D���n�i�

DR.SHERIF SAAD
(M.B.B.Ch., M.Sc., M.D.)
Consultant of Psychiatry
International member of American Psychiatric Association (APA)
International member of European Psychiatric Association (EPA)
                              
   
                          
POPULATION AGEING

Population ageing is unprecedented, without par-

allel in human history—and the twenty-first century
will witness even more rapid ageing than did the cen-
tury just past.

Population ageing is pervasive, a global phenome-

non affecting every man, woman and child—but
countries are at very different stages of the process,
and the pace of change differs greatly. Countries
that started the process later will have less time to
adjust.

Population ageing is enduring: we will not return

to the young populations that our ancestors knew.

Population ageing has profound implications for

many facets of human life
INSIDE THE HUMAN BRAIN

Adult weight: about 3 pounds

Adult size: a medium cauliflower

Number of neurons: 100,000,000,000 (100billion)

Number of synapses: 100,000,000,000,000 (100 trillion)

 DR ALOIS ALZHEIMER
1864 - 1915
In a 1906 lecture he first
described the disease which
now carries his name.
AUGUSTE D.
First seen by Dr Alzheimer in
1901 when she was in her
early 50s with memory impair-
ment, hallucinations and
impaired executive dysfunction
 DEMENTIA
- A syndrome characterized by acquired, progressive cognitive impair-
ment

- Affects 10% of individuals over 65

- Caused by at least 80 different diseases, many reversible. Unfortunately,

the most common diseases (85 – 90%) are irreversible

- Diagnosis will have prognostic and treatment implications

- All demented patients need a work-up.…and it’s mostly a good history

 DEMENTIA

- Dementia is a substantial cause of morbidity in any

ageing population, with profound social and econom-
ic effects.

- Dementia affects some 10% of any population over

65, and 20% over 80.
 WHAT IS DEMENTIA?
Dementia is a term used to describe a cluster of symptoms in-
cluding:
- Forgetfulness (progressive)

- Difficulty doing familiar tasks

- Confusion

- Poor judgment

- Decline in intellectual functioning

- Dementia is not the name of an actual disease

- Dementia is not a part of normal aging

DIAGNOSTIC CRITERIA FOR DEMENTIA (DSM-V)
Memory impairment: impaired ability to learn new information or to recall old
information

One or more of the following:

aphasia (language disturbance);
apraxia (impaired ability to carry out motor activities despite intact motor func-
tion);
disturbance in executive functioning-impaired ability to plan, organize, se-
quence, abstract

The cognitive deficits result in functional impairment (social/occupational)

The cognitive deficits do not occur exclusively solely during a delirium

NOT due to other medical or psychiatric conditions

 CAUSES OF DEMENTIA

- Alzheimer’s disease (approximately 70%)

- Vascular dementia – (Strokes and TIA’s)
- Parkinson’s disease
- Frontotemporal dementia (FTD)
- Normal-Pressure hydrocephalus (NPH)
- Dementia with Lewy Bodies
- Delirium/Depression
- Other, less common causes
 Reversible DEMENTIA

-D = Delirium

-E = Emotions (depression)& Endocrine Disease

-M= Metabolic Disturbances

-E = Eye & Ear Impairments

-N = Nutritional Disorders

-T = Tumors, Toxicity, Trauma to Head

-I = Infectious Disorders

-A = Alcohol, Arteriosclerosis
 PRIMARY SYMPTOMS

- ATTENTION

- MEMORY

- POSTROLANDIC (“COGNITION”)

- EXECUTIVE (FRONTAL/SUBCORTICAL)

- INSIGHT
 PRIMARY SYMPTOMS

- ATTENTION: clouded sensorium, delirium

- MEMORY: forgetfulness

- POSTROLANDIC (“COGNITION”): aphasia, apraxia, getting lost

- EXECUTIVE (FRONTAL/SUBCORTICAL): poor judgment,

disinhibition, abulia, urge incontinence

- INSIGHT: anosognosia, catastrophic reactions

 TWO TYPES OF DEMENTIA
POSTROLANDIC FRONTAL/SUBCORTICAL
POSTROLANDIC FRONTAL/SUBCORTICAL
- Memory deficits - Memory deficits

