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The effects of TMS in the treatment of
major depressive disorder
Lucija Abramovic
Biology of Disease
Supervisor: Dr DLJG Schutter
September 2009
Contents:
Abstract
1. Major depression disorder
1.1 Causes
1.1.1 Dysregulation of the Hypothalamic-Pituitary-Adrenal Axis
1.1.2 The mono-amine hypothesis
1.1.3 Circadian hypotheses
1.1.4 Cortical dysfunction
1.2 Treatments
1.2.1 Psychotherapy
1.2.2 Medication
1.2.3 Electro Convulsive Therapy
1.2.4 Other treatments
2. Transcranial magnetic stimulation
2.1 History of TMS in psychiatry
2.2 Main principles of TMS
2.2.1 Apparatus
2.2.2 Effects on the brain
2.3 TMS as a tool for MDD
2.3.1 History of TMS in the treatment of MDD
2.3.2 How is TMS related to the causes of MDD?
2.3.3 Limitations of TMS
2.3.4 Safety considerations
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3. Therapeutic effects of TMS
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4. Possible outcome predictors
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3.1 Reviews and meta-analyses
3.2 TMS compared to other treatments
3.2.1 TMS versus psychotherapy
3.2.2 TMS versus medication
3.2.3 TMS versus ECT
4.1 Patient-related factors
4.1.1 Medication resistance
4.1.2 Age
4.1.3 Anatomic variation
4.1.4 History of neural activity in the stimulated region
4.1.5 Medication
4.1.6 Duration of episode
4.1.7 Other patient-related variables
4.2 Treatment related- variables
4.2.1 Frequency
4.2.2 Stimulation site
4.2.3 Stimulation intensities
4.2.4 Number of stimulations
4.2.5 Number of sessions/ course duration
4.2.6 Coil type
5. Discussion: how to improve the long-term benefits of MDD
Acknowledgments
References
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Abstract
Major Depressive Disorder (MDD) is a common disorder that has a major influence on the
lives of patients. There are several hypotheses about the causes of MDD and the most
common treatments used are psychotherapy, antidepressants and ECT. However, some
patients do not respond to treatment. Transcranial magnetic stimulation has become an
alternative treatment option. This thesis describes the literature on the efficacy of TMS in
the treatment of MDD and compares it to other treatments.
1. Major depression disorder
Major Depression Disorder (MDD) is a mental disorder that is accompanied by low mood and
self esteem, and loss of interest in life. This is often accompanied by lack of energy, weight
changes and a decreased ability to concentrate. The diagnosis MDD is made based on the criteria
set in the Diagnostic and Statistical Manual (DSMIV, 2000)1. These symptoms are of major
influence on a person’s normal and social functioning in society. MDD also is a major health issue
for society, as the lifetime prevalence is 15.4% and the 12-month prevalence is 5.8% (Bijl et al.,
1998). Therefore the economic and social costs are very high. Next to MDD there are several
other types of depression like dysthymic disorder or bipolar disorder. In dysthymic disorder, a
chronic period of at least two years of depressive symptoms occurs, while in bipolar disorder
elevated states varies with depressive states. Several causes of MDD are hypothesised but the
exact underlying mechanism is still unknown.
1.1 Causes
Several possible causes of MDD are proposed in the literature. Probably a combination of factors
leads to the occurrence of depression, with mainly biological, psychological and social factors.
An epidemiological studie by Sullivan, Neale and Kendler (2000) shows that the risk for MDD is
31%–42% genetic. Non-genetic factors can be various aspects of personality, like neuroticism,
and its development. Furthermore, poverty and social isolation are associated with increased
risk of psychiatric problems in general. Child abuse and other disturbances in family functioning
are risk factors for depression (Fava and Kendler, 2000).
