Effectiveness of Herbal Medicine Compared to Antidepressants in Patients with Schizophrenia Spectrum Disorders Accompanied by Depression: a systematic review and meta-analysis

Abstract

Objectives

Depression affects approximately 28.6% of patients with schizophrenia spectrum disorders (SSD). Although herbal medicine (HM) has been proposed as a therapeutic option, its comparative effectiveness relative to antidepressants remains uncertain. This systematic review compared HM with antidepressants as adjuncts to antipsychotics in patients with SSD and comorbid depression.

Methods

Eight electronic databases were searched from inception to January 15, 2025, without language restrictions. Randomized controlled trials (RCTs) that compared HM plus antipsychotics with antidepressants plus antipsychotics in patients with SSD and depression were included. Primary outcomes were depressive symptom scores (Calgary Depression Scale for Schizophrenia or Hamilton Depression Rating Scale) and response rates. Secondary outcomes included overall psychiatric symptoms and adverse events. Risk of bias was assessed using the Cochrane RoB 2 tool; certainty of evidence was evaluated using the GRADE approach.

Results

Seven RCTs comprising 505 participants were included. Meta-analysis demonstrated no significant difference between HM and antidepressants in depressive symptoms (SMD −0.19, 95% CI [−0.54, 0.15]; very low-certainty evidence), response rates (RR 1.00, 95% CI [0.96, 1.04]; low-certainty evidence), or overall psychiatric symptoms (SMD −0.06, 95% CI [−0.84, 0.73]; low-certainty evidence). Adverse event rates showed a nonsignificant trend favoring HM (RR 0.56, 95% CI [0.06, 5.26]; low-certainty evidence).

Conclusion

Very low- to low-certainty evidence suggests no significant difference in effectiveness between HM and antidepressants as adjuncts to antipsychotics for depression in SSD. Although HM may serve as an alternative, high-quality, large-scale trials are required to establish definitive conclusions.

INTRODUCTION

Schizophrenia spectrum disorders (SSDs) comprise a group of severe psychiatric conditions characterized by symptoms in one or more of five domains: delusions, hallucinations, disorganized thinking, grossly disorganized or abnormal motor behavior, and negative symptoms [1]. These disorders substantially contribute to the global burden of disease [2]. Data from the Global Burden of Disease (GBD) 2019 study indicated that the absolute number of individuals living with schizophrenia increased by more than 65% between 1990 and 2019, rising from 14.2 million to 23.6 million, with a corresponding increase in disability-adjusted life years (DALYs) [2]. A major challenge within this population is the high prevalence of comorbid depression, which affects an estimated 28.6% of patients [3]. This comorbidity greatly affects quality of life and prognosis, making regular screening and the development of effective therapeutic strategies for depression a clinical priority among individuals with SSDs [3].

Current evidence-based guidelines from the British Association for Psychopharmacology recommend augmentation of antipsychotics with antidepressants as a first-line strategy for the treatment of depressive symptoms in patients with SSDs [4]. However, the safety of this approach has not been definitively established. Although some studies have suggested that combination therapy does not significantly increase adverse events [5], persistent concerns remain due to the low methodological quality of the available evidence. Additionally, certain drug combinations have been associated with an elevated risk of cardiovascular events [6]. These limitations underscore the need for alternative or complementary therapies that can manage depression effectively and safely in this vulnerable population.

Herbal medicine (HM) has emerged as a promising complementary option, with the potential to address both depressive and psychotic symptoms through multi-target and multi-pathway mechanisms [7-10]. An expanding body of evidence suggests that herbal formulas and their individual components modulate key pathophysiological pathways implicated in depression [7, 11]. These mechanisms include regulation of inflammatory responses, attenuation of hypothalamic-pituitary-adrenal (HPA) axis hyperactivity, and modulation of monoamine, glutamate, and gut-brain axis signaling [6, 12, 13]. This theoretical rationale has been supported by clinical findings; a recent systematic review and meta-analysis indicated that HM as an adjunct to antipsychotics significantly improves both depressive and psychotic symptoms compared with antipsychotics alone [10]. The convergence of mechanistic and clinical evidence supports the potential of HM as an effective adjunct to standard antipsychotic therapy.

Although emerging evidence supports HM as an effective adjunctive therapy, a key question remains unanswered: how it compares directly with the current standard of care, adjunctive antidepressants. To address this gap, the present systematic review and meta-analysis was conducted to evaluate the comparative effectiveness and safety of HM versus antidepressants for improving depressive and overall psychiatric symptoms among patients with SSD and comorbid depression. The findings are intended to provide a foundational evidence base regarding the potential of HM as a viable alternative to conventional antidepressant therapy and to inform the design of future high-quality clinical trials.

