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
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-high-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 Unpublished data was collected through personal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.
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
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.
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.
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
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,
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
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
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
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
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,
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].
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.
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]
Eff ica cy 'o f're pe titi ve 'tr an scr an ia l'ma gn eti c' sti mu la tio n'( rT MS )'in 'th e'tr ea tme nt' of' de pre ssi ve 'd iso rd ers :' a's ys te ma tic' ov erv iew 'o f'ra nd omi ze d'a nd 'sh am> co ntr olle d'cl in ica l'tr ia ls TRI AL S'1 )6 Pu bli ca tio n Study'type Pa tien t'ch ara ct eri st ica Inte rv ention Co mp ari so n Ef fic ac y'm easur em ent Re su lt/ O ut co m e 1:# Ray #S.# et# al # ran do m ize d 45 #rig ht# han de d## HF 9rT MS #(1 0#Hz) #at# 90 % #o f#MT sh am Str uc tu re d#In te rv ie w #G uid e Hi gh 9fr eq ue nc y#le ft# pr efr on tal #rT MS #w as #w ell# to le rate d#an d#f ou nd 2011# [41]# sh am 9co ntr olle d m od erate /se ve re #d ep re ssi on 20 #tr ai ns ,#6 #s#tr ai n#d ur ati on fo r#th e#Ham ilto n#D ep re ssi on # to #b e#e ffe cti ve #as #ad d9o n#to #stan dar d#p har m ac oth erap y#in # single 9blind IC D 91 0#D CR# cri te ria 12 00 #p uls es /d ay ,#1 0#d ay s# Rati ng #Sc al e#( SIG H9 D ) no np sy ch oti c#as #w ell# as #p sy ch oti c#d ep re ssi on .# rig ht# D LP FC Br ie f#P sy ch iatr ic#Rati ng #Sc al e#( BP RS ) 2:# Hu an g#ML .#e t#al # ran do m ize d 60 #fir st9 ep iso de #yo un g#m aj or # cital op ram #in #co m bin ati on #w ith # sh am 17 9ite m #Ham ilto n#D ep re ssi on rT MS #ac ce le rate d#th e#r ap id ity #o f#th e#an tid ep re ssan t#r es po ns e# 2012#[88]# sh am 9co ntr olle d de pr es siv e#p ati en ts 2#w ee ks #o f#ac tiv e#r TMS #tr eatm en t. cital op ram Rati ng #Sc al e#( HA MD 91 7) in #fir st9 ep iso de #yo un g#d ep re ssi ve #p ati en ts .#rT MS #can #b e#c on sid ere d double 9blind HF 9rT MS #(1 0Hz) #at# 90 % #MT Mo ntg om ery 9A sb erg #D ep re ssi on a# saf e#au gm en tati ve #tr eatm en t#to #SS RI. 20 #tr ai ns ,#8 00 #p uls es /d ay Rati ng #Sc al e#( MA D RS ) 4#s #tr ai n#d ur ati on 26 #s#i nte rtr ai n#in te rv al le ft# D LP FC 3:# Blu m be rg er# D M. #e t#al ran do m ize d 74 #su bje cts #w ith #TRD # HF 9rT MS #to #le ft# D LF PC #(1 0Hz) #an d sh am 17 9ite m #Ham ilto n#D ep re ssi on Th e#r em iss io n#r ate #w as #sig nif ican tly #h igh er# in #th e#b ilate ral #gr ou p 2012#[43]# sh am 9co ntr olle d 17 9ite m #Ham ilto n#D ep re ssi on # se qu en tial #LF 9rT MS #to #rig ht# D LP FC #(1 Hz) # Rati ng #Sc al e#( HA MD 91 7) th an #th e#s ham #gr ou p.