A Single Blind Study of Cranial Electrical Stimulation in Bipolar II Disorder
Condition: Bi-polar II Disorder
Study type: Interventional

Summary: 
      The purpose of this study is to assess the antidepressant effects of Cranial Electrotherapy
      Stimulation (CES) in the depressed phase of bipolar II disorder.; to examine the safety of
      daily CES in bipolar II patients; and to examine the effects of 20 minutes of daily CES on
      EEG reading.

      The investigators hypothesize:

        1. The CES will reduce symptom severity more than sham (placebo) CES.

        2. That CES administered for 20 minutes daily for four weeks is safe and well tolerated
           when treating bipolar II patients.

        3. That CES will shift the alpha and beta power fractions of EEG downward, and that this
           shift correlates with a decrease in level of anxiety and depression
    

Detailed description: 
      I. ABSTRACT

      Cranial electrical stimulation (CES) is a non-invasive brain stimulation technology that uses
      a small alternating current (1-2mA) applied to the scalp to affect brain function. The
      strength of the current is similar to that used by transcranial direct current stimulation
      (tDCS); the only difference is that in the case of CES the current is alternating. CES has
      been FDA sanctioned for the treatment of depression, anxiety and insomnia since 1978. CES was
      never subjected to the level of regulatory review now required for new technologies because
      it was "grandfather-ed" based on a device that predated the current FDA regulations. As a
      consequence, although hundreds of thousands of people have been treated with CES since its
      development in the 1950's, claims for its effectiveness have been largely anecdotal and the
      studies have been hampered by poor study design and inadequate blinding. It is important to
      study under well-controlled conditions whether this product, already in widespread use, is
      truly effective. This study will examine the efficacy of CES in treating the depressive phase
      of bipolar II disorder using a rigorous controlled design. It will be the first study of the
      use of CES in bipolar II disorder, and the first well controlled study of the antidepressant
      effects of CES. Because CES is already clinically available and large numbers of patients
      have received it (usually as an at-home, self treatment), it is important to conduct a
      randomized controlled trial rather than to merely replicate the anecdotal reports that
      already exist in the literature.

      II. RESEARCH PLAN

        1. Background and Rationale

           Regulatory Status of CES

           CES is currently FDA sanctioned and may be marketed for the treatment of depression,
           anxiety and insomnia. The Fisher-Wallace Cranial Stimulator (model SBL500-B), which
           became FDA sanctioned for the treatment of anxiety, insomnia, and depression in 1990
           (510K approval), uses 0.5-2 mA (milliampere) of alternating currents in three
           frequencies (15Hz, 500 Hz, 15,000Hz) and is the same device as the Liss Cranial
           Stimulator (model SBL201-M), a class III device, which has been marketed since the
           1970's for treatment of depression, anxiety and insomnia.

           State of the Evidence on the Clinical Efficacy of CES

           Although CES has been in wide usage both in Europe and the United States for more than
           50 years; there are few well controlled studies published which demonstrate its
           efficacy. Its mechanism of action is unknown, though recent EEG studies suggest an
           effect on brain oscillations (Marshall et al., 2006. Schroeder et al., 2001). It appears
           to be benign, and no adverse events have been reported in the literature except for mild
           headache and tingling under the electrodes.

           The results of a 1992 meta-analysis by the Harvard School of Public Health of the
           effectiveness of CES concluded that published studies on CES are hampered by poor study
           design and inadequate blinding.

           Using as their gold standard a randomized controlled trial comparing CES with sham in a
           double-blind manner, they rejected studies from the former Soviet Union, which were only
           uncontrolled. Searching human studies in English they found 18 randomized controlled
           trials of CES vs. sham, using a variety of CES devices to treat depression, anxiety,
           drug addiction, insomnia, headache and pain. In this analysis, they did not analyze
           differences in signal parameters or treatment regimens.

           Purpose of the Present Study

           This is a single-blind, randomized, sham controlled study to evaluate the efficacy of
           CES in treating the depressive phase in patients with bipolar II disorder. This will be
           the first well controlled study of the role of CES in treating depression as well as the
           first well controlled study of the role of CES in treating bipolar II disorder.

           We decided to focus on depression in the context of bipolar II disorder because there is
           a need to increase the number of effective treatments for the depressive phase of
           bipolar II disorder, and to identify effective antidepressants that do not promote a
           switch to mania. To this end, we will assess risk of hypomania or mania using
           standardized scales. Of note, there have been no reported cases of hypomania or mania
           with CES. Furthermore, we wanted to increase sample homogeneity by limiting the study to
           bipolar II patients, and have therefore excluded unipolar depressive disorder as well as
           bipolar I disorder.

           We will recruit 20 bipolar II patients aged 18-85 who are currently in a depressive
           phase of their illness (mixed and manic episodes will be excluded). They will be
           randomly assigned to two groups: a placebo group and an active group, for the first two
           weeks of the study. The CES device which we will use will be the Fisher-Wallace Cranial
           Stimulator, which uses 1mA (milliampere) of alternating current in three frequencies
           (5Hz, 500Hz, and 15,000Hz). In this study, patients will receive CES for 20 minutes a
           day, five days a week. Patients will be able to remain on their medications to avoid the
           risk to subjects by withdrawing them from medication, but the dosages must be kept
           stable for at least two weeks prior to entering the study and for the first month of the
           study.

        2. Recruitment Methods

           Patients likely to meet inclusion/exclusion criteria will be recruited from the
           inpatient and outpatient units at Beth Israel Medical Center via advertisements in
           newspapers and other media, or by physician referral from sites participating in the
           registry. Outpatients will also be screened at Beth Israel Medical Center.