1
For the convenience from now on I will only use the term depression in stead of Major Depressive Disorder
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1.1.1 Dysregulation of the Hypothalamic-Pituitary-Adrenal Axis
MDD has been suggested to arise from a chronic overactive
hypothalamic-pituitary-adrenal axis (HPA-axis) that is similar
to the neuro-endocrine response to stress, in which stress is
defined as non-specific stimuli that disturb homeostasis and
elicit an invariable stress response (Selye, 1936) Information
about stress is obtained from excitatory afferents of the
amygdala and inhibitory afferents of the hippocampus, but
also from ascending monoamine pathways. This input is
integrated in the parvocellular neurons of the paraventricular
nucleus of the hypothalamus (PVN), containing corticotrophinreleasing factor (CRF) (fig. 1). These neurons release CRF
into the hypophyseal portal system and the CRF binds to
specific receptors on cells of the anterior pituitary. In that
way the CRF leads to the release of adrenocorticotropic
hormone (ACTH). ACTH reaches the adrenal cortex via the
Figure 1: The HPA-axis. Stress leads to
CRF-release by the PVN. CRF leads to
ACTH release from the pituitary. This
results in glucocorticoid release from
the adrenal glands. Cortisol then
inhibits CRF release. (Nestler et al.
2002)
bloodstream. The adrenal glands then increase the secretion of corticosteroids, primarily
cortisol. The release of cortisol initiates a series of metabolic effects aimed to control the harmful
effects of stress through negative feedback to both the hypothalamus and the anterior pituitary.
The concentration of ATH and cortisol in the blood decreases once the state of stress diminishes.
In stress, cortisol is released, but the autonomic nervous system also stimulates the adrenal
medulla to release adrenaline. Also the heart rate, blood pressure and respiratory rates increase,
which contributes to increased arousal and anxiety. Chronic stress can disrupt the feedback
mechanism of corticosteroids and thereby cause prolonged high levels of glucocorticoids. This
damages the hippocampus and could initiate and maintain a hypercortisolemic state related to
some cases of MDD (Nestler et al., 2002). Structural MRI-scans of patients with MDD have
supported this hypothesis, as they showed smaller hippocampal volumes in patients (Bremner
et al., 2000). This loss of hippocampal neurons correlates with loss of memory and changes in
mood. Also increased levels of cortisol and enlarged pituitary and adrenal glands were found in
patients with MDD, as well as memory problems. This hypothesis states that depression can be
seen as a state of chronic stress in the body.
1.1.2 The mono-amine hypothesis
The mono-amine hypothesis (Hirschfeld, 2000) suggests that MDD is caused by deficiencies in
certain neurotransmittia. There is evidence that norepinephrine, dopamine and serotonin play a
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role in the development of MDD as
noradrenalin may be related to stress
responsiveness,
energy,
socialisation,
anxiety, motivation and interest in life,
serotonin to impulsivity and anxiety, and
dopamine is associated with motivation and
the reward-system (Nemeroff, 2002).
In
figure 2 is shown that some monoamines
Figure 2: effects of monoamines. Nemeroff, 2002
have overlap with their functions. Serotonin may help to regulate other neurotransmitter
systems and decreased serotonin activity may permit these systems to act in unusual ways. As
mentioned above, the noradrenergic system is involved in the mediation of stress responses and
therefore it is suggested that dysfunction of noradrenalin plays a role in the aetiology of MDD
(Nemeroff, 2002). However, there are some limitations to this theory. First, depletions of
monoamines in healthy subjects does not lead to MDD. Second, there are also antidepressants
that do not act trough the monoamine system but still work.
1.1.3 Circadian hypotheses
Another theory is that MDD might be related to abnormalities in the circadian rhythm. The
phase-shift hypothesis proposes that mood disturbances result from a phase advance or delay of
the central pacemaker that regulates temperature, cortisol, melatonin, and REM sleep. Normally,
mood varies across the 24-h cycle and depends on the circadian phase as well as the duration of
prior wakefulness. Because circadian and sleep processes directly affect mood regulation,
circadian and sleep disturbances can have effects on mood in depressed patients. This theory is
also supported by clinical studies. A recent study found that depressed patients show different
patterns of regional brain glucose metabolism across the day than healthy controls. Depressed
patients showed sustained activity in brainstem and hypothalamic regions involved in the
maintenance of wakefulness across times of day (Ho et al., 1996), whereas healthy subjects
showed increased brain glucose metabolism in the evening (Buysse et al., 2004). Abnormal
levels and patterns of melatonin secretion have also been observed in depressed patients in
some (Mendlewicz et al. 1979). Also 24-hour cortisol secretion appears to be more variable in
depressed patients (Sachar et al., 1973).
