Safety and efficacy of different initial doses of lurasidone in the schizophrenia treatment: A multi-center, randomized, open-label study

Abstract

BACKGROUND

Schizophrenia, a complex group of mental disorders, is primarily managed with antipsychotic medications. The safety and efficacy of different initial doses of lurasidone for acute schizophrenia remain uncertain, particularly concerning discontinuation rates due to adverse events (AEs).

AIM

To compare the safety of two initial doses of lurasidone for the treatment of acute schizophrenia in Chinese patients.

METHODS

This 6-week, randomized, open-label, multicenter trial allocated participants to receive either 40 mg/day or 80 mg/day lurasidone initially, with dose adjustment allowed after a one-week fixed-dose period. Safety assessments included the primary endpoint of discontinuation due to AEs, as well as evaluations of AEs, weight changes, and laboratory parameters. Efficacy assessments included responder rates and changes in scores on the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression-Severity scale, and Calgary Depression Scale for Schizophrenia.

RESULTS

Among 197 participants, no significant difference was found in discontinuation rate due to AEs between groups (3.03% vs 5.10%, P = 0.707). Treatment-emergent AEs were reported in 64.6% and 71.4% of participants in the 40 mg/day and 80 mg/day initiation groups, respectively. Response rates at weeks 1 and 2 showed no statistically significant differences. Both groups demonstrated significant improvements in PANSS total, Clinical Global Impression-Severity, and Calgary Depression Scale for Schizophrenia scores from baseline (all P < 0.01). Notably, the 80 mg/day initiation group showed greater improvement in the PANSS positive subscale score at visits 1 and 2 compared to the 40 mg/day initiation group (P < 0.05).

CONCLUSION

Initial doses of 40 mg/day and 80 mg/day lurasidone are safe and effective for acute schizophrenia, with no significant increase in AEs-related discontinuation rate at the higher dose.

Key Words: Schizophrenia; Discontinuation rate; Efficacy; Safety; Lurasidone

Core Tip: This randomized, multicenter study innovatively compares initial lurasidone doses (40 mg/day vs 80 mg/day) in Chinese patients with acute schizophrenia, addressing a critical gap in dose optimization. Key findings reveal no significant difference in discontinuation rates due to adverse events (3.03% vs 5.10%, P = 0.707), affirming the tolerability of higher initial dosing. Notably, the 80 mg/day group showed superior early improvement in Positive and Negative Syndrome Scale positive subscale scores (P < 0.05) without exacerbating metabolic risks. These results challenge conventional dosing paradigms, suggesting 80 mg/day as a viable initial option for rapid symptom control, while maintaining safety.

INTRODUCTION

Schizophrenia includes a range of mental illnesses that are marked by a significant relapse rate and an uncertain etiology. It frequently manifests in young adults, causing disturbances in perception, thinking, emotion, and behavior, with a protracted course[1]. A global lifetime prevalence estimate reported that schizophrenia affects 7‰ of the global population[2]. In addition, a recent epidemiological survey on mental disorders in 31 cities of China revealed a lifetime prevalence of schizophrenia of 6‰[3]. Antipsychotic medications have become essential for schizophrenia treatment. First-generation antipsychotics, including chlorpromazine, promethazine, and perphenazine, effectively manage psychotic symptoms by binding to dopamine D2 receptors with high affinity. However, they are associated with significant neurologic adverse effects, particularly extrapyramidal signs[4]. Second-generation or “atypical” antipsychotics, such as olanzapine and aripiprazole, were introduced with promisingly improved safety and effectiveness[5]. The pharmacology of these atypical drugs differs from that of typical antipsychotics because of their reduced binding to dopamine D2 receptors and enhanced binding to norepinephrine and serotonin receptors, which aids in alleviating negative symptoms and reduces adverse extrapyramidal symptoms[6,7]. Lurasidone, an atypical antipsychotic drug developed by Sumitomo Pharma, is widely used in numerous countries to effectively manage schizophrenia and bipolar depression[8]. This serotonin-dopamine antagonist demonstrates unique pharmacological properties. While fully antagonizing dopamine D2 receptor and 5-hydroxytryptamine 2A [5-HT(2A)] receptor, it also exhibits a strong binding affinity towards 5-HT(7) and 5-HT(1A) receptors, which contributes to improvement in negative symptoms, anxiety, and depression[9].

