Download Efficacy of repetitive transcranial magnetic stimulation (rTMS) in the

Örebro University School of Medicine
Degree project, 15 ECTS Jan 2015
Efficacy of repetitive transcranial magnetic
stimulation (rTMS) in the treatment of major
depressive disorder (MDD): a systematic
overview of randomized controlled trials
Author: Emeli Pontén
Supervisor: Maher Khaldi MD, PhD
1 ABSTRACT
Transcranial magnetic stimulation is the noninvasive technique to induce electrical currents in
brain tissue via magnetic fields, proven to have therapeutic effects on depression. The
magnetic coil located slightly above the scalp can either excite or inhibit cortical brain areas,
depending on the speed of the repetitive cycles. rTMS can be divided into two subtypes; highfrequency rTMS (10-20 Hz) and low-frequency rTMS (≤1 Hz) applied to the left and right
dorsolateral prefrontal cortex respectively. The primary objective of this thesis was to identify
the clinical efficacy of rTMS, that is the ability to attain remission in MDD patients through
repetitive transcranial magnetic stimulation. The electronic search included the databases
Cochrane Library and PubMed. Unpublished data was collected through personal
communication with researchers. My conclusion is that a substantial body of research
supports the efficacy of rTMS in MDD patients. However, optimizing the parameters and
identifying the factors which determine successful stimulation is paramount. Combining
excitatory and inhibitory stimulation with more efficient frequency protocols, may instigate
remission and maintenance rates. With no systemic side effects or drug interactions, this noninvasive brain stimulation technique implies a safe therapy solution for patients suffering
from depressive disorders.
Keywords: transcranial magnetic stimulation, rTMS, depression, MDD, neuromodulation, brain stimulation.
2 ABBREVIATIONS
MDD – major depressive disorder
rTMS – repetitive transcranial magnetic stimulation
dTMS – deep transcranial magnetic stimulation
ECT – electroconvulsive therapy
mT – millitesla; the unit of magnetic flux density
TRD – treatment resistant depression
HPA – hypothalamus-pituitary-adrenal cortex
BDNF – brain-derived neurotrophic factor
MEP – motor evoked potentials
APS – American Psychiatric Association
FDA – Food and Drug Administration
DSM-V – Diagnostic and Statistical manual of Mental disorders V
ICD-10 – International Classifications of Disease 10th ed.
HAMD – Hamilton Depression Rating Scale
BPRS – Brief Psychiatric Rating Scale
BDI – Beck Depression Inventory
CGI-S – Clinical Global Impression-Severity of Illness
STAI – State Trait Anxiety Inventory
TCA – tricyclic antidepressant
SSRI – selective serotonin reuptake inhibitor
SNRI – selective noradrenaline reuptake inhibitor
MAOI - monoamine oxidase inhibitors
MT – motor threshold
cTBS – continuous theta burst stimulation
iTBS – intermittent theta burst stimulation
DLPFC – dorsolateral prefrontal cortex
MRI – magnetic resonance imaging
HF-rTMS – high frequency rTMS
UHF-rTMS – ultra high frequency rTMS
LF-rTMS – low frequency right-sided
3 DEFINITIONS
Treatment resistant depression: Patients who do not improve although two adequate trials of
antidepressants of different classes, during one episode of depression.
Relapse: Another episode of depression occurring fewer than six months after treatment for
acute depression and a fifty percent increase in symptom severity.
Recurrence: Symptoms reoccurring after six months of remission.
Remission: Optimal outcome of treatment for depression (due to the lack of objective biologic
markers, significant symptoms may still exist even though patients may have a full response).
Measurements are made by various standardized psychiatric rating scales.
Response: Fifty percent reduction in a rating scale of depression [1,2].
BACKGROUND
The neurobiology of affective disorders is yet to be completely understood, but in response to
interdisciplinary ingenuity and successful trials new therapeutic modalities are introduced to
clinical practice. Direct stimulation of the brain with the aid of magnetic coils is currently
advancing treatment strategies for MDD - a common and debilitating psychiatric disorder
impacting a large proportion of the global population. Despite a range of antidepressant drugs,
there are many patients who fail to obtain an adequate therapeutic effect although completion
of trials. Brain stimulation modalities probe an alternative for these patients, as well as a safe
solution for antepartum depression.
Transcranial magnetic stimulation is definitely not a new technique, but applied in psychiatry
it can be considered a novel approach. The first time rTMS to the left prefrontal cortex was
proposed as a treatment method for MDD was in 1993. Thereafter, a multitude of studies have
demonstrated clinically meaningful antidepressant effects from rTMS, compared to sham. In
2007 an extended industry-sponsored trial was published, resulting in the US Food and Drug
Administration approval of rTMS as a treatment option for MDD in adults [3]. Accumulating
approval among neuroscientists, by showing statistically as well as clinically significant
antidepressant effects, has made rTMS a rapid growing field of interest even for the general
public. Nevertheless, there are numerous unanswered questions. including appropriate scalp
location, frequency protocol and adjustments of parameters.
