Progress in Neuropsychopharmacology & Biological Psychiatry 121 (2023) 110672

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Progress in Neuropsychopharmacology & Biological

Psychiatry
journal homepage: www.elsevier.com/locate/pnp

Transcranial direct current stimulation for bipolar depression: systematic

reviews of clinical evidence and biological underpinnings
Giordano D'Urso a, *, Elena Toscano a, Annarita Barone a, Mario Palermo a,
Bernardo Dell'Osso b, f, g, Giorgio Di Lorenzo c, h, i, Antonio Mantovani d, j, Giovanni Martinotti e, k,
Michele Fornaro a, Felice Iasevoli a, Andrea de Bartolomeis a
a
Section of Psychiatry, Clinical Unit of Psychiatry and Psychology, Unit of Treatment Resistance in Psychiatry, Laboratory of Neuromodulation, Laboratory of Molecular
and Translational Psychiatry, Department of Neurosciences, Reproductive and Odontostomatological Sciences, Clinical Department of Head and Neck, University of
Naples Federico II, Napoli, Italy
b
Department of Biomedical and Clinical Sciences Luigi Sacco, Ospedale Luigi Sacco Polo Universitario, ASST Fatebenefratelli Sacco, Milan, Italy
c
Laboratory of Psychophysiology and Cognitive Neuroscience, Department of Systems Medicine, Tor Vergata University of Rome, Italy
d
Dipartimento di Medicina e Scienze della Salute "V. Tiberio" Università degli Studi del Molise, Campobasso, Italy
e
Department of Neuroscience, Imaging, Clinical Sciences, University Gabriele d’Annunzio, Chieti-Pescara, Italy
f
Department of Psychiatry and Behavioural Sciences, Bipolar Disorders Clinic, Stanford University, CA, USA
g
CRC "Aldo Ravelli" for Neuro-technology & Experimental Brain Therapeutics, University of Milan, Italy
h
Psychiatric and Clinical Psychology Unit, Fondazione Policlinico Tor Vergata, Rome, Italy
i
IRCCS Fondazione Santa Lucia, Rome, Italy
j
Dipartimento di Salute Mentale e delle Dipendenze, Azienda Sanitaria Regionale del Molise (ASReM), Campobasso, Italy
k
Department of Pharmacy, Pharmacology, Clinical Sciences, University of Hertfordshire, Herts, UK

A R T I C L E I N F O A B S T R A C T

Keywords: Despite multiple available treatments for bipolar depression (BD), many patients face sub-optimal responses.
Transcranial direct current stimulation (tDCS) Transcranial direct current stimulation (tDCS) has been advocated in the management of different conditions,
Transcranial magnetic stimulation (TMS) including BD, especially in treatment-resistant cases. The optimal dose and timing of tDCS, the mutual influence
Bipolar disorder
with other concurrently administered interventions, long-term efficacy, overall safety, and biological un­
Psychotic depression
Dopamine
derpinnings nonetheless deserve additional assessment. The present study appraised the existing clinical evi­
Serotonin dence about tDCS for bipolar depression, delving into the putative biological underpinnings with a special
Glutamate emphasis on cellular and molecular levels, with the ultimate goal of providing a translational perspective on the
Synaptic plasticity matter. Two separate systematic reviews across the PubMed database since inception up to August 8th 2022 were
performed, with fourteen clinical and nineteen neurobiological eligible studies. The included clinical studies
encompass 207 bipolar depression patients overall and consistently document the efficacy of tDCS, with a
reduction in depression scores after treatment ranging from 18% to 92%. The RCT with the largest sample clearly
showed a significant superiority of active stimulation over sham. Mild-to-moderate and transient adverse effects
are attributed to tDCS across these studies. The review of neurobiological literature indicates that several mo­
lecular mechanisms may account for the antidepressant effect of tDCS in BD patients, including the action on
calcium homeostasis in glial cells, the enhancement of LTP, the regulation of neurotrophic factors and inflam­
matory mediators, and the modulation of the expression of plasticity-related genes. To the best of our knowledge,
this is the first study on the matter to concurrently provide a synthesis of the clinical evidence and an in-depth
appraisal of the putative biological underpinnings, providing consistent support for the efficacy, safety, and
tolerability of tDCS.

* Corresponding author at; Section of Psychiatry, Clinical Unit of Psychiatry and Psychology, Unit of Treatment Resistance in Psychiatry, Laboratory of Neuro­
modulation, Department of Neurosciences, Reproductive and Odontostomatological Sciences, Clinical Department of Head and Neck, University of Naples “Federico
II”, Via Pansini 5, Building 18, 3rd floor, 80131 Naples, Italy.
E-mail address: giordano.durso@unina.it (G. D'Urso).

