Practical Guidance on the Use of Lurasidone for the ... · schizophrenia was based on the results of a clinical development programme that included five similarly designed, 6-week-long,

COMMENTARY

Practical Guidance on the Use of Lurasidonefor the Treatment of Adults with Schizophrenia

Afzal Javed . Holger Arthur . Logos Curtis . Lars Hansen .

Sofia Pappa

Received: February 18, 2019 / Published online: May 16, 2019� The Author(s) 2019

ABSTRACT

Introduction: Lurasidone is an atypicalantipsychotic that was approved in Europe in2014 for the treatment of schizophrenia inadults aged C 18 years. Clinical experience withlurasidone in Europe is currently limited, andthere is therefore a need to provide practicalguidance on using lurasidone for the treatmentof adults with schizophrenia.

Methods: A panel of European psychiatristswith extensive experience of prescribing lurasi-done was convened to provide recommenda-tions on using lurasidone to treat adults withschizophrenia.Results: Extensive evidence from clinical trialsand the panel’s clinical experience suggest thatlurasidone is as effective as other atypicalagents, with the possible exception of clozap-ine. Lurasidone is associated with a lowerpropensity for metabolic side effects (in partic-ular, weight gain) and hyperprolactinaemiathan most other atypical antipsychotics and hasa relatively benign neurocognitive side effectprofile. Patients switching to lurasidone fromanother antipsychotic may experience weightreduction and/or improvements in the ability tofocus/concentrate. Most side effects withlurasidone (such as somnolence) are transitory,easily managed and/or ameliorated by doseadjustment. Akathisia and extrapyramidalsymptoms may occur in a minority of patients,but these can be managed effectively with doseadjustment, adjunctive therapy and/or psy-chosocial intervention.Conclusions: Given the crucial importance ofaddressing the physical as well as mentalhealthcare needs of patients, lurasidone is arational therapeutic choice for adults withschizophrenia, both in the acute setting andover the long term.Funding: Sunovion Pharmaceuticals EuropeLtd.

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A. Javed (&)Jepson House, Coventry and WarwickshirePartnership NHS Trust, Nuneaton, UKe-mail: [email protected]

H. ArthurNorthern Stockholm Psychiatry, Stockholm HealthCare Services, Stockholm, Sweden

L. CurtisYoung Adult Psychiatry Unit, Geneva UniversityHospitals, Geneva, Switzerland

L. HansenEarly Intervention in Psychosis Team, SouthernHealth NHS Foundation Trust, Southampton, UK

S. PappaWest London Mental Health Trust, London, UK

Neurol Ther (2019) 8:215–230

https://doi.org/10.1007/s40120-019-0138-z

Keywords: Antipsychotic; Cardiometabolicside effects; Lurasidone; Schizophrenia; Weightgain

INTRODUCTION

Several professional international and nationalorganisations have published guidelines for thetreatment of adults with schizophrenia,including the World Federation of Societies ofBiological Psychiatry [1, 2], the American Psy-chiatric Association [3], the National Institutefor Health and Care Excellence [4] and the Bri-tish Association of Psychopharmacology [5, 6].Key goals of treatment during the acute phase ofschizophrenia are to prevent harm, controldisturbed behaviour, reduce the severity ofpsychosis and its associated symptoms, deter-mine and address the factors that led to theoccurrence of the acute episode, achieve a rapidreturn to the best level of functioning anddevelop an effective alliance with the patientand family [1, 3]. During the stabilisation andmaintenance phases, the main goals are tofacilitate continued symptom reduction, con-solidate and maintain remission, promote theprocess of recovery, maintain or improve func-tioning and quality of life and monitor foradverse treatment effects [2, 3].

A common theme among current guidelinesis the importance of addressing the physical aswell as mental healthcare needs of patients[1–6], in order to ensure that overall health,wellbeing and quality of life are optimised overthe long term. Since antipsychotic agents areassociated with differential risks of a variety ofadverse effects, including extrapyramidalsymptoms (EPS) and cardiometabolic, neu-rocognitive, sexual and endocrinological sideeffects, there has been an increasing focus onthe importance of monitoring for such sideeffects and of choosing and adapting treatmentbased on each individual patient’s specificneeds, priorities and preferences [1–6].

Meta-analysis of available evidence hasindicated that, with the exception of clozapine,the efficacy of atypical antipsychotics is broadlysimilar [7]. Moreover, direct head-to-head evi-dence from clinical trials, such as the Clinical

Antipsychotic Trials of Intervention Effective-ness (CATIE) study and the Cost Utility of theLatest Antipsychotic drugs in SchizophreniaStudy (CUtLASS), has demonstrated that theefficacy of atypical agents is also similar to thatof typical agents [8, 9]. Atypical antipsychoticsdiffer pharmacologically from typical agents intheir lower affinity for dopamine D2 receptorsand greater affinities for other neuroreceptors,including the serotonin and noradrenalinereceptors [10]. Although this lower affinity forD2 receptors has resulted in atypical antipsy-chotics being less likely to cause EPS than typi-cal agents, the side effect profiles of availableatypical agents differ greatly, particularly withregards to their relative propensities for causingcardiometabolic and endocrinological adverseeffects (Fig. 1) [7]. There is also considerableheterogeneity among atypical antipsychoticsregarding activating or sedating properties [11].Predominantly activating medications includelurasidone, and predominantly sedating agentsinclude olanzapine and quetiapine [11]. Select-ing the optimal antipsychotic for a given indi-vidual therefore needs to be based on theclinical profile of that individual in terms ofpositive and negative symptoms, as well as onthe side effect profiles of the available antipsy-chotic agents.

