Real-world safety and effectiveness of lurasidone in Chinese children and adolescents with schizophrenia: Findings from a prospective cohort

Abstract

BACKGROUND

Early-onset schizophrenia in China represents significant clinical challenges because of limited therapeutic options and the lack of evidence-based guidelines.

AIM

To investigate the real-world use of lurasidone in Chinese children and adolescents with schizophrenia.

METHODS

This post-hoc analysis included patients with schizophrenia receiving lurasidone monotherapy, using data from a 12-week, prospective, observational, single-arm, open-label, multi-center post-marketing surveillance in China. Patients were stratified into pediatric and adult groups. Pediatric patients were further classified by whether their final titration dose exceeded 40 mg/day. Adverse events (AEs), Brief Psychiatric Rating Scale (BPRS) and International Classification of Diseases 11th Revision (ICD-11) symptom rating scores were collected.

RESULTS

Of 140 pediatric patients (51 male/89 female; mean age 15.4 years), 96.4% completed the surveillance. Compared with adults, pediatric patients demonstrated slightly lower mean initial lurasidone dose (35.7 ± 10.94 mg/day vs 39.4 ± 10.70 mg/day, P < 0.001) and earlier first dose adjustment (7.1 ± 8.87 days vs 10.3 ± 13.07 days, P = 0.001). Mean daily doses for pediatric patients and adults were 65.1 ± 17.95 mg/day and 61.7 ± 21.53 mg/day, respectively (P = 0.044). During surveillance, six AEs (weight gain, n = 4; drowsiness, n = 2) occurred in six pediatric patients (4.3%). All were mild. Mean weight gain was 0.1 ± 2.21 kg. AE incidences were 4.8% and 2.8% in > 40 mg/day and ≤ 40 mg/day group, respectively (P = 1.0000). Post treatment, 37.1% of pediatric patients achieved a ≥ 50% reduction in BPRS total score, compared with 27.8% of adults. Unadjusted analyses indicated greater reductions in BPRS anxiety-depression sub-score in pediatric patients compared to adults (P < 0.001). Similar trend of reductions in ICD-11 depressive mood (P = 0.052), cognitive (P = 0.013), and positive symptoms (P = 0.001) scores was seen in pediatric patients.

CONCLUSION

Chinese pediatric patients receive lurasidone treatment at lower initial doses, undergo faster titration, and achieve slightly higher mean daily doses. Lurasidone 40-80 mg/day was well-tolerated, with low AE rates, and suggested potential improvement, particularly for patients with more severe depressive symptoms. Lurasidone appears to be a promising treatment option for Chinese children and adolescents with schizophrenia.

Key Words: Schizophrenia; Children and adolescents; Lurasidone; Safety; Effectiveness

Core Tip: This is the first study to specifically evaluate lurasidone monotherapy in a substantial cohort of Chinese children and adolescents with schizophrenia, providing essential evidence on real-world dosing patterns, safety, and effectiveness. Pediatric patients were initiated on lurasidone at lower doses but underwent more rapid titration, ultimately reaching a slightly higher mean final and daily dose than adults. Lurasidone 40-80 mg/day was well tolerated with low rates of adverse events, suggesting potential clinical improvement, particularly in patients with more severe depressive symptoms. These findings suggest that lurasidone may be a promising treatment option for Chinese pediatric patients with schizophrenia.

INTRODUCTION

Schizophrenia is a severe mental disorder that affects 23 million people worldwide[1]. In China, the weighted 12-month prevalence of schizophrenia is 0.6%, generating 3.48 million disability adjusted life years and imposing a substantial burden on patients, families, and society[2,3]. Schizophrenia with symptom onset before the age of 18 years is termed early-onset schizophrenia (EOS)[4]. Previous reports have demonstrated that 18% of patients experience their first symptoms before the age of 18 years, while 8.2% receive a diagnosis before the age of 18 years[5]. Compared with adult-onset patients, EOS is often characterized by a more insidious onset, more severe positive and negative symptoms, and a greater risk of cognitive impairment, leading to poorer long-term functional outcomes[6-8].

