Effects of adjunctive trigeminal nerve stimulation in major depressive disorder in a dose-ranging trial

Abstract

BACKGROUND: • Neuromodulation via Cranial Nerve Pathways: • Vagus Nerve Stimulation (VNS) initially demonstrated the potential for clinical neuromodulation of key CNS structures via stimulation of cranial nerves. • Cranial nerve stimulation may alter the activity of deeper structures via pathways that traverse multiple synapses. • Fibers of the trigeminal nerve (Fig 1) innervate the face and project to the nucleus tractus solitarius (NTS), locus coeruleus, reticular formation, raphe nuclei, and thalamic structures, and from there to sensory, limbic, and other cortical and subcortical structures [1,2]. • Neuroimaging MOA Data (Fig 2) from 15O PET imaging indicated rapid and robust acute increases in rCBF from stimulation in anterior cingulate (BA 24, 32), inferior frontal gyrus (BA 44,6,22), and medial and middle frontal gyri incl DLPFC (BA 6,8,45,46) [2]. • Trigeminal Nerve Stimulation in Epilepsy: In Phase I and Phase II trials in drug-resistant epilepsy (DRE), significant reduction in seizure frequency was shown without serious adverse events [cf 1,3], using at-home neuromodulation with external Trigeminal Nerve Stimulation (eTNS), primarily while asleep. • TNS in Major Depressive Disorder: Subjects in the epilepsy trials reported significant improvement in mood symptoms [3], independent of seizure improvement, prompting an open adjunctive trial in unipolar MDD. • In an 8-week open trial in a treatment-resistant sample (average ATHF 5.2), significant improvements in mood were detected, with 55% achieving response and 36% achieving remission at the end of the 8-week trial [4]. • Independent open replication confirmed the observation of therapeutic benefit of eTNS in MDD [5]. METHODS: • Subjects: 43 adults (age 23-65, avg 43.0 (11.5 sd)) with evaluable data were enrolled with: nonpsychotic unipolar MDD; current MDD episode >4 months; nonresponse with >6 week use of at least one antidepressant in current episode (ATHF 1-10); ongoing treatment with at least one antidepressant medication, with dose held constant during trial participation. • Trial Design: Under double-blind conditions, the dose ranging period lasted 6 weeks to the primary endpoint, with randomized assignment to an active stimulation regimen (2Hz N=9; 20Hz N=12; 120Hz N=14) vs a sham regimen (0Hz N=8); subjects were then crossed over to active stimulation (120Hz) for an additional 6 weeks. • Assessments made every 2 weeks included the Beck Depression Inventory (BDI), Inventory of Depressive Symptomology (IDS-SR) and Hamilton Depression Rating Scale (HDRS17). • TNS Intervention: Subjects placed stimulating electrodes over supraorbital branches of the trigeminal nerve nightly for ~8 hr, primarily while asleep (Figs 1 & 3). All subjects continued on their medications without change in dose during the trial. • Statistical Analyses: performed with SPSS using ttest, ANOVA, chi square RESULTS: