Neuropsychiatric Disease and Treatment
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`Open Access Full Text Article
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`open access to scientific and medical research
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`REvI Ew
`
`Critical appraisal of lurasidone in the management
`of schizophrenia
`
`Silvio Caccia
`Luca Pasina
`Alessandro Nobili
`Istituto di Ricerche Farmacologiche,
`“Mario Negri”, Milan, Italy
`
`Correspondence: Luca Pasina
`Laboratory of Quality Assessment
`of Geriatric Therapies and Services,
`“Mario Negri” Institute for
`Pharmacological Research, via Giuseppe
`La Masa, 19, 20156, Milan, Italy
`Tel +39 2 39014579
`Fax +39 2 39001916
`Email luca.pasina@marionegri.it
`
`Abstract: Lurasidone is a new atypical antipsychotic in the benzoisothiazoles class of chemicals.
`Like most second-generation antipsychotics it is a full antagonist at dopa mine D2 and serotonin
`5-HT2A receptors, and is a partial agonist at 5-HT1A receptors, a property shared by some but
`not all older agents. It has much greater affinity for 5-HT7 subtype receptors than other atypical
`antipsychotics. Pharmacokinetic studies showed that lurasidone is reasonably rapidly absorbed,
`with bioavailability appearing to be increased by food. Lurasidone undergoes extensive metabo-
`lism to a number of metabolites, some of which retain pharmacological activities. Metabolism
`is mainly by CYP3A4, resulting in steady-state concentrations that vary between individuals
`and are potentially affected by strong inducers and inhibitors of this enzyme. Short-term clinical
`trials have demonstrated the efficacy of lurasidone in acute schizophrenia, with doses of 40
`and 80 mg/day giving significant improvements from baseline in the PANSS and BPRS scores.
`The most common adverse events are nausea, vomiting, akathisia, dizziness, and sedation, with
`minimal increases in the risk of developing metabolic syndrome. Lurasidone did not raise the
`risk of QTc interval prolongation, although additional studies are required. Long-term trials
`are also needed to assess the risk of new-onset diabetes. Ongoing trials in patients with bipolar
`disorder are being completed but, again, efficacy and safety have been investigated only in a
`few short-term clinical trials.
`Keywords: lurasidone, pharmacology, pharmacokinetics, efficacy, safety
`
`Introduction
`Schizophrenia is one of the most debilitating psychiatric disorders and affects about
`1% of the population worldwide.1 It causes recurring and progressive episodes of
`positive symptoms (eg, hallucination, delusions), negative symptoms (eg, alogia,
`anhedonia), disturbed cognitive function (eg, impaired attention), and aggressive/
`hostile and depressive/anxious abnormalities.2,3 It is associated with an increased risk
`of mortality and imposes a huge financial burden on society.4,5 Optimal treatment could
`lighten this burden,6 but it is challenging to develop antipsychotic drugs that stabilize
`the patient and reduce the symptoms and likelihood of relapse.
`Until recently, pharmacological treatment of schizophrenia was based on
` conventional agents such as chlorpromazine and haloperidol (generally called first-
`generation antipsychotics) whose action is thought to be the result of their high-affinity
`dopamine D2 receptor antagonism.7 Although efficacious against positive symptoms,
`these agents have limited efficacy against negative symptoms and can induce various
`severe adverse effects including extrapyramidal symptoms (EPS), which also probably
`reflect blockage of D2 receptors. Nowadays, however, these drugs have been replaced
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`which permits unrestricted noncommercial use, provided the original work is properly cited.
