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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5250_Библиотеки_им_академика_М_И_Перельмана.pdf
3 TMS and tDCS for Major Depressive Disorder
89. Jog MS, Kim E, Anderson C, Kubicki A, Kayathi R, Jann K, Yan L, Leaver A, Hellemann
G, Iacoboni M.In-vivo imaging of targeting and modulation of depression-relevant circuitry
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2021;11(1):138.
90. Zhou D, Li X, Wei S, Yu C, Wang D, Li Y, Li J, Liu J, Li S, Zhuang W, Li Y, Luo R, Liu Z,
Liu J, Xu Y, Fan J, Zhu G, Xu W, Tang Y, Cho RY, Kosten TR, Zhang XY.Transcranial direct
current stimulation combined with repetitive transcranial magnetic stimulation for depression:
a randomized clinical trial. JAMA Netw Open. 2024;7(11):e2444306.
91. Li X, Liu J, Wei S, Yu C, Wang D, Li Y, Li J, Zhuang W, Luo RC, Li Y, Liu Z, Su Y, Liu J,
Xu Y, Fan J, Zhu G, Xu W, Tang Y, Yan H, Cho RY, Kosten TR, Zhou D, Zhang X.Cognitive
enhancing effect of rTMS combined with tDCS in patients with major depressive disorder: a
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69
Bipolar Disorder
XinhuYang, XingbingHuang, ZhenjuanQin, YupingNing,
andWeiZheng
Abstract
Bipolar disorder constitutes a substantial source of personal distress and economic burden, as evidenced by the Global Burden of Disease Study. Conventional
therapeutic strategies, including pharmacotherapy and psychotherapy, are
endorsed by clinical guidelines and expert consensus. However, a signicant
proportion of individuals with bipolar disorder exhibit inadequate treatment
responses or develop treatment resistance, necessitating alternative or adjunctive
interventions. Over the past two decades, various neuromodulatory techniques,
such as transcranial magnetic stimulation (TMS) and transcranial direct current
stimulation (tDCS), have been investigated to address the complexities of bipolar
disorder, leading to increased interest in their therapeutic applications. This
chapter provides an overview of advanced TMS and tDCS paradigms in the context of bipolar disorder.
4
Keywords
Bipolar disorder · Transcranial magnetic stimulation · Transcranial direct current
stimulation · Efcacy · Safety
Xinhu Yang and Xingbing Huang have equally contributed to this chapter.
X. Yang · X. Huang · Y. Ning (*) · W. Zheng (*)
The Afliated Brain Hospital, Guangzhou Medical University, Guangzhou, China
Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the
Ministry of Education of China, Guangzhou Medical University, Guangzhou, China
Z. Qin
The Brain Hospital of Guangxi Zhuang Autonomous Region, Liuzhou, China
© The Author(s), under exclusive license to Springer Nature Singapore Pte
Ltd. 2025
W. Zheng, Y. Ning (eds.), TMS and tDCS for Psychiatric Disorders,
https://doi.org/10.1007/978-981-96-8504-2_4
71
72
X. Yang et al.
Abbreviations
BDI-II the Beck Depression Inventory-II
CANMAT the Canadian Network for Mood and Anxiety Treatments
CANTAB the Cambridge Neuropsychological Test Automated Battery
cTBS continuous theta burst stimulation
DLPFC dorsolateral prefrontal cortex
DSM-V Statistical Manual of Mental Disorders, Fifth Edition
dTMS deep transcranial magnetic stimulation
ECT electroconvulsive therapy
EEG electroencephalogram
FDA The Food and Drug Administration
fMRI functional magnetic resonance imaging
GDNF glial cell-derived neurotrophic factor
HDRS Hamilton Depression Rating Scale
HD-tDCS high-denition tDCS
HF high frequency
ISBD the International Society for Bipolar Disorders
iTBS intermittent theta burst stimulation
LF low frequency
MADRS Montgomery-Åsberg Depression Rating Scale
MDAUD major depressive disorder with comorbid alcohol use disorder
MDD major depressive disorder
MDE major depressive episodes
MRI magnetic resonance imaging
MST magnetic seizure therapy
MT the motor threshold
mPFC-dACC the medial prefrontal cortex–dorsal anterior cingulate cortex
NIBS noninvasive brain stimulation
OR odds ratio
RCT randomized controlled trial
RMT the resting motor threshold
rTMS repetitive transcranial magnetic stimulation
SAINT The Stanford Accelerated Intelligent Neuromodulation Therapy
sgACC subgenual anterior cingulate cortex
SMD standardized mean difference
TBS theta burst stimulation
tDCS transcranial direct current stimulation
TMS transcranial magnetic stimulation
TRD treatment-resistant depression
4 Bipolar Disorder
73
4.1 Introduction
Bipolar disorder represents a complex group of chronic psychiatric conditions, with
bipolar I disorder characterized by manic episodes and bipolar II disorder dened
by hypomanic episodes accompanied by major depressive episodes (MDE), as
specied in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
(DSM-V) [1]. These conditions are further delineated by distinct mood episodes,
including manic, depressive, and mixed states [2]. According to the Global Burden
of Disease Study [3], bipolar disorder affects approximately 39.5 million individuals worldwide, with prevalence rates varying signicantly across regions and demographic groups. The disorder results in profound alterations in mood, cognition, and
behavior, often severely impairing social functioning and overall quality of life. For
instance, individuals with bipolar depression frequently experience pervasive sadness, loss of interest in activities, and disruptions in sleep and appetite, which
adversely impact their personal well-being and ability to participate in occupational
and social activities. Moreover, bipolar disorder signicantly increases the risk of
suicidal behavior, posing a critical public health challenge [4].
The management of bipolar disorder involves diverse therapeutic strategies
aimed at mitigating symptoms across manic and depressive episodes. Evidencebased consensus statements and treatment guidelines recommend the use of mood
stabilizers, such as lithium and valproate, often in combination with atypical antipsychotics, as rst-line pharmacological interventions [1]. Psychosocial interventions, such as cognitive-behavioral therapy, play an essential adjunctive role, with
studies demonstrating their capacity to enhance health outcomes for patients with
bipolar disorder [5]. Despite these interventions, 60.5–75.7% of patients fail to
achieve satisfactory outcomes [6], underscoring the urgent need for innovative treatments, including noninvasive brain stimulation techniques to address these therapeutic gaps.
Among emerging approaches, noninvasive brain stimulation techniques such as
transcranial magnetic stimulation (TMS) and transcranial direct current stimulation
(tDCS) have garnered increasing attention for their potential in bipolar disorder
treatment. A recent meta-analysis highlights growing evidence supporting the efcacy of TMS in bipolar depression [7], although its benets for hypomania, mania,
and mixed states remain limited [8]. Similarly, a meta-analysis of tDCS suggests
moderate improvement in depressive symptoms (standardized mean difference
(SMD)=0.71) in bipolar depression [9]. However, these ndings remain preliminary, necessitating further research to rene these techniques and develop more
effective treatments. This chapter systematically explores the efcacy and safety of
advanced repetitive TMS (rTMS) paradigms and tDCS protocols for bipolar disorder. A comprehensive search of English-language databases, including PubMed,
Cochrane Library, EMBASE, and PsycINFO, was conducted from inception to
November 24, 2024. The analysis encompasses various rTMS modalities—unilateral rTMS, bilateral rTMS, accelerated rTMS, deep TMS, priming TMS, synchronized TMS, theta burst stimulation (TBS) such as intermittent TBS (iTBS),
accelerated iTBS, continuous TBS, and bilateral TBS—and magnetic seizure
74
therapy (MST), as well as tDCS paradigms, including conventional tDCS and highdenition tDCS (HD-tDCS). This chapter provides an in-depth review of these technologies, assessing their therapeutic efcacy, safety, treatment regimens, and
clinical applications, alongside recommendations for optimizing their use in managing this multifaceted disorder.
