Meta-Analysis of the Efficacy of Risperidone Treatment in Patients with First-Episode Schizophrenia

ABSTRACT

Introduction:

First-episode schizophrenia is a prevalent psychiatric disorder with a complex etiology. This meta-analysis evaluates the efficacy of risperidone in treating patients with first-episode schizophrenia.

Methods:

A literature search was conducted to identify studies on the efficacy of risperidone for first-episode schizophrenia. The literature was evaluated for quality, and a meta-analysis was then performed.

Results:

A total of 15 articles (6 in Chinese and 9 in English) were included. The meta-analysis revealed statistically significant differences in the cure rate (relative risk [RR]=0.51, 95% confidence interval [CI]: 0.46–0.57, p <0.001) and the total marked improvement rate (RR=0.58, 95% CI: 0.52–0.65, p <0.001) favoring risperidone over control groups. The incidence of weight gain (p <0.001) and extrapyramidal symptoms (p=0.005) was higher with risperidone.

Conclusion:

Risperidone shows increased cure and effective rates compared with control groups (including placebo and other antipsychotics) in the treatment of patients with first-episode schizophrenia. However, it may increase the risk of extrapyramidal reactions and weight gain.

INTRODUCTION

Schizophrenia is a chronic and severe mental disorder affecting an individual’s thoughts, feelings, and behaviours. This complex disease, stemming from dysfunctions in the nervous system, presents a challenging pathogenesis, complicating the prospects for a cure (1). It is characterized by disruptions in thought processes, perceptions, emotions, and behaviour. Hallucinations, delusions, disorganized speech and behaviors, impaired cognitive ability, diminished motivation, and difficulties in interpersonal relationships are common symptoms (2).

Emerging typically in late adolescence or early adulthood, schizophrenia follows a lifelong course of remissions and relapses. Beyond psychiatric symptoms, it is associated with substantial cognitive deficits, leading to impairments in executive functioning, working memory, and attention (3). These cognitive challenges often translate into difficulties in employment, independent living, and social interactions, substantially diminishing quality of life (4).

As a progressive disorder with a high disability rate, continuous treatment is generally necessary for patients with schizophrenia (5). This ongoing treatment need adversely impacts patients’ quality of life and imposes a considerable financial burden on their families, affecting both mental and physical well-being (6). Therefore, providing timely symptomatic treatment and promoting mental health rehabilitation is essential for helping patients achieve remission, restore functioning, and reintegrate into society.

Highlights

• Risperidone is effective in first-episode schizophrenia.

• Risperidone is associated with weight gain and extrapyramidal symptoms.

• Combination treatments may improve the safety profile of risperidone.

Currently, antipsychotic medications serve as the cornerstone of schizophrenia treatment. Typical antipsychotics such as haloperidol primarily act as dopamine receptor blockers, mainly by inhibiting the central dopamine D2 receptor. In comparison, atypical antipsychotics, such as olanzapine and quetiapine, demonstrate efficacy similar to typical antipsychotics. However, they have broader receptor binding profiles, targeting both dopamine D2 and serotonin 2A receptors, which may contribute to their improved tolerability and efficacy in treating the negative and cognitive symptoms of schizophrenia.

As an atypical antipsychotic, risperidone has shown promising efficacy in treating both the positive and negative symptoms of schizophrenia. Nonetheless, a systematic evaluation of the efficacy and safety of risperidone, particularly in treating first-episode schizophrenia, remains underreported in the literature. Consequently, this study aims to conduct a meta-analysis of the relevant literature, systematically evaluating the use of risperidone as an antipsychotic drug in the treatment of first-episode schizophrenia. This analysis intends to provide systematic and high-level reference information for future research and clinical practice.

METHODS

A comprehensive literature search was conducted across several databases, including PubMed, MEDLINE, Web of Science, China National Knowledge Infrastructure, Wanfang Data, VIP, the American Scientific Citation Index, Embase, and the Cochrane Library. The objective was to identify the relevant literature pertaining to the study. Keywords employed in the search included ‘risperidone’ , ‘first-episode schizophrenia’ , ‘schizophrenia’ , ‘first episode’ , ‘clinical observation’ , ‘clinical research’ , and ‘RCTs’ .

Inclusion and exclusion criteria and outcome indicators for the included studies

Inclusion criteria

The following criteria were applied to include studies in this meta-analysis: 1) the study must be a randomized clinical trial (RCT); 2) the patients in the study must meet the criteria of the Chinese Classification of Mental Disorders, the American Diagnostic and Statistical Manual of Mental Disorders, or the International Classification of Diseases; 3) there was no restriction on gender, but studies involving elderly and adolescent patients were excluded; 4) studies were included regardless of the methods of allocation concealment and blinding used; and 5) the literature was either in Chinese or English.

Exclusion criteria

To ensure consistency and objectivity, the following types of studies were excluded:

1) Retrospective research literature; 2) studies that were published more than once; 3) literature focusing on the relevant mechanisms of schizophrenia; 4) literature akin to expert reviews; 5) studies involving elderly or adolescent patients with first-episode schizophrenia; 6) studies including patients with coexisting medical conditions (e.g. neurological, cardiovascular, or metabolic disorders) or a history of substance abuse; 7) studies including patients with drug abuse or cognitive impairment due to head injury or stroke; 8) studies involving patients with color vision deficiencies (such as color blindness or color weakness) or blindness, especially those unable to understand the content of the scales used in the study; and 9) studies including individuals who were unable to speak, had intellectual disabilities, hearing impairments, or other barriers preventing normal verbal communication, thereby precluding them from completing questionnaires.

Outcome indicators

The following outcome indicators were used in the included studies: 1) the treatment’s effect on patients was evaluated using the positive and negative symptom scale (PANSS); 2) to evaluate the adverse reactions of patients during treatment, the treatment-emergent symptom scale was used. It is widely acknowledged that a PANSS reduction rate exceeding 75% signifies complete recovery, a rate between 50% and 74% is considered effective, a rate from 25% to 49% is viewed as ineffective, and a rate below 25% is deemed completely ineffective (7).

Basic characteristics of the included studies

Two researchers independently assessed the risk of bias for each included article, employing the Cochrane 5.3.0 tool. This assessment included the following aspects: 1) random sequence generation; 2) allocation concealment; 3) blinding of participants and personnel; 4) blinding of outcome assessment; 5) incomplete outcome data; 6) selective reporting; and 7) other sources of bias. Any disagreements were resolved through consultation with a third researcher. All 15 included studies met the quality criteria, as illustrated in Figure 1. The treatment durations in the included studies ranged from 4 to 12 weeks. The majority of these studies used oral risperidone formulations and excluded patients who were receiving concurrent antipsychotics or benzodiazepines. However, a few studies permitted specific concurrent medications, such as anticholinergics. The control groups in the studies either received a placebo or other antipsychotic medications, such as haloperidol, olanzapine, or quetiapine.

Figure 1.

Quality evaluation of the related literature.

Quality evaluation of the included randomized controlled trials (RCTs) related to the clinical efficacy and safety of risperidone treatment.

Data extraction from the included literature

Two literature evaluators conducted the search, extracted data, and evaluated the risk of bias in the collected literature, following the established relevant inclusion and exclusion criteria. They also checked the consistency of the included literature. In cases of disagreement, a third evaluator makes the final decision. The extracted data comprised general information about the included literature, recovery and efficacy rates, adverse reactions, the number of cases or study patients, and observation indicators.

Quality evaluation of the data from the included literature

The two literature assessors independently evaluated the quality of the included literature using the Cochrane-based risk-of-bias assessment tool. This tool assesseseach study item and its seven main indicators, including the generation of random sequences and selective publication.

Statistical methods

The meta-analysis was conducted using Cochrane Review Manager (RevMan, v. 5.3.0; Cochrane Collaboration, Britain) software. The basic steps of the meta-analysis were as follows: 1) The Chi-squared (χ²) test determined the heterogeneity among the results of the included studies. It is generally accepted that heterogeneity is significant if I² >50% and p <0.1, in which case the potential sources should be analyzed. 2) In the absence of clinical heterogeneity, the fixed-effects model was used for analysis. 3) When heterogeneity among the results was minimal (I² <50%, p >0.1), the combined effect size was calculated using the fixed effects model. Count data were primarily described by relative risk (RR) and its 95% confidence interval (CI). The publication bias was evaluated using the funnel plots.