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`by second-generation antipsychotics (also called atypical
`agents, whose prototype is clozapine), due to a more accept-
`able tolerability profile.8,9 While each drug of this atypical
`class has its own receptor profile, most of them show higher
`affinity for serotonin type 2A (5-HT2A) than D2 receptors,
`which have been linked to their better effects on the nega-
`tive symptoms of schizophrenia.10,11 Also, they all share the
`propensity to cause minimal EPS at doses that are clinically
`active against positive symptoms.12–14
`Nevertheless, D2-related treatment-stopping side effects
`such as weight gain, lipid dysregulation, and hyperglycemia
`can still arise with some of these antipsychotics,15–17 and
`they may be associated with cardiovascular adverse events,
`particularly prolongation of cardiac action potential QT
`intervals, an effect which may cause cardiac arrhythmias.18
`Recent pragmatic or effectiveness clinical trials such as the
`clinical antipsychotic trials of intervention effectiveness
`(CATIE) and cost utility of the latest antipsychotic drug in
`schizophrenia study (CUtLASS) have challenged the view of
`the advantages of second-generation antipsychotics over con-
`ventional agents,19–21 although this conclusion is debated.22,23
`Efforts are continuing to identify new molecules with a bal-
`ance of effects on dopamine and 5-HT receptors, as these
`would result in a better therapeutic profile. This has led to
`some new antipsychotic options,24,25 including the benziso-
`thiazole derivative lurasidone, which at the time of writing
`is the most recently introduced chemical.26
`Recent reviews have described the in vitro and in vivo
`neuropharmacology of lurasidone, and have summarized
`the trials examining its therapeutic efficacy and tolerability
`in the management of schizophrenia and schizoaffective
`disorder.27–29 Others have discussed its pharmacokinetic
`and metabolic profiles and compared these to other recently
`released antipsychotics.30 This review further examines the
`clinical pharmacology, pharmacokinetics, efficacy, and
`safety of this antipsychotic.
`
`Methods
`This review is based on a literature search on the international
`database PubMed. The keywords used were “lurasidone”
`and “schizophrenia”; no date constraints were utilized.
`Data were also collected from the product labeling avail-
`able at the manufacturer’s website (www.ds-pharma.com).
`A query “lurasidone” on the ClinicalTrials.gov website
`(www.clinicaltrials.gov) and the FDA’s website (www.fda.
`gov) did not result in the identification any additional com-
`pleted clinical studies. Twenty-nine records that matched the
`two keywords were originally identified from PubMed, with
`
`three of these being clinical trials (one phase II trial and two
`phase III trials).
`
`Pharmacological profile
`Chemically, lurasidone or (3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-
`(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl] cyclohexy-
`lmethyl}hexahydro-4,7-methano-2H-isoindole-1,3-dione
`hydrochloride is structurally related to perospirone and
`ziprasidone (see Figure 1 for chemical structures), and older
`benzisothiazoles with antipsychotic activity. In a similar
`chemical class are the benzisoxazole derivatives risperidone,
`its active metabolite paliperidone, and iloperidone. Besides
`the chemical structure, benzisothiazoles and benzisoxazoles
`shares some minor metabolic pathways.31
`As with its structurally related drugs and many other
`atypical antipsychotics, lurasidone has high affinity for the
`dopamine D2 and 5-HT2A receptors. However, it has the
`highest affinity of any atypical antipsychotic for the 5-HT7
`receptor, the blockade of which may also contribute to its
`antipsychotic effects.32 Experimental studies support the posi-
`tive effects of 5-HT7 antagonists on cognitive impairment,33,34
`memory,35 and mood symptoms.36
`Lurasidone also has high affinity for the 5-HT1A subtype,
`with which it interacts as a partial agonist in a similar way
`to some but not all antipsychotics (eg, the benzisothiazoles
`perospirone and ziprasidone, but not the benzisoxazoles
`risperidone and iloperidone).32 5-HT1A receptors, widely
`expressed in the central nervous system and upregulated in
`the frontal cortex, have been implicated in the enhancement of
`cognitive function in pharmacological models37 and patients
`with schizophrenia; the stimulation of these receptors could
`normalize frontal cortex function and reduce side effects
`induced by dopamine D2 receptor blockade such as EPS,
`including dystonia and diskinesia, abolishing catalepsy and
`the blockade of pituitary-located D2 receptors that control the
`prolactine release that has been observed experimentally and
`clinically with older atypical antipsychotics.37–39 The so-called
`“third-generation” antipsychotic aripiprazole is also a 5-HT1A
`receptor partial antagonist but, unlike benzisothiazole deriva-
`tives, it combines this activity with D2 partial antagonism and
`also exhibits high-affinity D3 antagonism.40
`Lurasidone has affinity for α2c-adrenergic receptors,
`which are also implicated in the enhancement of cognitive
`function, and low affinity for α1-adrenergic receptors, which
`suggests that it will have a low propensity for causing
`orthostatic hypotension. It has minimal affinity for 5-HT2C
`receptors, so would not be expected to cause weight gain.
