aripiprazole in the treatment of alzheimer's disease

1. Introduction

2. Alzheimer’s disease

3. Aripiprazole

4. Preclinical work

5. Clinical studies

6. Conclusion

7. Expert opinion

Drug Evaluation

Aripiprazole in the treatment ofAlzheimer’s diseasePeter Paul De Deyn†, Annemieke FJ Drenth, Berry P Kremer,Richard C Oude Voshaar & Debby Van Dam†University of Groningen, University Medical Center Groningen, Alzheimer Research Center,

Department of Neurology, 9713 GZ Groningen, The Netherlands

Introduction: Psychosis is a common and difficult to treat symptom in

Alzheimer’s disease (AD). It is a cause of diminished quality of life and care-

giver distress. Atypical antipsychotics are frequently used for the treatment

of dementia-related psychosis, despite FDA warnings because of increased

mortality associated with the use of these medications in dementia patients.

Aripiprazole is a newer atypical antipsychotic drug with partial agonist

activity at dopamine receptors and antagonist activity at 5-HT2A receptors,

with a low side-effect profile.

Areas covered: This descriptive review gives a short overview of the pathology

and epidemiology of AD, including psychotic symptoms, and describes the

mode of action of aripiprazole and results of preclinical studies. Finally,

randomized controlled trials evaluating the use of aripiprazole in AD-related

psychosis and agitation are discussed. Whenever relevant, meta-analytical

data from literature are referred to.

Expert opinion: In randomized placebo-controlled clinical trials, aripiprazole

shows modest efficacy in the treatment of AD-related psychosis. Neuropsychi-

atric symptoms alleviated were predominantly psychotic features and agita-

tion. In individual trials, aripiprazole was generally well tolerated, serious

side effects were seldom reported and included accidental injury and som-

nolence. Meta-analyses however demonstrated increased mortality as a

class effect for atypical, but also for typical antipsychotics. No increased

cardiovascular outcomes, cerebrovascular accidents, increased appetite or

weight gain were demonstrated in meta-analyses for aripiprazole-treated

patients with psychosis of dementia. Aripiprazole was found to induce

sedation. Aripiprazole should only be used in selected patient populations

resistant to non-pharmacological treatment with persisting or severe psy-

chotic symptoms and/or agitation, and in which symptoms lead to significant

morbidity, patient suffering and potential self-harm. The indication for

continuing treatment should be revised regularly.

Keywords: Alzheimer’s disease, aripiprazole, atypical antipsychotics, BPSD, dementia, NPS,

psychosis

Expert Opin. Pharmacother. (2013) 14(4):459-474

1. Introduction

Aripiprazole is an atypical antipsychotic agent with unique receptor and low side-effect profiles that has been licensed by the Food and Drug Administration(FDA) and European Medicines Agency (EMA) to treat schizophrenia in adultsand adolescents [1-3], manic and mixed episodes associated with bipolar I disorderwith or without psychotic features in children, adolescents and adults [4,5], majordepression when used along with antidepressants in adults [6,7] and irritabilityassociated with autistic disorder [8,9]. The relatively safe profile in approved uses

10.1517/14656566.2013.764989 © 2013 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 459All rights reserved: reproduction in whole or in part not permitted

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has led to off-label uses as well, including treatment ofschizophrenia in children, treatment of dementia-relatedpsychosis in geriatric patients and treatment of other behaviorproblems [10,11].Since the discovery of the antipsychotics in the 1950s, first-

generation antipsychotics (e.g., haloperidol and chlorproma-zine) have been the standard for treating psychotic disordersfor many decades. These classical neuroleptics or typical anti-psychotics display a rather narrow spectrum of therapeuticactivity, and are associated with many side effects, includingsedation, anticholinergic effects, extrapyramidal symptoms(EPS), orthostatic hypotension, weight gain, photosensitivityand elevated prolactin levels. They lack the tolerability ofnewer antipsychotics, since they bind to D2 receptorsthroughout the brain as powerful, long-lasting antagonists [12],as well as to a broad range of other receptors, including D1,5-HT2, histamine H1 and a2 adrenergic receptors [13,14].Second-generation antipsychotics (e.g., risperidone, olanza-

pine and quetiapine) or atypical antipsychotics bind better toD2 receptors in brain regions that control psychosis than inregions that cause motor side effects [14-16]. Such differentialbinding is a consequence of reduction of D2-receptor antago-nism where it is not desired, either by simultaneous blockadeof 5-HT2A receptors, or by short-acting blockade at D2

receptors, called hit-and-run antagonism. Therefore, thesesecond-generation antipsychotics have wider applicationsthan just the treatment of the positive symptoms of psychosis,but have also proven efficacy in treating the negativesymptoms of schizophrenia [14-16].Third- or next-generation antipsychotics are often referred

to as dopamine system stabilizers (DSSs) (for reviewsee [17]), since they act as partial D2-receptor agonists, whichhave a lower intrinsic activity at receptors than full agonists,

allowing them to act either as a functional agonist or afunctional antagonist, depending on the surrounding levelsof naturally occurring neurotransmitter (full agonist). DSSsact as functional antagonists with antipsychotic action in themesolimbic dopamine pathway, where excessive dopamineactivity is thought to cause positive symptoms, but show func-tional agonist activity in the mesocortical pathway, wherereduced dopamine activity is thought to be associated withnegative symptoms and cognitive impairment (Figure 1).DSSs do not simultaneously reduce dopamine activity inthose regions where normal dopamine levels are needed(nigrostriatal pathway) and thus do not cause motor sideeffects (Figure 2) [17].

Aripiprazole, 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]-butyloxy}-3,4-dihydro-2(1H)-quinolinone, is the first atypicalantipsychotic that may be classified as a DSS and that ispresumed to be active against both positive and negativesymptoms of schizophrenia, to have a low propensity forextrapyramidal side effects, to cause minimal weight gain orsedation and to produce neither elevation in serum prolactinlevels nor prolongation of QTc interval on electrocardiogram(ECG) (Box 1) [18].

Alzheimer’s disease (AD) affects 5 -- 15% of the populationover 65 years, and about 20% of individuals over 80 years [19].AD is characterized by declining cognitive function, butis also associated with a high prevalence of psychoticsymptoms [19] and behavioral disturbances [20,21].

More than 50% of people with dementia experience neuro-psychiatric symptoms (NPS). NPS are distressing for both thepatients [22] and their caregivers [23] and are frequently thetrigger for admission to residential or nursing homes [24].

Antipsychotic medication is the most studied treatment ofpsychosis, aggression and agitation in elderly patients with

Box 1. Drug summary.