# Th e#r em iss io n#r ate #in #th e#u nilate ral double 9blind Rati ng #Sc al e#g re ate r#th an #2 1 10 0% #MT #(1 20 % #MT #p ati en ts #>6 0#y ear s) gro up #d id #n ot# dif fe r#fr om #e ith er# gro up . un ilate ral #an d#b ilate ral #in te rv en tio n 4:# Fitzg eral d#P B.# et# al # ran do m ize d 67 #p ati en ts #w ith #TRD se qu en tial #b ilate ral #rT MS #an d#s tan dar d# sh am 17 9ite m #Ham ilto n#D ep re ssi on G re ate r#an tid ep re ssan t#r es po ns e#to #u nilate ral #le ft# sid ed #rT MS 2012#[89]# sh am 9co ntr olle d HF 9rT MS #to #le ft# D LP FC . Rati ng #Sc al e#( HA MD 91 7) co m par ed #w ith #sh am #o r#b ilate ral #rT MS . double 9blind bilate ral #sti m ulati on #w as #ap plie d#w ith # 1Hz# on #rig ht# D LP FC #fo llo w ed #b y HF 9rT MS #(1 0Hz) #o n#le ft# D LP FC #at# 12 0% #MT . 5:# G eo rg e#MS .#e t#al # ran do m ize d 19 9#an tid ep re ssan t#d ru g9f re e# HF 9rT MS #(1 0Hz) #at# 12 0% #MT sh am Mo ntg om ery 9A sb erg #D ep re ssi on Th e#o dd s#o f#attai nin g#r em iss io n#w ere #4 .2 #ti m es #gr eate r#w ith 2010#[4]# sh am 9co ntr olle d pati en ts #w ith #u nip olar 4#s #tr ai n#d ur ati on ,#2 6#s #in te rtr ai n#in te rv al Rati ng #Sc al e#( MA D RS ) ac tiv e#r TMS #th an #w ith #sh am #(9 5% #co nfi de nc e#in te rv al ,#1 .3 291 3.2 4). double 9blind no np sy ch oti c#MD D 30 00 #sti m uli# pe r#s es sio n 17 9ite m #Ham ilto n#D ep re ssi on le ft# D LP FC Rati ng #Sc al e#( HA MD 91 7) Cli nic al #G lo bal #Im pr es sio n Se ve rity #o f#Il ln es s#S cal e 6:# Jan icak #P G .#e t#al # ran do m ize d 30 1#p ati en ts #w ith #u nip olar ,# HF 9rT MS #(1 0Hz) #at# 12 0% #o f#MT sh am Mo ntg om ery 9A sb erg #D ep re ssi on In iti al #d ata# su gg es t#th at# th e#th erap eu tic #e ffe cts #o f#T MS #ar e# 2010#[40]# sh am 9co ntr olle d no np sy ch oti c#MD D 4#s #tr ai n#d ur ati on ,#2 6#s #in te rtr ai n#in te rv al ,# Rati ng #Sc al e#( MA D RS ) du rab le #an d#th at# TMS #m ay #b e#s uc ce ssf ully #u se d#as #an #in te rm itte nt double 9blind 30 00 #sti m uli# pe r#s es sio n 17 9ite m #Ham ilto n#D ep re ssi on re sc ue #str ate gy #to #p re clu de #im pe nd in g#r elap se . Rati ng #Sc al e#( HA MD 91 7) 24 9ite m #Ham ilto n#D ep re ssi on Rati ng #Sc al e#( HA MD 92 4)
Eff ica cy 'o f're pe titi ve 'tr an scr an ia l'ma gn eti c' sti mu la tio n'( rT MS )'in 'th e'tr ea tme nt' of' de pre ssi ve 'd iso rd ers :' a's ys te ma tic' ov erv iew 'o f'ra nd omi ze d'a nd 'sh am> co ntr olle d'cl in ica l'tr ia ls TRI AL S'7 )1 1 Pu bli ca tio n Study'de sign Pa tien t'ch ara ct eri st ica Inte rv ention Co mp ari so n Ef fic ac y'm easur em ent Re su lt/ O ut co m e 7:# N on gp iu r#A .#e t#al # ran do m ize d 40 #p ati en ts #w ith ac tiv e9p rim in g#HF 9rT MS #(4 98 Hz) # sh am 9p rim in g Mo ntg om ery 9A sb erg #D ep re ssi on Pre 9sti m ulati on #w ith #fr eq ue nc y9m od ulate d#p rim in g#s tim ulati on #in # 2011#[90]# sh am 9co ntr olle d m od erate /se ve re #d ep re ssi on at# 90 % #o f#MT ,#4 00 #sti m uli, #fo llo w ed # Rati ng #Sc al e#( MA D RS ) th e#th eta# ran ge #h as #gr eate r#an tid ep re ssan t#e ffe ct# th an #lo w 9fr eq ue nc by #LF 9rT MS #(1 #Hz) #at# 11 0% #o f#MT Str uc tu re d#In te rv ie w #G uid e sti m ulati on #al on e.