`It has negligible affinity for histamine H1 and muscarinic
`
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`Lurasidone in the management of schizophrenia
`
`R
`
`N
`
`N
`
`S
`
`N
`
`Drug
`
`Lurasidone
`
`(CH2)4
`
`Perospirone
`
`O
`
`O
`
`N
`
`O
`
`N O
`
`R
`
`H
`
`H
`
`CI
`
`(CH2)2
`
`Ziprasidone
`
`H N
`
`O
`
`Figure 1 Chemical structures of lurasidone, ziprasidone, and perospirone. R = H is 1-(1,2-benzisothiazol-3-yl)-piperazine (BITP).
`
`receptors, which are linked to sedation and weight gain, and
`have negative cognitive effects.32
`In vivo lurasidone and some of its metabolites were simi-
`lar to other antipsychotics in their efficacy in animal models
`predictive of antipsychotic activity.32 Improved cognitive
`effects and mood stabilization were also observed in various
`learning and memory impairment models in rats. Evaluation
`of the secondary pharmacodynamic properties of lurasidone
`showed only very weak potential for drug-associated EPS
`and central nervous system (CNS) depressive effects such
`as exaggeration of anesthesia, muscle relaxation, and inhi-
`bition of motor coordination. Findings are summarized in
`Table 1.27,32,41
`
`Pharmacokinetics
`Lurasidone is rapidly absorbed, reaching peak concentrations
`within 1.5–3 hours (tmax) after single and multiple oral doses.
`
`Its pharmacokinetics were linear in the range of 20 to 160 mg
`in healthy and schizophrenic subjects, but intersubject vari-
`ability was high in both populations (30%–50% in healthy
`subjects, 30%–60% in patients with schizophrenia) in terms
`of plasma maximum concentrations (Cmax) and area under
`the curve (AUC) over the dosing interval (AUCτ).41 Based
`on the amount of lurasidone that was excreted unchanged
`in urine in fasting healthy subjects, systemic bioavailability
`was between 9% and 19%. However, absorption increased
`when the drug was taken with food; in a study comparing
`the steady-state pharmacokinetics of lurasidone 120 mg with
`meals of various calorie and fat content versus the fasted
`state, lurasidone exposure as measured by AUC and Cmax
`increased two- to three-fold in the presence of food, although
`there was no significant difference in exposure based on the
`calorie/fat content of the meal. These findings have been
`reviewed elsewhere.28,29,42
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`Table 1 Main pharmacological properties of lurasidone
`Primary pharmacology
`In vitro studies
` 
` High affinity for human D2L, serotonin 5-HT2A, 5HT1A and 5HT7
`receptors.a
` Partial agonism at human 5HT1A and antagonism at human D2L and
`5-HT7 receptors.a
` High affinity for human α2c-adrenoceptorsa, and relatively high affinity 
`for α1, α2, α2A adrenoreceptor types.
` Little binding affinity for 5-HT3, 5-HT4, noradrenaline β, β1, β2,
`adenosine A1, A2, benzodiazepine, cholecystokinin CCKA, CCKB,
`L-type Ca2+ channel, N-type Ca2+ channel, GABAA, glutamate AMPA,
`kainate, NMDA, glycine, histamine H1, muscarin M1, M2, nicotine,
`opiate, sigma, 5-HT uptake sites, and dopamine uptake sites.
`Antipsychotic-like activity
`
` Inhibition of methamphetamine-induced hyperactivity in rats,a
`apomorphine-induced stereotyped behavior in rats, apomorphine-
`induced climbing behavior in mice and conditioned avoidance
`response in rats.
` Antagonism of central 5-HT2 receptors, as shown by dose-dependent
`inhibition of tryptamine-induced clonic forepaw seizurea,b and
`p-chloroamphetamine-induced hyperthermia in mice and rats.
`Mood-stabilizing effects
`
`Inhibition of conditioned fear stress-induced freezing behavior in rats.
`
` Increased punished drinking response (number of shocks received) in
`Vogel’s water lick conflict test.
` Increased social interaction time spent by pairs of naive rats under
`brightly illuminated conditions in the social interaction test.
`Cognitive effects
`
` Improvement of learning and of memory impairment induced by the
`NMDA-receptor antagonist MK-801 and memory impairment induced
`by the muscarinic receptor antagonist scopolamine in rats.