X. Yang et al.
4.2 TMS
4.2.1 rTMS
4.2.1.1 Unilateral rTMS
Efficacy
Unilateral rTMS is a noninvasive brain stimulation modality designed to selectively target a single cerebral hemisphere, widely utilized in clinical settings. This
technique employs electromagnetic induction to generate localized electrical currents within the cerebral cortex, thereby modulating neuronal membrane potentials
and altering electrical activity and metabolic functions in targeted brain regions
[10]. The United States Food and Drug Administration (FDA) has approved TMS
as a therapeutic option for treatment-resistant depression (TRD), providing an
alternative for patients unresponsive to conventional pharmacological interventions [11]. Meta-analyses have consistently validated the efcacy of unilateral
rTMS in managing bipolar disorder [12–14]. For instance, a systematic review and
meta-analysis of randomized controlled trials (RCTs) [14] demonstrated that highfrequency (HF) rTMS over the left dorsolateral prefrontal cortex (DLPFC) signicantly improved response rates compared to sham stimulation (50.70% vs. 28.07%,
P=0.02) in patients with bipolar depression. Similarly, low-frequency (LF) rTMS
over the right DLPFC showed a higher, albeit statistically marginal, response rate
(92.11% vs. 69.44%, P=0.06). However, due to insufcient data, the remission
rate for bipolar mania remains indeterminate [13]. Furthermore, unilateral rTMS
has been associated with reductions in the frequency and duration of depressive
episodes, alongside improved mood stability in individuals with bipolar disorder
[14]. These ndings highlight the variability in treatment outcomes, necessitating
individualized stimulation parameters and site selection to optimize therapeutic
efcacy.
Safety
Unilateral rTMS is generally regarded as a safe intervention for bipolar disorder
[15], especially when compared to other neuromodulation techniques such as electroconvulsive therapy (ECT), which is associated with a higher incidence of adverse
effects. Commonly reported side effects of unilateral rTMS include headache, scalp
discomfort, and mild muscle twitching [16]. A meta-analysis revealed that transient
headaches were reported by 15.4–28.6% of patients undergoing this treatment [13].
Although rare, serious complications such as seizures and intracranial bleeding
4 Bipolar Disorder
75
have been documented, emphasizing the importance of comprehensive patient
assessments prior to initiation [17]. Given the potential variability in patient
response and safety concerns, careful evaluation and monitoring remain critical for
ensuring the safe and effective application of unilateral rTMS in bipolar disorder
management.
Treatment Regimen
In clinical practice, the application of unilateral rTMS for bipolar I and II disorders
primarily focuses on managing bipolar depression, with two predominant perspectives regarding therapeutic parameters. The rst supports HF rTMS applied to the
DLPFC as an effective strategy for reducing depressive symptoms in both bipolar I
and II disorders. A systematic review has demonstrated the efcacy of HF rTMS in
alleviating the severity of bipolar depression [14]. The second perspective, although
supported by more limited evidence, advocates for LF rTMS, such as 1Hz, targeting the right DLPFC for bipolar depression [14].
A critical consideration in the treatment of bipolar disorder is the potential risk
of inducing mania. Existing studies suggest that rTMS does not signicantly
increase the risk of mania when compared to sham treatments [18]. However, further investigation into optimal rTMS parameters specic to bipolar disorder is necessary to enhance both safety and efcacy.
Clinical Recommendations
The Canadian Network for Mood and Anxiety Treatments (CANMAT) and the
International Society for Bipolar Disorders (ISBD) Guidelines [5] offer comprehensive recommendations for managing bipolar disorder, categorizing therapeutic
approaches into rst-line, second-line, and third-line options, alongside those that
are not recommended. Within this framework, rTMS is designated as a third-line
treatment for both acute bipolar I depression and acute mania (Table4.1). The denitions of evidence levels and treatment line ratings, as outlined by the CANMAT
and ISBD Guidelines, are provided in Table4.2 [5]. In contrast, the Chinese guidelines for the prevention and treatment of bipolar disorder do not include recommendations for the use of rTMS [19].
