Neuropsychiatric Disease and Treatment
`
`Dovepress
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`REVIEW
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`Lurasidone for the treatment of bipolar depression:
`an evidence-based review
`
`Rachel Franklin!
`Sam Zorowitz'!
`Andrew K Corse!
`Alik S Widge?
`Thilo Deckersbach!
`
`'Division of Neurotherapeutics,
`Department of Psychiatry,
`Massachusetts General Hospital,
`Harvard Medical School, Charlestown,
`*Picower Institute for Learning and
`Memory, Massachusetts Institute of
`Technology, Cambridge, MA, USA
`
`Correspondence: Thilo Deckersbach
`Room 2628,Building 149, 13th Street,
`Division of Neurotherapeutics,
`Departmentof Psychiatry, Massachusetts
`General Hospital, Harvard Medical
`School, Charlestown, MA, USA
`Tel +1 617 724 6300
`Fax +1 617 726 4078
`Email tdeckersbach@partners.org
`
`submit your manuscript
`Dove;
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`dx
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`This artide was published in the following Dove Press journal:
`Neuropsychiatric Disease and Treatment
`19 August 2015
`Number of times this article has been viewed
`
`Abstract: Bipolar disorder (BD) is a debilitating and difficult-to-treat psychiatric disease that
`presents a serious burdento patients’ lives as well as health care systems around the world. The
`essential diagnostic criterion for BD is episodes of mania or hypomania; however,the patients
`report that the majority of their time is spent in a depressive phase. Current treatment options
`for this component ofBD haveyetto achieve satisfactory remission rates. Lurasidoneis a drug
`in the benzisothiazole class approved by the US Food and Drug Administration in June 2013
`for the acute treatment ofbipolar depression. Its pharmacologicalprofile features high-affinity
`antagonism at D,, S-HT,,, and S-HT, receptors; moderate-affinity antagonism at o1,,-adrenergic
`receptors; low- to very low-affinity antagonism at ©, ,-adrenergic, o1,,-adrenergic, H,, M,, and
`5-HT,,. receptors; and high-affinity partial agonism at 5-HT|,. Preliminary findings from two
`recent double-blinded clinical trials suggest that lurasidoneis efficacious in treating bipolar |
`depression, with clinical effects manifesting as early as the first 2-3 weeks of treatment (as
`measured by the Montgomery—Asberg Depression Rating Scale and Clinical Global Impressions
`Scale for use in bipolar illness). Its therapeutic benefit appears to be comparableto the current
`US Food and Drug Administration-indicated treatments: quetiapine and olanzapine—fluoxetine,
`according to a measure of effect size known as numberneeded to treat. These studies reported
`relatively limited extrapyramidal and metabolic side effects as a result of treatmentwith lurasi-
`done, with the most commonside effect being nausea. Safety data drawn from these studies, as
`well as a more extensive body of schizophrenia research, indicate that in comparison with other
`atypical antipsychotics, treatment with lurasidoneisless likely to result in metabolic side effects
`such as weight gainor disturbances of serum glucoseorlipid levels. Lurasidone holdsclinical
`potential as a novel, efficacious pharmacological treatment for bipolar depression. However,
`current data on its use for the treatment of BD are limited, and more extensive research, both
`longer in duration as well as independently conducted, is needed.
`Keywords:lurasidone, bipolar depression, bipolar disorder, atypical antipsychotic
`
`Introduction
`Bipolar disorder (BD) is a chronic andoften severely disabling psychiatric condition. Col-
`lectively, forms of BD (type I, type II, or not otherwise specified) are estimated to affect
`approximately 4.4% of Americans or about 12.7 million people.'? Worldwide, BD was
`ranked 18th by the World Health Organization in worldwide causes of years lived with
`disability, surpassing all forms ofcancer.’ The economic burden in terms ofcost ofhealth
`care for patients with BDis estimatedto be four times greater than that for patients without
`mental disorders.’ Overall, the total economic burden ofBD to the US economyis difficult
`to estimate, but one 24-year-old study approximated the figure to be nearly $45 billion,*
`adjusted for inflation; in 2015, the estimate will be closer to $78 billion.®
`The essential diagnostic criterion for BD is episodes of elevated/irritable mood,
`usually either mania (type I) or hypomania (type II).’ Despite this, BD patients have
`
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`features, though long-term clinical data in conjunction with
`neurobiological models remain to be established.