Research has confirmed that early identification and timely, systematic treatment intervention can improve poor outcomes and increase the likelihood of recovery in patients with schizophrenia. Consequently, multiple guidelines recommend initiating treatment as early as possible[6,9,10], with second-generation antipsychotics (SGAs) typically recommended as first-line drugs[10]. Although fewer studies have investigated schizophrenia in children and adolescents than in adults, the existing evidence indicates that SGAs demonstrate comparable efficacy in younger populations[5,8]. Accordingly, several clinical guidelines recommend SGAs for the management of EOS[10,11]. Despite these recommendations, the prevention and treatment of schizophrenia in children and adolescents remain substantial clinical challenges[9]. Pediatric patients are generally more susceptible to antipsychotics-related adverse effects; therefore, decisions must carefully balance efficacy against the risk of potential adverse reactions, including metabolic disturbances (such as weight gain and dysglycemia), extrapyramidal symptoms (EPS) (including akathisia, dyskinesia, and dystonia), and endocrine abnormalities (including prolactin elevation)[10]. Importantly, given that only a small number of SGAs including paliperidone, risperidone, and aripiprazole, have been approved for pediatric patients with schizophrenia in China[12], treatment options remains limited, and medication labels often lack detailed, age-appropriate dosing information and comprehensive pediatric prescription guidance. This has contributed to the absence of unified, evidence-based national guidelines specifically for EOS management in China[13]. Consequently, clinicians frequently rely on off-label prescribing[12], underscoring the urgent need for more robust pediatric clinical evidence to support safe, effective, and standardized treatment approaches.

Lurasidone is a relatively novel SGA that was first approved in the United States in 2010 for the treatment of schizophrenia. Since then, it has been approved in multiple countries and was introduced to China in 2019. Lurasidone possesses a unique pharmacological profile characterized by high affinity for dopamine D2, serotonin 5-hydroxytryptamine receptor 2A (5-HT2A), and 5-hydroxytryptamine 7 (5-HT7) receptors[14]. Clinical trials in patients with schizophrenia have demonstrated that lurasidone improves positive, negative, affective, and cognitive symptoms, while maintaining a favorable safety profile. Notably, it has minimal effects on metabolic parameters and prolactin levels[14], factors that are of vital importance for children and adolescents during critical stages of growth and development[9,10].

Real-world evidence is essential for bridging the gap between controlled clinical trials and routine psychiatric practice, because it accounts for the heterogeneity of patient populations, varying dosing regimens, and comorbid conditions that are often underrepresented or excluded from randomized controlled trials (RCTs)[15]. Despite the increasing use of lurasidone in clinical practice, no large-scale study has comprehensively evaluated its safety and effectiveness as monotherapy in Chinese children and adolescents with schizophrenia.

Therefore, this post-hoc analysis derived from a large-scale prospective post-marketing surveillance (PMS), aimed to evaluate the real-world dosing patterns, safety profile, and multi-dimensional effectiveness of lurasidone in Chinese children and adolescents and to compare these factors with those observed in adults. By focusing on treatment outcomes over a 12-week period, we aimed to provide clinicians with evidence-based insights to inform the optimization of lurasidone therapy in this vulnerable population.

MATERIALS AND METHODS

Study design and patients

This study was a post-hoc analysis of a 12-week prospective, non-interventional, open-label, single-arm PMS. The PMS protocol has been described previously[16]. The PMS was conducted from December 2020 to December 2023 at 36 sites in China. An electronic data capture system was used to record the diagnostic and treatment-related information for the enrolled patients. The inclusion criteria were as follows: (1) A diagnosis of schizophrenia according to the International Classification of Diseases 10th Revision; and (2) Treatment with lurasidone (Latuda^®).

All patients diagnosed with schizophrenia and treated with lurasidone were included in the full analysis set (FAS). All patients who received at least one dose of lurasidone were included in the safety set (SS). For the current analysis, only patients who received lurasidone monotherapy were included. Participants were divided into pediatric (< 18 years) and adult (≥ 18 years) groups. To further evaluate the safety profile of lurasidone in pediatric patients, this group was further stratified according to their final titration dose (> 40 mg/day or ≤ 40 mg/day), enabling comparisons within the United States Food and Drug Administration-approved dose range of 40-80 mg/day.

The PMS protocol was approved by the ethics committee of the leading site of the Shanghai Mental Health Center (approval No. 2019-72). Written informed consent was obtained from all patients prior to enrollment. For participants younger than 18 years, written informed consent was obtained from a parent or legal guardian.

