DOI: 10.1111/bdi.

13283

REVIEW

Brain stimulation treatment for bipolar disorder

Julian Mutz

Social, Genetic and Developmental

Psychiatry Centre, Institute of Psychiatry, Abstract
Psychology & Neuroscience, King's
Aims: Bipolar disorders are clinically complex, chronic and recurrent disorders. Few
College London, London, UK
treatment options are effective across hypomanic, manic, depressive and mixed
Correspondence
states and as continuation or maintenance treatment after initial symptom remission.
Julian Mutz, Social, Genetic and
Developmental Psychiatry Centre, The aim of this review was to provide an up-­to-­date overview of research on the
Institute of Psychiatry, Psychology &
efficacy, tolerability and cognitive effects of electroconvulsive therapy (ECT), tran-
Neuroscience, King's College London,
Memory Lane, London SE5 8AF, UK. scranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS),
Email: [email protected]
magnetic seizure therapy (MST), deep brain stimulation (DBS) and vagus nerve stimu-
Funding information lation (VNS).
Biotechnology and Biological Sciences
Methods: References included in this review were identified through multiple
Research Council, Grant/Award Number:
2050702 searches of the Embase, PubMed/MEDLINE and APA PsycINFO electronic databases
for articles published from inception until February 2022. Published reviews, meta-­
analyses, randomised controlled trials and recent studies were prioritised to provide a
comprehensive and up-­to-­date overview of research on brain stimulation in patients
with bipolar disorders.
Results: The evidence base for brain stimulation as an add-­on or alternative to phar-
macological and psychological treatments in patients with bipolar disorders is limited
but rapidly expanding. Brain stimulation treatments represent an opportunity to treat
all bipolar disorder states, including cognitive dysfunction during euthymic periods.
Conclusion: Whilst findings to date have been encouraging, larger randomised con-
trolled trials with long-­term follow-­up are needed to clarify important questions re-
garding treatment efficacy and tolerability, the frequency of treatment-­emergent
affective switches and effects on cognitive function.

KEYWORDS
bipolar and related disorders, bipolar depression, bipolar disorder, deep brain stimulation,
electroconvulsive therapy, magnetic seizure therapy, mania, transcranial direct current
stimulation, transcranial magnetic stimulation, vagus nerve stimulation

1 | I NTRO D U C TI O N periods of depression, hypomania or mania, mixed states, subsyn-

dromal symptoms and euthymia. Bipolar disorders rank amongst the
Bipolar disorders are characterised by recurrent episodes of mood most debilitating non-­communicable diseases,1 with an estimated
disturbances and changes in energy level and behaviour, including lifetime prevalence of 1.06% for bipolar disorder type I and 1.57%

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
© 2022 The Author. Bipolar Disorders published by John Wiley & Sons Ltd.

Bipolar Disorders. 2023;25:9–24.  wileyonlinelibrary.com/journal/bdi | 9

10 | MUTZ

for bipolar disorder type II. 2 The annual costs of managing bipolar guidelines, however, recommendations regarding other brain stimu-
3
disorders in the UK were estimated at £342 million, with hospital lation treatments vary.36–­43
3,4
inpatient care representing the largest cost factor. Depressive In this review, I summarise the evidence for the most common
episodes are more prevalent than (hypo)manic episodes and are as- brain stimulation treatments for bipolar disorders (Panel 1). The re-
sociated with a greater disease burden.5,6 An estimated 55.2% of pa- view is divided into four main sections: (i) electroconvulsive therapy,
7
tients experience a recurrent episode within 2 years. Mixed states (ii) transcranial magnetic stimulation, (iii) transcranial direct current
are less common but are associated with an increased risk of suicide stimulation and (iv) magnetic seizure therapy, deep brain stimulation
and high levels of comorbidity.8 Many individuals with bipolar dis- and vagus nerve stimulation. Each section includes a brief introduc-
orders present with functional impairments,9 have an elevated risk tion, a review of research on treatment efficacy, effects on cognition
10,11
of morbidity and mortality, and report comorbid substance use and tolerability and a brief conclusion. Where possible, the research
disorders which may negatively affect their long-­term prognosis.12 on treatment efficacy is presented separately for bipolar depression,
Cognitive impairments are common, also during euthymic periods, (hypo)mania, mixed states, maintenance and euthymia. The review
and correlate with reduced daily functioning.13 The elevated suicide ends with a concluding remark, key challenges for the field and
14
risk, high prevalence of comorbidities and accelerated biological directions for future research.
ageing15–­17 may contribute to the lower life expectancy of individ-
uals with bipolar disorders.18 For an overview of the epidemiology,
pathophysiology, diagnosis and treatment of bipolar disorders, see 2 | S E A RC H S TR ATEG Y
19
Vieta et al. (2018).
Treatments include medications20 and psychotherapy. 21 Manic References included in this review were identified through multiple
episodes are treated primarily with pharmacological monotherapy searches of the Embase, PubMed/MEDLINE and APA PsycINFO
or a combination of antipsychotics with lithium or anticonvul- electronic databases for articles published from inception until
22
sants. Treatment with antidepressant medications may be as- February 2022, using combinations of the following search terms:
sociated with an increased risk of treatment-­emergent affective ‘bipolar’, ‘bipolar disorder’, ‘transcranial direct current stimulation’,
switches, 23 highlighting the challenge of treating depressive ep- ‘tDCS’, ‘transcranial magnetic stimulation’, ‘TMS’, ‘theta burst stimu-
isodes. 24 Treatment-­resistant bipolar depression is a major con- lation’, ‘TBS’, ‘electroconvulsive therapy’, ‘ECT’, ‘magnetic seizure
25
tributor to the overall disease burden. Due to their clinically therapy’, ‘MST’, ‘vagus nerve stimulation’, ‘VNS’, ‘deep brain stim-
complex presentation, mixed states are difficult to treat and often ulation’ and ‘DBS’. Additional references were identified through
unresponsive to pharmacotherapy. 26 The use of multiple medi- backward and forward citation searching in Google Scholar. Due to
cations in combination is common in patients with bipolar disor- the breadth of relevant studies, published reviews, meta-­analyses,
27
ders and may be associated with adverse effects that contribute randomised controlled trials and recent studies were prioritised to
to non-­
adherence or treatment discontinuation. Undesired ef- provide a comprehensive and up-­to-­date overview of research on
fects include weight gain, metabolic dysregulation and sedation. 28 brain stimulation in patients with bipolar disorders.
Cognitive function is critical to daily functioning and an import-
ant component of treatment response, given that many individu-
als with bipolar disorders show cognitive impairment. 29 However, 3 | E LEC T​R O C​O N V ​U L S ​I V E TH E R A PY
pharmacological treatments are primarily targeted towards the im-
provement of mood symptoms, and few treatments improve cog- Electroconvulsive therapy (ECT) was introduced in 1938. Its tech-
30
nitive dysfunction. As such, there is a need to improve existing nology and treatment delivery have since seen major improvements.
treatments and develop novel therapeutic options that are safe, Treatment protocols differ primarily in electrode placement (bitem-
effective and improve other features of bipolar disorders, includ- poral, right unilateral or bifrontal), electrical dosage (low, moderate
ing cognitive dysfunction. or high) and pulse width (brief or ultra-­brief) (Figure 1). For an over-
There is a growing interest in brain stimulation as an add-­on or view of the history of ECT, its clinical use, mechanisms of action and
alternative to existing treatments in patients with bipolar disorders. technical parameters, see McDonald et al. (2017).44
Much has been learned about the efficacy of brain stimulation treat-
ments for major depressive episodes,31–­33 mostly in patients who did
not respond to medication.34 However, it is unclear to what extent 3.1 | Efficacy
this evidence base applies to bipolar depression, and how effective
recent treatment protocols are in hypomanic, manic or mixed states. 3.1.1 | Bipolar depression
A 2016 review of brain stimulation for treatment-­resistant bipolar
disorders concluded that limited data were available to evaluate the Multiple studies suggest that ECT is an effective treatment for
efficacy and safety in this patient group, except for electroconvul- bipolar depression. A meta-­analysis of six prospective and retro-
sive therapy (ECT).35 ECT is indicated for bipolar depression, mania spective studies found remission rates of 50.9% (n = 402/790)
and mixed features in several national and international treatment in patients with major depressive disorder (MDD) and 53.2%
MUTZ | 11

PANEL 1 Overview of the brain stimulation treatments included in this review

Electroconvulsive therapy (ECT)

Electroconvulsive therapy uses an electric current applied to the head which induces a generalised seizure. The procedure is re-
peated 2–­3 times per week. The patient is sedated with general anaesthesia and given a muscle relaxant to prevent movement during
the procedure.

Transcranial magnetic stimulation (TMS)

Transcranial magnetic stimulation uses a magnetic field to depolarise superficial neurons and cause action potentials in the brain. TMS
can be targeted to a specific site in the brain and does not require the administration of an anaesthetic agent or a muscle relaxant.

Transcranial direct current stimulation (tDCS)

Transcranial direct current stimulation changes cortical tissue excitability through the application of a weak (typically 0.5–­2 mA)
direct current via scalp electrodes overlying targeted cortical areas.

Magnetic seizure therapy (MST)

Magnetic seizure therapy uses high-­frequency magnetic pulses to stimulate a specific target in the brain and to induce a seizure. The
patient is sedated with general anaesthesia and given a muscle relaxant to prevent movement.

Deep brain stimulation (DBS)

Deep brain stimulation involves the surgical implantation of electrodes into the brain. The electrodes are connected to a neurostimu-
lator that is implanted underneath the skin just above the chest. Electrical stimulation is delivered to specific brain regions.

Vagus nerve stimulation (VNS)

Vagus nerve stimulation involves the electrical stimulation of the afferent projections of the vagus nerve to the brain. During surgery,
electrodes are wrapped around the left vagus nerve and connected to a pulse generator that is implanted underneath the skin near
the upper chest.