#T he re #w as #sig nif ican t#im pr ov em en t#in #th e#ac tiv e# 90 0#s tim uli fo r#th e#Ham ilto n#D ep re ssi on # gro up #o ve r#ti m e#( SIG H9 D #sc or es ). Rati ng #Sc al e#( SIG H9 D ) Br ie f#P sy ch iatr ic#Rati ng #Sc al e#( BP RS ) rig ht# D LP FC Cli nic al #G lo bal #Im pr es sio n Se ve rity #o f#Il ln es s#( CG I9S ) 8:# Ple w nia# C.# et# al # ran do m ize d 32 #p ati en ts #w ith #MD D cT BS #an d#iT BS #in te ns ity #stan dar dize d# bilate ral #sh am Mo ntg om ery 9A sb erg #D ep re ssi on A#s ign ific an t#th erap eu tic #e ffe ct# of# se qu en tial #le ft# ex citato ry #an d 2014#[91]# sh am 9co ntr olle d at# 80 % #o f#MT . Rati ng #Sc al e#( MA D RS ) rig ht# in hib ito ry #th eta# bu rst# sti m ulati on #w as #fo un d. single 9blind 50 #Hz# th eta# bu rst# pr oto co l 17 9ite m #Ham ilto n#D ep re ssi on 2#tr ai ns #o f#6 00 #sti m uli Rati ng #Sc al e#( HA MD 91 7) bilate ral #in te rv en tio n Be ck #D ep re ssi on #In ve nto ry #(B D I) 9:# Sp ee r#A M. #e t#al ran do m ize d 24 #ac ute ly#d ep re sse d#p ati en ts HF 9rT MS #(2 0Hz) #o r#L F9r TMS #(1 Hz) # sh am 28 9ite m #Ham ilto n#D ep re ssi on # Pati en ts #o n#b oth #fr eq ue nc ie s#s ho w ed #gr eate r#im pr ov em en t#th an #o n# 2014#[92]# sh am 9co ntr olle d at# 11 0% #o f#MT Rati ng #Sc al e#( HA MD 92 8) sh am .#D ur in g#7 #w ee k#c on tin uati on #o f#ac tiv e#tr eatm en t,# double 9blind 16 00 #sti m uli/ se ssi on ad diti on al #im pr ov em en t#w as #o bs erv ed . le ft# D LP FC 10 :#B ae ke n,# C.# et# al ran do m ize d 20 #u nip olar #an ti9d ep re ssan t# HF 9rT MS #(2 0#Hz) #at# 11 0% #o f#MT sh am 17 9ite m #Ham ilto n#D ep re ssi on In te ns ive #HF 9rT MS #p ro to co l#w as #fo un d#to #b e#s af e#an d#w ell# to le rate d. 2013#[93]# sh am 9co ntr olle d fre e#T RD #p ati en ts # 40 #tr ai ns #o f#1 .9 #s#d ur ati on Rati ng #Sc al e#( HA MD 91 7) an d#r es ulte d#in #fas t#c lin ical #re sp on se s#in #th os e#T RD #III# pati en ts #w ith single 9blind (stag e#III# tr eatm en t#r es istan t) 15 60 #sti m uli/ se ssi on a# re lati ve ly#s ho rte r#d ur ati on #o f#th eir #cu rre nt# de pr es siv e#e pis od e. crossover 5#s es sio ns /d ay #fo r#4 #d ay s Pati en ts #w ith #u ns uc ce ssf ul#E CT #p rio r#to #HF 9rT MS #d id #n ot# re sp on d. 15 92 0m in #d elay #in be tw ee n#s es sio ns le ft# D LP FC 11 :#U lric h,# H. #e t#al ran do m ize d 43 #se ve re ly#d ep re sse d#p ati en ts U HF 9rT MS #(3 0#Hz) #as #an #ad d9o n sh am 17 9ite m #Ham ilto n#D ep re ssi on A#3 09Hz# le ft# pr efr on tal #rT MS #in #se ve re ly#d ep re sse d#p ati en ts #w as #saf e,# 2012#[96]# sh am 9co ntr olle d th erap y#to #stab le #an tid ep re ssan t Rati ng #Sc al e#( HA MD 91 7) no #ad ve rse #e ffe cts #o cc ur ed .#Im pr ov em en t#o f#p ro ce ssi ng #sp ee d double 9blind m ed icati on .# pe rfo rm an ce #in #th e#U HF #gr ou p#w as #d em on str ate d,# w hic h#c ov ar ie d# w ith #im pr ov em en t#o f#p sy ch om oto r#r etar dati on .
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].
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).
R E F E R E N C E S
1. Rush A, Thase M, Dube S. Research issues in the study of difficult-to-treat depression. Biol Psychiatry 2003;53(8):743-753.