Dosing regimen

In the PMS, the dosage and administration of lurasidone were determined by the treating investigators according to clinical judgment. In accordance with the lurasidone package insert in China, treatment is usually initiated at 40 mg/day, and may be increased to 80 mg/day based on the patient’s condition and treatment response.

Safety assessment

Safety assessments were conducted in the SS population, with the primary safety outcome defined as the incidence of adverse events (AEs) during the 12-week surveillance period. Safety outcomes included the incidence of AE, EPS, akathisia, and changes in body weight from baseline. Investigators assessed and recorded AEs and laboratory parameters, including liver and renal function, blood glucose, lipid profiles, and prolactin levels at baseline and at weeks 2/4, 6/8, and 12 following treatment initiation. All AEs were coded using the International Council for Harmonisation International Dictionary of Medical Terms (MEDDRA 24.0, Medical Dictionary for Regulatory Activities). An adverse drug reaction (ADR) was defined as an AE for which a causal relationship with lurasidone could not be ruled out.

Effectiveness assessment

Effectiveness outcomes were evaluated in the FAS. The severity of schizophrenia symptoms was assessed at baseline, and at weeks 2/4, 6/8, and 12 using the Brief Psychiatric Rating Scale (BPRS) and the International Classification of Diseases 11th Revision (ICD-11) symptom rating scale[10,16]. The BPRS comprises 18 items, rated on a 7-point scale, with a total score ranging from 18 to 126. It evaluates five symptom domains: Positive symptoms (conceptual disorganization, grandiosity, hallucinations, and unusual thought content), negative symptoms (blunted affect, motor retardation, emotional withdrawal, and disorientation), anxiety-depression (anxiety, guilt, depressive mood, and somatic concern), activation (tension, mannerisms and posturing, and excitement), and hostility-suspiciousness (hostility, suspiciousness, and uncooperativeness). Higher scores indicate greater symptom severity, whereas larger reductions from baseline reflect greater treatment effectiveness. The ICD-11 symptom rating scale assesses six symptom domains: Positive, negative, depressive, manic, psychomotor, and cognitive symptoms. Compared with more comprehensive instruments such as the Positive and Negative Syndrome Scale, it provides a conceptually similar but simpler framework for characterizing clinical heterogeneity. Each domain is rated on a 4-point ordinal scale, with scores of 0-3 corresponding to absent, mild, moderate, and severe symptoms, respectively. A score of 9 is assigned when a symptom cannot be rated because of insufficient information. This ordinal rating structure facilitates longitudinal tracking of symptom severity over time and supports standardized clinical documentation and patient management[10,17].

Statistical analyses

Statistical analyses were performed using IBM SPSS Statistics (version 26.0; IBM Corp., Armonk, NY, United States). Continuous variables are presented as mean ± SD for normally distributed data, or as median (interquartile range) for non-normally distributed data. Between-group comparisons of continuous variables (e.g., pediatric vs adult patients) were conducted using the independent samples t-test or Mann-Whitney U test, as appropriate according to data distribution. Within-group changes in effectiveness outcomes from baseline to endpoint were analyzed using the paired t-test or Wilcoxon signed-rank test, as appropriate. Categorical variables are presented as n (%) and between-group comparisons were performed using the χ² test or Fisher’s exact test, as appropriate. Given the substantial baseline differences between pediatric and adult patients, an analysis of covariance (ANCOVA) was used as the primary analytical approach to minimize baseline confounding. The model was adjusted for sex, baseline body mass index, family history, disease duration, number of episodes, and baseline BPRS total score. To evaluate the robustness of the findings, propensity score matching (PSM) was performed as a sensitivity analysis. Patients were matched using a 1:1 nearest-neighbor matching algorithm with a strict caliper width of 0.02. The covariates included in the PSM model were identical to those included in the ANCOVA. Between-group covariate balance after matching was assessed using standardized mean difference. All statistical tests were two-tailed, and a P value of < 0.05 was considered statistically significant. For patients who discontinued treatment before week 12, missing endpoint data were imputed using the last available observation.

RESULTS

Patient demographics and baseline characteristics

The analysis included 140 pediatric patients (male/female: 51/89), accounting for 9.5% of the 1481 patients who received lurasidone monotherapy (Figure 1). Among them, 96.4% (135/140) completed the 12-week follow-up period, while five were lost to follow-up. The mean age of the pediatric patients was 15.4 years (range: 10-17 years). Additional baseline demographic and clinical characteristics are presented in Table 1.

