Effect of lurasidone plus sulpiride on treatment efficacy, psychiatric manifestations, and quality of life among patients with schizophrenia

Abstract

BACKGROUND

First-generation antipsychotics demonstrate certain therapeutic benefits in schizophrenia; however, they often fail to significantly address negative symptoms. Thus, continued exploration is essential to refine these treatments.

AIM

To examine lurasidone plus sulpiride influence on treatment efficacy, psychiatric symptoms, and quality of life in patients with schizophrenia.

METHODS

A total of 110 patients with schizophrenia, admitted between October 2021 and October 2024, were recruited for this study. The control group (n = 50) received sulpiride alone. Conversely, the observation group (n = 60) was treated with a combination of lurasidone and sulpiride. A series of assessments were conducted to compare the two groups. These included evaluating treatment efficacy; recording the incidence of adverse events such as fatigue, xerostomia, insomnia, anorexia, and headache; assessing psychiatric symptoms using the positive and negative syndrome scale (PANSS); evaluating cognitive and social functions using the repeatable battery for the assessment of neuropsychological status (RBANS), and the personal and social performance scale (PSP); measuring quality of life using the schizophrenia quality of life scale (SQLS); and analyzing serum markers including interleukin 6 (IL-6), IL-17, and prolactin (PRL).

RESULTS

Overall treatment efficacy was significantly higher in the observation group than in the control group. The total incidence of adverse events was comparable between the two groups. After treatment, the scores for positive symptoms, negative symptoms, and general psychopathological symptoms on the PANSS in the observation group were significantly reduced compared to pretreatment levels, and were also lower than those in the control group. Additionally, RBANS and PSP scores in the observation group significantly increased post-treatment and were notably higher than in the control group. Regarding the quality of life, SQLS scores in the psychosocial, symptoms, and side effects and motivation and energy dimensions in the observation group were significantly lower after treatment than both baseline levels and those in the control group. Furthermore, post-treatment levels of IL-6 and IL-17 in the observation group were significantly reduced and lower than those in the control group, whereas the PRL level was significantly elevated.

CONCLUSION

The combination of lurasidone and sulpiride can effectively enhance treatment efficacy, alleviate psychiatric symptoms, and improve quality of life in patients with schizophrenia, supporting its broader clinical use.

Key Words: Lurasidone; Sulpiride; Schizophrenia; Treatment efficacy; Psychiatric symptoms; Quality of life

Core Tip: Although first-generation antipsychotics have limited effectiveness against the negative symptoms of schizophrenia, sulpiride combined with lurasidone may offer superior results. This study suggests that, compared with sulpiride monotherapy, the combined approach enhances treatment efficacy safely, with patients experiencing fewer psychiatric symptoms, improved cognitive and social functioning, and better quality of life. It also helps normalize abnormal levels of interleukin 6 (IL-6), IL-17, and prolactin.

INTRODUCTION

Schizophrenia, a heterogeneous syndrome, has an etiology intertwined with multiple factors, including chronic stress, low-grade systemic inflammation, and gut microbiota dysbiosis. Its underlying pathological mechanisms are closely associated with disruptions in synaptic signal transduction and impairments in cerebral neural plasticity[1,2]. Epidemiological data indicate a predilection for this disorder among men. Alarmingly, the lifetime risk of suicide among patients with schizophrenia can reach up to 26.8%, and their life expectancy is shortened by approximately 10-25 years compared with the general population[3-5]. Patients with schizophrenia commonly present with a spectrum of symptoms. Positive symptoms, such as hallucinations, peculiar behaviors, and delusions, are frequently observed. Concurrently, negative symptoms, including apathy, pronounced social withdrawal, and excessive somnolence, are also prevalent. They are often accompanied by cognitive deficits, such as impairment in executive function impairments, speech abnormalities, and disruptions in short-term memory. Collectively, these manifestations significantly impair patients’ daily routines, social interactions, and professional undertakings[6].

Antipsychotic medications remain the cornerstones of treatment. First-generation antipsychotics have proven effective in alleviating positive symptoms. However, their capacity to mitigate negative symptoms remains relatively constrained. Moreover, they are frequently associated with various side effects, which can adversely affect treatment adherence[7,8]. Conversely, second-generation antipsychotics have emerged as a more favorable option, effectively addressing the limitations of their predecessors. They provide significant clinical benefits, including improved management of negative symptoms and a reduced incidence of neurological side effects, thereby enhancing the overall treatment experience for patients[9].

