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Case notes z
Antipsychotics in dementia
Differential response to antipsychotics
in a patient with Alzheimer’s disease
Dina Rachis MBBS, Kuttalingam Shankar MRCPsych
Risperidone is the only antipsychotic currently licensed for the behavioural and
psychological symptoms of dementia. Drs Rachis and Shankar describe the case of an
elderly man with Alzheimer’s disease who developed behavioural symptoms and
delusions, who responded well to aripiprazole after treatment with risperidone failed.
V
irtually all
patients
with dementia
will develop
changes
in
behaviour and
personality as
the disease progresses.1 The nature
and frequency of symptoms vary
over the course of the illness, and
psychotic features tend to present
later, particularly when the patient
becomes more dependent. A review
of studies that assessed the prevalence of psychosis in Alzheimer’s
disease showed a median prevalence of 41.1 per cent (range 12.274.1 per cent).2 Antipsychotic drugs
have been commonly used, but in
recent years evidence for their efficacy has been overshadowed by concerns about harm, making their use
highly controversial.3
The most significant clinical
issue has been the increased mortality associated with antipsychotic use
among people with dementia. An
initial meta-analysis completed by
the US Food and Drug
Administration,4 which has been
confirmed by independent analyses,
highlighted a 1.5- to 1.7-fold
increase in mortality risk for people
with Alzheimer’s disease receiving
antipsychotics compared with
placebo, over 6-12 weeks in randomised clinical trials. Subsequent
work has demonstrated that this significant risk is elevated and persistent in cases of longer-term exposure
10
to antipsychotics.5 Initially the warning was restricted to risperidone and
olanzapine, but it has now been
extended to all antipsychotic drugs.
Risperidone is the only antipsychotic that has a licence for behavioural and psychological symptoms
of dementia, and also has the most
supportive evidence for its effectiveness. Aripiprazole has been studied
in three trials; two reported a
favourable response compared with
placebo6-8 and all studies reported
a favourable tolerability profile.
This case report describes an
elderly male patient with
Alzheimer’s disease, behavioural
symptoms and delusions, who
failed to respond to treatment with
risperidone but who subsequently
responded well to aripiprazole.
Presentation
An 81-year-old man suffering from
Alzheimer’s disease, diagnosed 18
months earlier, was admitted to the
dementia ward under Section 2 of
the Mental Health Act. He had
become physically aggressive
towards his wife and suspected her
of having an affair. He expressed suicidal ideation, stating that he would
walk in front of a train to end it all.
During assessment he relayed
an incident, which he believed
happened around one month ago,
when his wife told him that she was
going out for the evening with
another man. He responded by
telling her not to return home and
Progress in Neurology and Psychiatry May/June 2014
he stated that if he finds the proof
of the affair he would smack her.
He also mentioned that he had
previously been remanded by the
police for hitting his wife and was
prepared to fight the police as he
was not afraid. He confirmed he
had a happy marriage until one
month beforehand, when he
became angr y and believed he
could have killed his wife. He had
no remorse about hitting his wife,
but reinforced the fact that he
might need to do it again. From collateral history, it appeared that he
had never been physically aggressive towards his wife in the past.
Following admission, the
patient was physically examined,
blood investigations were carried
out and any possible physical
causes were excluded. He was
started on risperidone 0.5mg daily
and donepezil 5mg daily. His presentation did not improve on this
treatment regimen. He started to
isolate himself, refused food and
his sleep became disturbed. He was
already on an antidepressant medication (venlafaxine XL 75mg
daily), and the dose was increased
further to 150mg daily as possible
co-morbid depression was suspected as he continued to express
suicidal thoughts. His compliance
with medication started to deteriorate as well, but the staff managed
to give him his medication. Section
2 had to be changed to Section 3 as
he was repeatedly asking to go
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Antipsychotics in dementia
home, carr ying his possessions
around with him and looking for
an opportunity to abscond.
The patient became verbally and
physically aggressive towards staff
and he continued to believe that his
wife was having an affair. Due to his
presentation, the risperidone was
increased to 1mg at night and all
other medication was continued on
the same doses. He also started to
exhibit misidentification delusions,
mistaking a female service user for
his wife. The donepezil had to be
stopped as he developed a rash, and
instead memantine was started, and
the dose gradually increased to
20mg daily. The risperidone was further increased to 1.5mg daily for
eight days, but this did not make any
difference to his presentation and
therefore was stopped.
He remained physically and verbally aggressive, and it was reported
that he punched and pushed other
female service users. He continued
to express homicidal ideation
towards his wife as well as suicidal
ideation. It was felt another antipsychotic medication was needed to
help with his psychological and
behavioural symptoms. He was
therefore started on aripiprazole
5mg twice daily. Following this, his
behaviour improved, he became
more relaxed and started to spend
time in a small lounge on the ward,
which he believed to be his own
property. However, he accommodated other patients, and there was
only one isolated incident of aggression observed. He expressed no further suicidal or homicidal ideation.
He remained well on the same dose
until he was transferred to the longterm continuing care unit.
After a month, his aripiprazole
was reduced to 5mg daily. This
resulted in relapse of his psychotic
symptoms. He once again started to
talk about his wife having an affair.
