Neuropsychiatric Disease and Treatment
`
`Dovepi‘u-,~,
`
`REVIEW
`
`Lurasidone for the treatment of bipolar depression:
`an evidence-based review
`
`Rachel Franklin'
`Sam Zorowitz'
`Andrew K Corse'
`
`Alik S Widge2
`Thilo Deckersbach'
`
`'Division of Neurotherapeutics.
`Department of Psychiatry.
`Massachusetts General Hospital,
`Harvard Medical School, Charlestown.
`7~Picower Institute for Learning and
`Memory. Massachusetts Institute oi
`Technology. Cambridge. MA. USA
`
`Correspondence; Thilo Deckersbach
`Room 2628. Bu'lding I49. l3th Street.
`Division of Neurotherapeutics.
`Department of thiatry. Massachusetts
`General Hospital. Harvard Medical
`School. Charlestown. MA. USA
`Tel +l 6|7 724 6300
`Fax+l 6|7 726 4078
`Email tdeckersbach@partners.org
`
`submit your mamxcnpt
`Dove,
`htzp:
`1.
`
`This article was published in the following Dove Press iournal:
`Neuropsychiatric Useue and Treatment
`|9Atgust 20|$
`Number of times this aru'de has been viewed
`
`Abstract: Bipolar disorder (ED) is a debilitating and difficult-to-treat psychiatric disease that
`presents a serious burden to patients’ lives as well as health care systems around the world. The
`essential diagnostic criterion for DD is episodes of mania or hypomania; however, the patients
`report that the majority of their time is spent in a depressive phases Current treatment options
`for this component ofBD have yet to achieve satisfactory remission rates. Lurasidone is a drug
`in the benzisothiazole class approved by the US Food and Drug Administration in June 2013
`for the acute treatment of bipolar depression. Its pharmacological profile features high-affinity
`
`antagonism at Dz, S‘HTM, and 5-HT7 receptors; moderate-affinity antagonism at 0.x adrenergic
`receptors; low- to very low-affinity antagonism at t1l A-adrenergic, (VIA—adrenergic, Hn Mn and
`5-HT“. receptors; and high-affinity partial agonism at 5-HT“. Preliminary findings from two
`recent double-blinded clinical trials suggest that lurasidonc is efficacious in treating bipolar l
`depression, with clinical effects manifesting as early as the first 2 3 weeks of treatment (as
`measured by the Montgomery—fishers Depression Rating Scale and Clinical Global Impressions
`Scale for use in bipolar ilh1ess). lts therapeutic benefit appears to be comparable to the current
`US Food and Drug Administration-indicated treatments: quetiapine and olanzapine fluoxetine,
`according to a measure ofeffect size known as number needed to treat. These studies reported
`relatively limited extrapymmidal and metabolic side effects as a result of treatment with lumsi-
`done, with the most common side 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 lumsidone is less likely to result in metabolic side effects
`such as weight gain or disturbances of serum glucose or lipid levels. Lurasidone holds clinical
`potential as a novel, efificacious 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: lumsidone, bipolar depression, bipolar disorder, atypical antipsycltotic
`
`Introduction
`
`Bipolar disorder (BD) is a chronic and often 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 Organi7ation in worldwide causes of years lived with
`disability. surpassing all forms ofcancer.3 The economic burden in terms of cost ofhealth
`care for patients with ED is estimated to be four times greater than that for patients without
`mental disorders.‘ Overall. the total economic burden ofBD to the US economy is 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.6
`The essential diagnostic criterion for BD is episodes of elevated/irritable mood.
`usually either mania (type I) or hypomania (type 11).7 Despite this. BD patients have
`
`2M3
`Neuropsychiatric Dismse and Treatment 20|5:| l 2|43—2 | 52
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`Franklin et al
`
`Dove] ., us»
`
`features, though long-term clinical data in conjunction with
`neurobiological models remain to be established.
