REVIEW

Long-Acting Injectable Antipsychoticsin Schizophrenia: Literature Review and PracticalPerspective, with a Focus on AripiprazoleOnce-Monthly

Enrico Biagi . Enrico Capuzzi . Fabrizia Colmegna . Alessandra Mascarini .

Giulia Brambilla . Alessandra Ornaghi . Jacopo Santambrogio .

Massimo Clerici

Received: January 26, 2017 / Published online: April 5, 2017� The Author(s) 2017. This article is an open access publication

ABSTRACT

Introduction: Prevention of relapse is a majorchallenge in schizophrenia, a disease charac-terized by poor adherence to antipsychoticmedication leading to multiple rehospitaliza-tions and a substantial burden-of-care.Methods: We narratively review publishedclinical data from the development oflong-acting injectable (LAI) formulations ofantipsychotic drugs and examine the compara-tive effectiveness of oral versus LAIs inschizophrenia, with a focus on the sec-ond-generation LAI antipsychotic aripiprazole.Evidence is presented from studies with

naturalistic/pragmatic as well as explanatorytrial designs, supported by the clinical experi-ence of the authors.Results: LAI formulations of antipsychoticdrugs offer advantages over oral medicationsand there is good evidence for their use as afirst-choice treatment and in younger patients.Key phase III studies have shown aripiprazoleonce-monthly 400 mg (AOM 400) to be effec-tive and well tolerated, with high rates ofadherence and low rates of impending relapse.In a recent randomized trial with a ‘‘naturalis-tic’’ study design more representative of routineclinical practice, AOM 400 was well toleratedand had significantly greater effectiveness thanpaliperidone LAI overall and in youngerpatients aged B35 years.Conclusion: Results across the ‘‘full spectrum’’of efficacy in traditional clinical trials as well asthose encompassing the concept of effective-ness in a more naturalistic setting of real-lifeclinical practice support the use of AOM 400 asa valid long-term treatment option inschizophrenia overall, as well as earlier in thetreatment course, and not solely in situations ofpoor adherence or when oral antipsychoticshave failed.

Keywords: Adherence; Hospitalization; LAIantipsychotics; Relapse; Remission; Schizophre-nia and related psychotic disorders; Second-generation

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E. Biagi � E. Capuzzi � F. Colmegna � A. Mascarini �A. Ornaghi � M. Clerici (&)Department of Mental Health, ASST-MonzaOspedale San Gerardo, Monza, Italye-mail: massimo.clerici@unimib.it

E. CapuzziPhD Program in Neuroscience, Department ofMedicine and Surgery, University of Milano Bicocca,Milan, Italy

G. Brambilla � J. Santambrogio � M. ClericiDepartment of Medicine and Surgery, School ofMedicine and Surgery, University of Milano Bicocca,Milan, Italy

Adv Ther (2017) 34:1036–1048

DOI 10.1007/s12325-017-0507-x

INTRODUCTION

Schizophrenia is a pervasive and disabling psy-chotic chronic condition with a major burdenon patients, their families, and society [1, 2].During their lifetime, about 1% of the worldpopulation will develop schizophrenia, typi-cally preceded by prodromal symptoms of psy-chosis leading to a first psychotic episode andstarting in young adulthood, although the dis-tressing condition can occur at any age [2, 3].Individuals with schizophrenia have a shorterlife expectancy than the general population,with an increased risk of physical illness, espe-cially cardiovascular disease, as well as higherrates of suicide and accidental injury [2, 4–6].The long-term course of schizophrenia ismarked by episodes of partial or full remissionbroken by relapses, while social and occupa-tional functioning, quality of life and ability tolive an independent life are constrained, andthere is an increased risk of substance abuse,suicide and violent behavior, especially duringthe period of relapse [2, 7].

While the prevention of relapse, accompa-nied by delusions, which may potentially causeharm to the patient and their societal contacts,hallucinations, and disorganized speech andbehavior, is a major challenge in schizophrenia,the disease is also characterized by poor adher-ence to antipsychotic medication leading to aneed for multiple rehospitalizations and a sub-stantial direct and indirect cost burden [2, 8–12].

In this narrative review, we examine pub-lished clinical data from the development oflong-acting injectable (LAI) formulations ofantipsychotic drugs and review the evidence forthe comparative effectiveness of oral versuslong-acting antipsychotics in the managementof schizophrenia, with a focus on the sec-ond-generation antipsychotic LAI aripiprazole.Evidence from studies with naturalistic/prag-matic as well as explanatory trial designs ispresented, supported by the clinical experienceof the authors.