Figure 1 Diagram of patients. FAS: Full analysis set.

Table 1 Baseline characteristics of pediatric and adult patients receiving lurasidone monotherapy, mean ± SD/n (%).

Outcome measures	Pediatric (n = 140)	Adult (n = 1332)	P value
Male	51 (36.4)	598 (44.9)
Age, year	15.4 ± 1.66	35.3 ± 13.29	< 0.001
BMI, kg/m2	21.8 ± 3.58	23.3 ± 3.58	< 0.001
Duration of illness, year	0.8 ± 0.97	6.1 ± 8.08	< 0.0011
Number of episodes	1.4 ± 0.81	3.1 ± 3.58	< 0.0011
Number of psychosis-related hospitalizations	0.6 ± 0.84	2.3 ± 3.80	< 0.0011
Number with comorbid mental disorders		5 (0.4)
Number with family history of mental disorders	20 (14.3)	107 (8.0)	0.0122
BPRS
Total score-baseline	45.6 ± 15.67	43.9 ± 16.50
Anxiety-depression	10.8 ± 4.15	9.6 ± 4.30	0.001
Negative symptoms	8.3 ± 3.54	8.7 ± 3.72
Positive symptoms	10.8 ± 4.28	10.7 ± 4.58
Activation	6.3 ± 3.08	6.0 ± 3.14
Hostility-suspiciousness	9.3 ± 3.96	8.9 ± 3.97
ICD-11 symptom rating scale
Positive symptoms	2.3 ± 0.93	1.8 ± 0.88	0.001
Negative symptoms	1.4 ± 0.81	1.3 ± 0.75
Depressive mood symptoms	1.5 ± 0.91	1.0 ± 0.77	< 0.001
Manic mood symptoms	0.7 ± 0.85	0.7 ± 0.74
Psychomotor symptoms	1.2 ± 0.91	0.9 ± 0.80
Cognitive symptoms	1.7 ± 0.97	1.2 ± 0.79	< 0.001

¹P values calculated from Welch’s t-test.

²P values calculated from χ² test.

P values are derived from two-sample equal variance t-tests unless otherwise indicated. BMI: Body mass index; BPRS: Brief Psychiatric Rating Scale; ICD-11: International Classification of Diseases 11th Revision.

Dosing

The initial dose of lurasidone was slightly lower in pediatric patients than in adults (mean ± SD: 35.7 ± 10.94 mg/day vs 39.4 ± 10.70 mg/day, P < 0.001). In the pediatric group, 25.7%, 72.1%, 0.0%, and 2.1% of patients initiated lurasidone at 20 mg/day, 40 mg/day, 60 mg/day, and 80 mg/day, respectively, compared with 11.7%, 83.9%, 0.2%, and 4.2%, respectively, in the adult group. Pediatric patients underwent rapid titration, with the first dose adjustment occurring a mean of 7.1 ± 8.87 days after lurasidone initiation, increasing to 58.4 ± 19.65 mg/day. In contrast, adults had their first dose adjustment after 10.3 ± 13.07 days, increasing to 60.1 ± 20.95 mg/day. The mean final dose was 68.4 ± 19.35 mg/day in pediatric patients and 63.3 ± 21.50 mg/day in adults (P = 0.007), while the mean daily doses were 65.1 ± 17.95 mg/day and 61.7 ± 21.53 mg/day, respectively (P = 0.044).

Effectiveness

After 12 weeks of lurasidone treatment, 37.1% of pediatric patients (52/140) achieved a treatment response, defined as a ≥ 50% reduction in the BPRS total score. The mean BPRS total score decreased significantly from 45.6 ± 15.67 at baseline to 26.0 ± 9.88 at week 12 (P < 0.001). In the adult group, the response rate was 27.8% (370/1332), which was significantly lower than that in the pediatric group (P = 0.020). The mean BPRS total score in adults decreased from 43.9 ± 16.50 at baseline to 25.5 ± 9.02 at week 12 (P < 0.001, Figure 2). Furthermore, the reduction in the BPRS anxiety-depression subscale score was greater in pediatric patients than in adults (4.6 ± 3.47 vs 3.5 ± 3.33, P < 0.001), with scores decreasing from 10.8 ± 4.15 at baseline to 6.4 ± 2.85 at week 12. Similar trend was observed in ICD-11 rating scores, with greater reductions in depressive mood among pediatric patients (0.8 ± 1.06 vs 0.4 ± 0.79, P = 0.052). Pediatric patients also exhibited greater improvements in ICD-11 cognitive symptoms (0.8 ± 0.95 vs 0.4 ± 0.85, P = 0.013) and positive symptoms (1.5 ± 1.34 vs 0.8 ± 1.17, P = 0.001). After ANCOVA adjustment, the between-group difference in ICD-11 depressive mood symptom scores remained significant, whereas the difference in the BPRS anxiety-depression sub-score did not. In contrast, no significant between-group differences were observed after PSM (Table 2).

