Bipolar Disorder
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LurasidoneintheTreatmentofBipolarDepression.pdf
Review Article Lurasidone in the Treatment of Bipolar Depression: Systematic Review of Systematic Reviews
Michele Fornaro,1,2 Domenico De Berardis,3 Giampaolo Perna,4,5,6 Marco Solmi,7,8
Nicola Veronese,8,9 Laura Orsolini,10 Elisabetta Filomena Buonaguro,2 Felice Iasevoli,1
Cristiano André Köhler,11 André Ferrer Carvalho,11 and Andrea de Bartolomeis1
! Laboratory of Molecular and Translational Psychiatry, Department of Neuroscience, School of Medicine, University “Federico II”, Naples, Italy
" New York State Psychiatric Institute, Columbia University, New York, NY, USA # National Health Service, Department of Mental Health, Psychiatric Service of Diagnosis and Treatment, Hospital “G. Mazzini”, ASL $, Teramo, Italy
$ Department of Clinical Neurosciences, Hermanas Hospitalarias, Villa San Benedetto Menni Hospital, FoRiPsi, Albese con Cassano, ""%#" Como, Italy
& Department of Psychiatry and Neuropsychology, Maastricht University, '"%% MD Maastricht, Netherlands ' Department of Psychiatry and Behavioral Sciences, Leonard Miller School of Medicine, Miami University, Miami, FL ##!#', USA ( Department of Neurosciences, University of Padua, Padua, Italy ) Institute for Clinical Research and Education in Medicine (IREM), Padua, Italy * Department of Medicine (DIMED), University of Padua, Padua, Italy !%School of Life and Medical Sciences, University of Hertfordshire, Hat+eld, Herts, UK !!Translational Psychiatry Research Group and Department of Clinical Medicine, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil
Correspondence should be addressed to Michele Fornaro; [email protected]
Academic Editor: Chi-Un Pae
Copyright © !"#$ Michele Fornaro et al. %is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Introduction. A burgeoning number of systematic reviews considering lurasidone in the treatment of bipolar depression have occurred since its Food and Drug Administration extended approval in !"#&. While a paucity of available quantitative evidence still precludes preliminary meta-analysis on the matter, the present quality assessment of systematic review of systematic reviews, nonetheless, aims at highlighting current essential information on the topic. Methods. Both published and unpublished systematic reviews about lurasidone mono- or adjunctive therapy in the treatment of bipolar depression were searched by two independent authors inquiring PubMed/Cochrane/Embase/Scopus from inception until October !"#'. Results. Twelve included systematic reviews were of moderate-to-high quality and consistent in covering the handful of RCTs available to date, suggesting the promising e(cacy, safety, and tolerability pro)le of lurasidone. Concordance on the drug pro)le seems to be corroborated by a steadily increasing number of convergent qualitative reports on the matter. Limitations. Publication, sponsorship, language, citation, and measurement biases. Conclusions. Despite being preliminary in nature, this overview stipulates the e*ectiveness of lurasidone in the acute treatment of Type I bipolar depression overall. As outlined by most of the reviewed evidence, recommendations for future research should include further controlled trials of extended duration.
1. Introduction
Although the Diagnostic and Statistical Manual for Mental Disorders-Fourth Edition (DSM-IV) [#] poses mania as the
hallmark of bipolar disorder (BD), depression is o+en the most enduring facet of the illness as emphasized by the Fi+h edition of the Manual [!] requiring signi)cant treatment e*orts [&]. Yet, only a handful of randomized clinical trials
Hinda i Bi Med Re ea ch In e na i nal V l me 2017, A icle ID 3084859, 17 age h ://d i. g/10.1155/2017/3084859
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(RCTs) exist about bipolar depression in comparison to major depressive disorder (MDD), which may be because unipolar “endogenous” or “melancholic” major depression episodes (MDEs) have long been considered equivalent to bipolar MDEs, from clinical, neurobiological, and treatment- modality standpoints [,]. Regrettably, the only reservation was that antidepressants might switch to the manic pole; thus the enduring common clinical practice among clinicians was to seamlessly transpose the clinical data and wisdom from the treatment of unipolar to bipolar depression [-].
%is later misconception has long been corroborated by anecdotal reports suggesting that most clinicians may still perceive medications as belonging to a class with regard to a speci)c therapeutic action rather than based on aimed “neuroscience-nomenclature” approach grounded on the pharmacological pro)le of the drug ['], both in the specialty and in general practice settings accessed by patients with BD [$]. Yet, therapeutic “class e*ect” in BD is an exception rather than rule [.].
%e majority of patients with bipolar depression fail to respond adequately to pharmacotherapy [/], whereas the use of standard antidepressant medications, even when associ- ated with established mood-stabilizers, poses major e(cacy concerns beyond overall short- and long-term tolerability issues, especially for Type I BD (BD-I) and/or in the presence of associated mixed and/or atypical features, just to mention few [#", ##].
In contrast, evidence in support of the use of at least some of the second-generation antipsychotic (SGA) mono- or add- on therapy either for MDD [#!, #&] or bipolar depression [#,– #.] is increasing over the time, though additional safe and e*ective Food and Drug Administration- (FDA-) approved SGAs for bipolar depression are solicited [#/].
Currently, olanzapine-0uoxetine combination (OFC), quetiapine (either the standard or the extended release preparation), and lurasidone are the only FDA drugs granted (extended) approval for the (acute) treatment of bipolar depression in adults [!", !#].
Lurasidone received FDA approval for the treatment of schizophrenia in adults in October !"#" and was granted extended approval on June !"#& for the treatment of acute depression associated with BD-I in adults [!!], either as monotherapy [!&] or as adjunctive treatment to either lithium or valproate [!,] 0exible-dose regimen trials, further assessed in subsequent retrospective/prospective data analysis [!-].
Potential safety (namely, the risk to the subject/patient, usually assessed in by laboratory testing [e.g., clinical chem- istry and hematology], physical examination [vital signs], clinical adverse event[s], AEs, and other tests, e.g., the electro- cardiogram), tolerability (namely, the degree to which overt AEs can be tolerated by the subject/patient), and e,ectiveness (usually, “e*ectiveness” trials [pragmatic trials] measure the degree of bene)cial e*ect under “real world” clinical set- tings rather than the “e(cacy” tested by “explanatory” trials aiming at determining whether an intervention produces the expected result under ideal circumstances) of adjunctive lurasidone across a broad range of treatment resistant BD outpatients otherwise excluded by routine clinical trials (e.g., those with mixed and/or rapid-cycling features; those taking
additional psychiatric or nonpsychiatric medications; and/or older-age cases of BD) have been preliminarily postulated [!'–!/] though critically appraised by independent authors [&"].
