Alternating current cranial electrotherapy stimulation (CES) for depression

  • Review
  • Intervention

Authors


Abstract

Background

Depression is a mood disorder with a prevalence of approximately 1% to 3% worldwide, representing the fourth leading cause of disease burden globally. The current standard treatments of psychological therapy and antidepressant medications are not effective for everyone, and psychotropic drugs may be associated with significant adverse effects. Cranial electrical stimulation (CES) treatment, in which a low intensity electrical current is administered through the use of a small, portable electrical device, has been reported to have efficacy in the treatment of depression with minimal adverse effects. This systematic review investigated the scientific evidence regarding the efficacy and safety of CES in treatment of acute depression compared to sham, or simulated, CES treatment.

Objectives

To assess the effectiveness and safety of alternating current cranial electrotherapy stimulation (CES) compared with sham CES for acute depression.

Search methods

We searched The Cochrane Collaboration Depression, Anxiety and Neurosis review group's specialized register (CCDANCTR-Studies and CCDANCTR-References) to February 24, 2014 This register contains relevant randomized controlled trials from: The Cochrane Library (all years), MEDLINE (1950 to date), EMBASE (1974 to date), and PsycINFO (1967 to date). We examined reference lists of review papers and books on CES. We contacted authors, other experts in the field and CES manufacturing companies for knowledge of suitable published or unpublished trials.

Selection criteria

Randomized controlled trials of CES versus sham CES for the acute treatment of depressive disorder in adults aged 18 to 75 years.

Data collection and analysis

We planned to extract data from the original reports of included studies independently by two authors. The main outcomes to be assessed were:

(1) the efficacy of CES in reducing symptoms of depression as reflected in change scores on standardized depression rating scales.
(2) the tolerability of CES treatment to participants, as reflected in rates of discontinuation due to adverse effects.

We planned to analyze data using Review Manager 5.

Main results

No studies met the inclusion criteria for this review.

Authors' conclusions

There are insufficient methodologically rigorous studies of CES in treatment of acute depression. There is a need for double-blind randomized controlled trials of CES in the treatment of acute depression.

Plain language summary

Alternating current cranial electrotherapy stimulation in the treatment of depression

Review question

We reviewed the evidence on the use of cranial electrical stimulation (CES) in people with acute depression. More specifically, we were interested in examining the evidence from high quality clinical trials in which patients with acute depression were randomly assigned to treatment with either active CES or sham (simulated) CES, We found no high quality studies.

Background

We wanted to discover whether cranial electrotherapy stimulation (CES) is an effective treatment for depression.

Depression is a mood disorder characterized by predominantly depressed mood, appetite change, sleep disturbance, lack of energy, impaired concentration, lack of interest or pleasure, and sometimes suicidal thoughts, resulting in impaired functioning at work and in interpersonal relationships. In order to confirm a diagnosis of depression, these symptoms must be present for at least two weeks.

Currently, evidence-based treatment of depression consists of cognitive-behavioral psychological therapy or antidepressant medications for mild to moderate depression. For severe depression, antidepressant medications are the recommended treatment.

Cranial electrotherapy stimulation (CES) has been proposed as an alternative treatment for symptoms of depression. CES is a treatment in which a low intensity electrical current is administered to the head through the use of a small, portable electrical device. A sample treatment regimen might consist of daily application of the device for 30 minutes for a month, but treatment instructions vary with the device and condition being treated. In the United States CES devices require a prescription. In most other countries, marketing of CES devices is approved for stress reduction but not specific medical conditions such as depression.

Search date

The evidence in this review is current to February 2014.

Study characteristics

We found no studies meeting our criteria for inclusion.

Key results

We found no high quality clinical trials comparing CES with sham CES in people with acute depression. Currently, there is insufficient evidence to support the use of CES in treatment of acute depression.

Quality of the evidence

We found no high quality studies on the use of CES in treatment of acute depression. The key problem with the currently available research is the failure to use standardized rating scales for diagnosis and monitoring of depression,

Funding of this review

None of the authors received funding from any source to work on this review.

Declaration of conflicts of interest

None of the authors has any conflict of interest.

Background

Description of the condition

Unipolar depressive disorders constitute a category of mental illness characterized by disturbances in mood regulation, sleep and appetite biorhythms, cognitive function, interpersonal and occupational function, self-care activities such as grooming and, in extreme cases, suicidal behaviors. The defining feature of depressive disorders is the persistent experience of emotional pain, which may encompass sadness, anxiety, and irritability. For some people, the primary mood symptom is a profound blunting of emotion resulting in an inability to experience appropriate positive and negative emotions, with a consequent marked diminution of interest in activities previously associated with interest and pleasure. The mood disturbance is deemed out of proportion (in severity or duration, or both) to the circumstances that triggered the disorder. Inadequate coping skills (adaptive cognitive and behavioral responses to adversity) may be both a predisposing factor for depression and an expression of its occurrence (Akiskal 2009).

Unipolar depressive disorders are classified according to patterns of recurrence, chronicity, and severity. The two most widely used nosologic systems, the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revised (DSM-IV-TR; APA 2000), and the World Health Organization's International Statistical Classification of Diseases and Related Health Problems, 10th Revision, Version 2007 (ICD-10; WHO 2007) both define two primary depressive disorders: major depression/depressive episode (which is the more acute and severe of the depressive disorders) and dysthymia (a chronic, low-grade depression).