He became more suspicious of staff
and was reluctant to take medicawww.progressnp.com
tions from them. The dose of aripiprazole was increased back to
10mg daily and the psychotic symptoms once again resolved.
Discussion
This case report describes an elderly
patient with dementia whose delusions did not respond to risperidone, but responded well to
aripiprazole. The improvement that
we observed in our case is probably
related to difference in the mechanism of action between risperidone
and aripiprazole. Risperidone has a
wide spectrum of (mostly antagonistic) activity against many receptor
types including dopaminergic,
alpha-adrenergic, histaminergic and
serotonergic receptors. Aripiprazole
is a dopamine D2 and D3 receptor
partial agonist with additional partial agonist activity at serotonin
5HT 1A receptors and antagonist
activity at 5HT2A receptors. In addition, aripiprazole has a low affinity
for alpha-adrenergic, histaminergic
and muscarinic receptors.9
Venlafaxine can increase
dopaminergic transmission.10 This
could have contributed to the lack
of response to risperidone. On the
other hand, aripiprazole can preferentially increase dopamine
release in the medial prefrontal cortex and hippocampus 11 and
dopamine synthesis in the nucleus
accumbens.12 Furthermore, studies
have reported that hyperprolactinemia induced by haloperidol and
risperidone can be reversed with
adjunctive use of aripiprazole.13,14
In our patient, aripiprazole was
well tolerated. Aripiprazole has a
favourable side-effect profile compared to other atypical antipsychotics. 15 One criticism of
antipsychotics is their high level of
somnolence, which may be associated with falls as well as contributing to their therapeutic effect. In
Mintzer’s study,8 the incidence of
somnolence with aripiprazole was
z Case notes
low (7 per cent at 10mg daily dose)
and it did not increase in a dose
dependent manner. Higher somnolence rates have been reported for
other atypical antipsychotics; for
example approximately 36 per cent
with risperidone3 and olanzapine.16
Aripiprazole also has a favourable
metabolic profile compared with
other second-generation antipsychotics in terms of glycaemic control, lipid profile, prolactin levels
and weight gain. It is also has little
effect on QTc interval, which makes
it an attractive option in the elderly
population.17 However, a pooled
analysis of all three aripiprazole
studies in elderly patients with
dementia demonstrated an
increase risk in mortality (relative
risk 1.99; 95%CI: 0.86-4.62).18
Unlike functional mental illnesses, the aetiology of psychosis in
dementia may be different. The typical pathological lesions of
Alzheimer’s disease, neurofibrillary
tangles (NFT), exhibit a characteristic distribution pattern that is correlated with dementia stage. It has
been shown that people with
Alzheimer’s disease who develop
psychosis have a 2.3-fold greater
density of NFT in the neocortex
(middle frontal gyrus, anterior
third of the superior temporal
gyrus and inferior parietal lobule)
compared to Alzheimer’s disease
patients who do not develop psychosis.19 In a recent review of neuroimaging studies of delusions in
Alzheimer’s disease, the majority of
studies found pathology in the right
frontal lobe. The authors concluded that left frontal predominance, secondar y to right-side
pathology, may create a hyperinferential state resulting in the formation of delusions.20 These factors
may contribute to varying responses
to medications in the treatment of
psychosis in dementia.
Zubenko et al. reported a link
between psychotic symptoms and
Progress in Neurology and Psychiatry May/June 2014
11
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Antipsychotics in dementia
a reduction in serotonin levels,
with relative preservation of noradrenaline. Surprisingly, they did
not identify any association with
dopaminergic parameters. 21 In
another study, the SSRI citalopram
was comparable to risperidone in
the treatment of behavioural symptoms in dementia with psychotic
symptoms.22
Some studies have suggested that
the cholinergic drugs used to treat
patients with Alzheimer’s disease
may also affect behavioural symptoms. The cholinesterase inhibitors
tacrine and physostigmine and the
muscarinic agonist xanomeline have
been shown to yield a greater reduction in delusions, suspiciousness,
hallucinations and agitation than
placebo.23-25 Visual hallucinations
have also been shown to respond to
the cholinesterase inhibitor rivastigmine in Lewy body dementia.26
Although cholinergic drugs are not
a primary treatment for psychotic
symptoms in dementia, these findings reflect the close association
between cognitive difficulties and
psychosis. Moreover, pooled data
from three studies concluded that
memantine, an NMDA receptor
antagonist, was effective in psychosis
in moderately severe to severe
Alzheimer’s disease.27
Conclusion
Although risperidone is licensed
for the short-term management of
behavioural and psychological
symptoms in dementia, one has to
consider also the potential
risk/benefit ratio of other antipsychotic drugs. Aripiprazole, with its
different mode of action and sideeffect profile, may have a role in
the management of psychosis in
patients
with
dementia.
Nevertheless, in light of increased
risk of cerebrovascular accidents
and mortality with atypical antipsychotic drugs, the potential
improvement in the quality of the
12
patient’s life should be carefully
balanced against the relative risks
before initiating treatment.
Declaration of interests
None declared.
Dr Rachis is a CT3 Trainee in
Psychiatry and Dr Shankar is a
Consultant in Old Age Psychiatry in
Hertfordshire Partnership University
NHS Foundation Trust
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