Antipsychotic treatments for the elderly: Efficacy and safety of aripiprazole

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Abstract
Delusions, hallucinations and other psychotic symptoms can accompany a number of conditions in late life. As such, elderly patients are commonly prescribed antipsychotic medications for the treatment of psychosis in both acute and chronic conditions. Those conditions include schizophrenia, bipolar disorder, depression and dementia. Elderly patients are at an increased risk of adverse events from antipsychotic medications because of age-related pharmacodynamic and pharmacokinetic changes as well as polypharmacy. Drug selection should be individualized to the patient's previous history of antipsychotic use, current medical conditions, potential drug interactions, and potential side effects of the antipsychotic. Specifically, metabolic side effects should be closely monitored in this population. This paper provides a review of aripiprazole, a newer second generation antipsychotic agent, for its use in a variety of psychiatric disorders in the elderly including schizophrenia, bipolar disorder, dementia, Parkinson's disease and depression. We will review the pharmacokinetics and pharmacodynamics of aripiprazole as well as dosing, diagnostic indications, efficacy studies, and tolerability including its metabolic profile. We will also detail patient focused perspectives including quality of life, patient satisfaction and adherence.
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Antipsychotic treatments for the elderly: efcacy
and safety of aripiprazole
Izchak Kohen
1
Paula E Lester
2
Sum Lam
3
1
Division of Geriatric Psychiatry,
Zucker-Hillside Hospital, Glen Oaks,
NY, USA;
2
Division of Geriatric
Medicine, Winthrop University
Hospital, Mineola, NY, USA;
3
Division
of Pharmacy and Geriatrics, St. Johns
University College of Pharmacy and
Allied Health Professions, Queens,
NY, USA
Correspondence: Izchak Kohen
North Shore-LIJ Health System, Zucker
Hillside Hospital, Division of Geriatric
Psychiatry, Ambulatory Care Pavilion,
Room 2106, 75-59 263rd Street,
Glen Oaks, NY 11004, USA
Tel 718-470-7992
Fax 718-962-7712
Email ikohen@nshs.edu
Abstract: Delusions, hallucinations and other psychotic symptoms can accompany a number of
conditions in late life. As such, elderly patients are commonly prescribed antipsychotic medica-
tions for the treatment of psychosis in both acute and chronic conditions. Those conditions include
schizophrenia, bipolar disorder, depression and dementia. Elderly patients are at an increased
risk of adverse events from antipsychotic medications because of age-related pharmacodynamic
and pharmacokinetic changes as well as polypharmacy. Drug selection should be individualized
to the patient’s previous history of antipsychotic use, current medical conditions, potential drug
interactions, and potential side effects of the antipsychotic. Specifically, metabolic side effects
should be closely monitored in this population. This paper provides a review of aripiprazole,
a newer second generation antipsychotic agent, for its use in a variety of psychiatric disorders in
the elderly including schizophrenia, bipolar disorder, dementia, Parkinson’s disease and depres-
sion. We will review the pharmacokinetics and pharmacodynamics of aripiprazole as well as
dosing, diagnostic indications, efficacy studies, and tolerability including its metabolic profile.
We will also detail patient focused perspectives including quality of life, patient satisfaction
and adherence.
Keywords: aripiprazole, antipsychotics, elderly, adverse drug reaction
Introduction
Antipsychotic medications are commonly prescribed for older adults for the acute
management of psychosis in brief psychotic disorders or in psychosis due to a general
medical condition or from substance use. Chronic antipsychotic therapy is commonly
used in patients with psychosis, schizophrenia, dementia related psychosis, bipolar
disorder, and psychosis related to Parkinson’s disease.
Elderly patients are at increased risk of adverse drug events because of age-related
pharmacodynamic and pharmacokinetic changes. Additionally, as older adults are often
prescribed multiple medications, they are at increased risk for drug–drug interactions.
Common side effects in the elderly from antipsychotics include orthostatic hypoten-
sion, sedation, anticholingergic side effects, extrapyramidal symptoms (tremor and
rigidity), and tardive dyskinesia (lip smacking).
This paper provides a review of aripiprazole, a newer atypical antipsychotic agent.
We will review the indications and adverse drug reactions of this drug in the elderly.
Specifically, we will review pharmacokinetics and pharmacodynamics of aripiprazole
as well as dosing, diagnostic indications, efficacy studies, and tolerability. We will
also detail patient focused perspectives including quality of life, patient satisfaction
and adherence.
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Psychosis in the elderly
Delusions, hallucinations and other psychotic symptoms
can accompany a number of conditions in late life. A recent
Swedish investigation found that the prevalence of any
psychotic symptom in a population sample of 85-year-old
individuals without dementia was 10.1%.
1
Some conditions
that cause psychotic symptoms, such as delirium and
substance-induced psychosis are acute and tend to resolve
when the underlying condition is treated.
2
Psychotic
symptoms in elderly individuals may also arise secondarily
to Alzheimer’s disease (AD) or other dementias. AD is the
most common form of dementia in the elderly population,
accounting for 65% to 70% of dementia cases. Approximately
35% to 50% of AD patients manifest psychotic symptoms.
3
Psychosis associated with AD often presents with paranoid
and nonbizarre delusions.
4
Misidentification of care givers
is common in patients with AD, while schneiderian first rank
symptoms are rare.
5
Schizophrenia in the elderly
Schizophrenia, a chronic, mental illness affects about 1% of
the US population and is characterized by both positive and
negative symptoms, cognitive dysfunction and a decline in
psychosocial functioning.
6
The etiology of schizophrenia is
unknown, but it is believed that monoamine neurotransmitter
systems, particularly dopaminergic neurons, are involved.