`Lurasidone or (3aR.48,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-
`benzisothiazol-3-yl)piperazin-1-ylmethyl]cyclohexylm-
`ethy]} hexahydro-4,7-methano-2H-isoindole-1,3-dione
`hydrochloride”(as it is known chemically) (Figure 1 for 3D
`chemical structure) is a chemical in the benzisothiazole class,
`structurally related to perospirone and ziprasidone, as well
`as the benzisoxazole derivative risperidone.’! In vitro assays
`have demonstrated that lurasidoneis a full antagonist at D,
`(K=1.68 nM)”(Table 1) and 5-HT,, (K=2.03 nM) receptor
`subtypes, a property shared by other atypical antipsychotics
`such as risperidone, olanzapine, quetiapine, clozapine, and
`aripiprazole.” In comparison to similar drugs, lurasidone
`has the highest binding affinity for the 5-HT, receptor
`(K=0.5 nM).”? Other notable pharmacological properties
`include moderate-affinity o,,-adrenergic antagonism, par-
`tial agonism at the 5-HT,, receptor, and low affinity for the
`muscarinic (M,), histamine (H,) (both K, values > 1,000 nM),
`5-HT,,, (415 nM), o,, (47.9 nM), and o,, (40.7 nM)adren-
`ergic receptors.” Table 1 showsthe pharmacologicalprofile
`of lurasidone.
`
`There is limited evidence that lurasidone may provide
`cognitive benefits due to several properties of its binding
`profile. Blockingactivity at the S-HT, receptor (K=0.5 nM)
`maycontribute to therapeutic benefits as suggested by a study
`of the drug’s effect on learning when given in conjunction
`with an N-methyl-D-aspartate blocker.” Ishiyama et al found
`that rats were prevented from learning a passive-avoidance
`shock response when administered with N-methyl-D-aspar-
`tate receptor antagonist dizocilpine; this inhibition, however,
`was dose dependently reversed when the animals were given
`lurasidone, regardless ofpre- or post-training administration.
`
`reported through surveys and clinical status ratings that they
`spend the majority of their time in a depressive phase* and
`that these episodes are more disruptive to their functioning
`than mania.” Bipolar depression is notably distinct from
`unipolar depression in that its phenomenological features
`more commonly include psychosis, depressive mixedstate,
`anxiety, agitation, anergic depression,irritability, and anger
`attacks.'" Moreover, the increased risk of suicide in patients
`with BD (whose rates of suicide are one ofthe highest among
`patients with psychiatric illness)'!? is observed predomi-
`nantly during the depressive phase."!'?
`Treatment of BD aims for remission of symptoms, both
`manic and depressive. Efficacious treatment, however, is
`not easy to achieve; the remission rate for bipolar mania and
`depression after acute treatment is reported to be approxi-
`mately 40%—-50% and 25%—60%,respectively.'*'* (This esti-
`mate is possibly misrepresentative of long-term remission, as
`a commonfeature of BD depressionis insensitivity to acute
`treatment).'" Factors complicating treatment include toler-
`ance to medications and significant likelihood of relapse,'*
`even with continual pharmacological maintenance.
`Pharmacotherapy optionsfor BDare typically grouped by
`the targeted symptoms.Lithium,first- and second-generation
`antipsychotics, valproate, and carbamazepine are usually
`prescribed for the treatment of acute mania, while quetia-
`pine, olanzapine—fluoxetine, lamotrigine (maintenance),
`and antidepressants in conjunction with an antimanic agent
`(acute) are usually prescribed for the treatment of depres-
`sive symptoms.'*? Currently, only quetiapine, olanzapine—
`fluoxetine combination, and lurasidone are approved by
`the Food and Drug Administration (FDA) to treat bipolar
`depression. Further treatment options are greatly needed, as
`bipolar depression, the most prevalent and fatal feature of
`BD,is often not well covered by these regimens and nonre-
`sponse tofirst-line options is perhaps as high as 40%.'* In
`a review of therapeutic options for treatment-resistant BD
`depression, Sienaert et al found that although promising,
`current research forthis diagnosis is scarce."* In this review,
`we aim to summarize recent available literature regarding
`the compound lurasidone andits role in the treatment of
`bipolar depression.