In DSM-IV-TR, major depression is defined by the presence of significant depressed mood or diminished interest/pleasure in activities over at least two continuous weeks, together with four of the following additional symptoms resulting in functional impairment: change in appetite; insomnia/hypersomnia; objective psychomotor agitation/retardation; decreased energy; feelings of worthlessness or excessive guilt; diminished concentration or indecisiveness; and recurrent thoughts of death or suicidal ideation (APA 2000).

The corresponding ICD-10 diagnosis of acute depression encompasses mild, moderate, and severe depressive episodes. The three core symptoms of all depressive episodes are depressed mood, loss of interest and pleasure, and lack of energy, which lead to increased fatigability and reduced activity, persisting for at least two weeks. Additional symptoms may include impaired concentration, decreased self esteem and self confidence, ideas of guilt or worthlessness, bleak and pessimistic views of the future, ideas or acts of self harm and suicide, disturbed sleep (such as waking up several hours before the usual time), and diminished appetite. Grades of depression severity are distinguished by the number, severity, and types of symptoms present. Mild depressive episode is diagnosed if two of the three core symptoms occur, along with at least two of the other symptoms, and the severity of symptoms results in only mild impairment in usual function. In moderate depression, the person must have at least two of three core symptoms, plus three or four associated symptoms, and they must experience "considerable difficulty" in continuing with usual activities. Finally, in severe depression, all three core symptoms plus four of the additional symptoms, some to a severe degree, must occur, resulting in marked functional impairment (WHO 2007).

The incidence and prevalence of depression vary significantly across populations. In general, throughout the world, women are more likely to be diagnosed with depression than men. A review by the World Health Organization (WHO) conducted as part of the Global Burden of Disease (GBD) study estimated that the incidence of depressive episodes, defined using either ICD-10 or DSM-IV criteria, ranges from 2.6% in men in Southeast Asia to 7.2% among women in North America. The same review reported that prevalence ranges from 1.0% among Western Pacific men to 3.6% in North American women (Ustun 2004).

Depression exacts a heavy personal and societal cost. It has been estimated that, at the individual level, recurrent depressive illness results in the loss of 12 productive years of role functioning at work and home (Kopelowicz 2009). At the population level, depressive disorders comprise the fourth leading cause of disease burden globally, accounting for 4.4% of total disability-adjusted life-years (DALYs) and 12% of DALYs due to illness-related disability (Ustun 2004). They are projected to become the second leading cause of total DALYs by 2020 (Donohue 2007). The adverse economic effects of depression due to absenteeism, impaired work performance, and treatment costs are severe worldwide. In Europe, the cost was estimated at about EUR 118 billion in 2004 (Sobocki 2006) and in the United States was computed at USD 83 billion in 2000 (Donohue 2007).

While the pathophysiology of depression remains unclear, evidence indicates that both biological and psychosocial risk factors contribute to its occurrence (Rihmer 2009). Demographic risk factors associated with depression include female gender and age less than 45 years. Psychosocial and environmental factors associated with depression include: marital status and social support, lower socioeconomic status, urban residence, geography (northern latitudes associated with seasonal depression), and psychosocial stress (Rihmer 2009). Genetic factors are thought to account for 40% to 50% of the risk for depression (Lohoff 2010). Other biological risk factors include medical conditions such as cerebrovascular disease, cardiovascular disease, chronic pain, and dementia (Blazer 2005).

Description of the intervention

At present, the standard first-line therapies for depression include cognitive behavioral therapy (CBT), antidepressant medications, or combination treatments using both modalities (APA 2010; NICE 2009). Electroconvulsive therapy (ECT) is considered a treatment of choice for severe, refractory depression, in people with psychotic or catatonic features, and in those with nutritional compromise or suicidality. While ECT has the highest reported rates of response and remission, the efficacy of this treatment must be weighed against the possibility of complications resulting from general anesthesia use and the risk of adverse cognitive effects (APA 2010; NICE 2009).

The effectiveness of the most widely accepted therapies for depression, namely antidepressant medications and psychological therapies, is limited, leaving many people with significant residual symptomatology and in need of alternative treatment options. Indeed, comprehensive meta-analyses of antidepressant trials indicate that only 50% to 60% of such trials indicate superiority of drug therapy over placebo (Pigott 2010). Also, some people who may have benefited from antidepressant medications may experience adverse effects that lead to treatment discontinuation. At the same time, available evidence indicates that even the most rigorously evaluated psychological therapy protocols, such as cognitive behavioral therapy, are effective in only about 60% of people with depression (Mor 2009).

Cranial electrotherapy stimulation (CES) - also called 'cranial electrostimulation', 'electrosleep therapy', and 'electronarcosis' - is a non-pharmacological treatment in which low-intensity electrical stimulation is applied to the head, usually via ear-clips or scalp electrodes. CES has been used for the treatment of depression, anxiety, and insomnia. It is distinguished from the other main form of low-intensity cranial electrical stimulation, transcranial direct current stimulation (tDCS), by the use of alternating current (AC) rather than direct current (DC) electricity. Available evidence indicates that these differences in electrical stimulation result in significant differences in biological effects (Zaghi 2010). For instance, in tDCS the application of a unidirectional current between two scalp electrodes (from the anode to the cathode) results in polarization of brain electrical activity, with acutely increased brain electrical activity under the anode and suppressed brain electrical activity under the cathode (Rosa 2012). In contrast, the electrical effects of CES on brain activity are thought to be consistent across the area of stimulation. Furthermore, the neurochemical systems responsible for mediating the after-effects of tDCS are different from those implicated in CES effects; the NMDA (N-Methyl-D-Aspartate) neurotransmitter system is centrally involved in mediating tDCS effects, while, as noted below (see How the intervention might work), other chemical mediators such as norepinephrine, serotonin, and GABA (γ-aminobutyric acid) have been implicated in CES effects (Bystritsky 2008; Zaghi 2010).

Initially developed and investigated in the early 1900s, preliminary studies indicated that such electrical stimulation produced sedation, and it was thus initially called 'electrosleep' or 'electronarcosis' (Gilula 2005; Klawansky 1995). Much of the early clinical work using CES was conducted in Eastern Europe and the Soviet Union in the 1950s, but because these clinical trials were largely uncontrolled or otherwise of poor quality, the clinical efficacy of CES remained uncertain (Klawansky 1995). A number of additional clinical trials of CES in the treatment of depression, anxiety, substance abuse, and other conditions have been completed since the introduction of CES to the United States and Western Europe in the 1960s. However, since these later studies are also of variable quality, the utility of CES in depression and other disorders continues to be unclear (Rosa 2012).

CES therapy is self-administered using battery-powered electrical devices that may be held in one hand or clipped to a belt. These devices deliver a continuous flow of low-intensity alternating current electrical stimulation to the scalp using two adhesive electrodes moistened with a conducting solution (Gilula 2005). Since the electrodes are maintained in place through their adhesive properties (possibly reinforced with a headband) and the main device may be clipped to a belt, those using them may engage in sedentary activity such as working on a computer, watching television, or reading while undergoing treatment, although some evidence suggests that results are enhanced when treatment is administered in relaxing, comfortable positions (Gilula 2005).

A standard depression therapy protocol might consist of 20 to 60 minutes of stimulation daily for the first three weeks "at a comfortable level of current," then "treatments every other day or on an as-needed basis for as long as necessary" (Gilula 2005), but considerable variability exists between treatment parameters. No consistent metric is used to describe electrical dose during a single CES administration, and trial reports only inconsistently provide details on the various parameters of electrical stimulation used. Across clinical indications, ranges for the major electrical parameters are the following: frequency, 0.5 Hz to 167 kHz; current amplitude, 100 μA to 4 mA; duration of stimulation per application, continuous application of stimulation from five minutes to six consecutive days (Zaghi 2010); recommended days of use, 30 days to the time needed to achieve benefit (Gilula 2005).

Since no comprehensive database on currently available CES devices exists, the number and variety of existing CES products is unclear. The United States Food and Drug Administration (FDA) indicates that there are 11 different CES devices cleared for marketing in the USA, but the numbers available elsewhere are uncertain. One of the more popular devices is the Fisher-Wallace Cranial Stimulator (model SLB500-B), which is the same device as the Liss Cranial Stimulator (model SLB201-M); this has been marketed for depression, anxiety and insomnia since the 1970s. This device uses scalp electrodes delivering currents of 0.5 to 1.0 mA, with rectangular pulses in three frequencies (15, 500, 15,000 Hz). Another of the more popular devices, the Alpha-Stim Stress Control System, available since the early 1980s, delivers rectangular pulses with frequencies of 0.5, 1.5 and 100 Hz, with a total current output of 10 to 600 μA, and is attached via ear clips. Other devices use different electrode placements (over the orbits, frontal areas, occipital regions) with electrical parameters varying in the ranges described above. In most countries, CES devices are available at pharmacies and through other vendors without a prescription. However, in some countries, due to the regulation of medical device advertising and marketing, CES devices may be sold only as treatments for stress rather than as therapy for medical conditions such as depression or anxiety. The United States is the only country where CES devices require a prescription from a licensed healthcare practitioner.

How the intervention might work

The mechanism of action of CES is uncertain, but a number of different models have been proposed to account for the effects of CES on the brain (Kirsch 2002; Smith 2007). These models may be better understood with a review of some of the relevant biological models of depression, which remain controversial (Krishnan 2008).

The 'monoamine hypothesis' of depression, which has been popular since the 1960s, posits that depression results from reduced activity of key neurotransmitters (the monoamine molecules serotonin, norepinephrine, dopamine), the chemical signal molecules produced and released by neurons to communicate with other neurons. All of the currently marketed antidepressants work to increase availability of one or more of these neurotransmitters, generally by blocking their reuptake or degradation (Krishnan 2008).

There is some evidence that CES increases levels of monoamines and other neurotransmitters in the brain, but how it does so remains poorly defined. A study of CES application in dogs suggests that such brain stimulation works by increasing levels of the neurotransmitter dopamine in the central nervous system (Kirsch 2002). Furthermore, trials in humans indicate that CES alters brain levels of the monoamines serotonin and norepinephrine as well as the neurotransmitter GABA (Bystritsky 2008; Zaghi 2010). Finally, an experiment in which CES was found to attenuate opiate withdrawal in rats implies that CES may also increase endorphins, endogenous neurotransmitters that act on the same neuronal receptors as opiate drugs, and mediate a variety of functions including sleep, pain, and mood regulation (Smith 2007). All of these biochemical changes are presumably caused by the penetration of some of the applied electrical current through the scalp into brain tissues, where electrical impulses stimulate changes in neuronal activity such as increasing neurotransmitter release or production (Zaghi 2010). Notably, little if anything is known about the specific function of the various parameters of electrical stimulation, as study reports often omit details on the specific electrical parameters used (Zaghi 2010).