This article is based on previously conductedstudies, and does not involve any new studies ofhuman or animal subjects performed by any ofthe authors.

Treatment of Schizophrenia: Ensurethe Continuity of Therapy

The development and introduction of antipsy-chotic drugs significantly improved treatmentoutcomes and quality of life for patients withschizophrenia, and there is general acceptanceof their valuable contribution at all stages ofschizophrenia [2, 13–17]. Although an in-depthdiscussion of all therapeutic options for patientswith schizophrenia is beyond the scope of thisarticle, it is clear that all patients affected byschizophrenia will require long-term treatment.Long-term pharmacological therapy in thestable or maintenance phase should be indi-vidually tailored to the needs and preferences ofthe patient and directed at ensuring symptomremission and control of relapses; moreover, thepatient’s level of psychosocial functioning,independence and quality of life is maintainedor improved by long-term therapy, while themonitoring for adherence and adverse effects oftreatment is continued [4, 14, 18].

Antipsychotic pharmacological therapy shouldbe accompanied by psychoeducational andpsychosocial interventions customized to thepatient, including occupational therapy, com-munity-based treatment, family interventions,vocational rehabilitation and,whenappropriate,counseling and psychotherapy, behaviortherapy, and cognitive behavioral therapy(CBT) [2, 13–15, 17]. UK guidelines recommendCBT as first-line therapy in at-risk adult popula-tions [2].

Effective antipsychotic medications, in par-ticular long-acting injectable (LAI) formula-tions, facilitate and support the patient’s abilityto benefit from interventions designed toencourage successful rehabilitation and re-entryinto society [14].

Assuring continuity of treatment is essentialto the prevention of relapse, a key focus in thetreatment of schizophrenia. Therefore, thera-peutic interventions that enhance treatmentadherence, such as LAIs, are a clinical prioritywithin the treatment plan. Data from a sys-tematic review and meta-analysis show aweighted 1-year relapse rate of 77% in patientswith a first episode of schizophrenia who

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discontinue antipsychotic therapy, increasingto over 90% at 2 years, compared with a meanrelapse risk of 3% in those continuously treatedwith antipsychotics [19]. Similarly, patientscompletely adherent to their antipsychoticmedication are at significantly reduced risk ofhospitalization or emergency room visits for amental health reason [20]. It is also becomingclear that early intervention in patients withpsychosis has a beneficial effect on long-termoutcomes, while, conversely, delaying access toeffective mental health services may slow orprevent complete recovery, increase the risk ofrelapse and lead to poor long-term clinical andsocial outcomes [21]. Continuity of treatmentfrom the early stages of the disease may, indeed,significantly reduce the risk of recurrence andimprove patient outcomes [22].

Antipsychotic drugs with LAI formulationswere developed to reduce the problem ofnon-adherence, which is estimated to be as highas 40% or more [10, 14, 23]. LAI antipsychoticshave a number of advantages over oralantipsychotics. LAIs are formulated to maintainstable therapeutic blood levels during the per-iod between injections (commonly every 2–4 weeks, with the exception of a new formula-tion of paliperidone palmitate administeredevery 3 months), reduce the need to remindpatients to take their medication, lack an abruptdecline in blood level of the antipsychotic agentif an injection is missed, avoid bioavailabilityissues that occur with oral preparations (gas-trointestinal absorption problems and hepaticfirst-pass metabolism), and reduce the risk ofaccidental or deliberate overdose [2, 14]. Fur-thermore, LAIs facilitate the regular contactbetween patients and physician essential foreffective monitoring of the patient’s progress,allow physicians to rule out non-adherence as acause of relapse, and, should a patient miss aninjection, there remains some time to act toavert a crisis [24]. However, potential disad-vantages include reduced flexibility of admin-istration, a potentially extended period oftitration to optimal dose, and a longer durationrequired to achieve steady state, relative to oraladministration [25].

Long-acting formulations of second-genera-tion antipsychotic drugs, including risperidone,

olanzapine, paliperidone and aripiprazole, havebeen developed [25]. They provide physicianswith the opportunity of rapidly achievingsteady state of the antipsychotic agent, togetherwith good flexibility in available dosages. Forexample, aripiprazole is available in a long-act-ing formulation for administration once-monthly at dosage of 400 mg.

