Although the Diagnostic and Statistical Manual for Mental Disorders-Fourth Edition (DSM-IV) [
This 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 specific therapeutic action rather than based on aimed “neuroscience-nomenclature” approach grounded on the pharmacological profile of the drug [
The majority of patients with bipolar depression fail to respond adequately to pharmacotherapy [
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 [
Currently, olanzapine-fluoxetine 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 2010 and was granted extended approval on June 2013 for the treatment of acute depression associated with BD-I in adults [
Potential
While the overall effect size of OFC, quetiapine (regardless 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 benefits (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 ≥7% weight gain with olanzapine-fluoxetine combination) and thus a substantially more favorable likelihood to be helped or harmed [LHH] (> or ≫1) with lurasidone monotherapy and adjunctive therapy, compared to quetiapine and olanzapine-fluoxetine combination (LHH < or ~1) [
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 efficacy/tolerability profile drugs for bipolar depression still represents a priority for the prescribing clinicians, policy-makers, and the suffering ones, indeed.
More recently, calls have been made for updated brief reviews to provide decision-makers with the essential evidence 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 [
Therefore, while awaiting for additional primary research trials to allow reliable and large-scale quantitative extractions, varying approaches have been proposed [
Therefore, 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 prioritizing 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.
Overall methods and procedures resemble those adopted by recent peer-review articles involving the use of AMSTAR methodology [
A protocol was drafted 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 14, 2016, and included a combination of free text and MeSH terms (please refer to Table
Search strategy across alternative databases (queries run on October 14, 2016).
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1 | #1 |
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3 | Sets |
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4 | Bipolar disorder |
5 | Depression |
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6 | Sets 1–5 were combined with “OR” & “AND” |
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Hydrochloride, Lurasidone
Lurasidone HCl
HCl, Lurasidone
SM 13496
13496, SM
SM13496
SM-13496
SM-13,496
SM 13,496
SM13,496
Lurasidone
N-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinylmethyl)-1-cyclohexylmethyl)-2,3 bicyclo(2.2.1)heptanedicarboximide
Latuda.
Only systematic reviews were included. Case reports, controlled RCT (which were not part of a review), were excluded. Those narrative reviews indexed by major databases as “systematic” were nonetheless identified 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 “
For each review meeting the inclusion criteria data were abstracted independently by two reviewers (MF and DDB). All data was compared and identified anomalies rectified by mutual agreement. Data were obtained exclusively from the systematic reviews, while additional manual screening was planned to enrich the search strategy. The 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 affiliation); major biases, including sponsorship bias. In case of reviews covering multiple RCT studies, these later ones were punctually referenced in Table
Essential overview of the results. Overall, higher scores and letter grades would indicate more reliable content and related conclusions/perspectives/recommendations for future studies and unmet needs to be addressed. Scoring method detailed elsewhere [
Author, year |
Country of origin (leading author) | Information about the sample or coved original studies if multiple data sources |
|
Results drawn based on the accounted evidence/adopted procedures for revision. Main conclusions and perspectives recommended by the authors | Major biases (e.g., sponsorship bias) detected according to the R- AMSTAR methodology | Score of each 1 to 11 item assessed by R-AMSTAR | R-AMSTAR TOTAL SCORE |
Rank (grade letter) based on percentile of the given study |
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(McIntyre et al., 2013) | Canada | BD-I depression; monotherapy: acute phase |
1 RCT [ |