`
`Pharmacology and pharmacokinetics
`Figure | Three-dimensional structure of lurasidone, also known as (3aR,45,
`Thebiological basis of BD depression remains unknown: one
`7R,7aS)-2-4( 1R,2R)-2-[4-(|.2-benzisothiazol-3-yl)piperazin- |-ylimethyl]cyclohexy-
`
`Imethyi}hexahydro-4,7-methano-2H-isoindole-|,3-dione hydrochloride—or
`current theory, developed by Fountoulakisetal’’ postulates
`Latuda.
`is
`formula
`and molecular
`is 529.13698 g/mol
`Notes: Molecular weight
`that unlike unipolar depression, norepinephrine reuptake
`C,,H,,CIN,O,S. Teal atoms represent hydrogen, gray atoms carbon, red atoms
`and 5-HT,, agonism are heavily implicated as core deficits.
`oxygen, blue atoms nitrogen, and the yellow atomasulfur; the associated hydrogen
`chloride salt is not pictured.'®
`Pharmacologically, lurasidone is appropriate to treat these
`
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`Lurasidone for the treatmentof bipolar depression
`
`Table | Binding profile of the chemical lurasidone: endogenous neurotransmitter, characteristic activity type, and experimentalK,
`values associated with major receptors
`Binding profile of lurasidone*
`Receptor
`
`Neurotransmitter
`
`Binding affinity (K,)° (nM)
`Activity
`262
`Antagonist
`Dopamine
`|.68+0.09°
`Antagonist
`Dopamine
`6.7520.97
`Partial agonist
`Serotonin
`2.0340.46
`Antagonist
`Serotonin
`415
`Antagonist
`Serotonin
`0.495+0.090
`Antagonist
`Serotonin
`47.9478
`Antagonist
`Norepinephrine
`40.74£7.7
`Antagonist
`Norepinephrine
`10.820.64
`Antagonist
`Norepinephrine
`>1,000
`Antagonist
`Histamine
`H,
`>1,000
`Antagonist
`Acetylcholine
`M,
`Notes: “Experimental values reported by Ishibashi et al.* "The equilibrium dissociation constant, decreased value indicated increasedaffinity. “Values are means + standard
`error of the mean of three or more separate experiments.
`
`D,
`D,
`5-HT,,
`5-HT,,
`5-HT,.
`5-HT,
`Oy
`Oy
`
`This effect suggests that lurasidone may contributeto restora-
`tion of the memory consolidation process and maytherefore
`have benefits in reducing the cognitive impairments observed
`in bipolar depression.”*
`Additionally, the drug acts with moderate binding affin-
`ity as an antagonist at ot,-adrenergic receptor (K=10.8 nM),
`overexpression ofwhich has been shownto increase impair-
`ment in the Morris water maze,” further lending support to
`possible procognitive effects of lurasidone.
`Lurasidonealso interactsas a partial agonist at the 5-HT,,
`receptor (K=6.75 nM),”activation ofwhich has been shown
`to increase adult neuronal proliferation in the dentate gyrus
`of the hippocampus.” This influence in neurogenesis may
`be of cognitive therapeutic benefit, as demonstrated bypilot
`clinical studies using antipsychotics with adjunct 5-HT,,
`agonists.”°
`Overall, based on neurobiological evidence, lurasi-
`done may provide advantages in learning and memory via
`high-affinity 5-HT, and moderate-affinity «,.-adrenergic
`antagonism, as well as partial agonism at the 5-HT,,
`receptor.222327
`The 5-HT, receptor-blockingactivity of lurasidone may
`also underlie antidepressant properties of the drug. Selective
`antagonists and experiments in 5-HT, gene knockoutanimals
`have demonstrated anxiolytic-like and antidepressant-like
`effects in rodents, which demonstrated improvement on the
`Vogel drinking, elevated plus-maze, four-plate test, forced
`swimming, andtail suspensiontests.***° It is far from proven
`that these tests translate well to human depression, unipolar or
`bipolar, but they may be useful screens. These mood effects
`may be mediated by a cortical and hippocampal dopamine
`efflux caused by activity at the 5-HT, and 5-HT,, receptors.”