1.1.4 Cortical dysfunction
Yet another hypothesis proposes that symptoms of MDD are related to left hemispheric
dysfunction. Kanaya and Yonekawa (1990) measured regional cerebral blood flow (rCBF) in
patients and controls by single photon emission computed tomography. The mean rCBF was
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significantly lower in patients compared to controls. The decreases were more present in the
left hemisphere than the right hemisphere. After remission these changes turned toward the
levels of normal controls. An interesting finding was that they saw a negative correlation
between the severity of depressive symptoms and the mean rCBF in patients. Grimm et al.
(2007) investigate neural activity in left and right DLPFC related to unattended (unexpected)
and attended (expected) judgment of emotions. They showed that patients show opposite
changes in the left and right DLPFC, which supports the hypothesis that patients have an
imbalance in the left and right DLPFC.
1.2 Treatments
The most commonly used treatments to treat MDD are medication, psychotherapy and
electroconvulsive therapy, or a combination of treatments. The ‘Practice Guideline for the
Treatment of Patients with Major Depressive Disorder’ uses available evidence to develop
treatment recommendations for the care of adult patients with MDD (see figures 3 and 4).
However, most treatments have side-effects and still some of the patients do not react to any
form of treatment.
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Figure 3a: In the acute phase, in addition to psychiatric management, the psychiatrist may choose between several initial
treatment modalities, including pharmacotherapy, psychotherapy, the combination of medications plus psychotherapy,
or ECT. Selection of an initial treatment form should be influenced by both clinical and other factors (Practice Guideline
for the Treatment of Patients with Major Depressive Disorder, 2000). Figure 3b: Acute Phase Treatment of Major
Depressive Disorder. Choose either another antidepressant from the same class or, if two previous medication trials from
the same class were ineffective, an antidepressant from a different class (Practice Guideline for the Treatment of Patients
with Major Depressive Disorder, 2000).
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1.2.1 Psychotherapy
Specific psychotherapy alone may be used as an initial treatment modality for patients with mild
to moderate major depressive disorder (Practice Guideline for the Treatment of Patients with
Major Depressive Disorder, 2000). The most studied form of psychotherapy used to treat MDD is
Cognitive Behavioural Therapy (CBT). CBT works by teaching patients to learn a set of useful
cognitive and behavioural skills. It focuses on current issues and symptoms in contrast to more
traditional forms of therapy which tend to focus on a person’s history. The usual format is
weekly therapy sessions together with daily practice exercises designed to help the patient
apply CBT skills in their home environment. CBT involves several essential features, like;
cognitive restructuring, behavioural activation, and enhancing skills for problem-solving.
Cognitive restructuring helps to identify and correct inaccurate thoughts associated with
depressed feelings, and behavioural activation helps patients to engage more often in enjoyable
activities. CBT is a scientifically effective treatment for MDD with over 75% of patients showing
significant improvements. Patients can either take the treatment alone or in combination with
medication. The goal of CBT is to reduce depressive symptoms by challenging and reversing
these beliefs and attitudes (Beck et al., 1979).
1.2.2 Medication
Antidepressant medication can be used as an initial treatment modality by patients with mild,
moderate, or severe major depressive disorder. Clinical features that may suggest that
medication is the preferred treatment modality include history of prior positive response to
antidepressant medications, severity of symptoms, significant sleep and appetite disturbances or
agitation, or anticipation of the need for maintenance therapy (Practice Guideline for the
Treatment of Patients with Major Depressive Disorder, 2000).
Response rates to the first antidepressant administered range from 50-70 %, and it can take
from six to eight weeks before a patient is in remission. Selective serotonin reuptake inhibitors
(SSRIs) are the primary drugs prescribed. They are effective and have relatively mild sideeffects, e.g. nausea, weight gain. Because there are several SSRIs, patients can switch from one to
another to optimize effectiveness. An older class of anti-depressants, monoamine oxidase
inhibitors (MAOIs) should be restricted to patients who do not respond to other treatments
because of the risk of serious side effects and the necessity of dietary restrictions (Practice
Guideline for the Treatment of Patients with Major Depressive Disorder, 2000).
