NeuroSigma's Monarch eTNS System as the first non-drug treatment for pediatric ADHD approved by the FDA.
Photo Credit:NeuroSigma Inc.
Scientific Frontline: "At a Glance" Summary
- Main Discovery: A large multicentre clinical trial determined that the Monarch external Trigeminal Nerve Stimulation (eTNS) system, a device cleared by the US FDA for treating ADHD, is ineffective at reducing symptoms despite being safe to use.
- Methodology: Researchers conducted a randomized, double-blind, sham-controlled trial involving 150 children and adolescents (ages 8–18) across two UK sites, assigning participants to receive either active nightly stimulation or a credible sham (placebo) stimulation over a four-week period.
- Key Data: The active group received approximately 9 hours of stimulation nightly, while the sham group received only 30 seconds of non-therapeutic pulses per hour; analysis showed no statistically significant difference in ADHD symptom reduction or secondary outcomes like sleep and mood between the two groups.
- Significance: The findings directly challenge the validity of the smaller, unblinded pilot study used for the device's 2019 FDA clearance, highlighting the critical role of rigorous placebo controls in ruling out expectation effects in medical device trials.
- Future Application: Regulatory bodies are advised to re-evaluate the evidence supporting the device's clearance to prevent patients and families from investing in treatments that do not provide clinical benefit.
- Branch of Science: Clinical Neuroscience and Pediatric Psychiatry
- Additional Detail: Unlike the previous pilot study which failed to maintain blinding, this trial successfully blinded participants to their condition, suggesting the earlier reported benefits were likely driven by the placebo effect.
The device – which uses an approach called trigeminal nerve stimulation (TNS) - was cleared for use by the US Food and Drugs Administration (FDA) to treat ADHD in 2019 based on a small study. These new findings from a larger multicenter trial, published in the journal Nature Medicine, suggest authorities should revisit the original evidence that supported the FDA clearance. Notably, TNS is currently not recommended for use in the UK by NICE guidelines.
The trial was run in collaboration with University of Southampton and funded by the Efficacy and Mechanism Evaluation (EME) Programme, a partnership between the National Institute for Health and Care Research (NIHR) and the UKRI Medical Research Council (MRC), with further support from the NIHR Maudsley Biomedical Research Centre.
Attention-Deficit/Hyperactivity Disorder (ADHD) affects five to eight per cent of school-age children worldwide and is associated with age-inappropriate problems with attention and/or hyperactivity and impulsivity that can impair everyday functioning. Stimulant medications improve symptoms in 70 per cent of those who take them in the short term, but there is less evidence of their long-term effects.
To provide an alternative to medication, researchers have developed and trialed approaches that use non-invasive stimulation of the brain, working on the regions that have been identified as influential in ADHD.
One of these approaches involves stimulating the trigeminal nerve (TNS), targeting a branch of this facial nerve which is thought to activate the brainstem and from there other brain regions that may be relevant to ADHD, in particular the locus coeruleus, which plays a role in arousal which is typically diminished in people with ADHD. TNS is thought to stimulate other brain regions associated with attention such as frontal and thalamic areas via the brainstem in a bottom-up manner.
A previous small trial in the US with 62 children diagnosed with ADHD has shown that when TNS is applied every night for eight hours for one month it is effective in reducing symptoms – this research led to its clearance by the FDA for use in the US. However, the control condition involved no stimulation, and blinding was not tested after one month, raising questions about a potential placebo effect.
This new UK clinical trial across two sites in London and Southampton tested TNS in a wider range of 150 children and adolescents diagnosed with ADHD aged between eight and 18 years old and applied a more rigorous placebo condition. Half of the sample received real TNS for about 9 hours every night for four weeks through battery-powered electrodes applied to the forehead. The other half of the sample received the ‘sham’ condition where electrodes were still applied to the forehead every night for four weeks but participants only received 30 seconds of stimulation every hour at a lower frequency and pulse width, which are thought to be non-effective and hence act as a “control” condition.
Dr Aldo Conti, postdoctoral researcher at IoPPN and at Florence Nightingale Faculty of Nursing, Midwifery & Palliative Care, King’s College London and first author on the study said: “This multicenter trial was designed to address key limitations of the previous pilot study that informed FDA clearance of TNS for ADHD, particularly by using a rigorously controlled sham condition that supported successful blinding across the treatment period. Unlike the earlier study, which was limited to younger children, we also included adolescents, a clinically important group given well-documented challenges with long-term medication adherence. These design choices enabled a more robust and clinically relevant evaluation of TNS.”
By comparing the groups, researchers evaluated effectiveness of TNS by assessing the symptoms of ADHD as reported by parents, alongside other outcomes such as mind-wandering and attention, depression and anxiety, and sleep.
The trial showed that TNS was safe with no serious adverse events, and most participants considered it a mild or no burden to use. However, the results showed no significant change in ADHD symptoms, objective measures of hyperactivity, attention, and associated behaviors around mood and sleep.
Professor Samuele Cortese, NIHR Research Professor at University of Southampton and study lead for the Southampton site, stated: “Rigorous evidence, such as that generated by this study, is essential for supporting shared decision-making regarding interventions for ADHD. It empowers individuals with ADHD and their families to make informed choices about the treatment of ADHD. Clinicians, individuals with ADHD, and their families need to know which treatments work, and which do not based on the best evidence.”
Funding: The trial was run by the King’s Clinical Trials Unit and recruitment involved the Child and Adolescent Mental Health Services (CAMHS) clinics within the following NHS trusts: South London and Maudsley NHS Foundation Trust, Hampshire and Isle of Wight Healthcare (previously known as SOLENT NHS Trust), Central and North-West London NHS Foundation Trust, Oxleas NHS Foundation Trust and South-West London and St. George’s Mental Health NHS Trust.
Published in journal: Nature Medicine
Authors: Aldo Alberto Conti, Natali Bozhilova, Irem Ece Eraydin, Dominic Stringer, Lena Johansson, Robert Marhenke, Andrea Bilbow, Sahid El Masri, Joshua Hyde, Giovanni Giaroli, Holan Liang, Federico Fiori, Mitul Ashok Mehta, Paramala Santosh, Ben Carter, Samuele Cortese, and Katya Rubia
Source/Credit: King’s College London
Reference Number: psyc011626_01