0% READ
FULL TEXT
INTRODUCTION
Clinical context and therapeutic challenges in schizophrenia
Schizophrenia is a highly disabling psychiatric disorder with a global prevalence of approximately 1%, typically emerging in late adolescence or early adulthood (Jauhar et al., 2022; Jongsma et al., 2019). Its clinical heterogeneity encompasses three major symptom clusters: positive symptoms (hallucinations, delusions, thought disorder), negative symptoms (blunted affect, anhedonia, avolition, social withdrawal), and cognitive deficits (impaired attention, working memory, executive function, and slowed information processing) (Ardizzi et al., 2016; Insel, 2010; Panov & Panova, 2023). The disease often follows a relapsing–remitting course that culminates in chronic disability, loss of social and occupational functioning, reduced life expectancy, and severe burdens on caregivers and healthcare systems (Cai et al., 2024; Simek et al., 2025).
Pharmacological management, although improved over decades, faces substantial limitations. First-generation antipsychotics (dopamine D₂ receptor antagonists) and second-generation agents (dopamine–serotonin modulators) demonstrate efficacy primarily in positive symptoms but exert little benefit on negative or cognitive dimensions (Angeli et al., 2025; Cheng et al., 2024). Moreover, first-generation drugs frequently induce extrapyramidal symptoms (e.g., tremor, rigidity), whereas second-generation agents predispose patients to metabolic syndrome (weight gain, dyslipidemia, glucose intolerance), cardiovascular risks, and sedation. These adverse effects significantly compromise treatment adherence and long-term quality of life. Treatment resistance, occurring in up to one-third of patients, underscores the urgent demand for adjunctive strategies that combine multi-target regulation with enhanced safety profiles (Desai et al., 2021; Goud et al., 2025).
Emerging research implicates neuroinflammation, immune dysregulation, oxidative stress, and gut microbiome alterations as integral to schizophrenia pathogenesis. These findings highlight the interplay between central and peripheral mechanisms and justify integrative therapeutic paradigms (Soltani et al., 2024). Within, schizophrenia-like disorders are classified as “dian” (predominantly negative symptoms), “kuang” (marked by positive symptoms), or dementia-like syndromes. The core pathogenesis is conceptualized as “phlegm turbidity obstructing the orifices,” with spleen deficiency regarded as the root cause of phlegm accumulation. Accordingly, the principle of “strengthening the spleen, tonifying Qi, and resolving phlegm” represents a rational therapeutic strategy (Dubey & Kumar, 2025).
Si-Jun-Zi Tang (SJZT), a foundational spleen-fortifying and Qi-tonifying prescription, epitomizes this approach (Yuan et al., 2022). Modern studies have revealed its immunomodulatory, neuroprotective, gastrointestinal, and microbiota-regulating properties, providing biological plausibility for its role in schizophrenia management (Tseng & Li, 1996). This review integrates traditional and biomedical perspectives to evaluate SJZT’s therapeutic potential, current evidence, and translational prospects.
Theoretical Basis of SJZT in TCM
SJZT, first recorded in the Tai Ping Hui Min He Ji Ju Fang during the Song dynasty, is the prototypical formula for treating “spleen Qi deficiency.” It consists of four herbs—Panax ginseng (often substituted with Codonopsis pilosula for clinical safety), Atractylodes macrocephala, Poria cocos, and Glycyrrhiza uralensis-arranged according to the sovereign–minister–assistant–ambassador principle. Together, they restore spleen Qi, resolve dampness, harmonize functions, and secure the foundation of health (Ding et al., 2015; Sun et al., 2016).
Building on this formula, derivative prescriptions such as Liu-Jun-Zi Tang (adding Pinellia ternata and Citrus reticulata) and Xiang-Sha Liu-Jun-Zi Tang (further adding Aucklandia lappa and Amomum villosum) have been developed to address complex conditions involving phlegm, dampness, or Qi stagnation. This adaptability underscores SJZT’s status as a core “basic spleen-tonifying formula” (Chiou et al., 2018; Jiang et al., 2023).
Pharmacological studies corroborate its multi-target profile: enhancing T-lymphocyte regulation, reducing pro-inflammatory cytokines (IL-6, TNF-α), inhibiting NF-κB activation, strengthening gastrointestinal mucosal integrity, and modulating energy metabolism (Chen et al., 2020). Additionally, SJZT exerts neuroprotective effects by alleviating oxidative stress and promoting Brain-Derived Neurotrophic Factor (BDNF) expression. Recent findings further reveal its capacity to modulate gut microbiota composition, increase beneficial genera (e.g., Bifidobacterium, Lactobacillus), and maintain intestinal barrier integrity, aligning with the microbiota–gut–brain axis framework (Li et al., 2024). These properties converge with pathophysiological pathways implicated in schizophrenia.
