Pilot trial of home-administered transcranial direct current stimulation for the treatment of depression

Accepted Manuscript

Pilot Trial of Home-Administered Transcranial Direct Current Stimulation for the treatment of depression Angelo Alonzo , Joanna Fong , Nicola Ball , Donel Martin , Nicholas Chand , Colleen Loo PII: DOI: Reference:

S0165-0327(18)31832-9 https://doi.org/10.1016/j.jad.2019.04.041 JAD 10702

To appear in:

Journal of Affective Disorders

Received date: Revised date: Accepted date:

20 August 2018 13 March 2019 7 April 2019

Please cite this article as: Angelo Alonzo , Joanna Fong , Nicola Ball , Donel Martin , Nicholas Chand , Colleen Loo , Pilot Trial of Home-Administered Transcranial Direct Current Stimulation for the treatment of depression, Journal of Affective Disorders (2019), doi: https://doi.org/10.1016/j.jad.2019.04.041

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Home-administered tDCS for depression

Highlights Home-administered, remotely-supervised tDCS reduced depressive symptoms.

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Treatment was feasible, well-tolerated and safe.

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Mood and tolerability outcomes were comparable to clinic-based trials.

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Home-administered tDCS for depression

Title: Pilot Trial of Home-Administered Transcranial Direct Current Stimulation for the treatment of depression

Authors: Angelo Alonzo1a, Joanna Fong1, Nicola Ball1, Donel Martin1, Nicholas Chand1, Colleen Loo1,2 School of Psychiatry, University of New South Wales / Black Dog Institute, Hospital Road,

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Randwick NSW Australia 2031 2

St George Hospital, South Eastern Sydney Health, Level 2, James Laws House, Gray St,

Corresponding author:

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Kogarah NSW Australia 2217

Angelo Alonzo

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School of Psychiatry UNSW Black Dog Institute, Hospital Road Randwick NSW Australia 2031 Email: [email protected] Telephone: +61-2-9382 2987 Fax: +61-2-9382 8208

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Abstract Background Transcranial Direct Current Stimulation (tDCS) is a non-invasive, neuromodulation approach with promising efficacy for treating depression. To date, tDCS has been limited to clinical or

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research centre settings with treatment administered by staff. The aim of this study is to

examine the efficacy, tolerability and feasibility of home-administered, remotely-supervised tDCS for depression.

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Methods

In an open label trial, 34 participants used a Soterix 1X1 mini-CT device to self-administer 20-28 tDCS sessions (2 mA, 30 minutes, F3-anode and F8-cathode montage according to 10-

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20 EEG placement) over 4 weeks followed by a taper phase of 4 sessions 1 week apart. Participants were initially monitored via video link and then through completion of an online

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treatment diary. Mixed effects repeated measures analyses assessed change in mood scores.

Results

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Mood improved significantly from baseline (27.47 on Montgomery-Asberg Depression Rating Scale) to 1 month after the end of acute treatment (15.48) (p < 0.001). Side effects

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were largely transient and minor. Outcomes were comparable to those reported in clinicbased trials. Protocol adherence was excellent with a drop-out rate of 6% and 93% of scheduled sessions completed.

Limitations

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The tDCS and remote monitoring procedures employed in this study require a level of manual dexterity and computer literacy, which may be challenging for some patients. This study did not have a control condition.

Conclusions

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This study provides initial evidence that home-based, remotely-supervised tDCS treatment

Keywords: major depressive disorder transcranial direct current stimulation

safety

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psychiatric somatic therapies

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clinical trial

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may be efficacious and feasible for depressed patients and has high translational potential.

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Introduction Depression is a debilitating and prevalent condition with an estimated 350 million people suffering worldwide (World Health Organization, 2012). Major depressive disorder (MDD) ranks 11th globally as a cause of disability-adjusted life years (Murray et al., 2012). Although there are several established treatment options for depression such as

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pharmacotherapy, psychotherapy, repetitive transcranial magnetic stimulation (rTMS) and electroconvulsive therapy (ECT), a considerable proportion of patients do not respond to treatment (Carpenter et al., 2012; Cuijpers et al., 2008; Demitrack & Thase, 2009; Rush et al.,

line, stand-alone and/or adjunct therapies.

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2006). Thus, there is a need to investigate other potential treatments that may serve as first-

The development of transcranial Direct Current Stimulation (tDCS), a non-invasive brain stimulation technique, presents another treatment modality with excellent acceptability,

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tolerability, safety, and promising efficacy (Aparicio et al., 2016; Bikson et al., 2016; Brunoni et al., 2016; Nikolin et al., 2018). In tDCS, a weak direct current is transmitted into

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cerebral tissue via scalp electrodes (anode and cathode), modulating cortical excitability and

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plasticity (Nitsche & Paulus, 2000; Nitsche & Paulus, 2001; Player et al., 2014). Stimulation produces shifts in the membrane potential of neurons, resulting in a shift in the spontaneous

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rate of neuronal firing (Nitsche et al., 2008). Sustained stimulation can cause changes in synaptic plasticity that can persist beyond the stimulation period through long-term

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potentiation or long-term depression (Nitsche & Paulus, 2001). Depending on the electrode montage, tDCS can produce diffuse activation of the brain, with modulation extending to regions beyond the cortical areas directly beneath the electrodes through networks of functionally connected areas (Peña-Gómez et al., 2012). The therapeutic effects of tDCS are considered to depend on these mechanisms in treating the pathophysiology underlying neurological or psychiatric conditions such as depression.

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Conventionally in depression trials, the anode is placed over the left dorsolateral prefrontal cortex (DLPFC) and the cathode over the right DLPFC or fronto-temporal area (Bai et al., 2014; Brunoni et al., 2016) as hypoactivity in the left DLPFC has been implicated in the pathophysiology of depression (Grimm et al., 2008). The DLPFC is associated with executive functioning such as working memory, selective attention, cognitive flexibility and

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planning, and is an important node in the neurocircuitry of depression and mood control (de Kwaasteniet et al., 2015; Koenigs & Grafman, 2009; Matsuo et al., 2007; Ye et al., 2012) due to its role in top-down regulation of affective responses (Phillips et al., 2003).