`Effects on monoamine metabolism
`
` Enhancement of the contents of dopamine metabolites DOPAC
`and HvA and boosted dopamine turnover in the frontal cortex and
`striatum, like other antipsychotic agents.
`Secondary pharmacology
`Potential extrapyramidal symptom liability
`
` No cataleptogenic activity in either mice or rats, whereas comparator
`antipsychotics dose-dependently induced catalepsy.
` No significant effects on the pole-descending time and forepaw 
`reaction time in animal models, unlike comparator antipsychotics.
`Potential for CNS depression
`
` weaker effects than comparator antipsychotics on spontaneous
`locomotor activity, hexobarbital-induced anesthesia, muscle relaxation
`and motor coordination and MES-induced seizures in animal models.
`Notes: aThese properties are shared by metabolites ID-14283 and ID-14326, and
`bmetabolite ID-11614 or 1-(1,2-benzisothiazol-3-yl)-piperazine.
`Abbreviations: DOPAC, 3, 4-dihydroxyphenylacetic acid; HvA, homovanillic acid;
`MES, maximal electric shock; NMDA, N-methyl-D-aspartate.
`Adapted from references 27, 32, 41.
`
`
`
`
`
` 
`
`The mean apparent volume of distribution greatly exceeded
`the body water volume, averaging 6173 L at the recom-
`mended starting dose of 40 mg. Lurasidone has high binding
`to human plasma albumin and alpha-1-glycoprotein ($99%).
`The mean fraction of lurasidone distributed in red blood cells
`was approximately 12% in vivo in healthy subjects.
`In animal studies, lurasidone penetrated the placental bar-
`rier and distributed into the fetus, and was excreted in milk
`during lactation. The manufacturer’s prescribing information
`should therefore be consulted for administration guidelines
`for pregnant and nursing women.42
`Elimination is essentially by metabolism, primarily
`involving CYP3A4-mediated oxidative N-dealkylation,
`hydroxylation of the norbornane ring or cyclohexane ring,
`S-oxidation of the isothiazolyl ring, reductive cleavage of the
`isothiazole ring followed by S-methylation, and combinations
`of two or more of these pathways. The two main metabolites,
`the acidic derivative ID-20219 and its hydroxylated deriva-
`tive ID-20220, had negligible affinity for the rat D2 receptor
`and the human D2L receptor, or for the rat 5-HT2 and human
`5-HT1A, 5-HT2A, and 5-HT7 receptors.
`Besides ID-20219, lurasidone N-dealkylation yields
`to 1-(1,2-benzisothiazol-3-yl)-piperazine (ID-11614 or
`BITP), a metabolite common to perospirone and ziprasidone
`
`(Figure 1). This metabolite also had poor in vitro activity
`at the D2 and 5-HT2 receptors and no antipsychotic-like
`action in preclinical tests although it concentrated in rat
`brain, raising the acetylcholine content (see reference 31 for
`review). BITP shares some of the in vivo pharmacodynamic
`properties of lurasidone in rodent and non-rodent species.26
`After oral doses of radiolabeled lurasidone, exposure to
`ID-11614 varied depending on the species and dose, rang-
`ing from approximately 12% in rats and dogs at 50 mg/kg
`to 100% in monkeys at 10 mg/kg of the plasma exposure to
`lurasidone, but there is little and only incomplete informa-
`tion on its pharmacokinetics compared with the parent drug
`in humans.26
`Two other metabolites, the exo-hydroxy derivative
`ID-14283 and the endo-hydroxy derivative ID-14326 (see
`Figure 2 for chemical structures), showed affinity for D2
`and 5-HT2A comparable to lurasidone. Both also had high
`affinity for human receptor subtypes 5-HT1A and 5-HT7,
`similar to lurasidone’s affinity for these subtypes. In vitro
`functional activity studies suggested that both ID-14283 and
`ID-14326 were partial agonists of the human 5-HT1A receptor
`and potent antagonists of human D2 L and 5-HT7 receptors,
`further suggesting that hydroxylation at position 5 or 6 of
`lurasidone’s norbornane skeleton had little influence on its
`
`Once absorbed, lurasidone is similar to most lipophilic
`antipsychotics in that it extensively distributes in tissues. It
`rapidly enters the CNS, with a dose-dependent increase in
`D2 receptor occupancy up to 60 mg (77.4%–84.3%, depend-
`ing on the region) with no further increases after 80 mg, at
`about the tmax of plasma concentrations in healthy subjects.27
`
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`Lurasidone in the management of schizophrenia
`
`S N
`
`N
`
`N H
`
`NS
`
`N
`
`N
`
`ID-11614
`(BITP)
`
`Lurasidone
`
`O
`
`N
`
`O
`
`N
`
`S
`
`N
`
`N
`
`O
`
`N
`
`OH
`
`O
`ID-14326 (endo-OH)
`
`NS
`
`N
`
`N
`
`O
`
`N
`
`OH
`
`O
`ID-14283 (exo-OH)
`
`Figure 2 The active metabolites of lurasidone. BITP = 1-(1,2-benzisothiazol-3-yl)-piperazine.