2. Holtzheimer PE,3rd, McDonald WM, Mufti M, Kelley ME, Quinn S, Corso G, et al. Accelerated repetitive transcranial magnetic stimulation for treatment-resistant depression. Depress Anxiety 2010 Oct;27(10):960-963.
3. Kim D, Pesiridou A, O'Reardon J. Transcranial magnetic stimulation in the treatment of psychiatric disorders. Curr Psychiatry Rep 2009 Dec;11(6):447-452.
4. George MS, Lisanby SH, Avery D, McDonald WM, Durkalski V, Pavlicova M, et al. Daily left prefrontal transcranial magnetic stimulation therapy for major depressive disorder: a sham-controlled randomized trial. Arch Gen Psychiatry 2010 May;67(5):507-516.
5. Ulaby F, Michielssen E, Ravaioli U. Fundamentals of Applied Electromagnetics. 7th ed.: Pearson: Prentice Hall; 2014.
6. Walsh V, Pascual-Leone A. Transcranial Magnetic Stimulation: A Neurochronometrics of Mind. Cambridge, Massachusetts: Massachusetts Institute of Technology Press; 2003.
7. Sapolsky R. Stress, glucocorticoids, and damage to the nervous system: the current state of confusion. Stress 1996;1:1-19.
8. McEwen B. The neurobiology of stress: from serendipity to clinical relevance. Brain Res 2000;886:172-189.
9. Duman R. Depression: a case of neuronal life and death? Biol Psychiatry 2004;56:140-145. 10. Nibuya M, Morinobu S, Duman R. Regulation of BDNF and trkB mRNA in rat brain by chronic
electroconvulsive seizure and antidepressant drug treatments. J Neurosci 1995;15:7539–7547. 11. Xu H, Richardson S, Li X. Dose-related effects of chronic antidepressants on neuroprotective
proteins BDNF, Bcl-2 and Cu/ Zn-SOD in rat hippocampus. Neuropsychopharmacology 2003;28:53–62.
12. Smith M, Zhang L, Lyons W, Mamounas L. Anterograde transport of endogenous brain-derived neurotrophic factor in hippocampal mossy fibers. NeuroReport 1997;8:1829–1834.
13. Altar C, Laeng P, Jurata L, Brockman J, Lemire A, Bullard J. Electroconvulsive seizures regulate gene expression of distinct neurotrophic signaling pathways. J Neurosci 2004;24:2667–2677. 14. Muller M, Toschi N, Kresse A, Post A, Keck M. Long-term repetitive transcranial magnetic
stimulation increases the expression of brain-derived neurotrophic factor and cholecystokinin mRNA, but not neuropeptide tyrosine mRNA in specific areas of rat brain.
Neuropsychopharmacology 2000;23:205-215.
15. Neeper S, Gomez-Pinilla F, Choi J, Cotman C. Physical activity increases mRNA for brain-derived neurotrophic factor and nerve growth factor in rat brain. Brain Res 1996;726:49–56.
16. Russo-Neustadt A, Alejandre H, Garcia C, Ivy A, Chen M. Hippocampal brain-derived
neurotrophic factor expression fol- lowing treatment with reboxetine, citalopram, and physical exercise. Neuropsychopharmacology 2004;29:2189–2199.
17. Lauterborn J, Truong G, Baudry M, Bi X, Lynch G, Gall C. Chronic elevation of brain-derived neurotrophic factor by ampakines. J Pharmacol Exp Ther 2003;307:297–305.
18. Marvanova M, Lakso M, Pirhonen J, Nawa H, Wong G, Castren E. The neuroprotective agent memantine induces brain-derived neurotrophic factor and trkB receptor expression in rat brain. Mol Cell Neurosci 2001;18:247–258.
19. Farley P. The anatomy of despair. New Scientist 2004;182:42.
20. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 2003;301:805-809.
21. Leuchter A, Cook IA, Jin Y, Phillips B. The Relationship Between Brain Oscillatory Activity and Therapeutic Effectiveness of Transcranial Magnetic Stimulation in the Treatment of Major Depressive Disorder. Frontiers in Human Neuroscience 2013;7.
22. Doi W, Sato D, Fukuzako H, Takigawa M. c-Fos expression in rat brain after repetitive transcranial magnetic stimulation. Neuroreport 2001 May 8;12(6):1307-1310.
23. Hausmann A, Marksteiner J, Hinterhuber H, Humpel C. Magnetic stimulation induces neuronal c-fos via tetrodotoxin-sensitive sodium channels in organotypic cortex brain slices of the rat. Neurosci Lett 2001 Sep 14;310(2-3):105-108.
