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Expert Opinion on Investigational Drugs

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Aripiprazole for relapse prevention and craving inalcohol use disorder: current evidence and futureperspectives

Giovanni Martinotti, Laura Orsolini, Michele Fornaro, Roberta Vecchiotti,Domenico De Berardis, Felice Iasevoli, Marta Torrens & Massimo DiGiannantonio

To cite this article: Giovanni Martinotti, Laura Orsolini, Michele Fornaro, Roberta Vecchiotti,Domenico De Berardis, Felice Iasevoli, Marta Torrens & Massimo Di Giannantonio (2016)Aripiprazole for relapse prevention and craving in alcohol use disorder: current evidenceand future perspectives, Expert Opinion on Investigational Drugs, 25:6, 719-728, DOI:10.1080/13543784.2016.1175431

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Accepted author version posted online: 15Apr 2016.Published online: 21 Apr 2016.

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DRUG EVALUATION

Aripiprazole for relapse prevention and craving in alcohol use disorder: currentevidence and future perspectivesGiovanni Martinottia,b, Laura Orsolinib,c,d,e, Michele Fornarod,f, Roberta Vecchiottic,d,e, Domenico De Berardisa,d,g,Felice Iasevolih, Marta Torrensi and Massimo Di Giannantonioa

aDepartment of Neuroscience, Imaging and Clinical Science, University of ‘G. D’Annunzio’, Chieti, Italy; bSchool of Life and Medical Sciences,University of Hertfordshire, Herts, UK; cVilla S. Giuseppe Hospital, Hermanas Hospitalarias, Ascoli Piceno, Italy; dPolyedra Research, Polyedra,Teramo, Italy; eDepartment of Psychiatry and Neuropsychology, Maastricht University, Maastricht, Netherlands; fNew York State PsychiatricInstitute, Columbia University, New York, NY, USA; gNHS, Department of Mental Health, Psychiatric Service of Diagnosis and Treatment, Hospital ‘G.Mazzini’, Teramo, Italy; hLaboratory of Molecular Psychiatry and Psychopharmacotherapeutics, Section of Psychiatry, Department of Neuroscience,University School of Medicine ‘Federico II’, Naples, Italy; iAddiction Research and Human Pharmacology Groups, Neurosciences Research Program,IMIM-Institut Hospital del Mar d’Investigacions Mèdiques, Institute of Neuropsychiatry and Addictions, Barcelona, Spain

ABSTRACTIntroduction: Among other approaches, themodulation of the dopaminergic pathway has been advocatedin the therapeutic management of Alcohol Use Disorders (AUD). A potential avenue toward the modulationof the dopaminergic pathway across varying substance disorders seems to be provided by aripiprazole, asecond-generation antipsychotic characterized by a peculiar pharmacodynamics signature.Areas covered: In this review, the authors provided a qualitative synthesis and a critical perspective onthe efficacy of aripiprazole in relapse prevention and craving in AUD. A systematic search was carriedout through MEDLINE/Embase/PsycINFO/Cochrane Library from inception until September 2015, com-bining free terms and MESH headings for the topics of AUD and aripiprazole as following: (((Alcohol useDisorder) OR (Alcohol use)) AND aripiprazole).Expert opinion: Based both on a qualitative synthesis and a critical interpretation of the evidence, theauthors submit that aripiprazole would promote alcohol abstinence and reduce the alcohol seekingbehaviour possibly via dopaminergic and serotoninergic modulations at the fronto-subcortical circuitsunderpinning alcohol reward and craving, impulsive behaviour as well as reduce alcohol-relatedanxiety/low mood and anhedonia. However, due to the lack of published studies, a conclusive state-ment about any direct effect of aripiprazole in the prevention of craving and/or alcohol consumption isnot possible.

ARTICLE HISTORYReceived 6 November 2015Accepted 4 April 2016Published online20 April 2016

KEYWORDSAlcohol; alcoholdependence; alcoholaddiction; aripiprazole;craving; alcohol use disorder

1. Introduction

Addictive disorders, including substance use disorders (SUD)share common neurobiological underpinnings for reward, yetdiffering with regard to specific effects on neurotransmitters,despite a substantial converge on a common circuitry at thelimbic system. [1] Heterogeneous mechanisms of action invol-ving glutamate, gamma-amino-butyric acid (GABA), serotonin,endogenous opioids, and endocannabinoids have beenaccounted in the neurobiology of alcohol use disorders(AUD). In addition, considerable evidence emphasizes the cru-cial role of dopaminergic projections of the ventral tegmentalarea (VTA) of the midbrain to the nucleus accumbens (NAc)pathway in increasing overall dopaminergic transmission, thusmediating the acute rewarding effects of alcohol as well as thechronic changes in reward associated with addiction.[2]

The dopaminergic system is prominently involved in the pre-diction or anticipation and motivation components of reward.[3]According to the incentive-sensitization theory proposed byRobinson and Berridge,[4] drug addiction and craving mayoccur due to a sensitization of the mesolimbic dopaminergic

system. The intake of addictive drugs may determine long-last-ing structural changes in the brain architecture (‘neuroadapta-tion’) which may be responsible of a sensitization of those brainsystems involved in the process of incentive salience/motiva-tional (or drug ‘wanting’) subcomponent of the reward.[4,5]