While the overall e*ect size of OFC, quetiapine (regard- less of release formulation), and lurasidone in mitigating depressive symptoms is similar, the later one showed a lower propensity for weight gain as well as overall metabolic neutrality in the bipolar population [!", !#].
Lurasidone, compared to previous FDA-approved SGAs for bipolar depression, yielded comparable bene)ts (all had single-digit number needed [NNT] for treatment versus placebo response or remission) and less risk of harm (double- digit or greater numbers needed to harm [NNH] with lurasidone compared to single-digit NNHs for sedation with quetiapine and for !$% weight gain with olanzapine- 0uoxetine combination) and thus a substantially more favor- able likelihood to be helped or harmed [LHH] (> or"#) with lurasidone monotherapy and adjunctive therapy, compared to quetiapine and olanzapine-0uoxetine combination (LHH< or ##) [&#]. NNT, NNH, and LHH represent widely well-recognized indexes most clinicians are progressively becoming familiar with [&!]. Nonetheless, the overall clinical validity and generalizability of these later indexes have been seldom questioned by some [&&].
A burgeoning number of systematic reviews have nonetheless occurred since the pivotal RCTs leading to FDA extended approval of lurasidone, as the need for better e(cacy/tolerability pro)le drugs for bipolar depression still represents a priority for the prescribing clinicians, policy-makers, and the su*ering ones, indeed.
More recently, calls have been made for updated brief reviews to provide decision-makers with the essential evi- dence they need in a shorter time frame, but the possible limitations of such brief reviews, compared to full-systematic reviews, require further methodological research [&,].
In recent years, however, decision-makers who were once overwhelmed by the number of individual studies have become faced by a plethora of reviews [&-, &']. %is is compelling, especially when novel compounds of potential priority interest for the clinical practice like lurasidone, even in the treatment of BD, may need to await for additional RCTs to allow reliable meta-analytic pooling [&$, &.].
%erefore, while awaiting for additional primary research trials to allow reliable and large-scale quantitative extrac- tions, varying approaches have been proposed [&/] to pro- mote quality assessment of systematic reviews of system- atic reviews (or overviews) to be eventually accounted for subsequent umbrella reviews (broad coverage of systematic reviews and meta-analyses) [,"]. Among others, several approaches including the Preferred Reporting Items for Sys- tematic review and Meta-Analysis-Protocols, PRISMA-P [,#] (formerly, PRISMA, QUOROM), or organizations devoted to the preparation of systematic reviews, including the National Institute of Health and Clinical Excellence (NICE) in the UK, the Evidence-based Practice Centre Program in the US, the Joanna Briggs Institute, and the International Campbell and Cochrane Collaborations arose [&/]. It was not until !""/ that “A Measurement Tool to Assess Systematic Reviews”
BioMed Research International &
T1234 #: Search strategy across alternative databases (queries run on October #,, !"#').
Set Medline (via PubMed) # 5# Lurasidone Hydrochloride [MeSH Major Topic]! ! !! review[Publication Type] OR meta-analysis[Publication Type] & Sets 1-2 were combined with “OR” , Bipolar disorder - Depression ' Sets #–- were combined with “OR” & “AND” Most permissive (generic PubMed - no MeSH headings) ((Lurasidone) AND Bipolar) AND review[Publication Type]
Embase
Most permissive "# “lurasidone”/exp OR lurasidone AND “bipolar depression”:ab,tiAND review:it Scopus
Most permissive (TITLE-ABS-KEY (lurasidone) AND TITLE-ABS-KEY (bipolardisorder)) AND DOCTYPE (re) Cochrane Library
Most permissive “Lurasidone in Title, Abstract, Keywords and ‘bipolar disorder’ inTitle, Abstract, Keywords and ‘review’ in Publication Type ” Note. Words written in italic were used as MeSH headings; the others were used as free text.!Proposed entry terms, then accounted as free text integrations: Hydrochloride, Lurasidone Lurasidone HCl HCl, Lurasidone SM #&,/' #&,/', SM SM#&,/' SM-#&,/' SM-#&,,/' SM #&,,/' SM#&,,/' Lurasidone N-(!-(,-(#,!-benzisothiazol-&-yl)-#-piperazinylmethyl)-#-cyclohexylmethyl)-!,& bicyclo(!.!.#)heptanedicarboximide Latuda.
(AMSTAR) was documented [,!], proving to be a potentially reliable and valid assessment tool to speci)cally evaluate the methodological quality of systematic reviews [,&].
%erefore, the aim of the present overview was to assess the methodological quality of systematic reviews assessing the evidence about lurasidone in the treatment of bipolar depression, with the ultimate goals of (i) ranking and priori- tizing those reviews for which the methodology would allow reliable conclusions and recommendations for the future needs; (ii) critically pointing out which unmet needs and expectations have been highlighted by the clinician authors to be implemented by future lines of research about the pharmacological treatment of acute bipolar depression in adults with a special emphasis towards lurasidone, prompting for attention by policy and clinical decision-makers.
2. Materials and Procedures
Overall methods and procedures resemble those adopted by recent peer-review articles involving the use of AMSTAR methodology [,!, ,&], as applied to heterogeneous medical )elds of research [,-].
".!. Search Strategy for the Identi+cation of Systematic Reviews. A protocol was dra+ed before the implementation of the review (a copy is available from the authors). Searches were conducted of Medline (via PubMed), EMBASE and the Cochrane library (which includes the DARE database of abstracts of reviews on interventions), and Scopus, on October #,, !"#', and included a combination of free text and MeSH terms (please refer to Table #). Despite the relatively recent introduction of lurasidone, indexes were searched from inception aiming at gathering as much information as possible on the topic. Searches were limited to “systematic reviews” or “review” type publication across varying sources. No language restrictions were imposed although only English language results were retained. %is strategy was purportedly performed to get a better insight about any eventual language and regional publication di*erential trend on the topic. %e title and abstract of each article were scanned (independently by two reviewers: MF and LO) and full-reprints of articles of potentially eligible reviews were obtained. Potentially eligible reviews were then screened, again independently by two reviewers, per the review selection criteria outlined below. All
, BioMed Research International
resulting references were further screened for identi)cation of additional reviews.