24. Ikeda T, Kurosawa M, Uchikawa C, Kitayama S, Nukina N. Modulation of monoamine transporter expression and function by repetitive transcranial magnetic stimulation. Biochem Biophys Res Commun 2005 Feb 4;327(1):218-224.
25. Keck ME, Welt T, Muller MB, Erhardt A, Ohl F, Toschi N, et al. Repetitive transcranial magnetic stimulation increases the release of dopamine in the mesolimbic and mesostriatal system.
Neuropharmacology 2002 Jul;43(1):101-109.
26. Strafella AP, Paus T, Barrett J, Dagher A. Repetitive transcranial magnetic stimulation of the human prefrontal cortex induces dopamine release in the caudate nucleus. J Neurosci 2001 Aug 1;21(15):RC157.
27. Keck ME, Welt T, Post A, Muller MB, Toschi N, Wigger A, et al. Neuroendocrine and behavioral effects of repetitive transcranial magnetic stimulation in a psychopathological animal model are suggestive of antidepressant-like effects. Neuropsychopharmacology 2001 Apr;24(4):337-349. 28. Keck ME, Engelmann M, Muller MB, Henniger MS, Hermann B, Rupprecht R, et al. Repetitive
transcranial magnetic stimulation induces active coping strategies and attenuates the neuroendocrine stress response in rats. J Psychiatr Res 2000 Jul-Oct;34(4-5):265-276.
29. George M, Nahas Z, Molloy M. A controlled trial of daily left prefrontal cortex TMS for treating depression. Biol Psychiatry 2000;48:962-970.
30. Teneback C, Nahas Z, Speer A. Changes in prefrontal cortex and paralimbic activity in depression following two weeks of daily left prefrontal TMS. Neuropsychiatry Clin Neurosci 1999;11:426-435.
31. Ben-Shachar D, Gazawi H, Riboyad-Levin J, Klein E. Chronic repetitive transcranial magnetic stimulation alters beta-adrenergic and 5-HT2 receptor characteristics in rat brain. Brain Res 1999;816:78-83.
32. Fitzgerald PB, Hoy K, McQueen S, Maller JJ, Herring S, Segrave R, et al. A randomized trial of rTMS targeted with MRI based neuro-navigation in treatment-resistant depression.
Neuropsychopharmacology 2009 Apr;34(5):1255-1262.
33. Deng ZD, Lisanby SH, Peterchev AV. Coil design considerations for deep transcranial magnetic stimulation. Clin Neurophysiol 2014 Jun;125(6):1202-1212.
34. Rossi S, Hallett M, Rossini PM, Pascual-Leone A, Safety of TMS Consensus Group. Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clin Neurophysiol 2009 Dec;120(12):2008-2039.
35. Riehl M. TMS stimulator design. In: Epstein C, Wassermann E, Ziemann U, Walsh V, Paus T, Lisanby S, editors. Oxford Handbook of Transcranial Stimulation Oxford: Oxford University Press; 2008. p. 13-23-25-32.
36. Bersani FS, Minichino A, Enticott PG, Mazzarini L, Khan N, Antonacci G, et al. Deep transcranial magnetic stimulation as a treatment for psychiatric disorders: a comprehensive review. Eur Psychiatry 2013 Jan;28(1):30-39.
37. Hansen PE, Ravnkilde B, Videbech P, Clemmensen K, Sturlason R, Reiner M, et al. Low-frequency repetitive transcranial magnetic stimulation inferior to electroconvulsive therapy in treating depression. J ECT 2011 Mar;27(1):26-32.
38. Johnson KA, Baig M, Ramsey D, Lisanby SH, Avery D, McDonald WM, et al. Prefrontal rTMS for treating depression: location and intensity results from the OPT-TMS multi-site clinical trial. Brain Stimul 2013 Mar;6(2):108-117.
39. Rusjan PM, Barr MS, Farzan F, Arenovich T, Maller JJ, Fitzgerald PB, et al. Optimal transcranial magnetic stimulation coil placement for targeting the dorsolateral prefrontal cortex using novel magnetic resonance image-guided neuronavigation. Hum Brain Mapp 2010 Nov;31(11):1643-1652.
40. Janicak PG, Nahas Z, Lisanby SH, Solvason HB, Sampson SM, McDonald WM, 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. Brain Stimul 2010 Oct;3(4):187-199.