Electroencephalography (EEG) studies offer another perspective on CES effects on brain physiology, although many important aspects of the mechanism of action of CES remain unclear. EEG machines analyze regional and global electrical activity using a series of scalp electrodes attached to a computer. The activity of individual neurons, which is mediated through the neurotransmitters described above, involves generation of electrical impulses between neurons. EEG analysis can therefore provide information about brain function (Sterman 1996). Quantitative EEG researchers have reported EEG correlates of both normal physiological processes and of abnormal mental states associated with various neuropsychiatric disorders (Hughes 1999). A recent study of CES in healthy male volunteers found that CES produced changes in brain electrical activity similar to that produced by meditation (decreases in higher frequency alpha and beta waves, which are associated with stress and arousal), replicating findings of earlier trials (Schroeder 2001). However, the mechanisms whereby CES effects such changes are yet to be defined.

Why it is important to do this review

Because medical device regulation in the United States, and much of the rest of the world, has historically been weak or non-existent, CES device makers have been able to market their product without the submission of controlled clinical trial safety and efficacy results demanded of drugmakers. Indeed, until the 1976 passage of the Medical Device Amendments (MDA) to the federal Food, Drug and Cosmetic Act (FDCA), the United States FDA did not have any regulatory power over medical devices. In 1979, the FDA approved the marketing of CES devices for treatment of insomnia, depression, and anxiety but did not require submission of clinical trial data on safety and efficacy (Bystritsky 2008). Rather, CES devices and more than 1700 other devices already in commercial distribution in the United States, referred to as 'preamendments' devices, were exempted from the 'premarketing approval' process. 'Premarketing approval' would have required submission of clinical trial safety and efficacy data for review by a panel of scientific experts before approval for marketing. Furthermore, newer CES devices have been cleared for marketing without submission of clinical trial data through the '510(k)' provision of the FDCA; under 510(k), a new device may be granted marketing approval upon submission of evidence that it is "substantially equivalent" in its technological characteristics and intended use to an existing "predicate" device (i.e., a device already approved by the FDA) (Hines 2010).

In Europe, where device regulation "is 25 years behind the regulation of medical devices in the United States, and some 25 years behind the European regulations of pharmaceuticals" (Altenstetter 2003), CES devices were granted marketing approval in 1998. Notably, as in the United States, approval of medical devices for European marketing does not require randomized controlled clinical trials demonstrating efficacy (Altenstetter 2003). In Europe and many other countries throughout the world, CES devices are available without a prescription.

Three previous meta-analyses on psychiatric applications of CES have been published (Kirsch 2007; Klawansky 1995; Smith 2007). In 1995, Klawansky et al published a well-conducted meta-analysis on use of CES to treat anxiety, brain dysfunction, headache, and insomnia, but did not consider its use in depression (Klawansky 1995). More recently, Kirsch and Gilula reported on a meta-analysis of CES in depression but provided no information on prespecified trial search strategy or inclusion criteria. Furthermore, their summary effect size statistic represents an unweighted average of the percentage improvement on various clinical rating scale scores only in participants receiving active CES treatment, rather than between-group comparisons between participants receiving active and sham treatment. In addition, because they pooled data from open-label, uncontrolled trials, and blinded, controlled trials, where quality of allocation concealment is not explicitly addressed, it is likely that their treatment effect is biased toward an overestimate of effect size. Also, interpretability of their findings is further compromised by their inclusion of trials with marked heterogeneity of primary diagnoses (alcoholism, fibromyalgia, attention deficit-hyperactivity disorder (ADHD), insomnia). Finally, they excluded one negative controlled trial on the grounds that improvement in sham CES-treated participants (inactive treatment control group) "invalidated" the study (Kirsch 2007). Similar problems undermine the conclusions of a meta-analysis of CES trials in depression reported in Smith's monograph on CES (Smith 2007).

In the absence of a systematic review and meta-analysis on the topic, this review may help to elucidate the scientific evidence on the safety and effectiveness of CES, so that healthcare providers and people with depression may make informed choices on the use of CES as a treatment option.

Objectives

To assess the effectiveness and safety of alternating current cranial electrotherapy stimulation (CES) compared with sham CES for acute depression.

Methods

Criteria for considering studies for this review

Types of studies

Randomized, double-blinded (in which both participants and outcome assessors are blinded to treatment allocation), parallel-group trials were eligible for inclusion in this review.

In sham CES treatment, devices that are visually identical to those used in active treatment deliver either no current or only a brief, low-intensity current sufficient to produce skin tingling at the site of electrode attachment (O'Connell 2011).

Cluster-randomized trials were eligible for inclusion (although this trial design is rarely used in studies of biological therapies for depression).

Cross-over trials were eligible, but we planned to use only data from the first treatment period.

Types of participants

Adults (persons aged 18 to 75) with a primary diagnosis of a depressive disorder diagnosed according to standardized diagnostic criteria (e.g., DSM-IV (APA 2000), ICD-10 (WHO 2007)).

Trials in which participants have common comorbid psychiatric disorders, such as anxiety or substance misuse disorders, were to be included if they met all other inclusion criteria. Trials in which participants have comorbid medical conditions known to affect mood or response to antidepressant treatment were to be included if they met all of the other inclusion criteria.

Studies in which participants have dementia or other conditions characterized by structural brain damage or brain neurodegeneration, psychotic disorders, or personality disorders, were to be excluded.

Since the focus of this review is on treatment of acute depression, we planned to exclude trials of CES in chronic or refractory depression.

Types of interventions

Experimental intervention

Participants are treated with a CES device to administer a dose of alternating current electrical stimulation thought to be sufficient to penetrate the skull and induce changes in brain electrical activity. Electrodes are applied to the head via ear-clips or scalp electrodes held in place by a head band or adhesive material. Participants undergoing CES may either be resting comfortably or engaged in sedentary activity. As noted above (under Description of the intervention), electrical parameters used in active CES treatment vary across studies, as does the duration of treatment (both the amount of time CES is applied per treatment session and frequency of treatment sessions). Since there may be only a few trials eligible for inclusion in this review, trials were not to be excluded based on the electrical parameters used or frequency/duration of CES treatments, and dose-ranging trials were to be included if they contained a sham CES control arm.