FDA-approved agents should be prioritized over not (yet?) approved options. […“ Lurasidone has minimal propensity to weight gain and appears metabolically neutral, which would will be a significant advantage.”] | Although systematic in nature, most of the core procedures recommended for systematic review were not documented or implemented. Covered SGAs, including lurasidone, focused only on RCT leading to FDA approval, raising concerns for selection and publication biases | I = 1 |
Total score = 18 |
Percentile in the present set = 8.3 |
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(McIntyre et al., 2012) | Canada | The review focused on the pharmacodynamics and pharmacokinetics of lurasidone rather than original RCTs | Studies involving bipolar cases were underway at time of writing | Lurasidone would introduce simplicity of use and favorable metabolic advantages relative to several other SGAs. Outcomes in cognitive data analyses are awaited to determine if there is a key difference between lurasidone and other SGAs with respect to efficacy | Publication bias with respect to RCT trials (indeed, beyond the scopes of the review) | I = 1 |
Total score = 19 |
Percentile in the present set = 16.7 |
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(Franklin et al. 2015) | USA | The review focused on the pharmacodynamics and pharmacokinetics |
Two acute phase trials (mono- and adjunctive therapy, resp.) [ |
Lurasidone acts as high affinity D2 and 5-HT2A antagonist. Lurasidone, however, has somehow uniquely bind with high affinity with 5-HT7 compared to other SGAs. Lurasidone also acts as 5-HT1A partial agonist. |
Lack of assessment of maintenance preliminary data (publication bias) | I = 1 |
Total score = 20 |
Percentile in the present set = 25 |
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(Citrome 2013) | USA | The review is well-grounded with regard do evidence-based methodology and cover a broad number of SGA drugs. The review focuses on the pharmacology, efficacy and tolerability profile of lurasidone and other SGAs | Two acute phase trials (mono- and adjunctive therapy resp.) [ |
Although encouraging, the NNT and NNH computed about lurasidone for the acute treatment of BD-I would need additional primary research data to pool in order to allow more firm conclusions | Search strategy and selection of the not documented in full. This is with special reference to PICO/PIPO research questions | I = 1 |
Total score = 29 |
Percentile in the present set = 58.3 |
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(De Hert et al., 2012) [ |
Belgium | The review focuses on the effects of lurasidone (and asenapine, iloperidone and paliperidone) on body weight and metabolic adverse effects in both schizophrenia and BD patients | No RCT leading to FDA approval (extension) covered in the present piece of work | Based on the evidence available at writing time, lurasidone metabolic effects would resemble those of aripiprazole, amisulpride and ziprasidone closer than the other SGAs assessed in the review at issue. Additional studies are nonetheless warranted | Publication bias with respect to RCT trials (indeed, beyond the scopes of the review) | I = 3 |
Total score = 34 |
Percentile in the present set = 83.3 |
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(Greenberg and Citrome, 2016) | USA | The review focused on the pharmacodynamics and pharmacokinetics | No RCT leading to FDA approval (extension) covered in the present piece of work | The review provides a very comprehensive and updated synthesis of lurasidone pharmacological properties. Distinguishing features of lurasidone against alternative SGA are also outlined, with a special emphasis towards the very potent 5-HT7 activity excreted by lurasidone and its complex interactions with 5-HT1A partial agonist activity | Publication bias with respect to RCT trials (indeed, beyond the scopes of the review) | I = 1 |
Total score = 33 |
Percentile in the present set = 75 |
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(Tarazi and Stahl, 2012) [ |
USA | The review covers the preclinical and clinical data available about lurasidone, asenapine and iloperidone until writing time | No RCT leading to FDA approval (extension) covered in the present piece of work | The review provides an expert opinion perspective about titration, dosing and management of most common side effects eventually experienced by patients with BD in receipt of lurasidone. This allows making inference about some of the clinical unmet needs to be address by forthcoming studies | Publication bias | I = 1 |
Total score = 36 |