Drug name AripiprazolePhase IIIIndication Bipolar I disorder, schizophrenia, major depressive disorder, irritability associated

with autistic disorderPharmacology description Aripiprazole functions as a partial agonist at the dopamine D2 and the serotonin

5-HT1A receptors, and as an antagonist at serotonin 5-HT2A receptorsRoute of administration Oral or parenteral

Chemical structure C23H27Cl2N3O2

O ONH

N

N

Cl

Cl

Pivotal trial(s) This article focuses on the off-label use of aripiprazole in Alzheimer’s disease.The following references represent pivotal trials in this regard:[109,114,119,121]

Pharmaprojects -- copyright to Citeline Drug Intelligence (an Informa business). Readers are referred to Pipeline (http://informa-pipeline.citeline.com) and

Citeline (http://informa.citeline.com).

P. P. De Deyn et al.

460 Expert Opin. Pharmacother. (2013) 14(4)

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http://informa-pipeline.citeline.com

http://informa.citeline.com

dementia [25,26]. Safety and tolerability is a key aspect in thetreatment of elderly due to their increased sensitivity toadverse events (AEs), making atypical antipsychotics a moreattractive option than typical antipsychotics [25]. Movementdisorders, sedation and orthostasis can all lead to an increasedrisk of falls and associated events such as fractures, whereasanticholinergic events may prove problematic in the elderlyand require additional treatment.

After warnings of increased risks of cerebrovascular events(with risperidone, olanzapine and aripiprazole) [27], the FDAissued an advisory warning in 2005 that atypical antipsychotics

were associated with a 60 -- 70% increased risk of death com-pared with placebo in randomized controlled trials (RCTs)among older patients with dementia, and black box warningswere added to the labels of all atypical drugs [28]. Subsequentstudies found risks at least as high among users of typicalantipsychotics [29-31], and the FDA issued a similar warningfor these drugs in 2008 [32].

These reports have resulted in a rather negative view on theadministration of antipsychotics in patients with dementia.Both experts and relatives of patients see this as bad medicalpractice or suboptimal care. In many cases however,

Mesocortical pathway hypoactivity:

Tuberoinfundibular pathway(inhibits prolactin release)

- Negative symptoms- Cognitive impairment

Mesolimbic pathway hyperactivity:

Nigrostriatal pathway(part of extrapyramidal system)

Positive symptoms

Figure 1. The neuroanatomy of the dopaminergic pathways in the brain can explain the symptoms of schizophrenia and the

therapeutic affects and side effects of antipsychotics. The nigrostriatal pathway projects from the substantia nigra to the

basal ganglia or striatum and is part of the extrapyramidal nervous system thereby controlling motor function and

movement. The mesolimic pathway projects from the ventral tegmental area to the limbic system (nucleus accumbens). The

mesocortical pathway also originates in the ventral tegmental area but projects to the dorsolateral and ventromedial

prefrontal. The tuberoinfundibular pathway projects from the hypothalamus to the anterior pituitary gland, thereby

controlling prolactin secretion.

Full agonistdopamine

Full receptor activityD2 receptor

No receptor activity

Partial receptor activity

Antagoniste.g., haloperidol

Partial antagoniste.g., aripiprazole

Figure 2. Schematic representation of intrinsic activity at dopamine D2 receptors, which describes the ability of a compound

to stimulate receptors. Full antagonists are able to elicit a maximal response following receptor occupation and activation.

Partial agonists can activate receptors but are unable to elicit the maximal response of the receptor system. Antagonists will

not cause activation on receptor occupation.

Aripiprazole

Expert Opin. Pharmacother. (2013) 14(4) 461

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prescribing antipsychotics cannot be avoided because ofthe severity of the NPS and lack of effective treatmentalternatives [33].Up to one-third of all elderly patients in nursing homes are

treated with antipsychotic drugs in North America [34-38]

and despite the regulatory warnings, the prescription rate ofantipsychotics among elderly patients has not decreased [39].This review will discuss the psychotic problems related to

AD, the pharmacological properties and clinical effects ofaripiprazole and will review the efficacy and safety of thisdrug in AD-related psychotic symptoms.

2. Alzheimer’s disease

2.1 Epidemiology, diagnosis and pathologyAD is the most common form of dementia. In the Diagnosticand Statistical Manual for Mental Disorders IV (DSM-IV),dementia is defined as a clinical syndrome characterized by agradual loss of function in multiple cognitive domains leadingto a significant impairment in social and occupationalfunctioning [40]. Age is a major risk factor for dementia, theprevalence of dementia approximately doubles every 5 yearsover the age of 65 [41]. With the increase in life expectancy,the incidence of dementia is expected to rise accordingly.Wimo et al. estimated that by the year 2030, 63 millionpeople worldwide will be living with dementia [42].For clinical and research purposes, the diagnosis of AD is

commonly based on these DSM-IV criteria combined withthe criteria defined by the National Institute of NeurologicalDisorders and Stroke-Alzheimer Disease and RelatedDisorders (NINCDS-ADRA) working group [43]. Thesecriteria include insidious onset and progressive impairmentof memory and other cognitive functions. Motor, sensoryor coordination deficits should not be present early in thedisease. With these criteria, the diagnoses of possible andprobable AD can be made, while for a definite diagnosis ofAD histopathological evidence is required. Revision of thesecriteria has recently been proposed to include supportivefeatures consisting of several biomarkers, which have beendeveloped since the implementation of the NINCDS-ADRAcriteria [44]. These include magnetic resonance imaging(MRI), positron emission tomography (PET) scanning,cerebrospinal fluid biomarkers and genetic mutations [45].The histopathological hallmarks of AD are extracellular

deposits of Ab-peptides in amyloid plaques and intracellularneurofibrillary tangles (NFTs), which result from aggregationof axonal tau proteins, leading to a widespread synaptic lossand neurodegeneration [46,47]. MRI examination allows themeasurement of medial temporal lobe atrophy [48]. UsingPET scanning, reduced glucose metabolism bilaterally in thetemporal parietal regions can be found in AD patients [49,50].Cerebrospinal fluid examination can show low Ab-levels andincreased total tau concentrations [51,52]. Autosomal dominantmutations that cause AD have been identified on chromo-somes 21 (amyloid precursor protein), 14 (presenilin 1) and

1 (presenilin 2) [53]. In contrast to the original NINCDS-ADRA criteria, the revision of these criteria states that thediagnosis of definite AD can also be made in patients withclinical signs of AD and one of these mutations [44].