This study primarily aimed to determine the effects of lurasidone plus sulpiride on the treatment efficacy, alleviation of psychiatric symptoms, and quality of life in patients with schizophrenia. Currently, research on this specific combination therapy remains limited. Therefore, this study is intended to provide more refined clinical guidance to support informed treatment decisions. Sulpiride, exerts a selective inhibitory action on dopaminergic receptors. This pharmacological property renders it an effective therapeutic option for treating various central nervous system disorders, such as schizophrenia, depression, and other psychotic conditions[10]. Moreover, a study explored the combination of sulpiride with cell-penetrating peptides, a strategy that has shown promise in augmenting its antidepressant efficacy while concurrently reducing the serum levels of prolactin (PRL)[11]. However, despite its therapeutic utility, sulpiride, as a first-generation antipsychotic, often necessitates the incorporation of additional medications to maximize overall efficacy[12]. Lurasidone, a second-generation antipsychotic, is essentially a benzisothiazole derivative that has a strong affinity for dopamine D2, 5-hydroxytryptamine 2A (5-HT2A), 5-HT7, 5-HT1A, and norepinephrine α2C receptors, and can reduce antagonistic interactions in various dopaminergic pathways, thus ensuring a high degree of tolerability[13]. Its antagonism of 5-HT2A receptors also allows it to effectively inhibit the serotonergic excitation of cortical pyramidal cells, thus helping to alleviate the positive symptoms characteristic of schizophrenia[14]. Notably, a study also indicated that lurasidone may effectively improve the quality of life in patients with schizophrenia[15].

MATERIALS AND METHODS

General information

Inclusion criteria: (1) Patients were required to meet the diagnostic criteria for schizophrenia as per the Schizophrenia Pharmacotherapy Guidelines[16]; and (2) Patients should not have received any antipsychotic treatment within the preceding month and must have complete clinical records.

Exclusion criteria: (1) Individuals with coexisting mental disorders of other types; (2) History of craniocerebral trauma; (3) Alcohol dependence; (4) Hypersensitivity to the medications used in this trial; (5) Cognitive, language, or auditory impairments; (6) Severe encephalopathy; (7) Epilepsy; (8) Poisoning; (9) Severe endocrine disorders; and (10) Severe hepatic and renal dysfunction.

In strict accordance with these inclusion and exclusion criteria, 110 patients with schizophrenia admitted between October 2021 and October 2024 were retrospectively enrolled. Patients were categorized based on the administered therapy in a non-randomized manner, with 50 cases in the control group (sulpiride treatment) and 60 in the observation group (lurasidone plus sulpiride).

Sample size computation

The sample size was calculated to adequately power between-group mean comparisons. Parameters included Δ (effect size) = 10%, σ (standard deviation) = 15%, α = 0.05 (two-tailed), and power (1-β) = 80%. The initial calculation yielded 36 per group. However, after considering potential participant withdrawal (estimated at 20% attrition), the initial estimate of 36 participants per group was increased to 45.

Treatment protocols

The control group received sulpiride. The initial dosage was set at 100 mg per administration, three times daily (8:00, 14:00, and 20:00, postprandial). After 7 days of treatment, the dosage was increased to 300 mg per administration, also three times daily.

The observation group received lurasidone plus sulpiride, with the sulpiride regimen following the same protocol as the control group. Lurasidone tablets were orally administered at a dosage of 40 mg once daily after dinner. The treatment course for both groups was eight consecutive weeks.

Detection indicators

Treatment efficacy: Efficacy was gauged based on changes in positive and negative syndrome scale (PANSS) scores. After treatment, a reduction of > 75% in the PANSS score was designated as a “cure”; a decrease of 50%-75% was classified as a “significant improvement”; a decline of 25%-50% was considered an “improvement”; and cases failing to meet these thresholds were labeled as “ineffective”. The overall response rate was calculated as the proportion of patients achieving complete remission or significant improvement.

Adverse events: The occurrences of side effects, including fatigue, xerostomia, insomnia, anorexia, and headache, were monitored and documented in both groups following treatment. The cumulative incidence of these adverse events was subsequently calculated.

Psychiatric symptom assessment: The PANSS is a psychometrically validated rating scale that systematically assesses the severity of characteristic symptoms in schizophrenia. It comprises three components: (1) Positive symptoms (7-49 points); (2) Negative symptoms (7-49 points); and (3) General psychopathological symptoms (16-112 points). Higher scores on this scale indicated more severe psychiatric manifestations.

Cognitive and social function assessment: Neurocognitive assessment employed the repeatable battery for the assessment of neuropsychological status (RBANS) with five domains, namely, immediate memory, visuospatial ability, language, attention, delayed memory (total score 40-160); higher scores indicate better cognitive function. Social functioning was evaluated using the Chinese personal and social performance scale (PSP), a validated measure examining four functional domains (work/study, interpersonal relationships, and self-care) on a 0-100 scale, with higher values denoting superior social functionality.