https://doi.org/10.1016/j.pnpbp.2022.110672
Received 19 May 2022; Received in revised form 9 October 2022; Accepted 26 October 2022
Available online 1 November 2022
0278-5846/© 2022 Elsevier Inc. All rights reserved.
G. D'Urso et al.
1. Introduction
Bipolar disorder (BD) is a severe condition (Merikangas et al., 2011;
Soares-Weiser et al., 2007) accounting for a significant burden to the
suffering one in terms of suicidal risk and overall functioning (Ferrari
et al., 2016; Phillips and Kupfer, 2013). Depressive episodes represent
the prominent mood polarity of BD in most cases (Suppes et al., 2005).
Except for electroconvulsive therapy (ECT) – which remains largely
underutilized for several reasons in some geographical regions (Buccelli
et al., 2016; Cattaneo et al., 2022) – the available treatment options for
bipolar depression are limited and often unsatisfactory, as well as
possibly leading to considerable side effects including, but not limited
to, affective switch, induction of rapid-cycling course, and increased risk
for suicidality (Grunze et al., 2013; Vieta et al., 2010). In particular, no
significant benefit vs. placebo or active control was found for antide­
pressants in terms of response and remission (Sidor and MacQueen,
2012). Among anticonvulsant mood-stabilizers, only lamotrigine led to
higher rates of treatment response vs. placebo (Geddes et al., 2009).
Second-generation antipsychotics would significantly improve acute
bipolar depression with mixed features (Fornaro et al., 2016), especially
for lurasidone (Fornaro et al., 2017) and cariprazine (De Berardis et al.,
2016). Lithium, despite being the cornerstone treatment of BD, would
not even suffice as a standalone treatment for the management of acute
bipolar depression. In one study, intensive psychotherapy was shown to
induce significantly higher year-end recovery rates, shorter time to re­
covery and increased chance of being clinically well compared to
collaborative care, (Miklowitz et al., 2007). Yet, a significant proportion
of patients with acute bipolar depression fails to adequately respond to
established pharmacotherapy or psychotherapy, soliciting alternative or
integrative approaches, especially for treatment-resistant cases (Fornaro
et al., 2020).
Accruing evidence suggests the potential role in psychiatry of non-
invasive brain stimulation (NIBS) approaches, a kind of interventions
underpinned by shared non-invasive and painless delivery of electric
current into the brain through the scalp. Their use in patients with
psychiatric disorders is gradually shifting from the research setting to
the clinical practice, resulting also in ad hoc devoted psychiatric neu­
romodulation units (Sauvaget et al., 2018). Among the emerging brain
stimulation techniques, Transcranial Direct Current Stimulation (tDCS)
already showed promising results in treating psychiatric conditions such
as unipolar depression (Brunoni et al., 2016), auditory hallucinations
(Mondino et al., 2015) and negative symptoms of schizophrenia (Palm
et al., 2016), obsessive-compulsive disorder (D'Urso et al., 2016), post-
traumatic stress disorder (D'Urso et al., 2018), autism spectrum disor­
ders (D'Urso et al., 2015; D'Urso et al., 2014), substance use disorders
(Martinotti et al., 2019) as well as various neurological disorders (Fer­
rucci et al., 2018; Flöel, 2014; Kuo et al., 2014). This technique shows
great promise also for the treatment of bipolar depression, firstly for its
safety profile, with only nonspecific and mild adverse effects (i.e. skin
erythema, tingling/itching of the scalp, mild headache, sleepiness), as
well as very low risk of affective switches, rapid cycling or increased
suicidality (Bikson et al., 2016). Not less important, it is cheap and
possibly cost-effective compared to the current standard of care (Sau­
vaget et al., 2019).
TDCS treatment consists in a weak (0.5–2 mA) direct electrical cur­
rent delivered through one or more sponge electrodes placed on the
scalp overlying the targeted cortical areas (Nitsche et al., 2008). Electric
current enhances the cortical excitability under the positive electrode
(anode), while an opposite (inhibitory) effect is obtained under the
negative electrode (cathode)(Nitsche and Paulus, 2000, 2001). Other
factors than electrode polarity can influence the tDCS-induced excit­
ability changes, i.e., current intensity and direction (radial vs. tangential
to the cortex surface), session duration, concomitant pharmacological
treatment, and baseline brain activity (Rahman et al., 2013). In addition,
tDCS modulates the long-term effects of use-dependent plasticity, a
phenomenon that is believed to be mediated by strengthening synapses
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Progress in Neuropsychopharmacology & Biological Psychiatry 121 (2023) 110672
via a long-term potentiation (LTP)-like process (Rroji et al., 2015). TDCS
studies involving patients with unipolar depression (Brunoni et al.,
2016) employed a bifrontal montage with the excitatory electrode
(anode) placed over the left DLPFC (F3 in the 10-20 EEG system), and
the inhibitory electrode (cathode) over the right DLPFC (F4), or right
lateral orbitofrontal (F8), or right supraorbital cortex (Fp2). The ratio­
nale for these electrode positionings is that functional imaging studies
showed a prefrontal asymmetry in unipolar depressed patients, with
hypoactivity in the left dorsolateral prefrontal cortex (DLPFC) (Kennedy
et al., 1997) and relative hyperactivity in the right DLPFC (Grimm et al.,
2008).
However, no evidence is available to inform the choice of electrode
montage and other stimulation parameters (e.g., current intensity,
number, and duration of sessions) based on the specific mechanisms of
bipolar depression. In fact, unipolar and bipolar disorders have complex,
distinctive neurobiological underpinnings, being polygenic and multi­
factorial (Akula et al., 2016; Kerner, 2015), that account for dysfunc­
tional synaptic plasticity and cortical-subcortical brain network
dysregulation (Rodríguez-Cano et al., 2017). Despite advances in un­
derstanding putative pathophysiology and neurobiology (Akula et al.,
2016; Tomasetti et al., 2017), omics (MacDonald et al., 2019), and
functional neuroanatomy of bipolar disorders (Miller and Kelsoe, 2017),
the specific molecular pathogenesis of the depressive polarity is still
elusive, also not fully understood are the cellular and molecular mech­
anisms underlying the different biological interventions, including NIBS
and, specifically, tDCS.
Stating the above premises, we conducted two separate systematic
reviews, one dealing with the clinical evidence and the other one with
the neurobiological underpinnings of the use of tDCS in bipolar
depressed patients, with the ultimate goal of providing a translational
perspective on the matter and of highlighting the implications for future
research.
2. Experimental section
2.1. Literature search strategy for clinical studies
Aiming at achieving a high standard of reporting, we conducted the
systematic review of clinical studies owing to the recommendations of
the Cochrane group (Higgins et al., 2016) and PRISMA guidelines (Page
et al., 2021).
2.1.1. Eligibility
Inclusion criteria were: (1) English language studies published in
peer-reviewed journals or records otherwise indexed in peer-reviewed
journals, (2) Randomized controlled trials (RCT) comparing active
stimulation to sham or to treatment as usual, uncontrolled open-label
trials, and case reports including patients with an established clinical
diagnosis of BD-I, BD-II, BD not otherwise specified (NOS), not else­
where classified (NEC) subtypes (depending on the coding system or
edition), confirmed by a semi-structured interview, (3) studies using
tDCS as a tool to specifically treat depression symptoms (e.g., studies
using tDCS to treat OCD symptoms in depressed patients or as a primer
for other treatment approaches were not included), (4) studies providing
clinical assessments with depression rating scales before and after tDCS.
Exclusion criteria were: (1) studies without clear-cut data about
patients with bipolar depression, (2) studies with insufficient informa­
tion on mood symptoms (i.e., no depression rating scale scores),
2.1.2. Search procedure
A systematic search of PubMed was performed with no publication
date restrictions on October 16th, 2021 using the following search string:
("mood disorders" OR "bipolar disorder" OR "bipolar") AND ("depression"
OR "depressive") AND ("tDCS" OR "transcranial direct current
stimulation").
Reference lists of identified papers were also screened for additional
G. D'Urso et al.
studies. The “similar articles” function in PubMed was employed. The
search returned 92 studies (the last interrogation was conducted on
August 8th, 2022). Two reviewers (GDU, ET) independently screened the
title, abstract, and keywords of each study identified by the search and
applied the inclusion and exclusion criteria. Discrepancies between the
reviewers, blind to each other, were resolved by consulting a third
reviewer (AdB). An additional collaborator with considerable expertise
in the PRISMA methodology and bipolar disorder clinical evidence
(MF), assisted in the critical appraisal of the a priori-defined review
protocol. The details of the selection process are summarized in Fig. 1.
The studies included in the qualitative synthesis were 12.
2.1.3. Data extraction
Two reviewers independently extracted the following data, when­
ever available, according to a-priori-defined abstraction form: (1) de­
mographic data (sample size, age, sex, concomitant treatment
strategies); (2) clinical features (diagnosis, active mood symptoms,
depression rating scale scores at baseline and study endpoint); (3) tDCS
stimulation protocol (location of the anode and the cathode, electrode
size, current intensity, current density, number and frequency of ses­
sions, period of stimulation, endpoint data). The study outcome was
based on the scores of validated rating scales administered before tDCS,
after the acute phase of stimulation, and at subsequent endpoints.
2.2. Literature search strategy for neurobiological studies
A comprehensive search in the PubMed was performed on August,
th
8 2022 by using a string combining “tDCS” with 33 terms related to
neurotransmitters, signalling molecules, intracellular effectors or targets
relevant for the pathophysiology of the bipolar depression (see the
Fig. 1. The PRISMA Flow diagram depicts the flow of information through the different phases of the systematic review.
3
Progress in Neuropsychopharmacology & Biological Psychiatry 121 (2023) 110672
Supplementary Text for more details and the combination of terms).
2.2.1. Elegibility
We included publications in peer-reviewed journals and written in
English i) reporting original data or reviewing the molecular and bio­
logical effects of tDCS in bipolar depression; and ii) evaluating the pu­
tative mechanisms of action underlying tDCS efficacy in vitro or in vivo,
both in animal models of bipolar disorder or humans suffering from this
condition. Clinical papers not providing an explanatory model of tDCS
molecular action were excluded.
2.2.2. Selection strategy
Retrieved records and full-texts were managed by using Endnote X.
Each record retrieved was considered for the coherence of the subject
with the content of the review by two independent co-authors (FI and
AB). If the abstract text was coherent with the review, the full-text was
considered and the reference list was checked to find additional studies.
Inconsistencies were resolved by consensus in a meeting with another
researcher (AdB).
The database search and cross-referencing yielded 715 records.
Finally, 19 articles were included in the qualitative synthesis. The details
of the selection strategy are reported in the Prisma 2020 flow diagram
(please see Fig. 2).
3. Results
3.1. Clinical studies
Fourteen studies were eligible for systematic review (Baliga et al.,
2020; Brunoni et al., 2011a; Brunoni et al., 2013a; Gálvez et al., 2011; Li
G. D'Urso et al.
Fig. 2. The PRISMA Flow diagram depicting the flow of information through the different phases of the systematic review of neurobiological studies.
et al., 2019; Lin et al., 2021; Loo et al., 2012; Loo et al., 2018; Mardani
et al., 2021; Martin et al., 2013; Martin et al., 2011; Palm et al., 2012;
Pereira Junior Bde et al., 2015; Sampaio-Junior et al., 2018) including in
total 207 patients with bipolar depression. Data were obtained from the
publication itself (Baliga et al., 2020; Brunoni et al., 2011a, 2011b;
Gálvez et al., 2011; Lin et al., 2021; Loo et al., 2018; Mardani et al.,
2021; Pereira Junior Bde et al., 2015; Sampaio-Junior et al., 2018), by
directly contacting the authors (when data from patients with unipolar
depression and bipolar depression were combined) (Li et al., 2019) or
from a previously published review (Dondé et al., 2017) reporting data
obtained by direct contact with the authors of studies with missing in­
formation (Brunoni et al., 2013a; Loo et al., 2012; Martin et al., 2013;
Martin et al., 2011; Palm et al., 2012). The main features of these tDCS
studies are characterized in Table 1.
3.2. tDCS protocols
In RCTs, sham stimulation refers to the use of the same tDCS montage
used for active stimulation with a ramp of electrical current lasting for
several seconds at the beginning and/or at the end of 20-min (Loo et al.,
2012; Palm et al., 2012) or 30-min sessions (Loo et al., 2012; Sampaio-
Junior et al., 2018), to elicit weak scalp sensation, while not producing
enduring changes in cortical excitability. Instead, in the 2018 study of
Loo and colleagues (Loo et al., 2018), the sham consisted of 3 one-
minute ramps delivered 10 minutes apart and a constant current of
0.034 mA throughout the entire session. Sham tDCS data were made
available from the authors of only two of these studies (Loo et al., 2018;
Sampaio-Junior et al., 2018).
While most studies used the 10-20 EEG system for the electrode
positioning, Sampaio-Junior et al., 2018 used a novel tool for targeting
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Progress in Neuropsychopharmacology & Biological Psychiatry 121 (2023) 110672
the DLPFC, i.e., the omnilateral electrode system (OLE), optimized for
peak electric current densities over the DLPFC.
All included studies used tDCS as an add-on to medication regimens
with no drug adjustments during the tDCS administration, except for
cases of mood switching (Loo et al., 2012; Gálvez et al., 2011). All other
features of the tDCS protocols used in the included studies are reported
in table 1.
3.2.1. Effects on depressive symptoms
All the studies included in this review reported reductions of the
depressive symptoms scores over the tDCS treatment. The scales used to
assess the effects on depression symptoms were the Beck Depression
Inventory (BDI) (Beck et al., 1996) for four studies (Brunoni et al.,
2013a; Brunoni et al., 2011a, 2011b; Li et al., 2019; Palm et al., 2012),
the MADRS (Montgomery and Asberg, 1979) for eight studies (Gálvez
et al., 2011; Lin et al., 2021; Loo et al., 2012; Loo et al., 2018; Martin
et al., 2013; Martin et al., 2011; Pereira Junior Bde et al., 2015; Sam­
paio-Junior et al., 2018), the Hamilton Depression Rating Scale (HDRS)
(Hamilton, 1960) for five studies (Baliga et al., 2020; Brunoni et al.,
2011a, 2011b; Lin et al., 2021; Mardani et al., 2021; Sampaio-Junior
et al., 2018), and the Quick Inventory of Depressive Symptomatology
self-report (QIDS-SR) (Rush et al., 2003) for one study (Loo et al., 2018).
Four studies used more than one scale (MADRS and HDRS in Sampaio-
Junior et al., 2018; MADRS and QIDS-SR in Loo et al., 2018; BDI and
MADRS in Li et al., 2019; BDI anf HDRS in Brunoni et al., 2011a, 2011b).
The reported clinical improvements range from 19 (Brunoni et al.,
2011a, 2011b) to 31 % (Brunoni et al., 2013a) in the BDI, from 22 (Loo
et al., 2018) to 73% (Martin et al., 2013) in the MADRS, and from 18
(Brunoni et al., 2011a, 2011b) to 92% (Sampaio-Junior et al., 2018) in
the HDRS. For the Sampaio-Junior et al. (2018) and the Loo et al. (2018)
 Table 1
tDCS studies involving patients with bipolar depression. RCT: Randomized Controlled Study; OPN: Open Label Study; OBS: Observational Study; F3: 10-20 EEG system point for the left dorsolateral prefrontal cortex; F4:
10-20 EEG system point for the right dorsolateral prefrontal cortex; OLE: omnilateral electrode system; Fp2: 10-20 EEG system point for the right superior orbital cortex; F8: 10-20 EEG system point for the right lateral

G. D'Urso et al.
orbital cortex; EC: extracephalic (right upper arm); A: anode; C: cathode; NA: not available; BDI: Beck Depression Inventory; MADRS: Montgomery-Åsberg Depression Rating Scale; HDRS: Hamilton Depression Rating
Scale; QIDS-SR: Quick Inventory of Depressive Symptomatology self-report; SD: Standard Deviation.
Authors, year Study Bipolar Anode Cathode Electrodes Current Current Session N. of Frequency End-point Rating Baseline Endpoint Effect %
Design Patients position position Size Intensity density (A/ duration sessions (weeks) Scales score score Size change
Sample (cm2) (mA) m2) (min) (mean (mean (Cohen’s
+/- SD) +/- SD) d)

