Frequently Asked Questions

No. In this double-blind sham-controlled trial, active left DLPFC iTBS did not show superior benefit over sham for negative symptoms of schizophrenia. In intention-to-treat analysis, the between-group difference in symptom change was 0.75 (95% CI, -2.91 to 4.42; P=.68), and in per-protocol analysis it was -0.04 (95% CI, -3.77 to 3.76; P=.99), indicating no significant advantage for active treatment.

Both groups improved significantly over time on the SANS, but between-group differences and group×time interactions remained nonsignificant through 6 months of follow-up.

The study enrolled clinically stable adults with schizophrenia who had longstanding predominant negative symptoms. Eligible participants were right-handed, 18 to 60 years old, met ICD-10 criteria for schizophrenia, had predominant negative symptoms for at least 2 years, had SANS scores of at least 60 and SAPS scores of 50 or lower, and had been on unchanged antipsychotic treatment for at least 4 weeks.

Patients with comorbid depressive disorder, bipolar affective disorder, substance abuse or dependence within the past year other than nicotine or caffeine, Axis II personality disorders interfering with adherence, standard TMS contraindications, or known or suspected pregnancy were excluded.

The active intervention was a novel high-density iTBS protocol applied to the left dorsolateral prefrontal cortex at 100% of each patient's motor threshold. Each session delivered 720 pulses in 8 trains of 90 pulses, lasted 5 minutes 52 seconds, and was given 5 days per week for 3 weeks, for a total of 15 sessions.

The stimulation site was localized 5.5 cm anterior and 0.5 cm lateral to the motor cortex. Sham treatment used a sham coil, and patients in both groups continued their prescribed antipsychotic medications.

A total of 141 eligible patients were randomized: 71 to active iTBS and 70 to sham. Fourteen patients dropped out before completing treatment, leaving 127 completers: 66 in the active group and 61 in the sham group.

Postintervention assessment after 15 sessions was completed by 69 of 71 patients in the active group and 65 of 70 in the sham group. At 6 months, 59 patients in the active group and 57 in the sham group remained in follow-up.

No. Baseline SANS domain scores for affective flattening, alogia, avolition-apathy, anhedonia, attention, and the overall mean score were similar between groups, and this pattern remained unchanged after treatment and throughout 6 months of follow-up.

Both groups showed significant within-group declines over time, but there were no significant between-group differences or group×time interactions in any SANS domain, suggesting that improvements were comparable in the active and sham conditions.

No. Median SAPS scores were low at baseline, with mild severity in both groups, and Mann-Whitney U testing found no significant differences in total or domain SAPS scores between active and sham treatment at any time point.

Both groups showed gradual declines in positive symptom severity over time, but the differences between groups remained minimal and not statistically significant.

At treatment completion, 8 patients in the active group and 2 in the sham group met the study's criterion for significant improvement, but this difference was not statistically significant. During follow-up, the number of improved patients increased in both groups without significant separation between them.

By 6 months, 18 patients in the active group and 15 in the sham group showed significant improvement, again with no significant between-group difference at any time point.

Active iTBS was associated with more local adverse effects than sham. Local adverse effects occurred in 17 of 71 patients (23.9%) in the active group versus 4 of 70 (5.7%) in the sham group (P=.02).

Headache was reported by 8 active patients (11.2%) and 4 sham patients (5.7%), which was not a significant difference (P=.23). Fatigue and sleepiness occurred in 6 active patients (8.4%) and in no sham patients, which was significant (P=.01). Most adverse effects were mild and transient, although 1 patient in the active group discontinued because of worsening aggression and insomnia attributed to treatment.

No serious adverse events such as seizures were reported with this high-density iTBS protocol. The authors concluded that the intervention was generally well tolerated and feasible in this population, although active treatment caused more mild transient adverse effects than sham.

One participant in the active group discontinued after worsening aggression and insomnia, but overall the study supports the safety of iTBS in schizophrenia under the protocol used.

The authors identify several possible reasons for the neutral result. These include the chronic and treatment-resistant nature of the sample, possible placebo effects, overlap between primary and secondary negative symptoms, possible confounding from concurrent treatments during follow-up, and protocol modifications that may have reduced neuroplastic effects despite preserving tolerability.

Specifically, this study used a nonstandard high-density protocol with 720 pulses per session but only 15 sessions and longer intertrain intervals. The authors note that such safety-driven changes may have attenuated synaptic potentiation and limited efficacy.

The main limitations discussed by the authors are potential placebo effects, inability to fully separate primary from secondary negative symptoms, lack of formal assessment of blinding integrity and participant expectancy, and incomplete monitoring of additional treatments during follow-up. These factors could have influenced the within-group improvements seen in both active and sham arms.

The authors also note that occasional benzodiazepine use was not fully excluded and may have reduced responsiveness to TMS or iTBS. In addition, the modified stimulation protocol may not be equivalent to more standard iTBS schedules used in other studies.

This study suggests that this specific high-density left DLPFC iTBS protocol should not be expected to provide meaningful benefit over sham in clinically stable patients with longstanding predominant negative symptoms of schizophrenia. The trial found no significant efficacy advantage for active treatment across posttreatment assessment or 6 months of follow-up.

The authors conclude that future research should optimize stimulation parameters, stratify patients by symptom subtype and responsiveness, monitor adjunctive treatments more rigorously, and use extended follow-up to distinguish true treatment effects from nonspecific improvement.