Use of Alpha-Stim Cranial-electrotherapy Stimulation (CES) in the Treatment of Anxiety

The goal of this study is to evaluate the efficacy of Alpha-Stim technology in the treatment
of anxiety by using a double-blind clinical trial over a period of five weeks.
Cranial-electrotherapy stimulation (CES) is a noninvasive procedure that has been used for
decades in the United States to treat anxiety, depression, and insomnia. Although many
studies on CES have been published in previous decades, most have used relatively small
samples using various frequencies and links of treatment. Given the positive results of the
many general studies that have been performed to date, this study seeks to add to the
current literature by addressing previous criticisms using a large sample size (n=150)and
using participants that represent more than a single type of anxiety along with comorbidity.
Such a population is believed to better represent typical treatment complications.

Participants will be recruited via advertisements in a local newspaper and posting of
flyers around a local university campus. Participants will be screened through an intake
process using the Structured Clinical Interview for Axis I Disorders (SCID-I) to confirm a
diagnosis of an anxiety disorder. Comorbid conditions are acceptable, however, an anxiety
disorder must be the primary diagnosis. As part of the intake process, participants will
complete the Hamilton Anxiety Rating Scale (HAM-A)and the Hamilton Depression Rating Scale
(HAM-D17) to establish a baseline. These instruments will serve as the primary efficacy
measures. In order to participate, HAM-A scores must equal to or greater than 18 (Moderate
Anxiety). Depression will be monitored using The HAM-D17 as depression is a commonly
occurring condition with anxiety and the HAM-D17 is also sensitive to anxiety. Current
treatment with medications are also acceptable provided there will be no changes in dosage
or type during the study. See Inclusions and Exclusions for further information. All
participants will pay a fee of $30 to enter the study to cover administration costs and as a
way to measure placebo effect. Participants will be assigned a device to take home and
self-administer treatment 5-7 days a week. Participants will be required to log their
treatment times and dates with logs provided by the researcher. The student population will
not be given a take home device but will receive treatment at the Graduate Assistant's
Office or Student Care Office.

Electromedical Products International, Inc. has agreed to supply the devices needed to carry
out the research to include conductance solution, felt tabs, and batteries. Half of the
devices will be set by the manufacturer to deliver treatment at 0.5 Hz and at the lowest
therapeutic setting. The remaining devices will be shame and not deliver any therapeutic
benefit. The devices will not be able to be altered by the participant.

Participants will meet with the PI or research assistant to complete the HAM-A and HAM-D17
at weeks 1, 3, and 5 at a designated location either in the researchers private practice
office or university lab location. Adverse treatment reactions will also be noted. Treatment
logs will also be collected at these points. At weeks 1 and 3, participants will be given
fresh batteries, conductance solution, and felt tabs as needed. At the completion of the
study, participants found to be in the shame treatment group will be offered the normal
course of treatment. Participants not wanting to continue the study or do not wish to follow
through with normal treatment after being in the shame group will be refunded their fee.

The hypothesis this study seeks to address is:

H°: There is no difference between sham treatment and active CES on level of anxiety as
compared to scores on the HAM-A and HAM-D17.

H¹ : The active CES treatment group has significantly lower anxiety scores on the HAM-A and
HAM-D17 than the sham group at the endpoint of the study.

Statistical analysis will compare baselines scores (week 1) to midpoint scores (week, 3),
and scores at the endpoint of the study (week 5). Response to treatment will be defined as
an improvement of 30% or greater on the HAM-A and HAM-D17 at the endpoint of the study. The
impact of prescription medication as a confounding variable in relation to the effect of CES
on anxiety and depression will also be examined. Data analysis will consist of a repeated
measures design that will likely use a general linear model in SPSS and hierarchical linear
and quadratic growth models to assess individual change. The reason for this approach is
that hierarchical analysis of individual change is advantageous when there are multiple
repeated measure data patterns because it affords the research an opportunity to combine
into a single analysis (Raudenbush & Byrk, 2002). We will estimate both the individual
growth and mean growth for each point in the time series. Cross-validation of quadratic
will occur via the estimation of a piecewise linear growth models to assess whether growth
is more variable for one period over another during the study time frame.

Optimal design software has been used to make a preliminary determination that 100 or more
participants in a randomized quadratic growth individual change model will achieve a power
of .80 to .95 for a study expecting an effect size of between 0.6 to .80, respectively (0.62
is premised upon meta-analysis for CES undertaken by Klawansky, et al., 1995 and .8 is
considered a large effect by Cohen, 1988). We will employ power analysis again once sample
size is confirmed following recruitment of participants and expect upwards of 150 or more
participants. Missing data will be explained using an intent-to-treat analysis whereby we
employ redundant analysis procedures (i.e., survival analysis) to understand and context the
true treatment effect.

Inclusion Criteria:

- The subject is male or female outpatients age 18 to 65 years.

- The subject meets DSM-IV criteria for an anxiety disorder.

- Participants with comorbidity must carry an anxiety disorder as a primary diagnosis.

- Written informed consent must be obtained from the subject prior to study
participation.

- The subject is in good medical health or with chronic medical conditions which are
currently stable.

- No current abuse of alcohol or other substance.

- The subject has a total score greater than 15 on the Beck Anxiety Inventory and a
score greater than 45 on the Zung Self Report Anxiety Scale.

Exclusion Criteria:

- The subject meets DSM-IV criteria for an Axis I diagnosis (other than an Anxiety
Disorder) as the primary diagnosis (i.e., schizophrenia, mood disorder, psychosis,
anorexia nervosa).

- The subject is clinically judged by the investigator to be at risk for suicide or is
acutely suicidal.

- The subject is clinically judged by the investigator to be at risk for homicide or is
acutely homicidal.

- The subject has a psychiatric condition that would require inpatient, or partial
psychiatric hospitalization.

- Seizure disorders.

- Significant history of medical disease (i.e. cardiovascular, hepatic (e.g. cirrhosis,
hepatitis B or C) renal, gynecological, musculoskeletal, neurological,
gastrointestinal, metabolic, hematological, endocrine, cancer with a metastatic
potential or progressive neurological disorders) which could impair reliable
participation in the trial or necessitate the use of medication not allowed by this
protocol.

- Use of a pacemaker.

- The subject is pregnant, planning to become pregnant, or nursing. If a subject
becomes pregnant, she will be discontinued immediately and followed appropriately.

- Current psychotherapeutic treatment except for treatment with Specific Reuptake
Inhibitor (SSRIs) medications which include: Fluoxetine (Prozac), Paroxetine (Paxil),
Sertraline (Zoloft), Luvox (Fluvoxamine), Citalopram. Potential subjects may remain
on their medications provided that he or she has been on a stable dose prior to
entering this study; the dose and type of medication remains stable throughout the
remainder of this study; and it can be determined that this medication is not
exacerbating the anxiety symptoms.

- History of poor compliance or in the Investigator's judgment patients any subject
whose treatment as an outpatient would be clinically contraindicated

- The subject has attempted suicide one or more times within the past twelve months