`
`neuropharmacological action.42 After oral doses of 20 to
`80 mg/day of lurasidone hydrochloride in Japanese male and
`female patients with schizophrenia, the mean exposure (Cmax
`and AUC24) to ID-14283 and ID-14326 was approximately
`24% and 3%, respectively, of that to lurasidone – this indi-
`cates that these metabolites, particularly ID-14283, contribute
`to the antipsychotic action of lurasidone. As with the parent
`compound, the two metabolites showed similar differences in
`exposure under fed as opposed to fasting conditions.28 Both
`are slightly less bound to human plasma proteins than the par-
`ent drug (98.8%);42 however, brain uptake and concentrations
`compared to lurasidone have not yet been reported.
`In excretion studies in healthy subjects, after a single dose
`of radiolabeled lurasidone was administered approximately
`80% of total radioactivity was recovered in feces and 9% in
`urine.42 In single-dose pharmacokinetic studies in healthy
`subjects (doses ,100 mg/day), the mean terminal half-life
`ranged from 12.2 to 18.3 hours in some studies, but at steady
`state in patients with schizophrenia it rose to between 28.8
`and 37.4 hours.27 Thus, after repeated oral doses in schizo-
`phrenic patients, steady-state concentrations of lurasidone
`were achieved within 7 days.42
`
`Special populations
`Healthy elderly men had approximately 31% lower
` lurasidone Cmax than younger males, but their AUCs were
`similar.27 Exposure to lurasidone and its active metabolites
`in elderly patients with psychosis and in younger subjects
`was similar after 20 mg/day lurasidone hydrochloride.
`Therefore, as with most second-generation antipsychotics,
`no dose adjustment is needed in elderly people.42 Exposure
`in women was 18% higher than in men, which indicates that
`
`oral clearance was lower in women, as assessed by popula-
`tion pharmacokinetic analysis. Asians had 40% less clear-
`ance than Caucasians, but these differences in exposure are
`also not expected to be clinically relevant.41,42 Lurasidone
`pharmacokinetics have not been examined in pediatric and
`adolescent patients.
`Renal impairment led to increased mean exposure to
` lurasidone after oral doses of 40 mg lurasidone hydrochloride.
`Compared with healthy matched controls, mild, moderate,
`and severe renal disease led to mean Cmax increases of 40%,
`92%, and 54%, and AUC increases of 53%, 91%, and
`100%, respectively. The mean t1/2 was also prolonged with
`increasing severity of renal impairment.41 The manufacturer
`recommends that doses should not exceed 40 mg in moderate
`and severe renal-impaired patients. This same dose should
`also not be exceeded in patients with moderate or severe
`hepatic disease.42 In a single-dose study with 20 mg lurasi-
`done hydrochloride, mean AUC(0-last) was 1.5 times greater
`in subjects with mild hepatic impairment, 1.7 times greater
`in subjects with moderate impairment, and 3 times greater in
`those with severe impairment, compared to healthy matched
`subjects. Mean Cmax was 1.3, 1.2, and 1.3 times higher for
`mild, moderate, and severely impaired patients, respectively,
`when compared to healthy matched subjects. The mean t1/2
`for patients with moderate hepatic impairment was greater
`than in healthy subjects (112 versus 93 hours, but in healthy
`subjects this value is much higher than in previous studies);
`there are no data for severe hepatic impairment. Increased
`exposure to active metabolites and their elimination t1/2 were
`also observed with increasing severity of hepatic impairment
`compared with the healthy matched control group, although
`results were not detailed.41
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`Drug interactions
`The manufacturer recommends caution when lurasidone
`is co-administered with CYP3A4 inducers or inhibitors;
`ketoconazole (400 mg daily), for example, increased
`exposure to lurasidone by 7–9 times in healthy subjects
`taking 10 mg, while diltiazepam (240 mg/day), a moderate
`CYP3A4 inhibitor, doubled the AUC and Cmax of the parent
`drug and its active metabolite ID-14283 in healthy subjects.
