Practical Guidance on the Use of Lurasidone for the Treatment of Adults with Schizophrenia

The opinion of the panel is that lurasidone is efficacious in both the acute and maintenance phases of treatment of schizophrenia in adults. Extensive evidence from lurasidone’s clinical development programme (ESM Table S1) and the panel’s clinical experience suggest that it is as effective as other atypical agents, possibly with the exception of clozapine. In addition, lurasidone may be an option in patients who have previously not responded to other atypical antipsychotics. Since other approved antipsychotics are also effective in treating adults with schizophrenia, it is primarily the side effect profile of lurasidone that differentiates it from other agents.

Individuals with schizophrenia already have disease-related increased risks of metabolic problems, including obesity, hyperlipidaemia and diabetes, which are frequently exacerbated by the adverse metabolic side effects of antipsychotic therapy [30, 31]. Antipsychotic-induced weight gain is particularly distressing for patients, decreasing self-esteem and treatment adherence and increasing the likelihood of depression.

The opinion of the panel is that lurasidone is associated with a lower propensity for metabolic side effects (in particular, weight gain) than most other atypical antipsychotics. Furthermore, overweight patients may lose weight when treated with lurasidone, although the panel also acknowledges that a minority of patients may gain weight while taking lurasidone. During the 6-week lurasidone clinical studies, approximately 5% of patients experienced a ≥ 7% weight gain (Sunovion Pharmaceuticals Europe Ltd, data on file).

Drug-induced prolongation of the QT interval is associated with an increased risk of cardiovascular mortality, and evidence has shown that there is considerable variation between atypical antipsychotics regarding their propensities for causing QT interval prolongation [7, 32]. In a meta-analysis of evidence from randomised controlled trials (RCTs), observational studies and post-marketing surveillance studies, all conducted in patients with mental disorders treated with six atypical antipsychotics (aripiprazole, brexpiprazole, olanzapine, quetiapine, risperidone and ziprasidone), aripiprazole, brexpiprazole and olanzapine were found not to increase the QT interval [32]. In another meta-analysis of RCTs that included a wider range of antipsychotics, lurasidone was found to have the most favourable profile in terms of prolongation of the corrected QT interval (QTc) (Fig. 1) [7]. Lurasidone therefore does not appear to have a detrimental impact on QTc [7, 12], and none of the panel has observed clinically significant QTc prolongation with lurasidone treatment to date. As with all antipsychotics, however, the QTc should be monitored before and after initiating treatment with lurasidone (see section Monitoring of Physical Health).

In accordance with current guidelines regarding the core importance of physical health [1‐6], the panel is in agreement that lurasidone’s favourable metabolic profile, in comparison with those of most other antipsychotics, is a major consideration for long-term maintenance treatment and is therefore a key reason for considering lurasidone, for both clinicians and patients. Choosing an agent with a favourable metabolic profile can lead to improvements in physical health and wellbeing, self-esteem, quality of life and treatment satisfaction, which in turn increase the likelihood of treatment adherence and thereby reduce the risk of relapse and rehospitalisation.

Hyperprolactinaemia is associated with a range of adverse effects, including sexual dysfunction [33]. Moreover, sexual dysfunction related to antipsychotic-induced hyperprolactinaemia is an important driver of treatment non-adherence in schizophrenia [34]. Lurasidone has a relatively neutral impact on prolactin levels in comparison with other antipsychotics [7]. Experience with lurasidone did not show the presence of elevated levels of prolactin in a case series of over 30 patients in clinical practice (Afzal Javed, personal communication, 2019).

As with metabolic problems, neurocognitive dysfunction in schizophrenia comprises both illness- and medication-related effects. Many antipsychotics have detrimental neurocognitive side effects [35], and neurocognitive side effects are a major cause of antipsychotic non-adherence [36]. Importantly, neurocognition is a key mediator of functional outcome in schizophrenia [37‐39].

