Eur Arch Clin Neurosci DOI 10.1007/s00406-017-0769-y

ORIGINAL PAPER

Prefrontal transcranial direct current stimulation (tDCS) as treatment for major depression: study design and methodology of a multicenter triple blind randomized placebo controlled trial (DepressionDC)

Frank Padberg1 · Ulrike Kumpf1 · Ulrich Mansmann2 · Ulrich Palm1 · Christian Plewnia3 · Berthold Langguth4 · Peter Zwanzger5 · Andreas Fallgatter3 · Jana Nolden1 · Max Burger7 · Daniel Keeser1 · Rainer Rupprecht4 · Peter Falkai1 · Alkomiet Hasan1 · Silvia Egert6 · Malek Bajbouj7

Received: 13 August 2016 / Accepted: 14 January 2017 © Springer-Verlag Berlin Heidelberg 2017

Abstract Transcranial direct current stimulation (tDCS) Montgomery-Asberg Depression Rating Scale (MADRS) has been proposed as novel treatment for major depressive scores at week 6 post-randomisation compared to baseline. disorder (MDD) based on clinical pilot studies as well as Secondary endpoints also cover other psychopathological randomized controlled monocentric trials. The Depres- domains, and a comprehensive safety assessment includes sionDC trial is a triple-blind (blinding of rater, operator measures of cognition. Patients undergo optional investiga- and patient), randomized, placebo controlled multicenter tions comprising genetic testing and functional magnetic trial investigating the efficacy and safety of prefrontal resonance imaging (fMRI) of structural and functional con- tDCS used as additive treatment in MDD patients who have nectivity. The study uses also an advanced tDCS technol- not responded to selective serotonin reuptake inhibitors ogy including standard electrode positioning and record- (SSRI). At 5 study sites, 152 patients with MDD receive a ing of technical parameters (current, impedance, voltage) 6-weeks treatment with active tDCS (anode F3 and cathode in every tDCS session. Aside reporting the study protocol F4, 2 mA intensity, 30 min/day) or sham tDCS add-on to here, we present a novel approach for monitoring techni- a stable antidepressant medication with an SSRI. Follow- cal parameters of tDCS which will allow quality control of up visits are at 3 and 6 months after the last tDCS ses- stimulation and further analysis of the interaction between sion. The primary outcome measure is the change of the technical parameters and clinical outcome. The Depres- sionDC trial will hopefully answer the important clinical Frank Padberg and Ulrike Kumpf contributed equally. question whether prefrontal tDCS is a safe and effective antidepressant intervention in patients who have not suffi- * Frank Padberg ciently responded to SSRIs. [email protected]‑muenchen.de

1 Department of Psychiatry and , Ludwig Trial registry: ClinicalTrials.gov Identifier NCT0253016. Maximilian University Munich, Nussbaumstr. 7, 80336 Munich, Germany Keywords Major depression · Non-invasive 2 Institute for Medical Information Processing, Biometry stimulation · Selective serotonin reuptake inhibitor · Non- and Epidemiology (IBE), Ludwig Maximilian University response · tDCS Munich, Munich, Germany 3 Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany Background 4 Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany Major depression disorder (MDD) is a common, recurrent, 5 kbo-Inn-Salzach-Hospital, Wasserburg am Inn, Germany and frequent chronic disorder that is the leading contribu- 6 Münchner Studienzentrum, Technical University of Munich, tor to functional impairment and disability [1]. Treatment Munich, Germany is often challenging; an estimated 20–40% of patients 7 Department of Psychiatry and Psychotherapy, Charité- do not benefit sufficiently from existing antidepressant Campus Benjamin Franklin, Berlin, Germany

Vol.:(0123456789)1 3 Eur Arch Psychiatry Clin Neurosci interventions including trials of medication and psycho- cortex aiming an amelioration of depressive symptoms [6, therapy [2]. A 15–25% of patients manifest a chronic, 9]. Whereas conventional rTMS is a rather focal brain stim- treatment-resistant course of illness [3] resulting in a need ulation approach and may often not be optimally positioned for additional treatment options [4, 5]. Transcranial direct to interact with neural networks involved in MDD, tDCS current stimulation (tDCS), a non-invasive brain stimula- leads to less focal stimulation of larger regions between the tion method established in research, has been anode and the cathode, i.e. tDCS with the anode positioned proposed as one such alternative [6–11]. over the left DLPFC leads to modulation of large-scale According to the paradigm of the Research Domain resting-state network connectivity [25, 26]. The rationale Criteria (RDoC) future psychiatric research seeks to relate behind the F3/F4 electrode montage is a primary modu- psychiatric disorders to more distinct pathophysiological lation of a dysfunctional left DLPFC in major depression entities, e.g. to concepts of dysfunctional neural circuits [27] with the anode placed on F3 [28, 29]. However, the consisting of interconnected neuronal sets [12, 13]. This position of the cathode (F4) is equally important as it deter- view supports new therapeutic approaches in terms of mod- mines the current distribution in other brain regions as well ulating activity and excitability of dysfunctional network as the intensity of stimulation at the left DLPFC [30] by conditions. Based on the findings of neurophysiological affecting the current density under the anode [31]. and studies that under certain conditions the A recent meta-analysis regarding the effect of tDCS as a is capable of substantial long-lasting changes treatment for MDD in 7 RCTs found an overall superiority in these neuronal networks following the principles of of active tDCS over sham tDCS in the treatment of MDD researchers tried to stimulate the brain for [32, 33]. Two other meta-analyses came to the same result specific modulation of brain network activity. There is a [34, 35], one meta-analysis used only categorical meas- broad range of invasive and noninvasive brain stimulation ures instead of continuous outcome measures and failed (NIBS) techniques. TDCS is a NIBS-technique which has to demonstrate significant differences regarding improve- the advantage that it is relatively easy to use, causes low ment of depressive symptoms after active tDCS compared cost, is a relatively small device and has a benign profile of to sham tDCS [36] Differences in effect sizes described in adverse effects [14]. recent meta-analyses [33, 35] may be due to methodologi- The putative therapeutic effect of tDCS in MDD is cal variations. In the meta-analysis of Meron et al. (2015) hypothesized to be based on the modulation of dysregu- the outcome of the largest tDCS trial to date [28] was ana- lated frontal activity, connectivity and excitability that lysed at week 2 immediately after the daily treatment phase has been linked with an amelioration of negatively biased at a time point comparable to the primary outcome of other information processing [15, 16]. Results from neuroimag- studies. Repeating the analysis for week 6 the results of the ing studies suggest that depressive symptoms in patients categorical analysis became statistical significant and even and induced sadness in healthy subjects are associated with the magnitude of the continuous effect in the meta-analysis a hypoactivity of prefrontal areas [17–19] particularly the increased. left dorsolateral prefrontal cortex (DLPFC) and a reduced TDCS has been shown to exert antidepressant effects in glucose metabolism in these areas [20]. The increase of pilot studies [10] as well as in randomized controlled tri- activity in these hypoactive regions by means of antide- als [6, 28, 37]. However, also negative results have been pressive medical drug therapy or non-invasive brain stimu- reported in small trials as well as in trials including ther- lation interventions leads to an amelioration of depressive apy-resistant patients [29, 38–41]. Reasons for this heter- symptomatology and vice versa: in patients with an ame- ogeneity of results could be the small sample size in the lioration of depressive symptoms or with a remission of majority of studies, differences in therapy resistance, in MDD an increased activity of prefrontal areas compared to treatment duration and concomitant pharmacotherapy. baseline measurements before amelioration/remission can Results from the meta-analyses and larger trials [37] sug- be found [21]. gest that longer treatment periods lead to a better antide- Consequently, treatment strategies that modulate brain pressive effect of tDCS in patients with MDD. Loo and activity towards an increase of activity in the left DLPFC colleagues found a modest antidepressive effect of tDCS might treat depressive symptoms. The paradigm of activity- measured by the MADRS after 3 weeks of treatment; how- increasing high-frequency rTMS over the left DLPFC in ever, after 6 weeks of active tDCS the results were much depressed patients was tested in many studies and a con- more encouraging. These results suggest that an extension sistent antidepressive effect of this paradigm can be dem- of the treatment period to 6 weeks could lead to further onstrated [22, 23]. Recent studies used tDCS to stimu- and more lasting antidepressive effects [37]. The proto- late the motorcortex and showed an excitatory effect of col of our study takes these aspects into consideration and anodal tDCS [24]. Based on this approach in several stud- presents a multicenter RCT using a stimulation protocol ies anodal tDCS was used to stimulate the (left) prefrontal with 6 weeks of treatment according to an extension of the