The majority of randomised controlled trials (Bennabi et al., 2015; Blumberger et al.,

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2012; Brunoni et al., 2017; Brunoni et al., 2013; Loo et al., 2012; Loo et al., 2018; Loo et al., 2010; Palm et al., 2012) and meta-analyses (Berlim et al., 2013; Brunoni et al., 2016; Kalu et al., 2012; Meron et al., 2015; Mutz et al., 2018; Shiozawa et al., 2014) have found active

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tDCS to have superior antidepressant effects compared to sham stimulation. Indeed, the most recent meta-analyses have found tDCS to be associated with significant improvement in both

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response and remission rates compared with sham stimulation and that higher stimulation

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doses are positively associated with efficacy. Further, it was suggested that tDCS may be more effective in less treatment resistant patients (Brunoni et al., 2016; Mutz et al., 2018). In

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addition, there have been no chronic adverse effects associated with tDCS including after repeated use (Andrade, 2013; Aparicio et al., 2016; Bikson et al., 2016; Brunoni et al., 2011;

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Ho et al., 2015; Nikolin et al., 2018). To date, tDCS for depression has mainly been offered at a clinical or research centre,

administered by staff trained in tDCS technique with a typical treatment course involving one session every weekday for 2-4 weeks. This can present a barrier to treatment for otherwise suitable patients due to time, cost and travel constraints. For example, work / study commitments or familial responsibilities may preclude patients from attending a clinic during

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normal business hours. Geographic location, especially for patients residing in rural areas, may also limit accessibility. Moreover, the type and severity of symptoms experienced by patients in the depressed population may in themselves limit patients from accessing treatment. Symptoms such as lassitude, loss of motivation, social withdrawal and reduced executive functioning may prevent patients from making the necessary arrangements to

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complete a treatment course that requires regular attendance at a treatment centre.

Notably, with procedural modifications and specifically designed equipment, it is now possible to adapt tDCS for remotely-supervised, home-based use, where the treatment is administered by the patient or a carer at home. Treatment parameters, scheduling and

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outcomes monitoring are supervised remotely by clinic or research staff (Alonzo & Charvet, 2016; Charvet et al., 2015). To date, this has been piloted for treating a number of conditions including auditory hallucinations in schizophrenia (Andrade, 2013), multiple sclerosis

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(Charvet et al., 2017; Charvet et al., 2018; Kasschau et al., 2016; Kasschau et al., 2015), Mal de Debarquement Syndrome (Cha et al., 2016), Parkinson‟s disease (Agarwal et al., 2018;

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Dobbs et al., 2018), trigeminal neuralgia (Hagenacker et al., 2014), vascular dementia (André

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et al., 2017) and Prader-Willi syndrome (Azevedo et al., 2017) with promising results (for review, see Palm et al., 2018). Of note, Andrade (2013) has reported the case of a

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schizophrenia patient with severe, clozapine-refractory auditory hallucinations, who received daily to twice-daily, domiciliary, 30-min, 1-3 mA tDCS for at least 3 years with treatment

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still ongoing at the time of publication. The patient reported greater than 90% improvement within 2 months with benefits maintained for at least 3 years with regular tDCS sessions, supporting the long-term feasibility and efficacy of home-administered tDCS. Moreover, high rates of protocol adherence and low drop-out rates due to inability to tolerate the treatment have been reported (Charvet et al., 2017; Kasschau et al., 2016), suggesting that homeadministered tDCS is a viable treatment approach at least for the clinical samples examined

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thus far. For example, Kasschau et al. (2016) have reported a 95% completion rate with no discontinued treatments or adverse events across 192 treatment sessions in participants with multiple sclerosis. However, although tDCS has been increasingly studied for the treatment of depression, there has been no study to date specifically investigating the use of home-

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administered tDCS in a depressed sample. Notably, Clayton et al. (2018) have reported a case of one patient with comorbid multiple sclerosis and recurrent depressive episodes who

received a course of remotely-supervised tDCS following ECT treatment. However, although fatigue and mood ratings improved, the specific benefit of tDCS for the depressive symptoms

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remains to be determined due to the concurrent improvement in fatigue, the fact that a cognitive training task was administered with tDCS, and the modest improvement in

depressive symptoms as measured by the Hamilton Depression Rating Scale (15 to 11) which

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may or may not have been mitigated by prior treatment with ECT.

The aim of this study, therefore, was to examine the efficacy, feasibility and

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tolerability of home-administered tDCS as a treatment for depression in an adequately

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powered open label pilot trial. It was hypothesised that based on prior clinic-/research centrebased trials, participants would experience a significant improvement in mood outcomes

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without serious adverse effects.

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Methods

Trial Design: The treatment course consisted of an acute phase of 20 or 28 tDCS

sessions, conducted over 4 weeks. The original protocol scheduled sessions on weekdays (i.e., same frequency as centre-administered tDCS) (Group 1) but after the first 15 participants, to fully explore the potential of home-based treatment, which accommodates daily administration on weekends, and as a preliminary investigation of feasibility and

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whether symptom improvement may be enhanced by increased frequency, the protocol was amended to include daily sessions (i.e., 7 days per week) (Group 2). Indeed, the metaanalysis by Brunoni et al. (2016) including all tDCS RCTs at the time, found a positive association between increased tDCS „dose‟ (a composite measure that included current intensity, stimulation duration and number of sessions) and treatment efficacy (as measured

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by improvement in rating scales as well as response and remission rates), suggesting that increasing the session frequency could improve mood outcomes.

A taper phase of 4 tDCS sessions spaced 1 week apart was also added in Group 2, similar to recent protocols in other studies (Loo et al., 2018). Mood assessments were

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conducted at baseline, 2 weeks, and 4 weeks in the acute treatment phase. Participants were also assessed at 1 month (end of taper), 3 and 6 months following completion of the acute treatment phase. Participants, who met the criterion for clinical response, defined as ≥ 50%

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improvement on the Montgomery-Asberg Depression Rating Scale (MADRS) (Montgomery & Asberg, 1979) score from baseline to the 1-month follow-up, were given the option to

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continue with maintenance treatment with a basic schedule of a weekly session for 2 months

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and then fortnightly for a further 3 months. However, the maintenance schedule could be further adjusted by the study psychiatrist based on symptom severity as assessed by the

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MADRS. No formal algorithm for adjusting the frequency of sessions was implemented as there is still very limited evidence to date as to the optimal maintenance regimen with tDCS.