4 The combination of rTMS and antidepressant drugs is being investigated for the sake of
maintenance, however there is promising evidence that rTMS alone can deliver continuous
remission [4].
The interest for magnetic stimulation has to a big extent emerged from the ambition to replace
ECT. In contrast to ECT the magnetic stimulation does not need to induce a seizure for
antidepressant effect, which reduces the risks and side effects fundamentally. There is no need
for anesthetic drugs when executing the stimulation, and the much disputed side effect of
temporary memory loss after ECT therapy is not reported in any of the rTMS trials. Side
effects from rTMS are merely a matter of focal headaches, mild twitching of facial muscles
and skin/scalp sensations as the magnetic waves transcend into brain tissue.
Mechanisms of action
Electromagnetic induction is the discovery that a flux in pulse density through a magnetic coil
generates an electric field, and that a current through a wire cause a magnetic field around that
wire. When discharging current from a powerful electrical condenser into a coil, magnetic
fields of 1-10 mT are produced [5]. rTMS takes advantage of these laws of physics,
composing a fluctuating magnetic field at a set frequency which induces an electrical current
in brain tissue when positioned close to the scalp. The stimulation causes an electric activity
in the brain cortex and depending on the placement of the magnetic coil, different effects are
provoked by either depolarizing or hyperpolarizing neurons, i.e. affecting the firing of action
potentials. The method to stimulate the brain with magnetic coils was developed 1985 to
evaluate functions in the central motor system, including the spine. A single pulse from the
coil is sufficient to trigger a simple movement of distal limbs. Typically, the thumb is targeted
to control and adjust the efficacy of the coil, whereby it is moved to dorsolateral prefrontal
cortex regions for psychiatric effects. rTMS is the subcategory of TMS that we come across in
clinical practice, primarily executed with antidepressant purpose but also offered to patients
suffering from migraine, tinnitus, auditory hallucination in schizophrenia, Parkinson’s and
Alzheimer’s disease [6].
The magnetic stimulation is suspected to magnify synthesis of certain nerve growth factors,
such as brain-derived neurotrophic factor (BDNF). This factor plays a crucial role in
maintaining and regulating neuronal connectivity. Observations that acute and chronic stress
in humans suppress endogenous neurotrophic levels, has formulated the BDNF hypothesis.
5 The decrease in BDNF may lead to atrophy of hippocampus which is a structure known to
participate in emotional control. The exact relationship between BDNF and the
pathophysiology of depression remains unclear, but there is universal support for taking
BDNF into consideration when exploring antidepressant mechanisms [7-9]. Chronic
antidepressant medication, ECT, TMS, exercise as well as AMPA receptor potentiators and
NMDA antagonists, have all shown to increase mRNA/protein BDNF levels in the rat brain
[10-18]. Several antidepressant treatments, either in the medication trials or the brain
stimulation labs, have shown to alleviate depressive symptoms through the action of BDNF.
BDNF stimulates the development of new hippocampal cells, which is consistent with the line
of thought that neuroplasticity has a crucial role in remission. Duman et. al showed in animal
studies that the time it takes to induce neurogenesis is equivalent to the time of improvement,
namely three to four weeks. The causal sequence postulated from these results, was that raised
serotonin levels would increase the cAMP response element-binding (CREB) protein in nerve
cells, which in turn augments the level of growth factor BDNF [19,20]. Hence, benefits of
rTMS are often explained as enhanced neuroplasticity in certain brain pathways. New theories
expand this apprehension when presenting evidence that rTMS resets thalamocortical
oscillators, normalize regulatory brain functions, and promote reemergence of intrinsic
cerebral rhythms, whereby normal cerebral dynamics are restored. These events may be
crucial in engendering neuroplasticity prerequisites, thus placing emphasis on the importance
of regenerative aspects of neurons when evaluating antidepressant effects of rTMS. Forcing
an oscillatory reset, with the help of theta burst protocol for example, could explain the
antidepressant effects achieved with rTMS [21].
It has become apparent, in vivo and in vitro, that rTMS influences immediate-to-early gene
expression [22,23]. The mRNA expression changes of monoamine transporter (MAT) genes
that rTMS exerts has been proven for dopamine, as well as noradrenaline and serotonin [2426]. Additionally some studies argue that rTMS affects the neuroendocrine system [27,28].
What impact rTMS has on cortical activity is a revisited question. Observations have noted
changes in the prefrontal cortex and paralimbic activity, even after just a couple weeks of
rTMS treatment [29]. Brain imaging (fMRI, PET scan etc.) show improved blood circulation
and glucose metabolism in human brain regions subject to magnetic stimulation. Activity in
the cingulate increases markedly, as well as paralimbic blood flow, following a two-week
course of rTMS. The cingulate has a crucial role in the pathophysiology of depression, since it
has been recognized as blunted in depressed patients [30]. Some of the alterations in brain
6 physiology and neurochemistry may be unique to rTMS [31].