- Aphasia - Loss of behavioral plasticity and

adaptability, judgment
- Apraxia
- Personality changes
- Agnosia * Disinhibition
* Abulia
- Personality more or less preserved
- Urge incontinence
- MMSE valid
- MMSE useless
 TWO TYPES OF DEMENTIA
POSTROLANDIC FRONTAL/SUBCORTICAL
DEMENTIAS DEMENTIAS

- Alzheimer’s disease - Vascular dementia

- Frontotemporal dementia and Pick’s
- Diffuse Lewy body disease disease
- Alcoholic dementia
- Huntington’s disease, Wilson’s
disease, progressive supranuclear
palsy, late Parkinson’s disease
- AIDS dementia complex, neurosyphilis,
Lyme disease
- Normal pressure hydrocephalus
- Most head injuries
- Anoxia, carbon monoxide
- Multiple sclerosis
- Tumors
- ANY ADVANCED DEMENTIA
 COURSE OF AGING, MCI AND AD
Brain Aging
AAMI / ARCD

Brain
Cognitive Decline

“Brain”AD
Aging
MCI Mild

Moderate

Clinical AD Moderately
Severe

Severe

Time (Years) (Ferris, 4/03)

AAMI: age-associated memory impairment ARCD: age-related cognitive decline

 EARLY LATER MUCH LATER
SYMPTOMS SYMPTOMS SYMPTOMS

- Changes in mood (often - Disorientation & - Challenging

depression or anxiety) obvious confusion behaviors
- Changes in personality - Difficulty with - Agitation
(especially apathy or complex tasks - Noisy behavior
irritability) - Using the computer; - Aggressive behavior
- Memory problems Programming the video - Difficulty eating &
(particularly for recent recorder walking
events & the names of - Planning a trip
people or things) - Completing a tax return
- Word-finding - Difficulty recognizing
difficulties people & objects
- Difficulty calculating - Difficulty following a
change & managing conversation & making
financial affairs oneself understood
- Difficulty dressing &
doing other everyday
tasks
- Delusions,
Hallucinations
PATHOPHYSIOLOGY OF ALZHEIMER’S
DISEASE
 PUZZLE PIECES
Neurogenesis, Aging, CNS Insults, Cytokines, Amyloid β, Neurofibrillary tangles,
Neurotransmitters, ROS, Lipid peroxidation, Apoptosis
 DEMENTIA
Functional anatomy

- Disruption of cerebral
neuronal circuit

- Quantity of neuronal loss

and location of affected
regions are factors that
combine to cause the
specific disorder.
 DEMENTIA
Neuropathology and
Neurochemical changes

- Loss of neurons,
- Neuro fibrillary tangles,
- Senile plaques and
- Amyloid angiopathy are
seen, especially within
the frontal, temporal and
parietal cortex,
hippocampi, substantia
innominata and locus
caeruleus.
 AD and the Brain
Plaques and Tangles: The Hallmarks of AD
The brains of people with AD have an abundance of two abnormal
structures:
- beta-amyloid plaques, which are dense deposits of protein & cellular
material that accumulate outside and around nerve cells
- neurofibrillary tangles, which are twisted fibers that build up inside the
nerve cell

An actual AD plaque An actual AD tangle

 AD and the Brain
Beta-amyloid Plaques

Amyloid precursor protein (APP) is the precursor

to amyloid plaque.

1. APP sticks through the neuron membrane.

2. Enzymes cut the APP into fragments of protein,
including beta-amyloid.
3. Beta-amyloid fragments come together in clumps
to form plaques.