In mainland China, lurasidone at a dose of 40-80 mg/day is authorized for the treatment of adult schizophrenia, while the approved dose reaches up to 160 mg/day in the United States, Russia, India, Ukraine, Romania, and Colombia[10]. A phase III clinical study among Chinese patients with schizophrenia revealed that 40 mg/day or 80 mg/day of lurasidone was noninferior to 2-6 mg/day of risperidone and had a better safety profile[11]. Achieving optimal treatment outcomes with antipsychotic drugs, including lurasidone, requires continuous and regular medication use[12]. However, inappropriate discontinuation of antipsychotics is common in clinical practice, and a real-world study found that 49.3%-68.3% of patients do not adhere to their medication plan[13]. Similarly, randomized clinical trials have reported discontinuation rates of 16%-74%[14,15]. The primary reasons for discontinuation are lack of treatment response and intolerance to side effects[16]. A meta-analysis revealed that increasing the dose of antipsychotics can effectively improve treatment response[17], and the phase III clinical study among Chinese patients with schizophrenia revealed that the majority required target dose of 80 mg/day[11]. However, the association of increased dose with intolerance or discontinuation remains unclear. Previous studies revealed that the discontinuation rates due to adverse events (AEs) of 40 mg/day and 80 mg/day of lurasidone were 4.0% and 6.5%, respectively[18], but with no current research among the Chinese population. This study aimed to compare the safety and efficacy of two initial doses of lurasidone for the treatment of acute schizophrenia in Chinese patients. We especially aimed to assess the discontinuation rates due to AEs in both groups.

MATERIALS AND METHODS

Study design and ethical considerations

This randomized, multicenter, open-label, 6-week prospective study compares the safety and efficacy of different initial doses of lurasidone in acute schizophrenia treatment (clinical trial registration, No. NCT05011669). The study, conducted at 11 centers across China, was initiated in October 2021 and completed in June 2023. The ethics committees of Peking University Sixth Hospital and other participating sites approved the protocol, and the study adhered to the principles of Good Clinical Practice. All participants were required to provide informed consent before initiation.

Eligibility criteria

This study included 18-65 years old patients diagnosed with schizophrenia according to the International Statistical Classification of Diseases-10 criteria. Key inclusion criteria were: (1) Positive and Negative Syndrome Scale (PANSS) total score of ≥ 70 and ≤ 120 at screening and baseline, respectively, with a score of ≥ 4 (moderate) in two or more items on the following PANSS items: Delusions, conceptual disorganization, hallucinations, unusual thought content, and suspiciousness[19]; (2) Clinical Global Impression-Severity (CGI-S) score of ≥ 4 at screening and baseline[20]; and (3) Acute exacerbation phase, including first episode and recurrence/relapse. The exclusion criteria were as follows: (1) Serious or unstable physical diseases, including but not limited to severe or unstable cardiovascular disease, cerebrovascular disease, liver and kidney disease, etc.; (2) Severe liver function damage or serum alanine aminotransferase or aspartate aminotransferase levels ≥ three times the upper limit of the normal range; (3) History of gastrointestinal surgery or other conditions that could interfere with drug pharmacokinetics; (4) History of malignancy and any chronic organic disease of the central nervous system (excluding schizophrenia); (5) Requirement for treatment with any potent cytochrome P3A4 (CYP3A4) inhibitor; (6) Refractory schizophrenia and/or receipt of clozapine within 4 months before the baseline period; (7) Received any sustained-release injection antipsychotic drugs within the specified periods before screening; and (8) Any other condition that was judged by the investigator to be inappropriate for participation in this study.

Drug administration and concomitant medications

The study encompassed a screening/washout phase (up to 14 days) followed by a 6-week period of open-label treatment and a follow-up visit (7 days after the last dose of the study drug). After the screening visit, the patients who completed the 14-day washout period and met the entry criteria were randomized via the Interactive Web Response System (provided by Zhejiang Taimei Medical Technology Co., Ltd.). Patients accessed the Interactive Web Response System to obtain a randomization number and were subsequently allocated in a 1:1 ratio, to receive 6 weeks of lurasidone treatment at either a 40 mg/day or 80 mg/day initial dose. The initial dose in the 40 mg/day initiation group was 40 mg/day for 7 days, with the option to increase up to 80 mg/day or maintain at 40 mg/day starting on day 8. The initial dose in the 80 mg/day initiation group was 80 mg/day for 7 days, with the option to decrease to a minimum of 40 mg/day or maintain at 80 mg/day starting on day 8. This design - starting with a 1-week fixed-dose period followed by flexible-dose adjustments - balanced standardized initial treatment with clinical flexibility. The fixed-dose phase minimized early-dose confounding, ensuring reliable endpoint comparisons. Lurasidone was administered once daily with dinner (at least 350 kcal) or within 30 minutes after dinner. Prohibited medications were discontinued before the study, including other antipsychotics, mood stabilizers, antidementia drugs, anti-epileptic drugs, potent CYP3A4 inhibitors, herbal medicine for central nervous system disorders, grapefruit juice, and other foods that affect CYP3A4 enzyme activity. Concomitant medication and therapy were restricted following the protocol.