`Lurasidone or (3aR,4S,7R,7aS)-2-{( lR,2R)-2-[4-(‘l ,2-
`benzisothiazol-3-yl)piperazin-1-ylmethyl]cyclohexylm-
`ethyl }hexahydro-4,7-mcthano-2H-isoindole-1 ,3-dione
`hydrochloride20 (as it is known chemically) (Figure l for 3D
`chemical structure) is a chemical in the benzisothiazole class,
`structurally related to perospirone and ziprasidone, as well
`as the benzisoxazole derivative risperidone.21 In vitro assays
`
`have demonstrated that lurasidone is a full antagonist at D2
`(Ki=l .68 nM)22 (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.22 In comparison to similar drugs, lurasidone
`
`has the highest binding affinity for the 5-HT7 receptor
`(K,=0.5 nM).22 Other notable pharmacological properties
`include moderate-affinity aZC-adrenergic antagonism, par-
`tial agonism at the 5-HTIA receptor, and low affinity for the
`musearinic (Ml), histamine (H1) (both K". values > 1 ,000 nM),
`5-HT2C (415 nM), am (47.9 nM), and on“ (40.7 nM) adren-
`ergic receptors.” Table 1 shows the pharmacological profile
`of lurasidone.
`
`There is limited evidence that lurasidone may provide
`cognitive benefits due to several properties of its binding
`
`profile. Blocking activity at the 5-HT, receptor (Ki=0.5 nM)
`may contribute to therapeutic benefits as suggested by a study
`of the drug’s effect on learning when given in conjunction
`with anN-methyl-D-aspartate blocker.22 Ishi yama et al found
`that rats were prevented from learning a passive-avoidance
`shock response when administered with N—methyl-D-aspar-
`tate receptor antagonist dimcilpine; 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 phase8 and
`that these episodes are more disruptive to their functioning
`than mania.9 Bipolar depression is notably distinct from
`unipolar depression in that its phenomenological features
`more commonly include psychosis, depressive mixed state,
`anxiety, agitation, anergic depression. irritability, and anger
`attacks.” Moreover, the increased risk of suicide in patients
`with ED (whose rates of suicide are one ofthe highest among
`patients with psychiatric illness)”-'2 is observed predomi-
`nantly during the depressive phase.”12
`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 afler 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 common feature of BD depression is insensitivity to acute
`treatment)” Factors complicating treatment include toler-
`ance to medications and significant likelihood of relapse,"
`even with continual pharmacological maintenance.
`Pharmacotherapy options for BB are 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, lainotrigine (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
`ED, is often not well covered by these regimens and nonre-
`sponse to first—line options is perhaps as high as 40%}8 In
`a review of therapeutic options for treatment-resistant BD
`depression, Sienaert et al found that although promising.
`current research for this diagnosis is scarce." In this review,
`we aim to summarize recent available literature regarding
`the compound lurasidone and its role in the treatment of
`bipolar depression.
`
`Pharmacology and pharmacokinetics
`The biological basis of BD depression remains unknown: one
`current theory. developed by Fountoulakis et al'“ postulates
`that unlike unipolar depression, norepinephrine reuptake
`
`and 5-HTIA agonism are heavily implicated as core deficits.
`Pharmacologically, lurasidone is appropriate to treat these
`
`Figure I Three-dimensional structure of lurasidone. also known as (3aR,4S.
`7R.7aS)—2-{( l R.2R)v2-[4-( l.2-benzisodiazol-3-yl)pipernin- I -ylmethyl]cyelohery-
`lmedlyl}hmhydro-4.7-methano-ZH-iwindole- I .3-(ione
`hydrodiloride
`or
`Latuda.
`lormda is
`and moloodar
`Notes: Molecular way“ is 529.8698 g/mol
`CanCIN‘OIS. Teal atoms represent hyti'ogen. gray atoms when. red awn:
`oxygen. blue alums nitrogen and the yellow atom a sullur: the associated hydrogen
`chloride salt is not pictured"
`
`2H4
`
`submit your mamrmpz
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`

`Dave} )1 cu
`
`Lumidone for the treatment of bipolar depression
`
`Neurotransmitter
`
`Table I Binding profile of the chemical lurasidone: endogenous neurotransmitter. characteristic activity type. and experimental K.