Mardani et al., 21.40 ± 1.80 ±

RCTa,b 30 F3 F4 NA 2 NA 20 20 2x/10 days 1.5 HDRS 3.30 92
2021 8.10 2.21
28.7 ±
left- right- 1x/weekday+ 12.0 ±
2 MADRS 5.3 2.66 58
30 DLPFC DLPFC 25 0.80 30 12 Fortnightly 6 7.1
(active) HDRS 23.1 ± 3.39 60
Sampaio- (OLE) (OLE) (10+2) 9.2 ± 4.3
3.9
Junior RCTb
27.9 ± 17.5 ±
et al., 2018c left right- 2 x 0.5 1x/weekday+
MADRS 5.0 9.8 1.34 37
29 DLPFC DLPFC 25 min 0.80 30 12 Fortnightly 6
HDRS 23.5 ± 15.2 ± 1.36 35
(OLE) (OLE) (sham) (10+2)
4.7 7.2
31.05 ± 24.28 ±
MADRS
2.5 5.50 8.96 0.91 22
17 F3 F8 35 0,71 30 20 1x/weekday 4 QIDS-
(active) 15.42 ± 11.17 ± 0.73 28
SR
Loo et al., 4.83 6.70
RCT
2018 30.82 ± 20.00 ±
MADRS
0.034 4.53 8.75 1.55 35
19 F3 F8 35 0,09 30 20 1x/weekday 4 QIDS-
(sham) 15.65 ± 10.00 ± 1.00 36
SR
5.33 5.95
Loo et al., 2 35.5 ± 20.5 ±
RCT 4 F3 F8 35 0,57 20 30 1x/weekday 6 MADRS 2.30 42
2012 (active) 6.5 6.5
Palm et al., 24.0 ± 19.0 ±
RCTd 2 F3 Fp2 35 2/1e 0.57/0.28 20 10 1x/weekday 2 BDI 1.58 21
2012 4.0 2.0
Lin et al., 27.64 ± 17.23
5

OPN 22 F3 F4 35 2 0.57 20 10 2x/5 days 4 HDRS 1.14 38

2021 8.09 ±10.04
1x/weekday+
BDI
Li et al., 2019 OPN 5 F3 F4 35 2 0.57 30 12 Fortnightly 8 NA NA NA NA
MADRS
(10+2)

Progress in Neuropsychopharmacology & Biological Psychiatry 121 (2023) 110672

Pereira Junior
32.8 ± 22 ±
Bde et al., OPN 5 F3 F4 25 2 0.80 30 10 1x/weekday 2 MADRS 1.20 33
2.68 12.4
2015
10.5 ±
Martin et al., 3 MADRS 3.5 8.70 73
OPN 2 F3 F8 35 2 0,57 20 15 1x/weekday 39 ± 3
2013 12 MADRS 16.5 ± 4.44 58
6.5
35 0.57
Martin et al., 2 F3 F8 2 20 15 1x/weekday 3 MADRS 39 ± 3 17 ± 6 4.63 56
OPN A: 35 A: 0.57
2011 1 F3 EC 2 20 20 1x/weekday 4 MADRS 29 15 NA 48
C: 100 C: 0.2
34.21 ± 27.79 ±
Brunoni et al.,
BDI 8.33 11.07 0.65 19
2011a, OPN 14 F3 F4 35 2 0.57 20 10 2x/weekday 1
HDRS 30.77 ± 25.23 ± 0.57 18
2011b
8.96 10.43
Brunoni et al.,
23.21 ± 15.95 ±
2013a, OBS 19 F3 F4 35 2 0.57 20 10 2x/weekday 1 BDI 0.68 31
11.81 9.21
2013b
Baliga et al., Case F3 F4 35 2 0,57 30 10 1x/day 6 HDRS 20 4 NA 80
1
2020 Report F3 F4 35 2 0,57 30 10 1x/day 6 HDRS 25 4 NA 84
Gálvez et al., Case F3 F8 NA 2 NA 20 30 1x/weekday 6 MADRS 42 14 NA 67
1
2011 Report F3 EC NA 2 NA 20 14f 1x/weekday NA MADRS 28 NA NA NA
a
the comparison was not between active and sham tDCS but between medication+active tDCS and medication alone.
b
Enrolling only bipolar depressed patients.
c
Study clearly showing a greater improvement with active versus sham tDCS.
d
Crossover study.
e
1 patient had 1 mA and 1 patient had 2 mA.
f
Treatment interrupted for affective switch.
G. D'Urso et al.
studies there is also available information to directly compare the effects
of active versus sham tDCS, with only the former clearly showing a
significant superiority of real stimulation, while the second raised
serious concerns about the possible biological activity of the sham
protocol used.
3.2.2. Safety and tolerance
In the eligible studies, patients with unipolar or bipolar depression
were not considered separately concerning non-specific adverse effects.
In particular, six studies (Baliga et al., 2020; Gálvez et al., 2011; Loo
et al., 2012; Martin et al., 2013; Palm et al., 2012; Sampaio-Junior et al.,
2018) reported transient side effects, such as skin redness, itching and
tingling at the site of the electrodes, headache, nausea, fatigue, and vi­
sual effects, ranging from mild to moderate intensity. Only one of the
examined studies (Loo et al., 2018) reported serious adverse events
leading to hospital admission: increased suicidality (active treatment, 4
patients), headache and blurred vision related to medication-induced
hyponatremia (active treatment, 1 patient), gastroenteritis (sham
treatment, 1 patient), gangrene (active treatment, 1 patient) and stroke
(active treatment, 1 patient). Nevertheless, all these serious adverse
events were assessed as unrelated to study procedures. Solely the case of
increased suicidal ideation was assessed as possibly related to the tDCS
intervention, although it was noted that these patient already had a
history of suicidal thoughts and behaviors.
Four cases of an affective switch from depression to hypomania/
mania were observed with active tDCS (Gálvez et al., 2011; Loo et al.,
2012; Martin et al., 2011; Pereira Junior Bde et al., 2015). Furthermore,
Sampaio and colleagues (Sampaio-Junior et al., 2018) described nine
cases of a treatment-emergent affective switch (five in the sham and four
in the active group), which did not meet the criteria for a major
depressive episode with mixed features, hypomania, or mania according
to the DSM-5 guidelines and did not require hospitalization, trial
discontinuation or specific treatment.
During tDCS, patients received concomitant treatment with a mood
stabilizer and/or antidepressant, which were specified by authors,
except Loo and colleagues (Loo et al., 2012; Loo et al., 2018). Neither
rapid cycling induction nor suicidality onset was reported across all
patients and all tDCS procedures of the examined studies.
3.3. Neurobiological studies
Targeted stimulation of discrete neuronal networks, enhancing focal
excitability and synaptic strength of learning-related neuronal connec­
tions (Ghanavati et al., 2022), accompanied by the inhibition of the
excitability of others, would represent a promising way to improve
neuropsychological deficits characteristic of mood disorders. The
neurobiological literature aimed at dissecting the molecular effects of
tDCS is distributed in the mutually dependent and complementary fields
of synaptic plasticity, neurotransmission, and brain networks (please see
Table 2).
3.3.1. tDCS effects on astrocytic homeostasis and neuronal environment
Molecular and neurochemical changes induced by tDCS are still
poorly characterized and may affect neuronal survival and plasticity by
involving multiple biological pathways.
For instance, evidence from in vivo preclinical studies suggests that
tDCS can not only directly stimulate neurons (Takano et al., 2011), but
also indirectly stimulate glial cells. It has been proposed that tDCS may
influence the astrocyte activation by increasing astrocytic calcium sig­
nalling, significantly influencing the tripartite synapse architecture and
functioning. In fact, astrocytes are glial cells filling the space between
the presynaptic bouton and the post-synaptic spine, providing a func­
tional synaptic and vascular interface capable of organizing active
synaptic connections and supply of nutrients and biochemicals to neu­
rons (Hillen et al., 2018; Monai and Hirase, 2018). In addition to being
essential as “nurse” cells supporting neuronal function, astrocytes are
6
Progress in Neuropsychopharmacology & Biological Psychiatry 121 (2023) 110672
now recognized as active elements in the brain and neglected players in
mediating tDCS effects. Monai and colleagues observed a transient
astrocytic calcium raise in the cortex of mice treated with tDCS, prob­
ably via Ca2+/inositol trisphosphate (IP3) pathway (Monai and Hirase,
2018; Monai et al., 2016) (Fig. 3). In line with these findings, Callai et al.
reported an increase in S100B, a marker of astrocytic activation, in ce­
rebrospinal fluid (CSF) of naïve rats after a single session of tDCS (Callai
et al., 2022). As the Authors used a bimodal model of tDCS, these results
can be ascribed not only to the active electrode (cathode) which acti­
vates the cortex, but also to the influence of the reference electrode
(anode) which inhibits cortical regions. Therefore, the behavioural and
biochemical changes observed could depend as much on the activation
as on the inhibition of cortical regions under both electrodes.
Since astrocytic activation may contribute, up to a certain threshold,
to many beneficial aspects such as isolation and sequestration of brain
lesions and neuroprotection, tDCS-induced astrocyte activation has
recently been proposed as a relevant molecular target to treat mood
disorders (Monai and Hirase, 2018), helping to preserve a supportive
environment for the synaptic events of neighbouring neurons (Callai
et al., 2022; Monai and Hirase, 2018).
Mishima et al. found that tDCS affects morphology and motility of
microglia, reducing the surveillance area (Mishima et al., 2019). Of in­
terest, an increase in serum Glial cell line-derived neurotrophic factor
(GDNF), a survival promoting molecule which has been firstly charac­
terized in striatal astrocytes, has been observed in bipolar patients with
manic symptoms randomized to active tDCS (Lin et al., 1993; Veena­
kumari et al., 2022). Since is well known GDNF ability to promote
dopamine cell survival and differentiation in embryonic midbrain cul­
tures (Lin et al., 1993), clinical improvements obtained with tDCS may
be mediated by GDNF release and its subsequent effects in the homeo­
stasis and maintenance of dopaminergic pathways, thus representing a
protective mechanism to restrain neuronal loss (Fig. 3).
Moreover, a single tDCS session has been shown to reduce inflam­
matory mediators levels in the cortex of naïve rats (Callai et al., 2022).
These results from a preclinical research setting, were paralleled, at a
clinical level, by a 6-week randomized clinical study enrolling patients
suffering from type I or II BD, experiencing a moderate-severe depres­
sive episode. In particular, plasma levels of interleukin (IL)-8 decreased
significantly in the active group compared with the sham-tDCS, and
higher baseline IL-6 levels predicted greater depression improvements
in the active group (Goerigk et al., 2021). Therefore, innate immunity
biomarkers could be highly sensitive to tDCS delivery. To date, there are
no similar studies conducted on bipolar depression patients. However, a
previous controlled trial enrolling subjects affected by unipolar
depression, showed that plasma levels of IL-2, IL-2, IL-4, IL-6, IL-10, IL-
17a, and interferon-γ decreased over time in both the intervention and
placebo group (Brunoni et al., 2014), raising concerns about the speci­
ficity of the anti-inflammatory effect of the tDCS. Therefore, although
these studies are conducted in patients with different mood episodes and
results should be interpreted with caution, tDCS response in depression
may depend, at least in part, on its anti-inflammatory action. In light of
the neuroinflammatory model of bipolar depression, supported by
growing evidence encompassing elevated levels of peripheral inflam­
matory mediators (Grewal et al., 2022), stable immunological alter­
ations (Rege and Hodgkinson, 2013; Rosenblat and McIntyre, 2017),
comorbid systemic autoimmune diseases (Bachen et al., 2009; Chen
et al., 2021; Farhi et al., 2016; Hsu et al., 2014; Kupka et al., 2002), and
genetic findings (Tylee et al., 2018), the anti-inflammatory properties of
tDCS may be quite attractive. As inflammatory abnormalities may affect
the synapse and related transmission (Aguilar-Valles et al., 2020) (Corsi-
Zuelli and Deakin, 2021), a targeted anti-inflammatory action on spe­
cific brain regions may reverberate on discrete neurotransmitter systems
and functional circuits.
How tDCS may impact astrocytic homeostasis, inflammatory path­
ways, as well as synaptic plasticity functions remains do be determined,
but beyond acting on neuronal polarization, it should be noted that tDCS
G. D'Urso et al. Progress in Neuropsychopharmacology & Biological Psychiatry 121 (2023) 110672

Table 2
Studies investigating tDCS effects on synapse and transmission.
Authors Model Intervention Molecular effects Functional implications

Monai et al., Transgenic mice in which astrocytes Active anodal tDCS (0.1 mA Active anodal tDCS invoked large-amplitude Anodal tDCS induces astrocytic
2016 and cortical neurons express G- for 10 min) or sham over the and synchronized Ca2+ surges in astrocytes activation through the involvement of
CaMP7, a green fluorescent protein visual cortex across the entire cortex. These enhancements Ca2+ /IP3 signalling. These alterations
Ca2+ indicator; IP3R2 knockout were dependent on the α1 adrenergic receptor may depend on adrenergic receptors.
mice and were not observed in IP3R2 knockout mice
Callai et al., Winstar rats Single session of active Active bimodal tDCS increased S100B levels in Bimodal tDCS may exert an analgesic/
2022 bimodal tDCS (0.5 mA, 20 CSF, decreased pain sensitivity, and cerebral anti-inflammatory effect and induce
min) or sham over the TNF-α levels astrocytic activation
primary cortex
Mishima C57BL/6J and IP3R2 knock-out Anodal tDCS (0.1 mA, 10 Active anodal tDCS altered Iba1 Active anodal tDCS affects the
et al., 2019 mice; BAC-GLT1-G-CaMP7 line 817 min) or sham over the immunohistochemical patterns, enlarged morphology and dynamics of
mice; Iba1-GFP mice primary visual cortex in mice microglial somata, and reduced motility in microglia. These alterations may
under anesthesia or in awake awake mice. depend on adrenergic receptors
conditions
Goerigk et al., Patients with type I or II bipolar 12 sessions of bifrontal tDCS Active tDCS reduced IL-8 plasma levels. tDCS may exert an anti-inflammatory
2021 disorder in a moderate-to-severe (2 mA, 30 min) or sham over Higher levels of IL-6 levels predicted action
depressive episode (n=52) 6 weeks depression improvement in the active group.
Fonteneau Healthy subjects (n=32) Single session of bifrontal Active tDCS induced a significant decrease in tDCS induces striatal dopamine release
et al., 2018 tDCS (20 min, 2 mA) or sham [11C]-raclopride binding in the striatum
Bunai et al., Healthy subjects (n=17) Bifrontal tDCS (2mA, 13 min Active tDCS induced an elevation in GABA tDCS induces a significant increase in
2021 twice at an interval of 20 content in the left striatum. dopamine release in the right striatum
min) or sham tDCS also induced a reduction in [11C]- and GABA concentrations in the left
raclopride binding in the right striatum striatum.
Fukai et al., Healthy subjects (n=20) Bifrontal tDCS (2 mA, 13 min Active tDCS induces a reduction in [11C]- tDCS induces a significant release of a
2019 twice at an interval of 20 raclopride binding in the right ventral striatum dopamine in the right ventral striatum
min) or sham
Meyer et al., Healthy subjects (n=40) Single session of anodal Anodal F4 tDCS increase amplitude of low- tDCS increases spontaneous
2019 prefrontal tDCS (15 min at 2 frequency fluctuations as detected by fMRI mesostriatal neural activity
mA intensity) or inverse
montage
Tanaka et al., Sprague Dawley rats (n=25) Cathodal, anodal, tDCS (800 Extracellular dopamine levels increased for Cathodal tDCS induces an increase in
2013 μA, 10 min) or sham more than 400 min in the striatum as measured striatal extracellular dopamine levels
by in vivo microdialysis after cathodal tDCS.
No significant changes in extracellular
serotonin levels.
Leffa et al., Wistar Kyoto rats (n= 20) 8 sessions of frontal anodal Dopamine levels increased in the hippocampus tDCS significantly increases dopamine
2016 Spontaneous hypertensive rats tDCS (0.5 mA, 20 min) or and striatum in both strains. levels in striatum and hippocampus;
(n=28) sham Striatal BDNF levels increased in Wistar rats. dopamine release may, in turn,
increase neuronal activation by
regulating BDNF levels
Takano et al., Sprague–Dawley rats (n=12) Anodal prefrontal tDCS (400 Signal intensities in the frontal cortex and Anodal tDCS induces neuronal
2011 μA, 10 min) or sham nucleus accumbens were significantly activation in the frontal cortex and its
increased after stimulation as revealed by fMRI connected brain region, especially in
the nucleus accumbens
Hunter et al., Healthy subjects (n=11) anodal tDCS over right After tDCS an increase in Glx under the anodal The excitatory after-effects of anodal
2015 parietal cortex (2.0 mA, 30 electrode was detected by 1H-MRS. As revealed tDCS increases the glutamatergic
min) by fMRI, tDCS increased the within-network signaling and network connectivity
connectivity within the superior parietal,
inferior parietal, left frontal-parietal, salience
and cerebellar intrinsic networks tDCS
decreased the connectivity in the anterior
cingulate and the basal ganglia.
Mezger et al., Healthy subjects (n=20) bifrontal tDCS or sham (2 MRS failed to reveal significant changes of Glu, tDCS led to a reduction of Glu levels in
2021 mA, 20 min) Glx and GABA levels; subgroup analysis the MRS voxel close to the cathode in
revealed a Glu reduction only in female female but not in male participants
participants
Filmer et al., Healthy subjects (n=47) 3 sessions of anodal, cathodal As detected by MRS, subjects who showed a GABA and glutamate concentrations
2019 tDCS (0.7 mA, 9 min), or higher level of inhibition (more GABA relative were linked to the degree of efficacy
sham at left PFC to glutamate) in the prefrontal cortex were
affected by cathodal stimulation to a greater
extent
Alvarez- Healthy subjects (n=23) Bifrontal tDCS (2mA, 20 min) Glx concentrations increased from pre- to post- tDCS over the prefrontal cortex elicits
Alvarado or sham in combination with intervention in the active versus sham group. sustained increase in excitatory
et al., 2021 cognitive training for 2 weeks No difference in GABA concentration was neurotransmitter concentrations
detected by MRS
Rohan et al., Sprague Dawley Rats (n=34) Anodal tDCS (0.10 or 0.25 Ex vivo preparations of hippocampal slices tDCS induces a robust enhancement in
2015 mA for 30 min followed by 30 from rats showed a robust twofold synaptic plasticity
min of recovery time) enhancement in LTP induction and a 30%
increase in PPF
Yu et al., Sprague-Dawley rats (n=224) Active anodal tDCS (250 μA/ Anodal tDCS enhances hippocampal CA1 LTP; Anodal tDCS enhances LTP through
2019 0.25 cm2, 30 min) or sham BDNF protein levels increased in the activation of BDNF/TrkB signaling
over the hippocampus hippocampal CA1 tissue of tDCS-treated rats pathway
compared to sham-treated rats; TrkB
(continued on next page)

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G. D'Urso et al. Progress in Neuropsychopharmacology & Biological Psychiatry 121 (2023) 110672

Table 2 (continued )
Authors Model Intervention Molecular effects Functional implications

antagonist blocked tDCS-induced

enhancement of LTP ex vivo
Martin et al., Patients with unipolar and bipolar Active anodal tDCS (2.5 mA) Genotype differences in the BDNF Lack of association between BDNF and
2018a, depression, currently experiencing or sham (34 μA) over the Val66Metand COMT Val158Met COMT polymorphisms and the
2018b a major depressive episode (n=120) DLPFC for 30 min each polymorphisms were not associated with antidepressant effect of tDCS.
session for 20 sessions antidepressant effects of active tDCS
Kim et al., Sprague-Dawley rats (n=19) Anodal active tDCS or sham Unilateral anodal-tDCS resulted in significant Anodal tDCS enhance the expression of
2017 (250 μA, 20 min) over the increases in transcription of BDNF, CREB), plasticity-associated genes
right sensorimotor cortex synapsin I, CaMKII, arc in the ipsilateral cortex,
(250 μA, 20 min) for 7 as well as a significant increase in c-Fos and Arc
consecutive days mRNA in the ipsilateral hippocampus

TDCS= transcranial direct stimulation; PFC= prefrontal cortex; PPF= paired-pulse facilitation; LTP= long-term potentiation; IP3R2= inositol trisphosphate receptor
type 2; GFP= green fluorescent protein; CSF= cerebrospinal fluid; IL= interleukin; TNF-α= tumor necrosis factor α; BDNF= brain-derived neurotrophic factor; fMRI=
functional magnetic resosonance imaging; MRS= magnetic resonance spectroscopy; CREB= cAMP response element-binding protein;, CaMKII= Ca2+/calmodulin-
dependent protein kinase II; GABA= γ-aminobutyric acid; COMT= catechol-o-methyltransferase

Fig. 3. The effects of tDCS on the tripartite synapse. tDCS focally increases blood flow and blood-brain-barrier permeability. The stimulation leads to a transient
increase in astrocytic calcium signalling, subsequent astrocyte activation and release of S100B and GDNF. GDNF, in turn, provides support to synaptic plas­
ticity processes.