Quality of life evaluation: The schizophrenia quality of life scale (SQLS) was employed to assess the quality of life. The SQLS is divided into three domains: (1) Psychosocial (15 items); (2) Symptoms and side effects (8 items); and (3) Motivation and energy (7 items). Each SQLS subscale assigns scores ranging from 0 to 100 points. Lower scores indicate better quality of life.

Serum marker analysis: Before and following the treatment, 2 mL peripheral venous blood was collected from patients in a fasting state. After centrifugation, the serum was isolated. The levels of interleukin (IL-6), IL-17, and PRL were determined using the enzyme-linked immunosorbent assay.

Statistical analyses

Statistical Package for the Social Sciences 20.0 (IBM SPSS, Armonk, NY, United States) and GraphPad Prism 6 (GraphPad Software, Inc., San Diego, CA, United States) were used for comprehensive data analyses. Categorical data, such as sex, are presented as the frequency/count and percentage [n (%)], and compared using the χ² test. Quantitative data such as age and disease duration are expressed as the mean ± standard error of the mean. Between-group comparisons used the independent samples t-test; within-group comparisons before and after treatment, were assessed using the paired t-test. Statistical significance was set at a threshold of P < 0.05.

RESULTS

General characteristics

No significant disparities were observed in the general characteristics, including sex, age, disease duration, body mass index, years of education, concomitant medications, tobacco use, and regular exercise habits, between the control and observation groups (P > 0.05; Table 1).

Table 1 General characteristics of patients in the two groups.

Indicators	Control group (n = 50)	Observation group (n = 60)	χ²/t	P value
Sex (male/female)	30/20	31/29	0.767	0.876
Age (years)	54.46 ± 7.22	52.20 ± 8.61	1.474	0.144
Disease course (years)	6.26 ± 2.00	6.05 ± 2.60	0.467	0.641
Body mass index (kg/m2)	25.12 ± 2.18	24.45 ± 2.20	1.597	0.113
Years of education (years)	10.80 ± 2.73	10.00 ± 3.15	1.408	0.162
Concomitant medications (yes/no)	12/38	10/50	0.917	0.338
Tobacco use (yes/no)	18/32	15/45	1.571	0.210
Regular exercise habits (yes/no)	10/40	8/52	0.886	0.347

Concomitant medications: Benzodiazepines, anticholinergics, etc.; tobacco use defined as ≥ 1 cigarette per day; regular exercise habits: ≥ 3 sessions per week, each lasting ≥ 30 minutes.

Treatment efficacy

The overall treatment efficacy rate in the control group was 76.00%, whereas in the observation group, it reached 93.33%. The observation group demonstrated a significantly higher overall efficacy rate than the control group (P < 0.05; Table 2).

Table 2 Efficacy of the two patient groups, n (%).

Indicators	Control group (n = 50)	Observation group (n = 60)	χ²	P value
Cure	15 (30.00)	20 (33.33)
Improvement	23 (46.00)	36 (60.00)
Ineffectiveness	12 (24.00)	4 (6.67)
Overall efficacy	38 (76.00)	56 (93.33)	6.592	0.010

Adverse events

Safety-related data indicated that the cumulative incidence of adverse events including fatigue, xerostomia, insomnia, anorexia, and headache in the observation group was 10.00%. These data were comparable to the 16.00% observed in the control group (P > 0.05; Table 3).

Table 3 Incidence of adverse events in the two patient groups, n (%).

Indicators	Control group (n = 50)	Observation group (n = 60)	χ²	P value
Fatigue	2 (4.00)	1 (1.67)
Xerostomia	1 (2.00)	1 (1.67)
Insomnia	1 (2.00)	2 (3.33)
Anorexia	1 (2.00)	0 (0.00)
Headache	3 (6.00)	2 (3.33)
Total	8 (16.00)	6 (10.00)	0.884	0.347

Psychiatric symptom assessment

The PANSS was used to analyze the psychiatric symptoms in both groups. Before treatment, no significant differences were detected in the PANSS scores for positive, negative, and general psychopathological symptoms between the two groups (P > 0.05). After treatment, a significant reduction in PANSS scores was noted in both groups (P < 0.05). Moreover, the PANSS scores of the observation group were significantly lower than those of the control group across all symptom categories (P < 0.05; Table 4).

Table 4 Psychiatric symptom assessment of the two patient groups.