`values associated with major receptors
`Blndlng profile of lurasidone'
`Receptor
`
`Binding aflinity (K)'(nM)
`Activity
`262
`Antagonist
`Dopamine
`Dl
`I .681099‘
`Antagonist
`Dopamine
`D,
`6.75:0.97
`Partial agonist
`Serotonin
`5-HTI ‘
`2.03:0.46
`Antagonist
`Serotonin
`5-HTM
`4| 5
`Antagonist
`Serotonin
`5.HTK
`0.495i0.090
`Antagonist
`Serotonin
`5-HT7
`47.9318
`Antagonist
`Norepinephrine
`a”
`40.7i7.7
`Antagonist
`Norepinephrine
`<1“
`IOBi0.64
`Antagonist
`Norepinephrine
`(12c
`> I ,000
`Antagonist
`Histamine
`HI
`> | ,000
`Antagonist
`Acetylcholine
`MI
`Notes: iExperimental values reported by Islibashi et al.:1 “The equilibrium dissociation constant decreased value indicated increased alflnity. ‘Values are means 1 standard
`error 0! the mean of three or more separate experiments
`
`This effect suggests that lurasidone may contribute to restora-
`tion of the memory consolidation process and may therefore
`have benefits in reducing the cognitive impairments observed
`in bipolar depression?3
`Additionally. the drug acts with moderate binding affin-
`
`ity as an antagonist at aim-adrenergic receptor (K'.=10.8 nM),
`overexpression ofwhich has been shown to increase impair-
`ment in the Morris water maze,“ further lending support to
`possible procognitive effects of lurasidone.
`
`Lurasidone also interacts as a partial agonist at the 5—HTIA
`receptor (K'=6.75 nM),22 activation of which has been shown
`to increase adult neuronal proliferation in the dentate gyrus
`of the hippocampus.25 This influence in neurogenesis may
`be of cognitive therapeutic benefit. as demonstrated by pilot
`
`clinical studies using antipsychotics with adjunct 5-HTM
`agonists?“
`Overall, based on neurobiological evidence, lurasi-
`done may provide advantages in learning and memory via
`
`high-affinity 5-HT7 and moderate-affinity Dim—adrenergic
`antagonism, as well as partial agonism at the 5-HTM
`receptor.”“-‘-“
`
`The 5-HT7 receptor-blocking activity of lurasidone may
`also underlie antidepressant properties of the drug. Selective
`
`antagonists and experiments in 5-HT7 gene knockout animals
`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, and tail suspension tests?” It is far from proven
`that these tests translate well to human depression, unipolar or
`bipolar. but they may be usefiil screens. These mood effects
`may be mediated by a cortical and hippocampal dopamine
`
`efilux caused by activity at the 5-HT7 and 5-HTm receptors.Jo
`
`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 (MI), histamine
`(H1) (both K, values >l,000 11M). 5-HT2c (415 nM). (1M-
`(47.9 nM), and (In-(40.7 nM) adrenergic receptors}3 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 human trials
`of lurasidone (see “Safety and tolerability” section). This is
`thought to be due to the low levels of activity of lurasidone
`
`at H,34 and 5-HT2C” receptors.22 Decreased interaction with
`muscarinic and Ot-l adrenergic receptors may prevent nega-
`tive cognitive and cardiovascular side effects.“
`
`Despite being a highoaffinity D2 receptor antagonist,
`historically a harbinger of severe neurological side effects,33
`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)22 than other typical and even other atypical
`antipsychotics. This may be explained in part by the drug’s
`receptor saturation point. A study of lurasidone’s dopamine
`
`D2 receptor binding in healthy males using positron emission
`tomography demonstrated that doses less than 40 mg did not
`achieve adequate binding to reach antipsychotic effect;37
`however, increasing the dose from 60 mg to 80 mg did
`
`Neuropsychiatric Disease and Trmtment 20 I 5:l l
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`submit your manna-mt
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`Dove.