can increase regional blood flow (Cancel et al., 2018), nitric oxide levels,
(Barbati et al., 2020) blood-brain-barrier permeability (Shin et al.,
2020), changing the spatio-temporal solute distribution profile in the
extracellular space (Xia et al., 2020), leading to a widespread series of
molecular modifications in the CNS, which ultimately converge on the
synapse.
3.3.2. Dopamine neurotransmission
In vivo studies have convincingly demonstrated a major role for
dopamine release, dopamine D2/D3 receptors, and dopamine trans­
porter dysfunctions in bipolar disorders (Ashok et al., 2017; Pearlson
et al., 1995; van Enkhuizen et al., 2015; Wong et al., 1997). Multiple
studies, both in rodents and in humans, converge in indicating a recip­
rocal modulation of dopamine transmission and tDCS effects, suggesting
that tDCS impact on dopamine transmission may theoretically be
beneficial in bipolar disorder (Fonteneau et al., 2018; Ghanavati et al.,
2022; Imburgio et al., 2021; Meyer et al., 2019; Prowacki et al., 2022).
Notably, the application of cathodal, but not anodal, tDCS for 10 min
to rodents has been found to increase extracellular dopamine levels for
more than 400 min in the striatum. The same protocol of stimulation did
not change extracellular serotonin levels (Tanaka et al., 2013), thereby
implicating a dopamine-specific effect of this tDCS procedure. More­
over, it has been reported that the application of constant electrical of
0.5 mA intensity on the frontal cortex for 20 min/day for a total of eight
days elicited dopamine release in the striatum and hippocampus of both
Wistar Kyoto Rats (WKR) and spontaneous hypertensive rats (SHR)
(Leffa et al., 2016).
Other findings support the involvement of dopamine function in the
tDCS mechanism of action. In a double-blind sham-controlled study,
healthy subjects undergoing a single session of tDCS showed after the
stimulation period a dopamine increase in the ventral striatum
compared to sham controls (Fonteneau et al., 2018). An increase in
striatal dopamine release was also demonstrated in healthy subjects
undergoing [11C]-raclopride positron emission tomography (PET) scans,
after active tDCS delivery but not sham stimulation (Bunai et al., 2021;
Fukai et al., 2019).
Therefore, the increase in dopamine activity and release in subcor­
tical areas can secondarily affect the meso-cortico-limbic transmission,
representing a new element to take into account in the mosaic of puta­
tive tDCS mechanisms of action, beyond the simple “excitatory-inhibi­
tory” model.
It has been observed that the administration of the dopamine pre­
cursor L-dopa may reverse the effects of tDCS on cortical excitability. In
a protocol investigating motor cortex stimulation by tDCS in healthy
subjects, L-dopa abolished the excitability enhancement driven by
anodal tDCS while prolonging cathodal tDCS-induced excitability
reduction (Kuo et al., 2008). In another study, the effects of increasing L-
dopa doses on motor cortex excitability by tDCS were explored in 12