In AD, many of these clumps form, disrupting the

work of neurons. This affects the hippocampus
and other areas of the cerebral cortex.
 AD and the Brain

Neurons have an internal support structure partly made up of microtubules. A pro-

tein called tau helps stabilize microtubules.
In AD, tau changes, causing microtubules to collapse, and tau proteins clump
together to form neurofibrillary tangles.
 Course of Aging, MCI and AD

AAMI: age-associated memory impairment ARCD: age-related cognitive decline

 AD and the Brain
The Changing Brain in Alzheimer’s Disease

No one knows what causes AD to begin, but we do know

a lot about what happens in the brain once AD takes hold.

Pet Scan of Pet Scan of Alzheimer’s

Normal Brain Disease Brain
 RISK FACTORS OF DEMENTIA
- Age(above 60 mostly)
- Gender (males mostly)
- Genetics and family history(CADA-
SIL-cerebral autosomal dominant arteri-
opathy with subcorical infarcts and leu-
koencephalopathy)
-Smoking
-Prior stroke
-Heart diseases
-Alcohol use
-Atherosclerosis
-Cholesterol level of serum
-Diabetes
-Various others yet under study
 Management of Dementia

- The goal of treatment is to control the symptoms of dementia.

- Treatment depends on the condition causing the dementia.

- Some people may need to stay in the hospital for a short time.

- Stopping or changing medications that make confusion worse may improve brain
function.

- There is growing evidence that some kinds of mental exercises can help dementia.
 Treatment of Alzheimer’s Disease
Improving Symptoms
- Cholinesterase inhibitors
- Aricept, Exelon, Reminyl
- Memantine (NMDA)
- Psychotropic drugs for behavior
- Behavioral management
- Family support
Slowing Progression
- Anti-oxidants (vitamin E)
- Anti-inflammatory drugs
- Hormones (estrogen)
- Neuroprotective agents (NGF)
- Reducing vascular risk
- statins, homocysteine reduction
Delaying AD in MCI
- Cholinesterase inhibitors
- Aricept, Exelon, Reminyl
- Antioxidants (Vitamin E)
- Anti-inflammatory drugs (Viox)
Prevention
- Antioxidants (Ginkgo biloba)
- Anti-inflammatory drugs (ADAPT)
- amyloid antagonists
- secretase inhibitors
- anti-aggregation compounds
- amyloid vaccines
- Anti-neurofibrillar drugs
- Genetic engineering
TREATMENT OUTCOMES IN ALZHEIMER’S DISEASE

Cure

Maintenance
Functional ability

of function

Slowing of disease
progression
Treatment
Symptomatic
benefit

Natural Progression

Time (Ferris, 8/03)

At present, there is no cure for AD, but treatment has been shown to
provide significant benefits compared with no treatment
SYMPTOMATIC EFFECTS VERSUS SLOWING DISEASE
PROGRESSION

Mild
Impairment

Placebo
Symptomatic
Disease modifying
Severe

Baseline End
Treatment Period (Ferris, 8/03)
Behavioral and Psychological Symptoms
of Dementia (BPSD)
 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.

- Any verbal, vocal, or motor activities not judged to be clearly related to the
needs of the individual or the requirements of the situation

- An observable phenomena (not just internal)

 Prevalence of BPSD

- Present in all types of dementia

- 80-90% of patients develop at least 1 distressing symptom during the course

of their dementia

- 60% of community dwelling patients with dementia

- 80% of dementia patients in nursing homes

 BPSD – distressing for all

Individual – distress is key to treatment decisions

Family – non-cognitive symptoms are most distressing, could cope with a

'memory' disorder. Unpredictable violence or aggression = desperation

LTC staff need to understand and have tools for response

 Consequences of BPSD

- Caregiver stress

- Increased ER visits

- Prolonged hospital stays

- Increased use of medications

- Placement in LTC

- Increased financial costs

- **Decreased quality of life for patient and caregiver**

 Terminology

- Agitation – abnormal behavior (ie aggression, restlessness, etc.)