7
Most individuals with schizophrenia develop the disease
in the second or third decade of life. Many patients with
schizophrenia now live into older adulthood. Thus, about 80%
of older adults with schizophrenia have had an early onset
of the disease and have a chronic course spanning several
decades.
8
There is another smaller subset of patients who
develop psychotic symptoms after age 60 and are diagnosed
with very late onset schizophrenia-like psychosis.
9
Factors
distinguishing patients with very late onset schizophrenia
from early onset schizophrenia patients include a lower
genetic load, less evidence of a thought disorder, and evidence
of a neurodegenerative component.
10
The prevalence of
schizophrenia among individuals aged 45 to 64 is approxi-
mately 0.6% and prevalence estimates for elderly individuals
range from 0.1% to 0.5%.
11,12
Longitudinal follow-up of patients with schizophrenia
indicates a wide range of outcomes. About 20% of patients
experience remission of all symptoms.
13
Another 20%
experience worsening of their symptoms and the remain-
ing 60% remain largely unchanged.
14
Factors associated
with poorer prognosis include chronicity, insidious
onset, premorbid functional deficits, and prominent
negative symptoms.
15
In one large sample of chronically
institutionalized patients with schizophrenia, older age
was associated with lower levels of positive symptoms and
higher levels of negative symptoms.
16
Cognitive perfor-
mance tends to be stable, although it is worse in patients
with schizophrenia than in healthy adults.
17
The degree
of functional impairment varies among older adults with
schizophrenia. However, one study showed that 30% of
a group of older schizophrenic patients was employed at
least part-time since the onset of psychosis and that 73%
of them were living independently.
18
Psychosis in Alzheimer’s dementia
in the elderly
Alzheimer’s disease (AD) affects 5% to 15% of the population
over age 65 and about 20% of individuals over age 80.
19
There is a high prevalence of psychotic symptoms and
behavioral disturbance in AD. A review of studies showed
a median prevalence rate of psychosis in AD of 41.1%
(range, 12.2% to 74.1%).
20,21
Psychotic symptoms have
been linked to increased cognitive and functional decline
and increased risk of institutionalization in patients
with AD.
22
Antipsychotic medications are disproportionately used
among elderly persons and are prescribed for more than a
quarter of Medicare beneficiaries in nursing homes.
23
Such
medications are often used for dementia, delirium, psychosis,
agitation, and affective disorders.
24
Even though there is no
psychotropic medication that is approved by the US Food and
Drug Administration (FDA) for the treatment of psychosis in
AD, a number of consensus statements prior to 2004 recom-
mend the use of atypical antipsychotic agents as a first line
pharmacologic approach to treatment.
25
Analyses of safety data from several studies have raised
concerns about an increased risk of cerebrovascular adverse
events such as stroke in the use of certain atypical anti-
psychotics compared with placebo in elderly patients with
dementia.
26,27
This has led the FDA to issue warnings on the
use of atypical antipsychotics in the treatment of behavioral
symptoms in elderly patients with dementia.
19
In a Public
Health Advisory issued in April 2005, the FDA warned that
the use of atypical antipsychotic medications nearly doubled
the risk of death, as compared with the risk with placebo,
in 17 short-term, randomized, controlled trials involving
elderly persons with dementia.
28
The FDA has issued a
separate warning regarding the increased mortality risk in
elderly patients with dementia who are treated with atypical
antipsychotics including aripiprazole.
29
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Bipolar disorder in the elderly
Bipolar disorder in older adult populations has gained
increasing attention due to the growing proportion of elderly
in the United States and worldwide.
30
One study reported the
prevalence of bipolar disorder at 0.5% among individuals
age 65 and older as bipolar illness persists into later life.
31
A continuing unmet need is the identification of agents that
are generally well tolerated and effective in later-life bipolar
disorder. Medications that are first-line treatments in younger
patients, such as lithium, may be poorly tolerated in older
patients due to side effects and renal dysfunction. Additional
strategies for bipolar disorder in late-life are needed. There
are few evidence-based studies on which to base treatment
decisions in geriatric patients with bipolar disorder.
32
Psychosis in Parkinson’s disease
Psychosis affects at least 5% to 8% of medication-treated
patients with idiopathic Parkinson’s disease (PD).
33
Treatment
options include reducing medications used for the treatment of
PD-related motor symptoms or introducing an atypical anti-
psychotic drug. Only clozapine has been demonstrated to be
efficacious and tolerated in double-blind controlled trials.
34
Major depressive disorder in the elderly
Major depressive disorder (MDD) is common in older adults,
with estimates of prevalence of 6% to 10% in primary care
population.
35
Approximately 50% of older patient with
MDD do not respond completely to initial treatment with
antidepressant pharmacotherapy.
36
Recently, the use of
atypical antipsychotic agents has been studied as adjunctive
or augmentation pharmacotherapy for incomplete response
in young to middle-aged adults with major depression.
37
The addition of aripiprazole to standard antidepressant
pharamacotherapy has been examined in young and mid-life
patients with MDD.
38
Pharmacology and
pharmacokinetics/dynamics
of aripiprazole
Aripiprazole is a second-generation (atypical) antipsychotic
that is approved for schizophrenia, manic or mixed episodes
associated with biploar I disorder, and as an adjunctive treat-
ment of major depressive disorder. It exhibits high affinity for
D2, D3, 2-HT1a and 5-HT2a receptors, moderate affinity for
D4, 5-HT2c, 5-HT7, alpha 1 adrenergic and H1 receptors,
and no affinity for muscarinic receptors. It has moderate
affinity for the serotonin reuptake transporter.