(n = 168/316) in patients with bipolar depression, suggesting aged 65 years or older.49 In this study, patients had a reduced illness
similar effectiveness in both groups.45 Notably, most bipolar dis- severity and better cognitive function after treatment and experi-
order patients were more severely ill. Another review of 19 stud- enced no serious adverse events.
ies found that response rates were slightly higher in patients with
bipolar depression (77.1%, n = 437/567) than in patients with MDD
(74.2%, n = 1246/1680).46 Bipolar disorder patients required fewer 3.1.2 | Mania
sessions to respond to treatment (SMD = −0.23, 95% CI −0.44
to - ­0.02, p = 0.03). Consistent with the earlier meta-­analysis,45 Two important reviews have shown that ECT is an effective treat-
there was no evidence of group differences in remission rates ment for hypomanic or manic episodes. The first review summarised
(OR = 0.91, 95% CI 0.65–­1.26, p = 0.56). Randomised controlled retrospective and prospective studies conducted before 1992, con-
trials (RCTs) of ECT in bipolar depression are scarce, and there cluding that ECT was associated with clinical improvement or re-
are no sham-­controlled trials. A trial comparing ECT to algorithm-­ mission in 80% of 589 manic patients.50 A recently updated review
based pharmacotherapy in 73 patients found a higher response included data from 115 publications on the efficacy and safety of
rate in patients treated with ECT, but similar remission rates in both ECT in patients with (hypo)mania or mixed states.51 Of the seven
47
groups. Data from a retrospective study suggested that ECT had RCTs to date (n = 309), two trials compared ECT to pharmaco-
better anti-­suicidal effects than pharmacotherapy in patients with therapy, one trial compared ECT to sham ECT (both combined with
MDD or bipolar depression.48 However, there was no evidence chlorpromazine) and four trials compared different ECT protocols.
of superior anti-­suicidal effects in patients with mania or mixed Most of these trials supported the efficacy of ECT in mania. The
states.48 Research on ECT in older adults with bipolar depression only sham-­controlled RCT included 15 patients per group and found
is limited and the largest retrospective study included 34 patients a higher recovery rate and an accelerated treatment response with
12 | MUTZ

F I G U R E 1 Overview of the main ECT

electrode placements. Right unilateral
electrode placement (left), bitemporal
electrode placement (middle) and bifrontal
electrode placement (right).

ECT.52 Observational studies also suggest that ECT is an effective of 22 patients observed fewer full, but not total, hospitalisation
treatment for mania.51 However, most patients received concomi- days compared to the period prior to continuation and maintenance
tant medications, sample sizes were often limited and few studies ECT.65 The authors also summarised data from prior observational
have examined the relative efficacy of different treatment param- studies of continuation and maintenance ECT that included at least
eters. A review by Loo et al. (2011) concluded that ECT was likely some patients with bipolar disorders.65 Another review concluded
53
more effective than pharmacological treatments for mania. A re- that continuation and maintenance ECT was effective in mood dis-
cent meta-­analysis suggested that combining ECT with pharmaco- orders but insufficiently studied and likely underused.66 Of note, the
therapy was more efficacious than medications alone.54 data on bipolar disorders were limited to case studies and small ob-
servational studies that also included patients with MDD.

3.1.3 | Mixed states

3.2 | Cognition
ECT has been used to treat patients with mixed states since at least
1984, with a 70% response rate in 19 patients.55 However, its effec- Adverse cognitive effects, especially memory impairment, remain a
tiveness remains underresearched.56 No RCTs have compared ECT concern with ECT. A meta-­analysis of 84 studies that included 2981
53,57
to pharmacotherapy or sham ECT in this patient group. A 2008 patients with MDD found that most adverse cognitive effects were
review identified three studies that included 58 patients with mixed limited to the first 3 days after treatment.67 Data on the cognitive ef-
58
states who received ECT. One study that included 41 patients with fects of ECT in patients with bipolar disorders are limited. Findings
mixed states and 23 patients with bipolar depression observed im- from a RCT suggested no differences in cognitive function between pa-
provements in both groups, with a slightly greater improvement in tients with bipolar depression who received right unilateral brief-­pulse
mixed states.59 Another study observed similar effectiveness in bi- ECT or pharmacotherapy after 6 months,68 although autobiographical
60
polar depression (n = 38), mania (n = 5) and mixed states (n = 10). memory was worse in the ECT group after the acute treatment.69 In
Notably, the 10 patients with mixed states required more treatment patients with mania, preliminary evidence suggests that cognitive out-
sessions and a longer hospital stay, suggesting that mixed states are comes are better after bifrontal ECT than after bitemporal ECT.51
60
more difficult to treat. A case series of seven patients with mixed
states suggested that all patients remitted.61 Another review of seven
observational studies concluded that there was preliminary evidence 3.3 | Tolerability
57
for the effectiveness of ECT in patients with mixed states. The
largest study to date included 197 patients with pharmacotherapy-­ Besides cognitive effects, the most common adverse effects in-
resistant mixed states, 82 (41.6%) of whom responded and 60 (30.5%) clude confusion, headaches, nausea and muscle pain.70 Treatment-­
62
of whom remitted after on average 7.48 treatment sessions. emergent affective switches occur in 6%–­
38.6% of patients and
may be more common for bitemporal ECT than right unilateral ECT;
lithium treatment may lower their risk of occurrence.51 However,
3.1.4 | Maintenance a systematic review of these data is lacking. For an overview of
potential interactions between ECT and pharmacological treatments,
Maintaining symptom remission is a clinical challenge. No RCTs have see Loo et al. (2011).53 Preliminary evidence suggests that patients with
examined continuation or maintenance ECT to prevent relapse or bipolar depression had a decreased risk of adverse events with ECT,
recurrence in bipolar disorders. Data from observational studies are relative to patients with MDD.71 Across clinical indications, ECT-­related
63,64
limited but provide encouraging results. A retrospective study mortality was estimated at 2.1 per 100,000 treatment sessions.72
MUTZ | 13