rTMS devices and coil design
In the beginning the devices differed in moderate ways, the coil (i.e. magnetic field generator)
was round and manually positioned by the psychiatrist during treatment. Modern devices are
more sophisticated with coil designs varying in material, geometry of the coil configuration
and biophysical characteristics of the pulses emitted. Some devices target the brain bilaterally,
but most commonly the coil is fixed on the patient’s left side in order to target the left
dorsolateral prefrontal cortex (DLPFC). Neuronavigation is the 3D-imaging of the brain based
on structural MRI, plotting out the exact areas of the brain thought to be relevant for MDD
(for example BA 9 and 46) [32]. Whatever way the coil is positioned, the magnetic field
impulses can only reach the outer layers of cortex, approximately 1,5-2,5 cm deep. How to
ideally accomplish deeper stimulation is under investigation, as well as the research on what
potential benefits it could offer [33]. The figure eight coil emits a more focal activation
pattern, whilst the double-cone coil conforms to the shape of the head, which aids deeper
stimulation. However, to allow deep transcranial magnetic stimulation (dTMS), some of the
focal precision may be compromised [34]. The H-coil has the potential of reaching deeper
brain areas such as the cingulate, regions that the more superficial rTMS procedures stimulate
as well but indirectly. The geometric shape of the coil governs the focality and depth of
cortical penetration, crossing the scalp unimpeded due to the physical nature of
electromagnetic induction [35] The H-coil helmet, approved by the FDA (Jan 2013), shows
promising impact on deeper brain regions with increased stimulation energy and minimal loss
of focal accuracy [33,36].
Target population
The patient group earning special priority for this novel form of brain stimulation are
individuals whose condition has lacked improvement after several conventional approaches.
In contrast to other therapy forms such as TCA, SSRI and other antidepressant medications,
rTMS is not associated with the common side effects of weight gain, sexual dysfunction,
sedation etc. In another aspect, it is also much less invasive than electroconvulsive therapy
(ECT), deep brain stimulation (DBS), vagus nerve stimulation (VNS) and similar treatment
solutions. There is an expanding body of scientific evidence supporting the efficacy of rTMS
as a treatment option for a wide spectrum of brain disorders; generalized anxiety,
schizophrenia (auditory hallucinations and negative symptoms), cognitive impairment,
7 tinnitus and even nicotine or cocaine addiction. rTMS is still less effective than ECT for the
worst afflicted patients, but due to the adverse effects on cognitive function there is reason to
opt for rTMS as a treatment choice for individuals suffering from moderate-to-severe MDD
[37].
rTMS administration
The first TMS devices emitted a single pulse, now modern clinical devices are adjusted to
generate a rapid succession of pulses (rTMS). The treatment program typically consists of a
four second stimulation, with a subsequent twenty-six seconds of rest. This is repeated for
twenty to forty minutes. In order to maintain remission, a patient will need further treatments
(five days a week, for four to six weeks). Before the treatment commence, the optimal
strength of the magnetic field is calibrated for each patient. This is called the “motor
threshold” (MT), which is the strength needed to activate a specific muscle from the motor
cortex (typically m. abductor pollicis brevis). From this measurement treatment strength is
calculated, commonly between 80 to 120 percent of MT. The standard coil positioning in
clinical practice is the so-called “5cm rule” [38], i.e. a 5cm move of the coil from motor
cortex to dorsolateral prefrontal areas. Considering natural variations in head circumference,
focus of stimulation may be more precise for each individual with more sophisticated methods
such as neuronavigation [39]. rTMS passes the skin and skull unimpeded, causing electrical
charges within the adjacent cortical brain circuitry.
Many trials have had the aim to find a combination of technical parameters resulting in an
improved efficacy. Amongst these parameters are magnetic field frequency, strength and
duration of exposure. The left DLPFC is known to be hypoactive in depressed patients, while
the right DLPFC tends to be hyperactive. When the coil is positioned on the left side of the
DLPFC, the patient is exposed to high-frequency pulses (10-20 Hz) in an attempt to activate
this region and stimulate blood circulation. With right-side stimulation low frequencies are
operated (1-2 Hz), thought to have an inhibiting effect. The efficacy of high-frequency rTMS,
applied to the left DLPFC in MDD treatment, has been established by a wide range of
randomized controlled trials including extended multisite trials [4,38,40,41]. These findings
have been confirmed by several meta-analyses, and efficacies of other forms of rTMS
application have been added to the accumulating evidence base. Low-frequency rTMS
applied to the right DLPFC [42], and sequential application of the right and left DLPFC
respectively, are the main alternative schemes. The bilateral rTMS trials have been
8 inconsistent, showing both inferior as well as greater efficacy when compared to unilateral
rTMS [43,44].
Risks and adverse effects
The known risks of rTMS treatment are mild and transient. Incidences of seizures were
reported during the first years of treatment, leading to restrictions and the establishment of
safety guidelines [34,45]. Since these measures were obtained, development of seizure
activity is eminently unlikely, unless the patient has a history of seizures prior to rTMS
treatment [46]. Mild adverse effects, such as discomfort due to facial muscle twitching (14%)
and moderate headaches (9%) can be managed by reduction of the stimulus intensity by ten
percent for the facial twitches and regular analgesics for the headaches. There are no reports
of memory impairment, cognitive derangements or concentration difficulties after rTMS. ECT
may exert these side effects, but they are considered acceptable when treating patients with
severe MDD due to the pronounced efficacy and short latency period [42]. When rTMS was
compared to ECT, no significant differences appeared between these two techniques when the
patients did not have psychotic symptoms, but significant differences did appear in favor of
the ECT when the patients had psychotic symptomatology [47].