Safety and efficacy assessments

The primary safety indicator was the discontinuation rate due to AEs at the end of treatment. Secondary safety assessments included the incidence of AEs and adverse reactions (ADR) as well as changes in body weight and other metabolic parameters. PANSS, CGI-S, and Calgary Depression Scale for Schizophrenia (CDSS) evaluations were performed at baseline and 1, 2, 4, and 6 weeks[21]. The primary efficacy outcome was the proportion of responders (PANSS total score improvement ≥ 20%) at 1 weeks or 2 weeks. Secondary efficacy outcomes included changes in PANSS total score, PANSS subscales (positive, negative, and general psychopathology), PANSS 5-factor scales[22], CGI-S, and CDSS from baseline to the end of treatment and at each visit point.

Statistical analysis

This study enrolled 200 participants, with 100 participants in each group. The discontinuation rate due to AEs would be approximately 7% based on relevant literature for the safety evaluation of participants in this study[23]. The probability of at least one subject in each group of 100 participants discontinuing due to AEs was > 99.9%. Safety measures were evaluated in the safety set, which included all enrolled participants who received at least one treatment and had actual data recorded for safety indicators after treatment. Efficacy was evaluated in the full analysis set, which consisted of all participants who completed randomization and took at least one dose of study medication. Additionally, participants entering this population must have at least one PANSS evaluation after randomization for efficacy measures (with a baseline measurement for analysis of changes from baseline). Self-Rating Anxiety Scale version 9.4 or higher software was used for analysis. A paired t-test or Wilcoxon paired signed-rank test was used to analyze changes in efficacy indicators from baseline to each visit point within each group. Additionally, a mixed model for repeated measurements was used to further investigate the differences in efficacy measures between the two groups. Missing efficacy measures were imputed based on the last observation carried forward approach. Missing values were addressed through maximized data collection efforts and collaborative decision-making by the sponsor, investigators, and biostatisticians during the data review phase for unusable or erroneous data. For missing dates in AEs, specific imputation rules were applied, such as replacing entirely missing start dates with the first dosing date and adjusting end dates based on month-end, to ensure data integrity.

RESULTS

Patient characteristics and baseline demographics

A total of 224 participants were screened for the study, of whom 200 were enrolled and randomized. A total of 197 participants received drug treatment and were included in the full analysis set and safety set, of whom 99 received 40 mg/day of lurasidone and 98 received 80 mg/day of lurasidone for the first 7 days. A total of 151 (75.5%) participants completed the study, while 49 (24.5%) withdrawal prematurely (Figure 1). Comparable baseline patient demographics and clinical features were observed in both groups (Table 1).

Figure 1 Patient enrollment.

Table 1 Patient demographic and clinical characteristics at baseline (full analysis set), mean ± SD/n (%).

Characteristic	Lurasidone (40 mg/day), n = 99	Lurasidone (80 mg/day), n = 98	Overall, n = 197
Age (years)	35.7 ± 12.13	34.1 ± 11.15	34.9 ± 11.65
Male	37 (37.4)	29 (29.6)	66 (33.5)
Female	62 (62.6)	69 (70.4)	131 (66.5)
Body weight (kg)	64.98 ± 18.50	61.04 ± 12.21	63.02 ± 15.77
BMI (kg/m2)	23.89 ± 5.87	22.97 ± 4.30	23.43 ± 5.16
PANSS total score	86.5 ± 11.93	87.7 ± 12.03	87.1 ± 11.96
CGI-S score
4 points	12 (12.1)	18 (18.4)	30 (15.2)
5 points	60 (60.6)	61 (62.2)	121 (61.4)
6 points	26 (26.3)	16 (16.3)	42 (21.3)
7 points	1 (1.0)	3 (3.1)	4 (2.0)
CDSS score	3.0 ± 3.98	2.5 ± 3.91	2.8 ± 3.94
AIMS total score	0.1 ± 0.38	0.1 ± 1.11	0.1 ± 0.83
BARS score
0 points	85 (85.9)	90 (91.8)	175 (88.8)
1 point	4 (4.0)	2 (2.0)	6 (3.0)
2 points	7 (7.1)	4 (4.1)	11 (5.6)
3 points	1 (1.0)	2 (2.0)	3 (1.5)
4 points	2 (2.0)	0 (0)	2 (1.0)
SAS total score	0.4 ± 1.61	0.3 ± 0.99	0.3 ± 1.34
Prior antipsychotic medication	71 (71.7)	77 (78.6)	148 (75.1)
Number of episodes	2.7 ± 5.04	2.8 ± 3.52	2.8 ± 4.34

BMI: Body mass index; PANSS: Positive and Negative Syndrome Scale; CGI-S: Clinical Global Impression Scale-Severity; CDSS: Calgary Depression Scale for Schizophrenia; AIMS: Abnormal Involuntary Movement Scale; BARS: Barnes Akathisia Rating Scale; SAS: Self-Rating Anxiety Scale.