RESULTS

Results of the screening process of the sourced literature

A computerized search initially identified 2,432 documents related to the subject. Following a review of the titles and abstracts, 157 articles were deemed relevant. Subsequent exclusion of articles such as secondary research, case reports, and animal experiments resulted in 24 articles being read in full. Ultimately, 15 documents (8–22) were included in this study for meta-analysis. These comprised 9 documents in English and 6 in Chinese. The specific process is illustrated in Figure 2.

Figure 2.

The literature search and screening process. PRISMA flow diagram illustrating the literature search and screening process for identifying eligible RCTs evaluating the clinical efficacy and safety of risperidone treatment.

Comparison of clinical efficacy

Cure rate

This study included 15 articles relating to RCTs that reported on cure rates (8–22). The heterogeneity test yielded p=0.04 and I²=43%, indicating moderate heterogeneity; hence, the fixed-effects model was employed for analysis. The meta-analysis revealed that the cure rates in the risperidone-treated groups were significantly higher compared with the drug-naive groups (RR=0.51, 95% CI: 0.46–0.57, p <0.00001) (Figure 3).

Figure 3.

A Meta-analysis forest plot of the cure rate.

Forest plot from the meta-analysis comparing the cure rates between risperidone treatment groups and control groups (drug-naive or other antipsychotic treatments) across the included RCTs.

Total marked improvement rate

Fifteen relevant articles incorporating the total marked improvement rate ([number of cures + significant improvement] / total number of cases) were included in the meta-analysis of this study (8–22). The heterogeneity test results showed p=0.32 and I²=12%, indicating low heterogeneity. Consequently, a fixed-effects model was utilized for the analysis. The meta-analysis findings revealed substantially superior treatment effects in the risperidone-treated groups compared with the control groups, which received either a placebo or other antipsychotic medications such as haloperidol, olanzapine, or quetiapine, with statistically significant differences between the groups (RR=0.58, 95% CI: 0.52–0.65, p <0.00001) (Figure 4). There was no significant publication bias in both cure rate and total marked improvement rate (Figure 5).

Figure 4.

A Meta-analysis forest plot of total marked improvement rat.

Forest plot from the meta-analysis comparing the total marked improvement rates ([number of cures + significant improvement] / total number of cases) between risperidone treatment groups and control groups (placebo or other antipsychotic treatments) across the included RCTs.

Figure 5.

a, b. Funnel plots of the cure rate (a) and total marked improvement rate (b).

Safety comparison

Five adverse effects (weight gain, constipation, extrapyramidal symptoms, tachycardia, and dizziness) reported in the included 15 RCT (randomized controlled trial) articles were analyzed. Except for extrapyramidal adverse reactions, where the random effects model was applied (p <0.001, I²=64%), the heterogeneity of adverse events was low. Consequently, a fixed-effects model was employed for analysis. The meta-analysis results indicated that weight gain (p <0.001) and extrapyramidal symptoms (p=0.005) were more frequent in patients treated with risperidone compared with control patients who received other antipsychotic medications or placebo, with statistically significant differences (p <0.05). The other adverse effects did not exhibit statistically significant differences (Table 1).

Table 1.

Overall adverse event occurrence

ADR symptoms	Study number	ADR incidence (%)		Heterogeneity test		Meta-analysis results
		Control group	Risperidone	P-value I2	I2 (%)	Combined OR	95% CI	P-value
Weight gain	21	3.52	19.56	0.87	0	0.18	0.13–0.29	<0.001
Constipation	11	2.70	4.58	0.44	0	0.63	0.33–1.21	0.18
Extrapyramidal symptoms	21	18.43	29.43	<0.001	64%	0.27	0.21–0.65	0.005
Tachycardia	21	10.21	8.28	0.33	10	1.21	0.88–1.68	0.24
Dizziness	3	5.22	2.27	0.40	9	1.92	0.56–6.51	0.30

DISCUSSION

Clinically, schizophrenia is recognized as a chronic mental disorder primarily characterized by abnormalities in consciousness, sensation, perception, and emotion. A common manifestation of this disorder is the patient’s difficulty in distinguishing between reality and hallucinations. Additionally, patients may exhibit slow responses, withdrawal symptoms, or aggressive behaviors (23). Schizophrenia has a protracted course and is challenging to cure or may be incurable, often resulting in relapses that impose substantial mental and economic burdens on the families of patients.