METHODS

The protocol for this systematic review was registered a priori with the International Prospective Register of Systematic Reviews (PROSPERO) under registration number CRD42025643150. This review was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement (Supplementary Material 1) [14].

1. Search strategy

A comprehensive literature search was conducted across eight electronic databases. International databases included MEDLINE (via PubMed), EMBASE, and the Cochrane Central Register of Controlled Trials. Additionally, regional databases were searched, including three Korean databases (Korean Studies Information Service System, ScienceON, Oriental Medicine Advanced Searching Integrated System), one Chinese database (China National Knowledge Infrastructure), and one Japanese database (Citation Information by NII). All searches were performed on January 15, 2025, without restrictions on language or publication date.

To ensure completeness, the World Health Organization International Clinical Trials Registry Platform was screened for ongoing or unpublished trials, as were the Evidence Reports of Kampo Treatment available on the JSOM website. Reference lists of included studies and relevant reviews were manually examined to identify additional eligible articles. To minimize publication bias, grey literature sources, including conference proceedings and dissertations, were also searched. The full search strategy for all databases is provided in Supplementary Material 2.

2. Eligibility criteria

1) Types of studies

Only randomized controlled trials (RCTs) were included. Quasi-randomized trials, in which allocation was not truly random or was predictable, were excluded. No restrictions were imposed concerning publication status or language.

2) Types of participants

Studies enrolling patients of any age with a diagnosis of SSD and depressive symptoms were eligible. SSDs were defined according to established diagnostic criteria, including the Diagnostic and Statistical Manual of Mental Disorders (DSM), the International Classification of Diseases (ICD), or the Chinese Classification of Mental Disorders (CCMD), and encompassed schizophrenia, delusional disorder, brief psychotic disorder, schizophreniform disorder, and schizoaffective disorder. Studies addressing post-schizophrenic depression were also considered eligible. Studies involving patients with substance- or medication-induced psychotic disorders, or those primarily focused on treatment of antipsychotic-related adverse effects rather than comorbid depression, were excluded.

3) Types of interventions

The intervention consisted of oral HM, prescribed according to the principles of East Asian traditional medicine, administered as an adjunct to antipsychotic medication. Eligible HM formulations included decoctions, granules, tablets, capsules, and other oral preparations.

4) Types of comparators

The comparator was an antidepressant combined with an antipsychotic medication. Co-interventions, such as rehabilitation therapy, were permitted only if applied equally in both the intervention and control groups. Studies that incorporated additional treatments in the control group, including acupuncture, moxibustion, or cupping, were excluded to avoid confounding the effects of HM.

5) Types of outcome measures

The primary outcomes were scores on depression-specific rating scales, specifically the Calgary Depression Scale for Schizophrenia (CDSS) [9] and the Hamilton Depression Rating Scale (HDRS) [15], as well as response rates defined as ≥ 50% improvement from baseline CDSS or HDRS scores [16]. Secondary outcomes included the overall incidence of adverse events and changes in general psychiatric symptoms assessed using the Positive and Negative Syndrome Scale (PANSS) [17] or the Brief Psychiatric Rating Scale (BPRS) [18].

3. Study selection

Two reviewers independently screened the titles and abstracts of all retrieved records according to predefined eligibility criteria. Full-text articles of potentially relevant studies were subsequently obtained and independently assessed by the same two reviewers. Disagreements at any stage were resolved via discussion and consensus or, when necessary, through consultation with a third reviewer.

4. Data extraction

Two reviewers independently extracted data from the included studies using a pre-piloted, standardized form in Microsoft Excel (Microsoft, Redmond, WA, USA). The following information was collected: (1) study characteristics, including first author, publication year, country, study design, sample size, and study duration; (2) participant characteristics, including diagnostic criteria, baseline symptom scores, pattern identification, demographic data (sex and age), duration of illness, and treatment setting; (3) intervention details, including HM name, formulation, composition, modifications, manufacturer, and dosage; (4) comparator details, including the name and dosage of antidepressant medications; (5) antipsychotic medication details, including name and dosage in both groups; (6) outcomes, including all predefined primary and secondary outcomes; (7) results, including means and standard deviations for continuous outcomes, number of events for dichotomous outcomes, and sample sizes for all outcomes; and (8) other relevant information, including funding sources and conflicts of interest. Discrepancies in extracted data were resolved via discussion between the two reviewers or, if required, by consultation with a third reviewer.