Exposure and dose modification

The total exposure level of lurasidone was 2464.1 ± 987.69 mg with an average exposure duration of 35.7 ± 12.46 days. The average daily dose during the treatment period was 69.55 ± 13.43 mg (Table 2). In the 40 mg/day initiation group, 60 (60.6%) participants had their dose adjusted during the second week, with 44 participants increasing their dose to the maximum of 80 mg/day. In contrast, eight (8.2%) participants in the 80 mg/day initiation group had their dose adjusted during the second week, with five participants reducing their dose to 40 mg/day. More participants tended to increase the dose after the first week, and nearly half of the participants starting with a 40 mg/day dosage escalated their medication to 80 mg/day in the second week.

Table 2 Exposure and dose modification (full analysis set), mean ± SD.

	Lurasidone (40 mg/day), n = 99	Lurasidone (80 mg/day), n = 98	Overall, n = 197
Exposure days on drug (day)	38.6 ± 9.16	32.7 ± 14.55	35.7 ± 12.46
Total exposure level (mg)	2436.4 ± 803.89	2492.0 ± 1147.47	2464.1 ± 987.69
Average daily dose (mg/day)	62.45 ± 13.62	76.72 ± 8.58	69.55 ± 13.43
Dose modification during the second week (%)	60.6	8.2	34.5

Safety

Discontinuation rate due to AEs: Among 99 participants in the 40 mg/day initiation group, 3 discontinued treatments due to AEs, with a discontinuation rate of 3.03% [95% confidence interval (95%CI): 0.63-8.60]. Five participants in the 80 mg/day initiation group discontinued due to AEs, resulting in a discontinuation rate of 5.10% (95%CI: 1.68-11.51). No significant difference was found in the discontinuation rate due to AEs between the two treatment groups (3.03% vs 5.10%, P = 0.707).

AEs: In the 40 mg/day initiation group, 64 participants (64.6%) experienced 182 treatment-emergent AEs (TEAEs), whereas in the 80 mg/day initiation group, 70 participants (71.4%) experienced 178 TEAEs. The incidence of participants who experienced ADRs was 53.5% and 57.1% in the 40 mg/day and 80 mg/day initiation groups, respectively (Table 3). The TEAE and ADR rates were similar in the two treatment groups. The most prevalent TEAEs were akathisia [40 mg/day initiation group vs 80 mg/day initiation group (the same below): 19.2% vs 26.5%], tremor (3% vs 8.2%), insomnia (8.1% vs 8.2%), blood prolactin increased (7.1% vs 13.3%), nausea (9.1% vs 4.1%), and nasopharyngitis (3% vs 7.1%) (Supplementary Table 1). The safety profiles of two initial doses of lurasidone were similar, and no new safety information affected the known profile of lurasidone. A greater proportion of participants in the 80 mg/day initiation group experienced AEs leading to dose reduction than that in the 40 mg/day initiation group. Serious AEs (SAEs) occurred in 1 (1.0%) participant receiving an initial lurasidone dose of 40 mg/day and 4 (4.1%) participants receiving an initial lurasidone dose of 80 mg/day during the treatment period (Table 3). Most of the SAEs were worsening schizophrenia, while the remaining SAEs included suicidal behavior in one participant and metacarpal bone fracture of the righthand in one participant.

Table 3 Summary of adverse events and adverse reactions (safety set), n (%), events.

Category	Lurasidone (40 mg/day), n = 99	Lurasidone (80 mg/day), n = 98
Treatment-emergent adverse events	64 (64.6), 182	70 (71.4), 178
Serious adverse events (during the treatment)	1 (1.0), 1	4 (4.1), 4
Adverse reactions	53 (53.5), 122	56 (57.1), 115
Serious adverse reactions (during the treatment)	1 (1.0), 1	3 (3.1), 3
Adverse events leading to discontinuation of investigational product	3 (3.0), 3	5 (5.1), 5
Adverse events leading to dose reduction of investigational product	4 (4.0), 7	12 (12.2), 16
Adverse events leading to subject withdrawal from the trial	1 (1.0), 1	2 (2.0), 2
Adverse events leading to subject death	0, 0	0, 0

Weight gain and metabolic abnormalities: The proportion of participants whose metabolic parameters shifted from normal to clinically significant abnormal at the endpoint was similar in both groups (Supplementary Table 2). A significant increase in the mean weight was observed in the 40 mg/day initiation group by the endpoint (0.83 ± 2.83 kg, P < 0.01), whereas a slight decrease was found in the 80 mg/day initiation group (-0.08 ± 2.22 kg, P = 0.995), which was not significant. Notably, the 40 mg/day initiation group had a greater proportion of participants (12.1%) who gained at least 7% of their weight at the end of treatment compared with the 80 mg/day initiation group (4.1%) in Table 4.