Percentile in the present set = 100 |
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(Gao et al., 2015) [ |
USA | The review focuses on the NNT and NNH computed for the essential SGAs approved by the FDA for the treatment of acute bipolar depression in adults, including lurasidone | Two acute phase trials (mono- and adjunctive therapy resp.) [ |
Staining the relatively favorable profile of lurasidone, the authors recommend that the selection of an FDA-approved SGAs for bipolar |
Publication bias | I = 1 |
Total score = 26 |
Percentile in the present set = 50 |
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(Sanford and Dhillon, 2015) [ |
New Zealand | The review provides a synthesis about the use of lurasidone in adults with bipolar depression | Two acute phase trials (mono- and adjunctive therapy, resp.) [ |
The review stresses out the relatively favorable profile of lurasidone in terms of both acute and potentially long-term tolerability in the treatment of BD-I depression, either as mono- or as adjunctive treatment | Publication bias, tough the present review is among the most updated and concise available at writing time | I = 2 |
Total score = 30 |
Percentile in the present set = 66.7 |
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(Jaeschke et al., 2016) [ |
Poland | The present review covers both the 2016 updates about the use of lurasidone in BD and schizophrenia, including synthesis of the pharmacological profile and essential reference to both animal and human studies | Two acute phase trials (mono- and adjunctive therapy, resp.) [ |
This is a very accurate, yet concise, update of the evidence up to early 2016. Nonetheless, the authors failed to expand any conclusive sections about recommendations and the unmet needs for future clinical use and research development | Publication bias but no suspiciousness of sponsorship bias | I = 1 |
Total score = 36 |
Percentile in the present set = 100 |
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(Woo et al. 2013) [ |
South Korea | This is a “preliminary” review about the potential use of lurasidone in the treatment of bipolar depression associated with BD-I in adults | No RCT leading to FDA approval (extension) could be covered in the present piece of work at writing time | Despite the publication bias and intrinsic limitation of lack of evidence, the review is formulated in a critical manner, which would contribute to providing useful clinical recommendation for the actual use of the drug and its further development | Publication bias | I = 2 |
Total score = 24 |
Percentile in the present set = 41.7 |
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(Findlay et al. 2015) [ |
USA | The review focuses on the tolerability and efficacy profile of lurasidone in the treatment of BD-I depression in adults | Two acute phase trials (mono- and adjunctive therapy, resp.) [ |
Tough very concise and only partially “systematic” in nature, the present review provides inputs and hints about the clinical use of lurasidone which would pave the ground for further development and address of some of the unmet needs faced by the clinical prescribers and the suffering ones | Publication bias | I = 1 |
Total score = 23 |
Percentile in the present set = 33.3 |
BD = bipolar disorder; randomized clinical trial = RCT. R-AMSTAR = revised “assessment of multiple systematic reviews.” TRBD = treatment-resistant bipolar depression; PP = predominant polarity (of mood episodes over the lifetime course of BD) [
The methodological quality and risk of bias of the systematic reviews at interest were performed using the AMSTAR items [
The revised assessment of multiple systematic reviews (R-AMSTAR) based on appendix 1 included in the open-access work by Kung et al. [
Both auto- and hand-searches for “type I” (“duplicates among/across different databases”) and “type II” (“duplicate publications in different Journals/issues”) [
Reviews were then screened to exclude systematic reviews with duplicate primary studies unless they reported on different outcomes or provided alternative critical account of the evidence.
Principal outcomes related to the impressions and recommendations about efficacy and tolerability made by the authors given a systematic review at review beyond the raw data come from the covered original RCTs. Specifically, 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, specific outcomes 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.
Stating the lack of quantitative data to abstract (please refer to Figure
Flow chart of overview procedures.