".". Review Selection Criteria. Only systematic reviews were included. Case reports, controlled RCT (which were not part of a review), were excluded. %ose narrative reviews indexed by major databases as “systematic” were nonetheless identi)ed and then anyway screened for eventual inclusion and overall assessment. Both systematic reviews of RCTs and observational studies were eligible for inclusion. To be considered for inclusion, the review had to include evidence about the use of lurasidone (any dose) for bipolar disorder (any mood polarity), either for the acute or for the maintenance mono- or adjunctive treatment therapy. Systematic reviews covering drugs other than lurasidone or any additional non-BD prescription of lurasidone were likewise included in the present overview. Populations at interest were therefore “BD patients exposed to lurasidone.”
".#. Preliminary Data Abstraction. For each review meeting the inclusion criteria data were abstracted independently by two reviewers (MF and DDB). All data was compared and identi)ed anomalies recti)ed by mutual agreement. Data were obtained exclusively from the systematic reviews, while additional manual screening was planned to enrich the search strategy. %e primary study reports were likewise reviewed before assessment of systematic review reporting on the matter. Data abstracted from each systematic review included (i) authors and date of publication; country of origin (leading author most current a(liation); major biases, including sponsorship bias. In case of reviews covering multiple RCT studies, these later ones were punctually referenced in Table ! (please see the text for results).
".$. Assessment of Data Quality. %e methodological qual- ity and risk of bias of the systematic reviews at interest were performed using the AMSTAR items [,!, ,&] by two independent reviewers (MF and DDB). Risk of bias of primary studies was not assessed where this was covered by the corresponding systematic reviews. However, we did not record whether and how the reviews had assessed the quality of the primary studies and which method had been used (for example the Cochrane risk of bias tool) [-,]. Brie0y, the AMSTAR is a tool aiming at addressing relevant domains (as applicable): establishing the research question and inclusion criteria before the conduct of the review, data extraction by at least two independent data extractors, comprehensive literature review with searching of at least two databases, key word identi)cation, expert consultation and limits as necessary, detailed list of included/excluded studies and consideration of quality assessments in analysis and conclusions, appropriate assessment of homogeneity, assessment of publication bias, and a statement of any con0ict of interest. %erefore, (i) the extent of searching undertaken; (ii) description of review selection and inclusion criteria; (iii) assessment of publication bias; (iv) assessment of heterogeneity; and (v) comparability of included reviews are emphasized by the AMSTAR method [&/]. %e AMSTAR
checklist items are presented in the form of questions, with possible responses of “yes” (item/question fully addressed), “no” (item/question not addressed), “cannot answer” (not enough information to answer the question), and “not appli- cable,” https://amstar.ca/Amstar_Checklist.php; the actual eleven domains rated by the AMSTAR and its psychometric features have been further detailed elsewhere [,&].
%e revised assessment of multiple systematic reviews (R- AMSTAR) based on appendix # included in the open-access work by Kung et al. [,,] was nonetheless integrated [--] to the standard AMSTAR to generate quantitative scores of qualita- tive evidence [,,] since use of the original AMSTAR checklist alone would have posed subjectivity concerns and possibly reduced the reliability and replicability of assessments [-']. Speci)cally, stating the discrepancy existing about standard- ized scoring of the original AMSTAR domains [--–-$], grading of the R-AMSTAR could vary across di*erent authors and research themes [--]; we integrated two alternative scores methods in the assessment of each systematic review: (a) each of the individual eleven domains of the original instrument ranged between # and , (maximum); thus the R-AMSTAR total scores ranged between ## (minimum) and ,, (maxi- mum). Scoring for each domain could be determined based on the number of satis)ed criteria varying across di*erent domains rather than nonstandardized cut-o* scores [,,]; (b) based on the later scores values, a percentile ranking is obtained, for each individual score, which is then translatable into a letter grade based on the extent of PICO/PIPO research questions (population, intervention, comparison, prediction, and outcome) answered, with the following letters: A (best)–E (worst) range (variable across varying questions). Details about the domains and proposed scoring of the R-AMSTAR available in the public domain based on the appendix # are included in the work by Kung and colleagues [,,, --].
".&. Exclusion of Duplicate Primary Studies (Document in Systematic Reviews). Both auto- and hand-searches for “type I” (“duplicates among/across di*erent databases”) and “type II” (“duplicate publications in di*erent Journals/issues”) [-.] were performed based on %ompson Endnote X$! for Microso+ Windows!.
Reviews were then screened to exclude systematic reviews with duplicate primary studies unless they reported on di*erent outcomes or provided alternative critical account of the evidence.
".'. Outcomes. Principal outcomes related to the impressions and recommendations about e(cacy and tolerability made by the authors given a systematic review at review beyond the raw data come from the covered original RCTs. Speci)cally, overall conclusions drawn by the authors and unmet needs to be addressed by future studies were included providing a concise narrative synthesis based on each systematic review included in the present overview. Conversely, speci)c out- comes of treatment interventions reported by the original RCTs covered across varying reviews were not accounted herein. On the other side, it is worth mentioning that higher R-AMSTAR scores and letter grades (e.g., “A”) would indicate more reliable and trustworthy conclusions.
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T1 23 4 !: Es se nt ia lo
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at iss ue .
A dd
iti on
al st ud
ie sa
re no
ne th el es sw
ar ra nt ed
Pu bl ic at io n bi as
w ith
re sp ec tt o
RC T tr ia ls (in
de ed ,
be yo nd
th e sc op
es of
th e re vi ew
)
I= &
II = &
II I=
, IV
= !
V = ,
V I=
& V II = &
V II I=
! IX
= ,
X = &
X I=
,
To ta ls co re
= &,
Pe rc en til e in
th e
pr es en ts et = .& .&
Q ua rt ile -d er iv ed
gr ad e le tte
r= A
BioMed Research International $
T1 23 4 !: C on
tin ue d.
A ut ho
r, ye ar
of pu
bl ic at io n
C ou
nt ry
of or ig in
(le ad in g
au th or )
In fo rm
at io n ab ou
t th e sa m pl e or
co ve d or ig in al
st ud
ie si fm
ul tip
le da ta so ur ce s
N of
co ve re d
or ig in al (R C T
st ud
ie s, ot he r
de si gn
)
Re su lts
dr aw
n ba se d on
th e
ac co un
te d
ev id en ce /a do
pt ed
pr oc ed ur es
fo rr ev is io n.
