Background
Schizophrenia is a severe, chronic, and costly psychiatric disorder characterized by acute psychotic episodes. Affected individuals demonstrate a heterogeneous phenotype that includes a vast array of symptomology, variable responses to treatment, and poor health-related quality of life (HRQoL) [
1‐
4]. Patients with schizophrenia can suffer from: (1) positive symptoms such as delusions, hallucinations, conceptual disorganization, suspiciousness, agitation, and hostility; and (2) negative symptoms such as blunted affect, emotional and social withdrawal, lack of spontaneity, and poverty of speech [
5]. These disturbances have a pervasive impact on many areas of patient functioning and frequently reduce HRQoL. The cognitive deficits demonstrated by patients in the domains of executive function, attention, memory, and language are additionally recognized to negatively impact functional outcomes such as psychosocial functioning, work/education, and independent living [
6‐
8]. Patient HRQoL may also be impacted directly by the treatments that are used to manage schizophrenia [
9]. That is, while antipsychotic medications are likely to have a positive effect on patient well-being due to symptom improvements, differences in side effects among currently available therapies (e.g., rates of hyperprolactinemia, weight gain) may negatively impact functional status and overall HRQoL. The different drugs in the atypical antipsychotic class have varying pharmacological profiles, with differential impacts on the clinical response and adverse effects among patients; therefore, they can have a differential impact on HRQoL [
10,
11].
Patient adherence to treatment has also been considerably variable among different antipsychotics, and a patient’s subjective response or attitude to a therapy (i.e., how they perceive their clinical response and/or adverse effects) may impact adherence [
12]. Since tolerability issues are common in the treatment of schizophrenia, patients often discontinue therapy or switch between different types of antipsychotic medications in an effort to find an optimal therapeutic regimen [
13,
14]. Moreover, patients with schizophrenia are often only partially adherent with their prescribed medications [
15‐
17]. In a systematic review of 39 studies that assessed adherence using a variety of methods, approximately 40% of patients with the disorder were partially- or non-adherent to antipsychotic therapies [
17]. While the specific cause is somewhat unclear, adherence-related attitude may play a role in poor adherence, potentially being associated with patient perceptions of medication efficacy and adverse effects [
18‐
20].
Several studies have shown that poor adherence and/or treatment discontinuation are associated with an increased risk of relapse and re-hospitalization, both of which may negatively affect HRQoL [
21‐
23]. Thus, high discontinuation and switching rates between antipsychotics underscores the need to ensure that important outcomes of treatment—such as enhanced adherence rates and improvements in HRQoL—are achieved and maintained following the switch to another antipsychotic.
Lurasidone is a second-generation atypical antipsychotic that received approval in October 2010 by the United States (US) Food and Drug administration (FDA) for the treatment of adult patients with schizophrenia [
24]. Lurasidone can be differentiated from other available second-generation atypical antipsychotics by its receptor binding profile, with moderate affinities for the serotonin 5-HT7, noradrenaline α2c (antagonist), and serotonin 5-HT1A (weak-moderate partial agonist), in addition to the expected high affinity binding for dopamine D2 and serotonin 5-HT2A receptors. Lurasidone has little to no appreciable affinity for the 5-HT2C, histamine H1, and acetylcholine M1 receptors.
The results of a recently published study demonstrated that switching clinically stable yet symptomatic patients with schizophrenia or schizoaffective disorder to lurasidone from other antipsychotic agents was well tolerated, with low rates of patient discontinuation [
25]. This analysis aimed to assess changes in HRQoL in patients with schizophrenia who were switched to lurasidone from other antipsychotic agents in a six-week open-label multicenter parallel group trial using the Personal Evaluation of Transitions in Treatment (PETiT) scale. In addition to overall HRQoL, the study evaluated changes in several important domains of HRQoL in schizophrenia (adherence-related attitude, psychosocial functioning, social functioning, activity, patient perception of cognition, and dysphoria) as measured by PETiT domain scores. The secondary objective of the analysis included an assessment of general health status in patients switching to lurasidone using the Short-Form 12 (SF-12).