Control/comparator intervention

Participants receiving the control intervention receive sham CES. In sham CES, a CES unit visually identical to the active CES device is used to administer electrical stimulation to the skin under the electrodes sufficient to induce local tingling but insufficient to penetrate the skull. Local skin irritation can be achieved with electrical stimulation at a current intensity significantly less than is needed to pass through the underlying muscle and bone. In the most rigorous trial designs, the superficial current in the sham treatment is individually adjusted for each participant to match the tingling caused by active treatment, such that participants are unable to distinguish between the sham and active interventions (Feighner 1973; Hearst 1974; Marshall 1975).

Excluded interventions

We planned to exclude head-to-head trials comparing CES with another active intervention and no sham treatment arm.

Types of outcome measures

Validated self-rated and observer-rated depression scales are used to generate continuous variable measures of depression severity. They may also be used to generate dichotomous outcome variables such as treatment response/non-response and remission/non-remission. Thus, a common definition of depression treatment 'responder' is a participant experiencing a greater than 50% improvement in the baseline depression score. Remission is usually defined by the occurrence of a depression score below a specific value designating minimal residual depressive symptoms. Remission is arguably a more important and robust treatment goal, but may not be consistently reported.

We planned to provide a descriptive summary of adverse events, as reported in the clinical trials, and to examine rates of adverse events.

Primary outcomes
  1. Primary benefit outcome: differences in change scores between intervention and control groups on validated rating scales such as the following:

    1. Observer-rated depression rating scale such as the Montgomery-Asberg Depression Rating Scale (MADRS) (Montgomery 1979) and the Hamilton Rating Scale for Depression (HAM-D) (Hamilton 1960).

    2. Self-rated depression scale such as the Beck Depression Inventory (BDI) (Beck 1988; Beck 1993).

  2. Primary harm outcome: differences in rates of discontinuation due to adverse events between active treatment and control groups.

Secondary outcomes
  1. Response and remission rates.

  2. A validated global change measure such as the Clinical Global Impression of Change scale (CGIC) (Guy 1976).

  3. Differences in change scores on anxiety rating scales such as the Hamilton Anxiety Rating Scale (HAM-A) (Hamilton 1959).

  4. Rates of adverse events.

  5. Discontinuation rates due to lack of efficacy and to all causes.

Timing of outcome assessment

Outcomes may be reported at different follow-up periods. In general, since most CES treatment protocols for depression involve multiple treatments per week over at least a few weeks, we expected that outcome assessments would occur after one to two weeks of treatment, then every one to two weeks until trial completion (2 to 10 weeks). In some cases, longer-term outcomes of three, six, nine, or 12 months may be reported.

Search methods for identification of studies

The Cochrane, Depression, Anxiety and Neurosis Review Group's Specialized Register (CCDANCTR)

The Cochrane Depression, Anxiety and Neurosis Group (CCDAN) maintain two clinical trials registers at their editorial base in Bristol, UK: a references register and a studies-based register. The CCDANCTR-References Register contains over 35,000 reports of randomized controlled trials in depression, anxiety, and neurosis. Approximately 60% of these references have been tagged to individual, coded trials. The coded trials are held in the CCDANCTR-Studies Register and records are linked between the two registers through the use of unique Study ID tags. Coding of trials is based on the EU-Psi coding manual. Please contact the CCDAN Trials Search Co-ordinator (TSC) for further details. Reports of trials for inclusion in the Group's registers are collated from routine (weekly), generic searches of MEDLINE (1950-), EMBASE (1974-), and PsycINFO (1967-); quarterly searches of the Cochrane Central Register of Controlled Trials (CENTRAL), and review-specific searches of additional databases. Reports of trials are also sourced from international trials registers c/o the World Health Organization's trials portal (ICTRP), ClinicalTrials.gov, drug companies, the handsearching of key journals, conference proceedings, and other (non-Cochrane) systematic reviews and meta-analyses.

Details of CCDAN's generic search strategies can be found on the Group's website.

Electronic searches

The Trials Search Co-ordinator at CCDAN ran searches of their specialized registers (CCDANCTR-Studies and CCDANCTR-References) to 24 February 2014 using the following search terms:

CCDANCTR-Studies

Condition = (depress* or dysthymi* or "affective disorder*" or "affective symptom*" or "mood disorder*" or "adjustment disorder*") and Intervention = (electrotherapy or "electric stimulation" or "cranial electrostimulation" or "electric treatment" or "electrosleep" or "electronarcosis" or "cranial alpha stimulation")

CCDANCTR-References

Free-text = ((depress* or dysthymi* or "affective disorder*" or "affective symptom*" or "mood disorder*" or "adjustment disorder*") and ("electric stimul*" or "electric therap*" or "electric treatment*" or "electrical stimul*" or "electrical therap*" or "electrical treatment*" or electrotherap* or CES or "electrosleep" or "electronarcosis" or "cranial alpha stimulation"))

Additionally, the authors searched the WHO trials portal (apps.who.int/trialsearch/) and ClinicalTrials.gov.

Searching other resources

We searched references from related articles identified through the primary search for relevant clinical trials. In addition, we contacted the manufacturers of FDA-approved CES devices for any further unidentified clinical trials. We also contacted trial authors and experts in the field for other references.

Data collection and analysis

Selection of studies

Two of the authors of this review (HK and KL) independently reviewed the results of the search and identified trials potentially eligible for inclusion. We resolved disagreements on trial selection by discussion between the first two authors and where necessary by consultation with a third author (KC).