Furthermore, it has been reported that dopamine fibersprojecting from the VTA to the NAc are activated in responseto unpredicted rewards [6] and in response to cues that pre-dict rewards. These observations suggest that dopamine maymediate the process by which the positive incentive value istransferred from the actual reward to the cues that predict it.[6] Therefore, dopamine in the ventral striatum appears to beimplicated in the reinforcement learning of rewards, as itregulated the prediction and anticipation of rewards.[7]Ventral striatal dopamine also mediates the motivational com-ponent of reward. Indeed, depletion of dopamine in the NAcor treatment by dopamine antagonists have been demon-strated to decrease behavioral responses for large reward,although increasing responses for smaller rewards.[8] The stu-dies so far conducted indicate that ventral striatal dopamine

CONTACT Laura Orsolini l.orsolini@ospedaliere.it Villa S. Giuseppe Hospital, Hermanas Hospitalarias, Via dei Girasoli, 6, Ascoli Piceno 63100, ItalyPresent address for Felice Iasevoli is Polyedra Research, Polyedra, Teramo, Italy.

EXPERT OPINION ON INVESTIGATIONAL DRUGS, 2016VOL. 25, NO. 6, 719–728http://dx.doi.org/10.1080/13543784.2016.1175431

© 2016 Informa UK Limited, trading as Taylor & Francis Group

should be necessary to provide incentive motivation for rewardswhen the efforts required obtaining them is increased.[9] Theseeffects are mediated by both D1 and D2 dopamine receptors,[7]since knockout of both these receptors has been associated toincreased anhedonia. Deficits in dopamine neurotransmission inthe ventral striatum may impair reinforcement learning, that is:prediction and anticipation of rewards, and may disrupt motiva-tion to obtain large but too demanding rewards, which translatesin increased avolition conducts.

Specifically, a three-pathway psychobiological model of crav-ing was proposed for alcohol.[10] This multi-factorial model (i.e.neurobiological and psychological factors) of craving for AUDsuggests three craving pathways: reward, relief and obsessive.Reward craving (i.e. desire for the rewarding, stimulating and/orenhancing effects of alcohol) may result from either dopami-nergic/opioidergic dysregulation or a reward seeking personal-ity style or a combination of both.[10] Relief craving (i.e. desirefor the reduction of tension or arousal) may result from eitherGABAergic/glutamatergic dysregulation or a stress reactivitypersonality style. While an obsessive craving (i.e. a lack of con-trol over intrusive thoughts about drinking) is mediated eitherby a serotonin deficiency or a disinhibiting/low constraint per-sonality style.[10] According to this model, some medications inthe field of anti-craving drug therapy were also proposed.[11]

Stating the crucial role of dopaminergic transmission, it istherefore unsurprising that both dopamine agonist, partialagonist and antagonist drugs have been proposed also forthe management of AUD.[12] Among other classes of drugs,second generation antipsychotics (SGAs) have been proposedfor SUD, including AUD,[13] with evidence in support of thepractice.[14,15] In contrast to the SGAs, first generation anti-psychotics (FGAs) have been associated with negative findingsand a higher risk of relapse when compared with placebo,especially for flupentixol.[16]

FGA are predicted to induce a severe perturbation of dopa-mine neurotransmission in the striatum. FGAs are potent andrelatively selective blockers of D2 receptors, reaching highlevel of striatal D2 receptor occupancy even at intermediate-low doses. It has been observed that striatal D2 receptorsmediate ‘No-Go’ behaviors, while alcohol consumptionincreases dendritic branching and AMPA receptor activity inD1-expressing striatal neurons.[17] Notably, blockade of D1 butnot D2 receptors attenuates alcohol consumption.[17] In addi-tion, low striatal dopamine release and D2 receptor bindinghas been reported in brain imaging studies in AUD.[18] Lowdopamine binding to D2 receptors has been demonstrated tobe predictive of increased craving for alcohol and greaterpropensity to relapse.[19]

Taken together, these reports let hypothesize that antipsy-chotic agents with high D2 receptor blocking potential couldinduce a state of iatrogenic low striatal dopamine release andlow dopamine binding to D2 receptor, which may interferewith reward processes on one side and may per se increasecraving on the other. Conversely, the great part of SGA haslower D2 receptor blocking propensity, reaching therapeuticefficacy at lower levels of striatal D2 receptor occupancy.[20]Moreover, some of the SGA are regarded to provide a loosebinding to D2 receptors (a phenomenon known as fast-disso-ciation).[20] Furthermore, their antagonistic activity at 5-HT2A

receptors reduces the dopaminergic transmission, by suggest-ing that SGA could less potently affect reward processes, thuspreventing craving to occur.

Nonetheless, stating the relatively recent introduction ofthe SGA class, characterized by low dissociation constantsand high 50% fast-off time [20] and their off-label use in themanagement of SUD, little is known on the matter, especiallyconcerning the most relatively recently introduced com-pounds, as aripiprazole.