Lurasidone is an atypical antipsychotic thatis approved in Europe for the treatment ofschizophrenia in adults aged C 18 years, havingreceived approval for this indication in 2014[12]. In the USA, lurasidone is approved for thetreatment of schizophrenia in adults and ado-lescents (aged 13–17 years) and for the treat-ment of bipolar depression in adults, asmonotherapy and as adjunctive therapy withlithium or valproate [13]. In comparison withmost other atypical antipsychotics, lurasidonehas a lower propensity to cause cardiometabolicside effects, such as weight gain and QTc pro-longation (Fig. 1) [7]. It is, therefore, a poten-tially useful treatment option to address boththe physical and mental health of patients withschizophrenia.

Since clinical experience with lurasidone inEurope is currently limited, a panel of Europeanpsychiatrists with extensive experience of pre-scribing lurasidone was convened in London in

216 Neurol Ther (2019) 8:215–230

October 2017 to share and discuss their experi-ence and provide practical guidance for usinglurasidone for the treatment of adults withschizophrenia. In this article, we outline therecommendations of the panel, within the

context of available evidence for the use oflurasidone in this setting. This article is basedon previously conducted studies and does notcontain any studies with human participants oranimals performed by any of the authors.

Fig. 1 Effect of single antipsychotics, compared withplacebo, on weight change (a), prolongation of thecorrected QT interval (QTc) (b) and prolactin increase(c). For some drugs, little data are available, making theresults unreliable. For example, the results for weight gainwith reserpine are based on only one study with 20patients. This caused uncertainty about the true effect,which is expressed by a large 95% credible interval (CrI).The effect sizes of the single drugs have not been comparedwith each other, but 95% CrIs that do not overlap withthe y-axis indicate statistically significant differences

compared with placebo. ARI Aripiprazole, ASE asenapine,BRE brexpiprazole, CAR cariprazine, CPZ chlorpro-mazine, HAL haloperidol, ILO iloperidone, LOX loxapine,LUR lurasidone, OLA olanzapine, PAL paliperidone, QUEquetiapine, RES reserpine, RIS risperidone, SD standarddeviation, SER sertindole, SMD standardised mean differ-ence, ZIP ziprasidone, ZOT zotepine. Reproduced from[7] with permission from the American Journal ofPsychiatry (copyright� 2017; American Psychiatric Asso-ciation. All rights reserved)

Neurol Ther (2019) 8:215–230 217

PHARMACOLOGYAND PHARMACOKINETICSOF LURASIDONE

Lurasidone is a benzisothiazol derivative, withthe molecular formula C28H36N4O2S�HCl andmolecular weight 529.14 [13]. Similar to mostother atypical antipsychotics, lurasidone is anantagonist, with a high affinity for the dopa-mine D2 and serotonin 5-HT2A (5-hydroxy-tryptamine 2A) receptors (Table 1) [14, 15] and aslightly lower affinity for the dopamine D3

receptors [15]. As with some other atypicalagents (such as aripiprazole), it is also a partialagonist with a high affinity for 5-HT1A receptors[15]. However, lurasidone differs from otheratypical antipsychotics in being an antagonistwith a high affinity for 5-HT7 receptors [15].Lurasidone has negligible affinity at the his-tamine H1 and muscarinic M1 receptors [15],thereby reducing the likelihood of sedation and

weight gain [16], but also possibly increasingthe risk of inducing EPS [17].

Lurasidone has an elimination half-life of20–40 h, consistent with once-daily oral dosing(Table 2) [12]. It reaches peak serum concen-trations in approximately 1–3 h and steady statewithin 7 days [12]. In a food-effect study,lurasidone’s mean maximum plasma concen-tration (Cmax) and exposure (area under thetime–concentration curve) were approximatelythree- and two-fold greater, respectively, whenadministered with food versus without food[18]. Lurasidone undergoes hepatic metabolism,mediated primarily by cytochrome P450 (CYP)3A4 [12]. Although lurasidone is not an induceror inhibitor of CYP3A4, its plasma levels couldbe affected by co-administration with inhibitorsor inducers of this enzyme [12]. Further detailsof lurasidone’s pharmacokinetic profile aresummarised in Table 2.

Table 1 In vitro receptor binding profile of lurasidone compared with other atypical antipsychotics [14]

Receptora Antipsychotic

Lurasidone Olanzapine Quetiapine Risperidone Aripiprazole

D2 ??? ?? ? ??? ???