8
G. D'Urso et al.
healthy subjects. The authors found that low and high dosages of L-dopa
abolished both facilitatory and inhibitory potential amplitudes induced
by tDCS, whereas medium dosage prolonged inhibitory potentials, and
turned facilitatory potentials into inhibition (Monte-Silva et al., 2010b).
Thus, L-DOPA administration exhibited an inverted U-shaped dose-
response curve on tDCS-mediated excitability. Similar dose-dependent
effects are obtained by administering dopamine agonists such as
apomorphine in humans (Fresnoza et al., 2021).
A complex interaction between tDCS response and Catechol-Oxy-
MethylTransferase (COMT) genotypes has been reported. In a multi­
center trial recruiting unipolar and bipolar patients randomized to
receive active or sham tDCS sessions, COMT genotype was not associ­
ated with the antidepressant effects of tDCS (Martin et al., 2018a).
Another negative result comes from a recent study conducted on healthy
subjects displaying that the COMT Val158Met polymorphism (rs4680)
did not impact the beneficial after-effects of prefrontal tDCS on working
memory (Jongkees et al., 2019). However, other reports indicate a pu­
tative role of COMT genotype in tDCS responses. For instance, in
schizophrenia patients with treatment-resistant auditory hallucinations,
the reduction in the auditory hallucination sub-scale score achieved by
add-on tDCS was significantly potentiated in subjects carrying the
COMT Val genotype (Chhabra et al., 2018). Furthermore, the COMT Val
genotype was found to crucially modulate the efficacy of cathodal tDCS
to the dorsolateral PFC on response inhibition, a core aspect of executive
function, as highlighted during the performance of a parametric Go/No-
Go test in healthy volunteers (Nieratschker et al., 2015).
Taken together, these findings indicate a complex pattern of in­
teractions between the dopaminergic transmission and tDCS, worthy of
further investigations that could prove relevant for the treatment of the
bipolar disorder.
3.3.3. Serotonin neurotransmission
Dysfunctions in serotonin neurotransmission have been consistently
reported in bipolar disorder (Chou et al., 2010; Gao et al., 2016;
Oquendo et al., 2007). An in vivo microdialysis study conducted in rats
failed to detect any changes in striatal serotonin levels following cath­
odal or anodal tDCS (Tanaka et al., 2013). Although only a few reports
have investigated the potential role of serotonin in mediating the effect
of tDCS, it has been repeatedly demonstrated that serotonergic agents
enhance tDCS-mediated neuroplasticity in humans (Nitsche et al.,
2009), thereby putatively implicating serotonin neurotransmission in
the neurobiology of tDCS effects in bipolar disorder.
Notably, a single dose of the Selective Serotonin Reuptake inhibitor
(SSRI) citalopram in healthy subjects has been found to increase both
the amplitude and duration of the after-effects of anodal tDCS. Addi­
tionally, citalopram counterbalanced the diminution in excitability after
cathodal tDCS, inducing facilitation (Nitsche et al., 2009). Chronic an­
tidepressant treatment with citalopram for 35 days increased and pro­
longed the LTP-like plasticity induced by anodal tDCS for over 24 h, and
converted cathodal tDCS-induced long-term depression (LTD)-like
plasticity into facilitation. These effects were abolished by the N-methyl-
D-aspartate (NMDA) receptor antagonist dextromethorphan, putatively
indicating that the potentiating effects of SSRI administration on tDCS
procedures may be NMDA-receptor dependent, and may be compatible
with a neuromodulatory, but not a plasticity-driving function of sero­
tonin (Kuo et al., 2016). In contrast to what we have previously reported
with L-dopa and dopamine agonists, the effects of serotonergic agents on
anodal tDCS-induced excitability appear to be independent of the dose
(Melo et al., 2021).
The effects of tDCS on the serotonergic system and therefore the
differential sensitivity, as well as the inter-subject variability, could be at
least in part influenced by specific variants of the serotonin transporter
gene (5-HTTLPR) (Brunoni et al., 2013b).
In summary, serotonin can reverse the cathodal and enhance the
anodal effects of tDCS and the evidence suggests a bidirectional inter­
action mode: tDCS promotes the function of the serotonergic system and
9
Progress in Neuropsychopharmacology & Biological Psychiatry 121 (2023) 110672
serotonin facilitates tDCS effects.
3.3.4. Glutamate and GABA neurotransmission
Glutamate and the GABA/Glutamate balance have become central in
the arena of antidepressant and mood disorder drug discovery, including
bipolar depression. In particular, interest in agents acting at glutamate
receptors has grown in the last few years, since these agents could
represent innovative interventions, particularly for patients who are
poor responders to canonical antidepressants or require rapid onset of
the antidepressant action (Tomasetti et al., 2017).
TDCS has been demonstrated in multiple settings to modulate
glutamate and amino acids brain concentration (Santana-Gómez et al.,
2015; Alvarez-Alvarado et al., 2021; Hunter et al., 2015).
As regards the anodal stimulation, a preliminary study sought to
determine the effects of the selective NMDA receptor partial agonist D-
Cycloserine on the increase of motor cortex excitability in healthy in­
dividuals (Nitsche et al., 2004a). The authors found that 100mg D-
Cycloserine prolonged, but not increased, the anodal tDCS-induced
excitability enhancement, while no effects were observed on cathodal
tDCS-induced excitability reduction (Nitsche et al., 2004a). These data
lend support to the idea that the duration of anodal-mediated excit­
ability enhancement may be under the control of glutamatergic mech­
anisms. In a more recent study including healthy volunteers, the authors
tested whether tDCS effects on cortical excitability were modulated by
the interaction between nicotine and glutamate receptors since both
affect cortical plasticity via calcium channels. Therefore, anodal tDCS
was combined with 15 mg nicotine patches and three doses of dextro­
methorphan. Nicotine was found to abolish anodal tDCS-induced motor
cortex excitability enhancement, an effect that was prevented by an
average dosage of dextromethorphan (Lugon et al., 2017). Low-dose
dextromethorphan did not affect the impact of nicotine on tDCS-
induced plasticity, while high-dose dextromethorphan abolishing plas­
ticity. On the other hand, administration of the GABA receptor agonist
lorazepam, that is used as an anxiolytic and tranquilizing agent in many
psychiatric diseases including bipolar disorder, resulted in a delayed,
but then enhanced and prolonged anodal tDCS-induced excitability
elevation (Nitsche et al., 2004b)
Concerning the cathodal stimulation, a randomized magnetic reso­
nance spectroscopy (MRS) and connectivity study on twenty healthy
subjects observed no changes in glutamine and GABA concentration in
the stimulated right DLPFC before, during, and after tDCS procedures.
However, when considering only the data from the twelve female par­
ticipants, a Glutamate reduction after active compared to sham stimu­
lation was detected. No changes were observed in resting-state
functional connectivity (Mezger et al., 2021). Furthermore, research
targeting the motor cortex revealed that cathodal tDCS is able to reduce
the concentration of Glx in the site of stimulation (Stagg et al., 2009) and
of GABA in the contralateral cortex (Bachtiar et al., 2018). A different
MRS study showed that a higher baseline GABA/Glutamate ratio in­
creases the effect of cathodal tDCS over the left DLPFC in disrupting the
performance in a response selection training (Filmer et al., 2019).
The above findings reinforce the view that tDCS-mediated changes of
cortical excitability are under a relevant and multimodal glutamatergic
and GABAergic control. However, to date, no specific studies have been
conducted in bipolar depression or other mood disorders and therefore
this is an area needing further investigations, especially after the
approval by regulatory agencies of the first glutamatergic drug, esket­
amine, for the treatment-resistant depression (Kim et al., 2019; Popova
et al., 2019).
3.3.5. Synaptic plasticity and brain networks putatively involved in the
pathophysiology of bipolar depression: relevance for tDCS
TDCS has been considered to improve cognitive functions by
enhancing long-term potentiation (Fig. 4), an effect that could have
therapeutic implications in unipolar and bipolar depression (McClintock
et al., 2020). An enhancement of hippocampal CA1 LTP has been shown
G. D'Urso et al.
Fig. 4. Anodal tDCS increases the expression of immediate early genes such as Arc, c-Fos, BDNF and others, thus enhancing long-term potentiation. BDNF= Brain-
derived neurotrophic factor; AMPAR= α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor; NMDAR= N-methyl-D-aspartate receptor; LTP= long-term
potentiation.
in rodent slices up to 1 week after tDCS (Rohan et al., 2015). Yu et al.
have demonstrated that, in rats, tDCS-induced LTP is associated also
with memory enhancement in the hippocampal-dependent passive
avoidance learning task, which is blocked by the pretreatment with
ANA-12 (Yu et al., 2019). These animals also showed an increase in
Brain-Derived Neurotrophic Factor (BDNF) in the CA1 region of hip­
pocampus compared to sham-control animals (Fig. 4). In agreement
with these findings, albeit in different experimental conditions, tDCS has
been found to enhance expression and dendritic spine density in the
peri-infarct motor cortex of mice subjected to focal ischemia of the
motor cortex (Longo et al., 2022). Taken together, these results suggest
the possibility that tDCS-induced cortical plasticity may be mediated, at
least in part, by BDNF/TrkB pathway. The putative role of BDNF/TrkB in
the mechanism of tDCS effects is intriguing, given the pathogenic and
therapeutic role proposed for this signaling in major depression and
bipolar disorders (Chiou and Huang, 2019; D'Addario et al., 2018;
Schröter et al., 2020; Valvassori et al., 2019), as well as for the supposed
involvement of the BDNF/TrkB pathway in the mechanism of action of
lithium (De-Paula et al., 2016).
Once reviewed the evidence on the effect of tDCS on synaptic plas­
ticity and its potential implication in bipolar disorders, a further step is
to consider if and how the evidence supports an after-effect on synaptic
architecture and dendritic spine whose aberrations at both a structural
and functional level have been described in the molecular pathophysi­
ology of bipolar disorders (Alfieri et al., 2017; Konopaske et al., 2014;
Law et al., 2004; Martin et al., 2018b; Nanou and Catterall, 2018). At the
cellular level, tDCS has been shown to induce changes in dendritic spines
density and structure (Cirillo et al., 2017). Recently, postsynaptic den­
sity (PSD) has emerged as a key structure of the synapse dysfunction in
psychiatric disorders, including major depression and bipolar disorders
(Akula et al., 2016; de Bartolomeis et al., 2014a; de Bartolomeis et al.,
2014b; de Bartolomeis and Tomasetti, 2012; Föcking et al., 2016). PSD
is a cytoskeletal structure beneath the plasma membrane of excitatory
10
Progress in Neuropsychopharmacology & Biological Psychiatry 121 (2023) 110672
synapses constituted by a mesh of receptors (i.e.: NMDAR; α-amino-3-
hydroxy-5-methyl-4-isoxazole propionic acid receptor, AMPAR; Gluta­
mate Metabotropic Receptor type I, mgluR1 and 5), scaffolding, and
adaptor proteins (i.e. Homer, PSD 95; Shank)(de Bartolomeis et al.,
2022b; Iasevoli et al., 2013). Moreover, multiple lines of evidence
demonstrate the involvement of PSD proteins in the response to treat­
ments for psychiatric ilnesses including bipolar disorders (Barone et al.,
2021; de Bartolomeis et al., 2022a; Halff et al., 2021; Iasevoli et al.,
2020). Mood stabilizers administration has been found to modulate
shaping and composition of postsynaptic structures by affecting the
expression of Homers, Shanks, and others PSD proteins (de Bartolomeis
et al., 2012; Halff et al., 2021; Tomasetti et al., 2011). A relevant step in
the signaling cascades potentially involved in synaptic plasticity events
is represented by the induction or activation of immediate early genes
(IEGs) (Cirillo et al., 2017; de Bartolomeis et al., 2013; de Bartolomeis
et al., 2022b), which are genomic elements whose expression is rapidly
upregulated after neuronal activation. IEGs code for transcription fac­
tors (i.e., c-fos) or more rarely for molecules implicated in synaptic ul­
trastructure (i.e., Arc) or intracellular signaling pathways (Gallo et al.,
2018). At the biological level, IEGs are predicted to induce rapid and
transient molecular effects in neurons, which may have a strong impact
on neuronal plasticity (Sommerlandt et al., 2019). tDCS has been re­
ported to induce multiple early genes (Kim et al., 2017; Ranieri et al.,
2012), including c-fos and Arc. In particular, mRNA levels of BDNF,
cyclic AMP response element-binding protein (CREB), synapsin I, Arc,
and c-Fos were found significantly increased in the ipsilateral cortex
after 7 days of unilateral intervention, whereas only c-Fos expression
increased in the ipsilateral hippocampus (Kim et al., 2017)(Fig. 4).
Notably, has also been observed an increase after tDCS of CaMKII gene
expression, a molecule robustly correlated to the mechanism of action of
drugs with antidepressant effect (Celano et al., 2003; Tiraboschi et al.,
2004).
It is worth mentioning that a different form of NIBS, i.e. transcranial
G. D'Urso et al.
magnetic stimulation (TMS), has been demonstrated to induce Homer1a
in the cingulate cortex after swimming stress an animal model of
depression-like behavior (Sun et al., 2011). Homer1a is both an
immediate-early gene and a key structural and functional member of
PSD, involved in dendritic spine formation and architecture (de Barto­
lomeis et al., 2022b; Meyer et al., 2014), implicated in depression
pathophysiology as well as in the response to pharmacological and non-
pharmacological treatments (Serchov et al., 2015). Taking the TMS
study as a basis, it would be of interest to find out if also tDCS can
modulate Homer1a and in which brain areas.
It will be interesting for a better understanding of tDCS effects on
synaptic plasticity and dendritic architecture to test in further studies
whether tDCS can also modulate a relevant dendritic spine shaper such
as Homer and its interacting proteins, specifically with the regard to the
potential involvement of dopaminergic system that has been demon­
strated to have a major effect on postsynaptic gene expression (Toma­
setti et al., 2007) and that has already been suggested to have a
significant role in bipolar disorders pathophysiology both for the
depressive and manic phases of the disease (McCutcheon et al., 2021;
Salvoro et al., 2018).
We refer to an earlier publication for a more complete overview of
neurobiological mechanisms of tDCS effects (McLaren et al., 2018),
which is beyond the scope of the present review that focused specifically
on neurobiological mechanisms relevant to bipolar disorder.
4. Discussion
We submit that the present review is prime since it specifically aimed
at appraising evidence of tDCS efficacy in bipolar depression, a critical
area of research, and concurrently discusses its neurobiological un­
derpinnings. Whilst very informative about the clinical effects of tDCS,
the two systematic reviews on the matter carried by Donde’ and col­
leagues (Dondé et al., 2017; Dondé et al., 2018), could not include the
