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Lurasidone Hydrochloride (Latuda): Management of Manifestations of Schizophrenia [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2014 Jan.


No RCTs met the inclusion criteria for the updated review of lurasidone. Nevertheless, the key elements forming the basis of the manufacturer’s resubmission have been summarized and appraised in detail in this report.

The main reason for CDEC’s recommendation of “Do Not List” for lurasidone was a lack of evidence from RCTs to establish the comparative efficacy of lurasidone relative to other AAPs for the acute treatment of schizophrenia.1 As discussed at length in CDR’s original review, direct comparative evidence for lurasidone against other AAPs is sparse. In the acute-treatment trials, risperidone, olanzapine, and quetiapine were incorporated as active comparators for the purpose of assay sensitivity, but these trials were not designed for comparisons against lurasidone. In fact, the only study designed to assess non-inferiority of lurasidone with another AAP was a 52-week stable treatment trial that failed to confirm non-inferiority against risperidone on time to relapse.

Broadly speaking, there is a considerable body of evidence regarding the comparative efficacy of AAPs. Findings from the large clinical antipsychotic trial of intervention effectiveness (CATIE)48,49 suggested that olanzapine was more effective than risperidone and quetiapine, as indicated by time to treatment discontinuation, with a similar trend favouring olanzapine over ziprasidone. Lurasidone was not studied in this trial. Olanzapine was also shown to be superior to aripiprazole, quetiapine, risperidone, and ziprasidone for a change in PANSS scores in a systematic review and meta-analysis of blinded, head-to-head studies comparing second-generation antipsychotics (78 studies, N = 13,558).50

Without direct comparative evidence, well-conducted indirect comparisons can aid the assessment of relative efficacy and safety. The manufacturer submitted the IDCs separately, comparing lurasidone with aripiprazole and with ziprasidone. Overall, no statistically significant differences in efficacy were noted in these comparisons. However, several shortcomings were noted that limit the interpretation of these results, primarily the restricted focus to aripiprazole and ziprasidone as comparators, the lack of a systematic literature search, and the apparent absence of methods for considering heterogeneity across studies.

Recently, Leucht et al. (2013)2 conducted a comprehensive NMA that integrated direct and indirect comparisons of 15 orally administered antipsychotic drugs (including lurasidone) for acute-treatment of schizophrenia (defined as six weeks duration). The primary outcome was change in overall symptoms from baseline to end point, measured by the PANSS total score. The results suggested that there were no statistically significant differences in efficacy between lurasidone and aripiprazole, zotepine, haloperidol, quetiapine, sertindole, ziprasidone, chlorpromazine, asenapine, or iloperidone. However, lurasidone demonstrated statistically significantly lower efficacy than clozapine, amisulpride, olanzapine, risperidone, and paliperidone. Compared with placebo, the SMD in symptom improvement for the four newest AAP drugs available in Canada were similar: aripiprazole (0.43); ziprasidone (0.39); asenapine (0.38); and lurasidone (0.33). The older AAPs tended to be associated with larger SMDs: olanzapine (0.59); risperidone (0.56); paliperidone (an active metabolite of risperidone) (0.50); and quetiapine (0.44). These results were robust even when adjustments were made for known confounders such as year of publication. Lurasidone ranked second-last in terms of efficacy (after iloperidone), and lower than aripiprazole and ziprasidone. The results were broadly similar for the outcome of all-cause discontinuation, such that lurasidone had the third-highest risk of discontinuation after sertindole and haloperidol. Lurasidone was associated with statistically higher risks of all-cause discontinuation compared with olanzapine and risperidone, but there were no significant differences between lurasidone and quetiapine, aripiprazole, or ziprasidone.

