Effectiveness of CES on Emotional and Cellular Wellbeing

This study aims to test an auricular cranial electrotherapy stimulation (CES) device,
Alpha-Stim, to assess for changes in markers of cellular health and emotional well-being
improvement associated with anxiety and depression.

Returning Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF) Veterans have a
high incidence of anxiety, depression, insomnia, post-traumatic stress disorder (PTSD) and
chronic pain, leading to reductions in emotional well-being. This type of chronic emotional
distress can lead to detrimental biological outcomes. We will compare as an exploratory
outcome Veterans vs. non-Veterans response to Alpha-Stim treatment. At the cellular level,
impairment of the telomere/telomerase system may be a result of this dysregulation, given the
descriptions of shorter telomeres (a marker of cellular aging), as well as increased markers
of inflammation in subjects with depression, anxiety and PTSD, compared to aged matched
healthy populations. These negative cellular effects of emotional distress have not been well
studied in this population and may offer significant benefit.

In one study of auricular CES using the same protocol proposed here, 115 patients with
anxiety or anxiety and comorbid depression were studied over 5 weeks in a randomized, sham
controlled trial, showing significant improvements in both anxiety and depression symptoms.
Due to the complexity of overlapping negative affect symptoms that lead to impaired emotional
well-being in Veterans, the investigators chose in this proposal to evaluate a composite
measure of emotional distress (a combined anxiety and depression score) as the primary
outcome. Beyond depression and anxiety, CES has been associated with reductions in insomnia
and pain, both of which are also significant problems in Veterans, likely contributing to
reduced emotional well-being.

Primarily all interested and appropriate study subjects will undergo a screening at the
University of California, Los Angeles (UCLA) G. Oppenheimer Center for Neurobiology of Stress
and Resilience (CNSR). The investigators expect to enroll and screen no less than 55 subjects
in order to complete 22 evaluable subjects for analysis in each treatment group.

The Hospital Anxiety and Depression Scale (HADS) will assess symptom severity defined as
normal range (0-7), mild (8-10), moderate (11-14) or severe (15-20). Subjects with impaired
emotional well-being with mild to moderate anxiety and/or depression on the HADS scale will
be included. Subjects with a maximum combined HADS score of 28 will be included. Subjects
treated for anxiety, depression, psychiatric or mental health treatment must be on a stable
regimen (pharmacological or non-pharmacological) for the past 3 months.

If eligible the study coordinator will contact them to schedule a screening visit at UCLA.
During this visit, the research team will conduct baseline measurements via study
questionnaires, history and physical exam, and a standardized psychiatric evaluation (MINI).
Subjects meeting the inclusion criteria will have training in use of the Alpha-Stim device
and will have their first 1 hour treatment. Subjects who tolerate the CES treatment will have
blood drawn for biological measures and will take the device home to use daily for 8 weeks.
Mid-study the subjects will come back to UCLA to complete questionnaires and have vital signs
and weight measured. At the end of the 8 weeks, subjects will return to UCLA, return the
device, have vital signs and weight measured, have the final blood draw, and complete a final
set of questionnaires.

All in all, to complete the study, subjects will have an initial screening, mid and final
study visit, pre, mid, and final study questionnaires, and blood drawn in the first and final
visit.

Inclusion Criteria:

1. Male

2. Within the age range of 18-40 years old

3. Score 8-14 on either the anxiety or depression HADS scale as defined as mild (8-10) to
moderate (11-14)

4. Subjects who receive anxiety, depression, psychiatric or mental health treatment
(pharmacological or non-pharmacological) must be on a stable regimen for the past 3
months

5. No active suicidal ideation or psychosis (including schizophrenia and bipolar
disorder)

6. No uncontrolled or progressive severe medical illness (e.g., cancer, uncontrolled
diabetes mellitus, active cardiac disease)

7. No use of a pacemaker or any other implanted electrical device

8. No alcohol consumption greater than 2 units daily

9. Ability to independently complete the in-person study questionnaires and sign informed
consent form (ICF) without assistance

10. Willing to comply with all study procedures and be available for the duration of the
study

11. No participation in another clinical trial study

Exclusion Criteria:

1. Not a male

2. Younger than 18 years old or older than 40 years old

3. Score ≥15 on either the anxiety or depression HADS scale as defined as severe (15-20)

4. Subject who receive anxiety, depression, psychiatric or mental health treatment
(pharmacological or non-pharmacological) who have not been on a stable regimen for the
past 3 months

5. Active suicidal ideation or psychosis (including schizophrenia and bipolar disorder)

6. History of inpatient treatment or suicidal ideation within the last year

7. Use of a pacemaker or any other implanted electrical device

8. Unable to independently complete the in-person study questionnaires and sign ICF due
to impaired cognitive function

9. Unwilling to comply with all study procedures

10. Unavailable for the duration of the study

11. Current participation in another clinical trial study

12. Any other condition that the investigator believes would jeopardize the safety or
rights of the subject or would render the subject unable to comply with the study
protocol or make use of acquired data non-analyzable