M ai n co nc lu si on
sa nd
pe rs pe ct iv es
re co m m en de d
by th e au th or s
M aj or
bi as es
(e .g .,
sp on
so rs hi p bi as )
de te ct ed
ac co rd in g
to th e R-
A M ST
A R
m et ho
do lo gy
Sc or e of
ea ch
#t o ##
ite m
as se ss ed
by R- A M ST
A R
R- A M ST
A R
TO TA
L SC
O RE
(r aw
)
R an k (g ra de
le tte
r) ba se d on
pe rc en til e
of th e gi ve n st ud
y
(G re en be rg
an d
C itr om
e, !" #' )
U SA
% e re vi ew
fo cu se d
on th e ph
ar m ac o-
dy na m ic sa
nd ph
ar m ac ok in et ic s
N o RC
T le ad in g to
FD A ap pr ov al
(e xt en sio
n) co ve re d in
th e
pr es en tp
ie ce
of w or k
% e re vi ew
pr ov id es
a ve ry
co m pr eh en siv
e an d
up da te d sy nt he sis
of lu ra sid
on e ph
ar m ac ol og ic al
pr op
er tie
s. D ist in gu ish
in g
fe at ur es
of lu ra sid
on e
ag ai ns ta lte rn at iv e SG
A ar e
al so
ou tli ne d, w ith
a sp ec ia l
em ph
as is to w ar ds
th e ve ry
po te nt
-- H T$
ac tiv
ity ex cr et ed
by lu ra sid
on e an d
its co m pl ex
in te ra ct io ns
w ith
-- H T# A pa rt ia l
ag on
ist ac tiv
ity
Pu bl ic at io n bi as
w ith
re sp ec tt o
RC T tr ia ls (in
de ed ,
be yo nd
th e sc op
es of
th e re vi ew
)
I= #
II = !
II I=
, IV
= &
V = !
V I=
, V II = &
V II I=
, IX
= ,
X = &
X I=
&
To ta ls co re
= &&
Pe rc en til e in
th e
pr es en ts et = $-
Q ua rt ile -d er iv ed
gr ad e le tte
r= A
(T ar az ia nd
St ah l, !" #! )[ ,$ ]
U SA
% e re vi ew
co ve rs
th e pr ec lin
ic al an d
cl in ic al da ta
av ai la bl e ab ou
t lu ra sid
on e,
as en ap in e an d
ilo pe ri do
ne un
til w rit in g tim
e
N o RC
T le ad in g to
FD A ap pr ov al
(e xt en sio
n) co ve re d in
th e
pr es en tp
ie ce
of w or k
% e re vi ew
pr ov id es
an ex pe rt op
in io n pe rs pe ct iv e
ab ou
tt itr at io n,
do si ng
an d
m an ag em
en to
fm os t
co m m on
si de
e* ec ts
ev en tu al ly ex pe ri en ce d by
pa tie
nt sw
ith BD
in re ce ip t
of lu ra si do
ne .%
is al lo w s
m ak in g in fe re nc e ab ou
t so m e of
th e cl in ic al un
m et
ne ed st o be
ad dr es sb
y fo rt hc om
in g st ud
ie s
Pu bl ic at io n bi as
I= #
II = &
II I=
, IV
= !
V = ,
V I=
& V II = &
V II I=
, IX
= &
X = &
X I=
,
To ta ls co re
= &'
Pe rc en til e in
th e
pr es en ts et = #" "
Q ua rt ile -d er iv ed
gr ad e le tte
r= A
. BioMed Research International
T1 23 4 !: C on
tin ue d.
A ut ho
r, ye ar
of pu
bl ic at io n
C ou
nt ry
of or ig in
(le ad in g
au th or )
In fo rm
at io n ab ou
t th e sa m pl e or
co ve d or ig in al
st ud
ie si fm
ul tip
le da ta so ur ce s
N of
co ve re d
or ig in al (R C T
st ud
ie s, ot he r
de si gn
)
Re su lts
dr aw
n ba se d on
th e
ac co un
te d
ev id en ce /a do
pt ed
pr oc ed ur es
fo rr ev is io n.
M ai n co nc lu si on
sa nd
pe rs pe ct iv es
re co m m en de d
by th e au th or s
M aj or
bi as es
(e .g .,
sp on
so rs hi p bi as )
de te ct ed
ac co rd in g
to th e R-
A M ST
A R
m et ho
do lo gy
Sc or e of
ea ch
#t o ##
ite m
as se ss ed
by R- A M ST
A R
R- A M ST
A R
TO TA
L SC
O RE
(r aw
)
R an k (g ra de
le tte
r) ba se d on
pe rc en til e
of th e gi ve n st ud
y
(G ao
et al ., !" #- )
[, .]
U SA
% e re vi ew
fo cu se s
on th e N N T an d
N N H co m pu
te d
fo rt he
es se nt ia l
SG A sa
pp ro ve d by
th e FD
A fo rt he
tr ea tm
en to
fa cu te
bi po
la rd
ep re ss io n
in ad ul ts ,i nc lu di ng
lu ra sid
on e
Tw o ac ut e ph
as e
tr ia ls (m
on o-
an d
ad ju nc tiv
e th er ap y
re sp .) [! &, !, ]
St ai ni ng
th e re la tiv
el y
fa vo ra bl e pr o)
le of
lu ra sid
on e, th e au th or s
re co m m en d th at th e
se le ct io n of
an FD
A -a pp
ro ve d SG
A sf or
bi po
la r
de pr es si on
sh ou
ld be
ba se d
up on
pr io rit y gi ve n to
sa fe ty an d to le ra bi lit y iss ue s
Pu bl ic at io n bi as
I= #
II = !
II I=
& IV
= !
V = !
V I=
& V II = ,
V II I=
! IX
= &
X = !
X I=
,
To ta ls co re
= !'
Pe rc en til e in
th e
pr es en ts et = -"
Q ua rt ile -d er iv ed
gr ad e le tte
r= A
(S an fo rd
an d
D hi llo
n, !" #- )
[, /]
N ew
Ze al an d
% e re vi ew
pr ov id es
a sy nt he sis
ab ou
tt he
us e of
lu ra sid
on e
in ad ul ts w ith
bi po
la rd
ep re ss io n
Tw o ac ut e ph
as e
tr ia ls (m
on o-
an d
ad ju nc tiv
e th er ap y,
re sp .) [! &, !, ].
M ai nt en an ce
op en -t ri al is
lik ew
is e cr iti ca lly
ac co un
te d. [! .]
% e re vi ew
st re ss es
ou tt he
re la tiv
el y fa vo ra bl e pr o)
le of
lu ra sid
on e in
te rm
so f
bo th
ac ut e an d po
te nt ia lly
lo ng
-t er m
to le ra bi lit y in
th e
tr ea tm
en to
fB D -I
de pr es si on
,e ith
er as
m on
o- or
as ad ju nc tiv
e tr ea tm
en t
Pu bl ic at io n bi as ,
to ug
h th e pr es en t
re vi ew
is am
on g
th e m os tu
pd at ed
an d co nc is e
av ai la bl e at w rit in g
tim e
I= !
II = !