Aripiprazole is the first 5-HT1A and D2 partial agonist intro-duced in the SGA class (Box 1). It also displays a high bindingaffinity for the D3, 5-HT1A, 5-HT2A, 5-HT2B, and 5-HT7 receptors,and limited/negligible affinity for D1, D4, and D5, 5-HT1B, 5-HT3,5-HT6 subtypes and serotonin transporter. Affinity is onlymoderate at 5-HT1D and 5-HT2 C receptors. Aripiprazole hasalso moderate affinity at adrenergic α−1A, α-1B, α−2A, and α-2 C

receptors and at histaminergic H1 receptors. Affinity is negli-gible at cholinergic, GABAergic, glutamatergic, and opioider-gic receptors.[13,21,22] It has been reported to occupyapproximately 95% of D2 receptors in the striatum.[23]Aripiprazole has variable biological effects, depending on thebiological system taken into account and on the levels ofcompeting dopamine. Accordingly, it may act as a prevalentD2 receptor antagonist when the synaptic levels of dopamineare elevated and as a prevalent D2 receptor partial agonistwhen the levels of dopamine are low.[24] This biphasicmechanism may depend on the prevalence of agonistic 5-HT1A receptors-mediated effects at low doses and the preva-lence of inhibition of mesocortical dopaminergic neuronsactivity at high doses.[24] The peculiar effect exerted by aripi-prazole could be underpinned by its effect in stabilizing dopa-mine receptors through a modulation of functioning, ratherthan their sole blockade or stimulation. As both cortical (pre-frontal) and dorsal striatal mechanisms are involved in thereward, aripiprazole may own a promising mechanism tomodulate impulsiveness, mood and anxiety as well as thecraving swings usually observed in patients with AUD.

The use of aripiprazole in AUD has been also documented inanimal models of alcohol with both evidence in support and

Box 1. Drug summary

Drug name AripiprazolePhase IIIndication Alcohol addictionPharmacologydescription

Partial agonist of dopamine D2 and D3 receptor andserotonin 5-HT1A and 5-HT7 receptors; antagonist of5-HT2A and 5-HT6 receptors

Route ofadministration

Injectable/oral

Chemicalstructure

Pivotal trial(s) [31,32,37,38]

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

720 G MARTINOTTI ET AL.

discharge of the practice.[25–28] Aripiprazole is effective inreducing locomotor activity,[25,26] but only at a notably higherdose or after repeated treatment.[25] In addition, mice pre-treated with aripiprazole, showed a decreased hyperlocomotionin the presence of ethanol compared to placebo.[26]Furthermore, it is able to reduce or abolish anxiety-like beha-viors and ethanol-induced place preference as well as producean overall decrease in drinking behaviors.[27] A preclinical ani-mal model of chronic alcohol self-administration demonstratedthat oral administration of aripiprazole (1, 3, and 10 mg/kg) on4% alcohol intake reduced alcohol consumption, significantlyonly at 10 mg/kg (p < 0.01). This study reported that chronicalcohol intake would increase aripiprazole exposure, by sug-gesting that aripiprazole dose might have to be decreased.[28]

Moreover, thought rigorous and updated, the most recentsystematic review and metanalysis about the use of SGA,including aripiprazole, in the treatment of AUD, adopted strin-gent inclusion and exclusion criteria, namely, ‘RCTs only’; ‘nocomorbid psychiatric condition’; ‘absence of any concomitantdrug’, just to mention few.[12,29] Balancing high-poweredqualitative and quantitative extractions of the evidence withopen-label human studies, is therefore recommended, at thistime, in order to allow a critical perspective toward the devel-opment of experimental drugs to be tested in RCTs. Thisseems particularly relevant, especially considering the overallpaucity of the evidence available on the matter, includingnon-controlled reports and the need to divert the attentionalso towards special settings/population.

The present comprehensive critical review aims at provid-ing both qualitative synthesis and critical interpretation of thecurrent evidence about the efficacy of aripiprazole in therelapse prevention and craving attenuation in AUD.

2. Materials and methods

The present review was carried out in accordance to themethods recommended by the Preferred Reporting Items forSystematic Reviews and Meta-Analyses (PRISMA) guide-lines.[30]

2.1. Information sources and search strategy

Studies were identified searching the electronic databasesMEDLINE, PsycINFO, and the Cochrane Library. We combinedthe search strategy of free text terms and exploded MESHheadings for the topics of alcohol use disorder and aripipra-zole as following: ((Alcohol use Disorder) OR (Alcohol use) ANDaripiprazole). The strategy was first developed in MEDLINE andthen adapted for use in the other databases. Studies publishedin English through 21 September 2015 were included. Inaddition, further studies were retrieved from reference listingof relevant articles and consultation with experts in the fieldand or manual search.

2.2. Inclusion criteria, study population and study design

We considered studies that included aripiprazole treatment forAUD subjects if diagnostic criteria used were specified.Participants of both genders, 18 years of age or older were

considered. Both population-based and hospital-based studieswere included. Among hospital-based studies, inpatients, day-hospital, and outpatient subjects were included while emer-gency care records were excluded as considered non-repre-sentative. All experimental and observational study designswere included apart from case reports. Narrative and systema-tic reviews, letters to the editor, and book chapters wereexcluded.