Determining the appropriate duration ofantipsychotic therapy to ensure long-termcontinuity of the maintenance phase ofschizophrenia is the subject of some debate.There is evidence that, compared with contin-uing treatment, there is a higher risk of relapseif treatment is discontinued in patients despitetheir being stable on antipsychotics for up to5 years after an acute episode [26]. Therefore,treatment guidelines such as those of theCanadian Psychiatric Association and theWorld Federation of Societies of Biological Psy-chiatry (WFSBP) recommend continuation ofantipsychotic drugs for the treatment of first-episode psychosis for at least 2 years after firstremission, with a minimum of 5 years of relap-se-free stability before considering slow with-drawal of antipsychotic drugs over an extendedperiod (6–24 months) in patients with a historyof recurrences [27, 28]. However, as withlong-term therapy for any chronic disease,careful consideration of treatment-related sideeffects must be undertaken. First-generation, ortypical, antipsychotic agents are associated withsignificant and potentially disabling and dis-tressing side effects, including extrapyramidalside effects (parkinsonism, dystonia, akathisia,tardive dyskinesia), lethargy, sedation andweight gain [2]. Newer atypical or second-gen-eration antipsychotics were developed to bemore effective while reducing the likelihood ofdisabling side effects. In particular, they have alower risk of acute extrapyramidal symptomsand tardive dyskinesia, although they may beassociated with other side effects, such asweight gain, hyperprolactinemia and metaboliceffects [2].

Although LAI antipsychotics have often beenchosen only when oral formulations had failed,and many clinicians adopt the position that LAIantipsychotic agents should not be used asfirst-line therapy for schizophrenia, there is

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good evidence for their use as a first-choicetreatment, supported by recent guidelines andstudies [14, 29]. A recent large ‘real-world’cohort study of the use of oral and LAIantipsychotics after the first hospitalization ofpatients for schizophrenia found that lessthan half [45.7%, 95% confidence interval(CI) 43.7–47.6%] adhered to their dischargeantipsychotic during the first 60 days after dis-charge [29]. However, there was a significantlylower risk of all-cause antipsychotic discontin-uation with LAIs, and LAIs significantly reducedthe risk of rehospitalization, compared with oralantipsychotics. During a mean follow-up of2 years, the adjusted hazard ratio (HR) forrehospitalization for LAIs was about a third thatassociated with oral antipsychotics (HR 0.36,95% CI 0.17–0.75, P = 0.007) [29], indicatingthat LAIs were associated with substantiallybetter outcomes. Indeed, the Texas MedicationAlgorithm Program, following expert panelreview of the clinical evidence for the treatmentof schizophrenia, recommends that physiciansshould assess and consider the use of LAIs whenschizophrenic patients are inadequately adher-ent at any stage [30, 31]. Furthermore, theFrench Association for Biological Psychiatry andNeuropsychopharmacology guidelines for theuse and management of antipsychotic depots inclinical practice recommend LAI antipsychoticsbe considered as first-line treatment in themajority of patients who require long-termtherapy [32].

The concept of ‘effectiveness’, that is, acomprehensive pragmatic approach that inte-grates aspects of efficacy, safety and tolerabilityfrom the perspective of both patient and clini-cian, is essential to the satisfactory evaluation ofa long-term treatment [33, 34]. The comparativeeffectiveness of oral versus long-acting antipsy-chotics has been addressed in a number ofstudies, reviewed recently by Alphs et al. [35],with inconsistent findings, and by Suzuki, whoplaces comparisons between oral and long-acting antipsychotics in a clinical context,commenting that results from randomizedcomparative trials rely heavily on study designand population [36]. These inconsistent find-ings may be influenced by methodologicalconsiderations in clinical study design; that is,

naturalistic/pragmatic versus explanatory trialdesigns. Explanatory clinical trials are designedto measure the efficacy of a treatment in a rel-atively homogeneous patient population underhighly controlled and well-defined conditionsof frequent, intensive, and standardized clinicalassessments that make adherence to treatmentmore likely than in routine clinical practice[35]. Such trials are unlikely to recruit patientsat added risk of non-adherence, e.g., patientswith first-episode psychosis or substance abusedisorders, or those with a history of violence.In contrast, pragmatic trials measure theeffectiveness of an intervention in a moreheterogeneous patient population better repre-sentative of a more naturalistic clinical practicesetting. Indeed, two large meta-analyses ofrandomized controlled trials, which concludedthat there is no advantage of LAIs over oralantipsychotics in preventing relapse and hos-pitalization [37, 38], were largely dependent onhighly explanatory trials, whereas meta-analy-ses that have included trials with more prag-matic trial designs have shown significantadvantages for LAI formulations over oralantipsychotic in the naturalistic setting [39–41].LAI formulations have been consistently supe-rior to oral antipsychotics in mirror-imagestudies which compare treatment periods withoral antipsychotics with those of LAIs in thesame patients. Results from a recent systematicreview and meta-analysis of mirror-image stud-ies showed strong superiority of LAIs comparedwith oral antipsychotics in preventing hospi-talization in patients with schizophrenia [42].