Difficult-to-treat schizophrenia frequently recurs, and the medical community lacks a unified treatment or diagnostic standard (24). The currently accepted diagnostic criteria include a course exceeding 5 years and no improvement following 2 years of diverse psychiatric drug treatments. Recent focus has shifted towards enhancing cognitive function and quality of life, in addition to controlling psychotic symptoms and reducing recurrence rates (13). Studies have shown that treatment with antipsychotics, such as risperidone, clozapine, and aripiprazole, effectively controls symptoms, has low recurrence rates, and offers an excellent prognosis (25). Risperidone has a strong affinity for human 5-HT2A and dopamine D2 receptors. Its mechanism in treating schizophrenia involves antagonism post-ingestion; it alleviates positive psychotic symptoms by acting on dopamine D2 receptors and mitigates negative/affective symptoms through the antagonism of 5-HT2A and dopamine D2 receptors. Aripiprazole, a quinoline derivative, produces similar effects by blocking dopamine D2 and antagonizing 5-HT2A receptors. However, Gafoor et al. (26) observed that it also blocks norepinephrine and acts as a 5-HT1A receptor agonist, which makes it more effective than risperidone in improving negative symptoms.

This meta-analysis of 15 studies revealed no notable difference in the incidence of adverse effects between the patients treated with risperidone and those in the control groups. However, instances of lactation, meditation, menstrual abnormalities, and weight gain were substantially higher in the risperidone-treated group compared with the control (drug-naive) group. Adverse effects commonly associated with risperidone, such as extrapyramidal symptoms, weight gain, and endocrine abnormalities, are generally dose-dependent (27). The incidence of extrapyramidal symptoms is linked to the speed of metabolism, excessive dosages, and individual differences. Risperidone’s slow receptor dissociation leads to prolonged dopamine D2 antagonism, resulting in abnormalities such as lactation and menstrual issues in women, as well as increased risks of weight gain, hyperglycaemia, and cardiovascular and cerebrovascular diseases.

The treatment of first-episode schizophrenia aims for either a cure or substantial improvement to ensure good control and prognosis. The results of this study indicate that the risperidone-treated groups had higher rates of cure and overall effectiveness compared with the control groups, a statistically significant difference. These findings support the efficacy of risperidone in treating first-episode schizophrenia, a conclusion also affirmed by Agid et al. (28).

It was previously believed that the negative symptoms of schizophrenia were due to decreased dopamine activity in the prefrontal lobe, whereas the positive symptoms were associated with dopamine hyperactivity in the mesolimbic system, alongside serotonin (5-HT) involvement. The meta-analysis results of this study demonstrated a statistically significant difference in total response rates between the risperidone-treated and control groups. Furthermore, the negative symptom scores in the risperidone-treated groups were substantially lower than those in the control groups. These findings confirm risperidone’s effectiveness in treating first-episode schizophrenia and its beneficial impact on improving negative symptoms.

In conclusion, risperidone is an effective treatment for patients with first-episode schizophrenia, particularly in improving negative symptoms and mitigating other adverse effects. Notably, 2 studies have identified changes in sexual desire among patients treated with risperidone (29,30), a common adverse reaction in patients with schizophrenia. This suggests the need for closer attention, although there may be challenges due to privacy concerns, as patients are often reluctant to disclose such issues (31). Treatment adherence can be compromised by intolerance to drug side effects, leading to recurrence and disease progression (32). Therefore, clinicians are advised to develop personalised medication plans that cater to individual needs and specific adverse reactions.