The opinion of the panel is that patients who switch to lurasidone may experience improvements in the ability to focus/concentrate/‘start their thoughts’. In the panel’s clinical experience, in some patients, such improvements have been confirmed using objective tests, supporting some limited evidence from clinical trials suggesting that lurasidone treatment may be associated with improvements in executive functioning [40, 41]. However, such limited data must be viewed with caution. Since neurocognitive side effects are a common complaint of patients, particularly young patients, lurasidone’s relatively benign neurocognitive side effect profile may potentially be an important factor to consider when choosing treatment.

The opinion of the panel is that the focus of treatment should, from its outset, be the long-term wellbeing of the patient. The overall effectiveness of an agent is not just dependent on its efficacy and tolerability, but on a global impression of treatment satisfaction that also encompasses a patient’s functional status (social life, ability to work, etc.), wellbeing and quality of life. The panel would like to see quality of life as a primary outcome that is systematically measured in future research.

The overall prognosis of schizophrenia is dependent on long-term treatment adherence. It is important to ensure that the initial choice of treatment is correct, since patients often remain on medication that gives a good initial response. Moreover, a negative experience in the early stage of treatment can damage the long-term patient–doctor relationship. Appropriate choice of initial treatment will help optimise the likelihood of long-term adherence. Good cooperation and communication between acute and community services is required to ensure that patients receive the most appropriate treatment from the outset and do not continue to take medication over the long term that has adverse metabolic sequelae. Features of lurasidone considered most likely to encourage adherence and help optimise the long-term wellbeing of patients are its long-term efficacy, low propensity for metabolic side effects (particularly weight gain) and hyperprolactinaemia and relatively benign neurocognitive side effect profile. Naturalistic studies have provided further insights into adherence to lurasidone treatment. A real-world assessment of treatment adherence in patients with schizophrenia, based on insurance claims, demonstrated that adherence to lurasidone was better than adherence to other oral atypical antipsychotics [42]. In a subsequent prospective, non-interventional, observational study of patients consecutively prescribed lurasidone in a UK mental health trust, three variables were found to be significantly associated with treatment discontinuation: treatment resistance at initiation of lurasidone, poor tolerability to the antipsychotic prescribed immediately prior to initiating lurasidone and low lurasidone doses, compared with medium and high doses [43]. The authors concluded that adherence to lurasidone is likely to be improved by early dose optimisation and by targeting patients who are most likely to benefit from treatment (i.e. those without evidence of treatment resistance) [43] (see section Dosing for more information on the importance of early dose optimisation).

Given lurasidone’s efficacy (as acute and maintenance therapy) and side effect profile—in particular its relatively low propensity for causing adverse metabolic effects—the opinion of the panel is that it is appropriate to consider lurasidone early in the course of treatment for adults with schizophrenia. First-episode patients can be treated effectively with lurasidone and continue to receive lurasidone as long-term maintenance therapy.

Lurasidone is formulated as film-coated tablets at dose strengths of 18.5, 37 and 74 mg [12]. The opinion of the panel is that, for the majority of patients, lurasidone should be initiated without titration at a starting dose of 37 mg/day and increased as appropriate, according to response and tolerability, within the dose range 37–148 mg/day. Dosing during maintenance treatment should continue in the dose range 37–148 mg/day, according to response and tolerability. This applies to both previously untreated patients and those switching from other antipsychotics. The panel also acknowledges that if there are tolerability concerns, such as a previous history of EPS or akathisia, then it may be appropriate to adjust dosing for a short period of time before up-titrating again. In patients with moderate or severe hepatic impairment, moderate or severe renal impairment or end-stage renal disease, and/or those taking moderate CYP3A4 inhibitors, a lurasidone starting dose of 18.5 mg/day is recommended and the maximum dose should not exceed 74 mg/day (37 mg/day in patients with severe hepatic impairment) [12].

A randomised, double-blind, placebo-controlled trial conducted in adults with schizophrenia demonstrated that, in patients showing non-response to 2 weeks of treatment with lurasidone 74 mg/day (defined as < 20% improvement from baseline in the PANSS total score), a dose increase to 148 mg/day resulted in significant symptom improvement, compared with continuing treatment with lurasidone 74 mg/day [44]. Patients showing an insufficient response to treatment within 2 weeks should therefore be up-titrated gradually to a maximum dose of 148 mg/day, consistent with this clinical trial evidence [44]. This approach should be adopted before a switch to an alternative treatment is considered.