1 3 Eur Arch Psychiatry Clin Neurosci well-established protocol of a 4 weeks treatment period in of previous trials (uni- and bipolar depression mixed sam- the largest RCT [28] in this field. ples, modest sample sizes, shorter tDCS treatment periods, Concomitant treatment also seems to be a crucial fac- low SSRI dosage). Secondary endpoints including MRI tor influencing the effect of tDCS. Nitsche and colleagues and genetic and epigenetic tests and different neuropsycho- found a synergistic effect of tDCS and selective serotonin logical paradigms complete the multi-faceted approach of reuptake inhibitors (SSRI) regarding tDCS-induced excit- this study aiming to provide more insights into mechanisms ability changes of the motor cortex. The ingestion of a sin- of action of tDCS. gle dose of citalopram had a strong prolonging effect and caused an increase of the motor evoked potential (MEP) after anodal stimulation until 4–5 h after stimulation com- pared to tDCS with placebo medication. Thus, a modulat- Methods/design ing effect of serotonin on tDCS-induced neuroplasticity in healthy subjects has been observed [42] which has also Design been confirmed for extended citalopram intake [43]. In analogy, an enhancing antidepressant effect of the The DepressionDC study is a multicenter trial with five SSRI sertraline on anodal tDCS over the prefrontal cor- German sites involved (University of Munich, Charité tex has been demonstrated in the SELECT-tDCS trial, i.e. Berlin, University of Tübingen, University of Regensburg, the largest RCT to date (120 patients included) compared Isar-Amper-Klinikum Wasserburg). The chosen design is a within a 2 × 2 factorial design (1) tDCS + SSRI (sertraline), randomized, triple-blind, placebo-controlled, parallel group (2) tDCS only (+placebo medication), (3) sertraline only study. Triple blind means that the rater, the operator and the (+sham tDCS) and (4) double placebo [28]. The primary patient will be kept blind to treatment conditions (i.e. tri- outcome (MADRS score at 6 weeks after 12 tDCS ses- ple blind design). The rater is exclusively responsible for sions) showed superiority of combined tDCS + sertraline clinical rating and the operator for tDCS treatment. Both, treatment over all other conditions regarding amelioration rater and operator will be blinded. The treatment and the of the main symptoms of depression, i.e. low mood (appar- clinical rating will be conducted in two separate rooms. ent and reported sadness), psychomotor retardation (lassi- Participants are respectively assigned to active-tDCS/SSRI tude) and anhedonia (inability to feel) and an additive effect or sham-tDCS/SSRI. The aim is to prove the antidepressant of an antidepressant medication and tDCS was verified efficacy of tDCS compared to placebo in patients who are [44]. The hypothesis of an interaction between tDCS and on a stable antidepressant pharmacotherapy, which alone serotonergic drugs is supported by further findings from has not been effective. this study showing that antidepressant effects of tDCS are The study population consists of patients with MDD more pronounced in serotonin transporter polymorphism who did not respond to at least one antidepressant treatment (5-HTTLPR) long/long (vs short) allele carriers [45]. of adequate dose and duration in the current episode. The These findings are particularly promising and suggest adequate dose of AD treatment is defined as a minimum that tDCS could be used as add-on treatment to seroton- level of 2 in the Antidepressant Treatment History Form ergic compounds to increase their antidepressant efficacy. (ATHF). It is defined as a minimum dose of an antidepres- Thus, the DepressionDC trial investigates whether tDCS is sant medication for the respective time period. There is also safe and generates an additional antidepressant response in a minimum duration to get the level of 2 in the ATHF. The patients who have not sufficiently responded to SSRI mon- minimum dose varies according to the drug that is used. otherapy. In our opinion this is a clinically very important The ATHF offers a value for the minimum dose of a given approach paralleling the indication in the field of repeti- antidepressant at each level required. If the dose of SSRI tive transcranial magnetic stimulation (rTMS), though is low and not adequate according to the ATHF, it may be rTMS has been successfully applied as monotherapy in increased if the patient wants to participate in the study this respect [46]. However, we are aware that the hypoth- and has not sufficiently responded to SSRI treatment. Only esis of our trial is distinct from two other research ques- SSRIs will be allowed, no dual inhibitors or other antide- tions brought up by the SELECT-tDCS trial [28]: (1) Is a pressants with a partial effect on 5-HT-receptors or seroto- combined tDCS-SSRI approach as first line therapy more nin-modulating drugs will be allowed. The study comprises effective than the respective monotherapies, i.e. replicat- a screening/randomization phase, an intervention phase of ing the findings of the SELECT-tDCS trial for the whole 6 weeks duration, and a follow-up of 6 months (Fig. 1). group of SSRIs, (2) Does an SSRI establish or augment a Eligible patients will be randomized to one of the two putative antidepressant effect of prefrontal tDCS? Both groups. The study group will receive active tDCS treatment questions need to be answered in separate future trials. The and the control group will receive sham treatment both DepressionDC trial is also meant to overcome limitations combined with the prior medication with an SSRI.