Indicators	Control group (n = 50)	Observation group (n = 60)	t value	P value
Positive symptoms
Before treatment	23.24 ± 6.22	21.22 ± 7.68	1.495	0.138
After treatment	14.46 ± 2.92a	10.92 ± 2.63b	6.685	< 0.001
Negative symptoms
Before treatment	29.86 ± 10.60	30.42 ± 7.84	0.318	0.751
After treatment	25.00 ± 5.41a	18.78 ± 5.48b	5.962	< 0.001
General psychopathological symptoms
Before treatment	60.26 ± 13.15	61.33 ± 13.50	0.121	0.904
After treatment	43.68 ± 12.99a	35.95 ± 10.46b	3.457	< 0.001

^aP < 0.05, between the same groups compared with before treatment.

^bP < 0.01, between the same groups compared with before treatment.

Cognitive and social function assessment

The cognitive and social functions of the two groups were evaluated using the RBANS and PSP, respectively. Before treatment, no significant discrepancies were observed in the RBANS and PSP scores between the two groups (P > 0.05). A significant increase in both scores was observed after treatment (P < 0.05). Moreover, across all aspects, the scores of the observation group were markedly higher than those of the control group (P < 0.05; Table 5).

Table 5 Cognitive and social function assessment of the two patient groups.

Indicators	Control group (n = 50)	Observation group (n = 60)	t value	P value
Repeatable battery for the assessment of neuropsychological status (points)
Before treatment	79.36 ± 13.19	78.07 ± 12.39	0.528	0.599
After treatment	87.72 ± 10.04a	95.80 ± 11.09b	3.971	< 0.001
Personal and social performance scale (points)
Before treatment	49.54 ± 4.52	48.80 ± 6.65	0.668	0.505
After treatment	76.94 ± 5.50a	84.17 ± 7.54b	5.642	< 0.001

^aP < 0.05, between the same groups compared with before treatment.

^bP < 0.01, between the same groups compared with before treatment.

Quality of life evaluation

The SQLS was employed to assess the quality of life of the two groups. Before treatment, there were no significant intergroup differences in scores related to psychosocial aspects, symptoms and side effects, or motivation and energy (P > 0.05). After treatment, all these scores declined significantly (P < 0.05), with the observation group showing significantly lower scores in each category compared with the control group (P < 0.05; Figure 1).

Figure 1 Quality of life evaluation of the two patient groups. A: Pre-treatment and post-treatment psychosocial scores of the two groups; B: Pre-treatment and post-treatment symptoms and side effect scores of the two groups; C: Pre-treatment and post-treatment motivation and energy scores of the two groups. ^aP < 0.05 and ^bP < 0.01 vs the pre-treatment levels; ^cP < 0.05 vs control.

Serum biomarker analysis

The serum biomarkers of the two groups, namely, IL-6, IL-17, and PRL, were examined. Before treatment, no significant disparities were detected in the levels of these biomarkers between the two groups (P > 0.05). After treatment, a remarkable shift was observed: The concentrations of IL-6 and IL-17 decreased significantly, whereas the level of PRL increased substantially (P < 0.5). Notably, compared with the control group, the observation group exhibited lower levels of IL-6 and IL-17, along with a higher PRL level (P < 0.5; Figure 2).

Figure 2 Serum markers of the two patient groups. A: Pre-treatment and post-treatment interleukin 6 (IL-6) levels; B: Pre-treatment and post-treatment IL-17 Levels; C: Pre-treatment and post-treatment prolactin levels. PRL: Prolactin. ^aP < 0.05 and ^bP < 0.01 vs the pre-treatment levels; ^cP < 0.05 vs control.