2.3. Study selection and data extraction

Identified studies were independently reviewed for eligibilityby three authors (GM, LO, and MF) in a two-step-based pro-cess; a first screening was performed based on title andabstract while full texts were retrieved for the second screen-ing. At both stages, disagreements by reviewers were resolvedby consensus. Data were identified, selected and thenextracted by two authors (MF and LO) and supervised by athird author (GM) using an ad hoc developed data extractionspreadsheet. With the initial set of keywords, some 79 studieswere identified. Of these, 10 were excluded because dupli-cated. Of these remaining 15 relevant studies, 54 wereexcluded because did not meet the inclusion criteria or notconsistent with the aims of the review. Finally, the data extrac-tion spreadsheet was piloted on eight randomly selectedpapers and modified accordingly. Four open-label studiesand four randomized clinical trials (RCT) were included andproperly retrieved (as shown in Tables 1 and 2). Figure 1provides a synthetic flow chart of the multi-step selectionprocedure as was followed.

3. Results

3.1. Clinical lab studies

Voronin et al. [31] primarily evaluated the efficacy and safetyof aripiprazole as well as its possible mechanism of action onalcohol consumption, by enrolling 30 non-treatment seekingalcoholics in a clinical laboratory study. Subjects receiveddouble-blind treatment with up to 15 mg daily of aripiprazole(n = 15) or placebo (n = 15) for 8 days. After the priming drinkin the bar lab, there was no significant difference betweenplacebo and aripiprazole groups on the subjective high assess-ment scale (SHAS), which represents a measure of intoxicationand alcohol induced adverse effects (p = 0.79) and on overallalcohol urge questionnaire (AUQ) scores. Aripiprazole-treatedsubjects experienced more insomnia (p = 0.017) and nervous-ness (p = 0.042) compared to placebo group. Subjects whohad lower self-control (more impulsivity) compared to thosewho had higher self-control (less impulsivity) were more likelyto have fewer drinks per day when on aripiprazole comparedto placebo (p = 0.03).

An alcohol administration design was performed in orderto assess, as primary outcomes, the safety and tolerability of300 mg of topiramate and 30 mg of aripiprazole in heavydrinking volunteers, in an open-label trial.[32] Thirteen partici-pants not seeking treatment for alcoholism were randomizedand submitted to an alcohol challenge session (ACS). Eachweekparticipants were monitored for adverse effects, changes

EXPERT OPINION ON INVESTIGATIONAL DRUGS 721

Table1.

Summaryof

includ

edstud

iesexam

iningeffectsof

aripiprazole

inalcoho

luse

disorder.

Stud

y

Participants

Dose(m

ean)

mg/day

Stud

ydesign

(weeks)

Primaryou

tcom

es(scales)

Second

aryou

tcom

es(scales)

N(M

/F)

Age,year

(mean±SD

[range])

[31]

30(25/5)

27.5

±NA[NA]

ARI(15)vs

PBO

RCT(1)

Clinicallabo

ratory

stud

ySafety

andtolerabilityof

theinteraction

betweenAR

Iand

alcoho

l(POMS;BA

ES;SHAS

;AUQ)

Mechanism

ofactio

nof

ARIo

nalcoho

lconsum

ption

Attenu

atingcraving(OCD

S;AC

Q;A

UQ)

Role

ofimpu

lsivenesson

ARIrespo

nse

(BIS-11)

[32]

13(11/2)

38±NA[22–58]

ARI(30)plus

TPR(300)

Open-label(4)

Safety

andtolerabilityof

thecombinatio

nof

aripiprazole

andtopiramatewith

alcoho

l(AIMS;SA

FTEE)

Cravingattenu

ation

(OCD

S;AU

Q)

[33]

30(22/8)

28.9

±7[NA]

ARI(15)vs

PBO

RCT(2)

Analysisof

establishedbrainimaging

paradigm

toexploretheeffect

ofAR

Ivs

placeboon

alcoho

lcue-in

ducedbrain

activationanddrinking

(fMRI)

Attenu

atingcraving

(OCD

S)

[34]

35(23/12)

39.6

±7.6[NA]

ARI(5–15)–flexible

plus

ESC(10–20)

OR

ESC(10–20)

Open-label(6)

Clinicalchangesandcravingattenu

ation

(MAS

T;BD

I;AU

Q;C

GI-S)

Changesin

BOLD

sign

aldu

ring6-weektherapy(fM

RI)

[35]

11(NA)

37.7

±7.4[NA]

5–15

(7.7)–flexible

Open-Label(16)

Cravingattenu

ation

(VAS

;OCD

S)Alcoho

lrelapse

preventio

n

[36]

13(11/2)

37.9

±7.8[NA]

5–15

(7.7)–flexible

Open-Label(16)

Cravingattenu

ation

(VAS

;OCD

S)Short-term

efficacyin

term

sof

alcoho

lrelapse

preventio

nImprovem

entof

psychiatric

symptom

s(CGI-S;Q

OL;SCL-90)

Safety

andtolerability

(ECG

;urin

alysis,h

aematolog

ical/clinical

chem

icalanalysis;A

Es)

[37]

295(202/93)

47.3

±8.7

ARI(30)

vsPBO

RCT(12)

Percentof

days

abstinent(TLFB)

Abstinentdays

Heavy

drinking

days

Drin

ksfordrinking

day

Timeto

firstdrinking

day

Timein

days

tothefirstheavydrinking

day

Meanpercentof

heavydrinking

days

Attenu

ationof

cravingandalcoho

ldependence/abuse

(OCD

S;DrIn

C-2R;