Discussion
Along with efficacy and safety, maintenance or improvement of HRQoL is an important outcome of treatment for patients with schizophrenia. This study is the first to systematically examine the effects of switching clinically stable patients with schizophrenia from their current antipsychotic to lurasidone on HRQoL.
The PETiT scale offers a specific and integrated measure of HRQoL for patients who have switched antipsychotic medications, where a patient’s well-being is conceptualized as their subjective perception of their severity of psychotic symptoms, medication side effects, and level of psychosocial performance [
28]. The SF-12 offers a more generic and well-recognized evaluation of physical and mental status that permits comparison to outcomes with other disorders. In populations such as that included in the lurasidone switch study, where patients were clinically stable yet symptomatic at baseline, it would be expected that switching to a new medication might lead to only marginal improvements in terms of these HRQoL outcomes. Therefore, the statistically significant improvements demonstrated by the PETiT assessment after only six weeks of lurasidone therapy are notable and clinically important for patients switching from other antipsychotics.
The majority of patients in the switch study showed improvements from baseline to LOCF on the PETiT total score and the domains of adherence-related attitude, psychosocial functioning, activity, patient perception of cognition, and dysphoria. These findings indicate that, in this study, patients switching to lurasidone perceived improvements in a broad range of measures of well-being. The finding of improved adherence-related attitude following switch to lurasidone is of particular importance, considering the role of patient perception (e.g., of medication, clinical efficacy, AEs) in the traditionally high rates of non-adherence and discontinuation associated with antipsychotic medications [
15‐
17] and the potential cost and HRQoL implications of inadequate treatment (e.g., due to psychotic relapse, hospitalization) [
21,
30]. The higher PETiT scores observed among patients who completed lurasidone treatment provides evidence that patient-reported HRQoL may be associated with the likelihood of continuing treatment.
When examined by preswitch antipsychotic, changes in HRQoL were more variable. Patients switched from quetiapine, risperidone, aripiprazole, and ziprasidone showed statistically significant improvements in PETiT total scores. However, there were no significant changes in PETiT scores among patients switched from olanzapine. It is known that drugs in the atypical antipsychotic class differ in pharmacological profiles, clinical response, and the adverse effects experienced by patients [
10,
11]. Measures of HRQoL allow patients to consider both their clinical response and adverse effects and to emphasize the treatment effect that is of greater relevance to them. In this study, the improvements in HRQoL that were observed after switching to lurasidone from widely-used antipsychotic agents with variable adverse-effect profiles (quetiapine, risperidone, aripiprazole, and ziprasidone), and the maintenance of HRQoL after switching from the highly efficacious antipsychotic olanzapine, collectively suggest that lurasidone is both effective and well tolerated.
The PETiT analysis additionally showed differences in HRQoL depending on whether the pre-study medication was sedating or non-sedating. Patients switching from non-sedating medications showed statistically significant improvements in the total, adherence-related attitude, and psychosocial functioning scores of the PETiT scale; in contrast, the improvements observed in the sedating group were not statistically significant. The difficulty in switching patients from sedating to non-sedating atypical antipsychotics is a well-known challenge in the treatment of schizophrenia [
31]. Subjective tolerability—how a patient feels on their medication—may play a role in this challenge, potentially contributing to the greater improvements on the PETiT score in patients switching from non-sedating versus sedating antipsychotics [
22,
32,
33]. Results published earlier from this study also revealed differences in the time to treatment discontinuation and all-cause discontinuation between patients switched from sedating versus non-sedating antipsychotic agents [
25]. The authors suggested that attention should be paid to the emergence of insomnia or anxiety in persons who had received a sedating antipsychotic immediately prior to switching to lurasidone.
