Schizophrenia: lurasidone

Drug action

Lurasidone is a second-generation antipsychotic drug which selectively blocks dopamine and monoamine effects. It binds strongly to certain dopaminergic and serotonergic receptors (primarily D2, 5-HT2A and 5-HT7), as well as blocking some α‑adrenergic receptors. It is a partial agonist of the 5HT1A receptor. Lurasidone does not bind to cholinergic or muscarinic receptors (lurasidone [Latuda] summary of product characteristics).

Licensed therapeutic indication

Lurasidone (Latuda, Sunovion Pharmaceuticals Europe Ltd) is licensed for treating schizophrenia in adults aged 18 years and over. It was launched in the UK in August 2014.

Course and cost

Lurasidone is available as film-coated tablets containing 18.5 mg, 37 mg and 74 mg of lurasidone as lurasidone hydrochloride.

The recommended starting dose for most people is 37 mg once daily. No initial dose titration is required. Dose increases should be based on physician judgement and observed clinical response. Lurasidone is effective at a dose range of 37−148 mg once daily, and the maximum dose should not exceed 148 mg daily. It should be taken once daily together with a meal (lurasidone [Latuda] summary of product characteristics).

For people with moderate or severe renal impairment, end-stage renal disease, moderate hepatic impairment, or people taking moderate CYP3A4 inhibitors, the recommended starting dose of lurasidone is 18.5 mg once daily and the maximum dose should not exceed 74 mg daily. For people with severe hepatic impairment the recommended starting dose of lurasidone is 18.5 mg once daily and the maximum dose should not exceed 37 mg daily (lurasidone [Latuda] summary of product characteristics).

All strengths of lurasidone cost £90.72 per 28 tablets (MIMS, September 2014). Therefore the cost for 28 days' treatment with lurasidone at a dose of 37−148 mg daily is estimated to be £90.72 to £181.44.

Clinical effectiveness

Loebel et al. (2013a) found that lurasidone (at a mean modal dose of 124.2 mg lurasidone hydrochloride daily) was non-inferior to quetiapine prolonged release (at a mean modal dose of 637.6 mg daily) for preventing relapse of schizophrenia at 12 months. The probability of relapse was 23.7% with lurasidone compared with 33.6% with quetiapine prolonged release; HR 0.728, 95% CI 0.410 to 1.295; log rank p=0.280. This was in a population of adults with an acute exacerbation of schizophrenia, whose disease had responded to treatment with lurasidone or quetiapine prolonged release in a 6-week double-blind, placebo-controlled study (the primary relapse analysis population). A sensitivity analysis involving all participants treated with lurasidone or quetiapine in the original 6-week study, irrespective of responder status, found consistent results to the primary analysis and showed that the probability of relapse was 23.0% with lurasidone compared with 35.8% with quetiapine prolonged release (HR 0.660, 95% CI 0.381 to 1.143, log rank p<0.05).

The probability of hospitalisation at 12 months was statistically significantly lower for people in the lurasidone group compared with the quetiapine prolonged release group in the primary relapse analysis population (9.8% compared with 23.1% respectively, p<0.05).

Compared with people in the quetiapine prolonged release group, people in the group originally randomised to lurasidone had a statistically significantly greater improvement in the secondary efficacy outcomes of change from 6-week study baseline at 12 months in PANSS total score, PANSS positive subscale score and MADRS. For PANSS negative subscale score and CGI-S score there was no significant difference between lurasidone and quetiapine (p value not stated).

Citrome et al. (2012) was primarily a safety and tolerability study, and efficacy measures were secondary outcomes. Relapse rates were 20% with lurasidone (at a mean dose of 84.7 mg lurasidone hydrochloride daily) and 16% with risperidone (at a mean dose of 4.3 mg daily). The relapse HR comparing lurasidone with risperidone was 1.31 (95% CI 0.87 to 1.97; p=0.194). Non‑inferiority for lurasidone compared with risperidone was pre-planned as being demonstrated if the upper limit of the 95% CI was lower than the pre-specified non-inferiority margin of 1.6. The EPAR for lurasidone states that non‑inferiority of lurasidone relative to risperidone was not demonstrated since the upper limit was greater than 1.6. However, the non‑inferiority margin was based on expected relapse rates of 35% for both treatment groups after 1 year. The observed relapse rates were much lower than this and Citrome et al. (2012) report that the pre-planned non‑inferiority test of lurasidone compared with risperidone was not interpretable because of the much smaller number of observed relapse events.