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`,
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`Franklin et al
`
`Doveyrt-t-t
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`not effectively change receptor occupancy ('77%—84% and
`73%—79%, respectively). This curve may explain, in part,
`why incidents of parkinsonism are infrequently seen, as there
`appears to be a dopamine receptor saturation point well below
`the threshold for extrapyrarnidal symptomology.
`Lurasidone is primarily metabolized by CYP3A4, with
`the most common pathways being oxidative N—dealkylation,
`hydroxylation of the norbomane 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
`repeated oral doses at steady state.” Several known pharma-
`cologically active metabolites have been described such as
`ID-l4283, ID—l4326, and ID—l 1614 (25%, 3%, and <1% of
`
`parent exposure, respectively).33 In vitro studies demonstrated
`
`that both lD-14283 and lD—l4236 showed affinity for D2 and
`5-HT”, as well as partial agonism at 5-HT1A and antagonism
`at 5-HT7. ID-l4283 may contribute to the parent compound‘s
`efficacy, but has a shorter half-life (7 hours)?l
`
`Therapeutic efficacy
`Though there now exists a growing body of literature detailing
`the pharmacokinetic properties of lurasidone. a complemen-
`tary body of literature documenting its efficacy for the treat-
`ment ofbipolar I disorder is comparatively less due to the short
`time since initial approval.38 At the time of writing, only two
`controlled clinical trials have begun to investigate lurasidone
`as a treatment for bipolar I depression: as a monotherapy” and
`as an adjunct treatment with lithium or valprvoate.‘o
`
`The first 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 was the 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 scores in 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-BP scores for the 20—60 mg/day group (—1 .8) and the
`80—120 mg/day group (—1 .7) as compared to placebo (—1.l).
`Notably, these statistically significant decreases in MADRS
`and CGl—BP scores were observed in both dosage groups
`early in the course of treatment; differences between the
`groups in reported MADRS scores began at week 2, whereas
`
`A
`
`35 -
`
`30
`
`25-
`
`2
`°
`8 20 «
`(D
`gs
`<
`E
`
`MADRS change wlth treatment
`
`B
`
`6
`
`CGI-BP change with treatment
`
`3—
`
`2 4-
`8
`tn
`n.
`I?
`(D
`o 2
`
`
`
`Placebo
`
`80-120
`20-60
`Adjunct
`Placebo
`80-120
`20-60
`mgld
`mg/d
`—-_aseline—Week 6
`mg/d
`mg/d
`Figure 2 Dillerence: among behavioral outcomes by lurasidone treatment regimen between baseline and Week 6 as measured by MADRS score and CGl-BP score.
`Notes: (A) Mean change in MADRS from baseline to week 6 across dflerent treatments in patients with bipolar I depretsim (B) The mean change in depression severity
`score on the CGI scale from baseline to week 6 for the same traunem groups. Placebo. 20-60 rug/day and 80— l20 trig/day values reported in Loebel's monotherapy study”
`adjunct experimental valuu from Loehel et ah investigation of ltrasidone as adiunctlve treatment with lithium and valprmte.“
`Abbreviations: MADRS. Montgomery—Asher; Depression Rating 5d: CGl-BP. Clinial Global Impressions Sale [or use in tipular illness; d. day.
`
`Adjunct
`
`2|46
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`suhmlt your mlnulmpl
`Dove, we.
