间歇性θ爆发刺激治疗精神分裂症持续性阴性症状的效果及其与外周血炎症指标变化的关系

Efficacy of intermittent theta burst stimulation therapy in treating persistent negative symptoms of schizophrenia and its relationship with changes in peripheral blood inflammatory markers

中文关键词:  精神分裂症  持续性阴性症状  间歇性θ爆发刺激  炎症

英文关键词:Schizophrenia  Persistent negative symptoms  Intermittent theta burst stimulation  Inflammation

中文摘要:

      背景 精神分裂症阴性症状给社会带来了沉重负担，且现有抗精神病药物对此类症状的疗效有限。间歇性θ爆发刺激（iTBS）作为一种新型神经调控技术，具有一定的治疗前景，但iTBS对精神分裂症阴性症状的疗效证据及其与相关免疫炎症指标变化之间的关系，有待进一步阐明。目的 探讨靶向左侧背外侧前额叶皮层（L-DLPFC）的iTBS对精神分裂症持续性阴性症状的疗效，并分析其与外周血炎症指标变化的关系，以期为iTBS治疗精神分裂症持续性阴性症状提供参考，并为其潜在生物学机制的进一步研究提供线索。方法 采用随机、双盲、伪刺激对照临床试验，连续纳入2024年2月20日—2025年5月10日在徐州市东方人民医院住院治疗、符合《精神障碍诊断与统计手册（第5版）》（DSM-5）精神分裂症诊断标准的患者共60例，均符合持续性阴性症状判定标准。采用随机数字表法分为研究组和对照组各30例，两组分别接受为期4周、共20次的iTBS和伪刺激干预。于基线期、治疗结束时以及治疗后3个月，采用阳性和阴性症状量表（PANSS）评定临床症状。于基线期及治疗结束时，检测外周血炎症指标，包括白细胞计数、血小板计数、中性粒细胞计数、淋巴细胞计数和单核细胞计数，并计算中性粒细胞与淋巴细胞比值（NLR）、单核细胞与淋巴细胞比值（MLR）以及血小板与淋巴细胞比值（PLR）。采用线性混合模型分析比较两组PANSS评分。以体质量指数（BMI）和氯丙嗪当量为控制变量，采用Spearman秩相关分析考查治疗结束时炎症指标降低值与PANSS阴性症状分量表评分减分值之间的相关性。结果 ①PANSS阴性症状分量表评分的时间与组别的交互效应有统计学意义（F=5.410，P<0.01），治疗结束时及治疗后3个月，研究组PANSS阴性症状分量表评分均低于对照组（P均<0.01）。②治疗结束时，两组中性粒细胞计数、NLR、PLR的降低值比较，差异均有统计学意义（Z=-2.262、-2.048、-2.070，P均<0.05），但经FDR校正后，两组外周血炎症指标的降低值比较，差异均无统计学意义（P均>0.05）。③控制BMI和氯丙嗪当量后，研究组PANSS阴性症状评分减分值与中性粒细胞计数降低值呈正相关（r_s=0.382，P=0.045）。结论 靶向L-DLPFC的iTBS可能有助于改善精神分裂症持续性阴性症状，其临床疗效可能与中性粒细胞计数的变化相关。

英文摘要:

      Background Negative symptoms of schizophrenia impose a substantial burden on society， and the current antipsychotic drugs have limited efficacy in treating these symptoms. Intermittent theta burst stimulation （iTBS）， as a novel neuromodulation technique， shows potential therapeutic promise. However， the evidence for its efficacy in treating negative symptoms of schizophrenia and its relationship with associated immuno-inflammatory changes remain to be further elucidated.Objective To investigate the efficacy of iTBS targeting the left dorsolateral prefrontal cortex （L-DLPFC） on persistent negative symptoms of schizophrenia， and to analyze its relationship with changes in peripheral blood inflammatory markers， so as to provide references for the clinical application of iTBS in treating persistent negative symptoms and to offer clues for further research into its potential biological mechanisms.Methods A randomized， double-blind， sham-controlled clinical trial was conducted. A total of 60 patients with schizophrenia who were hospitalized at Xuzhou Oriental Peopple's Hospital from February 20， 2024 to May 10， 2025 were consecutively enrolled. All patients met the diagnostic criteria for schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders， fifth edition （DSM-5） and fulfilled the criteria for persistent negative symptoms. Participants were randomly assigned into the study group and the control group， with 30 patients in each group. The two groups respectively received 20 sessions of either active iTBS or sham stimulation over a 4-week period. Clinical symptoms were assessed using the Positive and Negative Syndrome Scale （PANSS） at the baseline， the end of treatment， and 3 months after treatment. Peripheral blood inflammatory markers were measured at the baseline and at the end of treatment， including white blood cell count， platelet count， neutrophil count， lymphocyte count， and monocyte count， the neutrophil-to-lymphocyte ratio （NLR）， monocyte-to-lymphocyte ratio （MLR）， and platelet-to-lymphocyte ratio （PLR） were also calculated. A linear mixed model was used to compare PANSS scores between the two groups. Spearman correlation analysis was performed to examine the association between reductions in inflammatory markers at the end of treatment and reductions in PANSS negative symptom subscale scores， with body mass index （BMI） and chlorpromazine-equivalent dose as covariates.Results ①The time-group interaction effect for the PANSS negative symptom subscale score was statistically significant （F=5.410， P<0.01）. At the end of treatment and 3 months after treatment， the study group had significantly lower scores on the PANSS negative symptom subscale than the control group （P<0.01）. ② At the end of treatment， group differences in reduction scores for neutrophil count， NLR， and PLR were significant （Z=-2.262， -2.048， -2.070， P<0.05）. However， after FDR correction， the between-group differences in reductions in peripheral blood inflammatory markers were no longer statistically significant （P>0.05）. ③ After adjusting for BMI and chlorpromazine equivalents， the reduction in PANSS negative symptom subscale scores was positively correlated with the reduction in neutrophil count in the study group （r_s=0.382， P=0.045）.Conclusion iTBS targeting the L-DLPFC may be beneficial in improving persistent negative symptoms of schizophrenia， and its clinical efficacy may be associated with changes in neutrophil count. ［Funded by National Natural Science Foundation of China （number， 82371510）； Social Development Project of Jiangsu Province （number， BE2023668）. www.chictr.org.cn number， ChiCTR2500101060］