Data extraction and management

Study design

Two authors (HK and KL) planned to independently tabulate in a data extraction form study design, sample size, participant characteristics (demographics, diagnoses including comorbid conditions, history of prior antidepressant treatment), parameters of the interventions, trial duration, outcome measures and time points at which participants are assessed, statistical methods used, and assessment of potential sources of bias.

Participant characteristics

We planned to record participant characteristics that might impact on treatment outcome including severity of illness, presence of comorbid psychiatric and medical conditions, history of treatment refractoriness, and compliance with the treatment protocol. We also planned to record methodological factors impacting on outcomes including electrical parameters, frequency and duration of treatment, choice of outcomes measures, and quality of blinding of assessors and participants.

Main planned comparisons

Alternating current cranial electrotherapy stimulation versus sham treatment.

Assessment of risk of bias in included studies

CES trials with inadequate blinding of either participants or raters present insurmountable problems with bias. Participants must be blinded to treatment allocation because participant self report constitutes an important element in clinician-rated scales of depression and adverse events.

Had any studies been included, two authors (HK and KL) would have independently assessed the risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). The domains are as follows.

  1. Sequence generation (checking for possible selection bias).

  2. Allocation concealment (checking for possible selection bias).

  3. Participant blinding (checking for possible performance bias and detection bias).

  4. Outcome assessor blinding (checking for possible performance bias and detection bias).

  5. Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations).

  6. Selective reporting bias (checking if expected outcomes were reported).

  7. Other sources of bias (such as stopping the trial early or changing methods during the trial).

We would have rated studies according to whether the risk of a particular type of bias is adequately controlled for or not with the following assessments: low risk of bias, high risk of bias, or unclear risk of bias.

Measures of treatment effect

Continuous outcomes

Since different trials are likely to use different continuous outcome scales, we planned to compute standardized mean differences (SMDs) together with 95% confidence intervals (CIs) as the summary measure of continuous outcomes. We also planned to generate separate SMD values for self-reported and observer-rated scales.

Dichotomous outcomes

For dichotomous outcomes, the summary statistic was to be the risk ratio (RR) together with its 95% confidence interval (CI).

Unit of analysis issues

Cross-over trials

Given the documented risk of carry-over from CES (Flemenbaum 1974; Kirsch 2002) we planned to use only the first treatment period data from cross-over trials in our analyses (Higgins 2011).

Cluster-randomized trials

Although randomization in cluster-randomized trials occurs at the level of clusters rather than individuals, results from such trials are often incorrectly analyzed as though randomization had occurred at the individual participant level. If such studies are included in future updates of this review, we will attempt to correct for these analytical errors by computing the design effect and estimating the 'effective sample size' using the intraclass correlation coefficient (ICC) where reported by trialists (Higgins 2011).

Multiple-armed trials

In trials including more than two treatment arms, such as two different 'doses' of CES (e.g., different electrical parameters) versus sham CES, we would combine the two different CES groups into one active CES treatment group compared with sham CES.

Dealing with missing data

If data are missing from studies included in future updates of this review, we will contact the authors of the trial report to obtain missing data. If standard deviations remain unavailable, we will estimate them using reported group means, standard errors, or P values. If a P value is used to compute standard deviations but is imprecisely reported (e.g., P < 0.05), we will use the limiting value for this statistic to approximate the actual value (e.g., in the case of a reported P < 0.05, we will set P = 0.05) (Higgins 2011).

In cases where missing data are imputed using 'last observation carried forward' (LOCF) or other approaches, we will explore assumptions for data imputation and the potential impact on findings in the Discussion section (Higgins 2011).

Assessment of heterogeneity

Qualitative assessment of heterogeneity would have been based on consideration of possible clinical and methodological differences between trials. We would have assessed clinical heterogeneity between trials by comparison of depression severity, age and gender of participants, and presence/absence of psychiatric and medical comorbidity. We would also have assessed methodological heterogeneity between trials by comparison of electrical parameters and outcome measures. In future updates of this review, if there are at least two trials per subgroup, we will perform subgroup meta-analyses using clinical and methodological subgroups. We will also assess the I² statistic as a quantitative estimate of heterogeneity (Higgins 2003). We will interpret I² values as follows: 0% to 40%, might not be important; 30% to 60%, may represent moderate heterogeneity; 50% to 90%, may represent substantial heterogeneity; 75% to 100%, considerable heterogeneity. Assessment of the importance of the I² statistic will depend on the magnitude and direction of effects as well as the strength of the evidence supporting this estimate of heterogeneity (P value of the associated Chi² test) (Higgins 2011).

Assessment of reporting biases

We attempted to minimize the impact of reporting bias by searching multiple sources, as indicated in our search methods above, including trial registries and unpublished trial results. In cases of incomplete results reporting, we attempted to obtain data omitted from published reports by contacting the clinical trialists. In updates of this review, we will consider the potential impact of location, language, citation, duplication, outcome reporting, and publication bias on meta-analytic results (Higgins 2011).

We will use qualitative (visual inspection) and quantitative (formal statistical tests) assessment of funnel plots for asymmetry to explore for publication bias if there are at least 10 trials in the meta-analysis (Higgins 2011). With continuous outcome variables, we will use the test proposed by Egger to assess for funnel plot asymmetry (Egger 1997; Higgins 2011). With dichotomous outcomes reported using odds ratios, we will use the test recommended by Peters 2006 to assess funnel plot asymmetry (Higgins 2011). We will interpret significant asymmetry indicated through these approaches as possible evidence of reporting bias.