- Psychosis – abnormal perceptions/beliefs that may lead to agitated

behavior (ie paranoid delusions)

Dementia treatment principle: agitation generally responds better than psy-

chosis
 Range of behavior
- Psychosis (delusions or hallucinations)
- Agitation/aggression
- Apathy/indifference
- Depression/dysphoria
- Anxiety
- Elation/euphoria
- Disinhibition
- Irritability/lability
- Aberrant motor behavior
- Insomnia
- Appetite disruption
From Neuropsychiatric Inventory (NPI) rating scale (Cummings et al. 1994)
 Peak Frequency of Behavioural
Symptoms as AD Progresses

100
Frequency (% of Patients)

Agitation
80

Diurnal
60 rhythm
Depression Irritability
Wandering
40 Social Aggression
withdrawal
Anxiety Mood
change
20 Paranoia
Hallucinations

Socially unacceptable behaviour

0 Suicidal Accusatory Delusions

ideation behavior Sexually inappropriate behavior

–40 –30 –20 –10 0 10 20 30

Months before/after Diagnosis

Jost and Grossberg, 1996.

 SUBTYPES OF BPSD
(COHEN-MANSFIELD)

Physically aggressive behaviors (hitting, kicking, biting)

Physically nonaggressive behavior (pacing, inappropriate

touching)

Verbally aggressive behaviors (cursing, screaming)

Verbally nonaggressive agitation (repetitive phrases or re-

quests, calling out)
 BPSD vs other causes

Acute/evolving/sudden is often medication related or other

medical disease

Progression of underlying dementia – generally more in-

sidious and persistent
 Neuroanatomical correlates of behavioural
disorders in dementia
Brain (2005), 128, 2612–2625
- Neurodegenerative diseases are associated with profound changes in social and emotional function. The emer-
gence of increasingly sophisticated methods for measuring brain volume has facilitated correlation of local
changes in tissue content with cognitive and behavioural changes in neurodegenerative disease. This study
examined neuroanatomical correlates of behavioural abnormalities, as measured by the Neuropsychiatric Inven-
tory, in 148 patients with dementia using voxel-based morphometry.

- Of 12 behaviours examined, 4 correlated with tissue loss: apathy, disinhibition, eating disorders and aberrant
motor behaviour. Increasing severity across these four behaviours was associated with tissue loss in the ventral portion
of the right anterior cingulate cortex (vACC) and adjacent ventromedial superior frontal gyrus (vmSFG), the right ventro-
medial prefrontal cortex (VMPC) more posteriorly, the right lateral middle frontal gyrus, the right caudate head, the right
orbitofrontal cortex and the right anterior insula.

- In addition, apathy was independently associated with tissue loss in the right ventromedial superior frontal gyrus
(vmSFG), disinhibition with tissue loss in the right subgenual cingulate gyrus in the VMPC, and aberrant motor
behaviour with tissue loss in the right dorsal ACC and left premotor cortex.

- These data strongly support the involvement of the right hemisphere in mediating social and emotional behaviour
and highlight the importance of distinct regions on the medial wall of the right frontal lobe in regulating different
behaviours.

- Furthermore, the findings underscore the utility of studying patients with dementia for understanding the neuroanatomi-
cal basis of social and emotional functions.
 Neuroanatomical correlates of behavioural
disorders in dementia
Brain (2005), 128, 2612–2625

* Three regions in different parts of the medial

frontal cortex had unique associations with specif-
ic behaviours.

- Apathy correlated with tissue loss in the ventral

portion of the vmSFG adjacent to the vACC.

