A Pilot Study of Cranial Electrotherapy Stimulation[CES] for Generalized Anxiety Disorder
Condition: Generalized Anxiety Disorder
MeSH terms: Anxiety Disorders
Study type: Interventional
Phase: Phase 4

Summary: 
      Cranial electrotherapy stimulation(CES) is a noninvasive procedure that has been used for
      decades in the United States to treat anxiety, depression, and insomnia in the general
      population. Whether CES is an effective treatment for patients with a DSM-IV diagnosis of
      generalized anxiety disorder (GAD) has not previously been explored. The goal of this study
      was is to evaluate the efficacy of CES in alleviating anxiety in patients with
      DSMIV-diagnosed GAD. Specifically our hypothesis was that CES would demonstrate possible
      efficacy in reducing symptoms associated with GAD from baseline to end of trial, as
      determined by: (1) change from baseline in the Hamilton Anxiety Scale (HAM-A) total score.
      a.) the proportion of responders (much or very much improved) as assessed by the CGI
      Improvement ratings by visit b.) the proportion of responders (50% reduction from total HAM A
      baseline score) according to the HAM A scores by visit c.) the proportion of patients in
      remission (HAM A score ≤7) by visit
    

Detailed description: 
      This study utilized a 6-week open-label design to test CES in the treatment of GAD. The study
      was funded by Saban Family foundation. The devises were provided by Electromedical Products
      Inc. (EPI) which is a technology company manufacturing the cranial stimulators. This company
      has no relationship with any of the investigators of the study. There are no explicit or
      implicit conflicts of interest. Participants were recruited from August 2005 to March 2006
      from the UCLA Anxiety Disorders Program at the Semel Institute for Human Behavior. Permission
      from UCLA's Institutional Review Board was obtained to conduct this study. All eligible
      subjects provided approved written consent prior to the initiation of any study related
      procedure.

      Patient Selection: Male or female outpatients aged 18 to 64 years were eligible if they had a
      current diagnosis of GAD. At screening, GAD diagnosis was confirmed by conducting the MINI
      interview.(Sheehan, Lecrubier et al. 1998) Patients had to have a score ≥ 16 on the Hamilton
      Anxiety Rating Scale (HARS) and < 17 on the 17-Item Hamilton Depression Rating Scale (HDRS)
      at baseline to be considered for enrollment.(Hamilton 1959; Hamilton 1960) Lower then usual
      HARS were permitted to include milder cases of GAD. Patients were excluded if they had a
      primary diagnosis meeting DSM-IV criteria for any other Axis I disorder other than GAD, as
      were patients who met DSM-IV criteria for mental retardation, any pervasive developmental
      disorder or neurological impairment. Also excluded were those with a recent (6 months)
      history or current diagnosis of drug or alcohol dependence or abuse, current suicidal
      ideation and/or history of suicide attempt or any personality disorder of sufficient severity
      to interfere with participation in the study. Other exclusion criteria included a history or
      presence of a medical disease that might compromise the study or be detrimental to the
      patient. Women who were pregnant or breastfeeding and women of childbearing potential who
      were not practicing a reliable form of contraception were also excluded from the study and
      the use of any psychotropic medication. Patients were permitted to be on a stable,
      therapeutic dose of SSRI or SNRI if they were taking their medications for at least 3 month
      and were still symptomatic after at least 3 months of treatment. Patients who used PRN
      as-needed benzodiazepines were permitted to enter the study if their use of the medications
      did not exceed two times per week. Women who were pregnant or breastfeeding and women of
      childbearing potential who were not practicing a reliable form of contraception were also
      excluded from the study. Study visits were conducted at baseline and at the end of 3 and 6
      weeks of treatment. Patients who met all of the eligibility criteria at baseline were
      enrolled and administered CES treatment.

      Results: Fifteen subjects expressed interest in the study and engaged in an initial telephone
      screen. Eight percent (n=3) of participants were deemed ineligible to participate. Reasons
      for ineligibility included age (n=1; 3%) and psychiatric co morbidity (n=2; 6%). Twelve
      subjects enrolled and received CES treatment. The mean age of the sample was 42.83±10.7
      years. Of the twelve individuals enrolled in the study 9 (75%) were female and 3 (25%) were
      male. Five participants (41.6%) had been taking psychotropic medications for at least 3
      months prior to enrollment and continued throughout the study; two participants took
      venlaflaxine and the remaining 3 patients took benzodiazepines on an as-needed basis no more
      than twice a week (2 took alprazolam, and 1 took lorazepam). Overall, 75% of patients (n=9)
      completed the study. Three subjects discontinued after baseline due to adverse events,
      including dizziness (n=2) and headache (n=1). A significant change (11.5 points) was found
      from baseline to endpoint in HARS scores (t= 8.59 p= 0.001). The mean change from baseline
      was significant after 2 weeks of treatment and continued to increase over time. At endpoint,
      6 (66%) of 9 patients had a 50% decrease on HARS and a score of 1 or 2 on CGI improvement,
      and were considered responders to treatment. An additional patient improved but did not meet
      criteria for response. Mean HDRS score changed from 10.5±15.01 at baseline to 6±3.64 at
      endpoint (t= 3.01, p=0.01). A significant change was also found from baseline (30.3±11.49) to
      endpoint (23.3±6.76) in UCLA 4D Anxiety Subscale scores (t=2.63, p= 0.03).

      Results of the current study demonstrate a significant improvement with CES, with a decrease
      in HARS score similar to that found in clinical trials with antidepressant and anxiolytic
      medications .(Katz, Reynolds et al. 2002; Rickels and Rynn 2002; Pollack, Meoni et al. 2003;
      Sheehan and Mao 2003; Bielski, Bose et al. 2005; Brawman-Mintzer, Knapp et al. 2006; Dhillon,
      Scott et al. 2006). The effect size is 2.4 appears to be very large. However, it is expected
      in an open trial where some part of the parts of the effect could be due to placebo response.
      The above cited studies had an effect size for placebo ranging from 0.74 to approximately
      1.72. Most of the recent pharmacological studies in GAD observed a large placebo response
      which makes it imperative to conduct placebo-controlled or sham-controlled study to fully
      evaluate the treatment effect in this population (Rickels and Rynn 2002)

      The patients generally liked the treatment and 3 of them continued to use the devise after
      the experiment was over and purchased their own CES stimulator. However, 3 of the subject
      experience the side effects which caused them to withdraw prematurely from the study.
      Presence of side effects in some of the patients could be the sign of some physiological
      effect in these patients which needs to be studied in future studies.
    

Intervention name(s): Cranial electrotherapy stimulation (CES)
Intervention type(s): Device
Intervention description(s): Cranial electrotherapy stimulation (CES) is a noninvasive procedure that involves applying a pulsed, low-amplitude electrical current to the head using electrodes placed on the earlobes. Cranial electrotherapy stimulation CES received U.S. Food and Drug Administration (FDA) approval for the treatment of insomnia, depression, and anxiety in 1979.
Other intervention name(s): Alpha-Stim Stress Control System (SCS)
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Cranial Electrostimulation Therapy