39
The proposed
mechanism of action for its efficacy is a combination of
partial agonistic activity at D2 and 5-HT1A receptors and
antagonistic activity at 5-HT2A receptors.
40
It is available in
several dosage forms: intramuscular injection solution, oral
solution, tablets, and orally disintegrating tablets.
41
Table 1 compares the pharmacokinetic parameters of
second-generation antipsychotics. Aripripazole has an active
Table 1 Pharmacokinetic parameters of selected antipsychotics
101
Drug Bioavailability (%) Half-life (h) Major metabolic
pathway
Active
metabolites
Dosage
forms
Aripiprazole 87 48–68
Dehydroaripiprazole:
75–46
CYP3A4,
CYP2D6
Y T, O, L
Clozapine 12–81 11–105 CYP1A2,
CYP3A4,
CYP2C19
Y T, O
Olanzapine 80 20–70 CYP1A2,
CYP3A4,
FMO3
Y T, I, O
Paliperidone ER
28 23 Renal unchanged
(59%)
Multiple pathway
N ER
Quetiapine 5–13 7 CYP3A4 Y T
Risperidone
68 3–24 CYP2D6 Y T, O, L
Risperidone Consta
®
3–6 days CYP2D6 Y LAI
Ziprasidone 59 4–10 Aldehyde oxidase,
CYP3A4
N C, I
Abbreviations: C, capsules; ER, extended release; I, injection; L, liquid solution, elixir or suspension; LAI, long-acting injectable; O, orally disintegrating tablets; T, tablet.
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metabolite (dehydroaripiprazole) that has affinities for D2
receptors and an elimination half-life of 94 hours. The drug
reaches the peak plasma concentration (T
max
) between 3 to
5 hours, and achieves a steady-state concentration within
14 days. It can be taken with or without food, but high-fat
meal delays T
max
by 3 hours. Aripiprazole has a high volume
of distribution (4.9 L/kg) and is highly bound to albumin
(99%). Due to its long half-life, high volume of distribution
and high protein binding, the elderly patients may experience
drug accumulation and drug interactions. It is particularly
true in patients who have low albumin levels, which may end
up with higher free aripriprazole drug concentration. Exces-
sive drug effect in this population may justify dose reduction
or extended dosing interval. In addition, aripriprazole is
metabolized primarily by dehydrogenation and hydroxyl-
ation (CYP3A4 and CYP2D6), as well as N-dealkylation
(CYP3A4). Due to CYP450 enzyme polymorphism, its
elimination half-life may be prolonged to up to 150 hours
in poor metabolizers which represents approximately 8% of
Caucasians. Approximately 25% of the drug is excreted in
the urine (1% as unchanged drug) and 55% in the feces
(18% as unchanged drug). Intramuscular doses have a bio-
availability of 100%, and a T
max
of 1 to 3 hours. Compared to
oral doses, intramuscular doses achieve a 19% higher peak
plasma concentration, as well as a 90% higher drug exposure
within 2 hours of dosing.
41,42
Aripiprazole interacts with drugs that are inducers or
inhibitors of CYP3A4 and CYP2D6 enzymes.
43
The dose
should be doubled when coadministered with CYP3A4
inducers, such as carbamazepine. The dose should be reduced
to half of the usual dose if coadministered with CYP3A4
inhibitors (ketoconazole) or CYP 2D6 inhibitors (fluoxetine,
paroxetine).
44
Appropriate measures should be done when
the interacting drugs are discontinued. No dosage adjustment
is required in patients with renal or hepatic impairment.
45
Intramuscular injections should be administered slowly into
deep muscle mass. Oral doses may be administered with or
without food. Tablet and oral solution may be interchanged
on a mg-per-mg basis, up to 25 mg. Doses using 30 mg tablets
should be exchanged for 25 mg oral solution.
41
Orally disin-
tegrating tablets are bioequivalent to the immediate release
tablets, and should be placed in mouth immediately upon
removal from foil blister. They dissolve rapidly in saliva and
may be swallowed without liquid.
Table 2 shows the relative side effect incidence of selected
antipsychotics in all age groups. However, use of antipsychot-
ics in the elderly is linked with many unique concerns. Firstly,
anticholinergic effects can be detrimental to those who may
already have urinary symptoms, cognitive impairment, dry
mouth, blurred vision and cardiac abnormalities. Secondly,
orthostatic hypotension and sedation may contribute to falls
in patients who have trouble with balance and gait. Thirdly,
extrapyramidal symptoms can be associated with long term
antipsychotic therapy. Patients with the comorbidity of PD
are especially at risk for tremor and muscle rigidity. Arip-
riprazole has lower incidence of these troublesome adverse
effects when compared to other available antipsychotics.
A retrospective study evaluated the use of aripriprazole for
schizophrenia/schizoaffective disorder, bipolar disorder
and major depressive disorder in elderly patients. The study
suggested that agitation/activation is the most commonly
reported side effect.
46
Aripiprazole efcacy studies
Schizophrenia
The recommended dosage for schizophrenia is 10 to 15 mg
once daily, titrate no more frequently than every 2 weeks,
to maximum of 30 mg daily. Aripiprazole demonstrated
its efficacy in four short-term placebo controlled trials that
enrolled acutely relapsed inpatients with schizophrenia. Three
of these studies also included an active control group treated
with either risperidone (one trial) or haloperidol (two trials).