2.2 Neuropsychiatric symptoms in ADNPS, previously referred to as behavioral and psychologicalsigns and symptoms of dementia (BPSD), frequently developin the course of AD. NPS occur in 50 -- 80% of patients withdementia [54]. They are associated with a negative effect oncognitive impairment and quality of life, are often a greatcause of caregiver distress and are a predictor of institutio-nalization [55,56]. In AD, NPS can be categorized in four sub-syndromes: i) hyperactive behaviors (agitation, euphoria,disinhibition, irritability and some types of aberrant motorbehavior), ii) psychosis (delusions, hallucinations, nighttimedisturbances and some types of aberrant motor behavior),iii) affective behaviors (depression and anxiety) andiv) apathy (plus eating abnormalities and some types of aber-rant motor behavior) [57,58]. With the exception of psychosisand depression of AD, there are few diagnostic criteria forNPS in dementia [59]. The type of NPS in AD patients canevolve over the course of the disease, with some symptomscommonly occurring earlier in the disease, such as depression,and some symptoms typically occurring in more advancedstages of AD, such as aggression and hallucinations(Figure 3) [60]. Apathy is the most common and persistentNPS in AD [61]. It is defined as diminished motivation forat least 4 weeks, accompanied by any two of the following:reduced goal-directed behavior, reduced goal-directed cogni-tive activity and reduced emotions [62]. Depression has ahigh prevalence in AD patients of up to 50%. There isconsiderable overlap between AD-related depression andapathy and late-life depression, which complicates diag-nosis [63]. Sleep disorders are also common in AD. Theyhave a negative impact on cognition and contribute to socialisolation [64,65]. Agitation and aggression are disturbingsymptoms that occur in approximately 20% of patientswith dementia living at home and in nearly 50% ofinstitutionalized patients [59].

2.3 Psychosis in ADPsychosis is reported in 30 -- 50% of AD patients. Symptomsof AD psychosis are delusions, hallucinations and misidentifi-cations [66,67]. Delusions are the most common sign presentin 36% of AD patients, while hallucinations are reported in18% [68]. In contrast to schizophrenia where delusions are fre-quently bizarre or complex, the delusions in AD are typicallyparanoid, non-bizarre and simple [66]. Typical delusions caninclude beliefs that others are stealing things, that patientsthemselves are in danger, that the caregiver is an imposter,that the spouse is having an affair, that the patient’s house isnot his/her home, that family members are planning to aban-don the patient as well as other emotionally negative delusionsof suspiciousness and paranoia [67]. Psychotic symptoms have



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been found to persist over months, but are unusual to persistover years. Psychosis is associated with a faster rate of cogni-tive decline [68]. Criteria for psychosis of AD were proposedby Jeste and Finkel and include: characteristic delusions orhallucinations in the presence of possible or probable AD;onset of the psychotic signs after onset of other dementiasymptoms; psychotic symptoms present intermittently for atleast 1 month; symptoms severe enough to cause disruptionof patients’ or others’ functioning; symptoms not occurringonly during a delirium and symptoms not better accountedfor by another psychotic disorder, medical condition ordrug [66].

Non-pharmacological treatment of psychosis and otherNPS may include environmental modifications, such asmusic, white noise, animals and plants; behavioral manage-ment techniques; structured activities and recognizableschedules; massage and exercise [69,70]. However, in severe orpersistent psychosis the need arises for pharmacological treat-ment using antipsychotics. Atypical antipsychotics are usedwidely in older patients with dementia, because of theirlower susceptibility to motor side effects compared withtypical antipsychotics, such as haloperidol [66]. The use ofatypical antipsychotics became even more controversialfollowing the aforementioned FDA black box warnings in2005 after reports of a 60 -- 70% increased risk of deathassociated with the use of atypical antipsychotics comparedwith placebo in older patients with dementia. Recently,Huybrechts et al. investigated whether the risk of overall andcause-specific mortality is equal across antipsychotic drugs orwhether there are regimens with safety advantages that shouldbe prescribed preferentially in older nursing homes residents.They compared the mortality for the different antipsychotic

drugs with the most commonly used drug, risperidone, in75,445 older nursing home residents using antipsychotics,and found that haloperidol users had a doubled risk of mor-tality (hazard ratio (HR) adjusted for propensity score = 2.05,95% confidence interval (CI) 1.89 -- 2.26). Aripiprazole wasnot associated with increased risk of non-cancer mortality(HR = 0.88, 95% CI 0.73 -- 1.07), and even with a lowerhazard rate for cerebrovascular disease (HR = 0.31, 95% CI0.13 -- 0.76). Quetiapine was associated with a decreasedrisk of mortality (HR = 0.81, 95% CI 0.75 -- 0.88) [71].This study is consistent with other reports that describea greater risk of death with conventional versus atypicalantipsychotics in older patients [72].

3. Aripiprazole

3.1 Mode of actionAripiprazole is a quinolinone derivative introduced as the firstDSS, with potent partial agonist activity at dopamine D2

and 5-HT1A receptors and antagonist activity at 5-HT2A

receptors [73-76]. Among the atypical antipsychotics, aripipra-zole displays the lowest affinity for a1 adrenergic, histamineH1 and muscarinic M1 receptors [77]. This profile may bethe reason for the low rates of reported side effects, includinggeneral AEs, a low incidence of reported weight gain and alow liability for inducing movement disorders. The mostfrequently reported AEs and side effects of aripiprazole treat-ment include akathisia, increased risk of stroke, orthostatichypotension, tachycardia, decreased seizure threshold,tardive dyskinesia, tremor, lethargy, sedation and gastroin-testinal disturbances. Aripiprazole may induce reductions ofplasma prolactin, as well as of plasma glucose and lipid

0-40 -30

Socialwithdrawal

Depression

Diurnal rhythmdisturbances

ParanoiaAnxiety

Mood change

Irritability

WanderingAggression

Hallucinations

Socially unacceptablebehaviour

Sexually inappropriatebehaviour

Agitation

Diagnosis

Delusions

Suicidalideation

-20 -10 0

Time (months)

+10

Pat

ien

ts (

%)

+20 +30

20

40

60

80

100

Figure 3. The frequency of neuropsychiatric symptoms (NPS) in autopsy-confirmed Alzheimer’s disease patients (n = 100) is

represented in time and in relation to diagnosis. In contrast to cognitive problems, NPS do not follow a progressive course.

The type of symptoms present in patients can evolve over the course of the disease, with some symptoms commonly occurring

earlier in the disease, and some symptoms typically occurring in more advanced disease stages.Based on [60]. Permission obtained from Wiley.

Aripiprazole


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concentrations, and may lead to reductions in corrected QTinterval. It has minimal drug interactions [78].