most current results, i.e. two open label studies (Li et al., 2019; Lin et al.,
2021) and three RCTs (Loo et al., 2018; Sampaio-Junior et al., 2018;
Mardani et al., 2021). In particular, the RCTs by Sampaio and colleagues
(Sampaio-Junior et al., 2018) and by Mardani and colleagues (Mardani
et al., 2021) are the only specifically designed for bipolar depressed
patients available to date and, taken together, enrolled more patients
with bipolar depression than all the previous studies in aggregate.
Moreover, our study reviews the neurobiological literature to dissect the
potential underpinnings of the tDCS effect in bipolar depression, in
terms of impact on neurotransmitter action, intracellular signaling,
synaptic plasticity, and brain networks modulation.
4.1. tDCS efficacy for the treatment of bipolar depression
Several RCTs and meta-analyses have demonstrated the efficacy of
tDCS in major depressive episodes (Moffa et al., 2020; Mutz et al., 2019;
Razza et al., 2021). However, most studies examining tDCS in the
treatment of depressive symptoms have enrolled both unipolar and bi­
polar depression patients, without corresponding stratification, thus
hindering the detection of eventual differences in the tDCS effects be­
tween the two groups.
One of the few studies specifically addressed to bipolar depressed
patients, by Sampaio and colleagues (Sampaio-Junior et al., 2018), was
a randomized double-blind sham-controlled trial that confirmed the
efficacy and safety of add-on prefrontal tDCS in a sample of patients with
BD type I or II who were in a major depressive episode. In particular, this
study showed that active tDCS was superior to sham for a sustained
response but not for sustained remission. Importantly, similar rates of
treatment-emergent affective switches were reported in active and sham
treatment groups. In their discussion, the authors hypothesized that
greater beneficial effects might be achieved by combining tDCS with
other treatments, i.e. pharmacotherapy, psychotherapy, or other brain
stimulation techniques, since tDCS alone can induce only small changes
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Progress in Neuropsychopharmacology & Biological Psychiatry 121 (2023) 110672
in the membrane potential. Moreover, in a pilot study from the same
group (Pereira Junior Bde et al., 2015), it was argued that the rate of
response and remission following tDCS in bipolar patients were similar
to those observed in unipolar ones, i.e. 40% and 20% respectively.
Accordingly, a recent open-label trial directly compared the response to
tDCS of unipolar and bipolar depressed patients and showed that both
groups improved equally not only in depression scores, but also in
cognitive performance, anxiety, and psychosocial functioning (Lin et al.,
2021).
On the contrary, Li and colleagues reported a higher rate of treat­
ment response in bipolar patients (40%) than in unipolar ones (30,8%)
(Li et al., 2019). Interestingly, in this trial a statistically significant
reduction of the MADRS score was not present at the end of the treat­
ment and was observed only four weeks later, pointing to a delayed
antidepressant effect of tDCS. Unfortunately, the authors did not specify
if there was any difference in the timing of response between unipolar
and bipolar patients.
Brunoni and colleagues (Brunoni et al., 2013a; Brunoni et al., 2011a,
2011b) were the first researcher to suggest that tDCS in bipolar
depression could have at least the same efficacy and tolerability as in
unipolar depression, so extending the claims of the earliest reports
describing tDCS as a promising emerging therapy for major depression
(Boggio et al., 2008; Ferrucci et al., 2009). Indeed, the authors observed
that in the clinician-rated measures of depression, symptoms improved
exclusively in patients with bipolar depression, although in that study
the total sample was relatively small and the sample of bipolar patients
was smaller than that of unipolar patients (14 bipolar vs. 31 unipolar).
This surprising finding has been interpreted as the result of a difference
in the baseline depression severity between the two groups, with bipolar
patients scoring much higher on clinician-rated scales (30.77 vs. 21.53
HDRS score). Moreover, in a meta-analysis from the same group, bipolar
depression has been suggested to be a positive predictor of tDCS
response, even if the number of bipolar patients in the overall sample of
the study was as low as 3.8% (Brunoni et al., 2016).
Loo and colleagues (Loo et al., 2012) confirmed the antidepressant
effects of tDCS on a mixed sample comprising unipolar (N=52) and bi­
polar (N=8) patients, with a significantly greater improvement in the
active group compared with the sham group over the 3-week study
period on the primary outcome measure (change in MADRS). The results
were clinically modest, with only a 28% decline in MADRS scores after
active stimulation and a small proportion of responders in the whole
sample. Of note, the four bipolar patients allocated in the active group
showed an average greater improvement, i.e., 42%. In a subsequent
randomized double-blind sham-controlled trial on a mixed sample of
unipolar (N=84) and bipolar (N=36) patients, the same group of authors
suggested that the modest overall mood improvement – with no statis­
tically significant difference between active and sham stimulation – may
have been caused by a greater placebo effect in the sham group (Loo
et al., 2018).
This hypothesis stimulates reflection on the different sham stimula­
tion protocols currently used in tDCS research and their possibly
different biological effects. Indeed, the inconsistency in sham protocols
among sham-controlled trials might be partially responsible for the
inconsistency of their clinical results (Fonteneau et al., 2019). In the
study by Loo et al. (2018), the authors speculated that the special sham
stimulation used (consisting in a 0.034 mA of constant current during
the whole session plus two ramps of 1 minute up to 0,5 or 1 mA) may
have been biologically active, and, when given for 20 sessions over 4
weeks as in this study, could have had comparable effects to 1mA and 2
mA continuous stimulation, so leading to a non-significant difference
between active and sham group at the end of the study.
The other three RCTs included in this systematic review (Loo et al.,
2012; Palm et al., 2012; Sampaio-Junior et al., 2018) used a different
sham procedure which entailed an active stimulation of only 30 seconds
with a ramp up and a ramp down identical to that used for the active
tDCS group and with either the same (Palm et al., 2012; Sampaio-Junior
G. D'Urso et al.
et al., 2018) or half (Loo et al., 2012) the current intensity. In our
opinion, this last sham procedure is the best option to date, being less
likely to produce an appreciable biological effect still ensuring the
subject blinding thanks to the skin sensation induced. In fact, in the
Sampaio-Junior et al. (2018) study, the patients were assessd for the
blinding and resulted unable to guess their actual group beyond chance.
Palm and his group (Palm et al., 2012) administered prefrontal tDCS
to 20 unipolar and 2 bipolar patients for only two weeks, obtaining no
meaningful therapeutic effect on their treatment-resistant depression
compared with placebo, even though subjective mood ratings using
Positive and Negative Affect Scale (PANAS) showed an increase in
positive emotions and a trend towards a reduction of negative emotions
after active tDCS. Authors suggested that this lack of efficacy could be
attributed to a higher degree of treatment resistance or a relatively
higher mean age in enrolled patients - compared with previous tDCS
studies - as an older age may be associated with a poorer antidepressant
response to transcranial brain stimulation. In our opinion, the disap­
pointing results of this trial were due mainly to the low number and
duration of tDCS sessions, factors that had not yet demonstrated as
crucial at the time of this study.
Martin and colleagues (Martin et al., 2013) examined the use of
continuation tDCS treatment to prevent relapse following clinical
response to an acute course of tDCS. The sample of their study consisted
mostly of patients who had failed at least one adequate course of anti­
depressant treatment before receiving acute stimulation. They observed
that continuation tDCS, given weekly for the first 3 months, resulted in
the majority of responders remaining well and that higher medication
resistance was predictive of relapse during this treatment period. Again,
these results refer to a mixed sample and it is not possible to clarify the
differential effect on unipolar (N=20) and bipolar (N=3) patients.
Another strategy to maintain the clinical effect of tDCS in the long
term was investigated by Aparicio and colleagues (Aparicio et al., 2019),
who compared the effects of the same maintenance protocol in unipolar
and bipolar depression. Twenty-four patients (16 with unipolar
depression and eight with bipolar depression) who presented acute tDCS
response (≥50% depression improvement in the Hamilton Depression
Rating Scale [HDRS] after receiving 15 tDCS sessions) were followed for
up to 6 months or until relapse, defined as clinical worsening and/or
HDRS > 15. During the follow-up, tDCS was administered twice a week
(maximum of 48 sessions) over 24 weeks with results of a low relapse
rate (26,5%) after a 6-month follow-up in tDCS responders, particularly
in non-treatment-resistant patients. Interestingly, even if at the end of
the study no significant difference in relapse rates was observed between
unipolar and bipolar patients, these last relapsed on average 3 months
later. The authors suggested that this finding could be ascribed to the
fact that bipolar and not unipolar patients were allowed to take mood
stabilizers during the trial and that probably these drugs have contrib­
uted to the longer survival of the tDCS effect.
The issue of the follow-up efficacy of tDCS in major depressive
episode (MDE) has been specifically assessed by a recent systematic
review and meta-analysis including 11 studies that followed up adults
patients undergoing and/or not undergoing tDCS maintenance sessions
in the follow-up period (Razza et al., 2021). According to the authors,
the observed reduction of depression scores at follow-up, compared to
the end of the acute tDCS treatment, was due to the contribution of the
studies involving maintenance tDCS sessions. Considering only the trials
including bipolar depressed patients and providing maintenance tDCS
(Aparicio et al., 2019; Loo et al., 2012; Loo et al., 2018; Martin et al.,
2013), the review shows that all of them reported a further improvement
at follow-up, with the exception of Loo et al., which reported no change.
Regarding the protocol used and the duration of the maintenance
treatment, the selected studies differ considerably, with one of them
performing 48 twice-per-week sessions (Aparicio et al., 2019), two
providing only four once-per-week sessions, and another involving a
more complex schedule of 18 sessions, 12 of which performed once
weekly, and the remaining six once fortnightly.
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Progress in Neuropsychopharmacology & Biological Psychiatry 121 (2023) 110672
In summary, despite the paucity of specific studies, the existing ev­
idence suggests that tDCS is effective in treating symptoms of bipolar
depression and that it is at least as beneficial in this clinical condition as
in unipolar depression, for which it is already a consolidated treatment.
Moreover, there are clues indicating that bipolar depressed patients
could benefit from tDCS even more than unipolar ones, both in terms of
acute response and of long-term effects, especially when appropriate
protocols of continuation tDCS are implemented after an acute response.
4.2. Interaction between tDCS and pharmacotherapy
Some of the articles included in this review analyzed the effect of
concomitant drugs taken during the tDCS treatment, a particularly
important issue in the case of bipolar patients, who often need chronic
regimens of psychotropic medications.
In a pioneering study on healthy subjects, Nitsche et al. observed that
carbamazepine abolished the excitability enhancement induced by
anodal stimulationon motor cortex (Nitsche et al., 2003). Subsequently,
the same group of researchers observed that administration of loraze­
pam to healthy individuals before tDCS led to a delayed, but more
pronounced and prolonged enhancement of the motor cortical excit­
ability induced by the stimulation (Nitsche et al., 2004b). However, the
mechanisms underlying this peculiar effect remain unclear.
In depressed patients, Brunoni and colleagues (Brunoni et al., 2013a)
observed that benzodiazepine use was associated with higher endpoint
depression scores, probably because the long-term changes in the
GABA/glutamate system induced by these drugs were responsible for
abolished tDCS effects. Moreover, as baseline depression severity was
similar for patients using and not using benzodiazepines, their use might
be a proxy for anxious depression and, thus, a predictor of poor tDCS
response. As to antidepressants, the authors observed that they generally
increased tDCS effects and suggested that chronic use of serotoninergic
drugs might still induce global facilitation for brain activation, so paving
the way for tDCS action. The same group, in two different studies
(Aparicio et al., 2019; Brunoni et al., 2011a, 2011b), ascribed to phar­
macotherapy the shorter-lasting effects induced by tDCS in patients with
MDD compared to those with BDD. In particular, mood stabilizers (used
only in patients with bipolar depression), played a role in maintaining
the initial tDCS-induced improvement, whereas antidepressants (used in
both groups) did not.
Finally, a recent RCT aimed specifically to compare the effect of
mood stabilizers (Lithium Carbonate+Sodium Valproa­
te+Carbamazepine) alone with that of mood stabilizers combined with
tDCS in bipolar depressed patients (Mardani et al., 2021). The results of
this trial indicate that depressive symptoms are reduced more in the
tDCS+drugs group compared to the drugs-alone group and that in the
tDCS+drugs group there was also an improvement in executive func­
tions (i.e. response inhibition), which was not observed in the drugs-
alone group. These effects were observed immediately after the two-
week intervention but were not maintained at a three-month follow-up.
In summary, studies involving depressed patients suggest that tDCS
beneficial effects could be reduced by concomitant benzodiazepines,
increased by serotonergic agents and mood stabilizers, and prolonged
only by mood stabilizers. However, evidence is still too scarce to allow
for any clinical recommendation on how to combine tDCS with drugs.
4.3. Impact of tDCS protocols on safety and efficacy
In the analyzed articles, a few non-specific tDCS side-effects, tran­
sient and low in intensity, were reported. They consisted in skin redness
and itching/burning/tingling at the site of the electrodes, headache,
nausea, fatigue, visual effects, agitation and were apparently montage-
and dosage-independent, provided that general safety recommendation
were followed (Bikson et al., 2016). The occurrence of anxiety was also
reported as a side-effect in depression studies, even though one trial
involving only bipolar patients (N=60) seems to point to a specific anti-
G. D'Urso et al.
anxiety action of the bifrontal tDCS montage in this category of patients