`
`Similarly, lurasidone injected subcutaneously in ado-
`lescent rats modulates levels of brain-derived neurotrophic
`factor by preventing adult decreases in brain-derived
`neurotrophic factor expression normally seen in animals
`exposed to prenatal stress.*' This effect provides support
`for the neurotrophic hypothesis of depression® and further
`implicates lurasidone as a potentially beneficial therapy for
`bipolar depression.
`Clinically, one of the most promising features of lur-
`asidone is its low affinity for muscarinic (M,), histamine
`(H,) (both K, values >1,000 nM), 5-HT,,. (415 nM),at,,-
`(47.9 nM), and «,,-(40.7 nM) adrenergic receptors.* Well-
`known side effects of many antipsychotics, such as sedation,
`weight gain, and negative cognitive symptoms, have been
`only minimally observed in both animal and humantrials
`of lurasidone (see “Safety and tolerability” section). This is
`thought to be due to the low levels of activity of lurasidone
`at H,* and 5-HT,,..** receptors.” Decreased interaction with
`muscarinic and @-] adrenergic receptors may prevent nega-
`tive cognitive and cardiovascularside effects.**
`Despite being a high-affinity D, receptor antagonist,
`historically a harbinger of severe neurologicalside effects,*
`in vivo studies of lurasidone to date have observed fewer
`
`central nervous system’s depressive effects, extrapyramidal
`symptoms, and anticholinergic side effects (such as dry
`mouth or amnesia)”thanother typical and evenotheratypical
`antipsychotics. This may be explainedin part by the drug’s
`receptorsaturation point. A study of lurasidone’s dopamine
`D, receptorbindingin healthy malesusing positron emission
`tomography demonstrated that doses less than 40 mg did not
`achieve adequate binding to reach antipsychotic effect;*’
`however, increasing the dose from 60 mg to 80 mg did
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`not effectively change receptor occupancy (77%-84% and
`73%-79%, respectively). This curve may explain, in part,
`whyincidents of parkinsonism are infrequently seen, as there
`appears to be a dopamine receptor saturation point well below
`the threshold for extrapyramidal symptomology.
`Lurasidoneis primarily metabolized by CY P3A4, with
`the most commonpathways being oxidative N-dealkylation,
`hydroxylation of the norbornane ring, and S-oxidation. The
`half-life, described in the product label as 18 hours, has been
`reported in some studies to be as long as 37 hours, given
`repeatedoral dosesat steady state.*? Several known pharma-
`cologically active metabolites have been described such as
`ID-14283, ID-14326, and ID-11614 (25%, 3%, and <1% of
`parent exposure, respectively).*In vitro studies demonstrated
`that both ID-14283 and ID-14236 showed affinity for D, and
`5-HT,,, as well as partial agonism at 5-HT,, and antagonism
`at 5-HT,. ID-14283 may contribute to the parent compound’s
`efficacy, but has a shorter half-life (7 hours).”"
`
`Therapeutic efficacy
`Though there now exists a growing bodyofliterature detailing
`the pharmacokinetic properties of lurasidone, a complemen-
`tary body ofliterature documentingits efficacy for the treat-
`mentofbipolar I disorder is comparatively less due to the short
`timesinceinitial approval.** Atthe time of writing, only two
`controlled clinicaltrials have begun to investigate lurasidone
`as a treatmentfor bipolar | depression: as a monotherapy*’ and
`as an adjunct treatment with lithium or valproate.*°
`
`Thefirst of the two clinical trials was a randomized,
`double-blind, placebo-controlled, fixed-flexible dose study
`investigating the efficacy of lurasidone as a monotherapy
`treatment for bipolar I depression. Patients were randomly
`assigned to a 6-week treatment group of 20-60 mg/day of
`lurasidone (N=166; mean daily dose =31.8 mg), 80-120 mg/
`day of lurasidone (N=169; mean daily dose =82.0 mg), or
`a placebo (N=170). The primary outcome measure was
`the change between baseline and week 6 scores on the
`Montgomery—Asberg Depression Rating Scale (MADRS);
`a secondary outcome measure wasthe change in the depres-
`sion severity score on the Clinical Global Impressions Scale
`for use in bipolar illness (CGI-BP).