Despite evidence that LAI antipsychotics arehighly efficacious in schizophrenia, and somereal-world evidence suggesting that prescribedLAI antipsychotics are often used concomi-tantly with oral antipsychotics and psy-chotropics [43], LAI antipsychotics remain anunderutilized treatment option.

In fact, there is research to show thatunderutilization of LAIs originates more fromideologic hesitation and attitudinal barriers onthe part of psychiatrists and physicians ratherthan on any skepticism from patients towardsLAI drugs [44–48], and there is increasingacceptance that psychiatrists should considerthe use of LAIs as a treatment option more often

Adv Ther (2017) 34:1036–1048 1039

in general, and also earlier in the treatmentcourse [49].

Aripiprazole Long-ActingInjectable in Schizophrenia

Aripiprazole is a second-generation antipsy-chotic. Unlike other currently available first-and second-generation antipsychotics, theantipsychotic efficacy of aripiprazole has beenmainly attributed to a combination of partialagonism at human dopamine D2 and serotonin5-HT1A receptors and antagonism at serotonin5-HT2A receptors [50–53]. Aripiprazole exhibitshigh affinity for dopamine D2 and D3, sero-tonin 5-HT1A and 5-HT2A receptors, moderateaffinity for dopamine D4, serotonin 5-HT2C and5-HT7, a1-adrenergic and histamine H1 recep-tors, and moderate affinity for the serotoninreuptake site [54]. Consequently, aripiprazolehas a low potential for clinically relevantweight gain, sedation, or metabolic adverseevents [54–58].

Aripiprazole is well absorbed and widelydistributed throughout the body [54]. Com-pared with Cmax of the tablet formulation,geometric mean maximum concentration ishigher (mean 19%) with aripiprazole 5 mgshort-acting intramuscular (IM) administra-tion [59]. Systemic exposure is generallysimilar after aripiprazole IM injection andafter oral tablet administration, over 24 h,and the IM route of administration is notexpected to alter aripiprazole metabolicpathways [59]. Aripiprazole dose is to bereduced with concomitant administration ofpotent CYP3A4 or CYP2D6 inhibitors andshould aripiprazole be given concomitantlywith potent CYP3A4 inducers, aripiprazoledose is to be increased [54].

An extended release formulation ofaripiprazole [Abilify Maintena�; aripiprazole400 mg once-monthly (AOM 400)] has beendeveloped [60]. AOM 400 and 300 are bothapproved in Europe for maintenance therapy ofschizophrenia in adult patients stabilized withoral aripiprazole. The formulation is a powderto be reconstituted in sterile water for IMinjection in the gluteal or deltoid muscle [60].The pharmacokinetics, tolerability and safety of

aripiprazole once-monthly were investigated ina 24-week, open-label, parallel arm pharma-cokinetic study that established a recom-mended dose of 400 mg [61], both as first andmaintenance dose. AOM 400 provided sus-tained mean plasma concentrations of arip-iprazole comparable to those achieved withmultiple consecutive daily doses of oral arip-iprazole 10–30 mg/day at steady state, withoutany clinically meaningful changes in adverseevents, laboratory values, vital signs, or elec-trocardiogram measurements [61].

The recommended maintenance dose ofAOM, 400 mg, can be reduced to 300 mg in theadvent of adverse events or in patients who areknown to be cytochrome P450 (CYP) 2D6 poormetabolizers. Patients taking AOM 400 con-comitantly with strong CYP3A4 (e.g., ketocona-zole, itraconazole) or strong CYP2D6 inhibitors(e.g., fluoxetine, paroxetine, quinidine) formorethan 14 days also require a dose reduction to300 mg [60]. Concomitant administration ofAOM in patients taking CYP3A4 inducers (e.g.,carbamazepine, rifampicin, phenobarbital) formore than 14 days is forbidden.

The registrational trials for AOM 400 con-sisted of two pivotal international randomized,double blind, multicenter, phase III studiesthat compared AOM 400 either with placebo[55] or with active and sub-therapeuticthreshold treatments [62] in adults aged 18–-60 years meeting DSM-IV-TR schizophreniacriteria and requiring maintenance antipsy-chotic therapy. Time to impending relapse (theprimary endpoint) was significantly delayedwith AOM 400 relative to placebo [55], whileAOM 400 was non-inferior to oral aripiprazole(10–30 mg) and superior to a subtherapeuticdose (50 mg) of once-monthly aripiprazole, forthe primary endpoint of impending relapserate [62]. AOM 400 was shown to be well tol-erated in both studies, with minimal injectionsite pain and a safety profile consistent withcomparators and with that reported for oralaripiprazole in previous registrational mainte-nance studies [55, 62].

In the placebo-controlled study, as well assignificantly delaying time to impendingrelapse compared with placebo, AOM 400reduced relapse rates, with 39.6% of placebo

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recipients meeting criteria for relapse at the52-week final analysis, compared with 10.0% ofAOM 400 recipients (HR 5.03, 95% CI3.15–8.02) [55]. Mean positive and negativesyndrome scale (PANSS) total scores improvedfrom a mean of 65.1 during the oral aripiprazoleand AOM stabilization phases, and were similarin both groups at the double blind baseline(54.4 for placebo and 54.5 for AOM 400). Inpatients randomized to AOM 400, theimprovements in PANSS total scores weremaintained throughout the 52-week treatmentperiod (mean change of ?1.4), while significantincreases in mean PANSS total scores wereobserved in the placebo group from as early asweek 2 and continued at all time points (?11.6at week 52, P\0.0001). As the efficacy of AOM400 was demonstrated at the preplannedinterim analysis, the study was terminated earlyto avoid further exposure to placebo.

In the active-controlled non-inferioritystudy, PANSS total scores deteriorated in thearipiprazole once-monthly 50-mg group duringthe treatment phase, and there were statisticallysignificant differences for AOM 400 versus botharipiprazole once-monthly 50 mg and oralaripiprazole at week 38 (study end). At week 38,the change from baseline in PANSS total scorewas –1.66 for AOM 400, ?0.58 for oral arip-iprazole, and ?3.08 for aripiprazole once-monthly 50 mg (P = 0.0272 for AOM 400 vs.oral aripiprazole and P = 0.0002 for AOM 400vs. aripiprazole once-monthly 50 mg) [62].

In these and other key phase III studies, 90%of patients across studies who were initiated onthe AOM 400 mg dose remained on that dosethroughout, and rates of discontinuation due tolack of efficacy were in the order of 2%–10%[55, 62–64]. As well as confirming 400 mg as aneffective, safe and well tolerated initial dose inschizophrenic patients, Raoufinia et al.demonstrated that the efficacy, safety and tol-erability of AOM 400 in patients who were sta-bilized with oral aripiprazole for 2 weeks afterthe 1st injection of once-monthly aripiprazolewas consistent regardless of whether patientswere previously stabilized on oral aripiprazole10 or 30 mg/day [64]. Overall, the pivotalstudies have shown that AOM 400 produces an

effective therapeutic effect over extended peri-ods of up to 52 weeks.

In a naturalistic study in a community set-ting, switching patients from oral antipsy-chotics to AOM 400 significantly reducedhospitalization rates (2.7% vs. 27.1% at3 months and 8.8% vs. 38.1% at 6 months,P\0.0001) [56]. This supports evidence from ameta-analysis showing that LAIs are moreeffective in reducing the rates of hospitalizationof patients with schizophrenia than oralantipsychotics [65].

The QUAlity of LIfe with AbiliFY Maintena�

(QUALIFY) study [57] is one of a very limitednumber of randomized studies designed as ahead-to-head comparison of the effects of twosecond-generation LAI antipsychotics with dif-ferent mechanisms of action on health-relatedquality of life and functioning. In this study,AOM 400 was compared with paliperidonepalmitate once monthly. In contrast to moretraditional pivotal studies, the QUALIFY studydesign integrated ‘‘pragmatic’’ or ‘‘naturalistic’’features, more similar to real-life clinical practicesettings. Rather than assessing affectivity andcognition as primary outcomes, the chosen pri-mary endpoint was change in the Hein-richs–Carpenter Quality-of-Life Scale (QLS), ahealth-related quality-of-life scale that assessesintrapsychic, social, and negative symptomsand their consequences for functioning inschizophrenia [60] This endpoint reflects a keylong-term aimof antipsychotic therapy. TheQLSconsists of 21 items in 4 domains consisting ofInterpersonal Relationships (8 items), Instru-mental Role (4 items), Intraphysic Foundations(7 items), and CommonObjects and Activities (2items) [66]. Items are ratedona7-point scale for 0(severe impairment) to 6 (normal/unimpairedfunctioning) with a total score between 0 and126; a higher score indicates better quality of lifeand/or functioning. A difference of 5.3 points onthe QLS total score is considered to be clinicallymeaningful [67]. The effects of treatment onclinical symptoms were evaluated using theCGI-S scale, which provides the physician’simpression of the current state of mental illnessof the patient on a 7-point scale (from 1, normal/not at all ill) to 7 (extremely ill) [57].

