Theta burst stimulation of temporo-parietal cortex regions for the treatment of persistent auditory hallucinations: a multicentre, randomised, sham-controlled, triple-blind phase 3 trial in Germany

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BACKGROUND: Auditory verbal hallucinations are a major burden for patients with schizophrenia spectrum disorder and are often resistant to pharmacological and psychotherapeutic interventions. Repetitive transcranial magnetic stimulation (rTMS) of the temporo-parietal cortex has been proposed as a treatment for persistent auditory verbal hallucinations. We aimed to compare the efficacy and safety of bilateral continuous theta burst stimulation (cTBS), a brief and efficient form of rTMS, in adults with auditory verbal hallucinations versus sham cTBS. METHODS: This multicentre, randomised, sham-controlled, triple-blind phase 3 clinical trial was conducted at seven German psychiatric university hospitals and followed a planned two-stage adaptive design. Eligible patients were aged 18-65 years, had experienced persistent auditory verbal hallucinations at least once per week for a minimum of 3 months, and scored 3 points or higher on item P3 (hallucinatory behaviour) of the clinician-rated Positive Scale of the Positive and Negative Syndrome Scale (PANSS). 138 adults with treatment-persistent auditory verbal hallucinations and schizophrenia spectrum disorder were randomly assigned (1:1) to receive 15 sessions of active (n=70) or sham cTBS (n=68) administered sequentially as 600 pulses to the left and 600 pulses to the right temporo-parietal cortex over a 3-week period. The primary outcome was the change in the auditory hallucinations subscale of the Psychotic Symptom Rating Scales (PSYRATS-AH) from baseline to the end of treatment at 3 weeks, analysed in the intention-to-treat population, which included all randomly assigned patients who received at least one stimulation session. Safety was assessed in all patients who received at least one stimulation session. Follow-up assessments were performed at 1, 3, and 6 months after the end of treatment. People with lived experience were not involved in the study. This trial was registered at ClinicalTrials.gov, NCT02670291. FINDINGS: Between Oct 24, 2015, and May 1, 2023, 2583 patients were screened for eligibility, of whom 138 patients were randomly assigned to active cTBS (n=70; 32 [46%] females and 38 [54%] males) or sham treatment (n=68; 24 [35%] females and 44 [65%] males). Race and ethnicity data were not collected. The primary intention-to-treat analysis (66 patients in the active cTBS group; 64 patients in the sham cTBS group), combining stages 1 and 2, showed patients in the active cTBS group had a significantly greater decrease in the PSYRATS-AH score at end of treatment than did patients in the sham cTBS group (-6·36 [SD 7·97] vs -3·74 [SD 5·79]; adjusted difference -2·36 [95% CI -4·71 to -0·01]; p=0·042). Overall, 85 adverse events (43 in the active cTBS group; 42 in the sham cTBS group) were reported in 22 (33%) of 66 patients in the active cTBS group and 21 (33%) of 64 patients in the sham cTBS group. Headache was the most common adverse event in both groups (n=13 active cTBS group vs n=17 sham cTBS group). One serious adverse event occurred in the active group. INTERPRETATION: Sequential bilateral temporo-parietal cTBS over 3 weeks was safe and effective for reducing auditory verbal hallucinations in adults with schizophrenia spectrum disorder. This trial establishes cTBS as a treatment option for the care of these patients. Further research is needed to evaluate maintenance strategies, identify treatment predictors, and assess long-term efficacy. FUNDING: German Research Foundation.

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