AT THE ASCP ANNUAL MEETING
MIAMI BEACH (FRONTLINE MEDICAL NEWS) – External trigeminal nerve stimulation resulted in a significant improvement in depressive symptoms when used as an adjunct to medication for treatment-resistant depression in a dose-finding study. The noninvasive, home-administered procedure was effective at a wide range of electrical frequencies, and improvement was seen as early as 2 weeks after beginning treatment, according to one measure used in the study.
Results of the double-blind, placebo-controlled study comparing eTNS to sham therapy for 43 adult patients with treatment-resistant major depressive disorder were reported by Dr. Ian A. Cook during a poster session at a meeting of the American Society of Clinical Psychopharmacology, formerly known as the New Clinical Drug Evaluation Unit meeting.
Dr. Cook is professor-in-residence in the departments of psychiatry and biobehavioral sciences, and bioengineering at the University of California, Los Angeles. Dr. Cook, also research scientist at UCLA’s Semel Institute for Neuroscience and Human Behavior, is on a leave of absence from the university to serve as the chief medical officer of NeuroSigma. The company has a license agreement with UCLA for the eTNS technology used in the study.
Interest in electrical stimulation of cranial nerves began in epileptology, Dr. Cook said in an interview. Scientists found that stimulating the vagus nerve via implanted devices reduced seizures. Dr. Christopher M. DeGiorgio, an epileptologist at UCLA, began experimenting with stimulation of a different cranial nerve, the trigeminal nerve, to treat his patients with intractable epilepsy and began receiving surprising feedback. Many reported that they had felt their mood lighten over the course of their participation in the experiment. This was true, said Dr. Cook, even for those whose epilepsy was not improved by trigeminal nerve stimulation, so it wasn’t simply a reduction in disease burden that had alleviated their depression symptoms. Those findings previously were published in 2013.
The path of the vagus nerve leads to brain areas thought to be involved in regulating mood – as does the path of the trigeminal nerve. However, unlike the vagus nerve, which can only be stimulated by an implanted device, the three branches of the trigeminal nerve lie just beneath the skin as they course across the face. In order to test the effect of external stimulation of the trigeminal nerve, investigators used a patch applied across the forehead to deliver mild electrical pulses to the supraorbital fibers of the V1 tract of the trigeminal nerve bilaterally.
The new dose-ranging study examined 43 adults with unipolar major depressive disorder whose symptoms had not improved after 6 weeks of at least one antidepressant medication. Patients were assigned to receive a sham regimen with no electrical stimulation (n = 8), or to active stimulation with 2 Hz (n = 9), 20 Hz (n = 12), and 120 Hz (n = 14). The electrical stimulation was self-administered at home by patients overnight for an 8-hour period nightly for the 6 weeks of the study period. After the 6-week dose-ranging period, patients were then crossed over to active stimulation at 120 Hz for an additional 6 weeks. Medication use continued unchanged for all patients during the course of the trial; blinding was confirmed by patient questionnaire.
No significant differences were seen in treatment outcomes among any of the intervention arms, so their results were pooled and compared to the sham arm for comparison. Noted Dr. Cook and coinvestigators in their poster: “Symptom improvement did not differ across the three active stimulation frequencies (“doses”), suggesting that low doses of stimulation may lead to meaningful symptom improvement in major depressive disorder (MDD) and that the cumulative integration of stimulation events may be an important determinant of clinical effects.”
Though both the sham and the intervention arms had initial improvement on the Beck Depression Inventory ( BDI ), only the intervention arm continued to improve, showing a 41.7% reduction in score, compared with a 10.9% reduction for the placebo arm (2-tailed P = .013). Improvement on the Inventory of Depressive Symptomatology ( IDS-SR ) was 30.3% for the intervention vs. 2.5% for the sham arm but did not reach significance (P = .060), and no significant difference was seen on the Hamilton Depression Rating Scale ( HDRS-17 ).
“The mechanism of action of eTNS is incompletely understood – as it is for many medications,” Dr. Cook said. However, foundational work using PET with O-15 did capture changes in cerebral blood flow occurring while subjects received eTNS, showing increased blood flow in limbic and frontal regions. “We believe that the rapid and significant increases in cerebral blood flow are important to the mechanism of action for psychiatric conditions, because the areas where that was observed have been implicated in the control of mood, anxiety, cognition, and behavior in the neuroimaging literature,” said Dr. Cook.
Though eTNS is an investigational device in the United States, it is approved for use in Europe. U.S. randomized, double-blind, sham-controlled studies are currently testing eTNS as monotherapy in children with attention-deficit/hyperactivity disorder and as adjunctive treatment for posttraumatic stress disorder in combat veterans.
The study was funded by NeuroSigma. In addition to his management role, Dr. Cook holds stock options in the company.
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