3.2 Dosing and formulationsAripiprazole displays linear kinetics and has an eliminationhalf-life of approximately 75 h after oral administration.Steady-state plasma concentrations are achieved in about14 days. Cmax (maximum plasma concentration) is achieved3 -- 5 h after oral dosing. Bioavailability of the oral tablets isabout 90% and the drug undergoes extensive hepatic meta-bolization (dehydrogenation, hydroxylation and N-dealkyla-tion), principally by the enzymes CYP2D6 and CYP3A4. Itsonly known active metabolite is dehydro-aripiprazole, whichtypically accumulates to approximately 40% of the aripipra-zole concentration. The parenteral drug is excreted only intraces, and its metabolites, active or not, are excreted viafeces and urine. When dosed daily, brain concentrations ofaripiprazole will increase for a period of 10 -- 14 days, beforereaching stable, constant levels [79]. A strong correlation existsbetween aripiprazole dose and plasma concentration. PETanalyses suggest that there are significant relationshipsbetween dopamine-receptor occupancy and both aripiprazoledose and blood concentration. Dopamine-receptor occupancyappears to plateau at doses above 10 mg, supporting theobservation found in dose--response studies that 10 mg/dayis the optimal dose for aripiprazole [80].

4. Preclinical work

Much preclinical work has focused on the presumed reducedside effects of aripiprazole versus second-generation antipsy-chotics [81-90]. Though aripiprazole has not been evaluated inestablished animal models for AD, several preclinical studiesunderpin the presumed efficacy of aripiprazole with regardto NPS-related behavioral changes, as well as cognitive deficitsin laboratory animals.

4.1 NPS-related behavioral changes4.1.1 Psychostimulant-induced behavioral

sensitizationPsychostimulant-induced behavioral sensitization has beenwidely and successfully used as an animal model ofstimulant-induced psychosis and schizophrenia and mayinclude motor stereotypy or perseverative behaviors, ambu-latory hyperlocomotion, reduced prepulse inhibition (PPI)and disrupted latent inhibition, indicating disrupted sensorydiscrimination [81]. Aripiprazole has been shown to signifi-cantly reduce psychostimulant-induced behavioral sensiti-zation in various rodent strains. Aripiprazole reducedpsychostimulant-induced hyperlocomotion in ddY outbredmice (0.3 and 1 mg/kg, p.o.) [82], Swiss mice (0.3, 1 or10 mg/kg i.p.) [83], ICR mice (3 -- 20 mg/kg s.c. [84];0.1 -- 1 mg/kg p.o. [85]) and in adult Sprague-Dawley rats(3, 10 or 30 mg/kg, i.p. [86]; 1.25 -- 10 mg/kg i.p. [87]). Ari-piprazole (0.1 -- 1 mg/kg i.p.) caused a dose-dependent

antagonism of psychostimulant-induced stereotypies (sniffing--licking--gnawing syndrome) and climbing behavior inCF-1 mice [88]. Aripiprazole has also been shown to dose-dependently reverse psychostimulant-induced disruption ofPPI in rats (1, 3, 10 and 30 mg/kg p.o.) [89] (3, 10 and30 mg/kg i.p.) [90].

4.1.2 Conditioned aversionThe conditioned avoidance test is a standard screening modelfor antipsychotic efficacy that may be performed in a two-way shuttle box or in a Skinner box. In both paradigms, theanimal learns to avoid a negative reinforcing foot shock [91].Aripiprazole was shown to dose-dependently reduce a condi-tioned aversion response in Sprague-Dawley rats (3, 10 or30 mg/kg s.c. [86]; 1, 3 or 10 mg/kg i.p. or 10 mg/kgp.o. [88]) and ICR mice (3 -- 20 mg/kg s.c.) [84]. However,aripiprazole (10 mg/kg, i.p.) failed to affect conditionedfreezing behavior related to foot shock exposure in rats [92].

4.1.3 Depression-related symptomsAripiprazole had proven efficacious in reverting depression-like behavioral alterations in rodents employing test para-digms assessing emotional despair (forced swim and tailsuspension tests) [93] and anhedonia (sucrose preferencetest) [94]. Nevertheless, several other studies failed to showantidepressive treatment effects [95-97].

4.1.4 AnxietyA myriad of behavioral paradigms are available to assessanxiety in rodents, including for example, the elevated plus-maze, open-field, contextual fear conditioning, approach-avoidance and marble-burying behavior. Anxiolytic efficacyof aripiprazole was indicated by several rodent studies [95,98],while other researchers did not observe significant treat-ment effects [99]. Interestingly, inhibition of marble-buryingbehavior is considered a correlational model for detection ofanxiolytics [100] and has also been suggested as a model ofobsessive-compulsive disorder [101]. Both anxiolytic and anti-compulsive activity [102], as well as lack of such treatmenteffects were suggested [99].

4.1.5 Other behavioral alterationsAripiprazole significantly counteracted N-methyl D-aspartate(NMDA)-receptor antagonist-induced increased sleeplatency [103]. With regards to antiepileptic activity, both seizure-attenuating effects [93], as well as lack of such treatment effectswere reported [104].

4.2 Learning and memoryBesides treatment of NPS-related symptoms, cognition-enhancing effects of aripiprazole were scrutinized in variousrodent models with variable success. While some studiesobserved improved spatial learning abilities [95,93], otherstudies failed to show significant treatment effects [105].Similar observations were made using non-spatial learning



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paradigms; while aripiprazole reversed learning deficits insome trials [85,106,107], it failed to do so in another study [108].

5. Clinical studies

5.1 Aripiprazole for the treatment of psychotic

symptoms in AD5.1.1 Efficacy of aripiprazole for psychotic symptoms

in AD: data form clinical trialsFour trials have evaluated the efficacy and tolerability of aripi-prazole compared with placebo for the treatment of psychosisin patients with AD (Table 1).

De Deyn et al. [109] evaluated the use of aripiprazole (aver-age daily dose 10 mg) in a 10-week double-blind, multicenterstudy in non-institutionalized AD patients with symptoms ofdelusions or hallucination present for 1 month or longer [66].Patients had to have a Mini-Mental State Examination(MMSE) [110] score of 6 -- 24, and a score of ‡ 6 on the delu-sion or hallucination items of the Neuropsychiatric Inventory(NPI) [111] assessment at baseline. After a minimum 7-daywashout period for previous psychotropic medication,patients were randomized to aripiprazole 2 mg/day or pla-cebo, administered once daily for 10 weeks. Aripiprazolecould be titrated to higher doses (5, 10, 15 mg/day) at2-week intervals if there was insufficient clinical response totreatment. Reductions from higher doses were permitted incase of tolerability problems. Use of the following medica-tions was prohibited during the treatment period: carbamaze-pine, valproate, lithium, sleeping agents (except zolpidem)and benzodiazepines (except lorazepam £ 4 mg). The primaryefficacy parameter was the mean change from baseline to endof study in the caregiver-assessed NPI psychosis subscalescore. Secondary efficacy parameters included change frombaseline in NPI total, Brief Psychiatric Rating Scale(BPRS) [112], Clinical Global Impression Severity of Illness(CGI-S) [113] and MMSE scores [110]; the psychosis responserate defined as a ‡ 50% decrease in NPI psychosis scorefrom baseline and mean CGI improvements (CGI-I).