Figure 2 Mean Brief Psychiatric Rating Scale total score over time. BPRS: Brief Psychiatric Rating Scale.

Table 2 Analysis of covariance-adjusted changes in Brief Psychiatric Rating Scale and International Classification of Diseases (11th Revision) symptom rating scores in pediatric and adult patients receiving lurasidone monotherapy through surveillance, mean ± SD/n (%).

Outcome measures	Pediatric (n = 140)	Adult (n = 1332)	Adjusted P value
BPRS
Total score-baseline	45.6 ± 15.67	43.9 ± 16.50
Reduction in total score-2/4 weeks	9 ± 8.73	9.2 ± 9.87
Reduction in total score-6/8 weeks	14.9 ± 12.28	14.5 ± 12.46
Reduction in total score-12 weeks	19.6 ± 13.72	17.3 ± 14.39
Reduction in total score-12 weeks ≥ 50%	52 (37.1)	370 (27.8)
Anxiety-depression-baseline	10.8 ± 4.15	9.6 ± 4.30	0.020
Reduction in anxiety-depression-12 weeks	4.6 ± 3.47	3.5 ± 3.33
ICD-11 symptom rating scale
Reduction in positive symptoms-12 weeks	1.5 ± 1.34	0.8 ± 1.17
Reduction in negative symptoms-12 weeks	0.6 ± 0.88	0.4 ± 0.82
Reduction in depressive mood symptoms-12 weeks	0.8 ± 1.06	0.4 ± 0.79	0.013
Reduction in manic mood symptoms-12 weeks	0.2 ± 0.45	0.2 ± 0.63	0.018
Reduction in psychomotor symptoms-12 weeks	0.3 ± 0.84	0.3 ± 0.76	< 0.001
Reduction in cognitive symptoms-12 weeks	0.8 ± 0.95	0.4 ± 0.85	0.036
Adherence
Patients completed 12 weeks-surveillance	135 (96.4)	1228 (92.2)	0.029

BPRS: Brief Psychiatric Rating Scale; ICD-11: International Classification of Diseases 11th Revision.

Safety

No serious AEs were reported among patients receiving lurasidone monotherapy. During the surveillance period, six pediatric patients (4.3%, 6/140) experienced a total of six AEs, comprising four cases of weight gain and two cases of drowsiness. All AEs were mild. In comparison, 54/1332 (4.1%) adult patients experienced 61 AEs. The most frequently reported AEs were weight gain (1.8%), prolactin elevation (0.8%), akathisia (0.4%), and nausea (0.3%) (Table 3). At week 12, the mean weight gain from baseline was 0.1 ± 2.21 kg in pediatric patients and 0.2 ± 2.07 kg in adults.

Table 3 Adverse events during surveillance, n (%).

Adverse events	Pediatric	Cases	Adult	Cases
Investigations	4 (2.9)	4	38 (2.9)	39
Weight gain	4 (2.9)	4	24 (1.8)	24
Prolactin elevation			10 (0.8)	10
Triglyceride elevation			2 (0.2)	2
Neurological disorders	2 (1.4)	2	9 (0.7)	10
Akathisia			5 (0.4)	5
Drowsiness	2 (1.4)	2	3 (0.2)	3
Gastrointestinal disorders			4 (0.3)	4
Nausea			4	4
Total	6 (4.3)	6	54 (4.1)	61

To further assess dose-related safety in the pediatric population, patients were stratified into > 40 mg/day and ≤ 40 mg/day final titrated dose groups. The incidence of AEs was 4.8% (5/104) in the > 40 mg/day group and 2.8% (1/36) in the ≤ 40 mg/day group. Corresponding ADR rates were 1.9% (2/104) and 2.8% (1/36), respectively. No significant differences were observed between the two dosage groups for either AE incidence or ADR incidence (Fisher’s exact test, P = 1.0000 for both).

