1  

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

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A B S T R A C T 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; high-

frequency 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 Unpublished data was collected through personal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 non-

invasive brain stimulation technique implies a safe therapy solution for patients suffering

from depressive disorders.

Keywords: transcranial magnetic stimulation, rTMS, depression, MDD, neuromodulation, brain stimulation.

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A B B R E V I A T I O N S

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

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D E F I N I T I O N S

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].

B A C K G R O U N D 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.

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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.

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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 [24-

26]. 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

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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,

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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

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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

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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

  11  

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

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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,

  13  

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 [77-

79]. 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].

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O B J E C T I V E S

To identify the clinical efficacy of rTMS, that is the ability to attain remission in MDD

patients through repetitive transcranial magnetic stimulation.

M E T H O D S

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.

  15  

R E S U L T S

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, double-

blind, randomized trial [96]

  16  

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3000#stim

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  17  

Efficacy'of'repetitive'transcranial'magnetic'stim

ulation'(rTMS)'in'the'treatm

ent'of'depressive'disorders:'a'system

atic'overview'of'random

ized'and'sham>controlled'clinical'trials

TRIALS'7)11

PublicationStudy'design

Patient'characteristicaIntervention

Comparison

Efficacy'measurem

entResult/O

utcome

7:#Nongpiur#A.#et#al#

randomized

40#patients#with

active9priming#HF9rTM

S#(498Hz)#sham

9priming

Montgom

ery9Asberg#DepressionPre9stim

ulation#with#frequency9m

odulated#priming#stim

ulation#in#2011#[90]#

sham9controlled

moderate/severe#depression

at#90%#of#M

T,#400#stimuli,#follow

ed#Rating#Scale#(M

ADRS)the#theta#range#has#greater#antidepressant#effect#than#low

9frequencyby#LF9rTM

S#(1#Hz)#at#110%#of#M

TStructured#Interview

#Guidestim

ulation#alone.#There#was#significant#im

provement#in#the#active#

900#stimuli

for#the#Hamilton#Depression#

group#over#time#(SIGH9D#scores).

Rating#Scale#(SIGH9D)Brief#Psychiatric#Rating#Scale#(BPRS)

right#DLPFCClinical#Global#Im

pressionSeverity#of#Illness#(CGI9S)

8:#Plewnia#C.#et#al#

randomized

32#patients#with#M

DDcTBS#and#iTBS#intensity#standardized#

bilateral#shamMontgom

ery9Asberg#DepressionA#significant#therapeutic#effect#of#sequential#left#excitatory#and

2014#[91]#sham

9controlledat#80%

#of#MT.

Rating#Scale#(MADRS)

right#inhibitory#theta#burst#stimulation#w

as#found.single9blind

50#Hz#theta#burst#protocol179item

#Hamilton#Depression

2#trains#of#600#stimuli

Rating#Scale#(HAMD917)

bilateral#interventionBeck#Depression#Inventory#(BDI)

9:#Speer#AM.#et#al

randomized

24#acutely#depressed#patientsHF9rTM

S#(20Hz)#or#LF9rTMS#(1Hz)#

sham289item

#Hamilton#Depression#

Patients#on#both#frequencies#showed#greater#im

provement#than#on#

2014#[92]#sham

9controlledat#110%

#of#MT

Rating#Scale#(HAMD928)

sham.#During#7#w

eek#continuation#of#active#treatment,#

double9blind1600#stim

uli/sessionadditional#im

provement#w

as#observed.left#DLPFC

10:#Baeken,#C.#et#alrandom

ized20#unipolar#anti9depressant#

HF9rTMS#(20#Hz)#at#110%

#of#MT

sham179item

#Hamilton#Depression

Intensive#HF9rTMS#protocol#w

as#found#to#be#safe#and#well#tolerated.

2013#[93]#sham

9controlledfree#TRD#patients#

40#trains#of#1.9#s#durationRating#Scale#(HAM

D917)and#resulted#in#fast#clinical#responses#in#those#TRD#III#patients#w

ithsingle9blind

(stage#III#treatment#resistant)

1560#stimuli/session

a#relatively#shorter#duration#of#their#current#depressive#episode.crossover

5#sessions/day#for#4#daysPatients#w

ith#unsuccessful#ECT#prior#to#HF9rTMS#did#not#respond.

15920min#delay#inbetw

een#sessionsleft#DLPFC

11:#Ulrich,#H.#et#al

randomized

43#severely#depressed#patientsUHF9rTM

S#(30#Hz)#as#an#add9onsham

179item#Ham

ilton#DepressionA#309Hz#left#prefrontal#rTM

S#in#severely#depressed#patients#was#safe,#

2012#[96]#sham

9controlledtherapy#to#stable#antidepressant

Rating#Scale#(HAMD917)

no#adverse#effects#occured.#Improvem

ent#of#processing#speeddouble9blind

medication.#

performance#in#the#U

HF#group#was#dem

onstrated,#which#covaried#

with#im

provement#of#psychom

otor#retardation.

  18  

D I S C U S S I O N

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].

  19  

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.

 

A C K N O W L E D G E M E N T S

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).

  20  

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