PA

5-HT1A ???

PA

– ?

PA

? ???

PA

5-HT2A ??? ??? ?? ???? ??

5-HT1C ? ?? ? ?? ?

5-HT7 ???? ? ?? ??? ???

a1 ?? ?? ??? ??? ??

a2a/2c ?? ?/?? ? ??/??? ??

M1 – ?? ?? – –

H1 – ??? ??? ?? ??

Binding strengths are shown for receptor antagonism, unless indicated otherwise: ?: weak; ??: moderately strong; ???:strong; ???? : very strong; PA partial agonista D Dopamine receptor, 5-HT 5-hydroxytryptamine (serotonin) receptor, a alpha adrenergic receptor, M muscarinicacetylcholine receptor, H histamine receptor

218 Neurol Ther (2019) 8:215–230

CLINICAL TRIALS OF LURASIDONEIN ADULTS WITH SCHIZOPHRENIA

Lurasidone’s approval as a treatment forschizophrenia was based on the results of aclinical development programme that includedfive similarly designed, 6-week-long, fixed-dose,placebo-controlled trials and several long-term,open-label maintenance studies (see ElectronicSupplementary Material [ESM] Table S1 fordetails) [19–27]. Details of these clinical trialshave been extensively published and reviewedelsewhere [28, 29]; therefore, only a brief over-view of key data is provided here.

In the acute treatment setting, lurasidonedemonstrated significant reductions in thePositive and Negative Syndrome Scale (PANSS)or Brief Psychiatric Rating Scale (derived fromPANSS) total scores, compared with placebo,across the dose range 37–148 mg/day (ESMTable S1) [19–23]. Lurasidone also demon-strated significant improvements versus placeboacross a range of secondary outcome measures,

including the Clinical Global Impression ofSeverity (CGI-S) (ESM Table S1). In a post hocanalysis of the PEARL 2 trial, lurasidone wasshown to be not significantly different fromolanzapine in terms of both PANSS total scoreand CGI-S score [22]. The most commonlyobserved side effects observed in adults withschizophrenia in the short-term trials (inci-dence C 5% and at least twice the rate for pla-cebo) were somnolence, akathisia, EPS andnausea [13].

The effectiveness and safety/tolerability oflurasidone as a maintenance treatment foradults with schizophrenia were established inan open-label extension study of an initialphase III trial [24]; a 12-month, double-blind,non-inferiority study versus quetiapine exten-ded-release (XR) [25]; a double-blind, placebo-controlled, randomised withdrawal study [26];and a double-blind, active-controlled safetystudy versus risperidone [27] (ESM Table S1). Inthese studies, lurasidone demonstrated sus-tained antipsychotic efficacy for up to12 months of treatment. In the 12-monthPEARL 3 extension study, lurasidone was shownto be non-inferior to quetiapine XR in terms ofrisk of relapse and significantly superior toquetiapine XR in terms of risk of rehospitalisa-tion [25]. In the 12-month safety study versusrisperidone, a comparable improvement inefficacy measures was observed with lurasidoneand risperidone, and the rates of relapse weresimilar [27]. However, the proportion ofpatients who experienced C 7% increase inbody weight with lurasidone was half thatobserved with risperidone (7 vs. 14%), and themedian increase in prolactin from baseline wassignificantly higher for risperidone than forlurasidone (p\0.001) [27]. In the PEARL 2extension study, patients who gained weightfollowing treatment with olanzapine in theinitial acute trial experienced decreased weightand improvements in lipid levels after switch-ing to lurasidone, while those treated withlurasidone or placebo in the acute trial experi-enced minimal changes during maintenancetreatment with lurasidone [24]. Overall, lurasi-done was not associated with clinically signifi-cant changes in cardiometabolic parameters

Table 2 Summary of lurasidone’s pharmacokinetic profile[12, 13]

Pharmacokinetic property Details

Absorption

Bioavailability 9–19%

Time to peak plasma

concentration

1–3 h

Time to reach steady state 7 days

Distribution

Protein binding (serum

proteins)

* 99%

Metabolism

Route Hepatic; CYP3A4-

mediated

Elimination

Route Faeces (80%);

urine (9%)

Elimination half-life 20–40 h

CYP Cytochrome P450

Neurol Ther (2019) 8:215–230 219

following acute and maintenance treatment inits clinical development programme.

CHOOSING LURASIDONE VERSUSOTHER AGENTS TO TREAT ADULTSWITH SCHIZOPHRENIA

Clinical trials are essential for the developmentand approval of new antipsychotics, but theresults do not necessarily reflect the effective-ness and tolerability of an agent when used inclinical practice. In particular, clinical trialsactively select patient populations that are rel-atively homogeneous, and they typicallyemploy rigid dosing and titration schedules,whereas patients encountered in clinical prac-tice have diverse clinical characteristics, neces-sitating individualised treatment. Real-worldstudies therefore provide useful complementaryevidence by demonstrating an agent’s effec-tiveness when used under everyday clinicalpractice conditions. In the case of lurasidone,there is currently a lack of published real-worlddata and, consequently, a need for guidancefrom those experts with clinical experience ofusing lurasidone in this setting.