`The CYP3A4 inducer rifampin (600 mg/day) reduced expo-
`sure to lurasidone by as much as 85% in a single-dose study
`(40 mg) in healthy subjects.42
`Lurasidone itself is a moderate inhibitor of CYP3A4 in
`human tissue preparations and in vivo at steady state
`(120 mg/day) it increased the Cmax and AUC(0–24) of midazo-
`lam (5 mg) by approximately 21% and 44%, respectively,
`although these changes are considered clinically irrelevant.
`Similarly, oral contraceptives containing ethinyl estradiol
`and norelgestromin resulted in negligible changes in Cmax
`and AUC when coadministered with lurasidone (40 mg/day).
`In vitro studies using human tissue preparations suggested
`that clinically relevant concentrations of lurasidone also
`moderately inhibited CYP2C8-, CYP2C9-, CYP2C19-, and
`CYP2B6-mediated reactions.41,42
`Lurasidone has not been shown to affect protein binding
`of biperiden, flunitrazepam, haloperidol, or diazepam, the
`few drugs that have been studied in vitro. Similarly, it did
`not affect protein binding of concomitant highly-bound drugs
`with affinity for albumin and alpha-1-glycoprotein.41
`Although lurasidone is not a substrate of the P-glycoprotein
`(P-gp; and nor is its active metabolite ID-14283), it had
`an inhibitory effect on digoxin transport in vitro in cells
`expressing human P-gp.27 However, co-administration at
`steady state (120 mg/day) with a single dose of digoxin
`(0.25 mg) increased the Cmax and AUC24 of digoxin by only
`about 10%.42
`No interaction was observed when lurasidone (120 mg)
`was administered with lithium (600 mg twice daily) to
`patients with schizophrenia, schizophreniform, or schizoaf-
`fective disorder.
`
`Efficacy in clinical studies
`Table 2 summarizes the nine clinical studies investigating
`the efficacy of lurasidone for schizophrenia in adults (mean
`age 39 years, range 18 to 72 years).28,29,41,43–47 Seven of these
`studies were short-term (6-week) randomized, double-blind
`placebo-controlled studies, with three of these seven being
`phase II trials and four being phase III trials. The FDA
`used five studies for drug approval.41 An active comparator
`
` (haloperidol, quetiapine, or olanzapine) was used in four
`trials.41,45 Data on efficacy was also available from a 3-week
`study that compared lurasidone with ziprasidone in stable
`patients with schizophrenia or schizoaffective disorders,43
`and from an 8-week dose–response trial in inpatients and
`outpatients with schizophrenia.48
`A dose–response study of lurasidone in which 20, 40, or
`80 mg/day was administered indicated that 40 and 80 mg/day
`were associated with significant improvements from baseline
`in the positive and negative syndrome scale (PANSS) and
`brief psychiatric rating scale (BPRS) scores, and achieved
`significantly better results than 20 mg/day.48 Some studies
`used changes in clinical global impression severity (CGI-S)
`score, clinical global impression improvement (CGI-I)
`score, and PANSS subscale score as secondary endpoints.
`At 6 weeks, efficacy primary and secondary measures were
`consistently in favor of lurasidone 80 mg/day over placebo
`(except in one failed trial). Two studies also showed efficacy
`for doses of 40 and 120 mg/day (see Table 2).41,43–45
`A pooled analysis based on a five-factor model of
`schizophrenia from four short-term, double-blind, placebo-
`controlled studies demonstrated that at 6 weeks, lurasidone
`was significantly better than a placebo in improving all five
`PANSS factors (positive, negative, disorganized thought,
`hostility, and depression/anxiety scores).49 Time of onset
`(in the first 3 to 7 days) and trajectory of improvement
`was similar across the 40–120 mg/day dose range when
`PANSS scores were considered. No differences sugges-
`tive of a dose–response relationship were found in GCI-S
`for 40–120 mg/day. Early onset, by day 7, was reported
`in the changes in CGI-S scores for 80–120 mg/day. This
`pooled analysis found no clear dose-response relationship,
`and generalizability was limited by the characteristics of
`patients enrolled in the studies: there were high percentages
`of patients who were white (32 %–52%), male (69%–79%),
`and aged between 37 and 41 years.