5. Risk of bias assessment

Two reviewers independently evaluated the risk of bias for each included study using the revised Cochrane risk-of-bias tool for randomized trials (RoB 2) [14]. The assessment encompassed five domains: (1) bias arising from the randomization process; (2) bias due to deviations from intended interventions; (3) bias due to missing outcome data; (4) bias in outcome measurement; and (5) bias in selection of the reported result. Each domain was judged as “low risk,” “some concerns,” or “high risk” of bias, leading to an overall risk-of-bias determination. As in the previous steps, disagreements between reviewers were resolved via discussion to achieve consensus or, when necessary, through consultation with a third reviewer.

6. Data synthesis

All statistical analyses were performed using Review Manager (RevMan, version 8.20; The Cochrane Collaboration, 2025). For continuous outcomes (e.g., CDSS, HDRS, and PANSS scores), standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated because different rating scales were applied across studies. For dichotomous outcomes (e.g., response rate and adverse event rate), risk ratios (RRs) with 95% CIs were calculated. Statistical heterogeneity among studies was assessed using the Chi-squared test (p < 0.10 considered significant) and quantified with the I² statistic. An I² value of 50% or higher was interpreted as substantial heterogeneity. A random-effects model was applied to all analyses to adjust for anticipated clinical and methodological diversity across trials.

If sufficient data had been available (i.e., more than 10 studies), potential publication bias would have been evaluated through visual inspection of a funnel plot and Egger’s regression test. Subgroup analyses were prespecified according to type of HM, treatment duration, and specific antipsychotic agents, where appropriate.

RESULTS

1. Study selection

The comprehensive search of eight electronic databases and additional sources identified 1,014 records. After removal of 55 duplicates, 959 unique records were screened based on titles and abstracts. Of these, 906 were excluded because they did not meet the eligibility criteria. The remaining 53 reports were sought for retrieval; however, two could not be obtained (conference abstract only, full text unavailable). Consequently, 51 full-text articles were assessed for eligibility. Of these, 44 were excluded for the following reasons: not an RCT (n = 4), absence of diagnostic criteria (n = 5), unclear diagnostic criteria (n = 2), no antidepressant comparison group (n = 12), antidepressant administered in both groups (n = 19), and antipsychotics administered only in the control group (n = 2) (Supplementary Material 3). Ultimately, seven studies [19-25] met all inclusion criteria and were included in both the qualitative synthesis and quantitative meta-analysis. The study selection process is presented in detail in Fig. 1.

Figure 1.

PRISMA flow diagram.

2. Study characteristics

All included studies were RCTs conducted in China and published between 2011 and 2015, comprising a total of 505 participants (treatment group: 254; control group: 251). Sample sizes ranged from 30 to 98 participants, and each trial had a treatment duration of 6 weeks. Participants were diagnosed with post-schizophrenic depression according to CCMD-3 in all but one study [23], which enrolled patients with schizophrenia and comorbid depression. Baseline depression severity was assessed using the HDRS (≥ 17 or 17–28) in six studies [19-22, 24, 25] and the CDSS (≥ 8) in one study [23]. The mean participant age ranged from 29 to 38 years. Five studies [19, 20, 22-24] administered Shugan Jieyu capsules, whereas two studies [21, 25] used herbal decoctions (Jieyu Anshen decoction and Anshen Jieyu decoction). All HM interventions were provided as adjuncts to routine antipsychotic therapy. Control groups received various antidepressants (citalopram, venlafaxine, paroxetine, fluoxetine, or sertraline) in combination with antipsychotics. General psychiatric symptoms were evaluated using the PANSS in three studies and the BPRS in one study. Adverse events were reported in all studies. None of the included trials disclosed funding sources or conflicts of interest (Tables 1, 2).

Table 1.