Unfortunately treatments with medication remain sub-optimal as still a large sample of patients
does not respond to any form of medication. This might be explained by the fact that MDD is not
a single clinical condition, but one with a lot of variation among patients, and thereby the same
treatment doesn’t work for everyone.
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1.2.3 Electro Convulsive Therapy
Electro Convulsive Therapy (ECT) is a treatment for patients
with a severe form of MDD that are functionally impaired and
often treatment resistant. Especially for patients in which
psychotic symptoms or catatonia are present, ECT might be a
beneficial treatment. For patients with an urgent need for
response to treatment, like suicidal patients or patients that
refuse to eat, ECT can be used as a treatment (Practice Guideline
for the Treatment of Patients with Major Depressive Disorder,
2000).
ECT is a treatment in which electrical pulses are sent trough the
brain via two electrodes to induce a seizure. In unilateral ECT the
electrodes are both placed one the same side of the patient's
head. This minimizes adverse side-effects like memory loss but is
thought to be less effective. In bilateral ECT the electrodes are
placed on both sides of the head. In bifrontal ECT the electrode
position is somewhere between bilateral and unilateral. The
Figure
4:
ECT
electrode
positioning. For the standard
bilateral placement the electrodes
are placed in position FT. It is
placed on the midpoint of the line
from the external canthus and
tragus. The electrode is then
placed 1 inch above this point at
both sides of the head. For de
dÉlia placement one electrode is
palced on the FT point as decribed
above and the other electrode is
placed halfway on the line
between the nasion and inion
(Rudorfer et al. 2003)
stimulus levels recommended for ECT are much more than an individual's seizure threshold:
about one and a half times seizure threshold for bilateral ECT and up to 12 times for unilateral
ECT (Rudorfer et al., 2003).
1.2.4 Other treatments
Research on the effects of light therapy has suggested that light deprivation is related to
decreased activity in the serotonergic system and to abnormalities in the sleep cycle (Lambert et
al., 2002). Therefore light-therapy might help to restore the neurotransmitter system and act as
an anti-depressant. A whole other branch of research focuses on the immune system. Because
MDD shows a similar response like illness behaviour, it is possible that MDD results from
unusual behaviour to abnormalities in circulation cytokines (Miller and O’Callaghan, 2005). Also
vagus nerve stimulation is a new treatment in which a small pacemaker-like stimulus generator
is implanted beneath the clavicle, with a lead wrapped around the left vagus nerve in the neck.
This can stimulate the vagus nerve for a fixed duration (Groves and Brown, 2005). Another
promising treatment for MDD that has been explored the past decade is transcranial magnetic
stimulation (TMS) as a focal and non-invasive alternative to ECT.
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2. Transcranial magnetic stimulation
Transcranial magnetic stimulation (TMS) is a non-invasive
method of brain stimulation in which magnetic fields are used
to induce electric currents in the cerebral cortex (Hasey, 2001).
A coil placed on the head is used to deliver magnetic pulses to
the cortex. These pulses freely pass the skull and induce an
electrical current in the underlying tissue, which then
depolarises the neurons. TMS is non-invasive and can
stimulate focused areas of the brain. Furthermore, TMS seems
to have therapeutic effects in psychiatric disorders (George et
al., 1999). The effects of TMS are somewhat similar to the
effects of ECT (Wassermann et al., 2001) because both rTMS
and ECT use electrical energy to induce neurological changes.
Figure 5: TMS coil placed above head
(Ridding and Rothwell, 2007).
However, the magnetic field is unaffected by the skull and can thereby be applied relatively
painlessly to conscious patients without the need for sedation, as in ECT (Hasey, 2001).