`In a 3-week study directly comparing lurasidone
`120 mg/day and ziprasidone 160 mg/day in stable outpatients
`with schizophrenia, efficacy was similar, with an earlier onset
`of improvement in PANSS total score by day 7.43,47 This study
`also evaluated the cognitive effect of lurasidone and found no
`between-group differences on a performance-based cognitive
`functioning assessment battery. Unlike ziprasidone, however,
`lurasidone showed significant within-group improvement
`from baseline on the matrices consensus cognitive battery
`(MCBB) composite score and on the schizophrenia cogni-
`tion rating scale (SCoRS). Another trial was considered
`failed because neither lurasidone (20, 40, or 80 mg/day) nor
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`Lurasidone in the management of schizophrenia
`
`(Continued)
`
`P: -16.0 (±2.1)
`O: -28.7 (±1.9) P , 0.001
`P = 0.022
`L 120 mg/day: -23.6 (±2.1)
`P = 0.002
`L 40 mg/day: -25.7 (±2.0)
`(MMRM):
`total score change from baseline
`Improvement on the PANSS mean
`P: -17.0 (± 1.8)
`P = 0.39
`L 120 mg/day: -20.5 (±1.8)
`P = 0.03
`L 80 mg/day: -23.4 (±1.8)
`P = 0.59
`L 40 mg/day: -19.2 (±1.7)
`(MMRM):
`total score change from baseline
`Improvement on the PANSS mean
`P: -3.8 (±1.6)
`L 120 mg/day: -11.3 (±1.6) P = 0.004
`L 40 mg/day: -9.4 (±1.6) P = 0.02
`from baseline (LOCF):
`Improvement on the BPRS change
`P: -4.2 (±1.3)
`L: -8.9 (±1.3) P = 0.012
`from baseline (LOCF):
`Improvement on the BPRS change
`MCCB score
`treatment for changes on the
`No significant difference between 
`baseline SCoRS.
`for lurasidone to improve from
`A statistical trend (P = 0.058)
`
`(primary outcomes)
`Main efficacy results
`
`Outcome measures
`
`Impression-Severity score
`Secondary: Clinical Global
`Primary: PANSS total score
`
`N = 114
`Placebo
`
`N = 121
`15 mg/day
`Olanzapine (O)
`
`N = 118
`120 mg/day
`N = 118
`40 mg/day
`
`478 patients
`schizophrenia
`exacerbation of DSM-Iv
`Patients hospitalized for acute
`
`6-week
`active controlled trial
`blind, placebo and
`Randomised, double-
`
`201141,45,46
`Meltzer HY, et al
`PEARL 2
`D1050231,
`
`Impression-Severity score
`Secondary: Clinical Global
`Primary: PANSS total score
`Impression-Improvement score
`Severity score; Clinical Global
`Clinical Global Impression-
`Secondary: PANSS total score;
`Primary: BPRS total score
`Severity scores
`Clinical Global Impression-
`Secondary: PANSS total score,
`Primary: BPRS total score
`
`Cognition Rating Scale (SCoRS)
`functioning, and Schizophrenia
`based assessment of cognitive
`Battery (MCCB), interview-
`MATRICS Consensus Cognitive
`
`N = 124
`Placebo
`
`N = 90
`Placebo
`
`N = 90
`Placebo
`
`–
`
`–
`
`–
`
`N = 123
`120 mg/day
`N = 118
`80 mg/day
`N = 121
`40 mg/day
`
`N = 49
`120 mg/day
`N = 50
`40 mg/day
`
`N = 90
`(fixed dose)
`80 mg/day
`
`–
`
`N = 151
`80 mg BID
`Ziprasidone (Z)
`
`daily N = 150
`120 mg once
`
`of patients)
`(number
`Placebo
`
`patients)
`(number of
`regimen
`comparator
`Active
`
`patients)
`(number of
`regimen
`Lurasidone
`
`500 patients
`schizophrenia
`exacerbation of DSM-Iv
`Patients hospitalized for acute
`
`6-week
`controlled trial