(Pereira Junior Bde et al., 2015).
Due to the small number of studies, the relative heterogeneity of the
protocols and endpoints used, it is hard to conclude about a differential
effectiveness of the various electrodes montage and/or of the other as­
pects of the tDCS procedure. However, while most studies used the
conventional 10-20 EEG system to position the electrodes over the target
areas, the largest sample RCT used the OLE, a novel electrode montage
specifically developed to achieve an improved targeting of the bilateral
DLPFC (Sampaio-Junior et al., 2018). Intriguingly, at the six-week
endpoint the authors reported the most marked symptom improve­
ment among the RCTs, if not considering the study by Mardani et al.
(2021), with a much closer endpoint (ten days).
Previous computational modeling research demonstrated that the
proximity of the two electrodes to one another is correlated to stimulus
focality, with a reduced amount of current reaching the deep brain
structures and an increased amount shunting superficially across the
scalp (Datta et al., 2008). How this can influence the clinical effect re­
mains to be determined.
As a matter of fact, the F3-F8 and F3-F4 montages have been used in
most clinical trials reporting significant antidepressant effects and both
are known to induce relatively high electric fields in dorsolateral pre­
frontal cortices. However, by increasing the distance between tDCS
electrodes, deeper limbic structures are stimulated, such as the amyg­
dala, hippocampus (Sadleir et al., 2010), and corticolimbic networks
(Bikson et al., 2008).
Martin and colleagues observed that tDCS antidepressant efficacy
improved after moving the cathode from F4 to an extracephalic position,
i.e. switching from bifrontal to fronto-extracephalic montage, although
these observations stem from the treatment of a small and mixed sample
(9 unipolar, 2 bipolar) (Martin et al., 2011). A fronto-extracephalic
montage may induce greater antidepressant effects by more direct and
widespread activation of limbic areas associated with the pathophysi­
ology of depression, including the anterior cingulate, the insula, the
basal ganglia, and the superior temporal gyrus (Bai et al., 2014; Bikson
et al., 2008). Moreover, preliminary results showed that alternative
tDCS montages, such as bitemporal electrodes positioning, might also be
useful for the treatment of depression (Ho et al., 2015).
A potential major advantage of tDCS in bipolar depression is
considered to be its low manic-switch potential, compared to standard
antidepressant therapy (Fornaro et al., 2018). The present review is in
agreement with this consideration. Indeed, in the eligible studies, four
cases of an affective switch from depression to hypomania/mania were
reported. In these cases, tDCS was administered using a bifrontal (F3-F4:
Pereira Junior Bde et al., 2015)(F3-F8: Loo et al., 2012) or a fronto-
extracephalic montage (F3-EC: Martin et al., 2011; Gálvez et al.,
2011). Martin and colleagues emphasized that their participants had not
previously reported hypomanic episodes with bifrontal tDCS and that
the onset of hypomania had occurred with the fronto-extracephalic
montage. Thus, the extracephalic stimulation may be more likely to
induce affective switches from depression to hypomania/mania,
through a greater stimulation of limbic regions, cerebellum and its
associated networks, involved in the pathophysiology of mania (Brooks
et al., 2010; Minichino et al., 2014). Nevertheless, a higher potential of
affective switch for a specific tDCS montage might also be considered a
proxy for a more robust antidepressant action, a possibility that deserves
to be investigated through a direct comparison between the different
montages in terms of their respective safety and efficacy. Indeed, a tDCS
montage involving the stimulation of the left DLPFC in combination
with that of a remote, non-frontal area such as the right cerebellum has
yielded intriguing evidence. In particular, it was reported a mood in­
crease in healthy subjects (Newstead et al., 2017), an improvement of
sleep (Minichino et al., 2014), neuropsychological performance (Bersani
et al., 2016), and neurophysiological parameters (Bersani et al., 2015) in
euthymic bipolar patients, and a reduction of abnormal behaviors,
motor tics and epileptic activity in autistic patients (D'Urso et al., 2021).
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Progress in Neuropsychopharmacology & Biological Psychiatry 121 (2023) 110672
However, two of the four participants who had switched from depres­
sion to hypomania/mania in the examined articles had been treated with
bifrontal tDCS stimulation (Loo et al., 2012; Pereira Junior Bde et al.,
2015). Thus, we underline that hypomanic/manic switches are also
possible with more focused bifrontal montages. Importantly, no study
reported an increase in rapid cycling or suicidality.
Regarding the other stimulation parameters, as the stimulus intensity
and duration, the number and frequency of sessions, and the overall
dosage of current administered, their optimal values for tDCS thera­
peutic effects are still unknown. As a possible reference, we know that in
rTMS studies longer treatments led to better results (Gross et al., 2007).
However, recent tDCS dose-outcome studies in healthy cohorts sug­
gested that there is not a simple linear association and that there may be
considerable inter-individual variability in response (Chew et al., 2015).
Loo and colleagues suggested that stimulation at 2.5 mA for 30 min over
20 sessions probably exceeds the optimal stimulus “dosage” for many
patients, even though they acknowledge that the exact influence of the
single stimulus parameters are yet unknown (Loo et al., 2012, 2018).
The optimal repetition interval for tDCS sessions is also a matter of
debate. Studies of motor cortex excitability report that the duration of
tDCS-induced plasticity is related to the stimulation duration and that
the second stimulation should be optimally timed to coincide with the
after-effects of the first, but not when homeostatic brain regulation oc­
curs because that period might be of limited neuroplasticity (Monte-
Silva et al., 2010a). However, these neurophysiological principles are
hard to be translated into treatment protocols. As a matter of fact, the
four clinical trials included in this review that involve twice daily tDCS
sessions do not specify the exact timing of the second daily session, with
three studies reporting only the minimal interval between the sessions, i.
e., three (Li et al., 2019) or four (Brunoni et al., 2011a, 2011b; Brunoni
et al., 2013a, 2013b) hours, and another study not mentioning at all this
aspect (Mardani et al., 2021).
In summary, the differential impact on unipolar and bipolar
depression of the many variables involved in tDCS protocols is far from
being ascertained. The only constant in the reviewed evidence is the
anodal stimulation of the left DLPFC to obtain the antidepressant effect.
The position of the cathode varies among studies and could influence the
magnitude of the antidepressant effect (the greater the distance between
the electrodes, the greater the effect) and the action on other concurrent
symptoms. As regards to the dosage of current, while it appears that a
greater number of tDCS sessions is necessary to obtain better clinical
results, there is no indication available on possible differences in the
number of sessions needed to treat unipolar or bipolar depression.
4.4. Neurobiology of tDCS effect in bipolar depression
The neurotransmission involvement in tDCS effects on bipolar
depression can be inferred from studies that explored the relationship
between tDCS, monoamine release, and reuptake in the preclinical and
clinical setting (Kuo et al., 2016). The most relevant information found
in neurobiological studies concerns dopamine, serotonin, glutamate,
and the reciprocal interaction between these neurotransmitters.
Moreover, multiple lines of evidence suggest an impact of tDCS on
synaptic strength, synaptic plasticity, and metaplasticity (Cirillo et al.,
2017; Yu et al., 2019). These effects of tDCS are specifically pertinent for
bipolar disorders whose molecular pathophysiology is conceptualized as
a disorder of synaptic plasticity and neuronal architecture involving
multiple processes (Akula et al., 2016), from receptors recycling and
scaffolding proteins re-arrangement to the induction of transcription
factors, then leading to the synthesis of key molecules relevant for
dendritic spine shaping.
The results reviewed point to the involvement of multiple neuro­
transmitter systems, overlapping signaling systems at the level of second
messenger and transcriptional control, and, finally, to significant
changes in brain plasticity and metaplasticity involving proteins that are
integral part of the dendritic spine.
G. D'Urso et al.
It should be aknowledged that it is premature to speculate if the
changes at neurobiological level are just an epifenomenon or a change of
significant functional impact in tDCS mechanism of action. However, it
is worth underlining that the changes described in animal models where
the neurostimulation is used without interference of other therapeutics
and in controlled context are in line with changes expected from a pu­
tative antidepressant effect.
In summary, even if to date no studies have specifically investigated
the neurobiological effects of tDCS in bipolar disorder, the exploration of
the molecular determinants putatively involved in the therapeutic effect
of tDCS in bipolar depression is moving fast forward, building on
converging results from different areas of tDCS application.
4.5. Study limitations
Among the limitations of this review, data on patients demographics,
onset and course of illness were lacking in detail. Moreover, we have not
conducted any comparison between the daily and the twice-a-day ses­
sions frequency, because of the great disparity in the respective number
of studies (in favor of daily sessions) and of too many concomitant
variables potentially influencing the tDCS response. Finally, the sample
size of bipolar depressed patients was small. However, this is in line with
the paucity of literature on tDCS across bipolar disorders. Even more
sources of variability are present in the analyzed neurobiological liter­
ature. Due to this remarkable lack of uniformity among studies and the
overall paucity of data regarding tDCS specifically for bipolar depres­
sion, we chose to perform a systematic review and not to adopt a meta-
analytic approach.
4.6. Implications for future research
In the last two decades, the research on rTMS as a treatment for
depression has been growing more and more, leading to the clearence of
this therapy by several national regulatory entities. On the contrary, the
less investigated tDCS has not yet been accepted as an official treatment
of depression, mainly because of insufficient evidence of efficacy. In our
opinion, further research on tDCS for depression, and particularly for
bipolar depression, is justified by some important advantages of this
technique over rTMS. Firstly, tDCS is safer, showing much less risk of
seizures, and has smoother side effects, i.e., mostly itching and tingling
at the site of stimulation, while TMS can be painful and induce strong
discomfort to the patient’s head. Secondly, tDCS is more feasible, given
that is cheaper and easier to administer, i.e., even by non-health pro­
fessional, if adequately trained. Moreover, the portability of the tDCS
device makes it possible a home-based treatment, which entails less
burden on daily routines of patients and their families. In addition, it
does not require immobility, which is a better option for restless patients
such as those with depression with mixed features and allows the
concomitant administration of cognitive training and/or psychotherapy.
Finally, in research settings, it is more suitable for double-blind and
sham-controlled studies, being the allocation concealment easier to
perform.
Further randomized controlled trials specifically targeted to patients
with bipolar depression or, in alternative, clearly separating the effects
of tDCS on unipolar and bipolar depressed patients are needed. More­
over, larger samples are warranted to confirm the described preliminary
findings and to ascertain the most beneficial tDCS treatment protocols.
Future trials are also needed to eliminate the sham tDCS placebo anti­
depressant effect, for which there is important evidence (Loo et al.,
2012, 2018). In addition, one of the most interesting areas to explore in
the future studies is the identification of response predictors. In fact, a
work from our group (D’Urso et al., 2017) we investigated which spe­
cific clinical characteristics were predictive of the acute antidepressant
effect of bifrontal tDCS in a sample of 171 depressed patients. Indeed, we
found that the reduction in HDRS scores after tDCS was strongly asso­
ciated with the baseline values of “Cognitive Disturbances” and
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Progress in Neuropsychopharmacology & Biological Psychiatry 121 (2023) 110672
“Retardation” factors of the scale. Similar studies aiming at the identi­
fication of response predictors specifically in bipolar depression may
have substantive clinical implications. In particular, since the mild an­
tidepressant response to tDCS may be due to the heterogeneity of
selected patients, the detection of response predictors could reveal
which subgroup of bipolar depressed patients would benefit more from
the treatment. Finally, despite preliminary indications, the exact nature,
and the potential synergistic action between tDCS and specific
concomitant treatments are yet to be determined. Future studies
combining tDCS with other interventions should not only focus on
pharmacotherapy but also on non-pharmacological trreatments, such as,
for example, cognitive-behavioral therapy (CBT), given the existing
evidence of psychotherapy efficacy in bipolar depression (Miklowitz
et al., 2007) and of a synergistic action of tDCS and CBT in unipolar
depression (D’Urso et al., 2013). As regards the field of neurobiological
studies, it would be interesting to explore commonalities and differences
between the mechanisms involved in pharmacological interventions and
non-invasive brain stimulation treatments as well as among different
non-invasive brain stimulation techniques.
5. Conclusions
The present systematic review examined the efficacy, safety, and
putative neurobiological underpinnings of tDCS in bipolar depression,
suggesting that the technique might be a promising therapeutic mo­
dality for this condition, even more than for unipolar depression.
Further randomized controlled trials and more specific neurobiological
studies are required to definitively conclude whether tDCS has utility for
the acute treatment or the prevention of bipolar depression.
Role of the funding source
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
Declaration of Competing Interest
GDU, ET, AB, MP, BDO, GDL, AM, GM, MF, FI have no interest to
declare; AdB has received research support from Janssen, Lundbeck, and
Otsuka and lecture fees for educational meeting from Chiesi, Lundbeck,
Roche, Sunovion, Vitria, Recordati, Angelini and Takeda; he has served
on advisory boards for Eli Lilly, Jansen, Lundbeck, Otsuka, Roche, and
Takeda, Chiesi, Recordati, Angelini, Vitria.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.pnpbp.2022.110672.
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