Adjunctive Transcranial Direct Current Stimulation for Cognition in Major Depression
Adjunctive Transcranial Direct Current Stimulation for Cognition in Major Depression
People who have depression often have symptoms besides sad mood. Cognitive symptoms, such as
 poor memory, concentration, and decision making, are associated with disability in many
 spheres of life, and these symptoms often persist even when antidepressant treatment improves
 other symptoms (mood, energy, sleep, anxiety). Antidepressants alone fail to produce full
 remission for many patients, so it is important to study adjunctive treatments which can be
 added onto medication treatment and help restore cognitive function. The method of
 transcranial direct current stimulation (tDCS) has been shown by others to improve working
 memory and cognitive functions, and also to help with other symptoms of depression. tDCS
 involves passing a small, constant current between saline-moistened pads placed on the scalp.
 In this proposed study, 20 individuals with major depression who have cognitive difficulties
 despite taking antidepressants will participate. Over the course of a two-week period, each
 person will receive 5 sessions of either active tDCS or inactive treatments, in addition to
 their medication. Each session lasts for 20 minutes, and will be administered on alternating
 days (M-W-F). Assessments of depressive symptoms, cognitive function, and brain activity will
 be made prior to any sessions, after the first one, and after the fifth (final) session;
 brain function will be assessed by measuring the brain's electrical activity ("brain waves").
Transcranial direct current stimulation (tDCS), also sometimes termed "DC polarization" or
 "brain polarization," is a non-invasive procedure that has been used successfully as a
 therapeutic intervention in a number of patient populations. tDCS involves the passing of
 very weak currents through an area of interest of the brain, by placing electrodes on the
 scalp at the appropriate locations. DC polarization has been shown to alter the amplitude of
 evoked potentials in the visual cortex (Antal et al., 2004), and cortical processing in the
 parietal lobe also can be modulated by tDCS (Rogalewski et al., 2004). From a more
 physiologically-relevant perspective, tDCS of the motor cortex has been shown to improve
 motor function in patients following stroke (Hummel and Cohen, 2005; Hummel et al., 2006;
 Boggio et al., 2006b) when applied to the prefrontal cortex. tDCS has been shown to improve
 working memory in healthy individuals (Fregni et al., 2005b), and in individuals with major
 depressive episode. In MDD it has more recently been shown to improve depression rating
 self-report scores (Fregni et al., 2006a) and cognitive performance (Fregni et al., 2006b).
 Performance on a executive function task (go/no-go) was also shown to be enhanced with tDCS
 in adults with MDD (Boggio et al., 2006a). tDCS has been evaluated in subjects with
 Parkinson's disease and found to have therapeutics benefit (compared with inactive treatment)
 on the Unified Parkinson's Disease Rating Scale and neuropsychological measures (reaction
 time, pegboard task) as well as motor evoked potentials (Fregni et al., 2006c).

 Several recent studies have affirmed the safety of tDCS. Iyer and colleagues (2005) showed
 that, in a sample of 103 subjects, no one asked for the tDCS procedure to be stopped due to
 discomfort. Gandiga and colleagues (2006) compared sham to active tDCS and showed no
 differences in self-report ratings of discomfort. Nitsche and colleagues (2004) performed
 structural MRI scans on healthy individuals who underwent 1 hour exposures to tDCS; they
 found no evidence of structural change in the brain or alterations in blood-brain barrier
 permeability.

 With regard to persistent challenges in the management of MDD, individuals with depression
 have shown cognitive deficits, particularly in working memory and other frontal lobe
 functions (Dunkin et al., 2000; Sweeney et al., 2000 Jaeger et al., 2006; Rose and Ebmeier
 2006; Rose et al., 2006) and declarative memory (e.g., Beaden et al., 2006). By improving
 cognitive function in subjects with cognitive complaints that persist despite
 pharmacotherapy, it may be possible to improve the completeness of recovery from depression
 and reduce any functional disability (Jaeger et al., 2006).

 There are no published reports yet of the effects of tDCS on brain function in subjects with
 MDD. Cordance is a quantitative electroencephalography (QEEG) measure which allows for
 non-invasive measurement of regional brain function (Leuchter et al., 1994a, 1994b, 1999;
 Cook et al., 1998). It is sensitive to changes in brain function in subjects who are
 responding to treatment for MDD (Cook and Leuchter 2001; Cook et al., 2002, 2005; Leuchter et
 al., 2002) and is being evaluated for use a a biomarker which predicts treatment outcome in
 MDD (NIMH Project R01MH069217, Cook PI). It is well suited to evaluating brain function in
 subjects with MDD during a clinical trial experiment.

 Our hypotheses are

 1. Subjects who are randomized to receive active tDCS treatments will show greater
 improvement in cognitive task performance than subjects who receive inactive treatments.

 2. Subjects who are randomized to receive active tDCS treatments will show greater
 improvement in depression symptom severity scores than subjects who receive inactive
 treatments.

 3. Subjects who are randomized to receive active tDCS treatments will show greater changes
 in prefrontal brain function, as assessed with quantitative EEG cordance, than subjects
 who receive inactive treatments.
Inclusion Criteria:

 -  Subject age is 18 to 75 years old

 -  Subject meets the DSM-IV diagnosis of Major Depressive Disorder based on the MINI,
 with a current major depressive episode in partial remission

 -  Subject has been receiving treatment with an antidepressant medication for ≥ 3 months
 at a therapeutic dose. Therapeutic doses will be operationalized as those ranges noted
 by the drug manufacturers in their respective Package Inserts.

 -  Subject's score on the 17-item Hamilton Depression Rating Scale (Ham-D) is > 8 despite
 treatment with antidepressant medication(s).

 -  Subject has subjective cognitive complaints.

 Exclusion Criteria:

 -  Subject is mentally or legally incapacitated, unable to give informed consent

 -  Subject suffering from a cognitive, bipolar, or psychotic disorder on the on the basis
 of a MINI interview; in situations where there is ambiguity about the origin of
 cognitive symptoms (i.e. depression with cognitive symptoms VS early dementia)
 subjects will not be enrolled.

 -  Subject meeting criteria for an Axis II diagnosis that would interfere with completion
 of the protocol

 -  Known drug dependency or substance abuse within the past six months

 -  Subject has had a course of ECT, Transcranial Magnetic Stimulation (TMS), or Vagus
 Nerve Stimulation (VNS) within the six months prior to enrollment

 -  Unstable medical illness, any history of seizures, brain surgery, skull fracture,
 significant head trauma, or previous abnormal EEG

 -  Ham-D score > 25 despite pharmacotherapy

 -  Subject is a UCLA student or staff member directly under instruction or employment of
 any of the investigators

 -  Subject has a medical illness which might be exacerbated by tDCS treatments (e.g. skin
 abrasions or infection of the scalp might be exacerbated by the placement of the
 saline-moistened electrode pads)

 -  Subject is using any of the following medications which interfere with EEG measures of
 brain function: Anticholinergics, Barbiturates, Benzodiazepines, Sedating
 Antihistamines (e.g. diphenhydramine (Benadryl) would be exclusionary, but not
 loratadine (Claritin)).

 -  Subject declines to give the study personnel permission to discuss their depression
 and participation in this study with their treating physician.

 -  Subject has had a suicide attempt or other self-injurious behavior in the past 6
 months

 -  Subject has an implanted pacemaker

 -  Subject has red/green colorblindness (cannot distinguish red from green)

 -  Subject's intake urine test is positive for drugs of abuse