`The investigators reported significantly greater decreases
`in MADRS scoresin both the 20-60 mg/day group (—15.4)
`and in the 80-120 mg/day group (—15.4) as compared to
`the placebo group (—10.7) (Figure 2A). Moreover, a sig-
`nificantly greater reduction in core depressive symptoms
`(MADRS-6 subscale score) between baseline and week 6
`was also observed for the lurasidone 20-60 mg group (—10.4)
`and the lurasidone 80-120 mg group (—10.4) as compared
`to the placebo group (—6.9). A similar pattern was found in
`the CGI-BPscoresfor the 20-60 mg/day group (—1.8) and the
`80-120 mg/day group (—1.7) as comparedto placebo (—1.1).
`Notably,these statistically significant decreases in MADRS
`and CGI-BP scores were observed in both dosage groups
`early in the course of treatment; differences between the
`groupsin reported MADRS scores began at week 2, whereas
`
`A
`
`35-
`
`30-
`
`25-
`
`2
`8
`8 20-
`i)
`& 15
`4
`=
`
`MADRSchangewith treatment
`
`B
`
`6
`
`CGI-BP changewith treatment
`
`2 4-
`8
`a
`Qa 3-
`=
`oO
`oO 2-
`
`
`
`Placebo
`80-120
`20-60
`Adjunct
`Placebo
`20-60
`80-120
`Adjunct
`
`
`
`my [Baseline—Week6|[Baseline—Week6|Week 6mae mold mad
`
`Figure 2 Differences among behavioral outcomes by lurasidone treatment regimen between baseline and Week 6 as measured by MADRS score and CGI-BP score.
`Notes: (A) Mean change in MADRS from baseline to week 6 across different treatments in patients with bipolar | depression. (B) The mean change in depression severity
`score on the CGIscale from baseline to week 6 for the same treatment groups. Placebo, 20-60 mg/day and 80-120 mg/day values reported in Loebel’s monotherapy study;””
`adjunct experimental values from Loebel et al's investigation of lurasidone as adjunctive treatment with lithium and valproate.”
`Abbreviations: MADRS, Montgomery—Asberg Depression Rating Scale, CGI-BP, Clinical Global Impressions Scale for use in bipolar illness; d, day.
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`Lurasidone for the treatmentof bipolar depression
`
`differences in reported CGI-BP scores began at week 1
`for the 80-120 mg group and week 2 for the 20-60 mg
`group. Caution is warranted, however, in interpreting these
`results as the authors included neither standard deviations
`nor confidence intervals in the differences in MADRSor
`
`et al*' compared the benefits of these three treatments using
`the numberneededto treat (NNT) measure.” Asanindicator
`of effect size, NNT measures how manypatients would need
`to be treated with one medication, on average, to observe
`one additional beneficial outcome of interest. Low NNTs
`
`CGI-BPscores. Nonetheless 53% and 51% of subjects met
`response criteria (defined as =50% reduction from baseline
`in MADRStotal) after 6 weeks of treatment with lurasi-
`done 20-60 mg and lurasidone 80-120 mg,respectively,
`as compared to only 30% in the placebo group.Finally, the
`lurasidone 20-60 mgandlurasidone 80-120 mg groups both
`showed proportionately higher remission rates (42%; 40%)
`than did the placebo group (25%).