ADDS)

Improvem

entof

psychiatric

symptom

atolog

y(CGI-S;Q

IDS-SR16;C

GI-I)

[38]

75(60/15)

40.3

±11.8

[NA]

ARI(5–15)vs

NAL

(50)

RCT(16)

Safety

andefficacyof

ARIo

nalcoho

ldrin

king

indices

CIWA-Ar

CGI-S

Cravingattenu

ation

(VAS

;OCD

S)Improvem

entof

psychiatric

symptom

s(CGI-S;SCL-90)

NA:

notavailable;AU

D:alcoh

olusedisorder;VAS

:visualanalogscale;OCD

S:ob

sessive-compu

lsivedrinking

scale;CG

I-S:clinicalglob

alimpairm

entseverityscale;QOL:qu

ality

oflifeindex;SCL-90:sym

ptom

schecklist-90

items;

AC:anticon

vulsants;A

D:antidepressants;A

P:antip

sychotics;AR

I:aripiprazole;PBO

:placebo

;TPR:top

iramate;AD

S:alcoho

ldependencescale;AU

DIT:alcoh

olusedisordersidentificationtest;TLFB:tim

elinefollow-back;CIWA-

Ar:clinicalinstitu

tewith

draw

alassessmentforalcoho

l-revised;H

AM-D:H

amilton

depression

scale;AIMS:abno

rmalinvoluntarymovem

entscale;SA

FTEE:systematicassessmentof

side

effectsin

clinicaltrials;A

UQ:alcoh

olurge

questio

nnaire;fMRI:fun

ctionalm

agnetic

resonanceimaging;

POMS:profile

ofmoodstates;A

CQ:alcoh

olcravingqu

estio

nnaire;B

AES:biph

asicalcoho

leffe

ctsscale;NAL:n

altrexon

e;SA

AST:self-administeredalcoho

lscreeningtest;B

IS-11:Barrattimpu

lsivenessscale-version11;B

AES:biph

asicalcoho

leffe

ctsscale;SH

AS:sub

jectivehigh

assessmentscale;AU

Q:alcoh

olurge

questio

nnaire;M

AST:Michiganalcoho

lscreening

test;B

DI:Beck

depression

inventory.

722 G MARTINOTTI ET AL.

in mood, and evaluation of concomitant medication use.During the ACS sessions, participants were administered alco-hol (about three beers) and asked to complete a few short

assessments after each drink including adverse effects.Findings demonstrated no evidence that adverse effects ofaripiprazole and topiramate are additive; therefore, their

Table 2. Summary of aripiprazole effects on alcohol use disorder dimensions.

StudyCraving[scale] Drinks per drinking day Heavy drinking days QOL CGI SCL-90

Clinical lab studies[31] NS

[OCDS]NS N/A N/A N/A N/A

[32] A[OCDS]

N/A N/A N/A N/A N/A

Neuroimaging studies[33] NS NS A N/A N/A N/A[34] A + ESC > ESC

[AUQ]N/A N/A N/A A + ESC > ESC N/A

Open-label studies[35] A

[VAS; OCDS]N/A N/A N/A N/A N/A

[36] A[VAS; OCDS]

N/A N/A A A A

Randomized clinical trials[37] NS

[OCDS]A

[medicationeffects scale]

NS[TLFB]

NS N/A NS N/A

[38] A[VAS]

N/A N/A N/A A A

NS: not significant; N/A: not available; VAS: visual analog scale; OCDS: obsessive-compulsive drinking scale; CGI-S: clinical global impairment severity scale;QOL: quality of life index; SCL-90: symptoms checklist-90 items; TLFB: timeline follow-back; AUQ: alcohol urge questionnaire; A: aripiprazole; ESC: escitalopram.

Records identified through database searching

(n = 79, of which 66 though PUBMED, 1= PsycINFO;

12 = Cochrane library)

Scre

en

ing

In

clu

de

d

Eli

gib

ilit

y

Ide

ntif

ica

tio

n

Additional records identified through other sources (n = 0)

Records after duplicates removed (n = 69)

Potential relevant citations (n = 31)

38 records excluded after screening of abstract and

title

Full-text articles assessed for eligibility

(n = 15)

16 articles were excluded, as they did not fulfill the inclusion and exclusion criteria.

Studies included in qualitative synthesis

(n = 8)

Figure 1. Adapted PRISMA 2009 flow diagram from [61.].

EXPERT OPINION ON INVESTIGATIONAL DRUGS 723

combination was generally safe and well tolerated. Second, itwas evaluated if lower as well as higher doses of these med-ications were comparatively effective in reducing alcohol urgeand consumption. Findings demonstrated a statistically signif-icant reduction of alcohol use by participants (p = 0.08).[32]

3.2. Neuroimaging studies

A study by Myrick et al. [33] investigating, as primary goal, theeffect of aripiprazole vs placebo on ventral striatum activationand in the attenuation of alcohol cue-induced brain activationcaused by medication treatment as well as the effects ondecreased alcohol use, using fMRI. Thirty non-treatment seek-ing alcoholics were recruited and randomized to either aripi-prazole (15 mg/day) or placebo in a double-blind manner for a14-day period. After this period, subjects underwent a fMRIbrain scan with alcohol cue stimulation, in order to measurechanges in regional brain activity while they were viewingalcoholic and nonalcoholic-beverage randomized pictures.No significant differences between the groups were observedregarding to alcohol craving ratings. Placebo-treated patientsshowed activation in limbic regions including right ventralstriatum while aripiprazole-treated subjects did not show theventral striatum activation (p < 0.01). Aripiprazole-treated sub-jects showed a reduction of heavy drinking days compared toplacebo group (p = 0.027).

