Placebo Response in Repetitive Transcranial Magnetic Stimulation Trials of Treatment of Auditory Hallucinations in Schizophrenia: A Meta-Analysis

Abstract

Several meta-analyses have assessed the response of patients with schizophrenia with auditory verbal hallucinations (AVH) to treatment with repetitive transcranial magnetic stimulation (rTMS); however, the placebo response has never been explored. Typically observed in a therapeutic trial, the placebo effect may have a major influence on the effectiveness of rTMS. The purpose of this metaanalysis is to evaluate the magnitude of the placebo effect observed in controlled studies of rTMS treatment of AVH, and to determine factors that can impact the magnitude of this placebo effect, such as study design considerations and the type of sham used. The study included twenty-one articles concerning 303 patients treated by sham rTMS. A meta-analytic method was applied to obtain a combined, weighted effect size, Hedges's g. The mean weighted effect size of the placebo effect across these 21 studies was 0.29 (P < .001). Comparison of the parallel and crossover studies revealed distinct results for each study design; placebo has a significant effect size in the 13 parallel studies (g = 0.44, P < 10 −4 ), but not in the 8 crossover studies (g = 0.06, P = .52). In meta-analysis of the 13 parallel studies, the 45° position coil showed the highest effect size. Our results demonstrate that placebo effect should be considered a major source of bias in the assessment of rTMS efficacy. These results fundamentally inform the design of further controlled studies, particularly with respect to studies of rTMS treatment in psychiatry.

Repetitive Noninvasive Brain Stimulation to Modulate Cognitive Functions in Schizophrenia: A Systematic Review of Primary and Secondary Outcomes

“…9 Moreover, one recently published meta-analysis (21 rTMS studies) showed that the effect size for sham rTMS is 0.29 for the treatment of auditory verbal hallucinations. 56 These high placebo rates question the promising findings from uncontrolled NIBS trials. 40 Second, cognitive measures are highly sensitive to practice effects.…”

Further Evidence of the Positive Influence of Repetitive Transcranial Magnetic Stimulation on Speech and Language in Patients with Aphasia after Stroke: Results from a Double-Blind Intervention with Sham Condition

“…Sixth, as regards the sham condition, as in previous studies [13, 14, 29], we employed the technique of tilting the coil by 90°; in doing so, both the sound and the skin sensation were equivalent to genuine stimulation, but with no effect on the underlying cortex. However, Dollfus et al [30] suggested employing a sham coil, which may be a more reliable method for a placebo procedure. Last, the research group of Bartoli et al [31-34] showed that patients after stroke might be at an increased risk of suffering from depression, insomnia, and suicidal ideation.…”

Challenges of differential placebo effects in contemporary medicine: The example of brain stimulation

“…This may reflect multiple factors such as growing public/media attention, more sophisticated technological device set-ups, changes in included patient populations and more realistic sham coils. TMS’s robust placebo responses are not limited to studies of depression and have also been well characterized in other neuropsychiatric fields including schizophrenia 34 , obsessive-compulsive disorder 35 , Parkinson’s disease 36 and chronic pain. 37 Other areas of TMS research such as epilepsy 38 and motor learning 39 have reported more modest placebo responses.…”