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QUALIFY was a 28-week, randomized,non-inferiority, open-label, rater-blinded, head-to-head study that comprised oral conversion toIM injection of AOM 400 or paliperidonepalmitate treatment [flexible dosing, per label,50–150 mg of paliperidone per month (EU andCanada) or 78–234 mg of paliperidone palmi-tate per month (US)] and continuation of IMinjections every 4 weeks. A total of 295 patientswere randomized to treatment, and 183 patients(68% of the AOM group and 57% of thepaliperidone once-monthly group) completedthe study. The primary endpoint was designedto determine non-inferiority and superioritybased on change in QLS total score from base-line to week 28, utilizing a mixed model forrepeated measurements. The non-inferioritycriterion was met if the lower bound of thetwo-sided 95% CI was greater than -5(non-inferiority margin) for the least squaresmean (LSM) treatment difference in change inQLS from baseline at week 28 for AOM 400versus paliperidone palmitate. If met, a prede-fined test of superiority was to be conducted.Superiority of AOM 400 over paliperidonepalmitate was taken to be confirmed if the lowerbound of the two-sided 95% CI was[0 [57].

LSM change from baseline to 28 weeks inQLS total score was 7.47 ± 1.53 for AOM 400,relative to 2.80 ± 1.62 for paliperidone palmi-tate; a statistically significant LSM differencebetween treatments of 4.67 (95% CI 0.32–9.02,P = 0.036) confirming the non-inferiority andestablishing superiority of AOM 400 overpaliperidone palmitate [57]. The variation inQLS from baseline seen with AOM 400 repre-sents a clinically relevant improvement inhealth-related quality of life and functioning. Inpre-defined clinical and treatment effectivenessanalyses, AOM 400 was also consistently supe-rior to paliperidone palmitate in youngerpatients (B35 years). In this group, the LSMtreatment difference from baseline at week 28favoring AOM 400 was 10.7 (95% CI 0.70–20.7,P = 0.037); results which appear to indicate agreater treatment benefit with aripiprazole inyounger patients than that seen with paliperi-done [57].

Adverse events were the most common rea-son for patient discontinuation in the study

(AOM 400: 11.1%; paliperidone palmitate:19.7%). Treatment-emergent adverse events(TEAEs) were more frequent with paliperidonepalmitate rather than AOM 400. The most fre-quent TEAEs during the 20-week LAI continua-tion phase of the study were weight gain,psychotic disorder, and insomnia, all of whichoccurred more frequently in paliperidonepalmitate-treated patients. Extrapyramidal symp-toms were uncommon and occurred in less than5% of patients in each group.

There were also significant improvements insecondary endpoints, including CGI-S scale.Clinical symptoms were significantly moreimproved at week 28 with AOM 400 comparedwith paliperidone palmitate (LMS between-treatment difference in change from baseline-0.28, 95% CI -0.48 to -0.09, P = 0.004) whenassessed with the CGI-S score. This effect waseven more pronounced in younger patients(B35 years) in whom the LMS between-treat-ment difference in change from baseline inCGI-S was -0.44 (95% CI -0.83 to -0.06,P = 0.026) in favor of AOM 400.

Post hoc analyses of data from the QUALIFYstudy have shown that the superior improve-ments in health-related quality of life andfunctioning were accompanied by a reducedrisk of sexual dysfunction and lower elevationof prolactin levels with AOM 400, comparedwith paliperidone palmitate [68]. These effectsmay be related to the differential activity ofaripiprazole and paliperidone on the dopamineD2 receptor.

Expert Opinion

The prevention of relapse, improving the qual-ity of life and psychosocial functioning of thepatient and maintaining recovery are keylong-term goals of pharmacological therapy forschizophrenia. Relapse can be distressing for thepatient and their caregivers and threatens thepatient’s ability to live an independent life,increasing the burden of care and the risk ofrehospitalization and relative costs. In addition,when relapse is impending or present, rates ofsubstance abuse, suicide and violent behaviorrise [2, 7]. Assuring continuity of treatment iskey for the prevention of relapse, as almost all

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patients with schizophrenia will relapse ifantipsychotic therapy is discontinued [19, 26].

Due to its pharmacological profile, aripipra-zole represents an innovative therapeuticchoice for major psychiatric disorders. Itsmodulatory properties on different neurotrans-mitter systems highlight a drug with a broadpharmacological profile and clinical effective-ness in the acute and long-term treatment, asdemonstrated in different clinical trials [69].