No significant differences in improvements in PANSS total scores and CGI-S scores were observed at any point during the 12-month study between the lurasidone and risperidone groups. When MADRS scores were considered, risperidone was found to be statistically significantly more effective than lurasidone at 12 months (difference 1.6, p=0.007) but not at any other time point analysed.

Study D1050238 (NCT01435928; reported in the EPAR for lurasidone).

Study D1050238 was a double-blind, placebo-controlled randomised withdrawal study of lurasidone in adults with a primary diagnosis of schizophrenia. The first part of the study consisted of a screening phase and an open-label stabilisation phase (up to a maximum of 24 weeks, n=676). Participants whose schizophrenia responded to lurasidone treatment, and met stabilisation criteria for at least 12 consecutive weeks were eligible to enter a double-blind randomised withdrawal phase (up to a maximum of 28 weeks, n=144 randomised to lurasidone, n=141 randomised to placebo). During the open-label stabilisation phase, participants received lurasidone 37 mg or 74 mg daily, flexibly-dosed. People who entered the double-blind withdrawal phase received either the same dose of lurasidone they were on at the end of the open-label stabilisation phase, or matching placebo.

The primary objective was evaluation of efficacy of lurasidone for maintenance treatment of schizophrenia, assessed by the time to first relapse event during the double-blind phase. Secondary objectives included safety and tolerability.

Overall 30% of people in the lurasidone group (43/144), and 41% of people in the placebo group (58/141) experienced relapse at some point during the study. Up to week 28, the probability of relapse was 42.2% in the lurasidone group and 51.2% in the placebo group, and there was a statistically significant increase in time to relapse with lurasidone compared with placebo (p=0.039). Sensitivity analysis found a statistically significant difference between the groups in favour of lurasidone (HR for lurasidone compared with placebo 0.66, 95% CI 0.45 to 0.98, p=0.041).

Overall, PANSS total score and CGI-S score increased (worsened) statistically significantly less in people in the lurasidone group compared with the placebo group (p=0.019 for PANSS total score and p=0.002 for CGI-S).

Safety and tolerability

Citrome et al. (2012) found that the proportion of participants reporting 1 or more adverse event was similar in the lurasidone (mean dose of 84.7 mg lurasidone hydrochloride daily) and risperidone (mean dose 4.3 mg daily) groups (84.5% compared with 84.7% respectively). Extrapyramidal symptom-related adverse events were less frequent in the lurasidone group (12.9% in the lurasidone group compared with 15.8% in the risperidone group; no p value given). Metabolic-related adverse events were statistically significantly less frequent in the lurasidone group (11.7% in the lurasidone group compared with 20.8% in the risperidone group, p=0.004). However, the rate of discontinuation due to all causes was statistically significantly higher in the lurasidone group compared with the risperidone group (64% compared with 52% respectively, p=0.004).

Statistically significantly more participants in the lurasidone group reported nausea (16.7%), vomiting (10.0%) and akathisia (14.3%) compared with the risperidone group (10.9%, 3.5% and 7.9% respectively). Conversely, statistically significantly more participants in the risperidone group reported constipation (6.9%) and weight gain (19.8%) compared with the lurasidone group (1.9% and 9.3% respectively).

Loebel et al. (2013a) found that the proportion of participants reporting 1 or more adverse event was 62.5% in the group originally randomised to placebo then switched to lurasidone (mean modal daily dose of 130.0 mg lurasidone hydrochloride), 64.2% in the group originally randomised to lurasidone (mean modal daily dose of 124.2 mg lurasidone hydrochloride) and 71.8% in the group originally randomised to quetiapine (mean modal daily dose of 637.6 mg). The majority of adverse events in all treatment groups were reported as being mild to moderate. Extrapyramidal symptom-related adverse events occurred more frequently with lurasidone (21.4% in the group originally randomised to placebo then switched to lurasidone, 11.9% in the group originally randomised to lurasidone, and 3.5% in the group originally randomised to quetiapine prolonged release [no p values given]). Akathisia was also more common with lurasidone (10.7% in the group originally randomised to placebo then switched to lurasidone, 12.6% in the group originally randomised to lurasidone, and 2.4% in the group originally randomised to quetiapine [no p values given]).