41. Ray S, Nizamie SH, Akhtar S, Praharaj SK, Mishra BR, Zia-ul-Haq M. Efficacy of adjunctive high frequency repetitive transcranial magnetic stimulation of left prefrontal cortex in depression: a randomized sham controlled study. J Affect Disord 2011 Jan;128(1-2):153-159.
42. Klein E, Kreinin I, Chistyakov A. Therapeutic efficacy of right prefrontal slow repetitive transcranial magnetic stimulation in major depression. Arch Gen Psychiatry 1999;56:315-320. 43. Blumberger DM, Mulsant BH, Fitzgerald PB, Rajji TK, Ravindran AV, Young LT, et al. A
randomized double-blind sham-controlled comparison of unilateral and bilateral repetitive transcranial magnetic stimulation for treatment-resistant major depression. World J Biol Psychiatry 2012 Sep;13(6):423-435.
44. Pallanti S, Bernardi S, Di Rollo A, Antonini S, Quercioli L. Unilateral low frequency versus sequential bilateral repetitive transcranial magnetic stimulation: is simpler better for treatment of resistant depression? Neuroscience 2010 May 5;167(2):323-328.
45. Wassermann EM. Risk and safety of repetitive transcranial magnetic stimulation: report and suggested guidelines from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation, June 5-7, 1996. Electroencephalogr Clin Neurophysiol 1998 Jan;108(1):1-16.
46. Janicak P, O’Reardon J, Sampson S, Husain M, Lisanby S, Rado J. Transcranial magnetic stimulation in the treatment of major depressive disorder: a comprehensive summary of safety experience from acute exposure, extended exposure, and during reintroduction treatment. J Clin Psychiatry 2008;69:222-232.
47. Rodriguez-Martin J, Barbanoj J, Perez V, Schlaepfer T, Clos S, Kulisevsky J, et al. Transcranial magnetic stimulation for treating depression. 2001(4).
48. Rorsman B, Grasbeck A, Hagnell O, Lanke J, Ohman R, Ojesjo L, et al. A prospective study of first-incidence depression.The Lundby study, 1957-1972. Br J Psychiatry 1990;156:336-342. 49. Ustun T, Ayuso-Mateos J, Chatterji S, Mathers C, Murray C. Global burden of depressive
disorders in the year 2000. The British journal of psychiatry: the journal of mental science 2004;184:386-392.
50. Ayuso-Mateos J, Vazquez-Barquero JL, Dowrick C, Lehtinen V, Dalgard OS, Casey P, et al. Depressive disorders in Europe: prevalence figures from the ODIN study. Br J Psychiatry 2001;179:308-316.
51. Kendler S. A Swedish national twin study of lifetime major depression. Am J Psychiatry 2006;163:109-114.
52. Lépine J. Depression in the community: the first pan-European study DEPRES (Depression Research in European Society). Int Clin Psychopharmacol 1997;12:19-29.
53. Burke K. Comparing age onset of major depression and other psychiatric disorders by birth cohorts in five US community populations. Arch Gen Psychiatry 1991;48:789-795.
54. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders: DSM-5. 5th ed. Washington: American Psychiatric Association; 2013.
55. World Health Organization. The ICD-10 classification of the mental and behavioural disorders: Clinical descriptions and diagnostic guidelines. Geneva: World Health Organization; 1992. 56. Beck A, Alford B. Depression: Causes and Treatment. 2nd ed. Philadelphia: University of
Pennsylvania Press; 2009.
57. Bale T. Sensitivity to stress: dysregulation of CRF pathways and disease development. Horm Behav 2005;48:1-10.
58. Burke H, Burke JJ, Rae D, Regier D. Depression and cortisol responses to psychological stress: a meta-analysis. Psychoneuroendocrinology 2005;30(9):846-856.
59. Charney D. Psychobiological mechanisms of resilience and vulnerability: implications for succesful adaptation to extreme stress. Am J Psychiatry 2004;161(2):195-216.
60. Claes S. CRH, stress and major depression: a psychobiological interplay. Vitam Horm 2004;69:117-150.
61. Schnitzler A, Gross J. Normal and pathological oscillatory communication in the brain. Nat Rev Neurosci 2005 Apr;6(4):285-296.
62. Başar E, Başar-Eroğlu C, Karakaş S, Schurmann M. Gamma, alpha, delta, and theta oscillations govern cognitive processes. Int J Psychophysiol 2001;39:241–248.
63. J. Feingold. Beta oscillations in frontal cortex and striatum represent post-processing of successful behavior. Massachusetts Institute of Technology: Harvard University: MIT Division of Health Sciences and Technology; 2011.