The LAI formulation of aripiprazole at doseof 400 mg (AOM 400) is effective in reducingthe risk of relapse, and it is well tolerated with asafety profile comparable to oral aripiprazole[55, 62]. Because of its specific mechanism ofaction and as demonstrated in clinical studies,AOM 400 has important effects on both positiveand negative symptoms of schizophrenia, sothat it provides a valid treatment option forpatients with a prevalence or persistence ofnegative symptoms (with or without cognitivedysfunction), also induced by other antipsy-chotics (e.g., haloperidol, risperidone andpaliperidone) such as decreased ability to initi-ate tasks, affective blunting, apathy, abulia,lowered levels of motivation or drive and poorsocial relationships. Based on the clinical expe-rience of the authors, after AOM 400 introduc-tion, an improvement of positive and negativesymptoms accompanied by a decrease in epi-sodes of irritability was reported, which allowedthe patients to increase social (e.g., interactionwith family, active social life, establishment ofsocio-sexual relationships) and working (e.g.,return to work, ready for work, satisfaction withthe work) functioning and ameliorate theoverall quality of life. All these factors furtherenhance adherence to treatment.

Of particular importance is the QUALIFYstudy, which had a more naturalistic studydesign than traditional pivotal studies, andwhich used the QLS scale as a primary endpointto compare the effectiveness of AOM 400 andpaliperidone palmitate [57]. As a widely usedand validated health-related quality of lifemeasure which focuses on intrapsychic, socialand negative symptoms, the QLS is valuablein measuring functioning in schizophrenia,including response to pharmacological therapy[66]. The four domains of QLS, i.e. intrapsychic

foundations (e.g., sense of purpose, motivation,curiosity, anhedonia, aimless inactivity, empa-thy, emotional interaction), interpersonalrelationships (e.g., household, friends, acqu-aintances, social activity and network and ini-tiative, withdrawal, sociosexual), instrumentalrole (e.g., occupational role, work functioning,work level, and work satisfaction), and com-monplace objects and activities (participationin the community) reflect all of the aspects thatthe clinician evaluates regarding quality of lifein the clinical practice and represent a centrallong-term goal of antipsychotic therapy forclinicians and patients.

In QUALIFY, as well as producing a statisti-cally significant difference in QLS total scorerelative to paliperidone palmitate, AOM 400significantly improved the intrapsychic foun-dations domain of the QLS, which also includesnegative symptoms, contributing most to thegreater, and clinically relevant, improvement inpatient functioning seen with AOM 400, com-pared with paliperidone palmitate [57]. Basedon the clinical experience of the authors, theimportant positive effect of aripiprazole LAI onclinical symptoms, functioning and health-re-lated quality of life is pivotal in order to involvepatients in rehabilitation programs, obtaininglong-term continuity.

Furthermore, AOM 400 was particularly effec-tive in younger patients, with a between-treat-ment difference of 10.7 points in patients agedB35 years,which is larger than thenon-inferioritymargin of minus 5 points and approximatelydouble the 5.3-point difference from baselineestimated by Falissard et al. to be the minimalclinically important difference for QLS [67].Another key secondary endpoint, CGI-S, whichshowed significant improvements from baselineat study end with AOM 400 relative to paliperi-done palmitate, was also greater in youngerpatients [57].

This evidence supports the benefits of earlyintervention with LAIs, seen in other studies[14, 21, 70], with early intervention in patientswith schizophrenia improving clinical and psy-chosocial long-termoutcomeswhile, on theotherhand, the risk of relapse or poor long-term out-comes increases when access to effective mentalhealth services is delayed. Newly diagnosed

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patients may not be fully aware of or have fullyaccepted the seriousness of their illness, and theyare often less adherent, making the use of along-acting medication a sensible strategy to beconsidered [24]. Treatment considerations thattend to reserve LAIs for patients in stages of thedisease when the symptoms are most severe,when treatment with oral medications fails, orwhen there are problems of poor adherenceshould be reexamined. Daily interactionsbetween caregivers and the patient to ensurecompliance with oral antipsychotic medicationscan be negative and stressful. With its demon-strated efficacy and effectiveness and uncertaintyabout adherence removed, AOM 400 may be ofparticular benefit for younger patients.