In total, 208 patients were randomized to aripiprazole(n = 106) or placebo (n = 102). Patients in both groups showedimprovement in the primary outcome measure NPI psychosisscore, although the difference did not reach statistical signifi-cance (p = 0.169). For patients with baseline NPI psychosisscores of ‡ 12 (i.e., more severely ill), post hoc analyses showedsignificantly greater improvements from baseline in CGI-Sscores (p = 0.015) and CGI-I responder rates (p = 0.035) witharipiprazole than with placebo. Of the secondary outcomemeasures, significantly greater improvements from baselinewith treatment of aripiprazole versus placebo were found inBPRS psychosis (p = 0.029) and BPRS core scores(p = 0.042). The authors concluded that aripiprazole offersonly modest benefits over placebo for treating psychosis in AD.

In a double-blind multicenter study, Mintzer et al. [114]

randomized institutionalized patients with AD and psychoticsymptoms to placebo or aripiprazole 2, 5 or 10 mg/day.

Patients had to have a MMSE score of 6 -- 22 points, andintermittent delusions, hallucinations or both for at least1 month. Patients were randomized to fixed doses of aripi-prazole (2, 5 or 10 mg/day) or placebo for a 10-week period.No dose modification was allowed for tolerability reasonsafter titration during the acute phase. Patients not respondingto treatment by week 6 were permitted to discontinue blindedtherapy and start open-label treatment with aripiprazole. Thedata of open-label treatment were not included in the study.Primary end point was the mean change from baseline inthe Neuropsychiatric Inventory-Nursing Home (NPI-NH)psychosis subscale [115] score to end of study. Secondary effi-cacy measures included the mean change from baseline inthe NPI-NH total score, CGI-S score, BPRS psychosis sub-scale [112], core and total scores, Cohen-Mansfield AgitationInventory (CMAI) total scores [116-118], MMSE scores andthe mean CGI-I score. Response rates were defined asa ‡ 50% decrease from baseline in the NPI-NH psychosisand total scores.

A total of 487 patients were randomized to aripiprazole2 mg/day (n = 118), 5 mg/day (n = 122), 10 mg/day(n = 126) or placebo (n = 121). Patients in the aripiprazole10 mg/day group showed a statistically significant greaterimprovement in NPI-NH psychosis subscale scores(p = 0.013). Aripiprazole 2 and 5 mg/day did not show asignificant difference versus placebo. Analysis of individualitem scores from the NPI-NH scale was described as well.This analysis showed significantly greater improvements atend point with aripiprazole 10 mg in the delusion, agita-tion/aggression, anxiety and irritability items. Statisticallysignificant improvements in BPRS core score were observedat end point for all three aripiprazole groups compared withthe placebo group. Patients in the 10 mg/day aripiprazolegroup showed significantly greater decreases in BPRS totalscore compared with placebo, while the aripiprazole 2 and5 mg/day groups did not. Significant improvement was foundin the CMAI scores in the aripiprazole 5 and 10 mg/daygroup, while not in the 2 mg/day group. The mean changein CGI-S score was also significant in the 10 mg/day group.Mean CGI-I scores did not differ significantly between theplacebo and aripiprazole groups. The authors concluded thataripiprazole showed efficacy in treating both psychotic symp-toms and other psychological and behavioral symptoms inpatients with AD. The most effective dose was 10 mg/day,although some patients could achieve sufficient symptomcontrol with a dose of 5 mg/day.

Streim et al. [119] included 256 institutionalized AD patientsin a multicenter, placebo-controlled trial. Patients were ran-domized to aripiprazole or placebo and treated for 10 weeks.Aripiprazole dosing was flexible, starting at 2 mg/day, withtitration to higher doses (5, 10 or 15 mg/day) in case ofinsufficient clinical response to treatment. Decreases fromhigher doses were allowed. Patients who were not respondingby week 6 were given the option of discontinuing double-blind therapy. Two co-primary measures were used to evaluate

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treatment effects: the mean change on NPI-NH psychosis sub-scale and CGI-S scores from baseline to end of study. Second-ary efficacy measures were mean change from baseline in thescores for the NPI-NH total scale, BPRS, CMAI, Cornell Scalefor Depression in Dementia [120], NPI-NH psychosis and totalcaregiver distress scores and Alzheimer’s Disease CooperativeStudy Activities of Daily Living (ADCS-ADL-SEV) total score,NPI-NH total and psychosis response rates.Of the total of 256 patients, 125 were randomized to

placebo and 131 to aripiprazole. The mean daily dose ofaripiprazole at week 10 was 9.0 mg. Psychotic symptomsimproved from baseline in both treatment groups. MeanNPI-NH psychosis subscale scores and CGI-S scoresimproved similarly from baseline with no significant differ-ence. In a post hoc analysis of CGI-S data stratified by baselinescores, aripiprazole produced significantly greater meanimprovements in CGI-S scores at end point in the moreseverely ill subjects (baseline CGI-S = 5 -- 7) versus placebo(p = 0.04). Results from the secondary efficacy measuresshowed significant improvement of the NPI-NH total(p = 0.009), BPRS total (p= 0.031), CMAI (p = 0.030),Cornell Depression scale (p = 0.006) and NPI-NH total care-giver distress scale (p = 0.003). Furthermore, according to the

NPI-NH total response rate, a greater percentage ofsubjects were responders with aripiprazole versus placebo(p = 0.006). The CGI-I score was statistically better in thearipiprazole than in the placebo arm further indicating clinicalsignificance of effects. The authors concluded that aripi-prazole 10 mg/day may be an efficacious dose for treatingpsychological and behavioral symptoms (greater improve-ments for aripiprazole vs placebo in symptoms of agitationor aggression, depression, anxiety, elation and euphoria,disinhibition and irritability) in this population.

Rappaport et al. [121] evaluated the tolerability of intramus-cular aripiprazole in acutely agitated patients with dementia ina double-blind placebo-controlled multicenter study. Institu-tionalized patients with AD, vascular or mixed dementiawho manifested moderate to severe acute exacerbations ofagitated behavior defined as Positive and Negative SyndromeScale (PANSS) Excited Component (PEC) score [122] ‡ 15and £ 32 were included. Efficacy analyses were performedfor the PEC, Agitation Calmness Evaluation Scale (ACES),CGI-S and CGI-I rating scales.