This meta-analysis also indicates that risperidone may cause other adverse effects, such as weight gain, elevated prolactin levels, and extrapyramidal symptoms. Consequently, its use should be avoided in patients with Parkinson’s disease, obesity, or in individuals who are pregnant or undergoing menopause to minimize adverse effects on physical health. However, clinical monotherapy for psychosis is not always ideal. For instance, Thomson et al. (33) reported that clozapine, despite its expected treatment effect, caused cardiovascular damage and granulocytopenia, thus limiting its clinical application. This was experimentally validated by Singh et al. (34), who found that combining conventional drugs with others produced synergistic effects, offering the best treatment for patients with refractory schizophrenia.

The meta-analysis highlights that risperidone substantially improves symptoms in first-episode schizophrenia. Nevertheless, combination treatments are generally considered more effective for the clinical treatment of mental illness. For example, Gani et al. (35) discovered that a combination of clozapine and risperidone for refractory schizophrenia improved efficacy and reduced the overall incidence of adverse reactions in patients treated with risperidone compared with those in control groups. Thus, the efficacy and safety of risperidone in combination with other drugs in treating first-episode schizophrenia warrants further research. This is not only to reduce adverse effects such as weight gain and extrapyramidal symptoms but also to enhance safety. In summation, the combination of risperidone with clozapine for refractory schizophrenia shows considerable clinical efficacy, substantially reducing PANSS scores and the incidence of adverse reactions, making it a worthy candidate for clinical application and further promotion (36).

This study presents several limitations. First, the quality of the RCTs included in this study was generally low, with most failing to mention the blinding and allocation concealment methods used, potentially leading to selective reporting and other biases. Moreover, the literature research for this meta-analysis lacked unpublished grey data and evidence from non-traditional sources, possibly excluding negative results and thereby impacting the systematic evaluation outcomes. Regarding the included literature, the methods for evaluating the recovery of patients with psychosis were not standardized and unified, indicating a need for further standardization of evaluation methodologies and the establishment of standardized rules. For instance, quantifying the processing power of computer software and conducting quantitative analyses of collected data could enhance the credibility of research results and establish a solid foundation for providing clinical and relatively quantifiable personalized treatment plans.

Second, some of the literature included in this study was observational research, potentially resulting in a lack of large sample, multicentre RCTs. Additionally, certain studies yielded multiple research results with heterogeneity, possibly leading to publication bias. In summary, the results of this meta-analysis require further validation through multicentre, large-sample, high-quality studies.

Third, due to language limitations, only studies published in Chinese and English were searched. This resulted in an incomplete final literature search as other languages were excluded, potentially compromising the rigour of the study’s results.

Fourth, there were issues of subjectivity. For example, patients’ subjective narratives of their recovery effects and the absence of unified and standard quantitative norms may have introduced bias. When organizing and collecting relevant literature, greater attention should be given to the standardized evaluation of patients’ recoveries to ensure professional and reliable meta-analyses and research evaluations. Consequently, the conclusions of this study’s meta-analysis necessitate further validation using additional sample data and multicentre RCT studies.

Lastly, it is crucial to acknowledge that our meta-analysis’ s evaluation of side effects was limited by the data available from the included studies, which reported side effect data inconsistently, especially in placebo-controlled comparisons. Relying solely on comparisons with drug-naive patients might not provide an accurate assessment of the relative risk of side effects associated with risperidone. Future research should include placebo-controlled comparisons and undertake more comprehensive side-effect evaluations when assessing risperidone’s safety profile. Such an approach will enable a more precise determination of the relative risk of side effects associated with risperidone treatment compared with placebo or other antipsychotic medications.

Despite our diligent efforts to synthesise the available evidence, the outcomes of our meta-analysis may be perceived as controversial or debatable owing to several factors. First, there was considerable heterogeneity among the included studies, particularly regarding study design and patient populations, which might have led to inconsistent or conflicting outcomes. Furthermore, the potential for publication bias, where studies reporting negative or null findings might be underrepresented, could have skewed our results in favor of a more favorable view of risperidone.

The results of our meta-analysis suggest that risperidone exhibits higher cure and efficacy rates compared with control groups, which include placebo and other antipsychotic drugs, in treating first-episode schizophrenia. This supports the potential of risperidone as a first-line treatment option for patients experiencing their first episode of schizophrenia. However, it is also apparent from our findings that treatment with risperidone may elevate the risk of adverse effects, notably weight gain and extrapyramidal symptoms.