3.4 | Conclusion 4.1 | Efficacy

ECT has received less attention as a treatment for bipolar disorders 4.1.1 | Bipolar depression
than for MDD, for which it is recommended by the National Institute
of Clinical Excellence in the UK.73 Few RCTs have been conducted in The first two studies that examined rTMS in mixed samples of pa-
bipolar depression or mania, and none in patients with mixed states tients with bipolar depression or MDD provided preliminary evi-
or for continuation and maintenance treatment. Results from most dence of the efficacy of high-­frequency rTMS of the left DLPFC75
RCTs and observational studies have been encouraging. An advan- and low-­frequency rTMS of the right DLPFC.76 A meta-­analysis of
74
tage of ECT is that it may be effective across bipolar disorder states. data from 19 RCTs included 181 patients with bipolar depression.77
Further studies of protocols that aim to reduce adverse cognitive ef- Combining data from various TMS protocols, the response rate of
fects (e.g., ultra-­brief pulse), studies in patients with mixed states 44.3% (n = 47/106) was higher than the 25.3% (n = 19/75) response
and studies of continuation and maintenance ECT are needed.53 rate in the sham control. The most recent meta-­analysis included
274 patients with bipolar depression, 145 of whom received active
treatment.78 Although rTMS was associated with higher response
4 | TR A N S C R A N I A L M AG N E TI C rates than sham treatment (OR = 2.72, 95% CI 1.44–­5.14), subgroup
S TI M U L ATI O N analyses suggested that only high-­frequency rTMS of the left DLPFC
was associated with increased response rates. The relative efficacy
Transcranial magnetic stimulation (TMS) alters neural activity in of different protocols requires further study. A study of 30 patients
relatively focal brain regions. Repetitive transcranial magnetic with bipolar depression observed a higher response rate and similar
stimulation (rTMS) involves delivering repeated pulses for pro- remission rates in patients treated with bilateral rTMS compared to
longed neuromodulation. Treatment varies in pulse frequency unilateral stimulation.79 Notably, neither of the meta-­analyses ex-
(low or high) and intensity relative to the motor threshold, and can amined data on treatment remission, changes in symptom severity
be targeted unilaterally or bilaterally. High-­f requency rTMS of the scores or global clinical impression.
left dorsolateral prefrontal cortex (DLPFC) is the most common Few sham-­controlled RCTs have been conducted exclusively in
protocol (Figure 2). More recent approaches include accelerated patients with bipolar depression. One trial found that rTMS was ef-
rTMS, priming TMS, deep TMS (dTMS), synchronised TMS and ficacious after 2 weeks of treatment, but not after 4 weeks.80 A fea-
32
theta burst stimulation. sibility study of 23 patients, two of whom were in a mixed state, did

F I G U R E 2 Standard repetitive transcranial magnetic stimulation (rTMS) protocols involve identical stimuli spaced by an identical inter-­
stimulus interval. Effects depend on stimulation frequency: low-­frequency rTMS (LF rTMS ≤1 Hz) depresses cortical excitability, whereas
high-­frequency rTMS (HF rTMS >5 Hz) increases cortical excitability. Theta burst stimulation (TBS) involves bursts of high-­frequency
stimulation (3 pulses at 50 Hz) repeated with an inter-­stimulus interval of 200 ms (5 Hz). In an intermittent TBS (iTBS) protocol, bursts are
delivered for 2 s, then repeated every 10 s (2 s of TBS followed by a pause of 8 s). In a continuous TBS protocol (cTBS), bursts are repeated
for 40 s without any pause. Adapted from Klomjai et al. (2015).163 [Correction added on January 13, 2023, after first online publication:
Figure 2 has been updated to correct the order of the labels "High-frequency" and "Low-frequency"].
14 | MUTZ

not find that high-­frequency rTMS of the left DLPFC was more ef- with high-­frequency rTMS of the left DLPFC during a mixed state.98
ficacious than sham.81 Similarly, a trial of 49 patients that examined However, a recent RCT in bipolar disorder and MDD patients with
sequential bilateral rTMS did not find evidence of efficacy relative to mixed states did not find that bilateral TBS had superior efficacy
sham.82 The first sham-­controlled RCT of dTMS included 50 patients compared to sham.99
and found that active treatment was superior to sham after 4 weeks
of treatment, but not at the 8-­week follow-­up.83 Data from open-­
label studies of dTMS suggested a significant decrease in Hamilton 4.1.4 | Maintenance
Depression Rating Scale (HDRS) scores in 19 patients,84 and an 80%
(n = 15/20) response rate in patients treated with bilateral dTMS.85 A small open-­label study of weekly maintenance rTMS found that
Theta burst stimulation has a great clinical appeal due to its re- three patients successfully completed 1 year of follow-­up whilst four
duced delivery time (<5 min compared to 37.5 min for rTMS). A study patients had multiple relapses, suggesting that maintenance rTMS
of twice daily intermittent theta burst stimulation (iTBS) did not sup- was only effective in some patients.100 Preliminary evidence also
86
port its efficacy compared to sham. Similarly, a study of 12 patients suggests that maintenance dTMS benefitted some patients with
with bipolar depression did not find evidence that iTBS was more bipolar disorders.101
87
efficacious than sham. A recent RCT of iTBS also did not find ev-
idence of efficacy over a 4-­week treatment period.88 In this study,
18 patients were randomised to iTBS and 19 to sham control. There 4.2 | Cognition
were three responders and remitters in each treatment group after
the initial course of treatment, and five (of 21 initial non-­responders) A review of RCTs found no evidence of differences in cognition be-
during an additional 4 weeks of open-­label treatment. Due to the low tween TMS and sham in bipolar depression (two studies) and pre-
response rates, the study was terminated early. Although a TMS de- liminary evidence that cognitive function improved with TMS during
vice was granted ‘breakthrough designation’ for bipolar depression by euthymic periods (one study).102 The first study to evaluate the cog-
89
the FDA, additional studies are needed to investigate its efficacy in nitive effects of dTMS in bipolar disorders included the per-­protocol
bipolar depression.90 subset of the Tavares et al. (2017) RCT.83 In this study, 20 patients
received dTMS and 23 patients received sham treatment.103 All cog-
nitive outcomes improved regardless of the treatment group, sug-
4.1.2 | Mania gesting that dTMS was neither associated with adverse nor beneficial
cognitive effects. A pilot RCT comparing rTMS (n = 16) to sham treat-
Multiple reviews explored the efficacy of TMS across bipolar disor- ment plus stable pharmacotherapy (n = 20) during a non-­acute state
der states, concluding that TMS was a promising but understudied found significant improvement in verbal learning in the rTMS group,
treatment.91–­93 Five studies examined the efficacy of rTMS in pa- but no group differences in other cognitive measures.30 The largest
tients with mania. These studies enrolled 93 patients and provided RCT of rTMS in euthymic patients (n = 52) found improved cognitive
somewhat inconsistent results, highlighting the need for further function across multiple measures relative to sham treatment.104
research. Most rTMS studies in mania targeted the right DLPFC,
following the protocol first used by Grisaru et al. (1998) who found
that the improvement in manic symptoms was greater following 4.3 | Tolerability
stimulation of the right than of the left DLPFC.94 However, the
first sham-­controlled trial in mania found no evidence of efficacy.95 The most common adverse effects are headaches, fatigue, scalp
Indeed, only one sham-­controlled RCT of rTMS provided evidence discomfort and pain at the stimulation site.93 The risk of TMS-­
96
of efficacy in mania. Notably, this was also the largest sham-­ induced seizures is very low, occurring in less than 1 per 60,000
controlled RCT. sessions in patients treated within guidelines and without known
risk factors.105 To date, no seizures have been reported in patients
with bipolar disorders. A meta-­analysis found the rate of treatment-­
4.1.3 | Mixed states emergent affective switches following rTMS to be low (0.9%), com-
parable to sham treatment (1.3%).77 Recent reviews identified four
An open-­
label study of low-­
frequency stimulation of the right cases of (hypo)manic switches.91,93 There have also been reports of
DLPFC included 40 patients with mixed states who received 3 weeks treatment-­emergent affective switches for iTBS. 88,99,106
of augmentation treatment, after being treated with a mood sta-
biliser for 4 weeks.97 This study found that rTMS improved both
depressive and manic symptoms. The HDRS suggested a 46.6% re- 4.4 | Conclusion
sponse rate and the Young Mania Rating Scale had a 15% response
rate, and several patients also remitted.97 A case report suggested There is a growing evidence base for TMS to treat bipolar depression.
that a patient who did not respond to ECT was successfully treated Further identification of target brain circuits and nodes is needed to
MUTZ | 15

develop these treatments in patients with bipolar disorders. 89 Few and bipolar depression did not find evidence of an improvement in
studies support the efficacy of TMS in hypomania, mania or mixed depression severity after tDCS compared to sham treatment in ei-
states. Most TMS studies in bipolar disorders examined rTMS as an ther patient group.118 This discrepancy could be explained by the
add-­on to pharmacotherapy, and few studies examined more recent sham control that was used in the latter trial, which involved the ap-
protocols. More research is needed to identify optimal treatment plication of a low level of electrical stimulation that could have had
parameters and patient characteristics for treatment stratification. a biological effect.
Finally, predictors of treatment-­emergent affective switching remain
to be explored as these were not limited to patients treated with
antidepressant medication. 5.1.2 | Mania

Data on tDCS in mania are scarce. A case report found that tDCS
5 | TR A N S C R A N I A L D I R EC T CU R R E NT as an add-­on to pharmacotherapy may improve manic symptoms.119
S TI M U L ATI O N Preliminary evidence also suggested changes in manic symptoms in pa-
tients with bipolar depression.117,120 However, more research is needed
Transcranial direct current stimulation (tDCS) involves delivering a to assess the potential efficacy of tDCS in (hypo)manic patients.
low-­amplitude electrical current through scalp electrodes to modu-
late cortical excitability of superficial brain regions. Anodal stimula-
tion causes depolarisation and increases neural excitability, whereas 5.1.3 | Mixed states
cathodal stimulation causes hyperpolarisation and decreases corti-
cal excitability. For an overview of transcranial electrical stimulation No research has yet examined the efficacy of tDCS in bipolar disor-
and its clinical applications, see Cho et al. (2022).107 der mixed states.