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Fig. 1 Study flow chart. TVA theory of visual attention, EmoCogMeter Cognitive Battery, iPad application, fMRI functional magnetic resonance imaging

In the screening phase, investigators will screen patients active and sham treatment groups. There is no disparity in based on the inclusion/exclusion criteria described below the treatments between the groups or between responders and in account to a geographic range that allows for the and non-responders. The study design is directed towards required visit frequency. After screening and inclusion, a comparison, between active treatment and sham added patients will be randomised at day 1 in one of the two study to an ongoing SSRI medication, after 6 weeks of treatment groups (active or sham). Randomization will be employed and at the end of the follow-up period. to avoid bias in the assignment of patients to groups, to In the follow-up period, two visits are foreseen 18 and increase the likelihood that known and unknown patient 30 weeks after randomization (12 and 24 weeks after the attributes are evenly balanced across study groups, and to last treatment). Within this period no restrictions are appli- enhance the validity of the causal statement which results cable with respect to additional antidepressant treatments, from the statistical comparisons across the study groups. however, additional treatments will be documented. Blinding will be used because the primary endpoint, the The anticipated recruitment period at 5 study sites is change in MADRS score from baseline, is subject to bias approximately 28 months and, therefore, the duration of the by participants and observers. study from first patient first visit (FPFV) to last patient last In the treatment period, treatment regimen in both visit (LPLV) is expected to last about 35 months. Blinding groups will consist of a total of 6 weeks of treatment, con- will be maintained for the entire time of patient recruit- sisting of 5 daily treatment sessions per week for 4 weeks ment, until the last patient has completed the study. and followed by 2 weeks consisting of 2 treatment sessions The study protocol has already been approved by the per week. The study allows for unbiased comparison of local ethics committee and the trial is strictly conducted

1 3 Eur Arch Psychiatry Clin Neurosci in accordance with the Declaration of Helsinki. Written to use contraceptive measures during the treatment phase informed consent will be obtained from all patients prior to for women with childbearing potential (i.e. <2 years participation. post-menopausal). Participants will be non-responders to at least one anti- depressant treatment, i.e., a minimum of 1 and a maximum Study centers of 4 antidepressant drug trials, of adequate dose and dura- tion [defined as a minimum level of 2 on the Antidepres- The following clinical sites take part in the study: Depart- sant Treatment History Form (ATHF)] in the current epi- ment of Psychiatry and Psychotherapy of the Ludwig Max- sode and are taking a SSRI of adequate dose and for ≥4 imilian University Munich (Coordinating investigator Prof. weeks (defined as a minimum level of 2 on the ATHF) in Frank Padberg), Department of Psychiatry and Psychother- the current episode which has not led to sufficient clini- apy, Charité-Campus Benjamin Franklin (PI Prof. Malek cal improvement. The following medications will not be Bajbouj), Department of Psychiatry and Psychotherapy, allowed throughout the study: antidepressants (except University of Regensburg (PI Prof. Berthold Langguth), SSRI), mood stabilizers and antipsychotics. Exclusively Department of Psychiatry and Psychotherapy, University of the following rescue medication may be prescribed dur- Tübingen (PI Prof. Christian Plewnia, Co-PI Prof. Andreas ing the course of the study: Zopiclone (on demand up to Fallgatter), kbo-Inn-Salzach-Hospital, Wasserburg am Inn 7.5 mg/day orally), Benzodiazepine up to a dose equivalent (PI Prof. Peter Zwanzger). These sites are responsible for to 2.0 mg of Lorazepam, Ibuprofen, Paracetamol, ASS for recruiting, screening, assessment of the required patient treatment of local , dental pain or headaches will be data according to the clinical protocol and tDCS-treatment. allowed, as necessary. The tDCS-stimulator and other required devices, a laptop All medications taken by a participating patient (both with the stimulator software already installed, a special prescription or nonprescription) must be documented. This synchronization-software as well as tablet-PCs with the includes medications taken within 28 days (4 weeks) before DepressionDC-program and iPads with the EmoCogMeter treatment initiation and during the course of the study. are provided for each site. If a patient receives psychotherapy during the study the Organisational project management, safety management, modality of psychotherapy (e.g. group sessions or indi- monitoring, data management and randomization is per- vidual therapy), duration and frequency has to be recorded. formed by the Münchener Studienzentrum (MSZ), an inde- Other non-pharmacological interventions except other pendent site. brain stimulation methods, which are not allowed, will be Psychologists and performing patients` rat- documented as well. Both concomitant medication and ings are trained by means of a teaching video for a stand- non-pharmacological treatment (i.e. psychotherapy) have to ardized evaluation of the patients. Persons involved in the be documented at screening and baseline visits as well as tDCS-treatment procedure are introduced step by step by once a week during the treatment period and at all follow- means of an instruction video guaranteeing a standardized up visits. process. Exclusion criteria are acute risk for suicide which is defined as a score of >4 in item 10 of the MADRS or as Participants assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS), agree to item 4 and/or agree to item 5, a high In- and outpatients (men and women) aged between 18 and degree of therapy resistance defined as >4 sufficient treat- 65 years with a primary diagnosis of Major Depression (in ment trials in the current episode (each trial with an ATHF accordance with the DSM-5 criteria) Episode as assessed score of >3), treatment with electroconvulsive therapy in by the Structured Clinical Interview for DSM-5 Axis I Dis- the present episode, treatment with deep brain stimula- orders, Research Version (SCID-RV) are recruited for the tion or and/or any other intracra- study. Patients with a single or recurrent episode with the nial implants (clips, cochlear implants), history of clinical additional requirements of a current episode with dura- tDCS treatment (except single experimental tDCS sessions) tion of ≥4 weeks are included in the study. The duration of and treatment with rTMS during the present depressive the current depressive episode should be less than 5 years episode, any relevant instable medical condition and preg- (the definition of an episode is demarcated by a period of nancy. Patients with any other relevant psychiatric axis-I- ≥2 months in which the patient did not meet full criteria and/or axis-II-disorder as assessed by the M.I.N.I. Inter- for the DSM-5 definition of major depressive episode). national Neuropsychiatric Interview (M.I.N.I. German The eligibility criteria include a total score of ≥15 in the Version 5.0.0) and the SKID-II or patients who are inves- Hamilton Depression Rating Scale (HDRS-21) at the tigator-site personnel directly affiliated with this study and/ screening visit, a negative pregnancy test and willingness or their immediate families (immediate family is defined as