Unlike the manufacturer-submitted IDCs, Leucht et al. also reported on comparative safety across AAPs. Lurasidone is purported to have a relatively neutral metabolic profile, similar to the other newer AAPs (i.e., aripiprazole and ziprasidone). The only metabolic outcome reported in the Leucht et al. paper was weight gain. Based on SMDs, the degree of weight change was similar across aripiprazole (0.17), ziprasidone (0.10), and lurasidone (0.10) compared with placebo. The effect estimate for lurasidone indicated a non-significant change in body weight compared with placebo. Olanzapine, quetiapine, and risperidone were associated with significantly more weight gain than lurasidone. For example, the effect estimate for weight change with olanzapine versus placebo was an SMD of 0.74. However, no information was available on other relevant metabolic outcomes, such as blood glucose and lipid parameters. A recent meta-analysis by De Hert et al. (2012)51 compared the body weight and metabolic AEs of newer second-generation AAPs (lurasidone, asenapine, iloperidone, and paliperidone) based on the changes in numerous metabolic measures, including weight change from placebo-controlled clinical trials. The authors reported that lurasidone was associated with a statistically significant increase in weight gain when compared with placebo (WMD = 0.49 kg), and it was concluded that this drug was similar to aripiprazole and ziprasidone in this respect.

In line with the results of the CDR review of lurasidone trials, the risk of EPS reported by Leucht et al. was higher with lurasidone than placebo and several other AAPs, and lurasidone was one of the least tolerated drugs in this respect. The odds ratio (OR) for this outcome against placebo was 2.46 and statistically significant for lurasidone, compared with 1.20 and non-significant for aripiprazole, and 1.00 for olanzapine. The comparison of lurasidone with aripiprazole was statistically significant in favour of the latter drug.

Another adverse effect reported by Leucht et al. was QTc prolongation, which occurred to a lesser degree with lurasidone than olanzapine and other older AAPs. The comparison of lurasidone with aripiprazole was statistically non-significant; whereas, lurasidone was associated with a significantly lower degree of QTc prolongation compared with ziprasidone. Increases in prolactin were larger with lurasidone than with aripiprazole, but there was no significant difference between lurasidone and either olanzapine or ziprasidone. With respect to sedation, there were no significant differences between lurasidone and aripiprazole, ziprasidone, olanzapine, risperidone, or quetiapine.

The Leucht et al. study provides important information regarding comparative efficacy and safety across AAPs in the acute-treatment setting (initial six weeks). However, a similar analysis is not available for stable patients. The only comparative RCTs of lurasidone with other AAPs in this setting are Studies 254 and 237 (both included in the original CDR review), in which the comparators were ziprasidone and risperidone respectively. Study 237 was a one-year trial specifically designed to compare treatments on time to relapse using a non-inferiority design, but failed to confirm the non-inferiority hypothesis. The only other study providing comparative evidence in the stable treatment setting was Study 234, the extension of Study 233. While this study confirmed the a priori non-inferiority hypothesis for time to relapse against quetiapine, interpretation of these results is limited by concerns that the original randomization performed in Study 233 may have been compromised in the extension. Such concerns arise because not all patients completing Study 233 consented to participating in Study 234 and there were high rates of withdrawal from both studies. Thus, similar to the results of the original CDR review, the comparative long-term efficacy and safety of lurasidone versus other AAPs remains uncertain.

The clinical context of antipsychotic therapy for schizophrenia is an important consideration in evaluating the available comparative efficacy and safety evidence for lurasidone. Patient group input received by CDR indicated the need for additional antipsychotic treatment options for patients with schizophrenia, and an individualized approach to treatment. Two main reasons were cited for this. First, there is variability in individual patient response, so that a particular drug may not be effective for all patients, and a trial and error approach to identifying optimal therapy is common. Second, AEs, particularly metabolic effects such as weight gain, can be very problematic for patients because of their impact on self-esteem, as well as the associated risks of diabetes and cardiovascular disease. Neurological adverse effects such as drowsiness and akathisia can also impair quality of life and result in treatment discontinuation. While there may be concerns regarding the comparative efficacy of lurasidone versus other commonly used antipsychotic drugs, it is possible that its observed AE profile may be advantageous for some patients, particularly with respect to its low propensity for causing weight gain.

Copyright © CADTH 2014.

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Lurasidone Hydrochloride (Latuda): Management of Manifestations of Schizophrenia [Internet].


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