Depression
There is a high prevalence of depression on a global scale; approximately fifty percent of
women and twenty-five percent of men will suffer a depressive episode at some point [48].
Depression prevalence reflects the difficulty in finding effective treatment for psychiatric
disorders, due to the complexity of the brain and interacting body systems. Depression has
perpetually earned the epithet “the most common disease and cause of disability world-wide”
[49]. Depression is the primary cause of suicide as well as long-term sick leave in private and
public sector in Sweden today. Many other countries are facing similar numbers [50-52]. Mild
and moderate depression is becoming more common in young and adults, possibly due to the
improved methods of diagnosing the condition. Surveys indicate that the age of onset is lower
today, and that children and adolescents are more depressed than ever before [53].
Affective mood disorders are commonly classified by the Diagnostic and Statistical Manual
of Mental Disorders V (DSM-V) [54] and the World Health Organization International
Classifications of Diseases 10th edition (ICD-10) [55]. Categories within the classification
9 systems are depressive episode, recurrent/major depressive disorder, persistent depressive
disorder (previously dysthymic disorder), bipolar disorder, schizoaffective disorder, disruptive
mood dysregulation disorder (children up to 18 years), and premenstrual dysphoric disorder.
A depressive episode can emit in any of these mood disorders. The criteria for a major
depression episode diagnose according to DSM-V are the following symptoms (occurring
during the same two week period and including at least “depressed mood” or/and “loss of
interest”):
1. Depressed mood most of the day, nearly every day, as indicated by either
subjective report or observation mad by others.
2. Markedly diminished interest or pleasure in all, or almost all activities, of
the day.
3. Significant weight loss or weight gain (> 5% change of body weight in a
month), increase or decrease in appetite daily.
4. Insomnia or hypersomnia.
5. Psychomotor agitation or retardation.
6. Fatigue, loss of energy, apathy.
7. Feelings of worthlessness or excessive, inappropriate guilt.
8. Diminished ability to think or concentrate, indecisiveness.
9. Recurrent thoughts of death, recurrent suicidal ideation with or without
attempts or plans for committing suicide.
Additional criteria for the diagnose major depressive episode; the symptoms do not meet the
criteria of mixed episodes, the symptoms cause clinically significant distress or impairment in
social, occupational, or other areas of functioning. Physiological effects of a substance or a
general medical condition, causing symptoms of depression, are excluded from this category
of mood disorder. The ICD-10 definition of major depression is presented with the same core
statements, the two systems do not conflict but rather complement each other. An episode is
classified as mild, moderate, severe or severe with psychosis.
Mood deviation is not the only characteristic of depression. When analyzed, a cluster of signs
and symptoms emerge. These may be conceptualized as a psychopathological spectrum,
ranging from mild to severe in intensity. Major depressive disorder (MDD) is defined by the
occurrence of one or more major depressive episodes. These episodes are in turn defined by
10 their length (minimum of two weeks of depressed mood or loss of interest) and the severity of
the depressive state (at least four additional depression symptoms) [54].
The descriptions of depression have been remarkably consistent since the very first
psychiatric endeavors. Symptoms have been classified congruously with epithets describing
emotional, cognitive, motivational, physical and vegetative manifestations. Biological factors
have been of considerable interest, whereby tests have been made of nearly all known
constituents of cerebrospinal fluid, urine and blood. The histopathology of the depressed brain
has been thoroughly investigated, in tandem with studies of other organs thought to influence
moods and emotion [56].
The HPA-axis of hormones is thought to be important since deviations appear in many
depressed patients. Stress hormones such as cortisol and adrenaline are elevated. In severely
depressed individuals the cortisol is measured at a static maximum, when it normally
fluctuates in blood concentration over twenty-four hours (low levels at night, high in the
mornings). Disturbances in the HPA-axis are related to chronic stress and depression. The
diurnal rhythm and plasma levels of cortisol are controlled by feedback mechanisms, in
depressed patients this is seen to be non-functioning [73]. In normal conditions cortisol
stimulates parts of the brain necessary for memory and learning, i.e. hippocampus. However,
a surplus of cortisol may lead to toxic reactions on the brain tissue, resulting in cognitive
impairments. Magnetic resonance imaging performed on certain depressed patients, has
revealed actual shrinking of the hippocampus. How the psychoneuroendocrine system
confronts social and mental stress is ruled by hereditary dispositions and acquired
hypersensitivity, such as early psychosocial trauma. Regulation of noradrenaline receptors in
the nervous system appears to be linked to stress sensitivity. People show very different stress
tolerance, where the least tolerable are more likely to succumb to depression [57-60].