A 6-week open-label study [34] carried out on 35 sub-jects affected with comorbid major depressive disorder(MDD) and AUD were randomized to only escitalopram(10–20 mg/day) or aripiprazole plus escitalopram (flexible5–15 mg/day of aripiprazole plus 10–20 mg/day of escitalo-pram). Depressive symptoms, craving for alcohol and alco-hol use, as primary outcomes, were assessed by Beckdepression inventory (BDI), the Korean alcohol urge ques-tionnaire (AUQ-K) and the clinical global impairment-symp-tomatology (CGI-S). The BDI and CGI-S scores were reducedin the aripiprazole plus escitalopram group compared toonly escitalopram group (respectively, p = 0.13 and p =0.30). The AUQ-K scores were significantly decreased in thearipiprazole plus escitalopram group (p = 0.02). No signifi-cant differences were evidenced in the number of patientsresponding to depression treatment (p = 0.15) either in thenumber of patients who remained alcohol free (p = 0.66),between the two groups. Response to antidepressant treat-ment (as reduction in follow-up BDI scores to less than 50%of initial BDI scores) were similar in both groups. Craving foralcohol was decreased in the aripiprazole plus escitalopramgroup compared to only escitalopram one. At baseline andfollowing 6 weeks of treatment, patients were assessed by1.5 Tesla functional magnetic resonance imaging (fMRI) inorder to evaluate their brain activity in response to alcoholdrinking cue presentation. Findings that patients withcomorbid AUD and MDD showed decreased activity inBOLD signal and metabolism in the anterior cingulate cortex(ACC) in response to alcohol drinking scenes, supported theevidence that anterior cingulate represents an importanthub mediating depressive symptoms and negative mood,suggesting the role of this brain region in craving for

alcohol. The authors also underlined that the activity ofanterior cingulate in the aripiprazole plus escitalopramgroup increased following the 6-week treatment period.These findings may suggest that dopamine release inducedby aripiprazole might control craving for alcohol duringalcohol-cue stimulation in patients with MDD, via activationof anterior cingulate.

3.3. Open-label trials

A preliminary open-label study was carried out on 11 detox-ified alcohol-dependent patients, in order to investigate theshort-term efficacy of aripiprazole, by evaluating alcoholrelapse rates and craving attenuation.[35] Subjects wereorally treated with flexible doses of aripiprazole (5–15 mg/day) for a 16-week period. A significant progressive reductionof craving in both the visual analog scale (VAS) (p = 0.002)and obsessive-compulsive drinking scale (OCDS) (p = 0.048),with a more significant effect on the compulsive component(p = 0.032) was observed both at the first follow-up and atthe end of the study. An open-label trial investigated, asprimary outcomes, the safety and tolerability of the aripipra-zole–topiramate combination on thirteen heavy drinking sub-jects not seeking treatment for alcoholism. Subjects weretitrated up to 300 mg of topiramate and 30 mg of aripipra-zole daily for 36 days.[35] In another study, flexible doses ofaripiprazole have been administered to 13 detoxified alcohol-dependent patients in a 16-week period.[36] Primary out-comes consist in investigate the short-term efficacy of aripi-prazole in alcoholics in terms of alcohol relapse prevention,craving attenuation and improvement of psychiatric symp-toms. Secondary outcomes comprised measurements ofsafety and tolerability. Aripiprazole-treated patients experi-enced a statistically significant reduction of craving as mea-sured by OCDS scores (p = 0.042), particularly on thecompulsive component (p = 0.032), and VAS (p = 0.002).Furthermore, a significant improvement on the clinical globalimpairment (CGI) severity scale (p = 0.001), quality of life(QOL) index (p = 0.011) and on SCL-90 general severityindex (p = 0.038), was observed. Withdrawal symptomswere significantly reduced during the study (p = 0.011).Finally, authors reported, among the most frequentlyreported side effects, nausea, and vomiting.[36]

3.4. RCT

A 12-week multicenter, double blind, parallel group, pla-cebo-controlled RCT aimed at comparing the efficacy andsafety of oral aripiprazole (2–30 mg daily) vs placebo in themaintenance of abstinence in 295 alcohol-dependentpatients (146 placebo and 149 aripiprazole), without con-current substance abuse or dependence (i.e. cocaine, heroin,etc.) or concurrent Axis I/II disorders. Aripiprazole wasstarted at 2 mg/day and titrated to 5 mg/day (days 3 and4); 10 mg/day at the day 7 visit; 15 mg/day (days 10 and11); 20 mg/day at day 14; 25 mg/day at day 21; and 30 mg/day at day 28 until the term of study. The primary efficacyoutcome, i.e. the percentage of days abstinent over 12