Efficacy

The opinion of the panel is that lurasidone isefficacious in both the acute and maintenancephases of treatment of schizophrenia in adults.Extensive evidence from lurasidone’s clinicaldevelopment programme (ESM Table S1) and thepanel’s clinical experience suggest that it is aseffective asotheratypical agents, possiblywith theexception of clozapine. In addition, lurasidonemay be an option in patients who have previouslynot responded to other atypical antipsychotics.Since other approved antipsychotics are alsoeffective in treatingadultswithschizophrenia, it isprimarily the side effect profile of lurasidone thatdifferentiates it from other agents.

Low Propensity for Metabolic Side Effects

Individuals with schizophrenia already havedisease-related increased risks of metabolic

problems, including obesity, hyperlipidaemiaand diabetes, which are frequently exacerbatedby the adverse metabolic side effects ofantipsychotic therapy [30, 31]. Antipsychotic-induced weight gain is particularly distressingfor patients, decreasing self-esteem and treat-ment adherence and increasing the likelihoodof depression.

The opinion of the panel is that lurasidone isassociated with a lower propensity for metabolicside effects (in particular, weight gain) thanmost other atypical antipsychotics. Further-more, overweight patients may lose weightwhen treated with lurasidone, although thepanel also acknowledges that a minority ofpatients may gain weight while taking lurasi-done. During the 6-week lurasidone clinicalstudies, approximately 5% of patients experi-enced a C 7% weight gain (Sunovion Pharma-ceuticals Europe Ltd, data on file).

Drug-induced prolongation of the QT inter-val is associated with an increased risk of car-diovascular mortality, and evidence has shownthat there is considerable variation betweenatypical antipsychotics regarding their propen-sities for causing QT interval prolongation[7, 32]. In a meta-analysis of evidence fromrandomised controlled trials (RCTs), observa-tional studies and post-marketing surveillancestudies, all conducted in patients with mentaldisorders treated with six atypical antipsy-chotics (aripiprazole, brexpiprazole, olanzapine,quetiapine, risperidone and ziprasidone), arip-iprazole, brexpiprazole and olanzapine werefound not to increase the QT interval [32]. Inanother meta-analysis of RCTs that included awider range of antipsychotics, lurasidone wasfound to have the most favourable profile interms of prolongation of the corrected QTinterval (QTc) (Fig. 1) [7]. Lurasidone thereforedoes not appear to have a detrimental impacton QTc [7, 12], and none of the panel hasobserved clinically significant QTc prolongationwith lurasidone treatment to date. As with allantipsychotics, however, the QTc should bemonitored before and after initiating treatmentwith lurasidone (see section Monitoring ofPhysical Health).

In accordance with current guidelinesregarding the core importance of physical

220 Neurol Ther (2019) 8:215–230

health [1–6], the panel is in agreement thatlurasidone’s favourable metabolic profile, incomparison with those of most other antipsy-chotics, is a major consideration for long-termmaintenance treatment and is therefore a keyreason for considering lurasidone, for bothclinicians and patients. Choosing an agent witha favourable metabolic profile can lead toimprovements in physical health and wellbe-ing, self-esteem, quality of life and treatmentsatisfaction, which in turn increase the likeli-hood of treatment adherence and therebyreduce the risk of relapse and rehospitalisation.

Low Propensity for Hyperprolactinaemia

Hyperprolactinaemia is associated with a rangeof adverse effects, including sexual dysfunction[33]. Moreover, sexual dysfunction related toantipsychotic-induced hyperprolactinaemia isan important driver of treatment non-adher-ence in schizophrenia [34]. Lurasidone has arelatively neutral impact on prolactin levels incomparison with other antipsychotics [7].Experience with lurasidone did not show thepresence of elevated levels of prolactin in a caseseries of over 30 patients in clinical practice(Afzal Javed, personal communication, 2019).

Low Propensity for Neurocognitive SideEffects

As with metabolic problems, neurocognitivedysfunction in schizophrenia comprises bothillness- and medication-related effects. Manyantipsychotics have detrimental neurocognitiveside effects [35], and neurocognitive side effectsare a major cause of antipsychotic non-adher-ence [36]. Importantly, neurocognition is a keymediator of functional outcome in schizophre-nia [37–39].

The opinion of the panel is that patients whoswitch to lurasidone may experience improve-ments in the ability to focus/concentrate/‘starttheir thoughts’. In the panel’s clinical experi-ence, in some patients, such improvementshave been confirmed using objective tests,supporting some limited evidence from clinicaltrials suggesting that lurasidone treatment may

be associated with improvements in executivefunctioning [40, 41]. However, such limiteddata must be viewed with caution. Since neu-rocognitive side effects are a common com-plaint of patients, particularly young patients,lurasidone’s relatively benign neurocognitiveside effect profile may potentially be an impor-tant factor to consider when choosingtreatment.