Characteristics of included studies

Study	Population	Sample size (M/F) & age	Intervention vs. control	Treatment duration	Outcome	Adverse events (n)
Huang 2011 [19]	PSD (CCMD-3); 17 ≤ HAMD ≤ 25	TG: 17/13, 38.2 ± 11.3 yrs; CG: 16/14, 38.2 ± 11.3 yrs	TG: Routine antipsychotics + Shugan Jieyu capsule; CG: Routine antipsychotics + Citalopram 20 mg/d	6 wks	HAMD; BPRS total score; Adverse event; Good response (Depression)	TG: fatigue (2); nausea and vomiting, dry mouth, headache and dizziness, anorexia (1); CG: fatigue (4); nausea and vomiting, dry mouth (3); somnolence, constipation (2)
Liu 2011 [20]	PSD (CCMD-3); HAMD > 17	TG: 18/12, 36.8 ± 10.2 yrs; CG: 16/14, 35.9 ± 10.4 yrs	TG: Routine antipsychotics + Shugan Jieyu capsule; CG: Routine antipsychotics + Venlafaxine SR (initial dose: 75 mg/d, max dose: 150 mg/d)	6 wks	HAMD; PANSS total score; Adverse event; Good response (Depression)	TG: nausea, anorexia (1); CG: insomnia (3); increased blood pressure, nausea (2)
Lei 2013 [21]	PSD (CCMD-3); HAMD ≥ 17	TG: 16/22, 37.2 ± 10.5 yrs; CG: 16/20, 36.9 ± 10.8 yrs	TG: Routine antipsychotics + Jieyu Anshen decoction; CG: Routine antipsychotics + Paroxetine (initial dose: 20 mg/d, max dose: 40 mg/d)	6 wks	HAMD; Adverse event; Good response (Depression)	TG: nausea (1); CG: nausea (3); somnolence (2); diarrhea, headache (1)
Wang 2013 [22]	PSD (CCMD-3); 17 ≤ HAMD ≤ 28	TG: 18/12, 37.0 ± 5.0 yrs; CG: 19/11, 36.8 ± 5.0 yrs	TG: Routine antipsychotics + Shugan Jieyu capsule; CG: Routine antipsychotics + Fluoxetine Hydrochloride 20 mg/d	6 wks	HAMD; Adverse event; Good response (Depression)	TG: nausea and vomiting, somnolence, diarrhea (2); dry mouth, anorexia, dizziness, insomnia, skin symptoms, diaphoresis, headache (1); CG: nausea and vomiting, somnolence (10); diaphoresis, visual disturbance (8); dry mouth, anorexia, dizziness (4); diarrhea (2); insomnia, constipation, headache (1)
Wang 2013 [23]	Schizophrenia (CCMD-3), with depression; CDSS ≥ 8	TG: 36/13, 30.8 ± 8.3 yrs; CG: 34/12, 32.9 ± 9.9 yrs	TG: Aripiprazole 10-20 mg/d (initial dose: 5 mg/day) + Shugan Jieyu capsule; CG: Aripiprazole 10-20 mg/d (initial dose: 5 mg/d) + Fluoxetine 20-40 mg/d (initial dose: 20 mg/d)	6 wks	CDSS; PANSS total score; Adverse event; Good response (Depression + Schizophrenia)	TG: akathisia (9); dystonia (7); dry mouth (6); nausea (5); visual disturbance (4); constipation tachycardia (3); headache, tremor, liver function impairment (2); insomnia, somnolence, dizziness, anorexia, nasal congestion, diaphoresis (1); CG: akathisia (9); insomnia (8); dry mouth (6); dystonia, liver function impairment (5); constipation (4); headache, visual disturbance (3); nausea (2); somnolence, tremor, diaphoresis, bradycardia, dyskinesia (1)
Wei 2014 [24]	PSD (CCMD-3); HAMD > 18; PANSS < 45	TG: 15/15, 29.4 ± 8.0 yrs; CG: 16/14, 29.5 ± 9.7 yrs	TG: Routine antipsychotics + Shugan Jieyu capsule; CG: Routine antipsychotics + Sertraline 50-100 mg/d	6 wks	HAMD; PANSS total score; Adverse event Good response (Depression)	TG: nausea and vomiting (4); anorexia, visual disturbance (2); dry mouth, dizziness and headache, insomnia, diarrhea (1), CG: dry mouth, dizziness and headache (4); anorexia (3); nausea and vomiting, insomnia, tremor, diarrhea (2)
Hu 2015 [25]	PSD (CCMD-3); HAMD ≥ 17	TG: 20/28, 37.6 ± 9.5 yrs; CG: 21/27, 36.3 ± 10.2 yrs	TG: Routine antipsychotics + Anshen Jieye decoction; CG: Routine antipsychotics + Paroxetine (initial dose: 20 mg/d, max dose: 40 mg/d)	6 wks	HAMD; Adverse event; Good response (Depression)	TG: nausea (2); CG: anorexia (5); dizziness, somnolence (2); vomiting (1)

BPRS, Brief Psychiatric Rating Scale; CCMD-3, Chinese Classification of Mental Disorders, Third Edition; CDSS, Calgary Depression Scale for Schizophrenia; CG, control group; HAMD, Hamilton Depression Rating Scale; M/F, male/female; mg/d, milligrams per day; PANSS, Positive and Negative Syndrome Scale; PSD, post-schizophrenic depression; SR, sustained release; TG, treatment group; wks, weeks; yrs, years.

Table 2.