Table 2 Relative side effect incidence of selected antipsychotics in the general population
101
Drug Sedation EPS Anticholinergic Orthostasis Weight gain Hyperprolactinemia
Aripiprazole
+ + + + + +
Clozapine
++++ + ++++ ++++ ++++ +
Haloperidol
+ ++++ + + + ++++
Olanzapine
++ ++ ++ ++ ++++ +
Quetiapine
++ + + ++ ++ +
Risperidone
+ ++ + ++ ++ ++++
Ziprasidone
++ ++ + + + +
Notes: + = low degree of symptoms, ++ = medium degree of symptoms, ++++ = high degree of symptoms.
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The primary measures were the Positive and Negative
Syndrome Scale (PANSS)
47
and the Clinical Global Impression
(CGI)
48
assessment. PANSS measures positive symptoms
(delusions, conceptual disorganization, hallucinatory
behavior, excitement, grandiosity, suspiciousness/persecution,
and hostility) and negative symptoms (blunted affect, emo-
tional withdrawal, poor rapport, passive apathetic withdrawal,
difficulty in abstract thinking, lack of spontaneity/flow of
conversation, stereotyped thinking). The CGI assessment
reflects the impression of a skilled observer about the overall
clinical state of the patient.
48
Overall, aripiprazole (10 to 30 mg daily) is more effica-
cious than placebo in all measure outcomes after 4 to 6 week
of therapy.
49–51
In a 6-week trial (n = 367), aripriprazole
10 mg daily is superior to placebo in PANSS total score,
but the lower dose groups did not demonstrate superiority
to placebo.
52
In another 4-week placebo controlled trial
(n = 103) comparing the dose range of 5 mg daily to 30 mg
daily. Aripiprazole demonstrated efficacy only in a responder
analysis based on the CGI-severity score. Overall, higher
dose of aripiprazole offered no advantage over the lowest
doses. A longer-term trial (n = 310) that enrolled patients
who were symptomatically stable on other antipsychotic
medications for at least 3 months. These patients were
discontinued from their antipsychotic medications and
randomized to aripiprazole 15 mg daily or placebo for up
to 26 weeks of observation for relapse. Patients receiving
aripiprazole experienced a significantly longer time to
relapse, defined as CGI Improvement score of 5 (minimally
worse), scores 5 (moderately severe) on the hostility or
uncooperativeness items of the PANSS, or 20% increase in
the PANSS total score.
53
These clinical trials did not include
sufficient numbers of subjects aged 65 and over to determine
whether they respond differently from younger patients.
Clinical trials of aripiprazole included few elderly
patients and more data are needed on the effects of aripip-
razole in this population, especially those with comorbid
medical illnesses.
54
In one study, aripiprazole was used
to treat 10 elderly hospitalized patients between 62 and
85 years of age who manifested signs of psychosis related
to schizophrenia or schizoaffective disorder. All patients
had been treated previously with atypical and classic anti-
psychotics. Response was assessed by clinical observation
of patients’ behavior and Clinical Global Impression Scale
assigned retrospectively. Seven patients responded to treat-
ment, two did not respond, and one had a partial response.
The mean Clinical Global Impression Scale scores improved
from 6 (severely ill) at baseline to 2.3 (much improved) at
discharge. Treatment was discontinued in the two patients
who did not respond. Of the 7 patients who responded,
4 presented with positive symptoms and showed significant
improvement while 3 presented with positive and negative
symptoms and both symptoms improved significantly. Four
patients had preexisting EPS and these symptoms decreased
in three patients. In addition, two patients were able to dis-
continue antiparkinson medications. The reduction of both
positive and negative symptoms of schizophrenia and the
lack of significant EPS, tardive dyskinesia, sedation, weight
gain, anticholinergic effects, and QTc prolongation gives
preliminary indication that aripiprazole may be a safe and
effective medication for elderly patients with schizophrenia
or schizoaffective disorder.
55
Psychosis in Alzheimer’s dementia
in the elderly
There have been three 10-week, placebo-controlled studies
that have evaluated the efficacy and tolerability of aripip-
razole for the treatment of psychosis related to AD.
19
In
the De Deyn et al study, there were 208 outpatients who
were given flexible dosing of aripiprazole (doses of 2 to
15 mg/day). There was no statistical difference between
aripiprazole and placebo in the primary outcome measure of
the caregiver-assessment NPI psychosis subscale. However,
the aripiprazole-treated patients showed significantly greater
improvement on the Brief Psychiatric Rating Scale (BPRS)
Psychosis and BPRS Core subscale scores at end point when
compared to placebo. There was no statistical significant
difference in the BPRS total score.
56
In the Streim et al study, there were 256 inpatients with
AD-related psychosis who were given flexible dosing of
aripiprazole (doses of 2 to 15 mg/day) with a mean aripip-
razole dose at end point of 8.6 mg/day. There was also no
statistical difference between aripiprazole and placebo in
the primary outcome measure of the caregiver-assessment
NPI psychosis subscale. There were decreases in the Clini-
cal Global Impression-Severity of Illness (CGI-S), but those
were only clinically significant in week 8. There was also
statistically significant improvement in the Cohen-Mansfield
Agitation Inventory (CMAI).
57
In the Mintzer et al study, 487 institutionalized nursing home
patients were randomized to fixed doses of either 2 mg/day,
5 mg/day, or 10 mg/day. On the 10 mg/d dose, there was a
statistically significant difference between aripiprazole and
placebo on the Neuropsychiatric Inventory-Nursing Home
(NPI-NH) Psychosis subscale score at week 10.
58
It is impor-
tant to note that the incidence of EPS-related AEs in these
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studies was low across all treatment groups.
19
There was no
significant difference between placebo and aripiprazole in
all the three studies for weight change.