The opinion of the panel is that, in general, a cross-titration approach should be used when switching to lurasidone from another antipsychotic. The previous antipsychotic should be gradually down-titrated as lurasidone is gradually up-titrated over a period of approximately 2 weeks. Since the elimination half-life of lurasidone is 20–40 h [12], its full clinical effect may not be observed until after 1 week of treatment with an adequate dose. In patients switching to lurasidone due to tolerability problems, a faster cross-titration may be used. Conversely, in those switching from an antipsychotic that is particularly sedating (e.g. olanzapine, quetiapine), a longer cross-titration may be preferable in order to minimise the likelihood of rebound effects. In patients switching from aripiprazole to lurasidone, cross-titration or an abrupt switch approach can be used, since aripiprazole has a long half-life and can take up to 16–19 days to be fully eliminated. For this reason, patients switching from aripiprazole due to side effects should be informed that they may continue to experience these side effects for some time after stopping aripiprazole treatment.

Lurasidone should be taken once daily with a meal [12], since food improves its absorption. If taken without a meal of at least 350 calories, exposure to lurasidone is substantially decreased [13, 18] and the patient will therefore not receive the appropriate dose.

In the panel’s clinical experience, lurasidone can be taken at any time during the day, as long as it is taken with a meal. The optimal timing of administration will depend on patient choice. Some patients find that taking lurasidone with their evening meal decreases the impact of side effects, such as akathisia and somnolence. However, since lurasidone may cause insomnia in some patients, others find that morning dosing is preferable. Changing the timing of administration can therefore be helpful in improving a patient’s experience of taking lurasidone and may help avoid treatment non-adherence. The requirement to take lurasidone with a meal can help patients establish a daily routine, which may also improve adherence.

Initial data and clinical experience suggest that the risk for EPS (acute dystonic reaction, akathisia, parkinsonism and tardive dyskinesia) with lurasidone, although low, may be at least equivalent and perhaps slightly higher than for the ‘average’ atypical antipsychotic [7, 17]. As such, the risk of EPS with lurasidone should be considered and the potential development of EPS assessed for and monitored. If EPS develop, they should be managed by reducing the dose of lurasidone, in accordance with existing guidelines [3, 45, 46]. Nevertheless, evidence from clinical trials and extensive clinical practice experience in the USA indicates that the risk of tardive dyskinesia with lurasidone is low [12]. The members of the panel have not observed any cases of tardive dyskinesia with lurasidone to date, but it is too early to comment on this possibility.

As with other antipsychotics, lurasidone treatment may be associated with akathisia. In clinical trials, the incidence of akathisia was 12.9% with lurasidone versus 3.0% with placebo [12]. The opinion of the panel is that, in clinical practice, akathisia may be observed with lurasidone treatment in a minority of patients, particularly when first initiated. However, approaches can be taken to minimise the risk of akathisia occurring and effectively manage it in the event of its occurrence.

In patients at risk of developing akathisia (such as young adults, the elderly, those with a history of drug/substance abuse and those with a previous history of akathisia with other agents), the panel recommends adjusting the dose for a short period of time before up-titrating again. Akathisia is also reported less frequently in patients who take lurasidone in the evening, as opposed to earlier in the day. The panel also recommends using the Barnes rating scale [47] if akathisia is suspected, since this scale is useful in differentiating akathisia from other conditions (e.g. anxiety, agitation), effective in identifying mild cases of akathisia (when it can manifest as an ‘inner urge to move’, which is often distressing for patients but difficult for them to describe) and helpful in benchmarking and monitoring progress. Proactively asking a patient’s opinion about the causality of their symptoms can be useful in differentiating akathisia from conditions such as anxiety.