In addition there are theories addressing disturbances in functional connectivity of the brain as
an essential component of the MDD pathophysiology. Brain connectivity is modulated by
oscillations of cortical electrical activity, i.e. Alpha (8-13 Hz), Beta (13-30 Hz), Theta (3,5-7
Hz), Delta (0,5-3 Hz) and Gamma (30-70 Hz) with its own set of characteristics. These five
different frequency bands coordinate functions across divergent brain areas. Alpha and theta
frequency oscillations at the border of 7-8 Hz are thought to play a central role in regulating
mood, memory, cerebral blood flow and neurotransmitter levels. New evidence suggests that
11 depressive disorders may be dependent on brain oscillatory activity. It has been reported that
MDD patients exhibit increased oscillatory synchrony in multiple frequency bands across
cortical regions. Restoring the normal oscillatory framework is a viable explanation for the
efficacy of rTMS [21,61-63].
Although the genetic component of depression is far from deterministic, there is no
controversy regarding the gene association with depressive disorders. Depression is frequently
discovered in both members of a pair of identical twins. Moreover, the fact that about seventy
percent of depressed patients can be treated with an antidepressant drug, strongly indicates
abnormal biochemical mechanisms as a component of depressive disorders. The abundance of
affected individuals and this success rate has made antidepressants among the most prescribed
classes of drugs on a global scale[56]. Granting the majority of MDD patients are helped by
an antidepressant drug, a sizeable proportion of patients suffering from this condition fail to
respond to monotherapy treatment [64,65]. Genetic vulnerability in combination with a
stressful environment may induce a cascade of biochemical events, which eventually propels
into destructive conditions in the brain. Although the pathophysiology is not fully understood,
it is clear that genetic, environmental and self-inflicted factors interact as a primer for
depression [66]. Certain traumas in childhood are linked to depression [67], nevertheless there
are people who may cope with recurrent traumas without ever developing depression, which
indicates an important genetic aspect. The impact of genetic predisposition is especially
noticed in bipolar depression [68], whereas unipolar depression has a genetic component with
less impact on the clinical outcome [69]. There are a few established hypothesis offering
suggestions for treatment strategies. The monoamine hypothesis advocates that the
transmission of monoamines is insufficient [70], serving as evidence base for currently
available antidepressants, targeting serotonin and/or noradrenaline reuptake [71]. When
monoamine reuptake inhibitors are effective, inhibition is immediate while antidepressant
effects occur a month later. Therefore, increasing synaptic availability of monoamines cannot
fully explain the efficacy of antidepressants. Monoamine depletion typically only cause a
transient depression and ingested precursors such as tyrosine and tryptophan do not improve
mood [72].
Neuroplasticity and brain cell turnover are also associated with major depression, which has
opted for new approaches in the search for more successful treatments. In animal studies,
brain stimulation treatments result in increased cell replication in the amygdala, gyrus cinguli,
12 hippocampus and the prefrontal cortex – areas crucial for mood and emotion [74].
Repeated relapses and chronicity occur in seventy to eighty percent of MDD patients, and the
suicide rate among them is approximately ten percent [75]. Within one year of discharge,
thirty percent of inpatients require re-hospitalization [76]. Psychotherapy and extended use of
antidepressants may counteract symptom recurrence, however if the affected individual
encounters several depressive episodes the risk of relapse remains high albeit treatment [7779]. Suicide risk among depressed individuals in Sweden has the last decade been up to thirty
percent higher than in general population [80]. Patients who are not adequately treated
represent the majority of depression-related suicides [81] The suicide rate in Sweden has
decreased, closely correlating with the increased prescription of antidepressant medication
[82]. Nevertheless, suicide accounts for thousands of deaths in Sweden annually [83]. A vast
majority of these victims suffered from depression.
In mild and moderate depression it has been disputed whether treatment is of any gain, since
placebo controls have been almost as successful as the treatments tested on these groups of
patients [84]. However, major depressive disorder has shown to be of a more resistant kind
where active medications offer significantly higher rates of remission than inactive control,
i.e. placebo [85]. Selective serotonin reuptake inhibitors (SSRI) dominate the market today,
since they come with modest side effects. Tricyclic antidepressant (TCA) is from an older
generation of antidepressants, still provided for those who do not improve with SSRI or
SNRI. Monoamine oxidase inhibitors (MAOI) are scarcely prescribed, with the more modern
options available [86].
13 OBJECTIVES
To identify the clinical efficacy of rTMS, that is the ability to attain remission in MDD
patients through repetitive transcranial magnetic stimulation.
METHODS
Inclusion criteria: Randomized, sham-controlled clinical trials assessing the therapeutic
efficacy of rTMS for MDD, during 2010-2015 in English.
Exclusion criteria: Comorbidity when found to be a confounding factor, focus on metabolic
and/or anatomical modulations rather than therapeutic remission, medication covariates, lack
of sham-control, small sample size (<20), inordinate treatment resistance in study population
and dubious study designs motivated exclusion of articles. Incomplete data or studies with
more than 1/3 withdrawals in the final quantitative analysis were also excluded, as that could
threaten the validity of the results.
Participants: All persons with major depression diagnosed by any recognized criteria,
irrespective of gender or nationality, ages 18-75.