II I=
& IV
= !
V = &
V I=
, V II = !
V II I=
& IX
= &
X = &
X I=
&
To ta ls co re
= &"
Pe rc en til e in
th e
pr es en ts et = '' .$
Q ua rt ile -d er iv ed
gr ad e le tte
r= A
(J ae sc hk
e et al .,
!" #' )[ -" ]
Po la nd
% e pr es en tr ev ie w
co ve rs bo
th th e
!" #'
up da te sa
bo ut
th e us e of
lu ra sid
on e in
BD an d sc hi zo ph
re ni a,
in cl ud
in g sy nt he sis
of th e
ph ar m ac ol og ic al
pr o)
le an d
es se nt ia lr ef er en ce
to bo
th an im
al an d
hu m an
st ud
ie s
Tw o ac ut e ph
as e
tr ia ls (m
on o-
an d
ad ju nc tiv
e th er ap y,
re sp .) [! &, !, ].
M ai nt en an ce
op en -t ri al is
lik ew
is e cr iti ca lly
ac co un
te d. [! .]
% is is a ve ry
ac cu ra te ,y et
co nc is e, up
da te of
th e
ev id en ce
up to
ea rly
!" #' .
N on
et he le ss ,t he
au th or s
fa ile d to
ex pa nd
an y
co nc lu siv
e se ct io ns
ab ou
t re co m m en da tio
ns an d th e
un m et ne ed sf or
fu tu re
cl in ic al us e an d re se ar ch
de ve lo pm
en t
Pu bl ic at io n bi as
bu tn
o su sp ic io us ne ss of
sp on
so rs hi p bi as
I= #
II = &
II I=
& IV
= !
V = ,
V I=
, V II = &
V II I=
, IX
= ,
X = ,
X I=
,
To ta ls co re
= &'
Pe rc en til e in
th e
pr es en ts et = #" "
Q ua rt ile -d er iv ed
gr ad e le tte
r= A
BioMed Research International /
T1 23 4 !: C on
tin ue d.
A ut ho
r, ye ar
of pu
bl ic at io n
C ou
nt ry
of or ig in
(le ad in g
au th or )
In fo rm
at io n ab ou
t th e sa m pl e or
co ve d or ig in al
st ud
ie si fm
ul tip
le da ta so ur ce s
N of
co ve re d
or ig in al (R C T
st ud
ie s, ot he r
de si gn
)
Re su lts
dr aw
n ba se d on
th e
ac co un
te d
ev id en ce /a do
pt ed
pr oc ed ur es
fo rr ev is io n.
M ai n co nc lu si on
sa nd
pe rs pe ct iv es
re co m m en de d
by th e au th or s
M aj or
bi as es
(e .g .,
sp on
so rs hi p bi as )
de te ct ed
ac co rd in g
to th e R-
A M ST
A R
m et ho
do lo gy
Sc or e of
ea ch
#t o ##
ite m
as se ss ed
by R- A M ST
A R
R- A M ST
A R
TO TA
L SC
O RE
(r aw
)
R an k (g ra de
le tte
r) ba se d on
pe rc en til e
of th e gi ve n st ud
y
(W oo
et al .! "# &)
[- #]
So ut h K or ea
% is is a
“p re lim
in ar y”
re vi ew
ab ou
tt he
po te nt ia lu
se of
lu ra sid
on e in
th e
tr ea tm
en to
f bi po
la rd
ep re ss io n
as so ci at ed
w ith
BD -I in
ad ul ts
N o RC
T le ad in g to
FD A ap pr ov al
(e xt en sio
n) co ul d
be co ve re d in
th e
pr es en tp
ie ce
of w or k at w rit in g
tim e
D es pi te th e pu
bl ic at io n bi as
an d in tr in si c lim
ita tio
n of
la ck
of ev id en ce ,t he
re vi ew
is fo rm
ul at ed
in a cr iti ca l
m an ne r, w hi ch
w ou
ld co nt ri bu
te to
pr ov id in g
us ef ul
cl in ic al
re co m m en da tio
n fo rt he
ac tu al us e of
th e dr ug
an d
its fu rt he rd
ev el op
m en t
Pu bl ic at io n bi as
I= !
II = !
II I=
! IV
= #
V = !
V I=
& V II = !
V II I=
! IX
= !
X = !
X I=
&
To ta ls co re
= !,
Pe rc en til e in
th e
pr es en ts et = ,# .$
Q ua rt ile -d er iv ed
gr ad e le tte
r= A
(F in dl ay
et al .
!" #- )[ -! ]
U SA
% e re vi ew
fo cu se s
on th e to le ra bi lit y
an d e(
ca cy
pr o)
le of
lu ra sid
on e in
th e
tr ea tm
en to
fB D -I
de pr es si on
in ad ul ts
Tw o ac ut e ph
as e
tr ia ls (m
on o-
an d
ad ju nc tiv
e th er ap y,
re sp .) [! &, !, ].
M ai nt en an ce
op en -t ri al is
lik ew
is e cr iti ca lly
ac co un
te d. [! .]
To ug
h ve ry
co nc is e an d
on ly pa rt ia lly
“s ys te m at ic ”
in na tu re ,t he
pr es en t
re vi ew
pr ov id es
in pu
ts an d
hi nt sa
bo ut
th e cl in ic al us e
of lu ra sid
on e w hi ch
w ou
ld pa ve
th e gr ou
nd fo rf ur th er
de ve lo pm
en ta nd
ad dr es s
of so m e of
th e un
m et ne ed s
fa ce d by
th e cl in ic al
pr es cr ib er sa
nd th e
su *e ri ng
on es
Pu bl ic at io n bi as
I= #
II = !
II I=
! IV
= #
V = !
V I=
& V II = !
V II I=
# IX
= &
X = &
X I=
&
To ta ls co re
= !&
Pe rc en til e in
th e
pr es en ts et = && .&
Q ua rt ile -d er iv ed
gr ad e le tte
r= B
BD = bi po
la rd
is or de r; ra nd
om iz ed
cl in ic al tr ia l=
RC T.
R- A M ST
A R = re vi se d “a ss es sm
en to
fm ul tip
le sy st em
at ic re vi ew
s.” TR
BD = tr ea tm
en t- re sis ta nt
bi po
la rd
ep re ss io n;
PP = pr ed om
in an tp
ol ar ity
(o fm
oo d
ep is od
es ov er
th e lif et im
e co ur se
of BD
)[ -& ]. FD
A = Fo
od an d D ru g A dm
in ist ra tio
n; BD
= bi po
la rd
is or de r; SG
A = se co nd
ge ne ra tio
n an tip
sy ch ot ic s. N N T = nu
m be rn
ee de d to
tr ea t; N N H
= nu
m be rn
ee de d to
ha rm
.P IC
O /P IC
O re se ar ch
qu es tio
ns :p op
ul at io n,
in te rv en tio
n, co m pa ri so n,
pr ed ic tio
n, an d ou
tc om
e.
#" BioMed Research International
Adapted PRISMA-P 2015 Flow Diagram (Moher et al., 2015) for “overview” use
Sc re
en in
g In
clu de
d El
ig ib
ili ty
Id en
ti! ca
tio n
Sources included in qualitative synthesis (n = 12)
Records assessed for eligibility (n = 12)
Sources further excluded (e.g. lack of accuracy of reporting)
Records excluded (e.g. not systematic or relevant to the topic at issue, redundant content, CME activity, not in the English language) (n = 26)
Records screened at the full- text level (n = 38)
Records a!er duplicates removed (n = 46)
Additional records identi"ed through other sources (contact with the authors, cross- references, n = 0)
Potentially relevant reviews identi"ed and screened for retrieval
Cochrane Library and 25 in Embase). (n = 149, of which 41 in PubMed; 83 in Scopus; 0 in
(n = 0)
F67894 #: Flow chart of overview procedures.
3. Results
Stating the lack of quantitative data to abstract (please refer to Figure # for study 0ow chart) (e.g., treatment e*ect estimates), overall synthesis of results could be presented in a narrative fashion (as outlined in Table !).
#.!. Overview of the Systematic Evidence. As depicted in Figure ! and Table &, most of the included “systematic” reviews fell in the upper tier of the quality range according to the percentile score (or related grade letter): R-AMSTAR total median score = !$.- (Interquartile-Range [IQR] = #&), whereas the range of raw R-AMSTAR scores was equal to #.–&'.
On average, only few original RCTs about lurasidone in the treatment of BD in adults could be “systematically reviewed” since !"#& (FDA extension of approval beyond schizophrenia). Moreover, both the pivotal acute mono- [!&] and adjunctive [!,] therapy trials were sponsored ones, as is preliminary data about maintenance [!/, &"]. Addi- tional details about study design, outcomes and measures of the RCTs consistently covered across the systematically reviewed reviews or drug development with focus on bipolar depression [-/] could therefore be retrieved in the respective references provided above.
T1234 & R-AMSTAR total score Frequency Percentile #.."" # ..& #/."" # #'.$ !"."" # !-." !&."" # &&.& !,."" # ,#.$ !'."" # -"." !/."" # -..& &"."" # ''.$ &&."" # $-." &,."" # .&.& &'."" ! #""." Note. Percentiles"!".$- would fall in the bottom !-th quartile (grade letter “D”); percentile range !".$'–!$.-" = lower -"th or letter C; percentile range !$.'–&&.$- = upper quartile till $-th, or letter B; percentiles#&&.$- would fall in the top quartile (up to #""th percentile), or letter grade “A.”
#.". Chemistry. Lurasidone hydrochloride (molecular formu- la C28H37ClN4O2S) is a benzisothiazolinone derivative. Its molecular weight is -!/.#, g/mol. Figure & shows lurasidone chemical structure. Please access https://pubchem .ncbi.nlm.nih.gov/compound/Lurasidone_HCl5section=Mo- lecular-Formula for additional details.
BioMed Research International ##
36 33.75
27.5
20.75 18
27.33333333
Quartile distribution
1 11
16
21
26
31
36
41
A xi
s t itl
e
Number of included studie! = 12; Median R-AMSTAR total scor" = 27.5
(#$% = 13). Minimum scor" = 18; maximum scor" = 36.
F67894 !: Companion box-plot and quartile distribution for Table !: Conversion of raw R-AMSTAR total scores into percentile scores (see Table &).
O
O
N N
N
N S
F67894 &: !D conformer of lurasidone (compound: CID ##!&$.'"). Additional reference at https://pubchem.ncbi.nlm.nih.gov/com- pound/Lurasidone_HCl5section=!D-Structure.
#.#. Essential Pharmacokinetics and Pharmacodynamics Sig- nature. Substantial consensus exists about the pharmaco- logical signature of lurasidone hydrochloride across sources assessing either preclinical or clinical studies on the matter ['"–',], as brie0y synthesized below.
#.#.!. Essential Pharmacokinetics of Lurasidone. Lurasidone is metabolized by the liver via cytochrome (CYP) &A, ['-] and it is best absorbed with &-" Kcal of food as detailed elsewhere ['']. Although the requirement to take lurasidone with food is minimal inconvenience ['$], the ability to take it just once a day is an advance over alternative medications or polypharmacy regimens ['&].
According to the US package insert, rifampin, a potent CYP&A,-inducer, decreased lurasidone area under the curve )vefold ['.]. %ere are no published studies of potent antiepileptic drugs CYP&A, inducers that are expected to dramatically increase lurasidone metabolism, including those seldom prescribed to BD patients too ['/]. Nonetheless, it is possible that in high doses, oxcarbazepine or topiramate may in0uence lurasidone levels [$"].
When prescribed as oral monotherapy for depression associated with BD-I in adults, initial dose should be !" mg/day, with no titration needed and maximum dose being #!" mg/day depending on patient response, tolerability, and pharmacokinetics issues (in contrast to usually higher dose range of ."–#!" mg/day o+en required for adult cases
of schizophrenia, when used as monotherapy in the absence of major pharmacokinetic interactions) ['#, $#, $!].
#.#.". Essential Pharmacodynamics of Lurasidone. Lurasi- done is a full antagonist at dopamine (DA) D! and serotonin (or --hydroxytryptophan [--HT]) !A (--HT!A) receptors, with binding a(nities (Ki) of ".,$ nanomole (nM) and ".//, nM, respectively ['#, $&]. However, lurasidone also has high a(nity for serotonin --HT$ receptors (".,/- nM; comparable to D! and --HT!A receptors) and has a(nity as partial agonist at --HT#A receptors with a Ki of '.&. nM [$!]. %is may be of potential interest because of preclinical )ndings of a possible procognitive e*ect mediated by action at the serotonin --HT$ receptor ['", '#]. Notably, --HT$ blockade has been postulated to boost --HT#A modulation by lurasidone antagonism elsewhere postulated as a rein- forcement of --HT#A activity [$,]. Lurasidone is also low- to moderate D& antagonist [$-].