Characteristics of Chinese herbal medicine interventions

Study	Preparation name	Formulation	Main composition	Modification	Daily dose (administration frequency)
Huang 2011 [19]	Shugan Jieyu capsule	Capsule	Hypericum Perforatum 1.8 g, Eleutherococcus Senticosus 1.5 g (per 1 C)	No conditional modification	2 C/d (bid)
Liu 2011 [20]	Shugan Jieyu capsule	Capsule	Hypericum Perforatum 1.8 g, Eleutherococcus Senticosus 1.5 g (per 1 C)	No conditional modification	2 C/d (bid)
Lei 2013 [21]	Jieye Anshen decoction	Decoction	Fossilia Ossis Mastodi, Ostreae Concha 30 g, Zizyphi Spinosae Semen 15 g, Acori Graminei Rhizoma, Liriopes Radix, Cyperi Rhizoma, Citri Rubrum Exocarpium, Biotae Semen 12 g, Curcumae Radix, Gardeniae Fructus, Fritillariae Cirrhosae Bulbus, Arisaematis Rhizoma, Polygalae Radix, Phyllostachydis Folium 10 g, Nelumbinis Plumula, Aucklandiae Radix 6 g (per day)	No conditional modification	(bid)
Wang 2013 [22]	Shugan Jieyu capsule	Capsule	Hypericum Perforatum 1.8 g, Eleutherococcus Senticosus 1.5 g (per 1 C)	No conditional modification	2 C/d (bid)
Wang 2013 [23]	Shugan Jieyu capsule	Capsule	Hypericum Perforatum 1.8 g, Eleutherococcus Senticosus 1.5 g (per 1 C)	No conditional modification	initial dose: 4 C/d (NR)
Wei 2014 [24]	Shugan Jieyu capsule	Capsule	Hypericum Perforatum 1.8 g, Eleutherococcus Senticosus 1.5 g (per 1 C)	No conditional modification	2 C/d (bid)
Hu 2015 [25]	Anshen Jieye decoction	Decoction	Fossilia Ossis Mastodi 30 g, Zizyphi Spinosae Semen 15 g, Bupleuri Radix 12 g, Curcumae Radix, Liriopes Radix, Cyperi Rhizoma, Aurantii Immaturus Fructus 12 g, Gardeniae Fructus, Fritillariae Cirrhosae Bulbus, Polygalae Radix, Arisaematis Rhizoma, Lophatheri Herba 10 g, Aristolochiae Radix 6 g, Nelumbinis Semen 5 g (per day)	No conditional modification	(bid)

bid, twice daily; C, capsule; NR, not reported.

3. Risk of bias assessment

The risk of bias for each outcome in the included studies was evaluated using the Cochrane RoB 2 tool (Table 3). All primary and secondary outcomes across the seven studies were judged to present “some concerns” regarding overall risk of bias. For the primary outcome of depressive symptoms (measured using the CDSS or HDRS), several factors contributed to this judgment. A major concern across all studies was bias in outcome measurement (Domain 4). Given the subjective nature of these depression scales, the absence of confirmed outcome assessor blinding introduced a substantial risk of detection bias. Additional concerns arose from the randomization process (Domain 1), given that no study reported details of allocation concealment, and from selection of the reported result (Domain 5), due to the lack of preregistered trial protocols. The secondary outcomes, including general psychiatric symptoms (PANSS, BPRS) and overall incidence of adverse events, were similarly judged to have “some concerns.” The assessment of PANSS and BPRS scores followed the same rationale as for the primary outcome—these subjective measures are also vulnerable to detection bias. For adverse events, absence of blinding may have introduced performance and reporting bias because knowledge of treatment allocation could have influenced the reporting and documentation of adverse events. In contrast, risk of bias due to missing outcome data (Domain 3) was consistently judged as “low” across outcomes; attrition was generally minimal and appropriately addressed (Supplementary Material 4).

Table 3.