Long-Term Wellbeing

The opinion of the panel is that the focus oftreatment should, from its outset, be the long-term wellbeing of the patient. The overalleffectiveness of an agent is not just dependenton its efficacy and tolerability, but on a globalimpression of treatment satisfaction that alsoencompasses a patient’s functional status (sociallife, ability to work, etc.), wellbeing and qualityof life. The panel would like to see quality of lifeas a primary outcome that is systematicallymeasured in future research.

The overall prognosis of schizophrenia isdependent on long-term treatment adherence.It is important to ensure that the initial choiceof treatment is correct, since patients oftenremain on medication that gives a good initialresponse. Moreover, a negative experience inthe early stage of treatment can damage thelong-term patient–doctor relationship. Appro-priate choice of initial treatment will helpoptimise the likelihood of long-term adherence.Good cooperation and communicationbetween acute and community services isrequired to ensure that patients receive themost appropriate treatment from the outset anddo not continue to take medication over thelong term that has adverse metabolic sequelae.Features of lurasidone considered most likely toencourage adherence and help optimise thelong-term wellbeing of patients are its long-term efficacy, low propensity for metabolic sideeffects (particularly weight gain) and hyperpro-lactinaemia and relatively benign neurocogni-tive side effect profile. Naturalistic studies haveprovided further insights into adherence tolurasidone treatment. A real-world assessmentof treatment adherence in patients with

Neurol Ther (2019) 8:215–230 221

schizophrenia, based on insurance claims,demonstrated that adherence to lurasidone wasbetter than adherence to other oral atypicalantipsychotics [42]. In a subsequent prospec-tive, non-interventional, observational study ofpatients consecutively prescribed lurasidone ina UK mental health trust, three variables werefound to be significantly associated with treat-ment discontinuation: treatment resistance atinitiation of lurasidone, poor tolerability to theantipsychotic prescribed immediately prior toinitiating lurasidone and low lurasidone doses,compared with medium and high doses [43].The authors concluded that adherence tolurasidone is likely to be improved by early doseoptimisation and by targeting patients who aremost likely to benefit from treatment (i.e. thosewithout evidence of treatment resistance) [43](see section Dosing for more information on theimportance of early dose optimisation).

Given lurasidone’s efficacy (as acute andmaintenance therapy) and side effect profile—in particular its relatively low propensity forcausing adverse metabolic effects—the opinionof the panel is that it is appropriate to considerlurasidone early in the course of treatment foradults with schizophrenia. First-episodepatients can be treated effectively with lurasi-done and continue to receive lurasidone aslong-term maintenance therapy.

CONSIDERATIONS WHEN USINGLURASIDONE TO TREAT ADULTSWITH SCHIZOPHRENIA

Dosing

Lurasidone is formulated as film-coated tabletsat dose strengths of 18.5, 37 and 74 mg [12].The opinion of the panel is that, for themajority of patients, lurasidone should be ini-tiated without titration at a starting dose of37 mg/day and increased as appropriate,according to response and tolerability, withinthe dose range 37–148 mg/day. Dosing duringmaintenance treatment should continue in thedose range 37–148 mg/day, according toresponse and tolerability. This applies to both

previously untreated patients and thoseswitching from other antipsychotics. The panelalso acknowledges that if there are tolerabilityconcerns, such as a previous history of EPS orakathisia, then it may be appropriate to adjustdosing for a short period of time before up-ti-trating again. In patients with moderate orsevere hepatic impairment, moderate or severerenal impairment or end-stage renal disease,and/or those taking moderate CYP3A4 inhibi-tors, a lurasidone starting dose of 18.5 mg/day isrecommended and the maximum dose shouldnot exceed 74 mg/day (37 mg/day in patientswith severe hepatic impairment) [12].

A randomised, double-blind, placebo-con-trolled trial conducted in adults withschizophrenia demonstrated that, in patientsshowing non-response to 2 weeks of treatmentwith lurasidone 74 mg/day (defined as \ 20%improvement from baseline in the PANSS totalscore), a dose increase to 148 mg/day resulted insignificant symptom improvement, comparedwith continuing treatment with lurasidone74 mg/day [44]. Patients showing an insuffi-cient response to treatment within 2 weeksshould therefore be up-titrated gradually to amaximum dose of 148 mg/day, consistent withthis clinical trial evidence [44]. This approachshould be adopted before a switch to an alter-native treatment is considered.

Switching to Lurasidone from OtherAntipsychotics

The opinion of the panel is that, in general, across-titration approach should be used whenswitching to lurasidone from another antipsy-chotic. The previous antipsychotic should begradually down-titrated as lurasidone is gradu-ally up-titrated over a period of approximately2 weeks. Since the elimination half-life oflurasidone is 20–40 h [12], its full clinical effectmay not be observed until after 1 week oftreatment with an adequate dose. In patientsswitching to lurasidone due to tolerabilityproblems, a faster cross-titration may be used.Conversely, in those switching from anantipsychotic that is particularly sedating (e.g.olanzapine, quetiapine), a longer cross-titration

222 Neurol Ther (2019) 8:215–230

may be preferable in order to minimise thelikelihood of rebound effects. In patientsswitching from aripiprazole to lurasidone, cross-titration or an abrupt switch approach can beused, since aripiprazole has a long half-life andcan take up to 16–19 days to be fully eliminated.For this reason, patients switching from arip-iprazole due to side effects should be informedthat they may continue to experience these sideeffects for some time after stopping aripiprazoletreatment.

Requirement for Food and Timingof Administration

Lurasidone should be taken once daily with ameal [12], since food improves its absorption. Iftaken without a meal of at least 350 calories,exposure to lurasidone is substantiallydecreased [13, 18] and the patient will thereforenot receive the appropriate dose.

In the panel’s clinical experience, lurasidonecan be taken at any time during the day, as longas it is taken with a meal. The optimal timing ofadministration will depend on patient choice.Some patients find that taking lurasidone withtheir evening meal decreases the impact of sideeffects, such as akathisia and somnolence.However, since lurasidone may cause insomniain some patients, others find that morningdosing is preferable. Changing the timing ofadministration can therefore be helpful inimproving a patient’s experience of takinglurasidone and may help avoid treatment non-adherence. The requirement to take lurasidonewith a meal can help patients establish a dailyroutine, which may also improve adherence.

Management of ExtrapyramidalSymptoms

Initial data and clinical experience suggest thatthe risk for EPS (acute dystonic reaction, aka-thisia, parkinsonism and tardive dyskinesia)with lurasidone, although low, may be at leastequivalent and perhaps slightly higher than forthe ‘average’ atypical antipsychotic [7, 17]. Assuch, the risk of EPS with lurasidone should beconsidered and the potential development of

EPS assessed for and monitored. If EPS develop,they should be managed by reducing the doseof lurasidone, in accordance with existingguidelines [3, 45, 46]. Nevertheless, evidencefrom clinical trials and extensive clinical prac-tice experience in the USA indicates that therisk of tardive dyskinesia with lurasidone is low[12]. The members of the panel have notobserved any cases of tardive dyskinesia withlurasidone to date, but it is too early to com-ment on this possibility.

As with other antipsychotics, lurasidonetreatment may be associated with akathisia. Inclinical trials, the incidence of akathisia was12.9% with lurasidone versus 3.0% with placebo[12]. The opinion of the panel is that, in clinicalpractice, akathisia may be observed withlurasidone treatment in a minority of patients,particularly when first initiated. However,approaches can be taken to minimise the risk ofakathisia occurring and effectively manage it inthe event of its occurrence.

In patients at risk of developing akathisia(such as young adults, the elderly, those with ahistory of drug/substance abuse and those witha previous history of akathisia with otheragents), the panel recommends adjusting thedose for a short period of time before up-titrat-ing again. Akathisia is also reported less fre-quently in patients who take lurasidone in theevening, as opposed to earlier in the day. Thepanel also recommends using the Barnes ratingscale [47] if akathisia is suspected, since thisscale is useful in differentiating akathisia fromother conditions (e.g. anxiety, agitation), effec-tive in identifying mild cases of akathisia (whenit can manifest as an ‘inner urge to move’,which is often distressing for patients but diffi-cult for them to describe) and helpful inbenchmarking and monitoring progress. Proac-tively asking a patient’s opinion about thecausality of their symptoms can be useful indifferentiating akathisia from conditions suchas anxiety.

The panel highlights that akathisia is unli-kely to respond to treatment with anticholin-ergic agents, unless patients experienceconcomitant parkinsonism [48]. If akathisiaoccurs, it can, however, be effectively managedin a variety of ways (Fig. 2). The lurasidone dose

Neurol Ther (2019) 8:215–230 223

may be decreased for a number of weeks andslowly up-titrated again. Short-term adjunctivetherapy can also be considered, in the followingorder:(1) a b-adrenergic antagonist (‘beta blocker’);(2) a 5-HT2A antagonist, such as mirtazapine

(15 mg) [49], trazodone (titrate up to100 mg over 5 days), mianserin (15 mg) orcyproheptadine (8–16 mg);

(3) a benzodiazepine;(4) clonidine (0.15 mg) or amantadine

(100 mg).Concomitant with these pharmacologicalapproaches, psychosocial intervention shouldbe employed. Patients should be proactivelyinformed of the potential risk of akathisia andreassured that, if it occurs, it is likely to be ofshort duration and can be managed effectively.Management of patient expectations can bevery effective in alleviating the impact of aka-thisia, if it occurs. The use of a relaxation/stretching technique [50] can also be beneficialin addition to pharmacological and psychoso-cial intervention. If the above approaches areineffective, it may be appropriate to consider

switching to an antipsychotic with a lower riskof akathisia.

Management of Other Side Effects

In clinical studies of lurasidone18.5–148 mg/day in patients with schizophre-nia treated for up to 52 weeks, and in the post-marketing setting, the most common sideeffects (C 10% patients) were akathisia andsomnolence [12]. These side effects were doserelated up to 111 mg/day. Other side effectsreported by patients in lurasidone clinicalstudies with an incidence of C 5% and at leasttwice the rate observed in patients treated withplacebo were nausea and EPS [13].