4.2.1.2 Bilateral rTMS
Efficacy
Bilateral rTMS has emerged as a promising therapeutic approach for bipolar disorder, although its efcacy remains mixed. Most research focuses on the depressive
phase, with a network meta-analysis showing that bilateral rTMS had greater efcacy than sham therapy for acute treatment of major depressive disorder (MDD) or
bipolar depression (summary odds ratio (OR)=4.92). However, a systematic review
[14] found no signicant difference in response rates between bilateral rTMS and
sham treatment (19.44% vs. 11.11%, P=0.32). Additional systematic reviews [20]
highlight the limited data on rTMS efcacy for other phases of bipolar disorder.
These ndings emphasize the need for further sham-controlled studies and
76
Table 4.1 TMS in bipolar disorder
Clinical Recommendations
Length
TMS
Unilateral rTMS Unclear Unclear Unclear Unclear Depressive episode:
Unclear Unclear Unclear Unclear Mania episode:
Bilateral rTMS Unclear Unclear Unclear Unclear Depressive episode:
Unclear Unclear Unclear Unclear Mania episode:
Accelerated rTMS Unclear Unclear Unclear Unclear Both episodeb [31]
Deep TMS Unclear Unclear Unclear Unclear Both episodeb [31]
Priming TMS Unclear Unclear Unclear Unclear Both episodeb [31]
Synchronized TMS Unclear Unclear Unclear Unclear Both episodeb [44]
iTBS Unclear Unclear Unclear Unclear Both episodeb [31]
Accelerated iTBS Unclear Unclear Unclear Unclear Both episodeb [31]
Continuous TBS Unclear Unclear Unclear Unclear Both episodeb [31]
Bilateral TBS Unclear Unclear Unclear Unclear Both episodeb [31]
MST Unclear Unclear Unclear Unclear Both episodeb [8]
Abbreviations: iTBS intermittent theta burst stimulation, MST magnetic seizure therapy, rTMS
repetitive transcranial magnetic stimulation, TBS theta burst stimulation, TMS transcranial
magnetic stimulation
a
The CANMAT and ISBD Guidelines mention adjunctive rTMS as third-line treatment only for
acute bipolar I depression and acute mania
b
Both episodes including depressive episode and mania episode
(min)
Duration
(sessions)
Episode: Levels +
ReferencesTarget Frequency
Third-Linea [5]
Third-Linea [5]
Third-Linea [5]
Third-Linea [5]
X. Yang et al.
large-scale clinical trials to determine the broader applicability of rTMS, including
its potential to manage manic and mixed episodes, stabilize mood, and reduce suicidal behaviors.
Cognitive dysfunction is increasingly recognized as a critical target for rTMS
interventions in bipolar disorder. Cognitive impairments are common among
patients with bipolar depression. A study involving 64 patients with bipolar disorder assessed the impact of 20 sessions of bilateral rTMS (10Hz on the left DLPFC
and 1Hz on the right DLPFC) on depressive symptoms and cognitive functions,
utilizing the Beck Depression Inventory-II (BDI-II) and the Cambridge
Neuropsychological Test Automated Battery (CANTAB) [21]. Results indicated
that bilateral rTMS improved depressive symptoms and enhanced cognitive functions, including sustained attention, working memory, and executive functions.
These effects are thought to stem from the modulation of cognitive control mechanisms (top-down processing) and the amelioration of negative emotional biases.
Safety
The adverse effects of bilateral rTMS include sensations such as scalp tingling, neck
soreness, and a burning sensation, along with potential auditory disturbances [22].