Risk of bias assessment for included studies

Study	Outcome	Domain 1	Domain 2	Domain 3	Domain 4	Domain 5	Overall bias
Huang 2011 [19]	HAMD	Some concerns	Low risk	Low risk	Some concerns	Some concerns	Some concerns
	BPRS total score	Some concerns	Low risk	Low risk	Some concerns	Some concerns	Some concerns
	Adverse event	Some concerns	Low risk	Low risk	Some concerns	Some concerns	Some concerns
Liu 2011 [20]	HAMD	Some concerns	Low risk	Low risk	Some concerns	Some concerns	Some concerns
	PANSS total score	Some concerns	Low risk	Low risk	Some concerns	Some concerns	Some concerns
	Adverse event	Some concerns	Low risk	Low risk	Some concerns	Some concerns	Some concerns
Lei 2013 [21]	HAMD	Some concerns	Low risk	Low risk	Some concerns	Some concerns	Some concerns
	Adverse event	Some concerns	Low risk	Low risk	Some concerns	Some concerns	Some concerns
Wang 2013 [22]	HAMD	Some concerns	Low risk	Low risk	Some concerns	Some concerns	Some concerns
	Adverse event	Some concerns	Low risk	Low risk	Some concerns	Some concerns	Some concerns
Wang 2013 [23]	CDSS	Some concerns	Some concerns	Low risk	Some concerns	Some concerns	Some concerns
	PANSS total score	Some concerns	Some concerns	Low risk	Some concerns	Some concerns	Some concerns
	Adverse event	Some concerns	Some concerns	Low risk	Some concerns	Some concerns	Some concerns
Wei 2014 [24]	HAMD	Some concerns	Low risk	Low risk	Some concerns	Some concerns	Some concerns
	PANSS total score	Some concerns	Low risk	Low risk	Some concerns	Some concerns	Some concerns
	Adverse event	Some concerns	Low risk	Low risk	Some concerns	Some concerns	Some concerns
Hu 2015 [25]	HAMD	Some concerns	Low risk	Low risk	Some concerns	Some concerns	Some concerns
	Adverse event	Some concerns	Low risk	Low risk	Some concerns	Some concerns	Some concerns

Domain 1: bias arising from the randomization process; Domain 2: bias due to deviations from intended interventions; Domain 3: bias due to missing outcome data; Domain 4: bias in outcome measurement; Domain 5: bias in selection of the reported result.

BPRS, Brief Psychiatric Rating Scale; CDSS, Calgary Depression Scale for Schizophrenia; HAMD, Hamilton Depression Rating Scale; PANSS, Positive and Negative Syndrome Scale.

4. Effects of interventions

1) Primary outcome: depressive symptoms

Seven studies [19-25] (505 participants) reported depressive symptom scores measured using the CDSS or HDRS. The pooled analysis demonstrated no statistically significant difference between HM and antidepressants as adjuncts to antipsychotics (SMD −0.19, 95% CI [−0.54, 0.15], p = 0.27). Substantial heterogeneity was identified among studies (I² = 60%, p = 0.02) (Fig. 2A). Six studies [19-22, 24, 25] (410 participants) reported response rates, defined as ≥ 50% improvement from baseline on depression scales. Meta-analysis indicated no significant difference between groups (RR 1.00, 95% CI [0.96, 1.04], p = 0.89), and no heterogeneity was observed (I² = 0%, p = 1.00) (Fig. 2B).

Figure 2.

Meta-analysis of depressive outcomes: (A) CDSS or HDRS scores; (B) Response rate. Response rate was defined as ≥ 50% improvement from baseline CDSS or HDRS scores. CDSS, Calgary Depression Scale for Schizophrenia; HDRS, Hamilton Depression Rating Scale.

2) Secondary outcomes

Three studies [19, 23, 24] (215 participants) evaluated general psychiatric symptoms using the PANSS or BPRS. The pooled analysis showed no significant difference between HM and antidepressants (SMD −0.06, 95% CI [−0.84, 0.73], p = 0.79). Heterogeneity was not substantial (I² = 46%, p = 0.16) (Fig. 3A). Two studies [19, 24] (215 participants) reported overall incidence of adverse events. The pooled RR was 0.56 (95% CI [0.06, 5.26], p = 0.19), indicating no significant difference between groups; there was no evidence of heterogeneity (I² = 0%, p = 0.43) (Fig. 3B). Common adverse events reported in both groups included gastrointestinal symptoms (nausea, vomiting, dry mouth), neurologic symptoms (somnolence, dizziness, headache), and other symptoms such as insomnia and akathisia (Table 1).

Figure 3.

Meta-analysis of secondary outcomes: (A) PANSS or BPRS scores; (B) Adverse event rate. BPRS, Brief Psychiatric Rating Scale; PANSS, Positive and Negative Syndrome Scale.

5. Subgroup analyses

The prespecified subgroup analyses based on type of HM, treatment duration, and specific antipsychotic agents were not performed due to insufficient data and the small number of included studies.

6. Publication bias

Assessment of publication bias using funnel plots and Egger’s regression test was not conducted because fewer than 10 studies were included in each meta-analysis.

7. Certainty of evidence

The certainty of evidence for depressive symptoms (CDSS or HDRS scores) was rated as very low. This rating was downgraded because of risk of bias (all studies were judged to have some concerns), inconsistency (substantial heterogeneity, I² = 60%), and imprecision (the CI included the null effect). The certainty of evidence for response rate was rated as low, downgraded for risk of bias and imprecision (total number of events < 300).

