Repetitive Transcranial Magnetic Stimulation for Auditory Verbal Hallucinations in Schizophrenia: A Randomized Clinical Trial

Abstract

Importance: Auditory verbal hallucinations (AVH) are a common symptom of schizophrenia, increasing the patient's risks of suicide and violence. Repetitive transcranial magnetic stimulation (rTMS) is a potential treatment for AVH.

Objective: To investigate the effect of imaging-navigated rTMS on AVH in patients with schizophrenia.

Design, setting, and participants: This 6-week, double-blind, sham-controlled, randomized clinical trial was performed at the Anhui Mental Health Center, Hefei, China, from September 1, 2016, to August 31, 2021. Participants included 66 patients with AVH and schizophrenia. Data were analyzed from May 1, 2022, to March 31, 2023.

Interventions: Participants were randomly assigned 1:1 to either imaging-navigated active or sham rTMS over the left temporoparietal junction for 2 weeks.

Main outcomes and measures: The primary outcome measured improvements in AVH from baseline to week 2 and week 6 using the Auditory Hallucination Rating Scale (AHRS) scores. In addition, the TMS-induced electric field strength was used to estimate improvements in AVH as a secondary outcome.

Results: A total of 62 participants (33 women [53%]; mean [SD] age, 27.4 [9.2] years) completed the 2-week treatments. Of these, 32 were randomized to the active rTMS group (18 women [56%]; mean [SD] age, 26.9 [9.2] years) and 30 to the sham treatment group (15 women [50%]; mean [SD] age, 27.8 [9.4] years). In the intention-to-treat analyses, patients receiving active rTMS showed a significantly greater reduction in AHRS scores compared with those receiving sham treatment at week 2 (difference, 5.96 [95% CI, 3.42-8.50]; t = 4.61; P < .001; Cohen d, 1.17 [95% CI, 0.62-1.71]). These clinical effects were sustained at week 6. Additionally, a stronger TMS-induced electric field within a predefined AVH brain network was associated with greater reductions in AHRS scores (B = 3.12; t = 3.58; P = .002). No serious adverse event was observed.

Conclusions and relevance: The findings of this randomized clinical trial suggest that imaging-navigated rTMS may effectively and safely alleviate AVH in patients with schizophrenia. Findings also suggest that the electric field strength in the individualized AVH network is a vital parameter for optimizing the efficacy of the rTMS protocol.

Trial registration: ClinicalTrials.gov Identifier: NCT02863094.

Figure 1.. Patient Flow Diagram

A total of 62 patients were included in the intention-to-treat (ITT) analysis. rTMS indicates repetitive transcranial magnetic stimulation.

Figure 2.. Clinical Outcomes of the Repetitive Transcranial Magnetic Stimulation (rTMS) Treatment

The error bars indicate 1 standard error of the mean. AHRS indicates Auditory Hallucination Rating Scale. ^aP = .004 between treatment groups. ^bP = .002 between treatment groups.

Figure 3.. Estimating Clinical Efficacy by Electric Field (E-Field) Strength

A, Illustration of stimulation target on the left temporoparietal junction (TPJ) (left), distribution of the transcranial magnetic stimulation (TMS)–induced e-field in 1 patient (middle), and the individualized auditory verbal hallucination (AVH) network (right). B, The Auditory Hallucination Rating Scale (AHRS) reductions were positively correlated with e-field strength within each patient’s individualized AVH network (r = 0.54; P = .001) but not with the e-field strength within the TPJ target (r = 0.14; P = .44). Solid line indicates the regression line; shading, 95% CI for the regression line.