1 3 Eur Arch Psychiatry Clin Neurosci a spouse, parent, child, or sibling, whether by birth or legal the left DLPFC (F3, active or sham) and one electrode over adoption) are excluded from the study. the right DLPFC (F4, active or sham). The rubber electrodes are positioned inside saline- Interventions/procedures soaked surface sponges. The amount of saline used to keep the sponges wet is standardized according to the instruction The tDCS protocol basically follows the method reported video (15–20 ml for each). by Brunoni et al. [28] but extends the duration of treatment Before the treatment can be started, the operator has to 20 sessions of 30 min daily tDCS over 4 weeks (5 days to insert the identification code of the respective patient. per week) followed by 4 sessions over 2 weeks. The reason Then, the battery-driven constant-current stimulator will for this extension is the risk of insufficient treatment which deliver either sham or active tDCS depending on the ID- may lead to a premature rejection of the efficacy of an code. The list of codes will be pre-programmed by the intervention as one has learned from earlier studies using manufacturer. Ramping up and down is performed at the rTMS [23]. Authors from prior tDCS studies also suggest beginning and at the end of each sham and active stimula- that an extension of the treatment period would lead to fur- tion. Ramping up is 30 s and ramping down is another 30 s ther and more lasting benefit [37]. Treatments should be Ramping up and down time is added to the 30 min of active conducted in the morning at least 3 h before the rater will or sham stimulation time. During the treatment period the meet the patient to prevent the bias of daytime fluctuations active group will receive 2 mA direct current with a current in receptiveness of the brain for tDCS. density of 0.0571 mA/cm². The control group will receive The montage used for tDCS is bifrontal: anode over F3 sham treatment with identical parameters. However, direct and the cathode over F4 (international 10–20 EEG system). current will only be active for 30 s during ramp in and ramp Prior to treatment, the operator must determine the posi- out periods. Patients will be told about a mild tingling or tion F3 and F4 according to the international 10–20 EEG itching sensation during the treatment. After each treatment system. An exclusively for the DepressionDC study man- the patient has to complete the Comfort Rating Question- ufactured cap is used that allows for a marking of the Cz naire (CRQ) to record adverse effects. electrode point, for the F3 and F4 electrode point and for During treatment patients should sit on a stimula- two more markings on each site at the edges of the sponge tion chair in a comfortable upright position. Patients were electrodes guaranteeing a correct positioning of the 35 cm2 instructed to stay awake and active without focused activi- sponge electrodes with F3 and F4 exactly in the center ties. Only if a patient threatens to fall asleep he or she is (Fig. 2). Three different cap sizes (EASYCAP GmbH, Ger- allowed to read provided magazines during stimulation many) are used: 56, 58 and 60 according to the head cir- which are as neutral as possible. cumference in cm. The operator will measure the head cir- Technical data, such as the electrode impedance and cumference at the first tDCS session to choose an optimally direct current, is going to be monitored continuously and fitting cap for every patient. In a second step, the operator will be transferred to the Münchner Studienzentrum, an determines Cz (10/20 EEG system). Then the cap is placed independent monitoring instance, to allow for an unblinded on the head according to Cz. Predefined spots on the cap evaluation of verum and sham stimulation and for a stim- allow marking reference spots for F3 and F4 positions ulation quality check. The transfer of the technical data is (Fig. 2). All study groups will receive one electrode over performed by a new stimulation software and hardware.

Fig. 2 Standardised positioning of the electrodes

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During the stimulation the technical data is recorded and tDCS. Additional information regarding the DC-Stimulator saved on a saving-tool that is connected to the stimula- Plus is provided in the device manual. tor. After the stimulation session the saving-tool can be removed from the stimulator and connected to the study laptop and the data is automatically transferred to the MSZ Assessments via cloud, which is established by Neuroconn exclusively for this purpose (Fig. 3). After a completed data transfer the The Time and Events Schedule (Table 1) summarizes the stimulation data are automatically deleted from the saving- frequency and timing of treatment and assessments. At the tool to guarantee that there is enough storage space for the screening visit every patient will be interviewed with the next stimulation on the saving-tool. Structured Clinical Interview for DSM-5 Axis I Disorders, TDCS stimulators are provided by Neuroconn GmbH. Research Version (SCID-5-RV) regarding the presence of Both hardware and software for recording and transfer- Major Depression. The SCID-5-RV is a semistructured ring technical data were developed by Neuroconn exclu- interview guide for making DSM-5 diagnoses. It is admin- sively for the DepressionDC study. The equipment at each istered by a clinician or trained professional study site consists of the DC-Stimulator Plus, saving-tools who is familiar with the DSM-5 classification and diag- and two programming-devices, a USB-mini-USB cable to nostic criteria. It is used to make sure that all of the study connect the programming-device with the study laptop, patients have symptoms that meet the DSM-5 criteria for a starter set of cables, sponges and rubber electrodes and Major Depressive Disorder. Additionally, the Mini Interna- an USB-stick with the computer software as well as the tional Neuropsychiatric Interview (M.I.N.I. German Ver- access-key. The DC-Stimulator Plus device is CE-certified sion 5.0.0) is used to insure patients do not have any other and covers all requirements of the transcranial stimulation. relevant psychiatric axis-I-disorder. The Structured Clini- The study mode encodes sham and active stimulation cal Interview for DSM-IV Axis II Personality Disorders using distinct identification codes for active and for sham (SCID-II) is performed at baseline visit to insure that all of

Fig. 3 Monitoring of tDCS parameters, transfer of the technical data by new stimulation software and hardware, evaluation of tDCS parameters, stimulation quality check

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Table 1 Synopsis of study visits, interventions and assessments Pre- Treatment Follow-up Phase Treatment Period Period Period Week -1 1 2 3 4 5 6 18 30 Study Visit S B 1 2 3 4 5 6 7 8 Day -8/-4 -3/-1 1 2 3 4 5 12 19 26 33 40 124 208 Screening, Treatment and Administrative Procedures Informed consenta √ SCID-5-RV, √ M.I.N.I., SCID-II CTQ, SNI, CD- √ RISC Medical and psychiatric (family) history, √ Demographic data, ATHF Concomitant √ √ √ √ √ √ √ √ √ √ treatmentb Physical √ √ Examination HDRS-21, EHI, √ FTND WHO-DAS, √ WHO-5, BSI-53 Efficacy Measures MADRS, BDI √ √ √ √ √ √ √ √ √ √ STAI-State, -Trait, SHAPS-D, CGI-S, √ √ √ √ √ GAF, SF-36 Safety Measures Vital signsc Basic Somatic √ √ √ Information C-SSRS √ √ √ √ √ √ √ √ CRQ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ EmoCogMeter √ √ √ d Adjunctive Investigations Genetic/epigentic √ √ √ tests (all centers) TVA (Munich) √ √ √ √ fMRI (Munich, √ √ √ Berlin) Driving ability (Munich, √ √ Wasserburg)

a Informed consent has to be obtained prior to any study-related procedure. b Medication, but also the kind of psychotherapeutic intervention (e.g. group therapy or individual therapy), duration and frequency have to be recorded. c Vital sings include pulse and systolic and diastolic blood pressure. Both measurements will be done while the patient is sitting. Basic Somatic Information include BMI and Head Size. d Optional investigations are conducted in single centers, e.g. visual attention paradigm (based on the visual attention theory, (Bundesen 1990)in Munich), fMRI investigations in Munich and Berlin. All centers can take part in sampling of probes for genetic testing.