Safety analyses based on observed cases (those participants with 6-week study baseline and extension study 12-month values available) found that both lurasidone and quetiapine prolonged release had minimal effect on weight, body mass index and waist circumference. At 12-months, minimal effects on metabolic parameters including lipids and measures of glycaemic control were observed in both lurasidone and quetiapine prolonged release groups. Median changes in prolactin levels were similar for lurasidone and quetiapine prolonged release at 12 months and no other clinically relevant differences were observed for any other laboratory values. There were no clinically significant treatment-emergent ECG abnormalities with lurasidone or quetiapine prolonged release.

In study D1050238 (NCT01435928) the overall safety profile of lurasidone was broadly comparable to placebo during the double-blind phase. Metabolic parameters, prolactin, and weight increase were similar in both groups, and no changes in QT interval were observed. No safety signal in terms of suicidality was noted with lurasidone.

The EPAR for lurasidone pooled safety data from studies including a total 5068 participants with schizophrenia (3502 treated with lurasidone, 724 with placebo and 842 with other medications). The EPAR concluded that lurasidone has a spectrum of adverse events that is similar to that for other second-generation antipsychotics. The incidence of some common adverse events including akathisia, somnolence and dizziness was dose related. In addition, there was some evidence of a dose-related effect on the incidence of extrapyramidal symptoms such as dystonia, tremor, Parkinsonism and salivary hypersecretion. These adverse events occurred most frequently in the lurasidone 111 mg daily group. Nausea and vomiting occurred with a higher incidence for lurasidone than for the comparators. Effects of lurasidone on blood lipids, glucose and glycated haemoglobin (HbA1c) were limited, and the effect on weight increase was moderate, which is considered to indicate a relatively favourable metabolic profile.

The summary of product characteristics for lurasidone (Latuda) states that in clinical studies, the most common adverse events occurring in at least 1 in 10 participants were akathisia and somnolence which were dose-related up to 111 mg daily.

The summary of product characteristics states that precautions for using lurasidone include people who have a high risk of suicide; people with Parkinson's disease; people with an increased risk of QT-interval prolongation; people with a history of seizures; people who are older and have dementia; people who already have diabetes or who at high risk of developing it; people at an increased risk of hypotension; and people with renal and hepatic impairment. It also states that antipsychotics can increase the risk of a person developing extrapyramidal symptoms, tardive dyskinesia, neuroleptic malignant syndrome, venous thromboembolism, hyperprolactinaemia, and weight gain.

The summary of product characteristics states that concomitant administration of lurasidone and strong CYP3A4 inhibitors (for example clarithromycin) or strong CYP3A4 inducers (for example carbamazepine) is contraindicated. When lurasidone is used with moderate CYP3A4 inhibitors a lower starting dose of 18.5 mg once daily is recommended and the maximum dose should not exceed 74 mg once daily. When lurasidone is used with mild or moderate CYP3A4 inducers, the efficacy of lurasidone should be carefully monitored and dose adjustment may be needed.

Because grapefruit juice inhibits CYP3A4, it may increase serum concentrations of lurasidone, however concomitant use of grapefruit juice and lurasidone has not been assessed. The summary of product characteristics states that people should avoid drinking grapefruit juice whilst taking lurasidone.

Some product-specific information and advice about antipsychotic drugs provided by the Medicines and Healthcare Products Regulatory Agency warned that there is an increased risk of stroke and a small increased risk of death when antipsychotics are used in older people with dementia. The summary of product characteristics for lurasidone (Latuda) states that lurasidone has not been studied in elderly patients with dementia, and that it should be used with caution in elderly patients with dementia who have risk factors for stroke.

Evidence strengths and limitations

The studies included in this evidence summary provide longer-term data on the efficacy, safety and tolerability of lurasidone for treating schizophrenia in adults, however they have some limitations.

The included studies report whether or not treatments had a statistically significant effect on several rating scales used to assess treatment response in schizophrenia. However, whether statistically significant effects on these scales are also clinically significant is difficult to establish. Mortimer (2007) discusses the usefulness of symptom rating scales in evaluating the outcome of people with schizophrenia.

The dropout rates seen in the studies were high. In Citrome et al. (2012), only 34% of participants were still taking lurasidone at 12 months compared with 44% still taking risperidone. In Loebel et al. (2013a) 52% of people were still taking lurasidone at 12 months, compared with 39% still taking quetiapine prolonged release. The EPAR for lurasidone states that it is questionable whether any of the various types of statistical analyses performed were conservative enough to address these missing values.