2.1 History of TMS in psychiatry
TMS is based on the discovery by Michael Faraday that a time-varying magnetic field can induce
an electric current in a nearby conductor (Faraday, 1831). This means that when an electrical
coil is moved through a magnetic field, an electric current will be induced and flow through the
coil. Some years later, Thompson (1910) stimulated volunteers with 50 Hz magnetic fields and
reported fainting and flickering. In 1981, Polson et al. (1982) performed the first stimulation of
superficial peripheral nerves with short-duration single pulses. The same group only three
years later introduced TMS when Barker et al. (1985) developed a compact machine that
allowed non-invasive stimulation of the cerebral cortex. The machine was designed to activate
neurons in the cortex and to produce an evoked potential in muscle tissue. Later, more focused
magnetic fields were used to map cortical regions involved in the functions of memory and
vision (Pascual-Leone et al. 1996; Paus et al, 1997). A more detailed early history is listed in
table 1.
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1771
Luigi Galvani
Animal Electricity
1819
Hans Christian Oersted)
Electromagnetism
1831
Michael Faraday
electromagnetic induction
1896
Arsenne d'Arsonval
"phosphenes and vertigo, and in some persons, syncope" when the subjects
1902
Beer
visual sensations, i.e., magnetophosphenes: "a faint flickering illumination,
1911
Thompson
colorless or a blush tint"
1976
Polson, Barker & Freeston
stimulation with brief magnetic field pulses and first demonstration of
head was placed inside an induction coil
peripheral nerve stimulation with simultaneous EMG recordings
1980
Merton & Morton
non-invasive brain stimulation with scalp electrodes
1985
Barker & al.
non-invasive, painless, cortical stimulation with magnetic fields
Table 1: brief history of magnetic stimulation (Barker, 1991; Geddes, 1991)
2.2 Main principles of TMS
In TMS a coil is placed on the scalp. The coil
conducts an electric current and this current
produces a magnetic field. This magnetic field can
pass through the skin and bone as shown in figure
6 and causes a secondary electric field in the brain.
The current in the brain has the opposite direction
as the current in the coil. The magnetic field is the
strongest near the coil and can stimulate neurons
up to 2 cm below the coil (Jalinous 1991). This
leads to changes in current in the underlying tissue
and can stimulate of inhibit neuronal functioning.
The electric field affects the transmembrane
potential
and
thereby
leads
to
membrane
depolarisation, which leads to neuron-firing.
Figure 6: The current in the coil generates magnetic
field B that induces electric field E. On the right E is
shown in two pyramidal neurons. E leads to local
membrane depolarisation
and neuron-firing.
Macroscopic responses can be detected with
functional imaging tools.
2.2.1 Apparatus
As mentioned above, the strength of the magnetic
field is achieved by brief current pulses of several
kilo-amperes. The basic electrical circuit of the
instrument consists of an energy storage capacitor,
a thyristor switch and the stimulating coil (fig. 7).
The energy storage capacitor stores energy. When
the thyristor switch is activated, the energy storage
Figure 7: schematic of simple magnetic stimulator
(Barker et al., 1999) R=resistance, D = diode, S1 =
switch
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capacitor is discharged trough the stimulating coil. This produces the magnetic field. The energy
returns from the coil through the diode. This diode and the resistance are important because
they reduce heating of the coil. Also the value of the resistance influences the fall times of the coil
current. This controls the magnetic field. The magnetic pulses induce electric currents in the
tissue (Jalineous, 1991).
Several different coils are available. A standard round coil consists of several circular turns of
copper wire of approximately 7 cm in diameter. This induces an electric current in a circle
beneath the coil. No current is induced in the centre of the coil and thereby stimulation is not
focal. Stimulation occurs under the coilwinding instead of the centre. For this reason figureeight-shaped coils were introduced. In these coils the currents are induced under each of the two
circles, but at the intersection of the two circles the current is the highest (Jalineous, 1991). Each
TMS pulse produces an electrical current in the brain that is approximately 100–200 μs. Because
of the two coils the stimulation can be focused on a surface from 1–2 cm2 (Thielscher et al.,
2004) and is twice as strong. The magnetic field decreases exponentially with distance from the
coil, so it is usually assumed that the stimulus activates neural elements in the cortex or
subcortical white matter.
2.2.2 Effects on the brain
The exact way in which TMS leads to neuronal activation
is still unknown. TMS probably targets near the bends of
neuronal axons because of their low activation threshold
by electrical currents. This activation depends on the
activation-threshold compared to the stimulus intensity.