Finally, the results of the more generic SF-12 assessment also support the feasibility of switching to lurasidone from other antipsychotics. Patients generally demonstrated little change or improvements in the PCS and MCS scores, indicating that their physical and mental health status was maintained or improved by switching to lurasidone. Given the clinical stability of the patient population at baseline and the short six-week duration of follow-up, it is not unexpected that no marked difference was observed in physical component using a generic instrument such as the SF-12 [
34].
Overall, it is well recognized that the HRQoL of patients with schizophrenia can be negatively impacted by the effects of atypical antipsychotic therapies [
9‐
11]. The findings of the current analysis are therefore important, as maintenance or improvement of patient well-being following switch to lurasidone may in turn make patients more likely to adhere to and continue on therapy. As noted previously, improvements in adherence and continuation of treatment may improve patient outcomes, such as reductions in relapse and re-hospitalization events [
23,
30].
This analysis is one of few published studies to examine changes in HRQoL, functioning, and health status after switching between antipsychotics. While four relatively recent investigations of patients switching to quetiapine XR [
35], aripiprazole [
36], ziprasidone [
37], or long-acting injectable risperidone [
38] reported on changes in cognitive function, psychotic symptoms, and tolerability, only one additionally described changes in quality of life using the Subjective Well-being Under Neuroleptics Scale – Brief Form [SWN-K] [
37]. This study reported no significant change in patient quality of life following switch to aripiprazole [
37].
Other studies have commented on the risk of tolerability problems, symptom exacerbations, or increased use of acute care services after switching patients between antipsychotics [
39‐
41]. However, the results of this clinical trial, as reported by McEvoy and colleagues [
25] and described herein, demonstrate that switching to lurasidone has a low risk of treatment failure, discontinuation, AEs, or of an adverse impact on patient well-being.
There are a few limitations of the current study. First, being an open-label evaluation with no control group, the outcomes were prone to greater bias than outcomes from a randomized controlled clinical trial. Notwithstanding this limitation, this naturalistic switch trial has potential application for clinical practice guidance on switching patients to lurasidone. Second, the six-week duration of the study may not have been long enough to fully capture changes in HRQoL and other outcomes. However, such outcomes remain a critical source of insight concerning numerous aspects of any disease, and in particular, the perception of patient well-being in psychiatric disorders such as schizophrenia. Analysis of the longer-term effect of lurasidone on HRQoL, in both the PETiT and SF-12 assessments, from the six-month extension phase of the trial is ongoing. Another limitation was the study’s small sample size for the subgroup analyses, and interpretation of the subgroup results warrants caution. Finally, as noted previously by McEvoy and colleagues [
25], the lack of information on the preswitch sedation status of patients is a limiting factor in terms of understanding the validity of categorizing the preswitch agents as “sedating” or “non-sedating”. Still, the clinical and now quality of life outcomes observed in this study suggest that this distinction may be clinically relevant to patients with schizophrenia. As suggested by McEvoy’s group, stratification of the data on the basis of agent or properties other than sedation could result in different outcomes than those reported here.
Despite these limitations, the study results suggest that stable yet symptomatic patients with schizophrenia may be efficiently switched from other antipsychotics to lurasidone, with potential improvements in psychosocial functional, attitude related to adherence, and overall mental health status.
Competing interests
Mariam Hassan, Antony Loebel, Jay Hsu, Andrei Pikalov, and Krithika Rajagopalan are employees of Sunovion Pharmaceuticals, Inc. George Awad has no competing interests to declare.
Authors’ contributions
MH and KR conceptualized the post-hoc analysis. GA, MH, KR, AL, AP and JH participated in the study analysis and data interpretation. AL, AP, and JH were involved in the conceptualizing, designing and analysis of the clinical trial. GA, MH, KR, AP, and AL critically reviewed and revised the manuscript for important intellectual content. All authors have reviewed and approved this manuscript.