Table 4 Change from baseline to endpoint for weight (safety set), n (%).

Measure		Lurasidone (40 mg/day), n = 99	Lurasidone (80 mg/day), n = 98
Weight, kg	Baseline, mean (SD)	64.98 (18.50)	61.04 (12.21)
	Mean change (SD)	0.83 (2.83)a	-0.08 (2.22)
	≥ 7% weight gain	12 (12.1)	4 (4.1)
	≥ 7% weight loss	3 (3.0)	4 (4.1)
BMI (kg/m2)	Baseline, mean (SD)	23.89 (5.87)	22.97 (4.30)
	Mean change (SD)	0.30 (1.06)a	-0.01 (0.86)
	≥ 7% BMI gain	12 (12.1)	4 (4.1)
	≥ 7% BMI loss	3 (3.0)	4 (4.1)

^aP < 0.01 vs baseline.

BMI: Body mass index.

Efficacy

Primary outcome: At week 1, the proportion of responders was similar between the two groups (39.39% vs 40.82%, P = 0.839) and at week 2, the 80 mg/day initiation group demonstrated a numerical, but not a statistically significant advantage (52.53% vs 57.14%, P = 0.515).

Secondary outcomes: Both treatment groups demonstrated significant improvements in the PANSS total score (P < 0.001) and 5-factor score (P < 0.001), CGI-S scale score (P < 0.001), and CDSS scale score (P < 0.01) at all visit points compared with those at the baseline (Supplementary Table 3). At both visit 1 and visit 2, participants receiving an initial dose of 80 mg/day lurasidone demonstrated significantly larger improvement in PANSS positive subscale score than those receiving 40 mg/day (adjusted P < 0.05, mixed model for repeated measurements). No significant difference in PANSS total score, PANSS negative subscale, or general psychopathology subscale at all visit points were found between the two treatment groups. Regarding the PANSS 5-factor scales, the 80 mg/day initiation group demonstrated significantly greater changes than the 40 mg/day initiation group on the positive factor scale at visit 2, cognitive scale at visits 2 and 4, and excitation scale at visits 1 and 3. In addition, the 80 mg/day initiation group demonstrated statistically greater improvement in the CGI-S scale at visit 2 and CDSS scale at visit 4 compared with 40 mg/day (Table 5).

Table 5 Change from baseline to Visit 1-4 for efficacy measures (full analysis set and mixed model for repeated measurements analysis).