Interventions:
1. High-frequency or low-frequency rTMS.
2. Right DLPFC or left DLPFC.
3. Static or theta burst stimulation.
4. Unilateral or bilateral stimulation.
5. Adjunctive rTMS to pharmacotherapy
Search strategy: MeSH terms – Depressive Disorder, Major. Transcranial Magnetic
Stimulation, Repetitive. Randomized Controlled Trials as topic. Treatment Outcome.
Databases: PubMed and Cochrane Library.
Outcome measures: Remission, maintenance and relapse rates.
14 RESULTS
Through electronic database searches I obtained 38 clinical trials that potentially fulfilled my
inclusion criteria (abstract study). Out of these, 27 were excluded according to exclusion
criteria (full article study). The 11 studies selected for overview were evaluated systematically
using a modified version of the SBU protocol from 2009 [87].
1: Ray, S. et al. Efficacy of adjunctive high frequency repetitive transcranial magnetic
stimulation of left prefrontal cortex in depression: a randomized sham controlled study [41]
2: Huang, ML. et al. Repetitive transcranial magnetic stimulation in combination with
citalopram in young patients with first-episode major depressive disorder: a double-blind,
randomized, sham-controlled trial [88]
3: Blumberger, DM. et al. A randomized double-blind sham-controlled comparison of
unilateral and bilateral repetitive transcranial magnetic stimulation for treatment-resistant
major depression [43]
4: Fitzgerald, PG. et al. A double blind randomized trial of unilateral left and bilateral
prefrontal cortex transcranial magnetic stimulation in treatment resistant major depression
[89]
5: George, MS. et al. Daily left prefrontal transcranial magnetic stimulation therapy for
major depressive disorder: a sham-controlled randomized trial [4]
6: Janicak, PG. et al. Durability of clinical benefit with transcranial magnetic stimulation
(TMS) in the treatment of pharmacoresistant major depression: assessment of relapse during
a 6-month, multisite, open-label study [40]
7: Nongpiur, A. et al. Theta-patterned, frequency-modulated priming stimulation enhances
low-frequency, right prefrontal cortex repetitive transcranial magnetic stimulation (rTMS) in
depression: a randomized, sham-controlled study [90]
8: Plewnia, C. et al. Treatment of major depression with bilateral theta burst stimulation: A
randomized controlled pilot trial [91]
9: Speer, AM. et al. Antidepressant efficacy of high and low frequency rTMS at 110% of
motor threshold versus sham stimulation over left prefrontal cortex [92]
10: Baeken, C. et al. Intensive HF-rTMS treatment in refractory medication-resistant unipolar
depressed patients [93]
11: Ulrich, H. et al. Ultra-high-frequency left prefrontal transcranial magnetic stimulation as
augmentation in severely ill patients with depression: a naturalistic sham-controlled, doubleblind, randomized trial [96]
15 Intervention
Comparison
Efficacy'measurement
Efficacy'of'repetitive'transcranial'magnetic'stimulation'(rTMS)'in'the'treatment'of'depressive'disorders:'
a'systematic'overview'of'randomized'and'sham>controlled'clinical'trials
Patient'characteristica
sham
Structured#Interview#Guide
for#the#Hamilton#Depression#
Rating#Scale#(SIGH9D)
Brief#Psychiatric#Rating#Scale#(BPRS)
TRIALS'1)6
Study'type
HF9rTMS#(10#Hz)#at#90%#of#MT
20#trains,#6#s#train#duration
1200#pulses/day,#10#days#
right#DLPFC
Result/Outcome
Publication
45#right#handed##
moderate/severe#depression
ICD910#DCR#criteria
High9frequency#left#prefrontal#rTMS#was#well#tolerated#and#found
to#be#effective#as#add9on#to#standard#pharmacotherapy#in#
nonpsychotic#as#well#as#psychotic#depression.#
1:#Ray#S.#et#al#
2011#[41]#
randomized
sham9controlled
single9blind
rTMS#accelerated#the#rapidity#of#the#antidepressant#response#
in#first9episode#young#depressive#patients.#rTMS#can#be#considered
a#safe#augmentative#treatment#to#SSRI.
60#first9episode#young#major#
depressive#patients
sham
citalopram
2:#Huang#ML.#et#al#
2012#[88]#
179item#Hamilton#Depression
Rating#Scale#(HAMD917)
Montgomery9Asberg#Depression
Rating#Scale#(MADRS)
randomized
sham9controlled
double9blind
The#remission#rate#was#significantly#higher#in#the#bilateral#group
than#the#sham#group.#The#remission#rate#in#the#unilateral
group#did#not#differ#from#either#group.
citalopram#in#combination#with#
2#weeks#of#active#rTMS#treatment.
HF9rTMS#(10Hz)#at#90%#MT
20#trains,#800#pulses/day
4#s#train#duration
26#s#intertrain#interval
left#DLPFC
sham
179item#Hamilton#Depression
Rating#Scale#(HAMD917)
3:#Blumberger#DM.#et#al
2012#[43]#
HF9rTMS#to#left#DLFPC#(10Hz)#and
sequential#LF9rTMS#to#right#DLPFC#(1Hz)#
100%#MT#(120%#MT#patients#>60#years)
unilateral#and#bilateral#intervention
Greater#antidepressant#response#to#unilateral#left#sided#rTMS
compared#with#sham#or#bilateral#rTMS.