Lurasidone preclinical pro)le was found predictive of antipsychotic, antimanic, antidepressant, and procognitive e*ects ['#], as well as e(cacy against negative symptoms of schizophrenia ['&]. Moreover, its lack of a(nity for some receptors (e.g., histamine H#, acetylcholine M#) would predict improved (metabolic and cognitive) tolerability with respect to alternative SGAs options approved by the FDA for BD in adults ['#, '&]. Favorable D!/--HT!A balance would predict lower propensity for extrapyramidal symptoms [',].
According to the original model proposed by Foun- toulakis et al. [$'], the stronger predictors for antidepres- sant e(cacy in bipolar depression would encompass nore- pinephrine alpha-#, dopamine (DA) D#, and histamine antag- onism, followed by --HT!A, by muscarinic and dopaminer- gic D! and D& antagonism, and eventually by norepinephrine reuptake inhibition and --HT#A agonist e*ect [$'].
Yet, it is worth noting that the model would therefore outline a complex interaction between the major neurotrans- mitter systems without a single target being either necessary or su(cient to elicit the antidepressant e*ect in bipolar depression [$'].
While serotonin reuptake inhibition may not play per se a signi)cant role in bipolar depression [$$], it is worth noticing that norepinephrine activity seems to be of great of importance ['#]. %us, early bipolar antidepressant activity excreted by lurasidone has been correlated with disinhibitory norepinephrinergic e*ects of agonistic activity at --HT#A (which may play a core mechanism in bipolar depression [$.] beyond major depressive disorder [$/]) and antagonism at alpha-# norepinephrine and serotonin --HT!A receptors, though the presence of norepinephrine reuptake inhibition (lurasidone is also weak alpha-!a (autoinhibitory, presynap- tic) antagonist (Ki = #".. nM) for lurasidone [',]) is essential in order to sustain it ['#], whereas dopaminergic activity overall may likewise play a major role [."].
Finally, while lurasidone pharmacodynamic signature would represent a good )t of the model proposed by Fountoulakis et al. (!"#!) [$'], additional peculiar phar- macodynamics of lurasidone ['#], including strong --HT$ (and D!) antagonism, otherwise suggestive of procognitive and mood-enhancing activity possibly via dopamine e:ux
#! BioMed Research International
too [.#–.&], and negligible or null --HT& and --HT!C interactions, otherwise accounted as major potential players for antidepressant activity in BD [.,–.'], could not )t the model, possibly due to lack of additional evidence on the matter (publication bias) rather than actual negligence of their neurobiological value on the matter ['#].
#.$. Adverse E,ects Consistently Documented across Varying Systematic Reviews Based on Original Studies. An updated synthesis on major and/or most common AEs with lurasi- done (even) in the treatment of BD is provided elsewhere [',]. Brie0y, the most commonly reported AEs were nausea, akathisia, EPS, and sedation. Negligible e*ects were seen with respect to changes in fasting glucose, total cholesterol, low-density lipoprotein cholesterol, prolactin elevation, and triglycerides’ levels, at least in contrast with alternative SGAs and/or higher average dose regimens used for schizophrenia patients [.$]. No electrocardiogram abnormalities, not even signi)cant increase in QT interval length, have been docu- mented in comparison with placebo or active competitor(s) from the SGA class. Stating the lack of histamine H# and muscarinic M#, as well as strong norepinephrine alpha-# antagonist, activities, lurasidone has also lower propensity to induce somnolence compared to most of the available SGA alternatives [..]. On the contrary, akathisia and dystonia were important, relatively common, AEs. In addition, it is worth noting that while the FDA black box warning about the risk of death in elderly patients with dementia has been issued as a class black box warning, lurasidone database does not have studies involving subjects with dementia and has no reported deaths in clinical trials in this population. Nonethe- less, we purposely avoided providing quantitative synthesis of AEs herein as evidence from RCTs studies involving adult cases of BD is tentative or otherwise hampered by strong publication bias (and selection bias of included samples), and cumulative reports derived by some systematic reviews merged data from schizophrenia cases controlled as well as noncontrolled reports, with this later cases known to be prone to higher neurological side e*ects and being usually exposed to higher dose of antipsychotic(s) on average [',].
4. Discussion
%e average quality of the included systematic reviews ranged between moderate-to-high scoring, as the mode (“most com- mon statistical presentation”) was equal to grade letter = “A” (namely, for . out #! included studies). Overall, concordance exists about the intriguing e(cacy, safety, and tolerability pro)le of lurasidone even in the treatment of acute depressive episodes associated with BD-I, especially when indirectly compared with other FDA-approved SGAs to date.
%is later issue has major implications for the policy- makers, the clinicians, the patients, and their caregivers, especially considering that most BD patients require long- lasting (virtually lifetime enduring) pharmacological treat- ments (ideally integrated by alternative treatment modal- ities), thus being particularly vulnerable to many of the
common AEs documented with some of the SGA class com- pounds already released, especially from cognitive and car- diometabolic standpoints [./]. %us, there is interest towards lurasidone as a safer and more tolerable, yet e(cacious, alternative to current pharmacological armamentarium.
Nonetheless, it must be remarked that the R-AMSTAR grading system is relative to the set at review, which does not necessarily mean absolute high quality of reporting for a given review out of the set at overview. %is further solicits additional primary research studies (namely, RCTs to )ll the gap of publication bias and allow meta-analysis of the evidence), as well as the need for higher quality of reporting of the forthcoming reviews (especially regarding the details documenting research protocols procedures and the biases encountered in the assessment of primary research, namely, publication and sponsorship bias, to this end). On the other side, the trend of publication of reviews about lurasidone con)rms the clinicians’ interest about this compound, even in the treatment of BD, as depicted in Figure ,.
Speci)cally, despite growing body of literature detailing the e(cacy and tolerability of lurasidone, a complementary body of literature documenting its e(cacy for the treatment of BD-I is comparatively less than the one concerning other SGAs, essentially due to the short time since initial approval (subsequently extended beyond the sole treatment of schizophrenia). %is later issue may also concur the explanation why most of the “systematic” reviews on the matter essentially focused on the pharmacodynamics and/or pharmacokinetics of the drug rather than on RCT studies [/"]. In this regard, it is also worth noticing that the upcoming clinical trials should ideally investigate the impact of cur- rent and/or lifetime mixed features as primary outcomes. Similarly, greater attention and strati)cation of the reported results by upcoming RCTs should focus on psychotic features and (emerging) suicidality, which would on turn demand for extended longitudinal follow-up, including 0exible-dose regimen arms, to better investigate medication adherence to lurasidone across varying dosing patterns [/#]. %is is particularly true considering that BD and mood disorders in general should be better evaluated from an extended longitudinal perspective, as originally postulated by Emil Kraepelin for “manic-depressive illness” [#$, #.].