For secondary outcomes, the certainty of evidence for general psychiatric symptoms (PANSS or BPRS scores) was rated as low, downgraded due to risk of bias and imprecision (the CI encompassed both potential benefit and harm). The certainty of evidence for adverse event rates was also rated as low, downgraded for risk of bias and serious imprecision (small sample size, < 400 participants, and a very wide CI crossing the line of no effect) (Table 4).

Table 4.

Summary of findings

Outcome	Importance	Total patients (studies)	Certainty of the evidence (GRADE)	Relative effect (95% CI)	Anticipated absolute effects (95% CI)
					Control group	Intervention group
Depressive symptoms (CDSS or HDRS)	Critical	505 (7 RCTs)	⊕◯◯◯ Very Lowa,b,c	-	-	SMD 0.19 lower (–0.54, 0.15)
Response rate (number of participants with a 50% or greater improvement in CDSS or HDRS)	Important	120 (2 RCTs)	⊕⊕◯◯ Lowa,d	RR 1.00 (0.96, 1.04)	696 per 1,000	696 per 1,000 (668, 724)
Schizophrenia symptoms (PANSS or BPRS)	Important	410 (6 RCTs)	⊕⊕◯◯ Lowa,d	-	-	SMD 0.06 lower (–0.84, 0.73)
Adverse event rate	Important	215 (3 RCTs)	⊕⊕◯◯ Lowa,e	RR 0.56 (0.06, 5.26)	550 per 1,000	308 per 1,000 (33, 1,000)

aOverall risk of bias in most studies was assessed as “some concerns.” bResults were inconsistent across studies. cFor continuous outcomes, the confidence interval of the effect estimate included 0. dFor dichotomous outcomes, the total number of events was less than 300, and the confidence interval of the effect estimate included 1. eFor continuous outcomes, the total number of patients was less than 400, and the confidence interval of the effect estimate included 1.

BPRS, Brief Psychiatric Rating Scale; CDSS, Calgary Depression Scale for Schizophrenia; CI, confidence interval; GRADE, Grading of Recommendations Assessment, Development and Evaluation; HDRS, Hamilton Depression Rating Scale; PANSS, Positive and Negative Syndrome Scale; RCT, randomized controlled trial; RR, risk ratio; SMD, standardized mean difference.

DISCUSSION

This systematic review evaluated the comparative effectiveness and safety of HM versus antidepressants, each administered as an adjunct to antipsychotic therapy, for the management of depressive symptoms in patients with SSDs. Findings from seven RCTs involving 505 participants indicated no statistically significant difference between the two approaches in reducing depressive symptoms, improving response rates, or alleviating general psychiatric symptoms. However, the certainty of evidence was rated as very low for depressive symptoms and low for other outcomes according to GRADE assessments, primarily due to methodological limitations and imprecision of effect estimates. Although formal equivalence cannot be concluded, the results suggest that HM can serve as an alternative to antidepressants for adjunctive treatment in this population. Caution is needed concerning this interpretation, given the limited quality of available evidence.

Analysis of the primary outcome demonstrated no significant difference in depressive symptom scores between HM and antidepressants (SMD −0.19, 95% CI [−0.54, 0.15]; very low-certainty evidence). Although substantial heterogeneity was observed (I² = 60%), the CI indicated that any true difference, if present, is likely to be small. Similarly, analysis of response rates, which included six studies with 410 participants, showed comparable outcomes between groups (RR 1.00, 95% CI [0.96, 1.04]; low-certainty evidence), without evidence of heterogeneity. For general psychiatric symptoms, three studies demonstrated no significant difference (SMD −0.06, 95% CI [−0.84, 0.73]; low-certainty evidence). Considered in conjunction with our previous meta-analysis, which indicated that HM as an adjunct to antipsychotics was superior to antipsychotics alone [10], these findings suggest that both HM and antidepressants can function as effective adjunctive options for patients with SSDs and comorbid depression. Nevertheless, the low to very low certainty of evidence limits confidence in these conclusions and underscores the need for high-quality trials.

The comparable effectiveness observed between HM and antidepressants may be explained by overlapping yet distinct mechanisms of action. Antidepressants primarily act on monoaminergic neurotransmission, particularly through inhibition of serotonin and norepinephrine reuptake [26]. In contrast, HM exerts multi-target and multi-pathway effects [7-10]. For instance, Hypericum perforatum (St. John’s Wort), the principal component of the Shugan Jieyu capsule used in five included studies, has been shown to modulate multiple neurotransmitter systems, including serotonin, norepinephrine, and dopamine [27], while also exerting anti-inflammatory and neuroprotective effects [28]. HM formulations used in the remaining studies comprised multiple herbal components that might synergistically regulate the HPA axis, modulate inflammatory cytokines, and influence gut–brain axis signaling [6, 12, 13]. These complementary mechanisms may produce antidepressant effects comparable to those of conventional pharmacotherapy while potentially resulting in a different adverse event profile.