64. Rush A, Trivedi H, Wisniewski S, Stewart J, Nierenberg A, Thase M. Bupropion-sr, sertraline, or vernlafaxine-xr after failure of SSRIs for depression. New England J Med 2006;354:1231-1242. 65. Marangell Lea. Switching antidepressants for treatment-resistant major depression. J Clin Psychiat
2001;62:12-17.
66. SBU. Treatment of depressive disorders, volume 1. A systematic overview. Stockholm: Statens beredning för medicinsk utvärdering (SBU); 2004.
67. Lloyd Cea. Life events and depressive disorder reviewed. Arch Gen Psychiatry 1980;37(5):529-535.
68. McGuffin P, Rijsdijk F, Andrew M, Sham P, Katz R, Cardno A. The heritability of bipolar affective disorder and the genetic relationship to unipolar depression. Arch Gen Psychiatry 2003;60(5):497-502.
69. Sullivan P, Neale M, Kendler K. Genetic epidemiology of major depression: review and meta-analysis. Am J Psychiatry 2000;157(10):1552-1562.
70. Lambert G, Johansson M, Agreen H, Friberg P. Reduced brain norepinephrine and dopamine release in treatment-refractory depressive illness: evidence in support of the catecholamine hypothesis of mood disorders. Arch Gen Psychiatry 2000;57(8):787-793.
71. Stahl S. Depression and bipolar disorder: Stahl’s essential psychopharmacology. 3rd ed. Cambridge, New York: Cambridge University Press; 2008.
72. Dubovsky S, Buzan R. Mood Disorders. In: Hales R, Yudofsky S, Talbott J, editors. Textbook of Psychiatry Wahington: American Psychiatric Press; 1999. p. 479-565.
73. Taylor M, Fink M. Melancholia: the diagnosis, pathophysiology, and treatment of depressive illness. Cambridge, New York: Cambridge University Press; 2006.
74. Castren E, Rantmaki T. The role of BDNF and its receptors in depression and antidepressant drug action: Reactivation of developmental plasticity. Dev Neurobiol 2010;70(5):289-297.
75. Angst J, Preisig M. Course of a clinical cohort of unipolar, bipolar and schizoaffective patients. Schweiz Arch Neurol Psychiatr 1995;146(1):5-16.
76. Stoudemire A, Hill C, Dalton S, Marquardt M. Rehospitalization rates in older depressed adults after antidepressant and electroconvulsive therapy treatment. J Am Geriatr Soc
1994;42(12):1282-1285.
77. SBU. Treatment of Depressive Disorders, volume 1. A systematic overview. Stockholm: Statens beredning för medicinsk utvärdering (SBU); 2004.
78. SBU. Treatment of depressive disorders, volume 3. A systematic overview. Stockholm: Statens beredning för medicinsk utvärdering (SBU); 2004.
79. Eaton W, Shao H, Nestadt G, Lee H, Bienvenu O, Zandi P. Population-based study of first onset and chronicity in major depressive disorder. Arch Gen Psychiatry 2008;65(5):513-520.
80. Osby U, Brandt L, Correia N, Ekbom A, Sparen P. Excess mortality in bipolar and unipolar disorder in Sweden. Arch Gen Psychiatry 2001;58(9):844-850.
81. Gonda X, Pompili M, Serafini G, Montebovi F, Campi S, Dome P, et al. Suicidal behavior in bipolar disorder: epidemiology, characteristics and major risk factors. J Affect Disord 2012;143(1-3):16-26.
82. Isacsson G, Holmgren A, Osby U, Ahlner J. Decrease in suicide among the individuals treated with antidepressants: a controlled study of antidepressants in suicide, Sweden 1995-2005. Acta Psychiatr Scand 2009;120(1):37-44.
83. Socialstyrelsen. Causes of Death 2011. Stockholm: National Board of Health and Welfare; 2012. 84. Fournier J, DeRubeis R, Hollon S, Dimidjian S, Amsterdam J, Shelton R, et al. Antidepressant
drug effects and depression severity: a patient-level meta-analysis. JAMA 2010;303(1):47-53. 85. Khan A, Leventhal R, Khan S, Brown W. Severity of depression and response to antidepressants
and placebo: an analysis of the Food and Drug Administration database. J Clin Psychopharmacol 2002;22(1):40-45.
86. Reid S, Barbui C. Long term treatment of depression with selective serotonin reuptake inhibitors and newer antidepressants. BMJ 2010;340:1468.