1 3 Eur Arch Psychiatry Clin Neurosci the study patients do not have any other relevant psychiatric (B), at visits 4 and 6 during the treatment period and at 18 axis-II disorder. and 30 weeks follow-up. CGI-S is a commonly used tool In principle, the study visits aim at monitoring efficacy for assessing the severity of the patient’s depression. The (clinical ratings) and tolerability (safety) measures. Effi- Connor-Davidson Resilience Scale (CD-RISC) is a self- cacy will be assessed using the MADRS at 10 timepoints, rated questionnaire that will be completed only at the base- allowing clinical assessment of disease severity, response line visit (B). The 10-item Connor-Davidson Resilience and remission rates. Additional measures such as the Beck Scale (10-item CD-RISC) is an instrument for measuring Depression Inventory (BDI-II, Version 1.5) allow for the resilience that has shown good psychometric properties in self-evaluation of the patients. Every study visit must begin its original version. Handedness will be assessed using the with the clinical assessment scales followed by the cogni- Edinburgh Handedness Inventory (EHI) only at the screen- tive assessment (required on visits 6 and 8, at visit 4 only ing visit (S). The EHI uses 10 items to assess the domi- in case of theory of visual attention (TVA) testing) and a nance of a person’s right or left hand in everyday activities. 30 min break before the self-rating questionnaires are given The Fagerström Test for Nicotine Dependence (FTND) will to the patient. If no cognitive testing takes place during be assessed only at the screening visit (S) if patients are the study visit, the self-rating instruments must be filled in smokers. The Global Assessment of Functioning (GAF) is directly after the clinical assessment scales. used to assess personal and social functioning at the base- Procedures to be performed at week 6 (visit 6) will also line visit (B), at visits 4 and 6 during the treatment period be performed in case of premature discontinuation of the and at 18 and 30 weeks follow-up. GAF is a commonly study. Patients will be discontinued if there is presentation used tool for assessing the daily functioning of the patient of suicidal ideation (based on MADRS item 10 score of and to evaluate to what extent the depressive symptoms >4 or as assessed by the C-SSRS, agree to item 4 and/or effects his daily functioning. These global interviewer-rated agree to item 5) or attempted suicide after receiving active measures have scores ranging from 0 to 100, with lower or sham tDCS. scores denoting poorer functioning. The GAF rates symp- The CRQ is a self-report questionnaire on adverse toms and functioning during the past month. The Short effects [47]. Patients will complete the CRQ after each Form Health Survey (SF-36) is a self-rated health status tDCS treatment session. The purpose of the questionnaire survey that has to be completed at the baseline visit (B), at is to assess possible adverse effects/events (AEs). It will visits 4 and 6 during the treatment period and at 18 and 30 serve as a safety and tolerability measurement instrument. weeks follow-up. The SF-36 is a 36-item self-report instru- Further scales and measures are listed in the synopsis ment to assess health related quality of life independent of of study visits, interventions and assessments (Table 1). specific disorders and is a validated tool across treatment In detail, the Brief Symptom Inventory-53 (BSI-53) is a studies. It comprises the following subscales: Physical self-rated questionnaire that is completed by patients only Functioning, Social Functioning, Emotional Role Func- at the screening visit. As a shortened version of the Symp- tioning, Emotional Physical Functioning, General Mental tom Checklist-90 the BSI-53 [48] covers the following nine Health Vitality, Bodily Pain and General Health Status. The symptom dimensions of depression: somatization, obses- Snaith-Hamilton-Pleasure Scale, German version (SHAPS- sion-compulsion, interpersonal sensitivity, depression, anx- D) is a self-rated scale that is completed at the baseline iety, hostility, phobic anxiety, paranoid ideation and psy- visit (B), at visits 4 and 6 during the treatment period and choticism. Each of the 53 items is being scored on a 5-point at 18 and 30 weeks follow-up. Since the inability to experi- Likert scale from 0 to 4 with higher scores indicating more ence pleasure, anhedonia, is recognized a central symptom intense distress over the past week. The Childhood Trauma of depression, the SHAPS-D is an important instrument Questionnaire (CTQ) is a self-rated questionnaire that is in this study to assess the hedonic capacity of the patients completed only at the baseline visit (B). Adverse childhood during the course of the treatment. The SHAPS-D relies experiences are assessed in retrospect using the CTQ [49]. on self-report and consists of 14 items. Patients will com- This self-report scale consists of 27 items that are assigned plete the self-rated Social Network Index (SNI) only at the to the following five subscales: emotional neglect, emo- baseline visit (B). The Social Network Index (SNI) assesses tional abuse, physical neglect, physical abuse and sexual participation in 12 types of social relationships [50]. The abuse. The Clinical Global Impression Improvement scale State Trait Anxiety Inventory (STAI) is a self-rated inven- (CGI-I) is a scale the clinician uses to assess how much tory that has to be completed at the baseline visit (B), at the patient’s illness has improved or worsened relative visits 4 and 6 during the treatment period and at 18 and to a baseline state, at visits 4 and 6 during the treatment 30 weeks follow-up. It consists of 40 questions on a self- period and at 18 and 30 weeks follow-up. Using the Clini- report basis. The STAI measures two types of anxiety: state cal Global Impression-Severity score (CGI-S) patients will anxiety, or anxiety about an event, and trait anxiety, or be assessed for the severity of illnesses at the baseline visit anxiety level as a personal characteristic. The World Health