Despite the apparent reluctance of somephysicians to offer LAIs, even when the poten-tial benefit to the patient is clear, in the clinicalexperience of the authors switching to AOM400 from other LAIs or oral antipsychotics wascompletely manageable. A discussion of opti-mal switching strategies to AOM from otherantipsychotic agents is beyond the scope of thisarticle. However, strategies for switching havebeen discussed by recent expert consensuspanels [71, 72], and a recent article by Raoufiniaet al. [64] provides a rationale and details rec-ommended strategies for the initiation of AOMin patients with schizophrenia. The effects ofAOM 400 are apparent from the start of therapy,and rapid amelioration of symptoms wasnoticed by caregivers and contributed to patientsatisfaction with treatment. A recent study thatevaluated hospitalization rates in patients swit-ched from oral antipsychotics to AOM 400 [56]found that the number of psychiatric hospital-izations significantly reduced after switching toAOM, further supporting the effectiveness ofusing AOM in the community setting.

The safety and tolerability of AOM 400was comparable to previous experience withorally-administered aripiprazole, with minimalweight gain or changes in metabolic parametersand prolactin levels [56]. Administration of AOM400 is straightforward, with minimal injectionsite pain and a reduced need for concomitanttreatment with other antipsychotic compoundsto achieve treatment aims. Patient-reportedtreatment satisfaction with AOM is high after

switching to AOM 400 maintenance therapy,with patients describing positive perceptions oftolerability with no or fewer side effects withAOM 400 than with prior antipsychotic medi-cation [73]. The authors have, in their clinicalpractice, patients on AOM 400 therapy for over30 months that have maintained a good qualityof life without relapses or rehospitalization.Patient satisfaction with therapy allows patientsto return to a productive life with enhancedsocial relationships and work reintegration. Theeffective control of symptoms, reduced rates ofsexual dysfunction, hyperprolactinemia, meta-bolic effects, and extrapyramidal symptomswithAOM 400 make it particularly suited for patientswith these side effects from other antipsychoticmedications.

Taking into account all of the considera-tions above, the choice of using AOM 400 inclinical practice might be oriented on youngpatients, who can hence benefit more from along-acting treatment effective on clinicalsymptoms, functioning and quality of life, onpatients presenting a history of positive andnegative symptoms with or without cognitiveimpairments, and on patients experiencingpersistent side effects with the current treat-ment such as metabolic effects, weight gain,extra-pyramidal symptoms and sexual prob-lems. Nevertheless, the promising resultsacross the ‘‘full spectrum’’ of efficacy in tra-ditional clinical trials, as well as thoseencompassing the concept of effectiveness ina more naturalistic setting of real-life clinicalpractice, support the use of AOM 400 beyondsituations of poor adherence or when oralantipsychotics have failed. Although furtherstudies are required to fully define the role ofAOM 400 in the treatment of schizophrenia,evidence is now available for its use acrossthe continuum of patients encountered inclinical practice.

CONCLUSIONS

Long-acting injectable antipsychotics can playan important role in enhancing adherence,preventing relapse, and reducing hospitaliza-tions in patients with schizophrenia. Evidence

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from traditional ‘‘explanatory’’ clinical trialsunder highly controlled and well-defined con-ditions, together with that from more ‘‘natu-ralistic’’ or ‘‘pragmatic’’ studies encompassingthe concept of effectiveness in a naturalisticsetting more representative of real-life clinicalpractice, support its early use and suggest abroader role for AOM as a valid long-termtreatment option in the treatment ofschizophrenia, not just in situations of pooradherence or when oral antipsychotics havefailed.

ACKNOWLEDGEMENTS

The authors thank Ray Hill and Gayle Robins,independent medical writers, who providedmedical writing support. Medical writing sup-port, article processing charges and the openaccess fee were funded by Lundbeck Italia. Allnamed authors meet the International Com-mittee of Medical Journal Editors (ICMJE) cri-teria for authorship for this manuscript, takeresponsibility for the integrity of the work as awhole, and have given final approval to theversion to be published.

Disclosures. Enrico Biagi, Enrico Capuzzi,Fabrizia Colmegna, Alessandra Mascarini, Giu-lia Brambilla, Alessandra Ornaghi, Jacopo San-tambrogio and Massimo Clerici have noconflicts of interest to declare.

Compliance with Ethics Guidelines. Thisarticle is based on previously conducted studies,and does not involve any new studies of humanor animal subjects performed by any of theauthors.

Data Availability. Data sharing is notapplicable to this article as no datasets weregenerated or analyzed during the current study.

Open Access. This article is distributed underthe terms of the Creative Commons Attribu-tion-NonCommercial 4.0 International License(http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use,

distribution, and reproduction in any medium,provided you give appropriate credit to the orig-inal author(s) and the source, provide a link tothe Creative Commons license, and indicate ifchanges were made.

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