Clinical Summary
Clinical Summary: Effects of Experimental Intermittent Theta Burst Stimulation on Negative Symptoms of Schizophrenia: A Double-Blind Sham-Controlled Study
Patients with schizophrenia often remain disabled by negative symptoms even when positive symptoms are controlled, and effective treatment options are limited. This trial asks a practical question for clinicians considering neuromodulation: does left DLPFC iTBS add meaningful benefit for persistent, predominantly negative symptoms beyond sham treatment?
Design
The prospective randomized controlled trial (RCT) was done using computer-generated random numbers.
N
The remaining 141 eligible patients provided informed consent (from both participants and caregivers/relatives) and were randomized by software to active (real iTBS) or sham iTBS groups.
Population
Right-handed patients (18–60 years of age) meeting ICD-10 criteria for schizophrenia with predominant negative symptoms for at least 2 years were included.
Duration
Each iTBS session lasted 5 minutes 50 seconds, delivered 5 days a week for 3 weeks (15 sessions).
Key Findings
- Negative symptoms improved within both groups over time, but active iTBS was not superior to sham: in ITT analysis, the mean difference in symptom change was 0.75 (95% CI: −2.91 to 4.42, P=.68) for the active group and −0.84 (95% CI: −6.76 to 5.07, P=.77) for the sham group.
- Per-protocol results were also negative: differences remained insignificant at postintervention, with −0.04 (95% CI: −3.77 to 3.76, P=.99) for the active group and −0.84 (95% CI: −6.76 to 5.07, P=.77) for the sham group.
- Baseline SANS total scores were similar between groups and remained comparable through 6 months: 73.14 ± 11.97 in the active group versus 72.38 ± 9.95 in the sham group (P=.68), with nonsignificant between-group differences and group×time interactions at all follow-ups.
- Clinically significant improvement counts did not separate active treatment from sham: at treatment completion, 8 participants in the active group and 2 in the sham group improved, and by 6 months, 18 active and 15 sham participants demonstrated significant improvement, with no significant differences at any time point.
- Adverse effects were more frequent with active stimulation: local adverse effects occurred in 17/71 (23.9%) in the active group versus 4/70 (5.7%) in the sham group (P = .02), and fatigue and sleepiness occurred in 6 (8.4%) active participants versus none in the sham group (P = .01).
Clinical Bottom Line
This high-density left DLPFC iTBS protocol did not outperform sham for predominantly negative symptoms of schizophrenia over 6 months. In clinically stable patients with longstanding negative symptoms, iTBS should not be expected to provide meaningful benefit over sham, although it was generally tolerated without serious adverse events such as seizures.
Practice Implications
- Do not offer this iTBS approach as an evidence-based treatment for persistent negative symptoms with the expectation of superiority over sham; discuss the neutral efficacy result up front.
- Counsel patients that active stimulation increased transient tolerability problems, with local adverse effects in 23.9% versus 5.7% and fatigue/sleepiness in 8.4% versus 0%; monitor discomfort, sedation, sleep, and behavioral changes during treatment.
- If neuromodulation is pursued, interpret outcomes cautiously in patients with chronic, treatment-resistant negative symptoms on stable antipsychotics, because patient selection and protocol details may strongly influence response.
- Track concurrent medications and other treatments during follow-up, since ongoing pharmacologic or psychosocial changes can confound interpretation of symptom improvement.
