Trigeminal Nerve Stimulation for Depression: Dose Finding

A total of 20 subjects with Major Depressive Disorder (MDD), ages 18 to 65, will be
consented and join this project at UCLA.

The project has two phases: a 12 week treatment phase and a 6 month follow-up phase. In the
first phase, a double-blind one-way cross-over design will allow us to compare the clinical
and physiologic responses to TNS at two frequencies of stimulation, "high" (~120 Hz) and
"low " (~20 Hz). Subjects will be randomized to start a six week period at either high or
low frequency stimulation (n=10 in each); both subjects and the staff who interact with them
will be blinded to assignment, and a separate member of the team will program the device
settings. At the six week point, the low frequency group subjects will be crossed over to
high frequency, while the high frequency group will continue at high frequency. At the end
of the 12 weeks, the TNS systems will be returned and the adjunctive treatment will end.
All subjects will be followed for another six months with monthly telephone calls to monitor
symptoms or changes in treatment that would signal a return of symptoms. The primary
endpoint is the change in depression severity for the two groups at the week 6 visit.

Inclusion Criteria

1. Outpatients with non-psychotic, unipolar Major Depressive Disorder assessed via the
MINI structured interview

2. A score of ≥ 14 on the HAM-D17 with Item 1 (depressed mood) ≥ 2

3. A history of treatment failure with at least one adequate trial of an antidepressant
over the previous 6 weeks, with no change in antidepressant medication or dose within
the previous 6 weeks, and ongoing use of at least one antidepressant (which will
continue during participation in the study)

4. Age range: 18 to 65 years old.

5. Patients with suicidal ideation are eligible only if the thoughts of death or of life
not being worth living are not accompanied by a plan or intention for self-harm.

Exclusion Criteria

1. Patient is mentally or legally incapacitated, unable to give informed consent.

2. Patients with psychosis (psychotic depression, schizophrenia, or schizoaffective
diagnoses (lifetime)); bipolar disorder (lifetime); dementia (lifetime); delirium or
any substance abuse disorder within the past 6 months; eating disorder within the
past year; obsessive-compulsive disorder (lifetime); post-traumatic stress disorder
within the past year; acute risk for suicide or self-injurious behavior. Patients
with diagnostic uncertainty or ambiguity (e.g. rule-out pseudodementia of depression)
will be excluded.

3. Patients with exposure to ECT or VNS within the past 6 months.

4. Past history of skull fracture; cranial surgery entering the calvarium; space
occupying intracranial lesion; stroke, CVA, or TIAs; cerebral aneurysm; Parkinson's
or Huntington's disease; or Multiple Sclerosis.

5. current pregnancy, breast feeding, plans to become pregnant in the 12-week treatment
phase of the study, or not using a medically accepted means of contraception.

6. Other medical contraindications to any of the study procedures