A total of 129 patients were enrolled in 3 sequentialcohorts, each beginning with 15 patients, and randomized(4:1) to treatment with an injection of i.m. aripiprazole or

Table 1. Efficacy of aripiprazole for psychotic symptoms in AD.

Study and

sample size

Symptoms/patient

population

Intervention Efficacy assessment Outcome

De Deyn et al.2005 (n = 206)

Psychosis of ADNPS > 1 month

Aripiprazole 2 mg,titrated upward ifnecessary(5, 10, 15 mg/day)

NPI psychosis, NPI total,BPRS psychosis, BPRS core,BPRS total, CGI-S, CGI-I,MMSE

Improvement BPRSpsychosis (p = 0.029);BPRS core (p = 0.042);decrease MMSE (p = 0.001)

Mintzer et al.2007 (n = 487)


Aripiprazolefixed dose2, 5, 10 mg/day

NPI-NH psychosis, NPI-NHtotal, CGI-S, BPRS psychosis,BPRS core,BPRS total, CMAI, MMSE

Aripiprazole 10 mgimprovement NPI NH(p = 0.013); CGI-S(p = 0,031); BPRS total(p = 0.030); BPRS core(p = 0.007); CMAI(p = 0.023); NPI-NHpsychosis (p = 0.019).Aripiprazole 5 mg:improvement BPRS; CMAI

Streim et al.2008 (n = 256)


Aripiprazole 2 mg,titrated upward ifnecessary(5, 10, 15 mg/day)

NPI-NH psychosis, CGI-S,NPI-NH total, BPRS total,BPRS psychosis, BPRS core,CMAI, Cornell depressionscale, NPI-NH total caregiverdistress, NPI-NH psychosiscaregiver distressADCS-ADL-SEV, MMSE

Improvement NPI-NH totalscale (p = 0.009); BPRStotal (p = 0.031); CMAI(p = 0.030); Cornelldepression scale (p = 0.006);NPI-NH total caregiverdistress (p = 0.003); NPI-NHpsychosis caregiver distress(p = 0.246)

Rappaport et al.2009 (n = 150)

Acute agitation in AD,vascular dementia andmixed dementia

Aripiprazole i.m.2 injections(5, 10, 15 mg)

PEC, ACES, CGI-S, CGI-I Aripiprazole 10 and 15 mgimprovement PEC

ACES: Agitation Calmness Evaluation Scale; AD: Alzheimer’s disease; ADCS-ADL-SEV: Alzheimer’s Disease Cooperative Study Activities of Daily Living; BPRS: Brief

Psychiatric Rating Scale; CGI-I: Mean CGI Improvement; CGI-S: Clinical Global Impression Severity of Illness; CMAI: Cohen-Mansfield Agitation Inventory;

MMSE: Mini-Mental State Examination; NPI: Neuropsychiatric Inventory; NPI-NH: NPI nursing home; NPS: neuropsychiatric symptoms; PEC: Positive and negative

syndrome scale (PANSS) Excited Component.



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i.m. placebo, followed by a second injection 2 h later. Patientswere clinically observed over 24 h. Patients were randomizedto two injections of aripiprazole 2 mg (n = 12), two injectionsof aripiprazole 5 mg (n = 78) or to a first injection of aripi-prazole 10 mg and a second injection of aripiprazole 5 mg(n = 13), or placebo (n = 26).

In general, improvements on the PEC, CGI-I, CGI-S andACES rating scales were greater with i.m. aripiprazole versusi.m. placebo. This suggests potential efficacy of i.m. aripiprazole10 and 15 mg in this target population.

In a recent meta-analysis of efficacy and safety of atypicalantipsychotic medications for off-label uses in adults,Maher et al. reported small but statistically significant benefitsfor aripiprazole, olanzapine and risperidone for global beha-vioral symptom scores associated with dementia in elderlypatients. For aripiprazole, the effect size was 0.20 (95% CI0.04 -- 0.35). For the outcome of psychosis, the pooled effectsize was 0.20 (95% CI -0.02 -- 0.42) for aripiprazole (threefirst trials described above) [123]. Aripiprazole was also shownto have a statistically significant improvement in agitation.The authors further argued that the observed effects on NPIwere clinically relevant.

5.1.2 Safety of aripiprazole for psychotic symptoms in

AD: data from clinical trialsIn the study of De Deyn et al. [109], safety assessmentsincluded AE reports, EPS rating scale [113,124,125], 12-leadECGs, vital signs and body weight measurements (Table 2).

The most common AEs (‡ 5% in either group) reportedduring the study (aripiprazole vs placebo) were accidentalinjury (8 vs 5%) and somnolence (8 vs 1%). Somnolencewas not associated with falls or accidental injury. Onlythree falls (aripiprazole n = 2, placebo n = 1) were consideredpossibly attributable to study medication. Mild transientcerebral ischemias were reported for one patient in eachgroup. Neither event was considered treatment relatedor led to discontinuation. In all, 17 patients discontinuedtreatment due to AEs (placebo n = 7; aripiprazole n = 10).Four deaths, all in the aripiprazole groups, were reported.None of the deaths were considered related to study medi-cation as judged by the participating clinicians. SeriousAEs were reported in 25 patients (12%). Most commonwas accidental injury (placebo n = 2, aripiprazole n = 5).Two of the serious AEs were considered possibly relatedto study medication, namely bradycardia and increasedsalivation. Mean changes in EPS rating scale scores frombaseline were small and similar in the two groups. Smallmean changes in body weight were observed with aripi-prazole and placebo (+0.17 vs -0.33 kg; p = 0.321). Twopatients in the aripiprazole group and one in the placebogroup had potentially clinically significant increases inQTc interval. Furthermore, the MMSE scores showed astatistically significant difference in minimal mean changesfrom baseline in the aripiprazole (-0.81) and placebo(+0.53) groups.T

able

2.Safety

ofaripiprazo

leforpsych

oticsymptomsin

AD.

Studyand

sample

size

AEassessment

CommonAEs

SeriousAEs

Deaths

CVAEs

EPS

Increased

QTcinterval

DeDeyn

etal.

2005(n

=206)

AEreports,12-lead

ECG,vitalsigns,

SAS,AIM

S,BARS

Accidentalinjury,

somnolence

Aripiprazole

12%

:accidental

injury

(n=2);bradycardia

(n=1);increasedsalivation

(n=1);psychosis(n

=1)

Aripiprazole

n=4;

placebon=0

Aripiprazole

n=1;

placebon=1

Low,nosignificant

difference

inEPS

Aripiprazole

n=2;placebo

n=1

Mintzeretal.

2007(n

=487)

AEreports,12-lead

ECG,vitalsigns,

SAS,AIM

S,BARS

Accidentalinjury,

somnolence,

asthenia

Placebo8%

,aripiprazole

2mg/day10%

,aripiprazole

5mg/day10%

,aripiprazole

10mg/day15%

Aripiprazole

2mgn=4;

aripiprazole

5mgn=3;

aripiprazole

10mgn=8;

placebon=3

Aripiprazole

n=7;

placebon=0

Low,nosignificant

difference

inEPS

Aripiprazole

2mgn=1;

aripiprazole

5mgn=1;

placebon=1

Streim

etal.

2008(n

=256)

AEreports,12-lead

ECG,vitalsigns,

SAS,AIM

S,BARS

Accidentalinjury,

somnolence

Aripiprazole

n=33;placebo

n=17;accidentalinjury

Aripiprazole

n=3,

placebon=3

Aripiprazole

n=0;

placebon=1

Low,nosignificant

difference

inEPS

Aripiprazole

n=2;placebo

n=1

Rappaport

etal.

2009(n

=150)

AEreports,12-lead

ECG,vitalsigns,

SAS,AIM

S,BARS

Somnolence

-Aripiprazole

n=1

(+24days)

Aripiprazole

n=1(+16days)

--

AD:Alzheim

er’sdisease;AE:AdverseEffects;

AIM

S:Abnorm

alInvoluntary

MovementScale;BARS:BarnesAkathisia

RatingScale;CVAE:Cerebrovascularadverseevent;ECG:Electrocardiogram;EPS:Extrapyramidal

symptoms;

SAS:Sim

pson-AngusScale.

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In the study of Mintzer et al. [114] (Table 2), safety assess-ment measures included medical review of AE reports, physi-cal examination, vital sign measurements, standard clinicallaboratory tests and 12-lead ECGs. EPS were rated usingthe Simpson-Angus Scale (SAS), the Abnormal InvoluntaryMovement Scale (AIMS) and the Barnes Akathisia RatingScale (BARS). AEs were reviewed for potential cerebrovascu-lar adverse events (CVAEs). The AE most frequently leadingto discontinuation in the aripiprazole group was asthenia(4%). The incidence of serious AEs across all treatmentgroups was: placebo 8%, aripiprazole 2 mg/day 10%, aripi-prazole 5 mg/day 10%, aripiprazole 10 mg/day 15%. Eigh-teen deaths occurred during the study (placebo 3 (3%),aripiprazole 2 mg: 4 (3%), aripiprazole 5 mg: 3 (2%), aripi-prazole 10 mg: 8 (7%)). None were considered related tostudy medication as judged by the participating clinicians.There was no significant difference in death rate betweengroups despite the apparent differences in magnitude of thenumber of deaths in the aripiprazole groups (n = 15) versusthe placebo group (n = 3). Expressed as percentages, mortalityrates were 3% in the placebo group, 3% in the 2 mg aripipra-zole group, 2% in the 5 mg aripiprazole group and 7% in the10 mg aripiprazole group. The lack of statistically significantdifference may be due to a Type II error as the effect appearedto be dose-dependent. CVAEs were reported for sevenaripiprazole-treated patients (2%) during the study period,compared with none (0%) in the placebo group. All CVAEsoccurred in subjects with prior history of cerebrovascular acci-dent (CVA), stroke or related risk factors. The incidence ofEPS-related AEs was low and similar across all treatmentgroups. One patient in each of the placebo, aripiprazole2 mg and aripiprazole 5 mg group showed a potentially signi-ficant increase in QTc interval. Small increases in body weightwere observed in both the placebo and aripiprazole treatmentgroups during the study.In the study of Streim et al. [119] (Table 2), safety assess-

ment measures included medical review of AE reports, physi-cal examination, vital sign measurements, standard clinicallaboratory tests and 12-lead ECGs. EPS were evaluated usingSAS, AIMS and BARS. The incidence of CVAEs was deter-mined by reviewing all primary AE index terms. Most AEswere of mild to moderate intensity and occurred in a similarproportion in each group. Accidental injury was the mostcommonly reported AE in both groups (aripiprazole 21%,placebo 30%), although most of these events were not consid-ered treatment related. Somnolence was the only AE witha ‡ 10% difference in incidence in aripiprazole versus placebo(14 vs 4%). Accidental injury was also the most common seri-ous AE (aripiprazole n = 2; placebo n = 6). Six subjects (threein each group) died during the study of within 30 days of dis-continuation. None of the deaths was considered treatmentrelated. One CVAE was reported for one placebo-treated patient; none were reported in the aripiprazole group.The incidence of EPS-related AEs was low and similar in bothgroups. Mean changes in bodyweight were small (< 1 kg) in

both groups. Three subjects (aripiprazole n = 2, placebon = 1) had potentially clinically significant increases inQTc interval.

In the study by Rappaport et al. [121] of i.m. aripiprazole forthe treatment of acute agitation in patients with dementia(Table 2), safety assessment measures included reports ofAEs, changes in ECGs, vital signs, laboratory tests and SAS,BARS and MMSE. AEs were mild to moderate in severity.Somnolence was the only AE with a higher incidence versusplacebo across all three aripiprazole treatment groups. Theonly death occurred 24 days after treatment, and was not con-sidered to be treatment related. Twelve patients experiencedserious AEs: placebo n = 2, aripiprazole 5 mg n = 3; aripipra-zole 10 mg n = 6; aripiprazole 15 mg n = 1. The only CVAEoccurred 16 days after treatment. No patient experiencedEPS. There were no clinically significant changes in vital signsor ECGs.

The rather favorable safety profile as outlined in the shortdescriptive safety summeries of the above-mentioned individualtrials may indeed be related to type II errors as has been shownlater in a series of meta-analyses. Indeed, a meta-analysis of15 placebo-controlled trials indicated that death occurred in3.5% of patients randomized to atypical antipsychotic agentscompared with 2.3% of patients in the placebo groups. Thepooled odds ratio (OR) for death was 1.54 (95% CI1.06 -- 2.23; NNH = 87) [126]. This may be considered to bea class effect. Large cohort studies also reported higher morta-lity in patients taking atypical antipsychotic agents comparedwith those not taking these drugs [31,127]. Maher et al. neitherfound increased cardiovascular outcomes, CVAs nor increasedappetite or weight gain for aripiprazole-treated patients in theirmeta-analyses of the three placebo-controlled clinical trials inpsychosis of dementia [123]. Aripiprazole did not significantlyincrease EPS but was found to induce sedation (pooled OR2.60; 95% CI 1.57 -- 4.54) [123].

6. Conclusion

Based on the individual randomized clinical trials discussedabove, the atypical antipsychotic drug aripiprazole demon-strates statistically significant although clinically modestbenefits for psychosis, behavioral symptoms, aggression andaffective symptoms in AD. However, in the trials by DeDeyn et al. [109] and Streim et al. [119] the primary outcomemeasures were not statistically significant, and conclusionswere mostly based on post hoc analysis. A recent meta-analysis of efficacy and safety of atypical antipsychoticmedications for off-label uses in adults reported small butstatistically significant benefits for aripiprazole for globalbehavioral symptom scores associated with dementia inelderly patients. For aripiprazole, the effect size was 0.20(95% CI 0.04 -- 0.35). For the outcome of psychosis, theeffect size was 0.20 (95% CI -0.02 -- 0.42). Aripiprazole wasalso shown to have a statistically significant improvement inagitation. The improvement was considered clinically



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significant on the NPI. Although safety profiles appear accept-able in the individual trials, meta-analyses have demonstratedsignificant safety issues. Increased mortality is considered as aclass effect not only for atypical but also for typical antipsy-chotics. However, no increased cardiovascular outcomes,CVAs or increased appetite or weight gain were demonstratedin meta-analyses for aripiprazole-treated patients with psycho-sis of dementia. Aripiprazole did not significantly increaseEPS but it was found to induce sedation.

Aripiprazole seems to bemost efficacious in this population ofelderly with psychosis of AD at dosages ranging between 5 and10mg/day. Very limited data are available on the use of aripipra-zole in other neurodegenerative diseases such as Parkinson’sdisease. In this disease, the reported effects are contradictorywhile aripiprazole is frequently used in clinical practice.

7. Expert opinion

Aripiprazole has been shown to be effective in treating acutemania and negative and positive symptoms of schizophrenia,but its effectiveness and safety in other neuropsychiatric ill-nesses is unknown. Nevertheless, it is being used in severalother psychiatric diseases and symptoms such as psychosis inAD. Unlike other psychotropic drugs, aripiprazole’s mecha-nism of action is a combination of partial agonistic activityat D2 and 5-HT1A receptors and antagonistic activity at5-HT2A receptors. Dopamine dysfunction patterns differ inschizophrenia compared with other diseases, therefore, theeffect of aripiprazole’s regional and functional selectivityat dopamine receptors is also likely to differ, resulting indifferences in response to treatment and tolerability.

Only four placebo-controlled randomized clinical trials haveevaluated the effect of aripiprazole in AD psychosis (three RCTswith oral administration) and AD with agitation (one RCTwith intramuscular administration). Aripiprazole inducedsignificant, though modest, benefits for global behavioral symp-tom scores (effect size 0.20 (95% CI 0.04 -- 0.35)). For theoutcome of psychosis, the pooled effect size was 0.20 (95%CI -0.02 -- 0.42) for aripiprazole for the psychosis in AD trials.Aripiprazole was also shown to have a statistically significantimprovement on agitation. The observed effects were clinicallysignificant in some but not all RCTs and meta-analysesdemonstrated clinically significant effects on NPI.

Safety is a very important issue in the treatment of psycho-sis in the elderly, since they are vulnerable to side effects and

often have severe comorbidity. The use of atypical antipsy-chotic drugs in patients with dementia has been controversialfollowing the FDA warnings in 2005 because of increasedrisk of death, and increased risk of cerebrovascular events.Since then, other studies have reported similar or a higherincrease in mortality with typical antipsychotics, such ashaloperidol, in these patients. In the studies by De Deynet al. [109] and Mintzer et al. [114], more deaths occurred inthe groups treated with aripiprazole compared with placebo.Although these deaths were said to be unrelated to studymedication or not statistically significant, it could be a factto take into account when considering treating AD patientswith aripiprazole.

Meta-analysis of aripiprazole-related data in psychosis ofAD did not indicate increased cardiovascular outcomes,CVAs and increased appetite or weight gain. Nor did aripi-prazole significantly increase EPS. Aripiprazole however wasshown to induce sedation [123].

Given the significant risk profile associated with the usageof (atypical) antipsychotics, non-pharmacological treatmentof psychosis in dementia is preferable. However, persistingor severe psychotic symptoms and agitation do necessitatethe consideration of pharmacological intervention and medi-cation should not be withheld from patients in whomother treatments have failed and in whom symptoms lead tosignificant morbidity, patient suffering and potential self-harm. Treatment should be initiated at low doses and titratedto the lowest effective dose. Aripiprazole dosages rangingbetween 5 and 10 mg/day are to be recommended. Aspsychotic symptoms in dementia are known to persist formonths, but are uncommon to persist for years, treatmentcan be continued for up to several months, but the indicationfor continuing treatment should be revised regularly.

Declaration of interest

This work was supported by the Fund for Scientific Research-Flanders (FWO), Interuniversity Poles of Attraction (IAPNetwork P7/16) of the Belgian Federal Science Policy Office,Methusalem excellence grant of the Flemish Government,agreement between Institute Born-Bunge and University ofAntwerp, the Medical Research Foundation Antwerp, theThomas Riellaerts research fund and Neurosearch Antwerp.D Van Dam is a postdoctoral fellow of the FWO. All otherauthors have nothing to declare.

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AffiliationPeter Paul De Deyn†1,2,3,6 MD PhD MMPR,

Annemieke FJ Drenth1,7 MD,

Berry P Kremer1,6 MD PhD,

Richard C Oude Voshaar4,5 MD PhD &

Debby Van Dam3,8 MSc PhD†Author for correspondence1University of Groningen,

University Medical Center Groningen,

Alzheimer Research Center,

Department of Neurology, 9713 GZ Groningen,

The Netherlands

Fax: +0031 50 3611707;

E-mail: [email protected] General Hospital, ZNA,

Department of Neurology/Memory Clinic,

Lindendreef 1, B-2020 Antwerp, Belgium3University of Antwerp, Institute Born-Bunge,

Department of Biomedical Sciences,

Laboratory of Neurochemistry & Behaviour,

Universiteitsplein 1, B-2610 Wilrijk, Belgium4Professor Old Age Psychiatry,

University Center of Psychiatry &

Interdisciplinary Center Psychopathology and

Emotion regulation,


University of Groningen, 9700 RB Groningen,

The Netherlands5University Medical Center Groningen,

University of Groningen,

Department of Psychiatry, 9700 RB Groningen,

The Netherlands6Professor of Neurology,



Department of Neurology, Hanzeplein 1,

9713 GZ Groningen, The Netherlands7Resident Neurology,



Department of Neurology,

9713 GZ Groningen, The Netherlands8Professor Animal Laboratory Sciences,

University of Antwerp, Institute Born-Bunge,

Department of Biomedical Sciences,

Laboratory of Neurochemistry & Behaviour,

Universiteitsplein 1, B-2610 Wilrijk, Belgium



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aripiprazole in the treatment of alzheimer's disease

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