`The second of the two clinical trials was also double
`
`blinded, but investigated lurasidoneas an adjunctto lithium
`or valproate in the treatment of bipolar I depression. Inclu-
`sion criteria required that patients should not have exhibited
`a response to a 28-day minimumtrial of either lithium or
`valproate, prescribed at therapeutic levels, as determined
`by a health care professional. Qualifying patients were then
`randomlyassigned to receive 6 weeksoflurasidone (N=183)
`or placebo (N=165)in addition to continuingtheir previously
`prescribed medication. Patients receiving lurasidone were
`initially administered a dosage of 60 mg; with each week
`after the first, health care professionals were allowed to adjust
`lurasidone doses by increments of 20 mg within a range of
`20-120 mg/day (the mean daily dose was 66.3 mg). As in
`the monotherapy study, the primary and secondary outcomes
`of interest were changes in the MADRS and CGI-BPscores,
`respectively, between baseline and week 6 ofthetrial.
`Similar to the results of the monotherapytrial, signifi-
`cantly greater decreases in MADRSand CGI-BPscores were
`observed for the adjunct lurasidone group (—17.1; —1.96)
`than for the placebo group (—13.5; —1.51) (Figure 2B).
`These differences were first observed beginning at week 3
`for the MADRSaswell as at week 2 for the CGI-BP, and
`remainedreliably different for the remainderofthe trial. As
`mentioned earlier, caution is again warranted in interpreting
`these results as the authors included neither standard devia-
`tions nor confidenceintervals in the differences in MADRS
`
`or CGI-BPscores. Finally, greater proportions ofpatients met
`response criteria (=50% reduction from baseline in MADRS
`total) and remission (57%; 50%) than were observed in the
`placebo group (42%; 35%).
`Although promising, these preliminary results regarding
`the therapeutic efficacy of lurasidone for the treatment of
`bipolar I depression should be considered with respect to
`the efficacy of preexisting treatments,specifically quetiapine
`and olanzapine—fluoxetine combination. Recently, Citrome
`
`Neuropsychiatric Disease and Treatment 2015:1 |
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`are indicative of large effect sizes, with an example NNT
`of 2 indicating that on average, one of every two patients
`treated with a medication would receive the desired clinical
`benefit.
`
`Citromeet al calculated the NNT for clinical response
`and remission for lurasidone based on the above twoclini-
`
`cal trials, as well as the NNT for quetiapine (immediate and
`extended release) and olanzapine—fluoxetine combination
`based on published 8-weektrials and product labeling (see
`article for details).Of the three reviewed quetiapine stud-
`ies, two studies set dosing levels at 300 mg/day and 600 mg/
`day;**“* the other prescribed quetiapine studies set dosing
`levels at 400 mg/day and 800 mg/day.’ In the two reviewed
`olanzapine—fluoxetine combinationstudies,the dosing levels
`were set at 6/25 mg/day, 6/50 mg/day, or 12/50 mg/day.**’
`Clinical response was defined as a =50% reduction from
`baseline on the MADRS, whereas remission was defined
`as a final MADRSscore of =12. For clinical response,
`NNTvalues of 5 (95% CI 3-8) and 5 (95% CI 4-11) were
`found for patients prescribed monotherapy lurasidone at low
`(20-60 mg/day) or high (80-120 mg/day) doses; an NNT
`value of 7 (95%, 4-24) was found for adjunct lurasidone
`(20-120 mg/day). In comparison, NNT values of 6 and 5
`were found for quetiapine and olanzapine—fluoxetine combi-
`nation in clinical response, respectively. For clinical remis-
`sion, an NNTvalueof 6 (95%, 4—14) was foundfor patients
`with a low dose (20-60 mg/day) ofmonotherapy lurasidone;
`an NNT value of 7 (95%, 4-21) was foundforpatients with
`a high dose (80-120 mg/day) of monotherapy lurasidone;
`and an NNT value of 7 (95%, 4-23) was found for patients
`with 20-120 mg/day adjunct dose of lurasidone. In com-
`parison, NNT values of 6 and 4 were found for quetiapine
`and olanzapine—fluoxetine combinationin clinical response,
`respectively.)It is worth noting that 95% confidence inter-
`vals were similarly not reported for the NNT values of the
`comparative treatments. Perhapsrelated to this, Citrome et
`al offer a conservative conclusion regarding the therapeutic
`efficacy oflurasidone relativeto its predecessors,stating only
`that it yielded comparable benefits for treatment.