Data synthesis

Where trials used different stimulation parameters (different doses of electrical stimulation) we planned to include them in a comprehensive meta-analysis to obtain a summary estimate of CES effect size in depression. We planned to use Review Manager 5 (RevMan 2012) for data synthesis.

If sufficient studies are found in subsequent versions of this review, we will base the decision to use fixed-effect or random-effects meta-analysis on the extent to which studies are deemed similar in populations, interventions, comparators, outcomes, and settings. We will perform fixed-effect meta-analyses if included trials, or a subgroup of trials, share key clinical and methodological features; otherwise we will use random-effects models to generate summary meta-analytic results.

In trials with serial assessments on participants, we will compute separate summary statistics for different follow-up periods as applicable: one week, two weeks, four weeks, six to eight weeks, 12 weeks, 24 weeks (Higgins 2011).

Subgroup analysis and investigation of heterogeneity

If trial data are available in future updates of this review, we will conduct subgroup analyses according to the following clinical or methodological features:

  1. Depression severity

  2. Gender

  3. Age

  4. Presence/absence of medical comorbidity

  5. Trial outcomes measures (i.e., self-rated versus observer-rated depression scales)

Sensitivity analysis

If trial data are available in future updates of this review, we will conduct a series of sensitivity analyses using the following criteria:

  1. Excluding trials with possible bias (as per 'Risk of bias' tables); specifically, we will consider trials rated to have inadequately or unclearly controlled for one or more type of bias possibly biased

  2. Excluding trials reporting only per protocol analyses

  3. Excluding trials reporting only observed cases analyzed

  4. Excluding cross-over trials

  5. Excluding cluster-randomized trials

  6. Excluding trials using imputed data

  7. Excluding trials with imputed standard deviations

Results

Description of studies

No studies met the inclusion criteria for this review (see Figure 1). We found one ongoing trials, and there are no trials awaiting classification.

Figure 1.

Study flow diagram.

Excluded studies

We excluded seven completed trials from the review, and most failed to meet more than one of the specified inclusion criteria (see Characteristics of excluded studies).

Five of the seven excluded trials (Greenblatt 1964; Levitt 1975; Marshall 1974; Passini 1976; Rosenthal 1972) failed to use standardized diagnostic criteria in diagnosis of depression, or failed to report the criteria used.

Although both Feighner 1973 and Hearst 1974 used specific research diagnostic criteria for diagnosis of depression, they recruited participants with chronic rather than acute depression. In both trials, participants had treatment-refractory depression of at least two years' duration.

In four of the excluded trials (Greenblatt 1964; Levitt 1975; Passini 1976; Rosenthal 1972), the choice of comparator groups constituted another reason for exclusion. Greenblatt 1964 used three active comparator arms and placebo, rather than sham CES. In the other three trials, the sham treatment did not produce a local tingling sensation, thus compromising blinding.

Studies awaiting classification

There are no studies awaiting classification.

Ongoing studies

We have listed one study as ongoing, NCT01325532, however, we expect that on completion it will not be eligible for inclusion in the review as we believe it is a single-blind study, rather than a double-blind study. We are not aware of any other ongoing studies.

Risk of bias in included studies

No studies met the inclusion criteria for this review.

Effects of interventions

No studies met the inclusion criteria for this review.

Discussion

Our review indicates that there is a dearth of rigorous clinical trial evidence supporting the use of cranial electrotherapy stimulation (CES) in treatment of acute depression. Indeed, at this time, no reports on double-blind trials with convincing sham arms are available. The lack of trial data on this intervention may be a function of unique regulatory systems in place for oversight of medical device marketing. While drug companies must conduct rigorous clinical trials in order to garner regulatory approval for marketing their treatments, medical device makers do not. In the United States, device manufacturers are able to secure marketing clearance based on demonstrating the similarity of their new devices to others that have already been approved by the Food and Drug Administration (FDA). Thus, there is no requirement that manufacturers of CES devices conduct clinical trials to demonstrate safety and efficacy. Without funding from industry, clinical investigators are severely limited in their ability to conduct intervention trials. If regulators mandated that device manufacturers submit the same quality of evidence for device approval as that provided by pharmaceutical companies for drugs, high quality clinical trials evidence regarding CES might become available.

Given the paucity of available methodologically rigorous clinical trial reports on CES in acute depression, we will, in future versions of this review, modify the inclusion criteria to allow consideration of high quality trials which might otherwise be excluded solely because of the current stringent restriction regarding the properties of sham CES treatment. Our stipulation that sham CES produce a local tingling sensation comparable to that experienced with active treatment meant that included trials had superior participant blinding. However this criterion may preclude consideration of otherwise high quality trials offering evidence on efficacy and safety of CES in acute depression. Thus, in future updates, we will continue to specify that included trials use sham CES as a comparator arm, but without the requirement that a local tingling sensation be produced by sham CES. The impact of sham CES design (with or without local tingling) on results can then be examined in the 'Risk of bias' section. If there are a sufficient number of trials to conduct a meta-analysis, the effect of sham design may also be explored through sensitivity analyses, excluding trials where sham treatment does not produce tingling.

Potential biases in the review process

Our selection and search criteria limited eligibility to only methodologically rigorous studies in acute depression. As a consequence of our stringent inclusion criteria and our search for both published and unpublished trial reports, the potential for bias in our review results is low.