Regarding safety, our meta-analysis of adverse events, based on two studies reporting quantitative data (215 participants), showed a trend toward lower adverse event rates in the HM group (RR 0.56, 95% CI [0.06, 5.26]; low-certainty evidence). However, this difference was not statistically significant, and the CI was wide. Descriptive data from all seven studies revealed a consistent pattern. Frequently reported adverse events in antidepressant groups included gastrointestinal symptoms (nausea, vomiting, dry mouth), neurologic symptoms (somnolence, dizziness, headache, tremor), and other effects such as insomnia, constipation, and visual disturbances. Similar symptoms were reported in HM groups, although the frequency appeared generally lower. For example, in the study by Wang and Ye [22], the fluoxetine group reported substantially higher rates of nausea and vomiting (n = 10) and visual disturbances (n = 8) compared with the HM group (n = 2 and n = 0, respectively). This pattern was observed in multiple studies, suggesting that HM has a more favorable safety profile. Nevertheless, definitive conclusions require larger trials with standardized adverse event assessment and reporting.

Several important limitations of this review should be acknowledged. First, all included studies were judged to have “some concerns” regarding overall risk of bias, mainly due to inadequate reporting of randomization procedures, absence of outcome assessor blinding, and lack of preregistered protocols. These methodological shortcomings may have introduced bias and reduced confidence in the findings. Second, substantial heterogeneity was observed for the primary outcome (I² = 60%), which could not be adequately explored because the limited number of studies precluded subgroup analyses. Planned subgroup analyses based on HM type, treatment duration, and specific antipsychotic agents were not conducted, preventing identification of potential sources of heterogeneity or effect modifiers. Third, imprecision was evident across outcomes; wide CIs encompassed potential benefit, harm, or no effect, thereby limiting definitive interpretation. Fourth, publication bias could not be evaluated because fewer than 10 studies were included in each meta-analysis, implying overestimation of treatment effects. Fifth, all studies were conducted in China and published in Chinese-language journals, which may restrict generalizability to other populations and health care settings. Sixth, treatment duration in all trials was limited to 6 weeks, which may be insufficient to assess long-term effectiveness and safety in a chronic condition such as schizophrenia with comorbid depression. Finally, only two studies provided quantitative adverse event data suitable for meta-analysis, limiting firm conclusions about comparative safety.

Despite these limitations, this review offers the first systematic synthesis of evidence directly comparing HM with antidepressants as adjunctive treatments for depression in SSDs. Given the very low to low certainty of the evidence, the findings should be interpreted cautiously and considered preliminary. The results suggest that HM can serve as an alternative for clinicians and patients who seek adjunctive options beyond conventional antidepressants; however, these findings should be regarded as hypothesis-generating rather than definitive guidance for clinical practice.

Future research should prioritize well-designed, adequately powered RCTs with extended follow-up, rigorous blinding procedures, preregistered protocols, and standardized outcome measures to address current evidence gaps and enhance certainty of findings. Studies conducted across diverse geographic and cultural settings are required to evaluate generalizability. Additionally, formal equivalence or noninferiority trials specifically designed to determine whether HM is comparable to antidepressants would yield more definitive evidence. Mechanistic investigations that examine the biological pathways through which HMs exert their effects, as well as potential herb–drug interactions, would further clarify their therapeutic role and inform clinical application. Comprehensive safety monitoring with standardized adverse event reporting is essential to define the risk–benefit profile of HM in this vulnerable population.

CONCLUSION

This systematic review provides the first direct comparison of HM and antidepressants as adjunctive treatments for depression in patients with SSDs. The findings indicated no significant difference between the two interventions in improving depressive symptoms, response rates, or general psychiatric symptoms, with a possible trend toward fewer adverse events in the HM group. However, the certainty of evidence ranged from very low to low due to methodological limitations, imprecision, and inconsistency across studies. Although these preliminary findings suggest that HM can serve as an adjunctive option for this vulnerable population, they should be interpreted cautiously and cannot support definitive clinical recommendations. Well-designed, large-scale RCTs with rigorous methodology, longer follow-up, inclusion of diverse populations, and comprehensive safety assessment are urgently required to establish the comparative effectiveness and safety of HM in this context.

SUPPLEMENTARY MATERIALS

Supplementary data is available at https://doi.org/10.3831/KPI.2026.29.1.21.