TCM Pathogenesis and Mechanistic Rationale for SJZT in Schizophrenia
From a TCM standpoint, schizophrenia arises from dysfunctions in the heart, spleen, liver, and kidney, leading to imbalances in Qi, blood, yin, and yang. “Spleen deficiency with phlegm obstruction” is regarded as the pivotal mechanism: impaired spleen function fails to transform food into Qi and blood, depriving the heart–mind of nourishment, manifesting as apathy and avolition. Simultaneously, dampness accumulates into phlegm, which clouds the orifices and disturbs mental clarity, giving rise to hallucinations, delusions, and disorganized thought (Shen et al., 2024; Yang et al., 2024).
Patients with spleen-deficiency schizophrenia often present with both psychiatric and somatic features: poor appetite, abdominal distension, loose stools, fatigue, pallor, scalloped tongue, and weak pulse-symptoms consistent with negative syndrome profiles. SJZT addresses this pathogenesis by replenishing spleen Qi, reducing phlegm formation, and harmonizing body–mind interactions (Shi et al., 2021).
Modern evidence supports this rationale: SJZT regulates immune-inflammatory responses, restores gut barrier integrity, mitigates oxidative stress, enhances synaptic plasticity, and modulates neurotransmitter systems (dopamine and glutamate) (Li et al., 2024). These converging mechanisms offer multi-target interventions for schizophrenia’s complex pathology.
Current Evidence on SJZT in Schizophrenia
Clinical Observations
Existing clinical evidence remains preliminary, largely derived from small-scale observational studies and case reports. Findings suggest that adjunctive SJZT may alleviate gastrointestinal discomfort, improve vitality, enhance emotional stability, and modestly reduce negative symptoms such as affective flattening and social withdrawal. Some reports indicate improved treatment adherence when SJZT is combined with antipsychotics, potentially due to reduced gastrointestinal side effects and enhanced tolerability (Hoenders et al., 2014; Pu et al., 2023; Tseng & Li, 1996).
Nevertheless, significant limitations exist: the absence of multicenter RCTs, lack of standardized herbal preparations, heterogeneous diagnostic criteria, and outcome measures restricted to symptom rating scales (e.g., PANSS). Few studies incorporate functional recovery, quality of life, or biological markers, leaving efficacy and safety unverified (Meng-Long et al., 2020; Wang et al., 2020).
Mechanistic Insights
Neurotransmitter regulation: Active constituents such as ginsenosides and polysaccharides modulate glutamatergic transmission (enhancing NMDA receptor activity, stabilizing synaptic plasticity) and may influence dopamine D₂ receptor dynamics, thereby targeting both negative and positive symptoms.
Gut–brain axis modulation: By reshaping microbiota composition, reinforcing intestinal barrier proteins (occludin, ZO-1), and influencing gut hormones (serotonin, cholecystokinin), SJZT indirectly regulates CNS function through immune and vagal pathways (Li et al., 2017).
Research Limitations
Challenges include: (1) insufficient sample sizes and lack of long-term follow-up, (2) poor standardization of herbal preparations, (3) absence of herb–drug interaction studies with antipsychotics, and (4) mechanistic studies limited to single targets, lacking integrative systems-level approaches.
Future Research Directions
Mechanistic and Translational Studies
Future research should integrate
Systems pharmacology and multi-omics (transcriptomics, proteomics, metabolomics, metagenomics) to construct compound–target–pathway networks.
Refined animal models mimicking spleen deficiency and schizophrenia (e.g., high-fat diet plus NMDA antagonist) to assess behavioral, neuropathological, and microbial outcomes. Computational methods such as molecular docking to validate compound–target interactions with D₂, NMDA receptors, and NF-κB.
Personalized and Biomarker-Driven Medicine
Combining TCM syndrome differentiation with objective biomarkers (e.g., gut microbial signatures, inflammatory markers, BDNF polymorphisms) may establish predictive models of treatment response. This integration can guide individualized therapy, optimize SJZT dosing, and enhance precision adjunctive strategies.
Interdisciplinary and Global Collaboration
Collaborations across psychiatry, neuroscience, pharmacology, microbiology, and TCM are critical. International consortia can harmonize protocols, validate efficacy across populations, and accelerate regulatory recognition. Partnerships with industry can facilitate the development of standardized SJZT formulations (e.g., granules, capsules) for clinical translation (Pu et al., 2023).
CONCLUSION
SJZT, rooted in the TCM theory of “spleen deficiency with phlegm obstruction,” aligns with modern insights into schizophrenia’s multisystem pathology. Its multi-target effects-including anti-inflammatory, immunomodulatory, gut–brain axis, and neuroprotective actions-offer a compelling rationale for adjunctive application. Preliminary evidence suggests benefits in alleviating somatic symptoms, improving negative symptoms, and enhancing tolerability of antipsychotics. However, robust clinical trials, standardized preparations, comprehensive mechanistic studies, and biomarker-driven frameworks are urgently needed. Advancing SJZT through integrative research pathways may bridge TCM and modern psychiatry, paving the way for holistic, personalized strategies in schizophrenia management.