19
Psychosis in Parkinson’s disease
One study evaluated the effect of aripiprazole on psychosis
in PD in an open-label pilot study. Fourteen patients meet-
ing entry criteria were started on aripiprazole 1 mg/day and
titrated up to a maximum dose of 5 mg as needed. Subjects
were evaluated on the Unified Parkinson’s Disease Rating
Scale (UPDRS) part III for motor function, the Neuropsychi-
atric Inventory (NPI), and the Brief Psychiatric Rating Scale
(BPRS) for psychiatric response. Statistically significant
improvement in mean BPRS and positive BPRS subscales
occurred with open-label aripiprazole, but 8 subjects discon-
tinued the study due to worsened Parkinsonism (3), worsened
psychosis (2), worsening of both (2), and lack of efficacy (1).
While some patients had a favorable response, aripiprazole
was associated with an exacerbation of motor symptoms.
In that small study on psychosis in PD, aripiprazole did not
appear promising.
59
Bipolar disorder
Aripiprazole is approved by the FDA for the treatment of
bipolar mania and for the long-term treatment of bipolar
disorder. To stabilize the acute manic or mixed episodes,
aripiprazole should be initiated at 15 mg once daily as
monotherapy or adjunctive to lithium or valproic acid;
may increase to 30 mg once daily if clinically indicated.
The effective stabilization dose should be continued for up
to 6 weeks. Aripiprazole demonstrated its efficacy in four
3-week, placebo-controlled trials in hospitalized patients
with bipolar I disorder with manic or mixed episodes. These
studies included patients with or without psychotic features,
and 2 studies also included patients with or without a rapid-
cycling course. The primary instrument used for assess-
ing manic symptoms was the Young Mania Rating Scale
(Y-MRS), an 11-item clinician-rated scale that assesses the
degree of manic symptomatology (irritability, disruptive/
aggressive behavior, sleep, elevated mood, speech, increased
activity, sexual interest, language/thought disorder, thought
content, appearance, and insight). The secondary instrument
included the Clinical Global Impression Bipolar (CGI-BP)
Scale.
60–62
As a maintenance therapy, aripiprazole is superior to
placebo on time to the number of combined affective relapses
(manic plus depressive), but it is unclear if it delays the time
to occurrence of depression in these patients. In addition,
these clinical trials did not include sufficient numbers of
subjects aged 65 and over to determine whether they respond
differently from younger patients.
One study looking at the use of aripiprazole in elderly
patients is an open-label, prospective trial of aripiprazole
therapy in 20 older adult patients with bipolar disorder.
30
Older adults with bipolar I disorder (confirmed by the Mini-
International Neuropsychiatric Interview) who were currently
suboptimally responsive to their prescribed medication
treatments received 12 weeks of open-label aripiprazole added
on to existing mood stabilizer medication treatment. Aripip-
razole was initiated at 5 mg daily and increased as tolerated.
Efficacy outcomes included psychopathology measures (the
Young Mania Rating Scale [YMRS]
63
and the Hamilton Rating
Scale for Depression [HAM-D]),
64
extrapyramidal symptoms,
and a level of functioning measure (the Global Assessment
Scale [GAS]). Twenty older adults (mean age = 59.6 years,
range 50 to 83 years) received aripiprazole therapy. Compared
to baseline, individuals had significant reductions in mean
depression scores (HAM-D baseline = 13.8, HAM-D end
point = 6.1, P 0.001), as well as mania scores (YMRS
baseline = 8.6, YMRS end point = 3.9, P 0.03). There
were also significant improvements in functional status as
measured by the GAS (P 0.001). The mean ± SD daily
dose of aripiprazole was 10.26 ± 4.9 mg/day. Overall,
aripiprazole was adequately tolerated in this older adult
population. Aripiprazole therapy may reduce symptoms in
bipolar older adults, and it appears to be reasonably tolerated.
However, larger, controlled trials are needed to confirm these
preliminary findings.
30
Agitation associated with schizophrenia
or bipolar mania
The recommended dosage is 9.75 mg (range 5.25 to 15 mg)
as a single intramuscular dose, repeat at no more frequently
than every 2 hours to a maximum of 30 mg daily; transit
to oral therapy as soon as possible if ongoing therapy is
indicated. The efficacy of aripiprazole for the treatment of
agitation was established in 3 short-term (24-hour), placebo-
controlled trials in agitated inpatients with schizophrenia or
bipolar I disorder (manic or mixed episodes, with or without
psychotic features). Each trial included an active controlled
arm of either haloperidol injection (schizophrenia studies) or
lorazepam injection (bipolar Mania study). The efficacy mea-
sures were the change from baseline in the PANSS Excited
Component at 2 hours post-injection and the Clinical Global
Impression of Improvement (CGI-I) Scale.
65,66
Again, these
studies did not include sufficient numbers of subjects aged
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65 and over to determine whether they respond differently
from younger patients.
Major depressive disorder
The use of aripiprazole for MDD in older patients has
been looked at only in a limited fashion. One open trial of
aripiprazole augmentation in 20 older adults with MDD
that had not remitted after 6 weeks of treatment with a
selective serotonin reuptake inhibitor (SSRI) was associated
with improvement in 50% of the patients.
67
Another
12-week, open-label pilot study of 24 patients diagnosed with
MDD who responded partially (17-item Hamilton Rating
Scale for Depression [HAM-D-17] score of 11 to 15) or not
at all (HAM-D score 15) to a 16-week trial of escitalopram
(up to 20 mg/day), followed by either duloxetine (up to
120 mg/day) or venlafaxine (up to 225 mg/day) for 12 weeks.