           Sample Description

           Patient recruitment will reflect the referral patterns to the outpatient clinic
           participating in the study. Given the gender distribution in the prevalence of bipolar
           II disorder, it is expected that approximately half the sample size will be female and
           half will be male. It is expected that the sample composition will be approximately 80%
           Caucasian, 10% African American, 5% Hispanic, and 5% Asian or other ethnic group.

        3. Study Procedures

      Screening, Informed Consent

      Investigators will screen patients based on the inclusion/exclusion criteria after a written
      informed consent, and general medical and psychiatric histories, are obtained. At enrollment,
      a general medical history and comprehensive physical and neurological examinations will be
      obtained, along with screening laboratory analysis of blood and urine (for medical
      exclusions, drug screen, and pregnancy screen if appropriate).

      During the baseline period (after informed consent) but prior to treatment with CES
      participants' physical functioning, emotional well being, life satisfaction, depression and
      manic symptoms will be assessed. And documentation of prior and current mood disorder
      treatments; documentation of other regularly-used, prescribed, and over-the-counter
      medications and supplements/botanicals; and the neuropsychological battery (described below)
      will be obtained.

      Patients will be maintained on the same dosage of their antidepressant medication beginning
      two weeks prior to entering the study (four weeks for fluoxetine). During phase I (two weeks)
      and phase II (two weeks), patients will be asked to keep their medications and dosages
      stable. In phase III of the study, medications and dosages may be adjusted as needed.

      EEG recording

      We will record a standard 64 channel EEG for five minutes before the first CES session and
      for five minutes after the first CES session, as well as after the 8th week to evaluate acute
      and long term effects of CES on EEG. The electrodes are given 25 minutes to stabilize and a
      CES sensation threshold is determined for the patient.

      Phase I, Randomization Phase

      Patients will be randomized to either the active CES or control group on a 1:1 basis.
      Patients will be asked about changes in medical state, medication or caffeine or alcohol
      intake, change in sleep patterns prior to beginning study procedures at each visit. CES
      sessions will be performed 5 days a week for two weeks.

      Sham CES is performed by turning the current on until the patient experiences a tingling
      sensation on the scalp, then decreasing the current to just below threshold. This is the sham
      procedure described in the literature.

      Criteria for Treatment Continuation / Discontinuation (Phase I):

      At the end of each week, a blinded rater will administer the Hamilton Depression Rating Scale
      (HRSD 17 item), Global Assessment of Functioning (GAF), Clinical Global Impression (CGI). At
      the end of Phase 1, patients will be classified into one of three groups:

        1. Stable remission: HRSD17 ≤ 7 at the end of the second week. These patients go to Phase 3
           and enter naturalistic follow up.

        2. Non-improving: Less than 30% decrease in the Hamilton Depression rating Scale (HRSD)
           from baseline. These patients will be crossed over to the open-label CES in Phase II.

        3. Improving: 30% or greater decrease in the HRSD from baseline. These patients will also
           be crossed over to receive open label CES in Phase II.

      Phase II, Open-Crossover Trial

      Phase II is the open label phase in which subjects will receive active CES for two weeks.

      Phase III, Naturalistic follow up

      2-month naturalistic follow-up for all study participants is included to examine whether
      antidepressant effects of CES persist beyond the acute, active treatment phase. Patients will
      be maintained on their medications unless changing types and dosages of medication is
      clinically indicated.

      Patients will be rated weekly, up to 2 months (8 follow up visits). The following assessments
      will be performed at the weekly follow-up visits: symptoms of depression and global
      assessment of functioning. Neuropsychological Testing will be done at baseline, two weeks,
      four weeks and eight weeks.

      Drop-out Criteria

      If a patient has a CGI Global Improvement score of 6 or higher (i.e. "Much Worse" or "Very
      Much Worse" compared to baseline) sustained across 2 assessments they will be withdrawn from
      the study and referred to appropriate treatment. Additionally, if a patient develops
      psychotic symptoms, develops acute suicidal intent and/or plan, needs psychotropic
      medications to be changed or increased to treat clinical worsening, or requires inpatient
      psychiatric admission, or develops manic symptoms; they will be withdrawn from the study and
      referred to appropriate treatment.

      Data Analysis

      An n of 20 was selected based on the precedent set by a previous CES study where a 50%
      reduction in GAD symptoms was observed with an n of 12 (p =0.01) (Bystritsky, Kerwin, &
      Feusner, 2008). We expect similar effect size in our study.

      4. Confidentiality

      Subjects will not be mentioned by name. Research records, like other medical and clinical
      records, will be kept confidential to the extent permitted by law. Any information obtained
      during this study will only be available to the research staff, institutional personnel, or
      to federal and New York State regulatory personnel. There are legal advocacy organizations
      that have the authority under state law to access otherwise confidential research records,
      though they cannot re-disclose this information without subject's consent. All information
      will be stored in locked files and will not have subject's name or any other identifying
      information associated with it.

      All data (written and electronic) will be coded. A master list matching the subject with
      codes will be kept under lock and key, separate from any research records or the computer
      database, with access restricted to research staff, to the extent permitted by law. Only
      staff directly involved in this project will have access to the master list linking subject's
      name to code numbers. Subject's name and other personal identifying information will be
      stored in files and in an electronically secure database at the hospital.
    

Intervention name(s): Active CES; Sham CES
Intervention type(s): Device; Device
Intervention description(s): The active CES treatment group will receive the following dose of CES delivered over the temples bilaterally: 2mA of alternating current qt 1Hz, 5Hz, and 15,000Hz for one 20 minute session per day for 5 times per week for four weeks.; The CES sham group will receive sham CES (device off) for 20 minutes 5 times per week for two weeks.
Other intervention name(s): FW-100 Fisher Wallace Stimulator; FW-100 Fisher Wallace Stimulator
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Outcomes Assessor)
Primary purpose: Treatment