In the panel’s clinical experience, most sideeffects with lurasidone are transitory, easilymanaged and/or ameliorated by adjusting thepatient’s dose. Somnolence/sedation is associ-ated with many antipsychotic treatments, andlurasidone is less sedating than other atypicalantipsychotics, such as quetiapine, olanzapineand risperidone [7], even at a high dose level. Asmentioned previously (see section Dosing), in

Fig. 2 Approaches for managing akathisia (Lars Hansen, personal communication, 2019). 5-HT2A 5-Hydroxytryptamine(serotonin) receptor 2A

224 Neurol Ther (2019) 8:215–230

Table 3 Summary of British Association of Psychopharmacology recommendations for monitoring physical health riskfactors [6]

• The measurements below should be assessed before starting an antipsychotic medication, or as soon as possibleafterwards, and then at the intervals indicated• If there is a change in antipsychotic medication then, when clinically relevant, it is appropriate to revisit all thesteps outlined below

Measurement Monitoring Key interventions

Weight and

BMI

• BMI should be used to monitor whether an individual is

becoming overweight or obese

• Weight should be measured frequently during the early

stage of treatment: ideally weekly for first 4–6 weeks and

then every 2–4 weeks up to 12 weeks (at a minimum,

once every 4 weeks for first 12 weeks of treatment)

• Weight and BMI should then be assessed at 6 months

and at least annually thereafter, unless clinical situation

demands more frequent assessment

• It is important to take ethnicity into account when

evaluating BMI results

• Lifestyle interventions: these should alwaysbe part of the first-line approach and, in

most cases, continued with any additional

intervention

• Antipsychotic switching: switching to an

antipsychotic with a lower propensity for

weight gain should be considered

• Adjunctive aripiprazole: recommended as

a possible intervention for weight gain

associated with clozapine and olanzapine

• Adjunctive metformin: should be

considered to attenuate or reduce weight

gain following antipsychotic treatment

Glucose control • Long-term blood glucose control should be monitored

using HbA1c

• In the early weeks of treatment, fasting or random

plasma glucose may provide a more appropriate measure

of glucose control

• Glucose control should be further assessed at 12 weeks,

6 months and then annually

• Annual screening for pre-diabetic states is

recommended for individuals with

psychosis receiving antipsychotic

medications

• Diabetes should be managed as per NICE

guidelines

Lipid profile • Lipid profile should be assessed at 12 weeks, 6 months

and then annually

• Total cholesterol/HDL cholesterol ratio will be required

to assess cardiovascular risk

• Random rather than fasting sampling can be used if a

fasting sample cannot be obtained

• Dyslipidaemia should be actively managed

according to NICE guidelines

• Use of statins is not contraindicated in

people treated with antipsychotics

Blood pressure • Blood pressure should be monitored at 12 weeks,

6 months and then annually

• Hypertension should be managed

according to NICE guidelines

Neurol Ther (2019) 8:215–230 225

patients switching to lurasidone from anantipsychotic that is particularly sedating, alonger cross-titration may help to minimise thelikelihood of rebound effects, such as insomnia.In newly treated patients, evening dosing withlurasidone may help minimise the impact ofsomnolence. In the panel’s clinical experience,nausea is very rarely reported with lurasidonetreatment. This may in part be due to therequirement to take lurasidone with a meal.

Monitoring of Physical Health

The panel is in agreement that guidelinesrelating to the monitoring of patients’ physicalhealth, such as those formulated by the BritishAssociation of Psychopharmacology (Table 3)[6] and The Maudsley Group [51], should befollowed. These include the measurement ofbody mass index, glycated haemoglobin, lipidsand blood pressure before the patient is startedon antipsychotic treatment and at regularintervals after treatment is commenced [6, 51].Although there is no signal for QTc prolonga-tion with lurasidone treatment, as with allantipsychotics, QTc should be measured beforeand after starting lurasidone treatment, in line

with existing guidelines (such as The MaudsleyPrescribing Guidelines [51]).

As previously mentioned (see section LowPropensity for Hyperprolactinaemia), lurasi-done has a modest impact on prolactin levels incomparison with other antipsychotics [7]. Aswith all antipsychotics, it is nevertheless pru-dent to monitor prolactin levels in patientstreated with lurasidone, particularly sinceapparently asymptomatic patients may haveincreased prolactin levels that can have adetrimental impact over the long term (e.g.decreased bone mineral density, increased riskof breast cancer) [33]. Hyperprolactinaemia isassociated with a range of adverse effects,including sexual dysfunction, irregular men-strual cycle, abnormal semen production,infertility, galactorrhoea and hirsutism [33]. Inthe panel’s clinical experience, sexual dysfunc-tion is one of the most important drivers oftreatment non-adherence. Patients shouldtherefore be proactively asked about sexual sideeffects, since they are unlikely to spontaneouslyvolunteer the information.