The changes resulting from TMS often outlast the period
of stimulation. However, the mechanisms underlying the
lasting effects of cortical excitability are not yet
completely clear. Short-term effects might be caused by
changes in neural excitability resulting from ion changes
Figure 8: EMG response to TMS. Stimulus
intensity = 110%. 20 ms after stimulus you
can see a large MEP followed by a cortical
silent period. The dashed vertical line
indicates the end of the silent period (Riding
and Rothwell, 2007)
around the activated neurons (Kuwabara et al., 2002). Longer-lasting effects might be due to
long-term depression and long-term potentiation of synaptic connections (Riding and Rothwell,
2007). Lasting effects of rTMS may also depend on the glutamatergic N-methyl-d-aspartate
(NMDA) receptor (Stefan et al., 2002; Huang et al., 2007) or a reduction in inhibition (Ziemann et
al., 1998).
In figure 8, an electromyographic response is shown, recorded while a subject was contracting a
small hand muscle after a single pulse of TMS. Approximately 20 ms after the stimulus a large
motor evoked potential (MEP) occurs. The MEP is followed by the cortical silent period, which is
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a period of relative quiescence of background EMG activity. The vertical line indicates the end of
the silent period (Riding and Rothwell, 2007).
2.3 TMS as a tool for MDD
In the past few years TMS has been widely investigated for treatments of several neurological
disorders, varying from stroke and Parkinson’s disease to obsessive compulsive disorder and
epilepsy. More than 15 years ago the first trial was conducted to investigate the effects of TMS in
MDD. After this first one a lot of trials followed, some with positive results, others with less
beneficial results.
2.3.1 History of TMS in the treatment of MDD
Single-pulse TMS was first used as a possible therapeutic tool for depression in 1993 by Hoflich
and colleagues. Since then, MDD continued to be the most commonly studied psychiatric
condition in the application of rTMS (Wassermann et al., 2001). The dorsolateral prefrontal
cortex (DLPFC) has been the primary area of interest for stimulation. There were two reasons to
choose the DLPFC. First, the prefrontal, cingulate, parietal and temporal cortical regions, as well
as parts of the striatum, thalamus and hypothalamus, are thought to regulate mood. Second, the
DLPFC was the most accessible for treatment with rTMS of these areas (Wasserman et al., 2001).
The first open studies using TMS in MDD involved single-pulse stimulators at frequencies lower
than 0.3 Hz. (Hoflich et al., 1993; Grisaru et al., 1994). When the rTMS devices came on the
market the single-pulse generators were quickly replaced. Rapid-rate or fast rTMS is generally
defined as a stimulation frequency greater than 1 Hz (George et al., 1999). George et al. (1995)
were the first to administer rapid-rate rTMS to the left DLPFC in six patients. MDD scores
significantly decreased after treatment with rTMS. The Hamilton Rating Scale for depression
(HDRS; Hamilton, 1960) was used to evaluate response, in which a decrease in score indicates
improvement in depressive symptoms. Most authors consider a score of >50% on de HDRS
compared to the start value a right measure for clinical outcome, but sometimes a decrease of six
points is taken as measure for clinical relevance (Eschweiler et al., 2000). Much more open trials
followed and later many controlled-trials were performed.
2.3.2 How is TMS related to the causes of MDD?
The clinical effects of TMS seem promising, and it is interesting to understand how TMS might
influence the probable causes of MDD as mentioned in paragraph 1.1. First, TMS seems to have
neuroendocrine effects. Keck et al. (2001) found changes in stress-induced corticothrophin and
corticosteron levels after rTMS in rats. Therefore we might presume that rTMS alters the HPAsystem. This might result from reduction in vasopressin levels, which play a role in the
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disinhibition of HPA-activity in patients with MDD (Post and Keck, 2001). Pridmore (1999)
showed that the cortisol levels in patients were normalised after TMS treatment. However,
Zwanzger et al. (2003) found no such evidence.
TMS also seems to affect monoamines. Ben-Shachar et al. (1997) measured monoamines in rats
10 seconds after TMS. They reported that the dopamine content was reduced in the PFC, while it
was increased in the striatum and hippocampus. Serotonin levels were only increased in the
hippocampus, and norepinephrine levels were not affected by TMS.