Scale	Visit	LS mean (SE)		Difference between groups
		Lurasidone (40 mg/day), n = 99	Lurasidone (80 mg/day), n = 98	LS difference (SE)	95%CI	P value1	P value2
PANSS total	Visit 1	-14.3 (1.41)	-17.0 (1.47)	2.7 (2.04)	-1.30 to 6.73	0.183	0.273
	Visit 2	-20.9 (1.64)	-25.4 (1.72)	4.5 (2.38)	-0.18 to 9.20	0.060	0.114
	Visit 3	-26.4 (1.81)	-30.6 (1.93)	4.2 (2.65)	-1.04 to 9.41	0.116	0.176
	Visit 4	-30.6 (1.92)	-34.2 (2.08)	3.7 (2.84)	-1.93 to 9.27	0.198	0.254
PANSS positive subscale	Visit 1	-4.1 (0.46)	-5.6 (0.48)	1.6 (0.67)	0.23-2.88	0.022a	0.143
	Visit 2	-6.7 (0.49)	-8.4 (0.52)	1.7 (0.72)	0.25-3.08	0.022a	0.063
	Visit 3	-8.6 (0.57)	-9.5 (0.61)	0.9 (0.83)	-0.77 to 2.52	0.294	0.581
	Visit 4	-9.7 (0.60)	-10.4 (0.65)	0.7 (0.88)	-1.02 to 2.46	0.416	0.708
PANSS negative subscale	Visit 1	-3.4 (0.43)	-3.5 (0.45)	0.1 (0.63)	-1.15 to 1.31	0.899	0.742
	Visit 2	-4.6 (0.52)	-5.8 (0.54)	1.2 (0.75)	-0.26 to 2.71	0.105	0.039
	Visit 3	-5.5 (0.56)	-6.7 (0.60)	1.3 (0.82)	-0.37 to 2.89	0.128	0.194
	Visit 4	-6.5 (0.62)	-8.2 (0.66)	1.7 (0.91)	-0.10 to 3.48	0.064	0.145
PANSS general psychopathology subscale	Visit 1	-6.8 (0.70)	-8.0 (0.73)	1.2 (1.01)	-0.80 to 3.19	0.239	0.298
	Visit 2	-9.5 (0.86)	-11.3 (0.90)	1.7 (1.24)	-0.74 to 4.16	0.169	0.424
	Visit 3	-12.3 (0.90)	-14.4 (0.96)	2.0 (1.32)	-0.55 to 4.65	0.121	0.225
	Visit 4	-14.3 (0.90)	-15.6 (0.98)	1.2 (1.33)	-1.39 to 3.87	0.353	0.446
Positive factor score	Visit 1	-2.3 (0.28)	-3.0 (0.29)	0.7 (0.40)	-0.06 to 1.52	0.071	0.599
	Visit 2	-4.0 (0.31)	-5.0 (0.33)	1.0 (0.45)	0.14-1.92	0.024a	0.199
	Visit 3	-5.3 (0.37)	-5.7 (0.40)	0.4 (0.55)	-0.64 to 1.53	0.419	0.923
	Visit 4	-6.1 (0.38)	-6.3 (0.42)	0.2 (0.57)	-0.94 to 1.30	0.754	0.672
Negative factor score	Visit 1	-3.3 (0.42)	-3.1 (0.44)	-0.2 (0.61)	-1.42 to 0.99	0.727	0.932
	Visit 2	-3.9 (0.52)	-5.0 (0.54)	1.1 (0.75)	-0.42 to 2.54	0.161	0.065
	Visit 3	-4.9 (0.56)	-5.9 (0.59)	1.0 (0.82)	-0.61 to 2.61	0.222	0.242
	Visit 4	-5.9 (0.59)	-7.4 (0.63)	1.5 (0.87)	-0.20 to 3.23	0.082	0.155
Cognitive scale score	Visit 1	-1.1 (0.20)	-1.6 (0.20)	0.6 (0.28)	-0.01 to 1.11	0.054	0.029a
	Visit 2	-1.8 (0.23)	-2.6 (0.24)	0.8 (0.33)	0.14-1.44	0.018a	0.008a
	Visit 3	-2.1 (0.24)	-3.2 (0.25)	1.1 (0.35)	0.38-1.76	0.002a	0.003a
	Visit 4	-2.4 (0.24)	-3.5 (0.26)	1.1 (0.36)	0.38-1.80	0.003a	0.003a
Excitation scale score	Visit 1	-2.1 (0.31)	-3.1 (0.33)	1.0 (0.45)	0.07-1.85	0.035a	0.119a
	Visit 2	-2.9 (0.31)	-3.8 (0.33)	0.9 (0.45)	0.00-1.79	0.051	0.168
	Visit 3	-3.6 (0.26)	-4.4 (0.28)	0.8 (0.38)	0.04-1.56	0.040a	0.274
	Visit 4	-3.7 (0.34)	-4.2 (0.37)	0.5 (0.50)	-0.50 to 1.48	0.330	0.326
Depression and anxiety scale score	Visit 1	-1.2 (0.16)	-1.3 (0.17)	0.1 (0.23)	-0.32 to 0.60	0.551	0.878
	Visit 2	-1.7 (0.18)	-1.6 (0.19)	-0.1 (0.27)	-0.60 to 0.45	0.781	0.517
	Visit 3	-2.1 (0.18)	-2.0 (0.20)	-0.1 (0.27)	-0.64 to 0.43	0.698	0.384
	Visit 4	-2.2 (0.19)	-2.0 (0.21)	-0.2 (0.28)	-0.76 to 0.34	0.451	0.226
CGI-S	Visit 1	-0.6 (0.12)	-0.9 (0.12)	0.2 (0.17)	-0.10 to 0.57	0.165	0.525
	Visit 2	-1.0 (0.11)	-1.4 (0.12)	0.3 (0.16)	0.01-0.66	0.044a	0.433
	Visit 3	-1.6 (0.13)	-1.8 (0.14)	0.3 (0.19)	-0.12 to 0.64	0.178	0.721
	Visit 4	-1.9 (0.14)	-2.1 (0.15)	0.2 (0.20)	-0.19 to 0.62	0.298	0.920
CDSS	Visit 1	-1.5 (0.20)	-1.2 (0.21)	-0.4 (0.29)	-0.95 to 0.21	0.213	0.029a
	Visit 2	-1.9 (0.22)	-1.3 (0.23)	-0.6 (0.32)	-1.22 to 0.05	0.072	0.050
	Visit 3	-2.0 (0.22)	-1.5 (0.24)	-0.5 (0.33)	-1.13 to 0.16	0.142	0.035a
	Visit 4	-2.3 (0.22)	-1.4 (0.24)	-0.9 (0.32)	-1.52 to -0.25	0.006a	0.031a

¹P values were derived from the Mixed Model for Repeated Measures model, in which fixed effects included treatment, visit, and treatment-visit interaction effects. Covariates were the baseline values, and random effects were the participants.