DISCUSSION

This is the first report to focus exclusively on lurasidone monotherapy in a large sample of Chinese children and adolescents with schizophrenia, providing clinically relevant real-world data on dosing patterns, safety, and effectiveness. Our findings suggests that lurasidone may improve symptoms in Chinese pediatric patients with schizophrenia, with potential additional benefits for those presenting with more severe depressive symptoms. Overall, lurasidone was well-tolerated, with a low incidence of AE, even among patients receiving higher doses. In Chinese pediatric patients with schizophrenia, lurasidone was initiated at a slightly lower dose than in adults but was titrated more rapidly, resulting in a marginally higher average daily dose during the surveillance period. Despite these differences, the overall dosing pattern was broadly comparable between pediatric and adult patient. Given that lurasidone has not yet been approved for the treatment of pediatric patients with schizophrenia in China and data on its use in this population remains limited, these findings provide valuable information to help inform clinical decision-making and future treatment recommendations.

The proportion of male patients in this pediatric cohort was 36.4%, which differs from findings reported in previous studies. Several investigations have shown that the male-to-female ratio in patients with EOS is slightly greater than 1[11,18], whereas others have reported no significant sex differences[19,20]. Because this analysis included only patients with schizophrenia who were treated with lurasidone, selection bias may have influenced the observed sex distribution. Given the established efficacy of lurasidone in improving affective symptoms in schizophrenia, investigators may have been more likely to enroll patients with prominent affective features. Evidence demonstrates that males with schizophrenia are more likely to exhibit pronounced negative symptoms and poorer social adjustment, whereas females tend to present with greater affective symptomatology[21]. This may partly explain the higher proportion of female in the pediatric cohort and could also account for the absence of significant differences in negative symptoms between pediatric and adult patients in this analysis. Supporting this interpretation, females in the overall monotherapy population (including both pediatric and adult patients) exhibited slightly greater baseline affective symptom severity than males, as reflected by higher BPRS anxiety-depression sub-scores (10.0 ± 4.31 vs 9.3 ± 4.25, P = 0.003) and ICD-11 depressive mood symptom scores (1.2 ± 0.84 vs 1.0 ± 0.77, P = 0.030). However, this pattern was less evident within the pediatric cohort. One possible explanation is the imbalance in baseline symptom severity, as male pediatric patients had higher baseline BPRS total scores than female patients (49.4 ± 16.09 vs 43.4 ± 15.08, P = 0.029), which may have obscured sex-related differences in affective symptoms. Additionally, pediatric patients exhibited more severe cognitive symptoms than in adults, a finding consistent with the greater cognitive deficits typically observed in patients with EOS.

This analysis showed that children and adolescents with schizophrenia initiated lurasidone at a mean dose of 35 mg/day, had their first dose adjustment after 1 week, reached a mean final dose of 68 mg/day, and received a mean daily dose of 65 mg/day during the surveillance period. Previous evidence indicates that children and adolescents are generally more sensitive to pharmacological treatment and may be more susceptible to adverse reactions[10]. Furthermore, developmental differences in volume of distribution, organ system maturation and drug-metabolizing enzyme activity, and higher elimination rates can substantially influence drug disposition in pediatric populations. Hormonal changes during puberty may further influence drug clearance and serum concentrations, resulting in pharmacokinetic and pharmacodynamic profiles that differ from those observed in adults[22]. In contrast, patients with EOS often present with more severe symptoms than adult-onset schizophrenia, and some may only respond to doses used in adults with chronic illness; moreover, underdosing may increase the risk of relapse[5]. Therefore, pharmacological treatment in pediatric patients should be individualized, following the principle of “start low, go slow, but go”[5]. The dosing patterns observed in this study are consistent with this principle. Pediatric patients generally initiated treatment at lower doses than adults but experienced more rapid dose titration, resulting in average daily doses comparable to, or slightly higher than, those observed in adults. Notably, the effective dose range of 40-80 mg/day also aligns with the approved dosing recommendations for children and adolescents with schizophrenia in the United States and Taiwan. In summary, starting with a lower dose, titrating more rapidly, and having a slightly higher overall average daily dose may be an optimized dosing strategy by clinicians balancing the safety and efficacy of the drug in pediatric patients.

This analysis demonstrated that lurasidone was associated with significantly improved symptoms among pediatric patients, including specific domain such as depressive and cognitive symptoms. Lurasidone is a high-affinity antagonist of D2, 5-HT2A, and 5-HT7 receptors and acts as a partial agonist of 5-HT1A receptors. These mechanisms are thought to contribute to its positive effects on positive, negative, affective, and cognitive symptoms. Clinical studies in adult patients with schizophrenia have consistently demonstrated improvements across these domains following lurasidone treatment[14,23]. This is particularly relevant for patients with EOS, who often exhibit significant cognitive impairment and are at increased risk of suicide, owing to prominent affective symptoms and frequent hospitalizations[6,24]. Although the pediatric population in the present analysis did not exhibit pronounced negative symptoms, cognitive and depressive symptoms were evident. In the unadjusted analysis, pediatric patients showed greater reductions in the BPRS anxiety-depression sub-score and ICD-11 depressive mood symptom score than adults. However, after adjustment for significant baseline discrepancies (including symptom severity, disease duration, and number of episodes) using ANCOVA, the between-group difference in the BPRS anxiety-depression sub-score was no longer significant. This finding was further corroborated by the PSM sensitivity analysis, which yielded a more balanced and more homogeneous comparison cohort. The overall pattern of results is consistent with the structural composition of the BPRS anxiety depression subscale and the ICD-11 depressive mood symptom subscale, and aligns with previous evidence demonstrating that the efficacy of lurasidone in improving depressive symptoms in patients with schizophrenia[10,16,25]. Differences between the ANCOVA results and the sensitivity analysis using PSM likely reflect inherent methodological distinctions. ANCOVA was adjusted for baseline confounding while retaining the full cohort and preserving age-related clinical heterogeneity, whereas PSM restricts comparisons to a narrower, more homogeneous subset of patients, potentially reducing its ability to detect domain-specific differences. The divergence between ANCOVA and PSM findings further suggests that, the observed differences between pediatric and adult patients may be influenced not only by symptom-specific treatment effects in depressive domain but also by baseline clinical severity, consistent with prior reports identifying baseline severity as an important predictor of treatment response[26]. Overall, these findings suggest that lurasidone is effective in improving depressive symptoms across age groups. Moreover, patients presenting with more severe baseline depressive features a profile frequently observed in our pediatric cohort may exhibit particularly pronounced clinical trajectories.

Compared with adults, patients with EOS are typically more susceptible to antipsychotic-related AEs including EPS, sedation, weight gain, and prolactin elevation[10]. Lurasidone has low or no affinity for H1 and M1 receptors, suggesting a favorable safety profile. Consistent with this, a network meta-analysis comparing lurasidone monotherapy with other atypical antipsychotics in adolescents with schizophrenia showed that lurasidone was associated with significantly less weight gain than (in descending order) olanzapine, quetiapine, risperidone, asenapine, and paliperidone extended-release (ER). Simultaneously, the risk of all-cause discontinuation was lower with lurasidone than with aripiprazole and paliperidone ER[27]. In the present analysis, weight gain AE occurred in only 2.9% of patients and drowsiness occurred in 1.4% of patients. No EPS or prolactin elevation-related AEs were observed, further supporting a favorable safety profile. Notably, the overall incidence of AEs was lower than that reported in previous RCTs involving Asian patients with schizophrenia and the AE incidence in the interim analysis of the same PMS cohort[16,28]. Several factors may account for these differences. First, this study was conducted in a real-world non-interventional study setting, which may differ from the more intensive monitoring employed in RCTs. Second, the present analysis only included patients receiving lurasidone monotherapy, thereby eliminating the potential influence of other drugs, especially other antipsychotics. In addition, some patients who may have been more susceptible to AEs, such as those on prophylactic medication for EPS, may have been underrepresented in this cohort. Given these findings, further evaluation of dose-related safety was warranted. The approved lurasidone dose ranges for schizophrenia in the United States is 40-160 mg/day for adults and 40-80 mg/day for adolescents, whereas in China the approved range for adults is 40-80 mg/day, corresponding to only half of the maximum dose approved in the United States[29,30]. Considering the generally greater pharmacological sensitivity and lower average body weight of Asian pediatric patients compared with Western populations, the tolerability of higher doses in this specific population requires careful evaluation. In routine clinical practice, 40 mg/day is generally considered the standard starting dose of lurasidone. To explore the safety of doses above this threshold in pediatric patients, we performed a safety-driven exploratory analysis to examine whether doses above 40 mg/day although within the approved Chinese adult labeling are also safe for children and adolescents. Accordingly, pediatric patients in this study were categorized based on whether their final titrated dose exceeded 40 mg/day to assess potential safety differences. No significant differences were observed in the incidence of AE or ADR between the two groups, suggesting the appropriateness of using a 40-80 mg/day dose range in Chinese pediatric patients.

