Psychosis and Agitation Associated with Dementia

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Psychosis and Agitation Associated with Dementia

• Prevalent 10-80
• Persistent n235, for 5 years (Devanand DP, 1997)
  
• Contribute to caregiver suffering review (Connell
  CM,2001)
• Accelerate functional and cognitive decline
  n181, for 1.5 years (Levy ML, 1996)
• Premature institutionalization 25 pairs, for 3
  years (Steele C, 1990)

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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.

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Incidence of and Risk Factors

• RESULTS
• 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.
• Parkinsonian gait, bradyphrenia, exaggerated
  general cognitive decline, and exaggerated
  semantic memory decline were significant
  predictors.
• Age, education, and gender were not significant
  predictors.

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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).

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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.

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Further Analysis of CCSMA Data

1. A latent class analysis revealed that these
   participants could be classified into three
   groups (classes) based on their neuropsychiatric
   symptom profile.
2. The largest class included cases with no
   neuropsychiatric symptoms (40) or with a
   mono-symptomatic disturbance (19).
3. A second class (28) exhibited a predominantly
   affective syndrome,
4. 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.
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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.
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The Relationship between Psychiatric Symptoms
and Regional Cortical Metabolism in Alzheimer's
Disease

1. Agitation/ Disinhibition factor score and
   metabolism in the frontal and temporal lobes
2. Psychosis factor score and metabolism in the
   frontal lobe
3. 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.
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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.
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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.

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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.
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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 2161-84,
   1992. .

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Misidentification Phenomenon

• A prevalence of 23 to 50 has been reported.1,2
• Common manifestations3
• The failure to recognize ones 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. 116-20, 1988.
2. Merriam A, Aronson N, Gaston P, et al. J Am
   Geriatr Soc. 267-12, 1988.
3. Leroi I. Voulgari A. Breitner JC. Lyketsos CG.
   American Journal of Geriatric Psychiatry.
   11(1)83-91, 2003 Jan-Feb.

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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. (Cohen-Mansfield J,
  1986)
• Behaviors that is disruptive, unsafe or
  interferes with care in a given environment.
  (Rosen J, 1994)

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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.

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Classification of Agitated Behaviors

• Aggressive behaviors
• Physically non-aggressive behaviors
• Verbal/vocal agitated behaviors

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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

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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.

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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

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Management of agitation and psychosis
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Assessment of Psychosis and Agitation

• The ABCs of dementia management
• Antecedents
• Behavior
• Consequences
• The strategy of identifying stimuli
• Stimulus-Response

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Antecedents

• Medical
• Urinary tract infection, pain,
• Environmental
• Noise, ambient temperature,
• Psychiatric
• New onset delusion,
• Social
• Recent housing relocation,
• Related to caregivers approach

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Characterizing Behavioral Disturbance

• Verbal or physical ?
• Aggressive or non-aggressive ?
• Frequency ?
• Severity ?
• Timing ?
• Location ?
• Level of disruptiveness ?
• Who was/were involved ?
• The use of psychopathology rating instrument

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Consequences

• Inadvertent reinforcement
• The consequences of the disruptive behaviors
  itself reinforce its propagation.

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Internal Stimuli
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External Stimuli
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Treatment of Psychosis and Agitation Associated
with Dementia

• Non-pharmacological interventions
• Pharmacological interventions

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Non-pharmacological Interventions

• Theoretical considerations
• Addressing unmet physical, emotional, and
  psychological needs
• Application of behavior modification principles
• Accommodation of reduced stress tolerance as a
  result of cognitive and physical decline

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Non-pharmacological Interventions

• Modalities
• Music therapy
• Real or simulated social contact
• Behavior therapy
• Staff training
• Activities
• Environmental modification
• Medical/nursing interventions
• Combined therapies

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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.
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Atypical Antipsychotics for Agitation Associated
with Dementia
Medications Starting Dose (mg/d) Therapeutic Dose (mg/d) Main Adverse Effects Special Precautions
Risperidone 0.25-0.5 1-2 Sedation, EPS, orthostasis, peripheral edema Active metabolite accumulates with renal failure
Olanzapine 2.5-5 5-15 Sedation, EPS, orthostasis Metabolic effects, anticholinergicity
Quetiapine 12.5-25 100-400 Sedation, orthostasis
Aripiprazole 2.5-5 5-15 Sedation
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Selective Serotonin Re-uptake Inhibitors for
Agitation Associated with Dementia
Medications Starting Dose (mg/d) Therapeutic Dose (mg/d) Main Adverse Effects Special Precautions
Sertraline 25 100-200 Nausea, diarrhea, insomnia Hyponatremia EPS
Escitalopram 5-10 10-20 Nausea, headache, constipation Hyponatremia EPS
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Benzodiazepines for Agitation Associated with
Dementia
Medications Starting Dose (mg/d) Therapeutic Dose (mg/d) Main Adverse Effects Special Precautions
Lorazepam 0.25 1-2 Sedation, ataxia, cognitive impairment Avoid chronic use
Oxazepam 15 15-30 Sedation, ataxia, cognitive impairment Avoid chronic use
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Anticonvulsants for Agitation Associated with
Dementia
Medications Starting Dose (mg/d) Therapeutic 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
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Acetylcholinesterase Inhibitors for Agitation
Associated with Dementia
Medications Starting Dose (mg/d) Therapeutic Dose (mg/d) Main Adverse Effects Special Precautions
Donepezil 5 5-15 Nausea, diarrhea, transient confusion Bradycardia possible
Rivastigmine 3 6-12 Nausea, diarrhea, transient confusion Bradycardia possible
Galantamine 8 16-24 Nausea, diarrhea, transient confusion Bradycardia possible
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Other agents for Agitation Associated with
Dementia
Medications Starting Dose (mg/d) Therapeutic Dose (mg/d) Main Adverse 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
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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.
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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.

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N404, 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
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The results of this post-hoc analysis partially
support the hypothesis that memantine would have
preferential effects on frontally mediated
behavioral disturbances.
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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

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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 laymens terms
• Written documentation of informed consent
• Balancing patient needs versus system needs
• Individualizing patient care is problematic in
  inflexible residential environments

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