Subjects received 2.5 to 15 mg per day of adjunctive aripip-
razole (mean dose, 9.0 mg/day) for 12 weeks. The criterion
for remission during treatment with aripiprazole was a
HAM-D score 10 for 2 consecutive weeks. Of 24 subjects
in the intent-to-treat study group, 19 completed 12 weeks
of augmentation with aripiprazole, 12 of 24 (50%) met
criteria for remission, and 2 of 24 discontinued due to side
effects (sedation, akathisia). The mean (SD) HAM-D score
decreased significantly by 6.4 (5.8) points (paired t test for
means, P 0.01, df = 16). There were no relapses among
the 12 subjects who participated in continuation treatment
over a median period of 27.6 weeks.
68
No known randomized
controlled trials have looked at this phenomenon.
Aripiprazole: safety and tolerability
Second-generation antipsychotics (SGAs) are used to treat
psychiatric conditions in elderly patients, including schizo-
phrenia, mood disorders, and dementia with agitation and
delusions.
25
Aripiprazole is a SGA with partial agonist
activity at the D2, D3, and 5HT1A receptors and antagonist
activity at the 5-HT2A receptors.
39
Data from Phase II and III trials
In Phase II and III trials, aripiprazole exhibited a favorable
safety and tolerability profile. It showed a low propensity
to cause significant adverse effects, such as extrapyramidal
side effects (EPS), weight gain, cardiovascular abnormali-
ties, hyperprolactinemia, hypercholesterolemia, or glucose
dysregulation.
49,69–70
In a meta-analysis assessing safety
and tolerability data from the Phase II and Phase III trials,
1539 patients receiving aripiprazole (n = 926), haloperidol
(n = 200), or placebo (n = 413) were assessed. The reported
incidence of common adverse effects with aripiprazole was
comparable to that of placebo.
71
The most common side
effects reported with aripiprazole (10% incidence) were
headache, insomnia, agitation, and anxiety. Other common
side effects were dyspepsia, nausea and vomiting, lightnead-
edness, somnolence, constipation and akathisia. Discontinu-
ation due to adverse events occurred at an incidence rate of
7% with aripiprazole compared to 8% with haloperidol and
10% with placebo.
71
The most frequent adverse events leading
to discontinuation of aripiprazole included psychosis (3.6%),
agitation (0.6%) and akathisia (0.6%). The incidence rate
of EPS-related adverse events had no significant difference
in between the placebo and aripiprazole treatment groups.
Tardive dyskinesia was only reported by 2 of the aripipra-
zole-treated patients (0.2%).
71
At endpoint, patients showed
minimal mean increase in body weight from baseline (1 kg)
on aripiprazole. In all, 8.1% of patients on aripiprazole
experienced clinically significant weight gain (7% increase
from baseline).
71
Aripiprazole was associated with decreased
in serum prolactin levels. There was no dose-response
relationship between aripiprazole and changes in the QTc
interval.
71
The median increase in fasting total cholesterol
from baseline observed with aripiprazole treatment was low
and did not differ significantly from placebo. Only 5.5%
of patients on aripiprazole had abnormally elevated fasting
glucose levels and only 1.4% of the patients on aripiprazole
had random levels of glucose above 200 mg/dL.
71
There were
no clinically important differences in the adverse event profile
when stratified by age, gender or race in patients receiving
aripiprazole.
71
Metabolic prole
Metabolic syndrome is age dependent and more prevalent
in older adults across cultures.
72
Additional studies, have
validated that aripiprazole has a favorable metabolic safety
profile.
40,73
One study of 31 patients with schizophrenia
showed that there was a significant decrease in body weight,
body mass index, and weight circumference after 3 months
of treatment with aripiprazole. There was also a significant
reduction in fasting glucose, fasting insulin, insulin resistance
index and serum lipid levels.
74
In addition, aripiprazole did
not induce hyperprolactinemia at end point compared with
baseline in a meta-analysis.
60
In one trial, as compared to
olanazpine, aripiprazole was associated with weight loss and
lesser changes in total cholesterol.
75
One retrospective chart review of 52 inpatient geri-
atric patients who received aripiprazole described side
effects attributed to aripiprazole in the charts of 9 (17.3%)
Neuropsychiatric Disease and Treatment 2010:6
54
Kohen et al
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of the patients. Of these 9 patients, 7 had not received
aripiprazole until the current hospitalization. Side effects
were reported in a higher percentage of male than female
patients (25% versus 15%); however, this did not reach
statistical significance. The most commonly reported side
effect was agitation/activation, which was documented in
the charts of 4 patients (8%). Extrapyramidal symptoms
were reported in 2 patients, and single cases of confusion,
fatigue, and lightheadedness were also reported. The mean
dose at which side effects were reported was 11.4 mg/day.
Side effects were the reported reason for aripiprazole
discontinuation in 12% or 6 of the patients.
46
Patient-focused perspectives
Quality of life
Quality of life is important for all individuals, especially
for people with schizophrenia on chronic medications.
However, quality of life can be difcult to dene and
quantify as it relies on individual perception and self-
assessment. Definitions vary from “whatever the individual
denes it to be” to those that emphasize fulfillment of
personal goals.
76
Quality of life in the geriatric population
can be even harder to define as it may depend less on sexual
dysfunction and more on functions of activities of daily
living (eg, bathing, dressing, food preparation). Addition-
ally, studies on quality of life and patient adherence with
aripiprazole (the STAR study) have excluded patients over
65 years of age.
77,78
Data on the impact of aripiprazole therapy on the quality
of life of schizophrenic patients are scarce and character-
ized by conflicting results.
79–81
The only double-blind study
which compared changes in quality of life among patients
on aripiprazole versus perphenazine treatment failed to
demonstrate statistically significant differences between the
groups.