In Loebel et al. 2013a, participants were enrolled from an initial 6-week study, and did not undergo re-randomisation. This could have potentially introduced selection bias into the groups. The EPAR for lurasidone states that the degree of selection bias meant that the results of the study could not be considered as sufficiently robust.

The EPAR for lurasidone states that in Citrome et al. (2012), non-inferiority of lurasidone compared with risperidone was not shown because the upper limit of the 95% CI was greater than the pre-specified non-inferiority margin. Citrome et al. (2012) report that the pre-planned non-inferiority test of lurasidone compared with risperidone was not interpretable because the observed relapse rate was much smaller than the planned relapse rate that the non-inferiority margin was based on.

To further support the maintenance of effect with lurasidone the manufacturer submitted data from the completed, but not yet fully published D1050238 study. This study demonstrated superiority of lurasidone compared with placebo in time to relapse of psychotic symptoms. These results were supported by sensitivity analyses.

The EPAR for lurasidone concludes that overall, taking the results from all 3 long-term studies into account, the long-term efficacy for lurasidone has been sufficiently demonstrated.

Alternative treatments

The NICE clinical guideline on psychosis and schizophrenia in adults recommends that people with a first episode of schizophrenia, or an acute exacerbation or recurrence of schizophrenia, should be offered oral antipsychotic medication in conjunction with psychological interventions. Regular combined antipsychotic medication should not be initiated, except for short periods (for example, when changing medication).

The NICE clinical guideline recommends that the choice of antipsychotic medication should be made by the service user and healthcare professional together, taking into account the views of the carer if the service user agrees. Information should be provided on, and there should be discussion about, the likely benefits and possible side effects of each drug, including metabolic, extrapyramidal, cardiovascular, hormonal and other side effects (including unpleasant subjective experiences).

NICE advises that clozapine should be offered to people with schizophrenia whose illness has not responded adequately to treatment despite the sequential use of adequate doses of at least 2 different antipsychotic drugs. At least 1 of the drugs should be a non-clozapine second-generation antipsychotic.

The second-generation antipsychotics currently listed in the British national formulary (September 2014) are amisulpride, aripiprazole, clozapine, olanzapine, paliperidone, quetiapine, and risperidone.

The BNF chapter on antipsychotic drugs describes the relative efficacy and adverse effects of different antipsychotics. A National Prescribing Centre patient decision aid provides a guide to the relative adverse effects of different antipsychotics, based on information available at that time (2009).

Table 3 Costs of alternative treatments

Likely place in therapy

The studies in this evidence summary demonstrate that lurasidone is superior to placebo and non-inferior to quetiapine prolonged release for preventing relapse in adults with schizophrenia. However, the EPAR states that non-inferiority to risperidone has not been demonstrated. The spectrum of adverse events with lurasidone is stated to be similar to other second-generation antipsychotic drugs in the EPAR for lurasidone.

The NICE clinical guideline on psychosis and schizophrenia in adults recommends that the choice of antipsychotic medication should be made by the service user and healthcare professional together, taking into account the views of the carer if the service user agrees. Information should be provided on, and there should be discussion about, the likely benefits and possible side effects of each drug, including metabolic, extrapyramidal, cardiovascular, hormonal and other side effects (including unpleasant subjective experiences).

It is likely that lurasidone may represent an additional treatment option alongside existing antipsychotics for adults with schizophrenia. Local decision makers will need to consider the available evidence on efficacy and safety, as well as the higher cost of lurasidone compared with some existing antipsychotic medications (see the alternative treatments section for more information). As with choice of all antipsychotic medicines, individual factors for people with schizophrenia are a key factor when making treatment decisions.

Estimated usage

The estimated number of people taking antipsychotic drugs in England and Wales is 365,394, 39% of whom (142,504) are taking drugs for schizophrenia. Sunovion Pharmaceuticals Europe Ltd anticipates that the uptake of lurasidone in England and Wales will be 0.39% (556 people) in year 1, with an increase to 2.59% (3,742 people) by year 3 (Sunovion Pharmaceuticals Europe Ltd personal communication, August 2014).

Expert advisers

Nick Kosky, Consultant Psychiatrist, Dorset HealthCare University NHS Foundation Trust.

Richard Morriss, Professor of Psychiatry and Community Health, University of Nottingham; Honorary Consultant Psychiatrist, Nottingham Healthcare Trust.

Declarations of interest

No relevant interests declared

Copyright

© National Institute for Health and Care Excellence, 2014. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.

ISBN: 978-1-4731-0726-7