- Disinhibition with tissue loss in the SGC, poste-

rior to the region associated with apathy, and

- Aberrant motor behaviour with tissue loss in

the dACC and premotor cortex.

vACC = ventral portion of the right anterior cingulate cortex, vmSFG = ventromedial superior frontal gyrus,
SGC = subgenual cingulate gyrus,
 Evaluation

- Obtain a clear description of problem behavior, temporal onset, course, circum-

stances

- Assess ability to express basic needs (hunger, thirst, fatigue)

- Look for delirium – acute/rapid change (dehydration, UTI, pneumonia, angina,

constipation, pain, uncontrolled DM)

- Look for mood disturbance (sadness, irritability, withdraw)

- Check med changes – always suspect the meds

- Ask about environmental precipitants: change in routine, roommate, caregiver,

overstimulation/understimulation, other disruptive patients, family illness
Non-pharmacologic interventions

FAMILY SUPPORT IS
VERY HELPFUL
 Behavioral interventions

- Tx underlying medical illness

- Correct sensory deficits

- Remove offending medications

- Keep environment comfortable, calm, homelike

- Regular daily activities and structure

- Assess sleep and eating patterns

- Educate and support caregiver

 Medication for BPSD

Currently there are

no FDA approved treat-
ments for
agitation and psychosis
in dementia
 FDA Blackbox on antipsychotics

WARNING:
INCREASED MORTALITY FOR ELDERLY
PATIENTS WITH DEMENTIA RELATED PSY-
CHOSES.
Elderly patients with dementia related psy-
choses are at increased risk for death com-
pared to placebo.
These drug is not approved for the treat-
ment of dementia related psychoses.
 FDA Blackbox on antipsychotics
- Meta-analysis of 17 double blind RCT’s in elderly dementia patients, April
2005.

- Atypicals associated with a 1.6-1.7 times greater risk of mortality

compared to placebo.

- Most deaths from cardiac or infectious etiology, in some studies –

strokes.

- Extended to all antipsychotics in June 2008

COMMON SIDE-EFFECTS OF ANTIPSYCHOTICS
- Extrapyramidal symptoms (akathisia, dystonia, psuedoparkinsonism,
and dyskinesia)

- Sedation

- Tardive dyskinesia – should screen regularly

- Dyskinesia Identification System: Condensed User Scale (DISCUS) Ab-

normal Involuntary Movement Scale (AIMS)

- Gait disturbances

- Falls

- Meta-analysis shows a significant increase in respiratory tract and uri-

nary tract infections and peripheral edema in patients treated with
risperidone, olanapine versus placebo (Ballard et al. 2011)
 Antipsychotic Therapy and Short-term Serious
Events in Older Adults With Dementia(2008)

Results: Relative to those who received no antipsychotic therapy, community-dwelling older

adults newly dispensed an atypical antipsychotic therapy were 3.2 times more likely (95%
confidence interval, 2.77-3.68) and those who received conventional antipsychotic therapy
were 3.8 times more likely (95% confidence interval, 3.31-4.39) to develop any serious event
during the 30 days of follow-up. The pattern of serious events was similar but less pro-
nounced among older adults living in a nursing home.

Conclusions:
Serious events, as indicated by a hospital admission or death, are frequent following the
short term use of antipsychotic drugs in older adults with dementia.

Antipsychotic drugs should be used with caution even when short-term therapy is being pre-
scribed. Arch Intern Med. 2008;168(10):1090-1096
 CATIE-AD Trial
Clinical Antipsychotic Trial of Intervention Effectiveness-Alzheimer's
Disease (CATIE-AD) investigators

First cost-benefit analysis of second generation antipsychotics in

treating non-cognitive symptoms in AD patients

- 421 AD patients with psychosis and aggression where randomly assigned to olanzapine,
quetiapine, risperidone, or placebo of “watchful waiting” over 9 months
- No statistical differences between groups, although placebo most often superior in
net health benefit analysis
- Olanzapine group – more impaired on ADL testing- ???sedation, gait disturbance
- Placebo group – best ADL score, lower dependence score, lower total health care costs -
$50-100
- Several methodological drawbacks:
- Subjects were outpatients, less impaired then some BPSD trials
- High dropout rate compared to other RCTs (likely a design feature)
- No washout period
- Dosage likely too low for quetiapine (mean 56.5mg/day)
- Authors concluded adverse events offset advantages in efficacy
Clinical Antipsychotic Trial of Intervention Effectiveness – Alzheimer’s Disease. Rosenheck, Cost-benefit analysis…., Arch Gen. Psychiatry 2007; 64(11):1259-1268.
 Antipsychotics in LTC