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Organisation Disability Assessment Schedule (WHO-DAS) of prior computer experience. This could lead to a better and the World Health Organisation Five Well-Being Index validity of the results [51]. (WHO-5) are both self-rated scales that are completed only A sync-app which allows for an easy data transfer was once at the baseline visit (B). The WHO-DAS was devel- exclusively developed for this study. The sync-app is oped by the WHO to produce standardized disability levels already installed on the study-laptop and when the tabletPC and profiles for the last month. It compromises the follow- is connected to the study laptop the data is automatically ing 6 domains of functioning: cognition (understanding and saved on the hard disk. Starting the sync-app the user can communication), mobility (moving and getting around), chose whether he/she wants to synchronize the data to self-care (hygiene, dressing, eating and staying alone), the server of the study center in Munich where the tablet getting alone (interacting with other people), life activi- data are collected and quality-checked or another feature ties (domestic responsibilities, leisure, work and school) can show all generated PDF files which can be chosen and and participation (joining in community activities). The printed out. An upgrade function allows for an update of WHO-5 was developed to assess one’s subjective quality the newest program version so that changes in the program of life, based on 5 items about positive mood (good spirits, in case of occurrence of faults or errors can be transferred relaxation), vitality (being active and waking up fresh and easily to the participating centers. rested), and general interest (being interested in things). The concomitant medication and all assessments Adjunctive investigations regarding the efficacy of the treatment (MADRS, BDI-II, Snaith-Hamilton-Pleasure Scale SHAPS-D, State Trait In Munich, patients will undergo an extended neuropsycho- Anxiety Inventory STAI, Clinical Global Impressions logical assessment using a ‘theory of visual attention’ para- Scale-Severity/-Improvement CGI-S/I, Global Assessment digm and functional magnetic resonance imaging (fMRI) of Functioning GAF, Short Form Health Survey SF-36) measuring resting state functional and structural connectiv- will be repeated at the last day of the treatment period ity at baseline, and after six weeks of tDCS treatment (visit (week 6, visit 6) and 18 and 30 weeks after randomiza- 6, acute phase) and at the second follow-up visit (Visit 8). tion (Follow Up Visit, Visit 7 and 8). Cognitive assessment Adjunctive fMRI investigations will be also carried out in (EmoCogMeter), additional investigations such as fMRI Berlin. All patients in all centers have the option to partici- and genetic testings will also be repeated at visit 6 and 8. pate in adjunctive investigation of genetic and epigenetic TVA will be repeated at visit 4, 6 and 8 to record different markers of antidepressant response and to take part in a aspects of cognitive performance at relatively short time driving-ability-testing. intervals during treatment and follow-up phase. Functional magnetic resonance imaging (fMRI)

Tablet program, sync‑app, EmoCogMeter Revealing the action of prefrontal cortex tDCS on brain physiology in health and pathological conditions is cru- Cognitive functions will be assessed across a wide range of cial for the development of its targeted and individualized neuropsychological domains (memory, attention, executive therapeutic application. The strength and direction of tDCS functions) using a tablet computer-based application (Emo- effects on brain connectivity depend on the prior activa- CogMeter) as previously published [51]. tion state of defined prefrontal cortex subregions and vary For the assessment of the clinical scales in the Depres- between healthy patients and MDD patients. The deter- sionDC study a special android tabletPC-based application mination of the respective interaction and its functional was developed. It can be used for both, self-rated question- anatomy is essential for developing tDCS to an improved naires and external assessment scales and allows for an treatment for these pathological conditions. Previous inves- easy but safe recording and storage of the patients` data. tigations have demonstrated tDCS mediated effects on cor- Scales and cumulative values are calculated automatically tex physiology in healthy patients applying resting state preventing calculation errors or transmission errors. PDF EEG and fMRI [52, 53]. However, such effects have not output files are provided depicting a summary of the most been explored in MDD patients. Thus, resting state func- important results of the questionnaires (source data for the tional and structural fMRI connectivity will be assessed CRF) and additionally scores of each single item are saved at baseline and after 6 weeks of tDCS treatment. An addi- in a second PDF file. A subsequent change of any score tional fMRI will be performed after further 24 weeks (Visit after a completed visit is not possible. Fuge and colleagues 8) following the end of tDCS treatment. fMRI data acquisi- suggest that patients experience an increased motivation tion will be done at the Institute of Clinical Radiology on a level and compliance when they use the tabletPC-based 3 T MRI scanner with parallel transmission and reception application instead of the paper–pencil method regardless technology (Skyra Magnetom).

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Theory of visual attention transmitter, neuromodulator and neurotrophin systems and their relevant pathophysiology. (2) Another line of evidence The ‘theory of visual attention’ [54, 55] is a mathematical is derived from findings of genetic effects on structural and model which is based on the biased-competition account functional connectivity involved in the pathophysiology of of visual attention [56]. Based on the assumptions of the depressive disorders [59]. Specific connectivity patterns model, independent quantitative estimates of four distinct presumably constitute functional networks underlying the attentional components—visual perceptual processing action of non-invasive brain stimulation including tDCS. speed, storage capacity, top-down attentional control, and Previous studies suggest a focus on the serotonin trans- spatial distribution of attention—are derived from patients’ porter gene (5-HTTLPR), the serotonin receptor 1A gene performance in a whole report and partial report task of (HTR1A), the tryptophan hydroxylase-2 gene (TPH2), briefly presented letter arrays. In the TVA whole-report the monoamino oxidase A gene (MAOA), the catechyl-o- task participants were briefly presented with six letters, methyl transferase gene (COMT), the brain derived neu- either all red or blue, appearing on an imaginary circle with rotrophic factor gene (BDNF), the apolipoprotein E4 gene a radius of 6 cm (5.73° of visual angle) around the fixation and genes involved in stress hormone functions (CRHR1 point. The task of the participant was to identify and report and FKBP5) and attachment (oxytocin receptor gene, as many letters as possible. OXTR) among others [59–61]. Thus, a large range of In the TVA partial-report task participants were genetic polymorphisms will be investigated to detect sin- instructed to report predefined target letters, which differed gle polymorphisms or patterns which are predictive for the from distractors with respect to colour (target = red; distrac- clinical response to tDCS. tor = blue). In each trial, either a single target (letter) or a All patients will have the option to give their informed target plus distractor (letter) or two targets appeared at the consent with genotyping using the PsychArray BeadChip corners of an imaginary square located 7.5 cm around the ­(Illumina®). The Psycharray Chip adresses 265,000 Tag- fixation point. All letters were masked for 500 ms. SNPs, 245,000 Exom marker and 50,000 markers, which In both tasks, letters could be reported in arbitrary order have been reported to be associated with the most com- and without speed stressing. The reported letters were mon psychiatric disorders. In addtion, an array of polym- typed on a keyboard by the experimenter who then initiated prphisms will be investigated covering the genes of oxy- the next trial by pressing the space bar. The partial report tocin (OXT) and its receptor (OXTR): OXT: rs2740210, paradigm provides an estimate of the specific aspects of rs4813627, OXTR: rs237885, rs53576, rs2254298, weighting, the weighting parameters top-down attentional rs237887, rs237915, rs2228485. control α, and spatial distribution of attention wλ. For genotyping, two tubes of 7.5 ml blood will be taken Studies investigating functional and structural brain at the baseline visit. DNA will be prepared following a connectivity show that visual attention is contingent upon standard procedure. Genotyping of Psycharray Chips will large neuronal networks which are also involving frontopa- be carried out in collaboration with the Life and Brain rietal pathways [57]. Neuroimaging studies investigating Center of the Department of Genomics, University of tDCS-effects on functional connectivity suggest that tDCS Bonn. Commercially avavilable genotyping assays will be modulates such network activity. We implemented the TVA applied for detection of OXT related polymorphisms using paradigm in the trial procedures to detect tDCS-induced the ABI 7000 (Taqman; Apllied Biosystems). changes on a network level and to investigate the effect of In addition to the analyses of genetic predictors for prefrontal tDCS on different components of attention. tDCS response, a similar array of candidate genes will be The TVA assessment will be performed at the baseline investigated in terms of epigenetic modifications during visit and visits 4, 6 and 8 in collaboration with the Neuro- the course of tDCS. Epigenetics has been widely identified Cognitive Psychology Unit, Dept. of Psychology, LMU as process that could play an important role in the patho- Munich. genesis of depression as it represents the main mediator of environmental effects in enhancing the vulnerability risk to Genetic predictors of response and epigenetic develop the disease. Epigenetic mechanisms such as DNA modification during tDCS methylation, histone modifications and miRNAs expres- sion changes impact functional changes to the genome that Depressive disorders show a significant heritability [58]. may result in it being “turned off” or “turned on”, without With respect to outcome of antidepressant treatment, two changing DNA sequence or structure. Epigenetic markers main lines of evidence suggest investigating genetic mark- on DNA can be influenced by environmental forces, such ers of response to tDCS as antidepressant intervention: (1) as stress, smoking, diet, and pollutants or even medications genetic markers of antidepressant response in general have and other therapeutic interventions as tDCS. In contrast to been suggested in prior trials and are related to various the genetic sequence, which is determined by inheritance