²P values were used to compare differences in change from baseline between the two groups at each visit point using either a paired t-test or Wilcoxon paired signed-ranks test. Missing values were imputed using the last observation carried forward approach.

^aP < 0.05 vs lurasidone (40 mg/day).

PANSS: Positive and Negative Syndrome Scale; CGI-S: Clinical Global Impression Scale-Severity; CDSS: Calgary Depression Scale for Schizophrenia; LS: Least squares; CI: Confidence interval; SE: Standard error.

DISCUSSION

This 6-week, randomized, open-label, multicenter trial evaluated the safety and efficacy of different initial doses of lurasidone in Chinese patients with schizophrenia. No significant difference in the discontinuation rates due to AEs was observed between the 40 mg/day and 80 mg/day initiation groups. Furthermore, the TEAE and ADR rates were similar in both groups, indicating comparable safety. However, dose reductions due to AEs were more common in the 80 mg/day group which might reflect dose-related tolerability challenges. Regarding efficacy, no significant difference in the response rates at weeks 1 and 2 was found between the 40 mg/day and 80 mg/day initiation groups. Both treatment groups demonstrated significant improvements in the PANSS total score and 5-factorscore, CGI-S scale score, and CDSS scale score at all visit points compared with those at the baseline. This study provides evidence that both initial doses of lurasidone are safe and effective for acute schizophrenia treatment.

Several previous studies have focused on the treatment of schizophrenia using different lurasidone doses. However, in contrast to these previous studies, which have typically used fixed doses for the entire treatment period, the present study employed fixed doses only for the initial 7 days and the dose could be adjusted over the subsequent 5 weeks based on the patient’s treatment response and individual requirements. We believe that the latter approach is more aligned with actual clinical practice. Two previous studies investigated drug discontinuation rates due to AEs in 40 mg/day and 80 mg/day lurasidone treatment groups, generating similar data in terms of numerical range. Numerically, one study reported a higher rate for the 40 mg/day group (6.0% vs 3.9%)[23], whereas the other study reported a higher rate for the 80 mg/day group (4.0% vs 6.5%)[18]. Noteworthily, no statistical comparison of discontinuation rates was made between these two dose groups in both studies, thereby limiting the direct comparison of their results. The present study revealed discontinuation rates due to AEs of 3.03% and 5.10% in the 40 mg/day and 80 mg/day initiation groups, respectively, and χ² test was used for comparison, resulting in a P-value of 0.707. A Japanese open-label extension study reported that dose escalation from 40 mg/day to 80 mg/day was well tolerated. However, this study lacked a parallel control group and did not directly compare AE incidence or discontinuation rates between the two doses. Among patients who received 40 mg/day lurasidone or placebo during the double-blind period, the incidence of AEs during the subsequent 80 mg/day phase was comparable (47.4% vs 48.0%)[24]. A European multicenter pooled analysis indicated similar AE rates between the 40-80 mg/day and 120-160 mg/day groups (50.4% vs 58.9%), with minimal differences in metabolic parameters and weight changes. However, due to sample size constraints, this study pooled data for 40 mg/day and 80 mg/day, precluding independent assessment of safety profiles at each dose[25]. Another study conducted in the United States and Europe evaluated the short-term safety and tolerability of once-daily lurasidone at 80 mg/day and 160 mg/day for acute schizophrenia exacerbations, finding both regimens to be well tolerated[10]. Collectively, these studies support the conclusion that lurasidone demonstrates a consistent safety profile across doses up to 160 mg/day. Furthermore, the current evidence does not suggest a dose-dependent effect on discontinuation rates due to AEs. The TEAE incidence and safety profile in the two treatment groups of this study were similar and consistent with those reported in previous studies[18,23], and no new safety risks were uncovered[26].

Regarding efficacy, a phase III study of lurasidone revealed that the 80 mg/day initiation group was numerically greater than the 40 mg/day initiation group (-23.4 vs -19.2) in terms of PANSS total score improvement, but with no statistical comparisons between the two groups[18]. This study revealed no statistically significant difference in PANSS total score changes from baseline between the two treatment groups and this could possibly be attributed to the administration plan, as the doses of the two groups were converted to flexible, and nearly half of the participants in the lower initiation dose group escalated the dosage to 80 mg/day during the second week. Initial treatment with 80 mg/day of lurasidone demonstrated greater improvements on the PANSS positive subscale score at visits 1 and 2 as well as on the cognitive scale score across multiple assessment points compared with 40 mg/day despite the dosage difference being confined to the early phase. These results did not conclusively determine that the early use of a higher dosage confers additional therapeutic benefits, but they presented an intriguing path for further exploration in clinical practice and future research.