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In practice, participants who entered the maintenance phase were monitored remotely via their entries on an online treatment diary. Research staff monitored participants‟ self-reported overall mood score on a scale of 1-10 (10 = feeling normal and not depressed at all – 0 = feeling as depressed as they could possibly be). If any sustained reduction was observed, the participant was contacted and a MADRS administered to ascertain their mood and if the

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MADRS score confirmed a worsening (e.g., 75% or greater of the participant‟s baseline score), the session frequency was increased. Cognitive testing was conducted at baseline and at the end of the acute treatment phase. This research was approved by the University of New South Wales Human Research Ethics Committee.

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Participants: Participants met criteria for a diagnosis of MDD according to the

Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) (American Psychiatric Association, 2000), as determined via an interview with a study psychiatrist, and confirmed with the Mini International Neuropsychiatric Interview (MINI; Version 5.0.0) (Sheehan et al.,

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1998). Participants were at least 18 years of age; currently experiencing a current major

depressive episode of at least four weeks‟ duration as part of a unipolar or bipolar depression; and scored at least 20 on the MADRS at trial entry. Exclusion criteria were any DSM-IV-TR

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psychotic disorder; drug or alcohol abuse or dependence in the preceding 3 months; concurrent benzodiazepine medication; high suicide risk; history of clinically defined

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neurological disorder or insult; metal in the cranium or skull defects; skin lesions on the scalp

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at the proposed electrode sites; and pregnancy. Participants provided written informed consent for this study. Treatment resistance was assessed using the Maudsley Staging Method

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(Fekadu et al., 2009).

Participants on antidepressant medication were permitted to enter the trial provided

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the medication dose was unchanged for 4 weeks prior to trial entry and during the acute treatment phase of the study. Bipolar participants were required to be on a mood stabiliser as prophylaxis against treatment-emergent mania (Brunoni et al., 2017) for at least 4 weeks prior to trial entry and throughout their participation in the study. Of the 5 bipolar participants included in the study, 3 were on an anticonvulsant, 2 on an antipsychotic, and 2 on lithium.

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A power analysis based on results from our prior trial of clinic-based tDCS (Loo et al., 2012), determined that a sample size of 34 participants was required to detect a significant improvement in depressive symptoms. Allowing for 5% drop-out, the study planned to recruit up to 36 participants to obtain a sample of 34 who had at least one post baseline rating. Interventions, materials and procedures: This study utilized a Soterix 1X1 tDCS mini-

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CT investigational device (Soterix Medical Inc., New York USA) specifically developed for home-based use under remote clinical supervision. Each session involved 2 mA tDCS for 30 minutes with ramp-up and ramp-down of 30 seconds. The anode was placed over the left DLPFC and the cathode over the right temporo-orbital area (F3 and F8 respectively

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according to the 10-20 EEG system). The current was applied via rubber electrodes inserted into single-use, saline-soaked sponge pockets measuring 5 cm by 7 cm and attached to a headband (see Figure 1). Stimulation parameters were pre-programmed into the device at the

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research centre by staff, including stimulation intensity, duration, total number of sessions and single-use activation codes for each session. All research staff were trained and

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supervised by a senior staff member (author A.A.) with 10 years‟ experience in tDCS

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treatment protocols including development of tDCS protocols for home-administration. Research staff were comprised of medical students, and research assistants with a degree in

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neuroscience or psychology.

[INSERT FIGURE 1 ABOUT HERE]

Participants initially attended a baseline visit at the study site for administration of

mood and cognitive assessments and a detailed demonstration of the tDCS device and procedures by research staff. Participants then practiced preparing the tDCS equipment, operating the device, and administering a short stimulation session, the aim of which was to

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familiarise participants with the typical sensations of tDCS and to check tolerability. Participants were instructed to abort stimulation if pain was experienced at the electrode site to minimise the risk of skin burns or damage (Loo et al., 2011). Following satisfactory completion of this training, participants underwent a credentialing procedure in which they self-administered the first tDCS session and were assessed against a checklist of procedures

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(see Supplementary Figure 1), confirming their ability to independently prepare the

equipment and to operate the device safely (Alonzo & Charvet, 2016; Charvet et al., 2015). Only participants who demonstrated competency in all procedures were enrolled in the study. They were loaned a home-based tDCS device, headband and electrodes, and provided with

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sponge pads and saline.

Research staff remotely observed treatment sessions administered by participants at home via video link for the first three home-administered sessions from the initial set-up

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through to completion of the tDCS session. For subsequent sessions, video link monitoring was conducted as needed. As an aim of the study was to examine the feasibility of tDCS

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treatment in a more natural, non-clinic based environment, participants were not restricted in

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terms of what activities they did during the stimulation period at home provided it did not constitute a potential safety risk.

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Besides the initial training/credentialing and video monitoring, other tolerability measures included sending participants the unique activation code prior to each session and

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only if the previous session was completed to ensure that participants were not able to perform tDCS sessions outside the study protocol. To ensure reliable stimulation, the tDCS device provided a live readout of the electrode contact quality – shown as GOOD, MODERATE or POOR and colour coded green, yellow and red respectively for easy identification – before and during stimulation with participants trained to make adjustments to improve contact quality if needed, such as tightening the headband and/or adding saline to

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the sponge electrodes. Prior to trial entry, participants were also required to have a safety plan in place for implementation in a clinical emergency (e.g., suicidality), which included strategies for coping with warning signs of suicidal ideation/crisis, contact details of treating doctor/s, the closest hospital emergency department, and contact details of next of kin/friends for support. Participants‟ regular treating doctors were notified of their patient‟s participation

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in the study and understood that primary responsibility for ongoing clinical care continued with them.

Throughout the study, participants were required to complete an online treatment diary for each treatment session. The diary reminded participants of safety checks and

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treatment procedures; recorded any side effects experienced, their severity (mild, moderate, severe), and temporal relationship with the tDCS session (before, during, after); monitored mood by which participants reported a global rating between 1 (low) to 10 (normal), and

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suicidal ideation, which was rated using item 9 of the Beck Depression Inventory (Beck et al., 1961) (range from 0 = “I don't have any thoughts of killing myself.” to 3 = “I would kill

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myself if I had the chance.”); and monitored session completion and adherence to the session

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schedule. The diary was monitored by research staff online and checked each weekday prior to sending treatment codes to the participant for subsequent treatment sessions.