1 3 Eur Arch Psychiatry Clin Neurosci and is virtually identical in all tissues, the epigenetic pattern ideation. Cognitive functions will be assessed using the is potentially dynamic throughout life, probably partially EmoCogMeter as previously described. reversible and may differ in different parts of the body [62, 63]. Taken together, a better understanding of the under- Sample size calculation lying role of genetic and epigenetic processes involved in the development and treatment response of depression rep- The sample size calculation is based on the effects resents the basis for future research and clinical interven- described in Brunoni et al. [28, 45]. Using the numbers tions. Changes of the DNA methylation status of patients from sham (active) tDCS and sertraline from Table 1 of will be analyzed at baseline, after 6 weeks and after further this publication allows the following conclusions on the 24 weeks (Visit 8). expected effects: The difference in MADRS scores between baseline and week 6 in the active group is (30.73 − 13.17=) Driving‑ability‑testing 17.56, for the control group (30.50 − 21.67=) 8.83. The absolute effect (difference between the difference in both According to the German guidelines for road and traf- groups) is (17.56 − 8.83=) 8.73. Assuming a correlation of fic safety various domains (including selective attention, 0.4 between baseline and measurement in week 6 gives an concentration, visual perception, reactivity, and stress tol- SD for the difference of about 12.14 (6.8²+13.14²-2 × 0.4 × erance) will be assessed with computerized psychomotor 6.8 × 13.14 = 147.418 = SD²). This justifies the conservative tests. Visual perception is assessed with the Tachistoscope assumption of a Cohen’s d of 0.5 (<8.73/12.14 = 0.72). Test (TAVT-MB). Stress-tolerance will be examined with A sample size of 64 in each group will have 80% power the Wiener Determinationstest (DT). Concentration will be to detect an effect size of 0.5 using a two group t-test with a measured with the attention and concentration test (COG). 0.05 two-sided significance level. The Reaction-Test (RT) is designed as a choice-reaction The computation assumes an allocation ratio between task. Participants have to respond to a specific combination groups of 1.0. This yields a total 128 observations. 610 of visual and acoustic stimuli. The driving-ability-testing patients will be assessed for eligibility, 152 will be allo- will be performed at the baseline visit and within 1 week cated to the trial, assuming a 15% dropout so that 128 will after the last stimulation in collaboration with Dr. A. Brun- be analysed (Fig. 1). nauer, Driving-Ability Unit, Dept. of Psychology, LMU Munich/ Unit, Dept. of Psychology, kbo- Randomization and blinding Inn-Salzach-Klinikum, Wasserburg. Randomization will be used to minimize bias in the assign- Endpoints ment of patients to study groups, to increase the likelihood that known and unknown patient attributes (e.g. demo- Both the efficacy and tolerability of prefrontal tDCS used graphic characteristics) are evenly balanced across study as an additive therapy to an antidepressant medication as groups, and to enhance the validity of statistical compari- treatment for major depression will be assessed by the sons across study groups. Stratifiers are used to reduce following primary and secondary endpoints as well as by variability and to distribute patients according to factors distinct safety and tolerability measures. According to the known to positively or negatively influence the clinical out- main hypothesis of this study the primary efficacy endpoint come. The strata are ‘center’, ‘gender’ and ‘MARDS < 31 is the change from baseline in MADRS scores at week 6 vs. MARDS ≥ 31’. Distribution of the patients to the two post-randomization compared to baseline in the sham and groups with respect to the strata and according to correct active tDCS group. randomization is performed by a new online randomiza- Secondary endpoints are clinical response (as measured tion tool. Double-blinded treatment will be used to reduce by an at least 50% reduction of the MADRS score from potential bias during data collection and the evaluation of baseline or remission) and remission rates (as defined by clinical endpoints. The study personnel do not have any a MADRS score ≤10 points), change of BDI-II, CGI and knowledge of whether the active mode or sham mode is GAF scores from baseline, change of measures for social being activated by the tDCS device. Thus, all study per- functioning and measures of general health from base- sonnel and the study patients will be blinded to the treat- line as assessed with the SF-36, change in anhedonia ment being administered. In addition, all patients will be from baseline as assessed with the SHAPS-D and change tDCS-naïve, except for single experimental tDCS ses- in state anxiety from baseline as assessed with the STAI. sions. Patients will be asked whether they believe they Safety will be assessed, including monitoring of AEs with have received active or sham stimulation after the first and the CRQ, vital signs, physical and neurological examina- the last treatment session at study visits 1 and 6 (blind- tion. The C-SSRS will be used to assess increase in suicidal ing check). An independent rater will evaluate the patient

