Bystritsky, A., Kerwin, L., Feusner, J. A pilot study of cranial electrotherapy stimulation for generalized anxiety disorder. Journal of Clinical Psychiatry. 2008; 69:412-417. 

Funding Source, Location of Study or Author’s Affiliation
Funding was provided by a grant from the Saban Family Foundation to Dr. Bystritsky. This study was conducted at the Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, California.

Device
Alpha-Stim^® SCS

Key Variables
Anxiety and depression.

Objective
To evaluate the effect of a specified treatment course with cranial electrotherapy stimulation (CES) on the anxiety and depression levels in general anxiety disorder (GAD) patients.

Design
An IRB approved 6-week open label study. Baseline measurements were done just prior to the first CES treatment and outcome variables measurements were done at endpoint of study right after the final CES treatment. The Mini-International Neuropsychiatric Interview was conducted at screening to confirm GAD diagnosis using DSM-IV criteria. Patients were eligible for the study if they met a cut-off score of >16 on the HAM-A and a score <I7 on HAM-D17.

Primary Outcomes Measures

• Primary outcome 1 Anxiety as measured by scores on the Hamilton Anxiety Rating Scale (HAM-A).
• Primary outcome 2 Depression as measured by scores on the Hamilton Rating Scale for Depression (HAM-D-17).
• Clinical Global Impression-Severity of Illness Scale (CGI-S).
• Clinical Global Impression-Improvement Scale (CGI-I) score beginning in week 2.

Secondary Outcomes Measures

• Four-Dimensional Anxiety and Depression Scale – Anxiety subscale (FDADS-A).
• Patient Global Impressions – Improvement (PGI-I) scale.

Key Inclusion Criteria

• Male or female outpatients 18-64 years who had a current diagnosis of GAD.
• Mini-International Neuropsychiatric Interview (MINI) was conducted at screening to confirm GAD diagnosis.
• Must have a score of >16 on the HAM-A and <17 on the HAM-D-17.

Key Exclusion Criteria

• Primary diagnosis meeting DSM-IV criteria for any Axis I disorder other than GAD.
• DSM-IV diagnosis of mental retardation, pervasive developmental disorder, or neurologic impairment.
• Current diagnosis or recent (6-month) history of drug or alcohol dependence or abuse.
• Current suicidal ideation and/or history of suicide attempt.
• Any personality disorder of sufficient severity to interfere with participation in the study.
• Presence or history of a medical disease that might put the patient at risk or compromise the study.
• Pregnant or breastfeeding women and those of childbearing potential who were not practicing a reliable form of contraception.

Protocol Summary
Baseline measures were done prior to start of treatment and outcomes measures were done at end point of study, six weeks. No change was made in the medical management of the patients during the study. After instruction on how to use the CES device, participants subsequently self-administered CES at home Those treated with benzodiazepines (alprazolam and lorazepam) took them on an as-needed basis no more than twice per week.

Device Application Protocol
Subjects self-administered CES for 60 consecutive minutes each day between the hours of 3:00 PM and 7:00 PM for a total of six weeks. Subjects recorded each treatment session in daily treatment logs, which were reviewed at three weeks and six weeks study visits. All subjects chose 300 µA as their preferred level of current.

Statistical Analysis Plan
Apriori hypothesis was that application of an Alpha-Stim would reduce anxiety. Response to treatment was defined as a reduction of 50% or more on the HAM-A and a CGI-I score of 1 or 2 (very much improved or much improved, respectively).

Results

Subjects
A total of 15 subjects expressed interest in the study and engaged in an initial telephone screen. 20% of participants (N=3) were deemed ineligible to participate because of age (N=1) and psychiatric comorbidity (N=2). Twelve (12) subjects enrolled and received CES treatment. The mean and SD age of the sample was 42.83±10.27 years. Of the 12 individuals enrolled in the study, 9 females and 3 males, 5 participants had been taking psychotropic medications (venlafaxine, N=2; alprazolam, N=2; lorazepam, N=1) for at least 3 months prior to enrollment and continued throughout the study. Two of these had failed 2 previous adequate trials of SSRIs. There were no statistically significant differences at baseline on any of the outcome measures. Nine (9) subjects completed the testing at the endpoint of the study, week 6.

Data Analysis
Data were analyzed using a one sample paired t-test to compare baseline to endpoint means on outcome variables with significance levels set at p=.05, 2-tailed. After treatment, participants exhibited a significant change from baseline (30.58±11.24) to endpoint (23.83±7.57) on the FDADS-Anxiety subscale scores (t=2.35, p=0.039, d=-.75) as well as on the HAM-A (baseline 21.25±5.82; endpoint 12.67±5.47; t=3.083, p=0.01, d=-1.52). In addition, a significant difference was exhibited in HAM-D-17 scores from 10.50±15.01 at baseline to 6.00±3.64 at endpoint (t=3.01, p=0.01, d=-.41).

Mean anxiety scores on HAM-A and FDADS-A

Mean depression scores pre- and post-treatment

Safety Outcome Measures
Three subjects withdrew from the study after baseline measures because of the side-effects of headache (N=2) or dizziness (N=1). These side-effects are suggestive of a central nervous system effect by CES.

Conclusion
This study indicates CES may improve anxiety and depression symptoms associated with GAD. The value of this study is that it forms a basis for a large randomized controlled trial on the effect of CES on GAD. This study is also valuable because the findings are consistent with the findings of RCT studies that showed CES significantly decreases anxiety.

Limitations
This study has the limitations of an open-label small pilot study, such as the small number of subjects. The authors also state because of the small N of the study, the placebo effect associated with GAD could be a confounding variable.

Study Quality: FAIR