This analysis had certain limitations. First, the PMS study corresponding to this analysis used a non-interventional design, which is inherently susceptible to confounding and bias. Although statistical adjustment methods were applied to reduce the impact of baseline confounding, definitive causal conclusions could not be drawn. Second, because of the single-arm observational design and the absence of a comparator group, this analysis did not compare the safety or effectiveness of lurasidone to other antipsychotics in China, and therefore, no conclusions regarding superiority or inferiority could be drawn. Third, although the ICD-11 symptom rating scale was used to complement the BPRS in assessing negative and cognitive symptoms, no published empirical studies have compared the value of this scale with that of widely used instruments. Consequently, its validity and reliability in assessing negative and cognitive symptoms may not be equivalent to those of specialized scales, such as the Scale for the Assessment of Negative Symptoms (SANS) and the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery (MCCB)[31,32]. Nevertheless, the present study used a non-interventional design to examine lurasidone treatment in a real-world clinical setting, where the routine implementation of comprehensive assessments such as SANS and MCCB may be challenging. This also suggests that more well-designed studies are warranted to further verify the clinical benefits of lurasidone in Chinese pediatric patients.

CONCLUSION

To our knowledge, this analysis is the first large-scale, real-world study reporting on the effectiveness, safety and dosage patterns of lurasidone in Chinese pediatric patients. The findings are consistent with evidence from international studies and suggest that lurasidone at doses of 40-80 mg/day may be effective in Chinese pediatric patients with schizophrenia, with a favorable safety profile, particularly regarding metabolic parameters, which may impact growth and development. These findings also suggest potential benefits of lurasidone for depressive and cognitive symptoms in this population. This analysis provides valuable real-world evidence supporting the clinical use of lurasidone in Chinese children and adolescents with schizophrenia, highlighting its potential as an effective and welltolerated treatment option.

ACKNOWLEDGEMENTS

The authors sincerely thank all the patients and their families, as well as the physicians and paramedical staff, for their participation in this study. Grateful acknowledgement is also given to the following research sites for their indispensable support in patient enrollment: The First Psychiatric Hospital of Harbin; Shandong Provincial Mental Health Center; The Second Affiliated Hospital of Xinxiang Medical University; Changchun Sixth Hospital; Daqing Third Hospital; Affiliated Psychological Hospital of Anhui Medical University, Hefei Fourth People’s Hospital, Anhui Mental Health Center; Ganzhou Third People’s Hospital; Hunan Brain Hospital (Hunan Second People’s Hospital); Tianshui Third People’s Hospital; Zhuzhou Third Hospital; Shanxi Mental Health Center (Taiyuan Mental Hospital); Jilin Sixth People’s Hospital; Hengyang Mental Health Center; Dalian Seventh People’s Hospital; Hebei Mental Health Center; Fujian Energy General Hospital; Quzhou Third Hospital; Xiangtan Mental Health Center; Tianjin Mental Health Center, Tianjin Anding Hospital; Yueqing Third People’s Hospital; Jinzhou Kangning Hospital; Liaoning Mental Health Center; The Fifth People’s Hospital of Zigong; Fuzhou Shenkang Hospital; Beijing Anding Hospital; Jiangxi Mental Health Center; Kailuan Mental Health Center; Guangyuan Mental Health Center; Changshu Mental Health Center; Shanghai Xuhui District Mental Health Center; Xi’an Mental Health Center; Chengdu Fourth People’s Hospital; Zhejiang Xiaoshan Hospital. This study would not have been possible without their dedicated efforts.