non-aggressive ?
Frequency ?
Severity ?
Timing ?
Location ?
Level of disruptiveness ?
Who was/were involved ?
The use of psychopathology rating instrument
Consequences
• Inadvertent reinforcement
– The consequences of the disruptive behaviors itself
reinforce its propagation.
Internal Stimuli
External Stimuli
Treatment of Psychosis and Agitation
Associated with Dementia
• Non-pharmacological interventions
• Pharmacological interventions
Non-pharmacological Interventions
•
Theoretical considerations:
1. Addressing unmet physical, emotional, and
psychological needs
2. Application of behavior modification principles
3. Accommodation of reduced stress tolerance as a
result of cognitive and physical decline
Non-pharmacological Interventions
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Modalities:
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3.
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7.
8.
Music therapy
Real or simulated social contact
Behavior therapy
Staff training
Activities
Environmental modification
Medical/nursing interventions
Combined therapies
Pharmacological Interventions
• A mean improvement rate of 61%(S.D.18%) for
typical and atypical antipsychotics combined,
compared with 35%(S.D.20%) for placebo.
• The improvement rate with atypical antipsychotics
appears to be slightly higher 72%(S.D.24%).
Kindermann SS. Dolder CR. Bailey A. Katz IR. Jeste DV. Drugs & Aging. 19(4):257-76, 2002.
Atypical Antipsychotics for Agitation
Associated with Dementia
Medications Starting
Therapeutic Main Adverse
Dose (mg/d) Dose (mg/d) Effects
Special
Precautions
Risperidone 0.25-0.5
1-2
Sedation, EPS,
Active metabolite
orthostasis,
accumulates with
peripheral edema renal failure
Olanzapine
2.5-5
5-15
Sedation, EPS,
orthostasis
Metabolic effects,
anticholinergicity
Quetiapine
12.5-25
100-400
Sedation,
orthostasis
—
5-15
Sedation
—
Aripiprazole 2.5-5
Selective Serotonin Re-uptake Inhibitors for
Agitation Associated with Dementia
Medications
Starting
Therapeutic
Dose (mg/d) Dose (mg/d)
Main Adverse
Effects
Special
Precautions
Sertraline
25
100-200
Nausea,
diarrhea,
insomnia
Hyponatremia;
EPS
10-20
Nausea,
headache,
constipation
Hyponatremia;
EPS
Escitalopram 5-10
Benzodiazepines for Agitation Associated
with Dementia
Medications
Starting
Therapeutic
Dose (mg/d) Dose (mg/d)
Main Adverse
Effects
Special
Precautions
Lorazepam
0.25
1-2
Sedation, ataxia, Avoid chronic
cognitive
use
impairment
Oxazepam
15
15-30
Sedation, ataxia, Avoid chronic
cognitive
use
impairment
Anticonvulsants for Agitation Associated
with Dementia
Medications
Starting
Therapeutic
Dose (mg/d) Dose (mg/d)
Main Adverse
Effects
Special
Precautions
Divalproex
sodium
125-250
250-1000
Nausea,
sedation
Thrombocytopenia,
liver function
abnormalities,
pancreatitis
Carbamazepine
50-100
200-1000
Sedation,
ataxia, nausea
Hyponatremia,
pancytopenia
Acetylcholinesterase Inhibitors for Agitation
Associated with Dementia
Medications
Starting Dose Therapeutic Main Adverse
(mg/d)
Dose (mg/d) Effects
Special
Precautions
Donepezil
5
5-15
Nausea, diarrhea, Bradycardia
possible
transient
confusion
Rivastigmine
3
6-12
Nausea, diarrhea, Bradycardia
possible
transient
confusion
Galantamine
8
16-24
Nausea, diarrhea, Bradycardia
possible
transient
confusion
Other agents for Agitation Associated with
Dementia
Medications
Starting Dose Therapeutic Main Adverse
(mg/d)
Dose (mg/d) Effects
Special
Precautions
Trazodone
50
50-150
Sedation,
orthostasis
Priapiam (rare)
Arrythmia
(at higher doses)
Memantine
5
20
Sedation
Not recommended
for patients with
severe renal
function
impairment
Memantine
1. A moderate-affinity, uncompetitive N-methyl-D-aspartate
(NMDA) receptor antagonist.
2. Might reduce the need for antipsychotics.
3. The dose recommended is 20 mg/d (10 mg twice a day).
4. Mostly excreted through the kidneys.
5. The most common side effects (≧5%) are dizziness,
constipation, confusion and headaches, less common
side effects (≦5%) are hypertension, somnolence and
visual hallucinations.
Gauthier S. Herrmann N. Ferreri F. Agbokou C. CMAJ. 175(5):501-2, 2006 Aug 29.
Behavioral Effects of Memantine in
Alzheimer Disease Patients Receiving
Donepezil Treatment.
• Cummings JL. Schneider E. Tariot PN. Graham SM.
• Memantine MEM-MD-02 Study Group.
• Clinical Trial. Comparative Study. Journal Article. Multicenter Study.
Randomized Controlled Trial. Research Support, N.I.H., Extramural.
Research Support, Non-U.S. Gov't
• Neurology. 67(1):57-63, 2006 Jul 11.
N=404, Probable AD
MMSE score of 5 to 14 at both screening and baseline
At least 50 years of age
Receiving ongoing therapy donepezil for at least 6 months and had been on a
stable dose (5 or 10 mg/day) for at least 3 months
The results of this post-hoc analysis partially support the hypothesis that
memantine would have preferential effects on frontally mediated
behavioral disturbances.
Pharmacological Management of
Behavioral Emergencies
• If PO administration possible:
– Risperidone 0.5 mg (range 0.25-1 mg) or
– Olanzapine 5 mg (range 2.5-5 mg) or
– Quetiapine 25 mg (range 25-50 mg)
• If IM administration necessary:
– Olanzapine 5 mg or
– Haloperidol 0.5 mg (range 0.5-1 mg); monitor EPS
• If IV access available:
– Haloperidol 0.5 mg (range 0.5-1 mg); monitor QTc prolongation
and/or ventricular arrhythmias at high dose
• For severe agitation, augment any of the above
preparations with:
– Lorazepam 0.5-1 mg PO/IM
Ethical Issues
• The ability to give informed consent
– Explain the side effects and their possible
consequences toward the patients and their care givers
in the laymen’s terms
– Written documentation of informed consent
• Balancing patient needs versus system needs
– Individualizing patient care is problematic in inflexible
residential environments
Thanks for Your Attention !