Agreements and disagreements with other studies or reviews

Our conclusions conflict with those of two reviews of CES in treatment of depression, both of which claimed that clinical trial evidence supported the efficacy of CES in treatment of depression (Gilula 2005; Smith 2007). However, both of these reviews failed to examine the methodological limitations of their included trials, and simply pooled results from widely divergent clinical studies. More specifically, these earlier reviews included trials in which depressive symptoms were an outcome, regardless of whether subjects were formally diagnosed with clinical depression. Indeed, in most cases, the primary disorder was substance abuse, pain, or "stress," and participants were not required to have a diagnosis of acute depression but rather only to have some depressive symptoms.

At the same time, our conclusions are consistent with those of a recent United States FDA review of CES in treatment of depression. The FDA expert panel concluded that the effectiveness of CES for the treatment of depression is "unclear," noting significant limitations in the quality of available clinical trials (USFDA 2012).

Authors' conclusions

Implications for practice

Rigorous clinical trial evidence is lacking on the use of cranial electrotherapy stimulation (CES) in acute depression. Thus, at present, there is insufficient evidence on which to base decisions for using CES in treatment of acute depression.

Implications for research

Randomized double-blind, sham-controlled trials of CES in people with rigorously diagnosed acute depression are needed. Available clinical trial evidence is limited to reports with diagnostically heterogeneous participants and poor blinding (inadequate sham). Future clinical trials of CES in depression should recruit participants with acute depression using established clinical criteria and without comorbid disorders such as active substance abuse disorders which may affect response of the mood disorder to treatment. Participants should be randomized to treatment with sham or active CES treatment and blinded to treatment assignment. To optimize allocation concealment, sham and active treatments should be administered with devices that are identical in appearance, attached in the same way, and that produce similar superficial electrical tingling sensations. Investigators, also blinded to participants' treatment assignment, should employ validated clinical rating scales to assess response. Trial reports should provide detailed information about such methodological features and report differences in clinical change scores between treatment arms, allowing estimates of treatment effect size.

Acknowledgements

CRG Funding Acknowledgement:
The National Institute for Health Research (NIHR) is the largest single funder of the Cochrane Depression, Anxiety and Neurosis Group.

Disclaimer:
The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR, NHS or the Department of Health.

Data and analyses

Download statistical data

This review has no analyses.

Contributions of authors

HK devised the protocol undertook data extraction, data management, interpretation of results, and writing the completed review.
KL participated in data extraction, interpretation of results, and writing up of the completed review.
KC participated in writing the completed review.

Declarations of interest

HK. None.

KL. None

KC. None.

Characteristics of studies

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Feighner 1973Inclusion criteria specified that participants present with chronic rather than acute depression. Participants had treatment-refractory depression of at least 2 years' duration.
Greenblatt 1964Diagnostic criteria for depression are not specified. Trial included inpatients with depression, regardless of primary psychiatric diagnosis. Thus, participants were diagnostically heterogeneous such that only about 25% of them presented with a primary diagnosis of depression. The major diagnostic groups were "psychoneurotics, manic-depressives, involutionals, schizophrenic reactions, schizoaffective type, and a mixed category of character disorders with depression." In addition, this trial used 3 active comparator arms, rather than sham CES as the control arm.
Hearst 1974Inclusion criteria specified that participants present with chronic rather than acute depression. Participants had treatment-refractory depression of at least 2 years' duration.
Levitt 1975Inclusion criteria did not require primary diagnosis of depression using specific diagnostic criteria. Rather, the trial examined improvement in symptoms of depression, anxiety and insomnia among a diagnostically heterogeneous group of chronically mentally ill inpatients (schizophrenia, alcoholism, depression with psychotic features, and mixed neuroses and personality disorders). In addition, sham CES did not produce a local tingling sensation, thus compromising the quality of the blinding.
Marshall 1974Formal diagnostic criteria were not used in selecting participants for this trial, but rather diagnoses were drawn from treating psychiatrists' clinical notes. The participants were inpatients "displaying predominantly depressive symptomatology" without "hyperactivity or agitation." In addition, the investigators used a modified version of the Differential Emotion Scale, called the DES+D II to assess depression, but the psychometric properties of this modified scale remain poorly established, and indeed, we found no published reports on the use of this scale.
Passini 1976Formal diagnostic criteria were not used in diagnosis of depression. Subjects were eligible if "staff observation" suggested that participants had symptoms of "either anxiety of depression." Participants presented with "alcohol/drug dependency," psychotic disorders, "depressive neurosis," manic depression, personality disorders, hypochondriasis, adjustment disorders and other conditions. In addition, sham CES did not produce a local tingling sensation, thus compromising the quality of the blinding.
Rosenthal 1972Formal diagnostic criteria for depression were not used in participant selection. Diagnoses are described as "neurotic and personality disorders with prominent anxiety, depression and insomnia." In addition, sham CES did not produce a local tingling sensation, thus compromising the quality of the blinding.

Characteristics of ongoing studies [ordered by study ID]

NCT01325532

Trial name or titleNCT01325532
MethodsRandomized, single-blind study
ParticipantsMen or women aged 18 - 65 years who meet DSM-IV criteria for Major Depressive Disorder; HAM-D-17 score ≥ 15, and ≤ 23
Interventions

Active CES:Cranial Electrical Stimulation via FW-100 Fisher Wallace Cranial Stimulator (CES): current - 100Hz, symmetrical rectangular biphasic, 20% duty cycle current for 20-minutes, 5 days/week for 3 weeks

Sham CES: via FW-100 Fisher Wallace Cranial Stimulator (device off) for 20-minutes each day 5 days/week for 3 weeks

OutcomesChange in HAM-D 17 score from baseline to visit 15
Starting date2010
Contact informationDavid Mischoulon, MD, PhD
Notes 

Ancillary