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Outcome measures: The primary outcome was change in the observer rated MADRS score from baseline to the 1-month follow-up. As previously noted, clinical response was

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defined as ≥ 50% improvement in MADRS score from baseline to the 1-month follow-up. Remission was defined as a MADRS score ≤ 10. Secondary outcome measures included the participant-rated Quick Inventory of Depressive Symptomatology (QIDS-SR) (Rush et al., 2003) and the Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LESQ-SF) (Endicott et al., 1993), both administered at the same time points as the MADRS. A computer-based cognitive test battery, CogState (https://www.cogstate.com), was introduced

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as an additional safety outcome measure after the first 15 participants. This battery included tests designed to assess verbal learning and memory (International Shopping List Task), attention and psychomotor function (Detection Task), visual attention (Identification Task), visual learning and memory (One Card Learning Task), working memory (Two Back Task), and executive function (Set Shifting Task).

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Statistical analyses: To assess the effects of acute treatment, outcome measures were analysed for change over time up to the 1-month follow-up using a mixed-effects repeated measures (MERM) analysis with Time as a repeated factor (baseline, 2 weeks, 4 weeks/end of acute phase, 1-month follow-up), Session Frequency in the acute phase as a between

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groups factor (Group 1 – 20 sessions, or Group 2 – 28 sessions) and subjects as a random factor. The proportion of responders and remitters at one month follow up was compared between Groups 1 and 2 using chi-square tests. Cognitive tests were analysed using repeated

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treatment) as the repeated factor

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measures analyses of variance (ANOVA) with Time (baseline, end of 4-week acute

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Results

Study recruitment continued until a sample of 34 participants with at least one post

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baseline rating was attained. 35 participants were enrolled in the study and only one participant did not pass credentialing due to inability to master the headband/electrode set-up

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within the 3-hour training session. This participant elected to not undergo further training and did not proceed in the study. The outcomes of 34 participants were included for analysis including one participant who withdrew from the study due to external stressors that led to too many missed sessions. The overall drop-out rate was 6% (including the participant who did not pass credentialing). Of the 33 participants who completed the acute treatment phase, 93% of the scheduled sessions were completed. Thirteen participants qualified for

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maintenance treatment and 10 opted to continue with maintenance sessions. The CONSORT diagram is presented in Supplementary Figure 2. Baseline demographic and clinical data are presented in Table 1.

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[INSERT TABLE 1 ABOUT HERE]

The means and standard deviations for primary and secondary outcome measures are presented in Table 2 and mean MADRS scores across all study time points are illustrated in

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Figure 2.

[INSERT TABLE 2 AND FIGURE 2 ABOUT HERE]

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Mood outcomes: The MERM analysis of MADRS scores found a significant main effect of Time from baseline to the 1-month follow-up [F = 21.84(3,11); p < 0.001]. There

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was no significant interaction between Time and Session Frequency [F = 1.57(3,11); p =

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0.25].

The MERM analyses also found significant main effects of Time in QIDS-SR [F =

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16.34(3,26); p < 0.001] and Q-LES-Q-SF [F = 13.01(3,26); p < 0.001] scores but there were no significant interactions between Time and Session Frequency (QIDS-SR: [F = 1.26(3,26);

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p = 0.31]; Q-LES-Q-SF: [F = 0.37(3,26); p = 0.78]. The number of responders (6/14, Group 1; 7/20, Group 2; 38% response rate overall)

and remitters (5/14, Group 1; 6/20, Group 2; 32% remission rate overall) at the 1-month follow-up did not significantly differ between the two groups (responders: χ2 = 0.22; p = 0.64; remitters: χ2 = 0.12; p = 0.73).

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Cognitive outcomes: Results from the cognitive tests are shown in Table 3. No significant changes were observed across the respective outcome measures over the acute treatment period.

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[INSERT TABLE 3 ABOUT HERE]

Adverse effects: Side effects reported across a total of 1149 sessions (413 sessions in Group 1; 736 sessions in Group 2; including maintenance sessions) are presented in Table 4. The most commonly reported side effects were mild to moderate tingling or burning/heat

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sensation during stimulation and redness at the electrode sites.

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[INSERT TABLE 4 ABOUT HERE]

Though some side effects occurred frequently (i.e., tingling, skin redness,

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burning/heat sensation), a rating of severe was reported in 25 sessions out of the 1149

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sessions (2.18% of sessions): burning/heat sensation 9 times, itching 5 times, redness 3 times, tingling 3 times, light-headedness twice, fatigue twice, and pain once. All side effects

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reported were transient and only one session was aborted due to pain (as per instructions given to participants). This occurred within 10 seconds of commencement of the session (4th

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session in maintenance phase) and may have been due to poor electrode contact. The participant completed all other study treatment sessions without incident. There were no instances of treatment-emergent mania or hypomania. Overall, the frequency and severity of side effects was similar to that of research clinic-based tDCS studies (Moffa et al., 2017; Nikolin et al., 2018).

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Discussion Results showed that overall, participants experienced a statistically and clinically significant improvement in mood from baseline to the 1-month follow-up, with the average improvement in MADRS scores being 45% at the 1-month follow-up (n = 27). The results of the present study are largely consistent with previous findings in that a

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significant effect of tDCS has been found in reducing depressive symptoms. Response and remission rates at the 1-month follow-up (38% and 32% respectively) are comparable with the largest meta-analysis to date of tDCS randomized, sham-controlled trials (RCTs) (Brunoni et al., 2016), which found response and remission rates of 34% and 23%

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respectively following active tDCS. A large effect size of 1.53 (Cohen‟s d) found for the present results when comparing MADRS scores from baseline to the 1-month follow-up is much larger than effect sizes typically reported in RCTs of tDCS but this is not unexpected

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given the open label design of the present study. Indeed, the effect size is comparable to that of other open label trials assessing clinic-based tDCS for depression (Ferrucci et al., 2009;

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Martin et al., 2011; Martin et al., 2018a).

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A notable finding is that home-administered tDCS, in which participants independently operated the device and equipment, has been demonstrated to have as benign a

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side effect profile as clinic-based studies (Nikolin et al., 2018). Further, this study has demonstrated that at least for depressed patients, routine video monitoring beyond the initial

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3 sessions administered at home may not be necessary for all patients. However, the authors do not necessarily recommend that such an approach would be suitable for all treatment applications in which remotely supervised tDCS may be utilised as a number of factors may need to be considered when deciding the degree of real time monitoring such as the disorder being treated, capability and confidence of the patient, severity of symptoms, and whether there are concurrent tasks prescribed with tDCS. For example, studies that have utilised

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monitoring for all sessions have been predominantly piloted in patients with Multiple Sclerosis and Parkinson‟s Disease in which tDCS was combined with a cognitive training task (e.g., Agarwal et al., 2018; Charvet et al., 2017; Dobbs et al., 2018; Shaw et al., 2017). As these diseases can specifically have debilitating effects on patients‟ motor coordination, movement and muscle strength, real time monitoring for all sessions may indeed be

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warranted to ensure that not only are participants able to reliably set up the tDCS equipment and self-administer treatment, but also to monitor the valid execution of the cognitive training task given the fluctuating severity of symptoms in these patient populations. In other

circumstances, however, other arrangements regarding the monitoring requirements may be

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more viable when tDCS alone is required to be administered such as permitting a caregiver or relative to administer/assist treatment at home with less frequent monitoring by study personnel (e.g., hallucinations in schizophrenia, Andrade et al., 2013; Schwippel et al., 2017;

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trigeminal neuralgia, Hagenacker et al., 2014) or permitting participants to administer treatment themselves without real time monitoring (e.g., Mal de Debarquement Syndrome,

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Cha et al., 2016; chronic tinnitus, Hyvärinen et al., 2016).

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Regarding tolerability, no serious adverse events were reported in the 1149 sessions completed in this study including the acute, taper and maintenance phases, suggesting that the

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protocols developed to maintain the safety and reliability of home-administered tDCS were effective. Although cognitive testing was limited to approximately half the sample, this

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showed no significant changes in performance on outcomes assessing several major domains of cognitive function (i.e., reaction time, working memory, learning and memory, and executive function), thus further supporting safety of the treatment. These findings are also consistent with a recent, large, individual patient data meta-analysis of clinic-based tDCS treatment for depression (Martin et al., 2018b).

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One strength of this study lies in demonstrating the feasibility of a protocol specifically developed for home-administered tDCS in depressed patients. Protocol adherence was excellent with only one participant withdrawing due to external stressors that led to too many missed sessions. The overall drop-out rate of only 6% compares favourably against a drop-out rate of 8.8% reported in an analysis of acceptability in RCTs of tDCS treatment for

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depression (Moffa et al., 2017). Of the 33 participants who completed the acute treatment phase, 93% of the scheduled sessions were completed. tDCS technique was mastered by the overwhelming majority of participants except for one participant who was unable to grasp the manual handling of the equipment within the first visit and elected to not proceed with the

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study. This may be an issue for future designs of tDCS devices to consider in terms of modifying equipment to be even more user friendly.

A further strength of this study is in providing preliminary evidence of the feasibility

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and therapeutic benefit of remotely-supervised, maintenance tDCS, complementing the earlier case report by Andrade (2013) of a schizophrenia patient who had benefited from

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daily, domiciliary tDCS for at least 3 years. The benefits and safety of maintenance tDCS for

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depression in participants attending a clinical research setting have also been previously reported (Martin et al., 2013; Valiengo et al., 2013) with therapeutic benefits tending to be

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better maintained with at least weekly treatment but weakening when spaced to fortnightly or monthly sessions. The optimal frequency of maintenance treatment remains to be determined

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and may also depend on the psychiatric or neurological condition being treated but one advantage of home-administered tDCS is that it may enable more flexibility to tailor the frequency of sessions to the individual patient depending on symptom severity as their ability to attend a treatment centre would not be a negating factor. Results of the present study also suggest that a flexible treatment regimen during the maintenance phase may sustain mood improvement for a longer period than a fixed treatment

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regimen (e.g., Martin et al., 2013). When inspecting the data of participants who received maintenance treatment, 9 of the 10 participants completed all study follow-ups through to 6 months with an average MADRS score of 13.88 at the 6-month follow-up compared with 14.38 at the 1-month follow-up. Somewhat unexpectedly, participants who did not receive maintenance treatment showed comparable MADRS scores (15.48 at 1-month follow-up and

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13.88 at 6-month follow-up), although it should be noted that a much smaller proportion of participants who did not receive maintenance treatment completed all study follow-ups

through to 6 months (29%), potentially biasing the follow-up scores for this subsample as participants who had relapsed or worsened after finishing the main trial phase may have been

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less likely to return for follow-up. Thus at this stage, while the present results suggest a flexible maintenance regimen is beneficial to participants who had responded to tDCS,

further research is needed to quantify the benefits of maintenance treatment compared to a

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more appropriate control group (e.g., responders who did not receive maintenance treatment) and to identify an optimal algorithm for adjusting treatment frequency.

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Although the trial protocol was designed to standardise the tDCS procedure to ensure

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safe and consistent self-administration, there are still potential limitations that may arise. First, though the procedure has been simplified compared to clinic-based tDCS, it

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nevertheless requires a level of conscientiousness to carry out the procedures competently and safely. Should participants neglect tasks such as routinely monitoring contact quality and

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electrode position, both their safety and the efficacy of the treatment could be compromised. Secondly, the home-administered tDCS process, particularly ensuring correct placement of the electrodes, requires an adequate level of manual dexterity and spatial awareness, which could present a challenge for some. While these limitations could be negated with real time monitoring for all treatment sessions, researchers/clinicians would need to consider that some of the advantages of home-based tDCS may be diminished in that treatment sessions would

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need to fit staff work hours rather than at the convenience of the patient, the staff costs to implement real time monitoring may be the same as – if not more than – research centre/clinic based treatment, and it may be less time efficient for staff to conduct real time monitoring compared to administering the treatment themselves to the patient at a clinic centre. Lastly, due to the necessity of video link monitoring for the initial sessions conducted

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at home and the use of an online treatment diary to monitor compliance and side effects, it is necessary that participants have and are able to use, a computer with internet access and video link software.