`Insummary,preliminary findings from two recent double-
`blinded clinicaltrials suggest that lurasidoneis efficacious in
`treating bipolar I depression, with clinical effects manifest-
`ing as early as the first 2-3 weeksof treatment (as measured
`by MADRS and CGI-BP). Its therapeutic benefit, however,
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`appears to be comparable to other atypical antipsychotics,
`on average. This is in line with a recent meta-analysis of
`212 clinical trials of antipsychotic drugs in schizophrenia,
`spanning more than 43,000 patients, that found lurasidone to
`be similar (if not weaker) than quetiapine and olanzapine in
`alleviating symptoms.* Of course, it is still early in the inves-
`tigationoflurasidone, with both clinical trials detailed above
`extended to 24-weektrials and data from weeks6 to 24still
`
`unpublished. Future research will no doubt shed furtherlight
`as to the true utility of lurasidone for bipolar I depression.
`
`The tolerability and safety
`of lurasidone
`Iflurasidoneis neither superior norinferior to other atypicals,
`might it have some advantage on the basis of side effects?
`Evidence onthe tolerability and safety of lurasidone comes
`from twoclinicaltrials in patients with bipolar depression and
`manyclinicaltrials in schizophrenia patients. Head-to-head
`randomizedclinical trials need to be conducted in order to
`
`conclusively evidence the relative superior or inferior effi-
`cacy of lurasidone comparedto other atypical antipsychotics.
`Although this article aims to review lurasidone in the context
`of bipolar depression, because there are only two published
`short-term studies of the drugin that patient population,it is
`important to also consider its safety and tolerability within
`schizophrenia patients.
`Lurasidone was granted FDA approvalforthe treatment
`of schizophrenia in October 2010 and then in June 2013
`for bipolar depression.** In reviewing relevant literature
`from 2009 to present, lurasidone has some evidence for
`a safety advantage over other recently approved second-
`generation atypical antipsychotics, including paliperidone,
`iloperidone, and asenapine.*!***' De Hert et al showed that
`treatment with lurasidone in BD and schizophrenia is less
`likely to result in hypercholesterolemia, hyperglycemia,
`hyperlipidemia, and other metabolic side effects such
`as weight gain.*!*’*! Short-term studies of lurasidone in
`schizophrenia patients suggest thatit is tolerable, safe, and
`has a low discontinuationrate.*! In schizophreniatrials, the
`most commonadverse events included nausea, somnolence,
`akathisia, sedation, and parkinsonism.** In an open-label
`6-month study in which 198 schizophrenic patients who
`were stable but symptomatic were switched to lurasidone,
`a total of 66.2% ofpatients had at least one adverse event,
`most of which were only mild or moderate.*? The study
`concluded that the drug was generally well tolerated and
`the investigators did not identify any new safety concerns.
`A handful of 1-year studies suggest that the long-term use of
`
`lurasidoneis well tolerated in patients with schizophrenia,
`having similar discontinuation rates to patients receiv-
`ing treatment with quetiapine XR (7% vs 5%).™*9 In this
`population, lurasidone appears to cause weight gain, but
`only modestly.*! Short-term clinical trials reported a mean
`increase in body weight of 26 kg in subjects treated with
`placebo and an increase in body weight of 75 kg in sub-
`jects treated with lurasidone. Only 5.6% of subjects in the
`lurasidone group showed a weight gain of 7% or more, as
`compared with 4% of subjectsin the placebo group. Caccia
`et al found that the weight gain was not dose related?! In
`Citrome’s 6-month open-label study, 17 subjects reported
`weight loss (>7% of their body weight) from the study
`baseline, whereas only 14 patients reported weight gain of
`the same proportion.* Although there is not much evidence
`regarding weight gain in long-term use of lurasidone in
`schizophrenia patients, lurasidone showed a more favor-
`able effect on body weight compared with quetiapine and
`risperidone in two long-term trials.**!