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`Neuropsychiatric Disease and Trmtment 20l 5:| I
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`

`Dave} :1 («A
`
`Lumidone tor the treatment of bipolar depression
`
`differences in reported CGI-BP scores began at week I
`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 stamdard deviations
`nor confidence intervals in the differences in MADRS or
`
`et al“l compared the benefits of these three treatments using
`the number needed to treat (NNT) measure.‘2 As an indicator
`of effect size, NNT measures how many patients would need
`to be treated with one medication, on average, to observe
`one additional beneficial outcome of interest. Low NNTs
`
`CGI-BP scores. Nonetheless 53% and 51% of subjects met
`response criteria (defined as 250% reduction from baseline
`in MADRS total) afier 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 mg and lurasidone 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 lurasidone as an adjunct to 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 minimum trial of either lithium or
`valproate, prescribed at therapeutic levels, as determined
`by a health care professional. Qualifying patients were then
`randomly assigned to receive 6 weeks of lurasidone (N=I 83)
`or placebo (N: l 65) in addition to continuing their 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 ing/day (the mean daily dose was 66.3 mg). As in
`the monotherapy study, the pritnary and secondary outcomes
`of interest were changes in the MADRS and CGI-BP scores,
`respectively, between baseline and week 6 of the trial.
`Similar to the results of the monotherapy trial, signifi-
`cantly greater decreases in MADRS and CGI-BP scores were
`observed for the adjunct lurasidone group (—I7.1; —l.96)
`than for the placebo group (-13.5; —l.51) (Figure 2B).
`These differences were first observed beginning at week 3
`for the MADRS as well as at week 2 for the CGI-BP, and
`
`remained reliably different for the remainder of the trial. As
`mentioned earlier, caution is again warranted in interpreting
`these results as the authors included neither standard devia-
`tions nor confidence intervals in the differences in MADRS
`
`or CGI-BP scores. Finally, greater proportions ofpatients met
`response criteria (250% 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 preexi sting treatments, specifically quetiapine
`and olanzapine—fluoxetine combination. Recently, Citrome
`
`Neuropsychiatric Disease and Trmtment 20 I 5:l l
`
`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.
`
`Citrome et al calculated the NNT for clinical response
`and remission for lurasidone based on the above two clini-
`
`cal trials. as well as the NNT for quetiapine (immediate and
`extended release) and olanzapine—fluoxetine combination
`based on published 8-week trials and product labeling (see
`article for details).43 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.‘5 In the two reviewed
`olanzapine—fluoxetine combination studies, the dosing levels
`were set at 6/25 mg/day, 6/50 mg/day, or 12/50 myday.““’
`Clinical response was defined as a 250% reduction from
`baseline on the MADRS, whereas remission was defined
`
`as a final MADRS score of $12. For clinical response,
`NNT values of5 (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—fiuoxetine combi-
`nation in clinical response, respectively. For clinical remis-
`sion, an NNT value of 6 (95%, 4—14) was found for patients
`with a low dose (20—60 ing/day) ofmonotherapy lurasidone;
`an NNT value of 7 (95%, 4—2 I) was found for patients 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 combination in clinical response,
`respectively.'“"2 It is worth noting that 95% confidence inter-
`vals were similarly not reported for the NNT values of the
`comparative treatments. Perhaps related to this, Citrome et
`al offer a conservative conclusion regarding the therapeutic
`efficacy of lurasidone relative to its predecessors, stating only
`that it yielded comparable benefits for treatment.
`In summary, preliminary findings from two recent double-
`blinded clinical trials suggest that lurasidone is efficacious in
`treating bipolar I depression, with clinical effects manifest-
`ing as early as the first 2—3 weeks of treatment (as measured
`by MADRS and CGI—BP). Its therapeutic benefit, however,
`
`submit your mamna-Ipl
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`

`Franklin et al
`
`Dove] a: m
`
`appears to be comparable to other atypical antipsychotics,
`on average. This is in line with a recent metaanalysis of
`212 clinical trials of antipsychotic drugs in schimphrenia,
`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-
`ti gation of lurasidone. with both clinical trials detailed above
`extended to 24-week trials and data from weeks 6 to 24 still
`
`unpublished. Future research will no doubt shed further light
`as to the true utility of lurasidone for bipolar I depression.