- Only 2 RCTs have examined antipsychotics in AD over 6 months

- Ballard et al (2005) found no difference between quetiapine,

rivastigmine, or placebo in agitation over 6 months
 Atypical vs. typical

- Atypical block excessive dopamine transmission, which is beneficial in

schizophrenics.
- Elderly patients (especially dementia) have accelerated dopamine loss
and tend to experience more severe motor side effects than younger pa-
tients.
- Less likely to trigger extrapyramidal symptoms/tardive dyskinesia
- No difference in safety, efficacy

Olanzapine 5-10 mg/day and Risperidone 1mg/day appear to have

low incidence of EPS, but somnolence remains a concern
 Haldol for agitation in dementia
(2005 Cochrane review)

- No significant improvement in agitation, compared with controls

- Aggression decreased (not other aspects of agitation)

- Dosages 1.2-3.5 mg/day

- Recommendations
- Haloperidol was useful in reducing aggression, but was associated
with adverse effects
- No evidence to support the routine use of this drug for other mani-
festations of agitation in dementia
- Haloperidol should not be used routinely to treat patients with agitat-
ed dementia
 THE AMERICAN PSYCHIATRIC ASSOCIATION
PRACTICE GUIDELINE ON THE USE OF
Antipsychotics to Treat Agitation or Psychosis in Patients with Dementia
May 01, 2016

Appendix A: Review of Available Evidence ................................................................... 45

Clinical Questions............................................................................................................... 45
Review of Supporting Research Evidence...........................................................................45
1A. Efficacy and Comparative Effectiveness of Second-Generation Antipsychotics for Over-
all BPSD...............................................................................................................................48
1B Efficacy and Comparative Effectiveness of Second-Generation
Antipsychotics for Treatment of Agitation.............................................................................81
1C. Efficacy and Comparative Effectiveness of Second-Generation
Antipsychotics for Treatment of Psychosis.........................................................................100
2. Appropriate Dosage and Duration of Antipsychotic Treatment
in Individuals With Alzheimer’s Disease and Other Dementia Syndromes........................113
3. Effects of Specific Patient Characteristics on Effectiveness and Harms of Antipsychotic
Medications in Individuals With Dementia..........................................................................116
4. Potential Adverse Effects and/or Complications Involved With Prescribing Second-Gener-
ation Antipsychotics to Patients..........................................................................................117

Appendix B: Expert Opinion Survey Data: Results......................................................177

Section I: Questions About Appropriate Use......................................................................177
Section II: Duration of Treatment.......................................................................................194
Section III: Clinical Experience Using Antipsychotics in
Patients With Dementia......................................................................................................199
 THE AMERICAN PSYCHIATRIC ASSOCIATION
PRACTICE GUIDELINE ON THE USE OF
Antipsychotics to Treat Agitation or Psychosis in Patients with Dementia
May 01, 2016
Non-emergency antipsychotic medication should only be used in patients with dementia when agitation and psychosis symptoms are
severe, are dangerous and/or cause significant distress to the patient.

Response to non-drug interventions should be reviewed prior to use of antipsychotic medication.

Before treatment with an antipsychotic, the potential risks and benefits should be assessed by the physician and discussed with the
patient and the patient’s surrogate decision maker, with input from the family.

Treatment should be initiated at a low dose and eased up to the minimum effective dose.

If the patient experiences significant side effects, the risks and benefits should be reviewed to determine if the antipsychotic should
be discontinued.

If there is no significant response after a 4-week time period, the medication should be tapered and withdrawn.