While the promising results of the present study should be considered in the context

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of its open label design, future trials incorporating a sham condition should be easily

amenable to home-administered tDCS devices as sham stimulation parameters can be readily programmed. Indeed, a sham-controlled trial of home-administered tDCS may prove to be an

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improvement on previous clinic-based sham-controlled trials as potential non-specific effects could be reduced given that participants attending clinic based trials sometimes report that the

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routine of attending sessions or having regular contact with research staff can provide an

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impetus for mood improvement and/or lifestyle changes (e.g., physical activity) that may benefit mood. Nonetheless, it cannot be discounted that home-administered treatment

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protocols such as in the present study may in themselves have their own unique placebo dynamic whereby a participant‟s mood may benefit from potentially feeling more engaged in

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their self-administered treatment and having some degree of autonomy as to when to administer tDCS based on their day to day schedule. Further, participants may also still feel encouraged to implement other secondary lifestyle changes simply due to participating in the trial although no such changes were reported by participants when followed up in this study. As noted earlier, participants in the present study were free to engage in other activities during the stimulation period as permissible given the tDCS set-up. However, future

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studies may also wish to consider the possibility of combining tDCS with a concurrent task designed to engage the same brain circuits modulated by tDCS in order to enhance therapeutic outcomes. Specifically, tDCS may improve deficient cognitive control and emotion regulation in depressed patients when combined with an appropriate cognitive training task (Feeser et al., 2014; Wolkenstein et al., 2013), although some studies suggest

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that tDCS effects may be task dependent (Bortoletto et al., 2015; Segrave et al., 2014). The effect of different concurrent activities on tDCS antidepressant efficacy thus remains an open area for future research.

Also important for future studies of therapeutic tDCS to consider is the identification

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of the optimal therapeutic „dose‟ taking into account the parameters that constitute tDCS treatment including session frequency, current density, stimulation duration and number of sessions. The present study was not designed or powered to examine the difference between

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tDCS given 5 or 7 days per week, and did not find a significant difference in mood improvement between participants who received 5 sessions per week compared to 7.

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Therefore, no firm conclusions can be drawn at this stage as to the optimal treatment

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frequency for tDCS. Moreover, as with established treatments for depression (e.g., antidepressants, ECT, TMS) to which response varies between patients and the treatment

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modified accordingly, the tDCS „dose‟ may to some extent also need to be individually

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adjusted based on prevailing symptoms and severity.

Conclusion

This pilot study constitutes the first known results on the efficacy, tolerability and

feasibility of home-administered tDCS for the treatment of depression. Overall, participants experienced significant reductions in their depressive symptoms that were maintained beyond the acute treatment phase with side effects that were benign, transient, and comparable to

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those typically reported in clinic-based tDCS trials. Should tDCS be further proven to be an effective treatment for depression, home-administered tDCS offers the potential to translate into cost savings for both patients and clinicians as well as increase the accessibility of tDCS by negating time and travel commitments that can become prohibitive for some patients and their caregivers. This is particularly pertinent for ongoing maintenance treatment. Further, the

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conditions for which tDCS is being trialled as a treatment.

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protocol presented in this study could be adapted for other psychiatric or neurological

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Declaration of Interest / Funding Some of the devices and consumables described in this study paper were loaned or provided by Soterix Medical Inc. Angelo Alonzo, Joanna Fong, Nicola Ball, Donel Martin, Nicholas Chand, and Colleen Loo report no biomedical financial interests or potential conflicts of

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interest.

This research did not receive any specific grant from funding agencies in the public,

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commercial, or not-for-profit sectors.

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Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Contributors

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Authors Loo, Alonzo, and Martin designed the study protocol. Authors Alonzo, Fong and Ball undertook the literature searches, statistical analyses and early drafts of the manuscript. Authors Alonzo, Fong, Ball and Chand administered study procedures and collated data. All

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authors contributed to and have approved the final manuscript.

Acknowledgements

The authors thank Drs Truls Bratten, Michael Bull, Sara Buten, Su Lynn Cheah, Olav

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D‟Souza, Veronica Galvez, Brooke Short, Anna Takacs and Vedran Vulovic for their

Declaration of Interest

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assistance in screening participants and clinical advice.

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Some of the devices and consumables described in this study paper were loaned or provided by Soterix Medical Inc. Angelo Alonzo, Joanna Fong, Nicola Ball, Donel Martin, Nicholas

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Chand, and Colleen Loo report no biomedical financial interests or potential conflicts of

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interest.