The present study revealed that 1 (1.0%) SAE developed in the 40 mg/day initiation group after the first dose, which was reported as suicidal behavior and was considered possibly related to the drug. The participant recovered after receiving medication treatment and completed the study follow-up period. In the 80 mg/day initiation group, 4 (4.1%) participants experienced SAEs after the first dose, all of which were worsening of schizophrenia. Of these cases, three were possibly related to the study drug and fully recovered, among which two participants discontinued the study medication, and the remaining one had already completed the administration plan when the SAE occurred. The last SAE was considered unrelated to the study drug, considering that the suggestive time to onset was 8 days after medication discontinuation. Moreover, schizophrenia worsening and suicidal behavior/ideation are also the most frequently reported SAEs in previous studies[18,27].

Weight gain is a significant predictor of poor compliance among patients with psychiatric disorders[28], and is generally considered an adverse effect of antipsychotic medications, particularly olanzapine, paliperidone, and risperidone, which tends to increase dose-dependently[29]. Interestingly, the current study revealed that the 40 mg/day initiation group experienced more weight increase and a higher rate of weight gain ≥ 7% compared to the 80 mg/day initiation group (12.1% vs 4%). However, this was not the first study to reveal that high-dose lurasidone has less weight gain than low-dose. At 6-week randomized controlled trial among patients who are mainly Asian revealed that 5.3% of those receiving 40 mg/day of lurasidone and 1.3% receiving 80 mg/day experienced a weight gain exceeding 7%[23]. A recent meta-analysis revealed that the estimated curve of weight gain dose response was a quasi-parabolic shape, indicating that weight gain initially increases with dosage but then decreases[30]. Noteworthy, the current study differs from previous ones in that the difference in dosage levels did not persist throughout the entire treatment period but mainly existed in the first week. In addition, body weight changes are influenced by various factors, including diet and physical activity. However, the current study lacks data on these aspects, which makes it challenging to draw a definitive conclusion. Nevertheless, overall, the findings of this study demonstrated that the risk of weight gain associated with lurasidone treatment for schizophrenia was relatively low. This observation is consistent with its mechanism of action, specifically its low affinity for the 5-HT(2C)- and H1-receptors, and aligns with the results of multiple previous studies[9,10]. However, the association between the dose and the weight gain remains unknown, which needs to be answered by future research with more targeted designs.

This current trial had several limitations. First, the maximum dose in the flexible-dose phase was restricted to 80 mg/day due to the labeling restrictions in mainland China. This indicates that the dose could be increased in the 40 mg/day initiation group, whereas it either needed to be decreased or maintained in the 80 mg/day initiation group. Second, the study enrolled patients with first episode and relapsed schizophrenia as well as inpatient and outpatient individuals who frequently receive distinct initial dosages in clinical settings. However, the research did not use stratified randomization or subgroup analysis to account for these categorical variables. Therefore, the generalizability of the results may be limited. To address this limitation, we plan to conduct a follow-up study specifically designed to investigate the impact of baseline characteristics on treatment outcomes and tolerability. This future work will provide a more comprehensive evaluation of how patient subgroups respond to lurasidone across different dosing regimens.

While lurasidone is indicated for both acute and chronic schizophrenia, this study exclusively enrolled acute-phase patients. This design was driven by the distinct characteristics of the acute phase: Pronounced symptom severity and robust pharmacological responses, which enhance the sensitivity of dose-response assessments. In contrast, chronic-phase patients - characterized by prolonged medication exposure, comorbidities, and functional decline - pose confounding risks for isolating the safety profile of initial dosing regimens. Thus, our investigation focused specifically on acute-phase patients, encompassing both first-episode and relapsed cases. Therefore, our findings cannot directly extend to chronic-phase populations. Prior studies have demonstrated the safety and effectiveness of lurasidone (40-120 mg/day) in maintenance therapy, with favorable profiles regarding prolactin levels and weight neutrality[31,32]. However, the optimal dosing strategy for long-term maintenance remains to be further investigated.

CONCLUSION

The present study reveals that both the 40 mg/day and 80 mg/day initial doses of lurasidone are safe and effective in treating acute schizophrenia. Moreover, the 80 mg/day initial dose does not cause a significantly higher discontinuation rate due to AEs compared with the 40 mg/day initial dose. Therefore, both initial doses can be considered well-tolerated options for treating acute schizophrenia.

ACKNOWLEDGEMENTS

The authors are grateful to all the patients and their families, physicians, and paramedics who participated in this study for their valued contribution.