5.1 | Efficacy 5.1.4 | Maintenance

5.1.1 | Bipolar depression Data on continuation or maintenance tDCS are scarce. A recent
meta-­analysis of patients with depressive episodes, some of whom
Certain treatment guidelines support the use of tDCS in patients with had bipolar depression, concluded that maintenance tDCS may fur-
MDD.108,109 The first tDCS study that included patients with MDD ther improve treatment response.121 However, further studies are
and bipolar depression observed a decrease in depressive symptoms needed to evaluate the effectiveness of continuation or mainte-
after five treatment days in both groups.110 The first meta-­analysis nance tDCS in bipolar disorders.
of tDCS in bipolar depression found that tDCS moderately improved
depressive symptoms (SMD = 0.71, 95% CI 0.25–­1.18).111 However,
this analysis included only 46 patients and tDCS was delivered as 5.1.5 | Euthymia
an add-­on to mood stabilisers. Preliminary evidence in patients with
bipolar disorder type I suggested that tDCS combined with pharma- At least four studies have examined the effects of tDCS on cogni-
cotherapy was associated with a greater depressive symptom reduc- tion in bipolar disorder patients during euthymic periods.122–­125 A
tion than pharmacological monotherapy.112 A recent open-­label trial study of 15 patients did not observe changes in working memory
that included 58 patients with MDD and 22 patients with bipolar or sustained attention performance after a single tDCS session.122
depression found that tDCS was associated with similar response Although findings from observational studies have been mixed,124,125
113
rates in both groups. This finding is consistent with an individual a RCT found that 3 weeks of prefronto-­cerebellar tDCS (n = 21) led
patient data meta-­analysis that included 109 (19.1%) patients with to an improvement in executive function and visuospatial memory
bipolar disorders and found no evidence that bipolar disorder status relative to sham treatment (n = 21).123 Preliminary evidence from 25
predicted treatment response relative to MDD (OR = 2.28, 95% CI euthymic patients also suggested that tDCS improved neurological
0.72–­7.22).114 However, a previous individual patient data meta-­ function and sleep quality.126 These findings are clinically interest-
analysis found that bipolar depression predicted increased tDCS ing because many patients with bipolar disorder experience sleep
response.115 A review that examined tDCS as a treatment across disturbance after mood symptom remission.127
bipolar disorder states (Figure 3) included 10 studies (n = 76) that
found tDCS to be moderately effective in treating depressive symp-
toms.116 The only sham-­controlled RCT exclusively in patients with 5.2 | Cognition
bipolar depression suggested that tDCS was more efficacious in re-
ducing depressive symptoms than sham treatment.117 However, one An open-­
label study found similar improvements in processing
of the largest tDCS trials to date that included patients with MDD speed, selective attention and executive function in patients with
16 | MUTZ

F I G U R E 3 Transcranial direct current stimulation (tDCS) electrode placements used in patients with bipolar disorders: (1) depressive
symptoms during depressive episodes, (2) manic symptoms during manic episodes, (3) symptoms during euthymia, (4) neurocognitive
functions during depressive episodes or euthymia, (5) sleep and neurological soft signs during euthymia. Blue: anode; red: cathode. Cb,
cerebellum; EC, extra-­cephalic (right upper arm); F3, left dorsolateral prefrontal cortex; F4, right dorsolateral prefrontal cortex; F8, right
lateral orbit cortex; Fp1, left superior orbital cortex; Fp2, right superior orbital cortex; Electrode placements from Dondé et al. (2018).116

bipolar disorders and MDD after ten sessions of tDCS over five no reports of major adverse events.133 The most common unde-
days.113 However, a sham-­controlled RCT (n = 59) did not provide evi- sired effects of tDCS are mild and transient and include tingling
dence of post-­treatment group differences in five cognitive domains, at the skin underneath the electrodes, dizziness and sleepiness.
suggesting that tDCS neither induced adverse cognitive effects nor However, no quantitative summary of adverse effects is avail-
improved cognitive function.128 Consistent with these findings, data able,116 likely due to insufficient reporting in most studies.131 Six
from a meta-­
analysis of patients with major depressive episodes cases of treatment-­e mergent affective switches (out of 113 pa-
found no evidence of cognitive effects that were independent of tients) were described in the Dondé et al. (2018) review116 and
129
changes in depressive symptoms. However, the authors noted the one patient included in a recent open-­label study also experienced
limited data on patients with bipolar disorder. Finally, data from a large a new hypomanic episode.113 To my knowledge, there have been
RCT suggested that tDCS improved some cognitive functions in pa- no reports of rapid cycling or increased risk of suicide associated
tients with bipolar depression.130 with tDCS.111