`Evidence does not suggest that lurasidone induces
`clinically significant changesin glucose levels or other meta-
`bolic parameters.*’** In a pooled data analysis from short-
`term studies on schizophrenia, Cucchiaro et al showedthat
`the mean increases in fasting glucose levels were 1.4 mg/dL
`in subjects receiving lurasidone and 0.6 mg/dL in subjects
`receiving placebo, which is not a statistically significant
`difference.” A long-term (12-month) study comparing
`lurasidone with quetiapine XR showed that there was no
`negative influence on glucose levels when taking lurasidone
`for an extended period.
`In short-term studies of lurasidone, there were no adverse
`events related to hyperlipidemia and there were no increases
`in low-density lipoprotein cholesterol, level of total choles-
`terol, or triglycerides.* In fact, one double-blind comparison
`study found that a decrease in triglycerides (—2.6 mg/dL)
`was associated with lurasidone, compared to an increase
`(+22.4 mg/dL) associated with ziprasidone.” In a long-
`term comparison study of risperidone and lurasidone, the
`median changesin low-density lipoprotein cholesterollevels
`and triglycerides in the lurasidone group were —2.0 mg/dL
`and —3.5 mg/dL, respectively.*
`Lurasidone is absorbed quickly, reaching peak serum con-
`centration in 1—3 hours.** Maximum concentration increases
`
`three-fold when administered with food, indicating that the
`site of absorption is likely the stomach.*' In a study aiming
`to elucidate the target amount of food needed to maximize
`serum concentration, the mean C,. was 52.9 ng/mL in
`the fasted state, 161 ng/mL for the 350 kcal/high-fat meal,
`
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`Lurasidone for the treatmentof bipolar depression
`
`135 ng/mL for the 500 keal/high-fat meal, and 131 ng/mL for
`the 800—1,000 keal/high-fat meal.® Therefore, lurasidoneis
`advised to be taken with about 350 kcal, althoughfat content
`per se does not appear to have an influence. Once absorbed,
`99.8% ofit is boundto albumin and o-1-glycoprotein.**
`Significant increases in prolactin levels were associated
`withlurasidone in several short-term studies in schizophrenia.”!
`Pooleddata fromfive short-term studies indicated that mean
`
`changes in prolactin levels were —0.6 ng/mLin the placebo
`group and +1.1 ng/mLin the lurasidone group.*” However,
`the prolactin changes due to lurasidone may be lower than
`those due to othersimilar drugs. One study found that mean
`changes in prolactin levels were greater in patients receiv-
`ing haloperidol (+8.5 ng/mL) and olanzapine (+3.7 ng/mL)
`than lurasidone (+1.1 ng/mL).* A long-term study that
`comparedrisperidone with lurasidone showed median
`changesin prolactin levels in the 0 ng/mL lurasidone group
`in male subjects and +0.95 ng/mL lurasidone group among
`female subjects. These levels were lower than those of
`the risperidone group, which were +7.50 ng/mL in males
`and +26.40 ng/mL in females.*°
`To date, there have been two peer-reviewedarticles that
`investigated lurasidonein the treatment ofbipolar I depression.
`Both of these were 6-week, randomized, double-blind, and
`
`placebo-controlledtrials conducted by Loebelet al as reviewed
`earlier. In the monotherapy study, dropoutrates due to adverse
`events were similar across all three groups,ranging from 5.9%
`to 6.6%. There were nostatistically significant differences
`in the effect of treatment on metabolic parameters reported,
`including weight,lipid, prolactin or cholesterollevels, waist cir-
`cumference, glycemic control, or clectrocardiogram readings.”
`Thepercent ofpatients with a 7% or greater increase in weight
`from baseline was 0.7% in both the 80-120 mgand placebo
`groups and 4.2% in the 20-60 mg group. In general, the
`high-dose group experienced more adverse effects. Nausea
`was the most common (N=29, 17.4%), followed by akathisia
`(N=18, 10.8%), headache (N=15, 9.0%), extrapyramidal
`events (N=15, 9.0%), and sedation (N=12, 7.2%).* Rates of
`serious adverse events were low across groups, and there were
`no deaths,suicidal behaviors, or suicides during the course of
`the study.*? In the second clinical trial, discontinuation rates
`were lower in the lurasidone + lithium/valproate group (6%)
`compared to the placebo + lithium/valproate group (7.9%).”°
`The lurasidone + lithium/