`
`The tolerability and safety
`of lurasidone
`
`Iflurasidone is neither superior nor inferior to other atypicals,
`might it have some advantage on the basis of side effects?
`Evidence on the tolerability and safety of lurasidone comes
`from two clinical trials in patients with bipolar depression and
`many clinical trials in schizophrenia patients. Head-to-head
`randomized clinical trials need to be conducted in order to
`
`conclusively evidence the relative superior or inferior effi-
`cacy of lurasi done compared to other atypical antipsychoti cs.
`Although this article aims to review lurasidone in the context
`of bipolar depression, because there are only two published
`short-term studies of the drug in that patient population. it is
`important to also consider its safety and tolerability within
`schizophrenia patients.
`Lurasidone was granted F DA approval for the 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."'5°-5' 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 that it is tolerable, safe, and
`has a low discontinuation rate.”1 In schizophrenia trials, the
`most common adverse events included nausea, somnolenee,
`
`akathisia, sedation, and parkinsonism.52 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% of patients 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-tenn use of
`
`lurasidone is well tolerated in patients with schizophrenia,
`having similar discontinuation rates to patients receiv-
`ing treatment with quetiapine XR (7% vs 5%).“55 In this
`population, lurasidone appears to cause weight gain, but
`only modestly.2| 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 subjects in the placebo group.’6 Caecia
`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.53 Although there is not much evidence
`regarding weight gain in long-temi 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 changes in glucose levels or other meta-
`bolic parameters?” In a pooled data analysis from short-
`term studies on schizophrenia. Cucchiaro et al showed that
`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-ten'n 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.60 In a long—
`tenn comparison study of risperidone and lurasidone, the
`median changes in low-density lipoprotein cholesterol levels
`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.38 Maximum concentration increases
`
`three-fold when administered with food, indicating that the
`site of absorption is likely the stomach.61 In a study aiming
`to elucidate the target amount of food needed to maximize
`
`serum concentration, the mean Cm was 52.9 ng/mL in
`the fasted state, 161 ng/mL for the 350 kcal/high-fat meal.
`
`2|48
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`Neuropsychiatric Disease and Treatment 20| 5:l l
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`Lumidone for the treatment of bipolar depression
`
`135 anL for the 500 kcal/high-fat meal, and 131 ng/mL for
`the 800—1,000 kcal/high-fat meal."2 Therefore. lurasidone is
`advised to be taken with about 350 kcal, although fat content
`per se does not appear to have an influence. Once absorbed,
`99.8% of it is bound to albumin and 0t-1 -glycoprotein.~‘-‘
`Significant increases in prolactin levels were associated
`with lurasidone in several short-term studies in schizophrenia21
`Pooled data from five short-tenn studies indicated that mean
`
`changes in prolactin levels were —0.6 ng/mL in the placebo
`group and +1.1 ng/mL in the lurasidone group.” However,
`the prolactin changes due to lurasidone may be lower than
`those due to other similar 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).63 A long-term study that
`compared risperidone with lurasidone showed median
`changes in 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-reviewed articles that
`investigated lurasidone in the treatment ofbipolar I depression.
`Both of these were 6-week. randomized, double-blind, and
`
`placebo-controlled trials conducted by Loebel et al as reviewed
`earlier. In the monotherapy study, dropout rates due to adverse
`events were similar across all three groups. ranging from 5 9%
`to 6.6%. There were no statistically significant differences
`in the effect of treatment on metabolic parameters reported,
`including weight. lipid, prolactin or cholesterol levels, waist cir-
`cumference, glycemic control, or electrocardiogram readings.”
`The percent ofpatients with a 7% or greater increase in weight
`from baseline was 0.7% in both the 80—120 mg and 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 wicides during the course of
`the study.39 In the second clinical trial. discontinuation rates
`were lower in the lurasidone +lithium/va1proate group (6%)
`compared to the placebo + lithium/valproate group (7.9%).‘0
`The lurasidone + lithium/valproate group experienced