81
A Cochrane systemic review revealed no conclusive
evidence of a clinically important improvement in quality
of life as assessed by the Quality of Life Scale among
154 patients receiving aripaprazole.
82
Patients with schizophrenia often have cognitive deficits
such as decreases in attention, executive function and motor
skills which impede their quality of life.
83
Typical antipsy-
chotics can contribute to such cognitive impairments through
parkinsonism motor impairment or anticholinergic side
effects. As an atypical antipsychotic, aripiprazole has shown
a modest improvement in cognitive function, however such
studies are few in number.
84
On open label study revealed
no improvement in neurocognitive function in patients on
aripiprazole as compared to olanzapine.
85
Patient satisfaction/acceptability
Patients over age 65 are at greater risk of metabolic side
effects of antipsychotics because of their age and presence
of comorbidities. Data on aripiprazole’s impact on metabolic
measures specifically in the geriatric population are not
available. Studies have suggested that aripiprazole has a
lower risk for weight gain than other atypical antipsychotics.
86
A randomized trial of 173 overweight patients of all ages
with schizophrenia or schizoaffective disorder compar-
ing aripiprazole with olanzapine found aripiprazole was
associated with weight loss and less effect in total cholesterol
at 16 weeks.
75
Some findings suggest that older patients
actually gain less weight than their younger counterparts
from second-generation antipsychotics (SGA).
87
Further-
more, patients with Alzheimer’s disease receiving SGAs
may exhibit less weight gain than younger patients without
dementia.
88
Regular physical activity is associated with reduced
incidence of metabolic syndrome from SGA. This is true
for older adults too. Park et al demonstrated that yearlong
exercise of at least 20 minutes daily at 3 or more metabolic
equivalents was associated with reduced incidence of meta-
bolic risk factors.
89
Reductions in body mass index were
strongly associated with favorable changes in risk factors
for metabolic syndrome.
90
While all patients on SGA should
be advised on exercise and diet to minimize the potential
effects of the metabolic syndrome, older patients may have
poor compliance due to physical or financial limitations.
Difficulty obtaining healthier food choices because of cost
or availability and inability to exercise due to physical func-
tional restrictions can make it harder for geriatric patients to
comply with lifestyle changes.
Adherence
Nonadherence with prescribed medication regimens can
result in increased morbidity, mortality, and resource
utilization.
91,92
Schizophrenic patients with poor adherence
with antipsychotic medications have greater symptom
levels,
93
sustained functional impairment,
94
poor community
adjustment,
95
higher risk of relapse,
96
and more rehospital-
ization and emergency room use.
97,98
A 2007 meta-analysis
of hospitalization costs associated with antipsychotic
nonadherence in the treatment of schizophrenia measured
the impact of nonadherence in terms of direct healthcare
costs or inpatient days. The study found poor adherence to
antipsychotic medications was consistently associated with
higher hospitalization costs with a higher risk of relapse and
rehospitalization. However, the studies this article reviewed
Neuropsychiatric Disease and Treatment 2010:6
55
Efcacy and safety of aripiprazole in the elderly
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did not include the newer atypical antipsychotics including
aripirazole, ziprasidone or paliperidone.
99
Discussion
A variety of psychiatric conditions in the elderly can be treated
with antipsychotic medications. Poor adherence to typical
antipsychotics due to adverse reactions led to the newer atypi-
cal antipsychotics. However, the metabolic side effects of the
second generation antipsychotics led to the development of
a newer atypical antipsychotic, aripiprazole.
Older patients often require complex decision-making for
medication management of psychiatric illness because they
frequently have co-morbidity with medical conditions and are
prescribed many other medications. They are at greater risk
of metabolic and other side effects of antipsychotics because
of their age and presence of comorbidities.
In particular, since the FDA black box warning that use
of atypical antipsychotic medications in elderly patients with
dementia nearly doubled the risk of death, clinicians, patients
and caregivers are left with unclear choices for treating people
with dementia with psychosis and/or severe agitation. Such
behaviors are common and can cause considerable caregiver
stress. The alternatives for treatment include no treatment,
use of other psychotropic drugs, and psychotherapeutic and
psychosocial interventions. No treatment may only be viable
in mild cases or if symptoms are not disturbing to the patient
or impairing function. There are limited studies on use of
antidepressants, cholinesterase inhibitors and memantine for
dementia related psychosis which generally were of limited
utility (details are beyond the scope of this paper). There are
limited randomized-control trials on the role of psychosocial
and behavioral treatments for this population; however an
individualized approach to such treatments may be appropri-
ate for some patients.
100
Even though there is no psychotropic
medication that is approved by the FDA for the treatment of
psychosis in AD, a number of consensus statements prior to
2004 recommend the use of atypical antipsychotic agents as
a first-line pharmacologic approach to treatment.
25
Careful
discussion of risks, benefits and alternative treatments should
be conducted by clinicians with patients’ caregivers when
using antipsychotic medications for patients with demen-
tia-related psychosis. Higher symptom burden will likely
contribute to greater acceptance of using antipsychotic in
hopes of improving quality of life.
In addition to its use in dementia, aripiprazole may be
effective for the treatment of a variety of psychiatric condi-
tions in the elderly including psychosis due to schizophrenia,
bipolar disoder, depression, and PD. Although the data on
aripiprazole’s efficacy in the treatment of psychosis in the
geriatric population are very limited, it may have an important
role to play in those conditions. As discussed in detail above,
aripiprazole has a favorable metabolic profile compared
to other second-generation agents in terms of glycemic
control, lipid profiles, prolactin levels and weight gain. When
appropriate, clinicians should weigh the limited evidence of
efficacy in the geriatric population with the potential benefits
of less metabolic complications as its metabolic risk profile
makes aripiprazole an attractive agent in this population.
