Susan Jeffrey

May 20, 2013

SAN FRANCISCO — Results of a small pilot trial suggest that trigeminal nerve stimulation (TNS), a noninvasive treatment already approved in Europe and Canada for refractory epilepsy and major depression, may also provide a nonpharmacologic treatment option for attention-deficit/hyperactivity disorder (ADHD).

The trial showed that treatment-naïve patients between the ages of 7 and 14 years had what the researchers describe as robust improvement in patient-, parent-, and investigator-reported ADHD symptoms and executive function, as well as on computerized testing of cognitive measures, coauthor Ian A. Cook, MD, professor of psychiatry and biobehavioral sciences and chair of the faculty at David Geffen School of Medicine at the University of California, Los Angeles (UCLA), told Medscape Medical News.

"So in light of all this, that it's such a well-tolerated kind of treatment, that it is so strong in its effects, both behaviorally and cognitively, under these open-label conditions, that there's great excitement to go forward with bringing this to availability for patients," Dr. Cook said. The study was funded by NeuroSigma Inc. Dr. Cook reports that he has stock options in NeuroSigma; his biomedical patents have been assigned to the Regents of the University of California.

The NeuroSigma Monarch eTNS System.

The results of this open-label pilot trial were presented here at the American Psychiatric Association's 2013 Annual Meeting by lead author James McGough, MD, MPH, professor of clinical psychiatry at the Semel Institute for Neuroscience and Human Behavior and the David Geffen School of Medicine at UCLA, and director of clinical teaching programs in both child and adolescent psychopharmacology and ADHD.

"I am very encouraged by the results of this 20-subject open-label study," Dr. McGough said in a statement. "The results of the study warrant moving forward with a larger double-blind phase 2 clinical trial."

Better Attention a Side Effect

The trigeminal nerve is 1 of the 12 cranial nerves; stimulation of the nerve allows access to brain areas important to functions such as attention, emotional processing, concentration, anxiety, and seizure generation, Dr. Cook said. Using positron emission tomography (PET), these researchers had previously shown that electrical stimulation of trigeminal nerves using an adhesive patch on the forehead attached to a stimulator resulted in increases in blood flow within 60 seconds in areas such as the anterior cingulate, parts of the medial-frontal gyrus, and the inferior-frontal gyrus, as well as simultaneous decreases in flow to the primary motor cortex and temporal-parietal cortical areas.

Dr. Ian Cook

"The former areas are of great interest to psychiatrists because they are implicated in disorders like mood disorders, anxiety disorders, cognitive disorders, and the decreases in blood flow are of great interest and relevance to the mechanism of action for neurologists, because these are areas that are important in the generation and propagation of seizure discharges."

NeuroSigma's Monarch eTNS System is already marketed to patients in the European Union (EU), with a physician's prescription. In September 2012, the company received CE Mark approval for use of the system as adjunctive treatment of epilepsy and major depressive disorder for adults and children aged 9 years and older in the EU. The system also recently received a class 2 medical device license from Health Canada that covers use of the system for treatment of drug-resistant epilepsy, major depressive disorder, and treatment-resistant depression.

Currently, the system has no approvals in the United States from the US Food and Drug Administration (FDA). Leon Ekchian, president and CEO of NeuroSigma, Inc, said the company plans first to apply for the epilepsy indication in the United States, with depression next and ADHD indications probably further down the road.

During studies of the system in refractory epilepsy and treatment-resistant depression, Dr. Cook said, they noticed that patients also reported that they were able to focus their attention better. "When this became something that they spontaneously volunteered over and over again, that, plus the PET studies and the anatomy, then led me to go to Dr. Jim McGough," Dr. Cook said. "He became very excited about whether this could be a nonstimulant approach to help kids with ADHD."

In this pilot feasibility trial, 20 participants with ADHD used TNS therapy each night for 8 weeks. The system uses an adhesive electrode pad that is placed on the forehead over the trigeminal nerve and is connected by thin wires to an external stimulator using a 9-volt lithium battery, placed on the pillow or in a pocket.

Rather than an adjunct to drug therapy, however, as it is used in depression or epilepsy, the children and adolescents received TNS as stand-alone monotherapy.

