Several Noninvasive Brain Stimulation Modalities Show Benefit for Treatment-Resistant Schizophrenia
Key Clinical Summary
- A large network meta-analysis found specific noninvasive brain stimulation (NIBS) modalities improved symptoms in treatment-resistant schizophrenia (TRS).
- Low-frequency repetitive transcranial magnetic stimulation targeting the left temporoparietal junction showed consistent benefit for auditory hallucinations.
- Several neuronavigated theta burst stimulation approaches improved negative and overall symptoms with acceptable tolerability.
Treatment-resistant schizophrenia (TRS) affects roughly one-third of patients with schizophrenia and remains a major therapeutic challenge. In a comprehensive systematic review and network meta-analysis published in Neuroscience & Biobehavioral Reviews, researchers evaluated the comparative efficacy of multiple noninvasive brain stimulation (NIBS) modalities for persistent symptoms in TRS. The study found that low-frequency repetitive transcranial magnetic stimulation targeting the left temporoparietal junction demonstrated consistent benefit for auditory hallucinations, while several neuronavigated theta burst stimulation approaches improved negative and overall symptoms.
Study Findings
The systematic review and network meta-analysis comprised 55 randomized trials encompassing 33 distinct NIBS modalities and 1981 patients with TRS. Included studies compared NIBS interventions with sham stimulation or other active treatments.
Primary outcomes included changes in positive symptoms, auditory hallucinations, negative symptoms, and overall symptom severity. Effects were calculated using standardized mean differences (SMDs) within a frequentist random-effects framework. Subgroup and sensitivity analyses were also performed.
The analysis found that low-frequency repetitive transcranial magnetic stimulation over the left temporoparietal junction (LF-rTMS-LTPJ) and neuronavigated continuous theta burst stimulation targeting the left temporoparietal cortex (cTBS-LTPC) significantly improved positive symptoms and auditory hallucinations compared with sham stimulation. LF-rTMS-LTPJ demonstrated a particularly robust effect on auditory hallucinations, with an SMD of −0.784 (95% CI, −1.202 to −0.366).
For negative and overall symptoms, multiple NIBS approaches showed significant benefit. Neuronavigated cTBS-LTPC and neuronavigated intermittent theta burst stimulation targeting the left dorsolateral prefrontal cortex ranked higher than other modalities in comparative efficacy analyses. All interventions were considered acceptable in terms of tolerability.
The authors reported no evidence of publication bias or statistical inconsistency. However, heterogeneity was high for outcomes related to positive symptoms and auditory hallucinations, and confidence in the evidence for these domains was rated as low.
Clinical Implications
These findings are clinically relevant for psychiatric clinicians managing patients with TRS who have persistent symptoms despite adequate antipsychotic trials. Auditory hallucinations are often refractory to pharmacologic strategies and may contribute substantially to disability and relapse risk. The consistent efficacy of LF-rTMS-LTPJ suggests this modality may be considered as an alternative treatment option in appropriate patients.
The broader benefits observed with neuronavigated theta burst stimulation approaches also highlight the potential importance of individualized targeting and stimulation parameters.
Expert Commentary
“The differential efficacy of NIBS modalities across stimulation protocols, symptom domains, and subgroups further highlights the need for personalized approaches for different groups of patients and outcomes,” wrote Harry Kam Hung Tsui, Department of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region of China, and study coauthors.
While the authors acknowledge that the analysis was limited by its small number of included studies, they concluded that the “results of the current study could guide the development of large-scale clinical trials investigating personalized NIBS approaches across symptom dimensions for patients with TRS.”