Table 3 continued

• The measurements below should be assessed before starting an antipsychotic medication, or as soon as possibleafterwards, and then at the intervals indicated• If there is a change in antipsychotic medication then, when clinically relevant, it is appropriate to revisit all thesteps outlined below

Measurement Monitoring Key interventions

Tobacco

smoking and

alcohol use

• Tobacco smoking and alcohol use should be enquired

about at all opportunities

• Those who smoke should be referred to

smoking cessation services

• Alcohol and other substance use should beassessed and treatment focussed on any

harmful substance use, abuse or

dependence

• Optimisation of antipsychotic treatment

may play a role in reducing substance

misuse

BMI Body mass index, HbA1c glycated haemoglobin, HDL high-density lipoprotein, NICE National Institute of Healthand Care Excellence

226 Neurol Ther (2019) 8:215–230

Shared Decision Making

The panel highlights that, wherever possible,patients should be involved in decisions relat-ing to their treatment. The clinical team shouldmake efforts to inform and supportpatients/families/carers in the decision-makingprocess in order to ensure that their expecta-tions are managed and their needs and wishesare taken into account. In addition to its provenefficacy, lurasidone’s low propensities formetabolic side effects (particularly weight gain),hyperprolactinaemia and neurocognitive sideeffects are key reasons why patients may choosethis medication, if they are educated on thesefeatures of lurasidone. Patients/families/carersshould also be fully informed about the poten-tial side effects that can occur with lurasidonetreatment and educated on how to managesuch side effects, if they occur. Long-termadherence is dependent on addressing thespecific individual needs of the patient. Man-agement of expectations is a key aspect of carethat can greatly impact patients’ sense of treat-ment satisfaction and reduce the likelihood ofnon-adherence.

CONCLUSIONS

Based on current evidence and clinical experi-ence, the opinion of the panel is that lurasidoneis an effective atypical antipsychotic for thetreatment of adults with schizophrenia, with afavourable side effect profile, characterised by alow propensity for metabolic side effects andhyperprolactinaemia, and a benign neurocog-nitive side effect profile. Most of the side effectsmost commonly associated with lurasidone,such as somnolence, are transitory and easilymanaged. Akathisia and EPS may occur in aminority of patients, but these too can beeffectively managed with dose adjustment,adjunctive therapy and/or psychosocial inter-vention. Given the increasing recognition ofthe importance of physical as well as mentalhealth in the management of schizophrenia,lurasidone’s effectiveness and side effect profilemake it a rational therapeutic choice for adultswith schizophrenia, both in the acute setting

and over the long term. Importantly, itsfavourable side effect profile addresses some ofthe key problems patients have with some otheratypical antipsychotics—such as weight gainand neurocognitive adverse effects—and there-fore may help encourage long-term treatmentadherence, thereby reducing the likelihood ofrelapse and rehospitalisation.

ACKNOWLEDGEMENTS

Funding. The panel meeting for the devel-opment of this article was organised and fundedby Sunovion Pharmaceuticals Europe Ltd. Arti-cle processing charges were also funded bySunovion Pharmaceuticals Europe Ltd.

Medical writing, Editorial, and OtherAssistance. Editorial support for the prepara-tion of the article was provided by John Scopesof mXm Medical Communications. Support forthis assistance was funded by Sunovion Phar-maceuticals Europe Ltd.

Authorship. The article is based on the dis-cussions from the panel meeting. The opinionsexpressed in the article are the independentviews of the authors and have not been influ-enced by third-party sponsorship. All namedauthors meet the International Committee ofMedical Journal Editors (ICMJE) criteria forauthorship for this article, take responsibilityfor the integrity of the work as a whole, andhave given their approval for this version to bepublished.

Disclosures. All authors received an hono-rarium for attendance of the panel meeting.Afzal Javed has received speaker fees from, andundertaken consultancy work and the organi-sation of scientific meetings for, Sunovion andLundbeck, over the past 3 years. Holger Arthurhas nothing to declare. Logos Curtis hasreceived honoraria for advisory boards, talksand support to attend conferences from Lund-beck, Otsuka, Servier, Sunovion, Takeda andVifor. Lars Hansen has received speaker feesfrom Sunovion, Lundbeck and Janssen, and

Neurol Ther (2019) 8:215–230 227

acted as a consultant for Sunovion and Janssen,over the past 5 years. Sofia Pappa has receivedspeaker fee and conference support from Jans-sen and Sunovion.

Compliance with Ethics Guidelines. Thisarticle is based on previously conducted studiesand does not contain any studies with humanparticipants or animals performed by any of theauthors.

Data Availability. Data sharing is notapplicable to this article as no datasets weregenerated or analysed.

Open Access. This article is distributedunder the terms of the Creative CommonsAttribution-NonCommercial 4.0 InternationalLicense (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommer-cial use, distribution, and reproduction in anymedium, provided you give appropriate creditto the original author(s) and the source, providea link to the Creative Commons license, andindicate if changes were made.

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