74#subjects#with#TRD#
179item#Hamilton#Depression#
Rating#Scale#greater#than#21
179item#Hamilton#Depression
Rating#Scale#(HAMD917)
randomized
sham9controlled
double9blind
sham
67#patients#with#TRD
sham
randomized
sham9controlled
double9blind
HF9rTMS#(10Hz)#at#120%#MT
4#s#train#duration,#26#s#intertrain#interval
3000#stimuli#per#session
left#DLPFC
The#odds#of#attaining#remission#were#4.2#times#greater#with
active#rTMS#than#with#sham#(95%#confidence#interval,#1.32913.24).
199#antidepressant#drug9free#
patients#with#unipolar
nonpsychotic#MDD
sham
Initial#data#suggest#that#the#therapeutic#effects#of#TMS#are#
durable#and#that#TMS#may#be#successfully#used#as#an#intermittent
rescue#strategy#to#preclude#impending#relapse.
Montgomery9Asberg#Depression
Rating#Scale#(MADRS)
179item#Hamilton#Depression
Rating#Scale#(HAMD917)
Clinical#Global#Impression
Severity#of#Illness#Scale
HF9rTMS#(10Hz)#at#120%#of#MT
4#s#train#duration,#26#s#intertrain#interval,#
3000#stimuli#per#session
4:#Fitzgerald#PB.#et#al#
2012#[89]#
randomized
sham9controlled
double9blind
randomized
sham9controlled
double9blind
301#patients#with#unipolar,#
nonpsychotic#MDD
sequential#bilateral#rTMS#and#standard#
HF9rTMS#to#left#DLPFC.
bilateral#stimulation#was#applied#with#
1Hz#on#right#DLPFC#followed#by
HF9rTMS#(10Hz)#on#left#DLPFC#at#120%#MT.
5:#George#MS.#et#al#
2010#[4]#
6:#Janicak#PG.#et#al#
2010#[40]#
Montgomery9Asberg#Depression
Rating#Scale#(MADRS)
179item#Hamilton#Depression
Rating#Scale#(HAMD917)
249item#Hamilton#Depression
Rating#Scale#(HAMD924)
16 Study'design
40#patients#with
moderate/severe#depression
Patient'characteristica
Intervention
20#unipolar#anti9depressant#
free#TRD#patients#
(stage#III#treatment#resistant)
24#acutely#depressed#patients
32#patients#with#MDD
HF9rTMS#(20#Hz)#at#110%#of#MT
40#trains#of#1.9#s#duration
1560#stimuli/session
5#sessions/day#for#4#days
15920min#delay#inbetween#sessions
left#DLPFC
HF9rTMS#(20Hz)#or#LF9rTMS#(1Hz)#
at#110%#of#MT
1600#stimuli/session
left#DLPFC
cTBS#and#iTBS#intensity#standardized#
at#80%#of#MT.
50#Hz#theta#burst#protocol
2#trains#of#600#stimuli
bilateral#intervention
sham
sham
bilateral#sham
sham9priming
Comparison
179item#Hamilton#Depression
Rating#Scale#(HAMD917)
179item#Hamilton#Depression
Rating#Scale#(HAMD917)
289item#Hamilton#Depression#
Rating#Scale#(HAMD928)
Montgomery9Asberg#Depression
Rating#Scale#(MADRS)
179item#Hamilton#Depression
Rating#Scale#(HAMD917)
Beck#Depression#Inventory#(BDI)
Montgomery9Asberg#Depression
Rating#Scale#(MADRS)
Structured#Interview#Guide
for#the#Hamilton#Depression#
Rating#Scale#(SIGH9D)
Brief#Psychiatric#Rating#Scale#(BPRS)
Clinical#Global#Impression
Severity#of#Illness#(CGI9S)
Efficacy'measurement
Intensive#HF9rTMS#protocol#was#found#to#be#safe#and#well#tolerated.
and#resulted#in#fast#clinical#responses#in#those#TRD#III#patients#with
a#relatively#shorter#duration#of#their#current#depressive#episode.
Patients#with#unsuccessful#ECT#prior#to#HF9rTMS#did#not#respond.
Patients#on#both#frequencies#showed#greater#improvement#than#on#
sham.#During#7#week#continuation#of#active#treatment,#
additional#improvement#was#observed.
A#significant#therapeutic#effect#of#sequential#left#excitatory#and
right#inhibitory#theta#burst#stimulation#was#found.
Pre9stimulation#with#frequency9modulated#priming#stimulation#in#
the#theta#range#has#greater#antidepressant#effect#than#low9frequency
stimulation#alone.#There#was#significant#improvement#in#the#active#
group#over#time#(SIGH9D#scores).