724 G MARTINOTTI ET AL.

weeks, as assessed by the timeline follow-back (TLFB)method, was reported similar between aripiprazole and pla-cebo (58.7% vs 63.3%; p = 0.227). Among the secondaryoutcomes, the percentage of subjects with an increase of50% or more in abstinent days, the percentage of subjectswithout a heavy drinking day (i.e. more than five drinksdaily for men or four for women) and the time to firstdrinking day, were not significantly different between twogroups (respectively, p = 0.228; p = 0.978; p = 0.067). Whilethe percentage of subjects completely abstinent from alco-hol throughout the study is significantly higher in placebogroup (p = 0.016). The average number of drinks/drinkingdays was significant lower for aripiprazole (p < 0.001). OCDSand the drinker inventory of consequences-2 R version(DrInC-2 R), as behavioral measures of alcohol abuse anddependence, showed no significant differences betweentwo groups. While statistically significant differences werereported in alcohol dependence scale (ADS) (aripiprazolesuperior to placebo; p = 0.004) and quick inventory ofdepressive symptomatology-self report version (QIDS-SR16)(placebo superior to aripiprazole; p = 0.009). Higher discon-tinuation rates were reported in aripiprazole group (40.3%)vs placebo (26.7%), mainly due to adverse events (AEs), e.g.insomnia (6.9%), anxiety (3.4%), and restlessness (2.7%).Aripiprazole-treated subjects discontinued significantly ear-lier the study compared to placebo group (p = 0.008),particularly when aripiprazole dose exceeded 15 mg daily.Treatment-related AEs were reported higher with aripipra-zole than with placebo (82.8% vs 63.6%), particularly includ-ing fatigue (p < 0.0001), insomnia, restlessness (p < 0.0001),somnolence (p = 0.002), anxiety (p = 0.001) and disturbancein attention (p = 0.007). The extrapyramidal symptoms(EPS)-related AEs with aripiprazole reported included akathi-sia (6.2% vs 0.7%), tremor (3.4% vs 2.8%) and dyskinesia(1.4% vs 0%). Overall, aripiprazole-treated patients reportedmore positive subjective treatment effects and less overallseverity of AUD compared to placebo group.[37]

A randomized, double-blind, confrontation trial with nal-trexone investigating as primary outcome the efficacy ofaripiprazole on alcohol-drinking indices, was carried out on75 detoxified alcohol dependent subjects in a 16-week per-iod. Patients were subsequently randomized into groups,receiving 50 mg of naltrexone and flexible dose (5–15 mg/day) of aripiprazole, respectively. The number of subjectsremained alcohol free for the length of study, the numberof subjects relapsed, the mean number of abstinent daysand heavy drinking days were not significantly different inthe two groups. The aripiprazole-treated patients showed asignificant reduction in VAS (p < 0.05) while naltrexone-treated patients had significant reduction in the OCDS(p < 0.001), OCDS sub-score obsessive (p < 0.001) andcompulsive (p < 0.001) and in the VAS (p < 0.05).Withdrawal symptoms, as assessed by CIWA, were signifi-cantly reduced in both groups (p < 0.0001). Aripiprazole-treated patients reported significant improvement on theCGI severity scale (p < 0.01) while naltrexone-group wasnot associated with a significant improvement (p =0.072).[38]

4. Conclusion

Abnormalities in dopaminergic neural transmission have beenstrongly hypothesized to contribute to the pathophysiology ofAUD through an amplification ofmotivational (craving) as well asreward aspects.[39–43] Furthermore, the mesolimbic dopaminepathway that projects from the VTA to a structure within theventral striatum, the NAc, has been implicated as a major site forthe reinforcing actions of many addictive drugs including alco-hol.[38,44,45] It has been proposed that during initial attempts ofabstinence, the dopaminergic system may be down-regulated(low dopamine levels) determining a low hedonic tone.[46–48]The presence of anhedonia, defined as diminished interest orpleasure in response to rewarding stimuli, as it reflects deficits inhedonic capacity and is closely linked to the reward processes(i.e. reward evaluation, motivation to seek reward and decision-making), could facilitate the level of craving and drug-seekingbehavior.[8,46] On the other hand, relapse drinking or initiationhas been associated with increased dopamine concentrations atthe striatum.[49,50] Therefore, all drugs acting in the modulationof the dopaminergic system may theoretically reduce cravingand prevent relapse, by promoting abstinence, in alcohol-depen-dent patients.[40,51] Therefore, in this context of altered braindopamine function, aripiprazole might provide a novel thera-peutic approach in the different stages of the pathogenesis ofalcoholism, by attenuating both craving (during the abstinentphase) and anxiety, depression and impulsivity, potentiallyresponsible of relapse, and worsening of drinking behaviors.[31,34,52]

Nevertheless, clinical studies published so far reportedmixed and unclear findings. In fact, despite the main goal ofthe present review was at providing an overview of currentevidence on efficacy of aripiprazole in relapse prevention andcraving attenuation in AUD, the paucity of available datareported to date on the matter, precludes any conclusivestatement about any direct or otherwise definitive efficacy ofaripiprazole in alcohol craving and prevention relapse. Futureresearch studies should assess the clinical and brain activitiesafter administration of aripiprazole in patients with AUD withor without other substance use and/or abuse. Further con-trolled randomized trials should be carried out in order toassess the short- and long-term efficacy of aripiprazole inalcoholics in terms of alcohol relapse prevention, cravingattenuation and improvement of psychiatric symptoms.