As depicted in Figure
R-AMSTAR total score | Frequency | Percentile |
---|---|---|
18.00 | 1 | 8.3 |
19.00 | 1 | 16.7 |
20.00 | 1 | 25.0 |
23.00 | 1 | 33.3 |
24.00 | 1 | 41.7 |
26.00 | 1 | 50.0 |
29.00 | 1 | 58.3 |
30.00 | 1 | 66.7 |
33.00 | 1 | 75.0 |
34.00 | 1 | 83.3 |
36.00 | 2 | 100.0 |
Companion box-plot and quartile distribution for Table
On average, only few original RCTs about lurasidone in the treatment of BD in adults could be “systematically reviewed” since 2013 (FDA extension of approval beyond schizophrenia). Moreover, both the pivotal acute mono- [
Lurasidone hydrochloride (molecular formula C28H37ClN4O2S) is a benzisothiazolinone derivative. Its molecular weight is 529.14 g/mol. Figure
2D conformer of lurasidone (compound: CID 11237860). Additional reference at
Substantial consensus exists about the pharmacological signature of lurasidone hydrochloride across sources assessing either preclinical or clinical studies on the matter [
Lurasidone is metabolized by the liver via cytochrome (CYP) 3A4 [
According to the US package insert, rifampin, a potent CYP3A4-inducer, decreased lurasidone area under the curve fivefold [
When prescribed as oral monotherapy for depression associated with BD-I in adults, initial dose should be 20 mg/day, with no titration needed and maximum dose being 120 mg/day depending on patient response, tolerability, and pharmacokinetics issues (in contrast to usually higher dose range of 80–120 mg/day often required for adult cases of schizophrenia, when used as monotherapy in the absence of major pharmacokinetic interactions) [
Lurasidone is a full antagonist at dopamine (DA) D2 and serotonin (or 5-hydroxytryptophan [5-HT]) 2A (5-HT2A) receptors, with binding affinities (Ki) of 0.47 nanomole (nM) and 0.994 nM, respectively [
Lurasidone preclinical profile was found predictive of antipsychotic, antimanic, antidepressant, and procognitive effects [
According to the original model proposed by Fountoulakis et al. [
Yet, it is worth noting that the model would therefore outline a complex interaction between the major neurotransmitter systems without a single target being either necessary or sufficient to elicit the antidepressant effect in bipolar depression [
While serotonin reuptake inhibition may not play per se a significant role in bipolar depression [
Finally, while lurasidone pharmacodynamic signature would represent a good fit of the model proposed by Fountoulakis et al. (2012) [
An updated synthesis on major and/or most common AEs with lurasidone (even) in the treatment of BD is provided elsewhere [
The average quality of the included systematic reviews ranged between moderate-to-high scoring, as the mode (“
This 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 treatments (ideally integrated by alternative treatment modalities), thus being particularly vulnerable to many of the common AEs documented with some of the SGA class compounds already released, especially from cognitive and cardiometabolic standpoints [
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. This further solicits additional primary research studies (namely, RCTs to fill 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 confirms the clinicians’ interest about this compound, even in the treatment of BD, as depicted in Figure
Number of studies and quality as assessed by the “Revised-A measurement tool to assess the methodological quality of systematic reviews” (R-AMSTAR) [
Specifically, despite growing body of literature detailing the efficacy and tolerability of lurasidone, a complementary body of literature documenting its efficacy 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). This 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 [
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. Though assessed for methodological quality, additional biases inherent to the original field 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 often (citation bias). This is compelling for novel compounds as the mentioned publication bias may represent an issue especially in the absence of negative results reports and in the presence of sponsored RCTs only to date.
The Program to Evaluate the Antidepressant Impact of Lurasidone (PREVAIL) planned in 2009 by lurasidone manufacturer with the goal to evaluate the efficacy and tolerability of lurasidone as both a monotherapy and as an adjunctive therapy in adult patients purportedly excluded psychotic cases of depression associated with BD-I [
Interest about lurasidone in the treatment of depression with mixed features, even when associated with sub- [
Despite the need for the future assessment of the above specific features and/or special populations, as outlined by most of the reviewed systematic reviews and additional commentaries on the matter, overall evidence of efficacy of lurasidone as (acute antidepressant) monotherapy for adult patients with BD has an additional translational value [
Additional outcomes in cognitive data analyses are nonetheless awaited to determine if there is a key difference between lurasidone and other SGAs with respect to efficacy [
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., fixed 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 [
The need for additional information on special populations and/or clinical presentations is likewise compelling, especially considering that trials based on the Diagnostic and Statistical Manual Fifth Edition (DSM-5) [
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, efficacious pharmacological treatment for bipolar depression [
Since this is a systematic review of systematic reviews, no ethical approval was needed.
The authors declare that there are no conflicts 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.