Result/Outcome
sham
A#309Hz#left#prefrontal#rTMS#in#severely#depressed#patients#was#safe,#
no#adverse#effects#occured.#Improvement#of#processing#speed
performance#in#the#UHF#group#was#demonstrated,#which#covaried#
with#improvement#of#psychomotor#retardation.
Efficacy'of'repetitive'transcranial'magnetic'stimulation'(rTMS)'in'the'treatment'of'depressive'disorders:'
a'systematic'overview'of'randomized'and'sham>controlled'clinical'trials
Publication
randomized
sham9controlled
TRIALS'7)11
7:#Nongpiur#A.#et#al#
2011#[90]#
43#severely#depressed#patients
UHF9rTMS#(30#Hz)#as#an#add9on
therapy#to#stable#antidepressant
medication.#
right#DLPFC
active9priming#HF9rTMS#(498Hz)#
at#90%#of#MT,#400#stimuli,#followed#
by#LF9rTMS#(1#Hz)#at#110%#of#MT
900#stimuli
randomized
sham9controlled
single9blind
9:#Speer#AM.#et#al
2014#[92]#
randomized
sham9controlled
double9blind
8:#Plewnia#C.#et#al#
2014#[91]#
10:#Baeken,#C.#et#al
2013#[93]#
randomized
sham9controlled
single9blind
crossover
11:#Ulrich,#H.#et#al
2012#[96]#
randomized
sham9controlled
double9blind
17 DISCUSSION
There is an acute need for novel treatment options for the patients resistant to medication. It is
moreover critical to find a replacement for ECT owing the cognitive disabilities the seizures
may impose on the patient, as well as effective treatments for antepartum depression. With a
four-fold efficacy over sham-control [4], scarce and modest side effects, rTMS may
potentially represent a paradigm shift in psychiatric treatment.
My conclusion is that a substantial body of research supports the efficacy of rTMS in patients
with depression. However, optimizing the parameters and identifying the factors which
determine successful stimulation is paramount. Combining excitatory and inhibitory
stimulation with more efficient frequency protocols, may instigate remission and maintenance
rates. Padberg et al. indicated early on that high intensity of the magnetic pulses, i.e. high MT,
was directly correlated with superior remission rates [97]. These findings ought to be
implemented in clinical practice. Neuronavigation performance should be considered in rTMS
treatment, in order to coordinate the magnetic pulses to Broddman area 9 and 46. These brain
regions are typically targeted in rTMS treatment [32,98], thought to induce the antidepressant
effect.
It has been complicated in rTMS research to establish a potent evidence base considering the
difficult task of double-blinding the trials, which is imperative to eliminate performance bias
i.e. internal validity. rTMS trials differ from pharmaceutical in this matter, where the active
compound and placebo drug are identical, making the administration blinded for all
participants and professionals in a study. This is impossible for rTMS where placebo has been
accomplished by tilting or shielding the coil. Some trials have applied electrodes to the scalp
in order to simulate the somatosensory experience of active treatment [99], but the technician
setting up the device is inevitably aware of the difference. Although vigorous ingenuity and a
disciplined staff, there is a problematic issue of authenticity when labeling these trials as
double-blind. It would be judicious to depict these trials as “single-blind with evaluation by
external blinded assessors” [47]. There is also issues when creating a convincing sham-control
since many patients experience twitching in the scalp and upper face with subsequent
headaches. These immediate side effects cannot be artificially achieved or masked during
active treatment, since the patient is awake and fully conscious [34,99,100]. The sham-rTMS
has been shown to exert some metabolic effects on the brain tissue and MEP, resulting in a
diverted placebo effect that may confound results [101].
18 Principal threats to internal validity of randomized controlled trials are selection bias, lack of
strict double-blinding procedures, scant number of patients, heterogeneous pathology and
inadequate methods of evaluation. rTMS trials in particular need to address these challenges,
owing to the technical circumstances and the complex nature of depression.
Furthermore the variations in coil substance and electronic operation may affect biophysical
characteristics of the magnetic pulse, i.e. duration and width of the magnetic field. Attributes
of the pulse itself should be considered when comparing the results of different studies, in
respect of both safety and efficacy [35]. For maintenance of the acute benefits in clinical
practice, antidepressant monotherapy has shown to be a safe strategy [40]. When the rTMS
parameters are further optimized, extended remission durability may rule out the need for
antidepressants in maintenance therapy.
Methodological improvements in rTMS include high-intensity stimulation (110-120% of MT)
[92] with a high number of stimuli (3000 pulses per session) [102], neuronavigation with
magnetic resonance imaging for unerring scalp positioning [103] and, if possible,
identification of the neurocircuitry and oscillatory dysfunctions associated with the
progression of major depressive disorder. Maintenance strategies are critical to ascertain, for
the purpose of making rTMS a clinically realistic treatment.
ACKNOWLEDGEMENTS
The author is grateful for the advice and support of William F. Stubbeman, MD (Private
Practice TMS Psychiatry, Los Angeles), Joshua Berman, MD, PhD (Director for the Program
in Experimental Brain Stimulation, Columbia University NYC) and Maher Khaldi, MD, PhD
(Supervisor, Örebro University School of Medicine).
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