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Antipsychotics for the Treatment of Behavioral and Psychological

Symptoms of Dementia (BPSD)

Friendy Ahdimar
Dr. Alifiati Fitrikasari, SpKJ (K)
Abstract
Behavioral and psychological symptoms of
dementia (BPSD), i.e. verbal and physical
aggression, agitation, psychotic symptoms
(hallucinations and delusions), sleep
disturbances, oppositional behavior, and
wandering, are a common problem
complicating dementia.

90% of patients with Alzheimers disease (AD)


may present at least one BPSD.
Anti-psychotics (AP) are the most commonly
used in BPSD.

It were safety, but have a potential increase in


cerebrovascular side effects and mortality.

This review will summarize the pathophysiology


and neuropharmacology of BPSD and describe
the characteristics of the AP most commonly
used in efficacy and safety in BPSD.
INTRODUCTION
Dementia is the most problems in elderly
populations .
It were very difficult to manage by the caregivers
and the care teams.
BPSD may not be obvious during the early stages
of AD.
Psychotic symptoms are risk factors for
development of aggressive behaviour and agitation
and associated with a poorer functional prognosis.
It will discuss about efficacy and safety AP which
commonly used in BPSD.
PATHOPHYSIOLOGY OF
BPSD
Origin of BPSD in AD derives from identifiable
anatomical and biochemical abnormalities.

Baseline psychological factors are involved


with biological factors, which appearance in
behavioural problems.

Cromosomal abnormalities are a risk factor


for the development of BPSD.
Polymorphism and serotonin
receptors genes is associated with
visual and auditory hallucinations
Two polymorphisms having an
additive effect on visual
hallucinations.
Polymorphism of the dopamine
receptors genes is associated with
psychosis.
The typical pathologic lesions of AD is
correlated with dementia stage.

Negative psychiatric symptoms (such as


depression) can be evident before a diagnosis
of AD is made,

Positive symptoms (agitation, aggressive


behaviour) appear at later stages of dementia,
after the appearance of cognitive abnormalities
psychosis in AD is associated with a
reduction in prefrontal, left frontal-
temporal, and right parietal
metabolism.

Lower neurone count in the dorsal


raphe was associated with delusions
and hallucinations.
Hypoperfusion left anterior temporal
cortex in AD showing aggressive
behaviour.

Association between the density of


Lewys bodies in the amygdala and
parahyppocampal cortex presence
severe visual hallucination .
PHARMACOLOGY OF ANTIPSYCHOTICS

Most pharmacologic treatment for BPSD are


based on drugs increasing the activity of
Acetylcholine, or by decreasing or
modulating dopamine and serotonine.

For decades, Firstgeneration AP have been


used since the 50s. Phenotiazines,
butyrophenones and thioxanthenes which
have high affinity for D2 receptor.
D2 receptors in basal ganglia is correlated
with extra-pyramidal effects (EPS) and
hyperprolactinemia.

Clozapine : low incidence of EPS and a risk


of agranulocytosis (low affinity D1,D2 and
high affinity D4,serotonin).
Risperidone affinity with 5HT2/D2. have similar
proportion risperidone and haloperidol.

Olanzapine : profile similar to clozapine.

Quetiapine : activity similar to clozapine, and


acts selectively in the limbic system.

Ziprasidone : structurally different from other AP,


shows a high 5HT/D2 ratio, affinity for D2 is high .
Benzamides (sulpiride, amisulpiride) :
highly selective antagonist D2,D3.
Besides that modulate dopamine
release.

Aripiprazole is a stabilizer of the


dopamine/serotonin system.
EFFICACY OF
ANTIPSYCHOTICS

In 1950s , AP mainly for schizophrenia.

Since then, these agents have been used for BPSD

Studies showed a conventional AP superiority would


be limited to symptoms of aggression, behavioural
and psychotic symptoms
Atypical AP licensed by FDA in 1990, exclusively for
treatment of schizophrenia.

Risperidone : 1 mg, 2 mg/day for psychotic symptoms


and aggression on patients with Alzheimers disease,
vascular dementia or mixed demention (for 12 weeks).

Olanzapine : 5 - 10 mg/ day effective for improving


behavioural symptoms, psychosis and aggression
In contrast, patients with moderate to severe
psychotic symptoms of dementia randomly in
olanzapine (2.5-10.g per day), risperidone
(0.5-2 mg per day) and placebo.

In 10-week, double-blind, placebo controlled


study shown that quetiapine at 200 mg/day is
effective and well tolerated for treating
agitation in patients with dementia.
Aripiprazole at 10 mg /day appeared no benefit
over placebo for controlling delusions and
hallucinations and it was well tolerated.

Alzheimers disease and psychosis, aggression


or agitation, in olanzapine (mean dose 5.5 mg
per day) and risperidone (mean dose 1.0 mg
per day) in treating neuropsychiatric symptoms
was equally beneficial and superior to the effect
of placebo and quetiapine (mean dose 56.5 mg
per day).
For the result : potential side effect associated
with antipsychotic medications in dementia
may outweigh possible benefits.

However, an increased risk of EPS and


cerebrovascular events associated with atypical
AP would outweigh the modest effectiveness of
these medications.

Due to increased risk of e effects, atypical AP in


clinical would not be suitable and should be
limited to those patients presenting with
significant distress and risk associated with
symptoms.
SAFETY OF
ANTIPSYCHOTICS
Atypical AP reported to be better safety profile
compared to conventional medications,
especially for EPS such as parkinsonism and
tardive diskinesia.

Benefit of risperidone relative to haloperidol at


2 mg/day or higher. Olanzapine : no increased
incidence of EPS (at 5 -15 mg/ day) compared
placebo group.

Overall, evidence suggests that in dementia


patients, EPS are less frequently associated
with atypical AP relative to conventional agents.
Risperidone increase in the risk of CVEs in dementia
patients.

Olanzapine was calculated increase the risk of CVEs but


in studies not significance.

In spite, studies failed to support the conclusion of a


possible increased risk of CVEs and death associated
with atypical AP.
Conventional AP : 40% excess risk of death
compared with atypical AP.

Atypical AP for dementia : risk of lengthening of


QTc interval at ECG.

Atypical AP may not increase the risk of QTc


prolongation, ventricular arrhythmias and
sudden death and with respect to cardiac
toxicity, but safer than conventional
medications.
Risk of weight gain, diabetes and
hyperlipidemia reported high for clozapine and
olanzapine, moderately high for quetiapine and
low for risperidone.

FDA reminded that atypical AP have not been


approved for dementia which represents an off-
label indication.
CONCLUSIONS
BPSD represent one of the main mental
issues in the geriatric population.

Based on safety considerations : non


pharmacological generally recognized as the
first-line strategy for the treatment of BPSD.

Antipsychotic prescription is limited and


strictly regulated for BPSD and still an off-
label indication for most of agents of AP.
Evaluation of the potential benefits and risks of
both classes of AP as well as patients individual
risk profile.

Finally, evidence for potential pharmacological


alternatives to AP is lacking.

In the near future, research efforts should be


directed to investigate and identify alternative
therapeutic strategies which combine non-
pharmacological treatments with drug therapy
and need to be tailored to patients with
dementia and their families.
THANK YOU

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