In patients who show adequate response to the medication, an attempt to taper and withdraw the antipsychotic should be made
within four months of starting.

In patients whose antipsychotic medications are being tapered, symptoms should be assessed at least every month during tapering
and for at least four months after the medication is discontinued.

A long-acting injectable antipsychotic should not be used unless it is administered for a co-occurring chronic psychotic disorder.

If non-emergency antipsychotic medication treatment is to be used, haloperidol should not be used first.
 Recommendations
- Look for etiology of symptoms

- Use caution in these fragile and vulnerable patients

- Need shared decision making – staff, families, patients

- Identify target signs and symptoms, and set a limited time frame (many patients improve without treatment
over 2-4 weeks)

- Treat only severe symptoms, emotional distress, physical safety

- Use the lowest dosages for shortest time

- Possible doses used:
- Risperidone 0.5-1.5 mg/day
- Olanzapine 5-10 mg/day
- Quetiapine 50-200 mg/day
- Aripiprazole 7-12 mg/day

- Monitor, assess regularly

- Taper and trial discontinuation regularly

 Serotonergic agents
Pharmacological treatment of Neuropsychiatric symptoms
of dementia: A review of the evidence. JAMA 2005;293(5); 596-608

- Well tolerated

- Beneficial for depression

- Not clearly effective in treating of other symptoms.

 CITALOPRAM VS. RISPERIDONE STUDY
A double-blind comparison of citalopram and risperidone for the treatment
of behavioral and psychotic symptoms associated with dementia.
Am J Geriatr Psychiatry. 2007 Nov;15(11):942-52. Epub 2007 Sep 10.
(53 patients were randomized to citalopram and 50 to risperidone)�
- Efficacy:
- Citalopram overall 32% reduction of symptoms
- Risperidone - 35% reduction

- Total adverse-event scores

- Increased 19% with risperidone
- Decreased by 4% with citalopram

- Citalopram worked on psychotic symptoms like hallucinations and delusions!

- Suggests agitation and psychosis in younger and older populations have different neu-
rochemistry
 Trazodone for agitation in dementia
(2004 Cochrane review)

- Rationale: BPSD may be due to serotonergic dysfunction

- A sedating atypical serotonergic antidepressant with a lower rate of adverse effects

may help

- Limited data from two small studies

- Conclusions: Insufficient evidence to recommend the use of trazodone

www.cochrane.org/reviews/en/ab004990.html
 Valproate preparations for BPSD
(2004 Cochrane review)

- No evidence of efficacy of valproate preparations for treatment of BPSD

- Adverse reactions
- Sedation occurred more frequently than in controls
- Urinary tract infection was more than in controls

- Low dose with valproate preparations is ineffective in treating BPSD

- High dose therapy is associated with an unacceptable rate of adverse effects

 Carbamazepine
- The Good News:
- 4 RCTs demonstrate benefit for aggression and agitation (Tariot el al. 1994;
Cooney et al. 1996; Tariot et al. 1998; Olin et al. 2001)

- Tariot et al. (1998) completed a nursing home study where 72% of patients
improved versus only 21% placebo

- One of the largest effect sizes of all BPSD trials

- The Bad News: Concerns about tolerability in elderly, drug-drug interactions, and ad-
verse events unfortunately limit its use
 Benzodiazepines
- Several studies support efficacy

- Main concern is high rate of adverse events in the elderly

- Excessive sedation, falls, cognitive impairment, paradoxical agitation

- Guidelines support only short-term as-needed use

 Cholinesterase inhibitors

- Initial studies focused on cognition, yet there is increasing evidence of a possible behav-
ioral benefit as well

- Meta-analysis of ChEI studies - Modest but significant behavioral benefit compared

with placebo Trinh et al. (2005)

- Several post-hoc analyses of studies with galantamine and donepezil suggest benefi-
cial effects on psychosis, agitation, mood, apathy, and aberrant motor behaviors

(Mega et al. 1999; Herrmann et al. 2005; Cummings et al. 2006)

S. Gauthier et al, Int J Clin Pract, June 2007, 61, 6, 886–895
- 2126 AD Patients
- 6 Months
- Random, plac contr, D blind
- 6-12 mg Exelon
- MMSE
- BEHAVE-AD
- ADCS-COG
 Summery of behavior effects of Rivastigmine

- Rivastigmine treatment in mild-to moderate AD is associated with improvements in

behavioural symptoms, a decreased requirement for antipsychotic drugs and delays in
nursing home placement; reductions in caregiver burden, caregiver time and costs have
also been reported.