These side effects are generally transient and tend to resolve upon discontinuation
4 Bipolar Disorder
77
Table 4.2 Denitions of level of evidence and line of treatment ratings according to the 2018
CANMAT/ISBD guidelines
Level of evidence
ratings
Level Evidence
1 Meta-analysis with narrow condence interval or replicated double-blind
2 Meta-analysis with wide condence interval or one DB RCT with placebo or
3 At least one DB RCT with placebo or active control comparison condition
4 Uncontrolled trial, anecdotal reports, or expert opinion
Line of
treatment ratings
First Level 1 or level 2 evidence for efcacy plus clinical support for safety/
Second Level 3 or higher evidence for efcacy plus clinical support for safety and/
Third Level 4 evidence or higher for efcacy plus clinical support for safety/
Not
recommended
CANMAT Canadian Network for Mood and Anxiety Treatments, ISBD International Society for
Bipolar Disorders
a
This chapter is adapted from the study by Keramatian etal. [5]
b
The text specically notes when lack of clinical support for safety and/or tolerability, or risk of
treatment-emergent switch, has affected recommendations
a
(DB) randomized controlled trial (RCT) that includes a placebo or active
control comparison (N≥30in each active treatment arm)
active control comparison condition (N≥30in each active treatment arm)
(N=10–29in each active treatment arm) or health system administrative
data
tolerability, and no risk of treatment-emergent switch
or tolerability and low risk of treatment-emergent switch
tolerability
Level 1 evidence for lack of efcacy or level 2 evidence for lack of efcacy
plus expert opinion
b
b
of the treatment. rTMS is contraindicated in patients with metallic implants or intracranial conductive devices, and caution is warranted when administering the therapy to individuals taking medications that lower the seizure threshold. Expert
guidelines [23] estimate the incidence of rTMS-induced seizures at stimulation frequencies above 1Hz to be less than 1%.
The risk of seizures associated with rTMS is inuenced by the stimulation frequency and the total number of pulses delivered. Although rare cases of rTMSinduced status epilepticus have been reported, the treatment does not appear to
increase the long-term risk of seizures in patients [24]. Careful assessment of the
potential risks and benets is essential when considering rTMS as a therapeutic
option, ensuring patient safety while maximizing therapeutic efcacy.
Treatment Regimen
Bilateral rTMS is predominantly utilized in the treatment of bipolar depression rather
than bipolar mania. This approach combines LF stimulation of the DLPFC with HF
stimulation of the left DLPFC within a single treatment session [14]. Evidence from
a recent study [25] indicates that bilateral stimulation demonstrates greater efcacy
compared to unilateral protocols. In this regimen, the right DLPFC is stimulated at
78
X. Yang et al.
1Hz for 10s with 2-s intervals, delivering 150 trains and 1500 pulses per session
over 20 sessions, culminating in a total of 30,000 pulses. Following this, the left
DLPFC is stimulated at 10Hz for 5s with 10-s intervals between pulses, resulting in
75 trains (3750 pulses per session). The stimulation intensity for the right DLPFC is
set at 120% of the resting motor threshold (RMT), while the left DLPFC is stimulated at 100% RMT to enhance tolerability. Treatments are typically conducted once
daily over 4–6weeks [14]. Conversely, current evidence suggests that unilateral
stimulation may be more suitable for patients experiencing mania [26].
Clinical Recommendations
The CANMAT and ISBD guidelines classify rTMS as a third-line treatment for
acute bipolar I depression and acute mania [5]. However, the Chinese guidelines for
the prevention and treatment of bipolar disorder do not include recommendations
for rTMS application [19]. This divergence highlights regional differences in clinical practice and perspectives on the role of rTMS in bipolar disorder management
(Table4.1), underscoring the need for more globally unied treatment protocols
informed by robust evidence.