The panel highlights that akathisia is unlikely to respond to treatment with anticholinergic agents, unless patients experience concomitant parkinsonism [48]. If akathisia occurs, it can, however, be effectively managed in a variety of ways (Fig. 2). The lurasidone dose may be decreased for a number of weeks and slowly up-titrated again. Short-term adjunctive therapy can also be considered, in the following order:

Concomitant with these pharmacological approaches, psychosocial intervention should be employed. Patients should be proactively informed of the potential risk of akathisia and reassured that, if it occurs, it is likely to be of short duration and can be managed effectively. Management of patient expectations can be very effective in alleviating the impact of akathisia, if it occurs. The use of a relaxation/stretching technique [50] can also be beneficial in addition to pharmacological and psychosocial intervention. If the above approaches are ineffective, it may be appropriate to consider switching to an antipsychotic with a lower risk of akathisia.

In clinical studies of lurasidone 18.5–148 mg/day in patients with schizophrenia treated for up to 52 weeks, and in the post-marketing setting, the most common side effects (≥ 10% patients) were akathisia and somnolence [12]. These side effects were dose related up to 111 mg/day. Other side effects reported by patients in lurasidone clinical studies with an incidence of ≥ 5% and at least twice the rate observed in patients treated with placebo were nausea and EPS [13].

In the panel’s clinical experience, most side effects with lurasidone are transitory, easily managed and/or ameliorated by adjusting the patient’s dose. Somnolence/sedation is associated with many antipsychotic treatments, and lurasidone is less sedating than other atypical antipsychotics, such as quetiapine, olanzapine and risperidone [7], even at a high dose level. As mentioned previously (see section Dosing), in patients switching to lurasidone from an antipsychotic that is particularly sedating, a longer cross-titration may help to minimise the likelihood of rebound effects, such as insomnia. In newly treated patients, evening dosing with lurasidone may help minimise the impact of somnolence. In the panel’s clinical experience, nausea is very rarely reported with lurasidone treatment. This may in part be due to the requirement to take lurasidone with a meal.

The panel is in agreement that guidelines relating to the monitoring of patients’ physical health, such as those formulated by the British Association of Psychopharmacology (Table 3) [6] and The Maudsley Group [51], should be followed. These include the measurement of body mass index, glycated haemoglobin, lipids and blood pressure before the patient is started on antipsychotic treatment and at regular intervals after treatment is commenced [6, 51]. Although there is no signal for QTc prolongation with lurasidone treatment, as with all antipsychotics, QTc should be measured before and after starting lurasidone treatment, in line with existing guidelines (such as The Maudsley Prescribing Guidelines [51]).

As previously mentioned (see section Low Propensity for Hyperprolactinaemia), lurasidone has a modest impact on prolactin levels in comparison with other antipsychotics [7]. As with all antipsychotics, it is nevertheless prudent to monitor prolactin levels in patients treated with lurasidone, particularly since apparently asymptomatic patients may have increased prolactin levels that can have a detrimental impact over the long term (e.g. decreased bone mineral density, increased risk of breast cancer) [33]. Hyperprolactinaemia is associated with a range of adverse effects, including sexual dysfunction, irregular menstrual cycle, abnormal semen production, infertility, galactorrhoea and hirsutism [33]. In the panel’s clinical experience, sexual dysfunction is one of the most important drivers of treatment non-adherence. Patients should therefore be proactively asked about sexual side effects, since they are unlikely to spontaneously volunteer the information.

The panel highlights that, wherever possible, patients should be involved in decisions relating to their treatment. The clinical team should make efforts to inform and support patients/families/carers in the decision-making process in order to ensure that their expectations are managed and their needs and wishes are taken into account. In addition to its proven efficacy, lurasidone’s low propensities for metabolic side effects (particularly weight gain), hyperprolactinaemia and neurocognitive side effects are key reasons why patients may choose this medication, if they are educated on these features of lurasidone. Patients/families/carers should also be fully informed about the potential side effects that can occur with lurasidone treatment and educated on how to manage such side effects, if they occur. Long-term adherence is dependent on addressing the specific individual needs of the patient. Management of expectations is a key aspect of care that can greatly impact patients’ sense of treatment satisfaction and reduce the likelihood of non-adherence.