Interventional Psychiatry

Efficacy of high-frequency transcranial magnetic stimulation to improve negative symptoms in patients with Schizophrenia: A meta-analysis of randomized controlled trials
Hui Chen, Jie Li, Xiaohan Jia, Xinlei Wang, Rongrong Qiao, Gang Yao, Jing Zhong

Abstract:

Negative symptoms in schizophrenia pose a persistent therapeutic challenge, contributing to functional deterioration and poor quality of life. While oral antipsychotics show limited efficacy in these domains, emerging evidence suggests that high-frequency repetitive transcranial magnetic stimulation (hf-rTMS) as a potential neuromodulation intervention for negative symptoms in schizophrenia. To systematically evaluate the therapeutic efficacy of hf-rTMS and define hf-rTMS stimulation parameters associated with the optimal outcomes in improving negative symptoms, we conducted a comprehensive meta-analysis synthesizing data from randomized controlled trials (RCTs) investigating hf-rTMS protocols for patients with schizophrenia. A comprehensive literature retrieval was conducted via the PubMed and ScienceDirect databases from their inception to February 8, 2025. The primary outcome was the change in negative symptoms scores from baseline to post-treatment, as measured by the Positive and Negative Syndrome Scale (PANSS) or the Scale for the Assessment of Negative Symptoms (SANS). Twenty-three RCTs involving 1024 participants (mean [range] age, 39.7 [29.8-54.1] years; mean [range] proportion of female patients, 28.02 % [0 %-70.0 %]) were included. Compared to sham, a pooled effect size of -0.47 [95 % CIs= -0.71 to -0.24] in favor of hf-rTMS strategies that associated with significantly reduced in negative symptoms of schizophrenia. Furthermore, hf-rTMS demonstrated improvement across all symptom dimensions (Hedge's g = -0.30 [95 % CIs= -0.46 to -0.13]). The findings indicate that a protocol applying stimulation at 110 % of the motor threshold over the left dorsolateral prefrontal cortex (DLPFC) for at least 15 sessions was associated with improvement in negative symptoms. Clinical doctors should consider this dose-response association when prescribing hf-rTMS treatment.

Annotation

The finding:

This meta-analysis of 23 randomized controlled trials including 1,024 participants assessed the effectiveness of high-frequency repetitive transcranial magnetic stimulation (hf-rTMS) for negative symptoms in schizophrenia. The combined results indicated that hf-rTMS significantly decreased negative symptom severity compared to sham stimulation, with a moderate effect size (Hedges g = −0.47, 95% CI −0.71 to −0.24). There was also a smaller but meaningful improvement in overall psychopathology scores (PANSS total; g = −0.30). Subgroup analyses revealed that the most effective protocol involved stimulating the left dorsolateral prefrontal cortex (DLPFC) at approximately 110% of the motor threshold for at least 15 sessions. Additionally, patients with a shorter illness duration and lower doses of antipsychotics experienced greater improvements.

Strengths and weaknesses: 

A key strength of this study is that it included only randomized controlled trials, used standardized outcome measures (PANSS and SANS), and followed PRISMA guidelines with formal risk-of-bias assessment, increasing methodological rigor. The meta-analysis also explored treatment parameters (stimulation site, intensity, session number), which provides clinically useful guidance about optimal rTMS protocols.

However, there are several limitations. The included trials were relatively small and heterogeneous, with significant between-study variability in stimulation parameters and patient characteristics. The analysis also relied on study-level rather than patient-level data, limiting the ability to determine which individual patients benefit most. Additionally, long-term outcomes and durability of treatment effects were not well studied, and publication bias was detected.

Relevance: 

These findings are important for C-L psychiatrists because negative symptoms of schizophrenia often persist despite adequate antipsychotic treatment and significantly contribute to functional impairment, especially in medically complex hospitalized patients. hf-rTMS may serve as a non-pharmacologic augmentation strategy for patients with refractory negative symptoms, particularly when medication adjustments are limited by medical comorbidities or side effects. Its favorable safety profile and minimal systemic effects make neuromodulation attractive in medically ill populations commonly seen in C-L settings. While rTMS is usually administered in outpatient psychiatry, awareness of the evidence can assist C-L psychiatrists in identifying suitable referrals and incorporating neuromodulation into multidisciplinary treatment plans.