The researchers found that the children tolerated treatment well and that the treatment had measurable effects on ADHD symptoms, cognition, and executive functioning. For example, "robust" improvements in ADHD symptoms were found using the Conners ADHD Index, completed by parents (F = 5.9, df = 2/35, P < .001), and the investigator-completed ADHD-IV Rating Scale (F = 34.3, df = 2/35, P < .001).

Using the Clinical Global Impression Scale, 75% of the children were improved or very much improved at week 8. Significant improvements were also seen on most subscales of the Behavior Rating Inventory of Executive Functioning (BRIEF), completed by parents.

"Even more interestingly," he said, improvements were seen on computerized measures of response inhibition and working memory, outcomes less likely to be susceptible to placebo effects in an open-label design, as noted by the researchers. Improvements were seen, for example, on the Incongruent Reaction Time measure of the Attention Network Task (F = 6.0, df = 2/33, P = .006) and the Sternberg Spatial Working Memory measure Load 3 Reaction Time (F = 3.3, df = 2/35, P = .05).

Treatment was well tolerated; effects thought to be related to the device were headache in 2 children, which resolved spontaneously, and eye-twitching in 1 patient, stemming from improper placement of the electrode. There was no sign of anxiety, agitation, emotional irritability or lability, or cognitive changes.

"TNS therapy for youth with ADHD appears to be both feasible and without significant risk," Dr. McGough and colleagues conclude. "Subjective improvements on ratings of behavior and executive function in this uncontrolled pilot suggest a potential role for TNS in treating ADHD that merits further investigation."

Future research should evaluate TNS dose effects, time to response, and time to offset of response in anticipation of designing definitive blinded randomized controlled studies, they add.

"In many ways, the use of neuromodulation techniques is something that has great potential to change the way that people with brain disorders are assisted by physicians," Dr. Cook noted. "We have used medications for many decades and have made a tremendous impact on patients' lives, and yet when you look at studies like STAR*D, when you look at other big studies, there are many patients who either don't respond well to the pharmacologic interventions or are unable to tolerate the side effects. Having this kind of new approach really opens up new potential to help a lot more people."

Out of the Box

Asked for comment on these findings, Jeffrey Newcorn, MD, associate professor of psychiatry and pediatrics at Mount Sinai Hospital, New York City, called it a "new, out-of-the-box idea."

"I'm intrigued by it; I'd love to see more data on it," he told Medscape Medical News. "In a way, it's reminiscent of TMS [transcranial magnetic stimulation] for depression. The idea of using stimulation of brain neurotransmitter activity is getting some traction across other disorders and provides a conceptual basis for understanding it."

He was also interested that there were effects from this stimulation seen on PET imaging in areas of the brain implicated in ADHD.

Patients in this study were treatment-naïve, he pointed out. "People who are treatment-naïve are probably most susceptible to placebo effects, while on the other hand, people who are treatment-naïve are not going to have their impressions of treatment contaminated by having been treated with something else. There are trade-offs, pluses and minuses, but I would say on balance, treatment-naïve is best."

He cautioned that it is a small, open-label trial in 20 patients. "There is a lot we need know about the intervention before we know if it's useful. It's probably several years away from prime time. But those are all obvious points — they report on 20 people. A lot of drugs do well in their initial studies, so we don't know." Still, he is interested to know more about it, he said.

The study was funded by NeuroSigma Inc. Dr. McGough reports that during the past year he has received consulting honoraria from Sunovion, Targacept, and Theravance, and research support from the National Institutes of Health, NeuroSigma Inc, and Shire Pharmaceuticals. Dr. Cook reports that during the past year he has received research support from Covidien, the National Institutes of Health, NeoSync, Neuronetics, and Shire; has provided advisory/consulting/reviewer service for Allergan, Covidien, Neuronetics, NeuroSigma, Pfizer, the NIH (ITVA), and the Veterans Administration (DSMB); has participated on the speakers bureau for Neuronetics; has stock options in NeuroSigma; and that his biomedical patents have been assigned to the Regents of the University of California.

The American Psychiatric Association's 2013 Annual Meeting. Abstract NR8-49. Presented May 20, 2013.


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