A new clinical trial is underway to assess the efficacy of deep brain stimulation (DBS) of the hippocampus in patients with treatment-resistant schizophrenia (TRS). The DBS-HITS (Deep Brain Stimulation of Hippocampus in Treatment-resistant Schizophrenia) study, a collaboration between the Shanghai Mental Health Center and Huashan Hospital, Fudan University, employs a crossover, randomized, controlled, double-blinded design to evaluate the impact of hippocampal DBS on psychotic symptoms and cognitive function in individuals who have not responded to conventional treatments. Given the limited success of existing therapies for TRS, this trial could offer a novel approach to managing this debilitating condition.
Study Design and Patient Population
The DBS-HITS trial will enroll six participants diagnosed with schizophrenia according to DSM-V criteria, who have experienced the illness for at least five years with substantial functional impairment. A key inclusion criterion is treatment refractoriness, defined as a lack of response to at least two adequate antipsychotic trials (excluding clozapine) and clozapine resistance, demonstrated by a lack of response to adequate clozapine trials or intolerance to the drug due to severe side effects. Participants must also exhibit persistent prominent positive symptoms, as indicated by specific scores on the Positive and Negative Syndrome Scale for Schizophrenia (PANSS). Exclusion criteria include comorbid psychotic disorders, severe neurological or physical illnesses, substance abuse, pregnancy, and suicide risk.
The study spans 12 months, including pre-operative assessment, DBS surgery, stimulation parameter programming, a crossover phase of DBS on/off, and final follow-up evaluation. After the crossover phase, all participants will continue personalized high-frequency stimulation, with long-term follow-up as needed.
Surgical Procedure and Stimulation Parameters
Participants will undergo stereotactic surgery under general anesthesia to implant bilateral DBS electrodes targeted at the ventral hippocampus (vHipp). The Leksell surgical planning system will be used to fuse preoperative MRI and stereotactic CT images to precisely locate the target brain region. Customized tetrapolar electrodes will be inserted along the trajectory of the vHipp, connected to an implantable pulse generator (IPG) in the subclavicular region.
Following surgery and a period of monitoring, DBS will be switched on, and stimulus parameters will be optimized and individualized over three months. Subsequently, participants will be randomized to either active (DBS-ON) or sham (DBS-OFF) stimulation for three months, followed by a crossover to the other group for another three months. Both participants and evaluators will be blinded to the group assignment.
Outcome Measures and Data Analysis
The primary outcome of the DBS-HITS trial is the between-group and within-group comparison of response rates in PANSS total, PANSS positive, and PANSS negative scores. Secondary outcomes include changes in the Scale for the Assessment of Negative Symptoms (SANS), Clinical Global Impression Scale (CGI), Clinician-Rated Dimensions of Psychosis Symptom severity Scale (CRDPS), Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB), Associative Memory (AM) Task, EEG signals, and neurotransmitter metabolism as measured by PET-CT.
The study also aims to analyze the correlation between EEG signals and neurotransmitter metabolism with clinical and cognitive assessment outcomes, seeking to identify potential biomarkers predictive of DBS treatment response in schizophrenia.
Safety Considerations
The DBS-HITS working group prioritizes participant safety, addressing potential risks related to surgery, hardware, and stimulation. A multidisciplinary team will manage risks through comprehensive informed consent, thorough preoperative examinations, strict adherence to clinical trial and surgical protocols, and a complete adverse event response and reporting system. The study protocol includes provisions for temporary or permanent suspension in the event of serious adverse events (SAEs).
Potential Impact
The DBS-HITS trial represents a significant effort to explore novel therapeutic avenues for treatment-resistant schizophrenia. By targeting the hippocampus, a brain region implicated in both cognitive and emotional processing, DBS may offer a means to alleviate the debilitating symptoms of TRS and improve the quality of life for affected individuals. The results of this study could pave the way for larger-scale trials and, ultimately, a new treatment option for this challenging patient population.