5.3 | Tolerability 5.4 | Conclusion

tDCS is generally well tolerated131 and associated with few ad- Most tDCS studies in patients with bipolar disorders were limited
verse events.132 In patients with bipolar disorder, there have been by their open-­label study design and/or small sample size. Only one
MUTZ | 17

sham-­controlled trial examined tDCS exclusively in bipolar disorder or remission during a six-­month continuation treatment phase.141 To
patients. Although some of the initial results have been encourag- date, there are no published data on the efficacy of MST to treat
ing, more research on tDCS in patients with bipolar depression is other bipolar disorder states.
needed. There are almost no data on patients with hypomanic or
manic episodes or mixed states, highlighting the urgent need for
studies in these groups. Continuation and maintenance tDCS also 6.1.2 | Cognition
remain understudied. Alternative protocols, including the use of
multiple electrodes (HD-­
tDCS), transcranial alternating current Although data on the cognitive effects of MST are scarce,142 a previ-
stimulation (tACS) or transcranial random noise stimulation (tRNS), ous review did not suggest adverse cognitive effects.136 The only
should be explored in bipolar disorders. A key advantage of tDCS study of MST exclusively in patients with bipolar depression ob-
and related protocols is the greater portability, which could enable served minimal cognitive effects of MST across 24 tests.139
home-­based treatment delivery. Finally, treatment protocols could
be stratified by patient characteristics or adjusted at the individual
level using machine learning algorithms aimed at optimising treat- 6.1.3 | Tolerability
ment parameters.134
Preliminary evidence suggests that patients with bipolar depres-
sion or MDD who received MST reported fewer adverse effects,
6 | OTH E R TR E ATM E NT PROTO CO L S including less confusion and faster reorientation time, compared
to ECT (2–­8 min and 18–­26 min, respectively).136 Although cases
Brain stimulation treatments that have been studied in fewer pa- of treatment-­emergent mania have been reported in patients with
tients include magnetic seizure therapy, deep brain stimulation and MDD,143 there has been only one report of a patient with bipolar de-
vagus nerve stimulation. pression who received MST and experienced a hypomanic episode
several days after the study completion.139

6.1 | Magnetic seizure therapy

6.2 | Deep brain stimulation
Magnetic seizure therapy (MST) involves the induction of a seizure
using magnetic stimulation delivered at a high frequency (typically Deep brain stimulation (DBS) involves the surgical implantation of
100 Hz) under general anaesthesia. The magnetic stimulation avoids electrodes into the brain which are connected to a neurostimula-
impedance of the scalp and skull, does not directly target the tempo- tor that is implanted near the chest. Electrical stimulation is con-
ral lobe regions and causes a shorter seizure than ECT. As such, MST tinuously delivered and can be titrated. DBS is primarily used in
was hypothesised to minimise adverse cognitive effects relative to treatment-­resistant Parkinson's disease and movement disorders but
ECT whilst maintaining its effectiveness.135 has also been studied in treatment-­resistant obsessive-­compulsive
disorder144 and treatment-­resistant MDD.145

6.1.1 | Efficacy
6.2.1 | Efficacy
The evidence base for MST in bipolar disorders is very limited. A
2015 review identified only five patients with bipolar disorders who Few studies have examined DBS in patients with bipolar disorders.146
136
had received MST. Two studies provided preliminary evidence The largest sample to date included seven patients with bipolar dis-
that MST might alleviate depressive symptoms. Kayser et al. (2011) order type II who had a similar decrease in depressive symptoms
observed similar levels of efficacy in patients treated with MST or as ten patients with MDD.147 Another case report suggested that a
137
low-­dose right unilateral ECT. Kayser et al. (2013) observed faster patient with treatment-­resistant bipolar depression was successfully
recovery and reorientation times after MST compared to ECT.138 treated with DBS over the course of nine months.148 To date, there
The first open-­label trial exclusively in bipolar depression included are no published data on the efficacy of DBS to treat other bipolar
treatment-­resistant patients who received up to 24 treatment ses- disorder states.
sions. The authors observed a reduction in mean HDRS scores from
28.08 (SD = 4.41) at baseline to 17.77 (SD = 8.48) at follow-­up, a
38.5% response rate and a 23.1% remission rate in 26 patients who 6.2.2 | Cognition
139
received at least eight treatments. In a separate report, the au-
thors showed that MST was associated with reduced suicidal idea- No studies have examined the cognitive effects of DBS in patients
tion.140 57.1% (n = 4/7) of the initial responders maintaining response with bipolar disorders.
18 | MUTZ

6.2.3 | Tolerability that VNS was associated with improvements across several meas-
ures of cognitive function.159
The most common adverse effects in patients with MDD in-
cluded pain around the incision, wound infection, headaches
and agitation.149 Due to the paucity of data on patients with bi- 6.3.3 | Tolerability
polar disorders, there are no published systematic investigations
of adverse effects. There have been some reports of treatment-­ No systematic studies have examined VNS-­related adverse events
emergent (hypo)manic symptoms in patients with Parkinson's in bipolar disorders. An individual-­level meta-­analysis of more than
c ompulsive disorder.150–­1 52 A re-
disease, MDD or obsessive-­ 1000 patients with depression suggested that VNS was gener-
146
view of DBS in bipolar disorders identified one patient who ally well tolerated.160 The most frequent adverse effects included
experienced two episodes of hypomania during treatment that cough, incision site pain, headaches and changes in the patient's
were resolved with adjustment of treatment parameters.153 No voice. Treatment-­emergent (hypo)manic symptoms appear to be in-
treatment-­e mergent affective switches were observed in the frequent according to data from 20 bipolar depressed patients who
largest study to date.147 participated in a study of depression in which manic symptoms were
examined over a year.161 Another report also concluded that manic
episodes during VNS were rare.162
6.3 | Vagus nerve stimulation