DISCUSSION

In this study, a retrospective analysis was conducted on 110 patients with schizophrenia to compare the clinical efficacy and safety of lurasidone plus sulpiride compared to sulpiride monotherapy. The results revealed that this combination therapy increased the efficacy rate from 76.00% to 93.33%, indicating that it may optimize therapeutic outcomes in patients with schizophrenia. Regarding safety, the combination therapy did not significantly increase the incidence of adverse events, including fatigue, xerostomia, insomnia, anorexia, and headache (10.00% vs 16.00%). In a 22-month double-blind placebo-controlled trial, Correll et al[17] reported that only 14.7% of patients discontinued taking lurasidone because of adverse reactions, a figure (the original) remarkably similar to our data. Lurasidone’s limited interference with weight gain, blood sugar, lipids, and PRL levels explains why it seldom increases adverse reactions in schizophrenia therapy[18]. Additionally, existing evidence underscores its long-term therapeutic safety and tolerability—benefits that possibly stem from its negligible effects on metabolic parameters and weight fluctuations[19]. In terms of psychiatric symptoms, the utilization of lurasidone plus sulpiride for patients with schizophrenia led to a more pronounced alleviation of positive, negative, and general psychopathological symptoms. In the study by Loebel et al[20], lurasidone significantly improved symptoms across five dimensions: (1) Positive symptoms; (2) Negative symptoms; (3) Thinking disorder; (4) Hostility/excitement; and (5) Depression/anxiety in patients with schizophrenia, which is similar to our observations. A study indicated that the mitigation of negative symptoms in patients with schizophrenia by lurasidone is, in part, attributable to its promotion of dopamine release in the prefrontal cortex[21]. Meanwhile, the antagonistic actions of lurasidone on dopamine and 5-HT receptors are pivotal in alleviating the clinical symptoms of patients with schizophrenia. The synergistic combination of lurasidone and sulpiride is particularly advantageous, as it enables the integration of the distinctive benefits of both agents, thereby optimizing the therapeutic outcomes[22]. The enhanced treatment efficacy observed with this combination could be ascribed to their differing pharmacological pathways, facilitating a multi-targeted effect that leads to significant symptom relief[10,13,14].

Furthermore, the administration of lurasidone plus sulpiride to patients with schizophrenia significantly bolsters their cognitive and social functions, evidenced by a more substantial elevation in RBANS and PSP scores under the combination protocol compared with monotherapy. In patients with schizophrenia, the advancement of the disease course, coupled with the progressive emergence of negative symptoms, often precipitates deteriorating cognitive impairment, which invariably results in an inevitable decline in social functionality[23]. A small-scale systematic review indicated that lurasidone exerts a more pronounced effect on improving cognitive ability compared with placebo, quetiapine, ziprasidone, or conventional treatment[24]. A study on a rat model pointed out that the neuroprotective effect of lurasidone can be attributed, to some extent, to its increase in the expression of the language-related protein forkhead box P2 in hippocampal cells, and the increase in the levels of the neuroprotective SxIP motif and microtubule-plus-end-binding proteins[25]. The SQLS data also showed that the treatment of patients with schizophrenia with lurasidone plus sulpiride can more effectively improve the quality of life in terms of psychosocial scores, symptom, and side effect scores, and motivation and energy scores. Dembek et al[26] reported that lurasidone significantly enhances the quality of life of patients with bipolar depression in various aspects, including overall life satisfaction, social and family relationships, medication satisfaction, and the ability to perform activities of daily living, which corroborates our findings. As regards serum biomarkers, with the administration of lurasidone plus sulpiride, the levels of IL-6, IL-17, and PRL in patients with schizophrenia have more substantially improved. Accumulated evidence reveals that the IL-6 Level is intricately linked to the chronic manifestations of patients with schizophrenia; moreover, a pronounced positive correlation has been established between IL-17 and the severity of mental disorders. Concurrently, low PRL levels have been significantly associated with more severe symptomatology in schizophrenia[27-29]. The immunopathogenesis of schizophrenia may be partly driven by IL-6 through its involvement in the IL-6/retinoic acid receptor-related orphan receptor C/IL-22 axis, whereas disturbances in IL-17 signaling might induce neuropsychiatric symptoms in affected individuals[30,31]. Numerous investigators have put forward novel treatment strategies for individuals with schizophrenia. For instance, Bredin et al[32] elucidated that the application of aerobic, resistance, and combined exercise training modalities in patients with schizophrenia can notably mitigate psychiatric symptoms. Additionally, Achtyes et al[33] demonstrated that agonists of the trace amine-associated receptor 1, when administered in the treatment of patients with schizophrenia, not only effect a remarkable improvement in clinical symptoms but also exhibit a certain degree of tolerability.

The findings of this study are constrained by several factors. The small sample size calls for larger, multicenter studies to enhance reliability. Second, the uneven group sizes might weaken the statistical power, indicating a need for prospective analyses with balanced sampling. Lastly, incorporating mechanistic investigations, such as basic experimental studies, could provide deeper insights into treatment-related mechanisms.

CONCLUSION

Compared with sulpiride monotherapy, lurasidone plus sulpiride offers a significantly greater improvement in therapeutic efficacy while maintaining a satisfactory safety profile in patients with schizophrenia. This combination also effectively alleviates psychiatric symptoms, enhances cognitive and social functioning, and improves quality of life. Moreover, it favorably modulates abnormal serum levels of IL-6, IL-17, and PRL. These findings provide meaningful clinical insights into the potential of this combination therapy and offer promising guidance for more effective treatment strategies in schizophrenia.