`blind, placebo-
`Randomised, double-
`
`149 patients
`schizophrenia
`exacerbation of DSM-Iv
`Patients hospitalized for acute
`180 patients
`DSM-Iv schizophrenia
`exacerbation of
`Patients hospitalized for acute
`
`6-week
`controlled
`blind, placebo-
`Randomised, double-
`6-week
`controlled trial
`blind, placebo-
`Randomised, double-
`
`PEARL 141
`D1050229,
`
`D105000641
`
`et al44
`Nakamura M,
`
`ziprasidone
`schizoaffective disorders,
`schizophrenia or
`meet DSM Iv criteria for
`Adult outpatients who
`
`21 days
`(ziprasidone) trial
`blind, controlled
`Randomised, double-
`
`Potkin, et al43
`Short-term efficacy studies
`
`randomised patients
`Diagnoses and number of
`
`publication)
`Study (year of
`Table 2 Summary of main efficacy lurasidone clinical studies
`
`duration (weeks)
`Type of study and
`
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`measure; PEARL, Program to Evaluate the Antipsychotic Response to Lurasidone.
`Abbreviations: L, lurasidone; H, haloperidol; Z, ziprasidone; P, placebo; BPRS, brief psychiatric rating scale; PANSS, positive and negative syndrome scale; LOCF, last observation carried forward; MMRM, mixed-effect model repeated
`
`Impression-Improvement score
`Severity score; Clinical Global
`Clinical Global Impression-
`Secondary: PANSS total score;
`Primary: BPRS total score
`
`N = 72
`Placebo
`
`N = 72
`10 mg/day
`Haloperidol (H)
`
`N = 71
`80 mg/day
`N = 67
`40 mg/day
`N = 71
`20 mg/day
`
`356 patients
`schizophrenia
`exacerbation of DSM-Iv
`Patients hospitalized for acute
`
`6-week
`active controlled trial
`blind, placebo and
`Randomised, double-
`
`D105004941
`Failed trial
`
`Impression-Severity score
`Secondary: Clinical Global
`Primary: PANSS total score
`
`–
`
`N = 151
`80 mg BID
`Ziprasidone (Z)
`
`N = 150
`120 mg/day
`
`301 patients
`schizoaffective disorders
`schizophrenia or
`Stable outpatiens with chronic
`
`3-week
`controlled trial
`blind, active
`Randomised, double-
`
`Cucchiaro J, et al47
`
`P: -7.9 (±1.4)
`H: -9.8 (±1.4) P = 0.75
`L 80 mg/day: -8.0 (±1.4) P = 1.00
`L 40 mg/day: -5.2 (±1.4) P = 0.44
`L 20 mg/day: -5.0 (±1.4) P = 0.36
`change from baseline (LOCF):
`Improvement on the mean BPRS
`
`Z: -4.5 P , 0.05
`L 120 mg/day: -6.2 P , 0.05
`(MMRM):
`total score change from baseline
`Improvement on the PANSS mean
`P: -10.3
`O: -27.8 P , 0.001
`L 160 mg/day: -26.5 P , 0.001
`L 80 mg/day: -22.2 P , 0.001
`(MMRM):
`total score change from baseline
`Improvement on the PANSS mean
`
`Impression-Severity score
`Secondary: Clinical Global
`Primary: PANSS total score
`
`N = 120
`Placebo
`
`(primary outcomes)
`Main efficacy results
`
`Outcome measures
`
`patients)
`(number of
`Placebo
`
`N = 116
`XR 600 mg/day
`Quetiapine (O)
`patients)
`(number of
`regimen
`comparator
`Active
`
`N = 121
`160 mg/day
`N = 125
`80 mg/day
`
`488 patients
`schizophrenia
`exacerbation of DSM-Iv
`Patients hospitalized for acute
`
`6-week
`active controlled trial
`blind, placebo and
`Randomised, double-
`
`PEARL 341
`D1050233,
`
`patients)
`(number of
`regimen
`Lurasidone
`
`randomised patients
`Diagnoses and number of
`
`duration (weeks)
`Type of study and
`
`public