- The positive effects of Rivastigmine on functional and behavioural symptoms of AD

help to reduce the time, stress and overall burden associated with caregiving, both in the
informal home care and nursing home environments.
 Memantine

- Studies have examined the effect of memantine on BPSD in moderate-severe AD

- Post-hoc analysis suggests benefits, particularly for aggressive, agitated behav-

iors (Gauthier S et al 2005; Cummings et al. 2006)

- Memantine also appears to delay emergence of agitation and reduce caregiver distress
(Cummings et al 2006)

- Other reviewers question the clinical significance of the benefit

 Dementia Guideline

Issue date: March 2011 Review date: April 2014

Issue date: March 2011 Review date: April 2014

 Review of AD treatments

Neuroscience team | Cycle meeting Dubai | Mohamed Orabi | 11 Sept 12

Severity of AD
Conclusion
 What if we stop meds?

- 3 placebo controlled withdrawal studies indicated: no worsening of

behavior when long-term administration of neuroleptics were
stopped

(Cohen-Mansfield et al. 1999; Bridge-Parlet. 1997; Ballard et al. 2004)

 Sexually inappropriate behaviors

- Likely more due to disinhibition, than hypersexuality

- Occurs in 7-25% of significantly impaired older

- SSRI

- Antiandrogen
- Progesterone 5 mg po daily (10 mg IM weekly)
- Leuprolide 5-10 mg IM monthly
Parkinsonian motor disturbances & medications
- Dementia with Lewy bodies (DLB), Parkinson disease (PD) and up to 50% of Alzheimer
disease (AD)

- Neuroleptic antipsychotics are dopamine receptor antagonist

- Severe motor deterioration (neuroleptic sensitivity)

- Small trial (9 subjects) Quetiapine (25-300 daily, mean 120) vs placebo

- No difference in cognitive or behavioral scores
- Adverse reactions – similar, except ↑ dizziness in quetiapine
Quetiapine for agitation or psychosis in patients with dementia and parkinsonism. Neurology - Volume 68, Issue
17 (April 2007)

- Quetiapine - dosages of 200 mg/day or higher may be needed to control agitation

in demented patients

Zhong K, Tariot PN, Mintzer J, et al. Quetiapine for the treatment of agitation in elderly institutionalized patients
with dementia: a randomized, double-blind trial. Presented at the American College of Neuropsychopharmacolo-
gy Annual Meeting; December 12–16, 2004; San Juan, Puerto Rico.
 Manic-like syndromes
- Symptoms : pressured speech, disinhibition, elevated mood, intrusiveness, hyperactivi-
ty, reduced sleep

- Likely secondary to the dementia

- Coexist with confusional state

- Irritable/hostile > euphoria

- Consider Valporate- 125 BID

 Apathy or depression?
- Often confused with depression, since symptoms overlap (diminished interest, hyper-
somnia, fatigue, lack of insight, psychomotor retardation)

- Apathy traits: emotional indifference, denying feelings of depression, reduced ability to

initiate in multiple domains (cognitive, motor, gait)

- Medications to increase dopaminergic transmission: Bupriopion, amantadine, psycho-

stimulants (Ritalin,etc), rivastigmine (Exelon), donepezil (Aricept).

- SSRIs may help but produce agitation.

Behavioral and Psychological
Symptoms of Dementia
(BPSD)
THANK YOU