87. SBU. Transcranial magnetic stimulation and depression: a systematic overview. Stockholm: Statens beredning för medicinsk utvärdering (SBU); 2009.
88. Huang ML, Luo BY, Hu JB, Wang SS, Zhou WH, Wei N, 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. Aust N Z J Psychiatry 2012
Mar;46(3):257-264.
89. Fitzgerald PB, Hoy KE, Herring SE, McQueen S, Peachey AV, Segrave RA, et al. A double blind randomized trial of unilateral left and bilateral prefrontal cortex transcranial magnetic stimulation in treatment resistant major depression. J Affect Disord 2012 Jul;139(2):193-198.
90. Nongpiur A, Sinha VK, Praharaj SK, Goyal N. Theta-patterned, frequency-modulated priming stimulation enhances low-frequency, right prefrontal cortex repetitive transcranial magnetic stimulation (rTMS) in depression: a randomized, sham-controlled study. J Neuropsychiatry Clin Neurosci 2011 Summer;23(3):348-357.
91. Plewnia C, Pasqualetti P, Grosse S, Schlipf S, Wasserka B, Zwissler B, et al. Treatment of major depression with bilateral theta burst stimulation: A randomized controlled pilot trial. J Affect Disord 2014;156:219-223.
92. Speer AM, Wassermann EM, Benson BE, Herscovitch P, Post RM. Antidepressant efficacy of high and low frequency rTMS at 110% of motor threshold versus sham stimulation over left prefrontal cortex. Brain Stimul 2014 Jan-Feb;7(1):36-41.
93. Baeken C, Vanderhasselt MA, Remue J, Herremans S, Vanderbruggen N, Zeeuws D, et al. Intensive HF-rTMS treatment in refractory medication-resistant unipolar depressed patients. J Affect Disord 2013 Nov;151(2):625-631.
94. Diefenbach GJ, Bragdon L, Goethe JW. Treating anxious depression using repetitive transcranial magnetic stimulation. J Affect Disord 2013 Oct;151(1):365-368.
95. Richieri R, Guedj E, Michel P, Loundou A, Auquier P, Lancon C, et al. Maintenance transcranial magnetic stimulation reduces depression relapse: a propensity-adjusted analysis. J Affect Disord 2013 Oct;151(1):129-135.
96. Ullrich H, Kranaster L, Sigges E, Andrich J, Sartorius A. Ultra-high-frequency left prefrontal transcranial magnetic stimulation as augmentation in severely ill patients with depression: a naturalistic sham-controlled, double-blind, randomized trial. Neuropsychobiology
2012;66(3):141-148.
97. Padberg F, Zwanzger P, Keck ME, Kathmann N, Mikhaiel P, Ella R, et al. Repetitive transcranial magnetic stimulation (rTMS) in major depression: relation between efficacy and stimulation intensity. Neuropsychopharmacology 2002 Oct;27(4):638-645.
98. Trojak B, Meille V, Jonval L, Schuffenecker N, Haffen E, Schwan R, et al. Interest of targeting either cortical area Brodmann 9 or 46 in rTMS treatment for depression: A preliminary randomized study. Clin Neurophysiol 2014 Dec;125(12):2384-2389.
99. Arana AB, Borckardt JJ, Ricci R, Anderson B, Li X, Linder KJ, et al. Focal electrical stimulation as a sham control for repetitive transcranial magnetic stimulation: Does it truly mimic the cutaneous sensation and pain of active prefrontal repetitive transcranial magnetic stimulation? Brain Stimul 2008 Jan;1(1):44-51.
100. Lefaucheur JP, Andre-Obadia N, Antal A, Ayache SS, Baeken C, Benninger DH, et al. Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS). Clin Neurophysiol 2014 Nov;125(11):2150-2206.
101. Marangell LB, Martinez M, Jurdi RA, Zboyan H. Neurostimulation therapies in depression: a review of new modalities. Acta Psychiatr Scand 2007 Sep;116(3):174-181.
102. Padberg F, Zwanzger P, Keck ME, Kathmann N, Mikhaiel P, Ella R, et al. Repetitive transcranial magnetic stimulation (rTMS) in major depression: relation between efficacy and stimulation intensity. Neuropsychopharmacology 2002 Oct;27(4):638-645.
103. Lefaucheur JP, Brugieres P, Menard-Lefaucheur I, Wendling S, Pommier M, Bellivier F. The value of navigation-guided rTMS for the treatment of depression: an illustrative case.