$.!. Study Limitations. Sponsorship, publication biases, and shortage of grey literature on the matter may have limited the availability of negative result trials documented either by primary or secondary research reports. %ough assessed for methodological quality, additional biases inherent to the original )eld trials (e.g., selection bias) may have hampered the generalizability of the overall conclusions drawn herein. Both the psychometric properties and scoring guidance of the adopted R-AMSTAR may still lack in terms of validity (measurement bias). In addition, most of the included studies were written in the English language (potential language bias). English-written papers are likely to be published more rapidly (time-lag bias) and cited more o+en (citation bias). %is is compelling for novel compounds as the mentioned publication bias may represent an issue especially in the
BioMed Research International #&
(McIntyre et al. 2012)
(De Hert et al. 2012)
(Tarazi and Stahl 2012)
(McIntyre et al. 2013)
(Citrome 2013)
(Woo et al. 2013)
(Franklin et al. 2015)
(Gao et al. 2015)
(Sanford and Dhillon
2015)
(Findlay et al. 2015)
(Greenberg and Citrome
2016)
(Jaeschke et al. 2016)
Total score 19 34 36 18 29 24 20 26 30 23 33 36
19
34
36
18
29
24
20
26
30
23
33
36
R- A
M ST
A R
to ta
l s co
re ra
ng e1
1– 44
11.00 13.00 15.00 17.00 19.00 21.00 23.00 25.00 27.00 29.00 31.00 33.00 35.00 37.00 39.00 41.00 43.00
F67894 ,: Number of studies and quality as assessed by the “Revised-A measurement tool to assess the methodological quality of systematic reviews” (R-AMSTAR) [,,] total score for systematic reviews, per year. Note: !"#' records could be updated till late October.
absence of negative results reports and in the presence of sponsored RCTs only to date.
$.". Lurasidone in the Treatment of Bipolar Depression: Major Clinical Implications and Recommendations for Future Clinical Studies to “Meet the Unmet Needs”. %e Program to Eval- uate the Antidepressant Impact of Lurasidone (PREVAIL) planned in !""/ by lurasidone manufacturer with the goal to evaluate the e(cacy and tolerability of lurasidone as both a monotherapy and as an adjunctive therapy in adult patients purportedly excluded psychotic cases of depression associ- ated with BD-I [-/]. While this later strategy was intended to ensure improvement of depressive ratings due to speci)c antidepressant e(cacy of lurasidone rather than e*ect of the psychotic features (excluded per protocol), concerns regard- ing the chance of Berkson’s bias for subsequent e(cacy results are documented in the developed acute and open-phase extension trials which lead to FDA approval. %us, future trials should ideally include representative samples of BD-I depression with concurrent psychotic features too [/!] and stratify results accordingly, as alternative post hoc analyses (e.g., [-/, '$, /&]) from the same original RCTs adopted strati)cation of reporting of the results either for patients aged -- years or older (Dols, et al.), history of treatment resistant depression [!/, &"] and/or mixed features [/,]. Moreover, lurasidone loose D! postsynaptic occupancy (fast dissociation time) compared to alternative antipsychotics may represent itself a plus in the management of psychotic features associated with core mood disturbances as well [/-].
Interest about lurasidone in the treatment of depression with mixed features, even when associated with sub- [/,] or
full-threshold bipolarity rather than major depression [/', /$], is also a matter of vivid clinical debate, although the actual di*erential diagnostic role of “irritability” remains an argument of debate against current DSM-- approach [#", .,, /.].
Despite the need for the future assessment of the above speci)c features and/or special populations, as outlined by most of the reviewed systematic reviews and additional commentaries on the matter, overall evidence of e(cacy of lurasidone as (acute antidepressant) monotherapy for adult patients with BD has an additional translational value [!", !#], as many individuals with BD are treated with polyphar- macy even in circumstances where the most adequate initial approach would be monotherapy [#$, #.], with potential detrimental e*ects on overall treatment adherence [//, #""].
Additional outcomes in cognitive data analyses are nonetheless awaited to determine if there is a key di*er- ence between lurasidone and other SGAs with respect to e(cacy ['&, #"#], stating both the core relevance of cognitive symptoms of bipolar depression [#"!, #"&] and the recom- mendations for future trials to account for personalized or individualized medicine (including biomarkers) even in BD [#",].
Among others, clinical concerns raised upon overview of qualitative and quantitative evidence of lurasidone in BD would regard the need for inclusion of active compound alternative arms in future RCTs (e.g., )xed versus standard dose head-to-head comparisons of lurasidone against OFC, quetiapine, or alternative SGAs). Once again, long-term maintenance double-blind (extension) studies are likewise warranted [#"-]. Ideally, independent controlled trials would
#, BioMed Research International
test whether any signi)cant statistical and/or clinical thresh- old e*ect would be detected in RCTs directly comparing mono- versus adjunctive therapy regimens (regardless the presence of a third arm including placebo).
%e need for additional information on special popu- lations and/or clinical presentations is likewise compelling, especially considering that trials based on the Diagnostic and Statistical Manual Fi+h Edition (DSM--) [#"'] speci)ers of mixed features or rapid-cycling speci)er are missing (or yet to be disclosed to the public at writing time), as well as additional information about otherwise relevant course and speci)ers not (yet?) accounted by the DSM, including, but not limited to, predominant polarity index [-&], strati)cation of results and speci)c analyses about gender, and di*erential comorbidity pro)le, which may in turn play a di*erential impact on both e(cacy and tolerability outcome measures as recently stressed out by comprehensive evidence-based guidelines for treating BD [#"$].
$.#. Concluding Remarks and Future Perspectives. Overall, the present overview outlined concordant unmet needs and recommendations about the use and potential future avenues of lurasidone in the treatment of bipolar depression in adults, with a special emphasis towards its therapeutic potential for cases of treatment resistant and/or mixed features of bipolar depression. In conclusion, lurasidone holds clinical potential as a novel, e(cacious pharmacological treatment for bipolar depression ['']. However, the present overview con)rms that current data on its use in the BD-I population are limited by publication bias and standardization of trial studies design. To this end, while its monotherapy and once a day admin- istration coupled with relatively favorable metabolic and cognitive pro)le indeed represent an intriguing opportunity for policy-makers and budget holders as well the prescribing clinicians and the patients, more extensive research, both longer in duration and independently conducted, is needed.
Disclosure
Since this is a systematic review of systematic reviews, no ethical approval was needed.
Conflicts of Interest
%e authors declare that there are no con0icts of interest regarding the publication of this paper. None of the authors contributing to the present work has any tie to disclose in conjunction with any drug manufacturer.
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