4.2.1.3 Accelerated rTMS
Efficacy
Increasing the frequency of rTMS sessions to more than once daily, known as the
accelerated rTMS protocol, seeks to enhance antidepressant efcacy while reducing
the overall treatment duration, thereby alleviating the time burden on both patients and
clinicians [27]. Although no targeted meta-analysis of accelerated rTMS for bipolar
disorder currently exists, several studies suggest its potential effectiveness. In a realworld clinical setting, Massé-Leblanc etal. [28] evaluated 247 adults with treatmentresistant unipolar or bipolar depressive episodes (bipolar I or II disorder) diagnosed
according to DSM-IV or DSM-V criteria. Posttreatment analysis revealed that 46.3%
of patients met response criteria and 36.1% achieved remission based on the
Montgomery-Åsberg Depression Rating Scale (MADRS). Similarly, George etal. [29]
examined 41 patients experiencing depressive episodes and suicidal ideation, reporting
a more rapid reduction in suicide ideation scores in the active stimulation group.
Safety
The accelerated rTMS protocol has demonstrated safety and tolerability in patients
with depression [30], including older adults [31]. Common adverse effects observed
in real-world clinical applications include headaches (37.1%), stimulation site pain
(32.2%), and fatigue (22.4%) [28]. While generally well-tolerated, patient responses
and potential side effects require careful monitoring to ensure safety and optimize
treatment outcomes.
Treatment Regimen
In clinical applications, the protocol described by Massé-Leblanc etal. [28] utilized a gure-of-eight coil for TMS therapy. This included a unilateral 20 Hz
4 Bipolar Disorder
79
stimulation protocol targeting the left DLPFC or a bilateral approach combining
20 Hz stimulation of the left DLPFC with continuous theta burst stimulation
(cTBS) inhibiting the right DLPFC.In contrast, George etal. [29] implemented
accelerated rTMS using a gure-eight solid core coil applied to the left prefrontal
cortex at 120% of the motor threshold (MT). This protocol involved 10Hz stimulation, a 5-s train duration, and a 10-s intertrain interval, delivering 6000 pulses per
session over three sessions daily for 3days, amounting to nine sessions and 54,000
stimulations in total.
Clinical Recommendations
Current research focuses primarily on the depressive phase of bipolar disorder, for
which specic grade recommendations are lacking [31] (Table4.1). There is insufcient evidence to extend recommendations to the treatment of manic or mixed
states, highlighting the need for further clinical studies and validation. Clinicians
are encouraged to adopt personalized treatment plans, tailoring rTMS protocols to
individual patient needs and therapeutic goals.
4.2.2 Deep TMS
4.2.2.1 Efficacy
Deep TMS (dTMS), an advanced TMS modality, utilizes the H7 coil to target the
medial prefrontal cortex–dorsal anterior cingulate cortex (mPFC-dACC) and other
cortical regions with suprathreshold stimulation [32]. Compared to conventional
TMS coils, the H-coil, integrated into a wearable helmet, offers broader and deeper
neural stimulation [33]. In a clinical trial [34], patients with bipolar depression
underwent 20 sessions of either active or sham dTMS targeting the left DLPFC with
an H1 coil at 18Hz, using 2-s trains at 120% of the MT.Active dTMS showed signicantly greater improvements than sham treatment at the endpoint, although the
benet was not sustained at follow-up. The active group exhibited a higher response
rate (48%) than the sham group (24%), with an OR of 2.92 (P=0.08), but remission
rates were comparable between the groups. Notably, no treatment-emergent mania
switch episodes were reported.
In contrast, applying HF dTMS to the bilateral prefrontal cortex in patients
with depressive episodes of bipolar disorder or MDD did not yield signicant
improvements in depressive symptoms [34]. However, another sham-controlled
study [34] demonstrated short-term efcacy of dTMS targeting the left DLPFC in
bipolar depressive episodes. Active dTMS signicantly reduced Hamilton
Depression Rating Scale (HDRS) scores compared to sham from baseline to week
4 (P=0.03) and week 6 (P=0.02), though no differences were observed at follow-up (week 8). Response rates at week 4 also showed a trend favoring the active
treatment group (48%) over the sham group (24%, P=0.08). These ndings align
with research by McGirr etal. [35], which demonstrated the superior efcacy of
traditional gure-eight coil rTMS targeting the right DLPFC in acute bipolar
depression compared to sham. Conversely, other studies have reported