Deep brain stimulation for clozapine-resistant schizophrenia: a systematic review of target-specific outcomes and stereotactic technical considerations

Treatment-resistant schizophrenia (TRS) affects approximately 20-30% of patients, and a substantial proportion develop clozapine-resistant schizophrenia (CRS). Deep brain stimulation (DBS) has emerged as a potential neurosurgical intervention targeting dysfunctional cortico-striato-limbic circuitry. However, technical heterogeneity and limited clinical data constrain interpretation of outcomes. This systematic review was conducted in accordance with PRISMA guidelines and prospectively registered in PROSPERO (CRD420251080715). Seven electronic databases were searched from inception through January 31, 2025. Clinical studies investigating DBS in TRS or CRS were included. Methodological quality was assessed using Joanna Briggs Institute (JBI) tools. Data extraction emphasized stereotactic targeting methods, hardware configurations, stimulation parameters, and clinical outcomes. The total number of study is 6. We excluded paper by Manssuer 2023. The total study population comprises 21 patients. Seven studies involving 21 patients met inclusion criteria. Targets included the nucleus accumbens (NAcc; n = 11), substantia nigra (SNr; n = 1), habenula (HB; n = 2), subgenual cingulate (SCG; n = 4), subgenual anterior cingulate cortex (sgACC; n = 3). Reported PANSS total score changes ranged widely (11%-85.7%), reflecting substantial inter-individual variability and methodological limitations. Surgical complications occurred in 3 of 21 patients (14.2%), including infection and hemorrhage. All cases utilized open-loop stimulation and conventional cylindrical leads. Current evidence suggests a preliminary therapeutic signal for DBS in highly selected CRS patients, particularly with NAcc targeting. However, conclusions remain limited by small sample sizes, technical heterogeneity, and absence of controlled trials. Future investigations should prioritize standardized stereotactic reporting, volumetric lead reconstruction, and long-term safety assessment within specialized neurosurgical research settings. PROSPERO CRD420251080715.