5. Expert opinion

Clinical studies are scarce in number and inconclusive, thoughclearly pointing out an overall favorable evidence in supportof aripiprazole. However, the scanty available data limits thegeneralizability and statistical power of the findings here pro-vided. A series of limitations have been here analyzed anddiscussed. First of all, most studies here retrieved recruited asmall sample size without homogeneous inclusion/exclusioncriteria, often not including multiple substance dependence orother axis I/II comorbid disorders. On the other hand, a sampleincluding a high level of comorbidity may influence the out-comes. Second, the relatively short length of the studies may

EXPERT OPINION ON INVESTIGATIONAL DRUGS 725

limit the observation of relapse/recovery/abstinence.Furthermore, some studies do not take into account the dif-ferent effects that specific ranges of aripiprazole dosages mayexert on response, remission, relapse as well as side-effectpattern. Some studies evaluated efficacy of aripiprazole incombination with other drugs, such as escitalopram or topir-amate, not specifically assessing the role of aripiprazole inAUD outcomes. In addition, primary outcomes (e.g. level ofcraving; prevention relapse rate; safety and tolerability in alco-holics patients, and so on) are often not homogeneousthroughout the studies, by limiting the analysis of the datahere retrieved. Finally, different study designs may limit com-parability of data (‘measurement bias’). Furthermore, a lack ofstandardization of the outcome measures, dose range evalua-tion, and different population selections all can influenceresults.

The issue of the dosage is also crucial. Overall, aripiprazole,at low-medium dosages (ranging 5–15 mg daily), seems toreduce craving and alcohol consumption,[35,36,38] eventhough data are also contrasting [33] or likely influenced bythe presence of co-administration with other drugs.[34] Inparticular, aripiprazole seems to be particularly effective insubjects who have high impulsivity/low self-control in naturaldrinking conditions [31] and in the improvement of comorbidpsychiatric symptomatology.[34,38] Furthermore, some stu-dies demonstrated that aripiprazole dosage should bedecreased in subjects with chronic alcohol consume due tothe risk of increasing aripiprazole exposure.[28,37] Whilehigher doses of aripiprazole seem to be more likely associatedwith the onset of AEs (e.g. insomnia, anxiety, and restlessness),anhedonic states, and may induce worsening of craving andhigher rates of drop-outs and relapse due to its antagonisticactivity on D2.[32,37] Partial dopamine agonists, such as aripi-prazole, may represent a tool to reverse dopamine depletionseen during ethanol abstinence and, due to their own multi-receptorial activity, may represent a novel strategy to balancedopamine neurotransmission along the behavioral continuumof alcoholism.[53] Regarding the serotonin system, the 5-HT1Apartial agonist effect of aripiprazole may modulate the pre-frontal cortex (PFC) to improve impulse control through theprojections from the raphe nucleus to the VTA and NAc.[54]Taken together, these considerations suggest that dopaminerelease induced by aripiprazole might be associated withincreased activation of anterior cingulate, which, on turn,may control craving for alcohol and substances. This is alsothe most likely issue accounting for the inconsistent resultsabout the use of high dose aripiprazole as documented by thelargest RCT performed to date.[37]

While current evidence to date do not allow any firm con-clusion about the efficacy of aripiprazole in the prevention ofcraving and/or alcohol consumption and in the maintenanceof abstinence, a list of specific kinds of patients could outlinedto aid the prescribing clinicians: (1) subjects with comorbidpsychiatric conditions, especially major depression, bipolardepression, psychotic disorders, dissociative disorders, andborderline personality.[34,36] For all these latter conditions,of dual diagnosis aripiprazole proved to be effective, althoughits direct effect on alcohol craving urge for confirmation stu-dies [55]; (2) subjects with poly-substance-abuse, a condition

characterized by high rates of concurrent psychiatric symp-toms, especially when polyabuse of alcohol and novel psy-choactive substances occur.[56,57] The safety profile ofaripiprazole suggests its suitability for use also when the useof other substance cannot be ruled out; (3) subjects with aCloninger II personality profile, characterized by higher levelsof impulsiveness, sensation seeking, early onset of alcoholmisuse, antisocial behaviors, reward craving.[58–60] In theseconditions, aripiprazole showed some level of evidence indifferent studies.[31]

In conclusion, aripiprazole may represent a possible optionin the broad, heterogeneous setting of AUD. Its direct effecton alcohol craving and relapse prevention need to be con-firmed and we are still far from considering this drug as a drugof choice in alcoholism. However, waiting for further evidenceon the matter, we can consider aripiprazole as the drug ofchoice in those cases of AUD where dual diagnosis, multiplesubstance abuse, and peculiar personality traits representrelevant phenomena.

Declaration of interest

L Orsolini, M Fornaro, R Vecchiotti and D De Berardis are employees ofPolyedra, Teramo, Italy. The authors have no other relevant affiliations orfinancial involvement with any organization or entity with a financialinterest in or financial conflict with the subject matter or materials dis-cussed in the manuscript apart from those disclosed.

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