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Benjamin, E.J., Bennett, D., Bernabé, E., Bhalla, K., Bhandari, B., Bikbov, B., Abdulhak, A.B., Birbeck, G., Black, J.A., Blencowe, H., Blore, J.D., Blyth, F., Bolliger, I., Bonaventure, A., Boufous, S., Bourne, R., Boussinesq, M., Braithwaite, T., Brayne, C., Bridgett, L., Brooker, S., Brooks, P., Brugha, T.S., Bryan-Hancock, C., Bucello, C., Buchbinder, R., Buckle, G., Budke, C.M., Burch, M., Burney, P., Burstein, R., Calabria, B., Campbell, B., Canter, C.E., Carabin, H., Carapetis, J., Carmona, L., Cella, C., Charlson, F., Chen, H., Cheng, A.T.A., Chou, D., Chugh, S.S., Coffeng, L.E., D, C.S., Colquhoun, S., Colson, K.E., Condon, J., Connor, M.D., Cooper, L.T., Corriere, M., Cortinovis, M., De Vaccaro, K.C., Couser, W., Cowie, B.C., Criqui, M.H., Cross, M., Dabhadkar, K.C., Dahiya, M., Dahodwala, N., Damsere-Derry, J., Danaei, G., Davis, A., De Leo, D., Degenhardt, L., Dellavalle, R., Delossantos, A., Denenberg, J., Derrett, S., Des Jarlais, D.C., Dharmaratne, S.D., Dherani, M., Diaz-Torne, C., Dolk, H., Dorsey, E.R., Driscoll, T., Duber, H., Ebel, B., Edmond, K., Elbaz, A., Ali, S.E., Erskine, H., Erwin, P.J., Espindola, P., Ewoigbokhan, S.E., Farzadfar, F., Feigin, V., Felson, D.T., Ferrari, A., Ferri, C.P., Fèvre, E.M., Finucane, M.M., Flaxman, S., Flood, L., Foreman, K., Forouzanfar, M.H., Fowkes, F.G.R., Fransen, M., Freeman, M.K., Gabbe, B.J., Gabriel, S.E., Gakidou, E., Ganatra, H.A., Garcia, B., Gaspari, F., Gillum, R.F., Gmel, G., Gonzalez-Medina, D., Gosselin, R., Grainger, R., Grant, B., Groeger, J., Guillemin, F., Gunnell, D., Gupta, R., Haagsma, J., Hagan, H., Halasa, Y.A., Hall, W., Haring, D., Haro, J.M., Harrison, J.E., Havmoeller, R., Hay, R.J., Higashi, H., Hill, C., Hoen, B., Hoffman, H., Hotez, P.J., Hoy, D., Huang, J.J., Ibeanusi, S.E., Jacobsen, K.H., James, S.L., Jarvis, D., Jasrasaria, R., Jayaraman, S., Johns, N., Jonas, J.B., Karthikeyan, G., Kassebaum, N., Kawakami, N., Keren, A., Khoo, J.P., King, C.H., Knowlton, L.M., Kobusingye, O., Koranteng, A., Krishnamurthi, R., Laden, F., Lalloo, R., Laslett, L.L., Lathlean, T., Leasher, J.L., Lee, Y.Y., Leigh, J., Levinson, D., Lim, S.S., Limb, E., Lin, J.K., Lipnick, M., Lipshultz, S.E., Liu, W., Loane, M., Ohno, S.L., Lyons, R., Mabweijano, J., MacIntyre, M.F., Malekzadeh, R., Mallinger, L., Manivannan, S., Marcenes, W., March, L., Margolis, D.J., Marks, G.B., Marks, R., Matsumori, A., Matzopoulos, R., Mayosi, B.M., McAnulty, J.H., McDermott, M.M., McGill, N., McGrath, J., Medina-Mora, M.E., Meltzer, M., Mensah, G.A., Merriman, T.R., Meyer, A.C., Miglioli, V., Miller, M., Miller, T.R., Mitchell, P.B., Mock, C., Mocumbi, A.O., Moffitt, T.E., Mokdad, A.A., Monasta, L., Montico, M., MoradiLakeh, M., Moran, A., Morawska, L., Mori, R., Murdoch, M.E., Mwaniki, M.K., Naidoo, K., Nair, M.N., Naldi, L., Narayan, K.M.V., Nelson, P.K., Nelson, R.G., Nevitt, M.C., Newton, C.R., Nolte, S., Norman, P., Norman, R., O'Donnell, M., O'Hanlon, S., Olives, C., Omer, S.B., Ortblad, K., Osborne, R., Ozgediz, D., Page, A., Pahari, B., Pandian, J.D., Rivero, A.P., Patten, S.B., Pearce, N., Padilla, R.P., PerezRuiz, F., Perico, N., Pesudovs, K., Phillips, D., Phillips, M.R., Pierce, K., Pion, S., Polanczyk, G.V., Polinder, S., Pope Iii, C.A., Popova, S., Porrini, E., Pourmalek, F., Prince, M., Pullan, R.L., Ramaiah, K.D., Ranganathan, D., Razavi, H., Regan, M., Rehm, J.T., Rein, D.B., Remuzzi, G., Richardson, K., Rivara, F.P., Roberts, T., Robinson, C., De Leòn, F.R., Ronfani, L., Room, R., Rosenfeld, L.C., Rushton, L., Sacco, R.L., Saha, S., Sampson, U., Sanchez-Riera, L., Sanman, E., Schwebel, D.C., Scott, J.G., Segui-Gomez, M., Shahraz, S., Shepard, D.S., Shin, H., Shivakoti, R., Singh, D., Singh, G.M., Singh, J.A., Singleton, J., Sleet, D.A., Sliwa, K., Smith, E., Smith, J.L., Stapelberg, N.J.C., Steer, A., Steiner, T., Stolk, W.A., Stovner, L.J., Sudfeld, C., Syed, S., Tamburlini, G., Tavakkoli, M., Taylor, H.R., Taylor, J.A., Taylor, W.J., Thomas, B., Thomson, W.M., Thurston, G.D., Tleyjeh, I.M., Tonelli, M., Towbin, J.A., Truelsen, T., Tsilimbaris, M.K., Ubeda, C., Undurraga, E.A., Van 27

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Der Werf, M.J., Van Os, J., Vavilala, M.S., Venketasubramanian, N., Wang, M., Wang, W., Watt, K., Weatherall, D.J., Weinstock, M.A., Weintraub, R., Weisskopf, M.G., Weissman, M.M., White, R.A., Whiteford, H., Wiebe, N., Wiersma, S.T., Wilkinson, J.D., Williams, H.C., Williams, S.R.M., Witt, E., Wolfe, F., Woolf, A.D., Wulf, S., Yeh, P.H., Zaidi, A.K.M., Zheng, Z.J., Zonies, D., Lopez, A.D., 2012. Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990-2010: A systematic analysis for the Global Burden of Disease Study 2010. The Lancet 380, 2197-2223.

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60. Nitsche, M., Paulus, W., 2001. Sustained excitability elevations induced by transcranial DC motor cortex stimulation in humans. Neurology 57, 1899-1901.

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61. Palm, U., Hasan, A., Strube, W., Padberg, F., 2016. tDCS for the treatment of depression: A comprehensive review. Eur Arch Psychiatry Clin Neurosci 266, 681694.

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65. Phillips, M.L., Drevets, W.C., Rauch, S.L., Lane, R., 2003. Neurobiology of emotion perception I: the neural basis of normal emotion perception. Biol. Psychiatry 54, 504– 14. 66. Player, M.J., Taylor, J.L., Weickert, C.S., Alonzo, A., Sachdev, P.S., Martin, D., Mitchell, P.B., Loo, C.K., 2014. Increase in PAS-induced neuroplasticity after a treatment course of transcranial direct current stimulation for depression. J. Affect. Disord. 167, 140-147.