1 3 Eur Arch Psychiatry Clin Neurosci following treatment and complete the patient assessment the missing values in patients. This allows applying logis- scales. The independent rater will not see the patient until tic regression (using centers as random effect and baseline completion of the treatment. MADRS as fixed effect) to analyze response rate as well as remission rate. In principle, the strategy for handling miss- Safety monitoring ing data will be described in detail in the statsitical analysis plan (SAP) of the study. Assessment of safety is performed For safety monitoring an independent safety monitoring using descriptive statistics. board (SMB) will be established. The underlying prin- ciples for the SMB are ethical and safety aspects for the Organisational infrastructure patients. It is the task of the SMB to examine, whether the conducting of the study is still ethically justifiable, whether Organisational project management, safety management, security of the patients is ensured, and whether the pro- monitoring, data management and randomization is per- cess of the study is acceptable. For this, the SMB has to be formed by the Münchner Studienzentrum (MSZ), an aca- informed about patient recruitment, and the observed AEs. demic clinical research organisation at the Technical Uni- Occurring serious adverse events (SAEs) will be recorded versity of Munich. in a study specific safety form and transferred into a data- base by the safety management (MSZ), which processes Ethics approval further SAE documentation in written form to the SMB. Trial sites must be experienced in clinical trials and must Before the start of the trial, the trial protocol, informed have adequate study infrastructure, e.g. a ‘good clinical consent document and any other relevant trial documents practice’ (GCP)-trained Principle Investigator (PI), deputy, were submitted to the independent ethics committees. study nurses and other trained study personal. Patients will be discontinued if there is presentation of suicidal idea- Good clinical practice (GCP) tion (based on MADRS item 10 score of >4 or as assessed by the C-SSRS, agree to item 4 and/or agree to item 5) or The procedures set out in this trial protocol, pertaining to attempted suicide after receiving active or sham tDCS, but the conduct, evaluation and documentation of this trial, are may be also withdrawn from the study for other serious rea- designed to make sure that all persons involved in the trial sons, e.g. switch to hypomania or even mania. Further rea- abide by Good Clinical Practice and the ethical principles sons for withdrawal from the study are pregnancy and the described in the current revision of the Declaration of Hel- belief of the investigator that for safety reasons (e.g. an AE) sinki. The trial will be carried out in keeping with local it is in the best interest of the patient to stop treatment. legal and regulatory requirements.

Statistical methods Discussion The main analysis consists of an intention-to-treat (ITT) analysis for the change in MADRS to baseline at 6 weeks DepressionDC will be an urgently needed replication and by adjusting for baseline effect, sex and center. This can extension trial of the largest tDCS trial to date [28] regard- be done by analysis of covariance (ANCOVA) or by a lin- ing the efficacy of tDCS as add-on to SSRI treatment for ear mixed effect model using random effects for centers MDD. It`s the first multicenter study in this field and con- and baseline as a fixed effect. In the final analysis a mul- siderable time and effort was invested when improving the tiple comparison is planned which will be performed in a methods and presenting a study design that overcomes the hierarchical manner (change over 6 weeks, change over 18 problems of former trial designs regarding this issue. weeks, change over 30 weeks). The main hypothesis of this study is: the mean change in All statistical analyses will be repeated on the per-pro- MADRS score from baseline at 6 weeks in the tDCS study tocol (PP) sample as sensitivity analysis on an exploratory group is higher compared to the mean change in MADRS significance level of 5%. score from baseline at 6 weeks in the tDCS-control group. Missing values will be imputed using the longitudinal The design is triple-blind with an effective stimulation data structure for the primary endpoint based on techniques quality control performed by an independent unblinded site to handle monotone informative missing patterns (for and standardization of the most important steps (MADRS example created by patients with high scores in MADRS rating; tDCS procedure) is implemented in this trial which item 10). leads to well reproducible results. On the one hand this Secondary outcomes are restricted to measurements trial aims to demonstrate the therapeutic efficacy of tDCS at week 6, 18, and 30. Imputation will be used to replace in a large multicenter study by verifying the hypothesis

1 3 Eur Arch Psychiatry Clin Neurosci that tDCS when combined with an SSRI is superior to an 01EE1403G), funded by the Federal Ministry of Education and SSRI alone regarding the amelioration of depressive symp- Research (BMBF). tomology in patients with MDD. On the other hand this Compliance with ethical standards study should make a contribution to the understanding of the mechanisms of action of tDCS. In this study different Conflict of interest F.P. has received speaker’s honorarium from parameters are measured and different diagnostic meth- Mag&More GmbH and support with equipment from neuroConn ods are used to take a closer look at the tDCS effects on GmbH, Ilmenau, Germany, Mag&More GmbH and Brainsway Inc., different functional levels. MRI investigations measuring Jerusalem. A. Hasan has been invited to scientific meetings by Lun- dbeck, Janssen-Cilag, and Pfizer, and he received paid speakership resting-state functional and structural connectivity at base- by Desitin, Otsuka and BAK. He is a member of the Roche Advisory line, after 6 weeks of tDCS treatment (acute phase) and 24 Board. The other authors do not report conflicts of interest. weeks after the last tDCS session (follow-up) will presum- ably provide insights into mechanisms of action of tDCS on Funding The clinical trial is funded by the Federal Ministry of Edu- cation and Research (Bundesministerium für Bildung und Forschung the network level of the human brain. Investigations con- [BMBF]) within the German Center for Brain Stimulation (GCBS, cerning the genetic and epigenetic level will help to find out FKZ 01EE1403G). more about genetic predictors of response and epigenetic modification during tDCS aiming to improve tDCS meth- Trial status Enrolment for this study began in January 2016. At the ods and to understand mechanisms of action of tDCS on a time of submission, we have enrolled 18 participants. genetic basis. Furthermore, the TVA is used to demonstrate tDCS effects on different aspects of attentional control. Changes in top-down attentional control and spatial distri- bution of attention after 4 weeks of daily tDCS, after two References more weeks of tDCS twice a week and 24 weeks after the last tDCS session can be recorded, and thus the acute and 1. Murray C, Lopez A (1996) The global burden of disease: a long-term impact of tDCS on the performance in this field comprehensive assessment of mortality and disability from dis- is evaluated. The EmoCogMeter is used to investigate the eases, injuries and risk factors in 1990 and projected to 2020, ed. H.S.o.P. Health. Harvard School of Public Health, Cambridge influence of tDCS on different neuropsychological domains 2. 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Prog Neu- ropsychopharmacol Biol Psychiatry 35(1):96–101 sants SSRIs have a more favourable side-effect profile. An 8. Dell’Osso B et al (2012) Transcranial direct current stimulation additive therapy with tDCS to an antidepressant medica- for the outpatient treatment of poor-responder depressed patients. tion could lead to better remission rates without increased Eur Psychiatry 27(7):513–517 side-effects. 9. Ferrucci R et al (2009) Transcranial direct current stimula- tion in severe, drug-resistant major depression. J Affect Disord The aim of the study is to investigate the efficacy and 118(1–3):215–219 tolerability of prefrontal tDCS used as an additive therapy 10. Fregni F et al (2006) Treatment of major depression with tran- to an antidepressant medication as treatment for major scranial direct current stimulation. Bipolar Disord 8(2):203–204 depression. This study will help to extend the spectrum of 11. Martin DM et al (2011) Fronto-extracephalic transcranial direct current stimulation as a treatment for major depression: an open- therapeutic options in MDD. label pilot study. J Affect Disord 134(1–3):459–463 12. Insel T et al (2010) Research domain criteria (RDoC): toward a Acknowledgements This work was supported by the German new classification framework for research on mental disorders. Center for Brain Stimulation (GCBS) research consortium (FKZ Am J Psychiatry 167(7):748–751

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