Additional studies on efficacy of aripiprazole use in the
elderly population are needed, although early studies show
some promise.
Disclosures
The authors have no conflicts of interest to report.
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    • "So far, there has been no convincing evidence for the improved efficacy of high doses, but the risk of extrapyramidal side effects (Pierre, 2005) and hyperprolactinemia (Byerly et al., 2007) was dose related. In recent years, mortality of schizophrenia has shown a decreasing trend following the general improvement of psychiatric and medical care, enabling many patients with schizophrenia to live into older adulthood (Kohen et al., 2010 ). Compared with their younger counterparts , older schizophrenia patients are more likely to have drug-induced side effects and poor general health (Uchida et al., 2009b; Meyers and Jeste, 2010); therefore, treatment guidelines for younger adult patients are not entirely applicable to this population. "
    [Show abstract] [Hide abstract] ABSTRACT: This study aimed to examine the use of high doses of antipsychotic medications (≥600 mg/day chlorpromazine equivalent) in older Asian patients with schizophrenia and its demographic and clinical correlates. Information on hospitalized patients with schizophrenia aged ≥50 years was extracted from the database of the Research on Asian Psychotropic Prescription Patterns study (2001-2009). Data on 2203 patients in six Asian countries and territories, including China, Hong Kong, Japan, Korea, Singapore and Taiwan, were analyzed. Socio-demographic and clinical characteristics and antipsychotic prescriptions were recorded. The frequency for high-dose antipsychotic medications was 36.0% overall, with 38.4% in 2001, 33.3% in 2004 and 36.0% in 2009. Multiple logistic regression analysis of the whole sample showed that compared to patients receiving low-medium antipsychotic doses, those on high doses had a longer illness duration (odds ratio (OR): 2.0, 95% confidence interval (CI):1.2-3.3, p = 0.008), were more likely in the 50-59-year group (OR: 0.95, 95% CI: 0.94-0.97, p < 0.001), more often had current positive (OR: 1.5, 95% CI: 1.2-1.8, p < 0.001) or negative symptoms (OR: 1.3, 95% CI: 1.03-1.6, p = 0.03), and more commonly received antipsychotic polypharmacy (OR: 5.3, 95% CI: 4.1-6.7, p < 0.001). Extrapyramidal symptoms (p = 0.25) and tardive dyskinesia (p = 0.92) were not more frequent in the high-dose group. High doses of antipsychotic medications were used in more than one third of older Asian patients with schizophrenia. The reasons for the frequent use of high antipsychotic doses in older Asian patients warrant further investigation. Copyright © 2013 John Wiley & Sons, Ltd.
    Full-text · Article · Apr 2014
    • "om boarder " delusion. [113,114] A recent study found that 78% of patients with LBD had hallucinations, 56% had misidentifications, and 25% had delusions. [115] Since the psychotic symptoms with LBD occur earlier in the course of the disease and are more frequent than in AD, they tend to cause more caregiver distress at the early stages of illness. [55] Special pharmacologic treatment decisions need to be considered with the psychosis of PDD and LBD. Worsening Parkinsonism with the use of antipsychotics merits careful attention, especially since sensitivity to antipsychotic medications is one of the suggestive diagnostic features of LBD, and dopaminergic blockade can worsen parkinsonia"
    Full-text · Article · Jan 2014
    • "Many patients with schizophrenia live into older adulthood (Kohen et al., 2010). In contrast to younger patients, older patients with schizophrenia are a special population characterized by higher likelihood of drug-induced side effects, poorer general health and the need for lower doses of psychotropic medications (Meyers and Jeste, 2010; Uchida et al., 2009 ). "
    [Show abstract] [Hide abstract] ABSTRACT: Objective: This study examined the prescribing patterns of several first- (FGAs) and second-generation antipsychotic (SGAs) medications administered to older Asian patients with schizophrenia during the period between 2001 and 2009. Method: Information on hospitalized patients with schizophrenia aged 65 or older was extracted from the database of the Research on Asian Psychotropic Prescription Patterns (REAP) study (2001-2009). There were no older patients in Thailand, therefore data on 467 patients in eight Asian countries and territories including China, Hong Kong SAR, India, Japan, Korea, Malaysia, Singapore, and Taiwan were analysed. Cross-sectional socio-demographic data, clinical characteristics and antipsychotic prescriptions were assessed using a standardized protocol and data collection procedure. Results: Of the 467 patients, 192 patients (41.1%) received FGAs only, 166 (35.5%) received SGAs only and 109 (23.3%) received a combination of FGAs and SGAs. Of the FGAs, haloperidol was the most commonly used (31.3%; mean 9.4 ± 6.7 mg/day), followed by chlorpromazine (15.4%; mean 126.4 ± 156.4 mg/day) and sulpiride (6.6%; mean 375.0 ± 287.0 mg/day). Of the SGAs, risperidone was the most commonly used (31.5%; mean 4.5 ± 2.7 mg/day), followed by olanzapine (13.1%; mean 13.6 ± 6.5 mg/day), quetiapine (7.3%; mean 325.0 ± 237.3 mg/day) and aripiprazole (1.9%; mean 17.6 ± 7.7 mg/day). Conclusions: FGAs and higher doses of certain SGAs (risperidone, olanzapine and quetiapine) were still commonly dispensed to older Asian patients with schizophrenia. Considering older patients' reduced tolerability of potentially severe side effects associated with FGAs and higher doses of certain SGAs, continuing education and training addressing the rational use of antipsychotics in this population is clearly needed.
    Full-text · Article · Jul 2012
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