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75. Wolkenstein, L., Plewnia, C., 2013. Amelioration of cognitive control in depression by transcranial direct current stimulation. Biol Psychiatry 73, 646–651 76. World Health Organization, 2012. Depression: a global public health concern. . WHO Department of Mental Health and Substance Abuse.

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77. Ye, T., Peng, J., Nie, B., Gao, J., Liu, J., Li, Y., Wang, G., Ma, X., Li, K., Shan, B., 2012. Altered functional connectivity of the dorsolateral prefrontal cortex in firstepisode patients with major depressive disorder. Eur. J. Radiol. 81, 4035-4040.

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Figure 1: Electrode montage showing F3 anode (left dorsolateral prefrontal cortex) and F8 cathode (right fronto-temporal). Red arrows indicate measurements participant check to maintain consistent electrode placement: A – mid point over nasion; B – right edge of anode as marked on headband; C – distance from bottom right corner of anode to left eyebrow.

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35

n = 20

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n = 13 25

n = 14 n = 18b

20

n = 12d

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MADRS

n = 14

n = 14f

n = 19

n = 20

15

n = 7c

10

5 Group 1

Group 2

0 Baseline

Post 2 wks

n = 5e

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n = 9a

Post 4 wks

1-month f/up

3-month f/up

6-month f/up

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Time point

Figure 2: MADRS (mean, standard error) across rating time points. „n =‟ refers to sample size

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at time point. a6 of the original 14 participants who started in Group 1 were responders at the

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1-month follow-up. b7 of the original 20 participants who started in Group 2 were responders at the 1-month follow-up. c2 met the criterion for response. d5 met the criterion for response. 1 met the criterion for response. f5 met the criterion for response.

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Group 2

n

14

20

Gender (m/f)

8/6

13/7

Bipolar (Y) Age (m, SD)

1 48.64 (11.56)

4 46.10 (13.55)

Education (m, SD)

16.44 (3.12)

17.00 (5.97)

Age of onset (m, SD)

26.79 (9.50)

26.15 (11.86)

Duration of current MDE in months (m, SD) Duration of previous MDE in months (m, SD)

30.07 (61.32) 58.50 (48.50)

34.75 (47.28) 63.25 (69.07)

Number of previous MDE (m, SD)

7.36 (8.21)

Number of antidep failed in current MDE (m, SD)

1.36 (1.47)

Number of antidep failed in past MDE (m, SD)

4.07 (4.08)

Maudsley total score (m, SD)

6.29 (2.49) 8 (57)

5.30 (8.71) 2.25 (1.97) 1.55 (2.35) 6.95 (2.37) 10 (50)

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Concurrent mood stabiliser (Y, %)*

3 (21)

7 (35)

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Table 1: Clinical and demographic data for Group 1 and Group 2. *Includes bipolar and unipolar participants on mood stabiliser medication as an augmenting agent.

Table 2: Means and standard deviations (SDs) for outcome measures 1-month follow-up

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Baseline N = 34

MADRS

Q-LES-Q-SF

Mean

SD

27.47

4.91

15.48

9.97

15.53

3.17

9.48

5.64

10.48

49.44

16.25

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QIDS-SR

SD

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Mean

N = 27

34.88

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MADRS = Montgomery Asberg Depression Rating Scale; QIDS-SR = Quick Inventory of Depressive Symptomatology self-report; QLESQ-SF = Quality of Life Enjoyment and Satisfaction Questionnaire – Short Form.

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Table 3. Cognitive test results before and after acute treatment

N

Post treatment M (SD)

N

Reaction Time Detection Task (Log10, ms) Identification Task (Log10, ms)

2.52 (0.08) 2.71 (0.08)

19 19

2.55 (0.09) 2.72 (0.06)

17 17

1.29 4.08

.28 .06

Working Memory Two Back (Arcsine correct)

1.23 (0.17)

19

1.25 (0.21)

17

0.09

.77

Learning and Memory ISL Total Correct ISL Delayed Recall One Card Learning (Arcsine correct)

26.3 (3.87) 9.17 (1.79) 1.02 (0.14)

19 18 19

Executive Function Set shifting (Total errors)

39.8 (16.9)

19

25.2 (5.40) 8.71(2.29) 0.97 (0.08)

17 17 17

0.76 0.59 1.47

.40 .46 .24

37.7 (21.8)

17

0.65

.43

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ISL is International Shopping List Task. 1 N = 17.

Time F1 p

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Table 4: Total incidence of side effects in 1149 treatment sessions.

114 266 145 137 87 49

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5.1

1

16 13 9 6 3 2 4 1 0 1

3.9 3.1 2.2 1.5 0.7 0.5 1.0 0.2 0.0 0.2

17 2 3 0 0 0 9 0 4 0

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1

15.5 36.1 19.7 18.6 11.8 6.7

256 521 260 213 109 77

22.3 45.3 22.6 18.5 9.5 6.7

0.1

22

1.9

2.3 0.3 0.4 0.0 0.0 0.0 1.2 0.0 0.5 0.0

33 15 12 6 3 2 13 1 4 1

2.9 1.3 1.0 0.5 0.3 0.2 1.1 0.1 0.3 0.1

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34.4 61.7 27.8 18.4 5.3 6.8

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142 255 115 76 22 28

0.2

0

0.0

1

0.1

0.2 0.0

0 1

0.0 0.1

1 1

0.1 0.1

0

0.0

1

0.1

1

0.1

0 0

0.0 0.0

1 1

0.1 0.1

1 1

0.1 0.1

0

0.0

1

0.1

1

0.1

1 0

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Tingling Burning Redness Itching Fatigue Headache Lightheadedness Blurred Vision Pain Dizziness Nausea Dry Skin Flashes Other: Insomnia Brain fog Sleepiness Veins in forehead Right temple tremor Tinnitus Slower cognitive processing Reduced breathing Vivid dreams Short term memory side effects

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Side Effect

Group 1 (413 sessions) Group 2 (736 sessions) Combined (1149 sessions) Incidence Percentage Incidence Percentage Incidence Percentage of Sessions of Sessions of Sessions (%) (%) (%)

34