Vagus nerve stimulation (VNS) involves the electrical stimulation of 6.4 | Conclusion
the afferent projections of the vagus nerve to the brain. During sur-
gery, electrodes are wrapped around the left vagus nerve and con- Few studies have examined MST, DBS and VNS in bipolar disor-
nected to a pulse generator that is implanted near the upper chest. ders, highlighting the need for further research in this population.
The stimulation is less focal than DBS but can also be titrated. VNS An advantage of DBS and VNS is optimal treatment adherence.
was first developed for treatment-­resistant epilepsy but has since Although the slow treatment effect onset associated with VNS
been approved for treatment-­resistant MDD. may be undesirable in some patients, the effect of DBS occurs
instantly. These protocols can be used in conjunction with most
other treatments, including medication and ECT. However, due to
6.3.1 | Efficacy their invasive nature, DBS and VNS remain limited to the most
difficult-­to-­t reat patients.
A 5-­year follow-­up study of almost 500 patients with treatment-­
resistant MDD supported the efficacy of VNS to treat depressive
symptoms.154 A retrospective analysis of 25 patients with bipolar 7 | CO N C LU S I O N
depression found similar outcomes as in patients with MDD over
the course of 2 years.155 A case series of patients with bipolar dis- There is a growing interest and a rapidly expanding evidence base
order156 and a 1-­year prospective study of nine patients with rapid for brain stimulation as an add-­on or alternative to pharmacologi-
cycling bipolar disorder also provided encouraging results.157 The cal and psychological treatments for bipolar disorders. For most
largest study to date showed that over the course of 5 years, 63% treatment protocols, few studies were conducted exclusively in
(n = 61/97) of patients with bipolar depression who received VNS patients with bipolar disorders. However, results from many of
in addition to usual care responded to treatment, compared to 39% these studies and from studies that included patients with bipolar
(n = 23/59) of patients who received usual care. These patients also disorders and MDD have been encouraging. Brain stimulation rep-
had a faster treatment response (median time to initial response: resents an opportunity to treat all bipolar disorder states, which
13.7 months compared to 42.1 months, respectively), a longer usually require multiple pharmacological treatments. Treatment
period until relapse (15.2 months compared to 7.6 months) and a protocols such as deep brain stimulation or vagus nerve stimula-
greater reduction in suicidality.158 As such, VNS could be effective tion could overcome some of the challenges associated with the
in maintaining symptom remission. clinically complex presentation of bipolar disorders in difficult-­to-­
treat patients. Novel brain stimulation protocols could address the
lack of treatment options for cognitive dysfunction. Nevertheless,
6.3.2 | Cognition larger randomised controlled trials with long-­term follow-­up are
needed to clarify important questions regarding treatment ef-
There are no published data on the cognitive effects of VNS in bipo- ficacy, tolerability, frequency of treatment-­
emergent affective
lar disorders. However, a study of 14 patients with MDD suggested switches and cognitive effects (Panel 2).
MUTZ | 19

PANEL 2 Key challenges for the field and directions for future research

Refine treatment parameters

Optimal treatment parameters, including electrode placement and stimulation target, may vary across bipolar disorder states, as well
as within and between patients. Treatment configurations that target state-­specific brain alterations should be further investigated.

Stratify by diagnostic subtypes

There are limited data on how patient characteristics relate to treatment efficacy and tolerability. An important step towards strati-
fied, and eventually personalised, treatment delivery is to examine brain stimulation within and between bipolar disorder subtypes.

Study continuation and maintenance treatment

Treatment is often stopped after successful mood symptom remission, despite preliminary evidence suggesting that further treat-
ment might benefit some patients with bipolar disorders. The evidence base for continuation and maintenance treatment needs to
be expanded.

Research portable and accelerated treatment protocols

The considerable time involved in treatment attendance and delivery remains an obstacle to the more widespread use of most brain
stimulation protocols. Further research into portable devices for home use and accelerated treatment protocols is needed.

Standardise reporting of adverse events

It is unclear whether studies that do not report adverse effects did not collect these data or observed no adverse effects. Standardised
reporting of adverse effects, including treatment-­emergent affective switches and cognitive effects, would be useful for evidence
synthesis.

Investigate experimental therapeutic protocols

Cranial electrotherapy stimulation, focal electrically administered seizure therapy, low amplitude seizure therapy, transcutaneous vagus
nerve stimulation, transcranial focused ultrasound stimulation and quadripulse stimulation lack data on patients with bipolar disorders.

AU T H O R C O N T R I B U T I O N ORCID
Julian Mutz conceived and wrote this review. Julian Mutz https://orcid.org/0000-0001-5308-1957

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