Double Blinded Randomized Trial of Subcutaneous Trigeminal Nerve Stimulation as Adjuvant Treatment for Major Unipolar Depressive Disorder

Abstract

BACKGROUND More than 30% of major depressive disorder patients fail to respond to adequate trials of medications and psychotherapy. While modern neuromodulation approaches (ie, vagal nerve stimulation, deep brain stimulation) are yet to prove their efficacy for such cases in large randomized controlled trials, trigeminal nerve stimulation (TNS) has emerged as an alternative with promising effects on mood disorders. OBJECTIVE To assess efficacy, safety, tolerability, and placebo effect duration of continuous subcutaneous TNS (sTNS) in treatment-resistant depression (TRD). METHODS The TREND study is a single-center, double-blind, randomized, controlled, phase II clinical trial. Twenty unipolar TRD patients will receive V1 sTNS as adjuvant to medical therapy and randomized to active vs sham stimulation throughout a 24-wk period. An additional 24-wk open-label phase will follow. Data concerning efficacy, placebo response, relapse, and side effects related to surgery or electrical stimulation will be recorded. We will use the HDRS-17, BDI-SR, IDS_SR30, and UKU scales. EXPECTED OUTCOMES The main outcome measure is improvement in depression scores using HAM-17 under continuous sTNS as adjuvant to antidepressants. Active stimulation is expected to significantly impact response and remission rates. Minor side effects are expected due to the surgical procedure and electrical stimulation. The open-label phase should further confirm efficacy and tolerability. DISCUSSION This study protocol is designed to define efficacy of a novel adjuvant therapy for TRD. We must strive to develop safe, reproducible, predictable, and well-tolerated neuromodulation approaches for TRD patients impaired to manage their lives and contribute with society.

Implantable Subcutaneous Peripheral Nerve Stimulation Improves Degenerative Ataxia

“…We acknowledge that we present a single case report and not a double-blind cross-over trial. Another limitation is that the patient was aware that he received real tDCS and PNS, and placebo response besides depression should be considered when designing and interpreting clinical trials in cerebellar ataxia patients [ 20 ].…”

Transcutaneous electrical cranial‐auricular acupoint stimulation versus escitalopram for mild‐to‐moderate depression: An assessor‐blinded, randomized, non‐inferiority trial

“…Transcutaneous trigeminal nerve stimulation (TNS) was also effective in reducing depression. 18,19 It is well documented that both cranial nerves have extensive interconnections with specific brainstem structures, in particular the raphe nuclei where most serotonin (5-HT)-synthesizing neurons of the brain are located, the locus coeruleus which contains noradrenaline (NA)-producing neurons, 7,29,[58][59][60][61][62] and the nucleus solitaries, the primary visceral sensory relay station that modulates the autonomic nervous system. 63 Transcutaneous stimulation of the trigeminal nerve changed neuronal activity and excitability in distributed subcortical and cortical regions.…”

“…Several controlled trials 23‐27 and case studies 28,30 have revealed that transcutaneous auricular vagus nerve stimulation (taVNS) significantly improved depression and insomnia. Transcutaneous trigeminal nerve stimulation (TNS) was also effective in reducing depression 18,19 . It is well documented that both cranial nerves have extensive interconnections with specific brainstem structures, in particular the raphe nuclei where most serotonin (5‐HT)‐synthesizing neurons of the brain are located, the locus coeruleus which contains noradrenaline (NA)‐producing neurons, 7,29,58‐62 and the nucleus solitaries, the primary visceral sensory relay station that modulates the autonomic nervous system 63 .…”

“…7,8 Numerous studies have revealed benefits and effectiveness of electroacupuncture on the trigeminal nerve-innervated frontal acupoints, in particular Yin-Tang (EX-HN3) and Bai-Hui (DU20), in the treatment of depression, [9][10][11][12] insomnia, 13,14 anxiety, 15 obsessive-compulsive disorder (OCD), 16 and cognitive decline. 17 Transcutaneous trigeminal nerve stimulation was also effective in treating depression 18 and other psychiatric and neurological disorders. [19][20][21] Meanwhile, transcutaneous auricular vagus nerve stimulation (taVNS) could produce similar therapeutic effects as observed in its invasive counterpart, suggesting a noninvasive alternative to conventional form.…”

Non-Invasive Rhythmic Musical-Electric Trigeminal Nerve Stimulation Improves Consciousness in Patients with Disorders of Consciousness

“…This nerve is critical for socially relevant somatosensorymotor functions of the face and has abundant anatomical projections to somatosensory nuclei of the thalamus in the midbrain 21,22 , making it a strong candidate for non-invasive modulation of neural oscillations in thalamocortical circuits. Application of trigeminal nerve stimulation (TNS) has yielded encouraging results in various neurological diseases, such as epilepsy 23 , depressive disorder 24 and migraine 25 . For DOC, so far only a single study in a single patient has been published, with promising results 26 .…”