Studies using low-frequency TMS support the hypothesis that MDD is partly caused by an
imbalance between the left and right hemisphere (Flitzgerald et al. 2006).
2.3.3 Limitations of TMS
There are some important limitations of TMS. One limitation is that the magnetic field decreases
rapidly with distance from the coil (Roth et al., 1991). This limits the stimulation of deeper brain
areas. Also, when large magnetic fields are used to stimulate deeper in the brain, a large area of
superficial cortex is also strongly activated. The results are than hard to interpret. Another
limitation is that the site of stimulation is not focal. However, with the newer coils the focus can
be limited to an area in the order of 1–2 cm2 (Thielscher et al., 2004).
2.3.4 Safety considerations
TMS treatment might have some adverse effects. The most serious side effect of TMS is when a
subject develops a seizure. It is hypothesized that the MEP threshold might give a value to
someone’s susceptibility for an epileptic seizure, as the motorcortex is one of the most sensitive
areas for an epileptic seizure. However, this is still uncertain. Other adverse effects were effects
on the hearing as a result of the click after a pulse. Also headache and local pain can be caused by
TMS. This is probably the result of stimulation on muscles (Wassermann, 1998).
Wassermann (1998) wrote a report with guidelines for the use of TMS (fig. 9). To prevent
adverse effects, Keel et al. (2002) proposed a questionnaire to screen subjects prior to TMS
treatment for risks.
Figure 9: guidelines from Wassermann 1998
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3. Therapeutic effects of TMS
Several meta-analyses and reviews have studied the effect of randomized controlled trials to
investigate the efficacy of rTMS in the treatment of MDD. In this chapter the literature will be
reviewed to describe the effects of TMS therapy in treating a major depressive episode.
Furthermore, TMS will be compared to other treatments that are generally used in practice to
treat MDD.
3.1 Reviews and meta-analyses
A large number of controlled trials and meta-analyses support the antidepressant effects of TMS.
Holtzheimer et al., 2001 published a meta-analysis over 12 controlled rTMS trials. They showed
large effect sizes in favour of the active rTMS treatment and the weighted mean effect size was
0.81. Nevertheless, when looking at the clinical efficacy (measured by a reduction of more than
50% on the HDRS) only a small group of subjects really improved compared to the sham group
(13.7 % of all patients treated with rTMS compared to 7. 9% of the patients treated with shamTMS). Burt et al., 2002 reviewed two meta-analyses comparing open studies and controlled
studies and found moderate to large effect sizes. Furthermore they suggested that placebo
effects contributed substantially to positive outcomes in the open studies. Unfortunately the
results strongly support for the efficacy of rTMS but the clinical results were not that big. The
patients improved by 37% in the open studies, and 23.8% (active) and 7.3% (sham) in the
controlled studies as measured by HDRS and MADRS. Kozel and George (2002) calculated a mean
effect size of 0.53 for 10 controlled trials of left prefrontal rTMS, supporting the positive
statistical evidence for rTMS as an antidepressant treatment. A problem with this study is that
they had a relative small number of subjects. A nice review by Loo et al., 2005 discussed different
meta-analyses and sham-controlled studies and concluded that the meta-analyses indicate that
rTMS treatment has been shown to have superior outcomes compared with a sham control,
though inspection of the mean change in rating scale scores suggests that a two-week treatment
course provides modest clinical outcomes. A meta-analysis by Herrmann and Ebmeier (2006)
found that rTMS was more effective in the treatment of MDD than sham rTMS with an effect size
of 0.71 in patients with treatment resistant MDD. The real rTMS reduced depressive symptoms
with a mean of 33.6% (Herrmann and Ebmeier, 2006). They tried to find factors that predict the
outcome of rTMS in patients with MDD. Unfortunately there were no parameters that clearly
predicted the treatment outcome after rTMS. This might have been the result of insufficient
study sizes and heterogeneous characteristics of the studies. What Herrmann and Ebmeier did
find was that studies with patients taking unstable medication or a stimulation of less than 90%
of the motor threshold may result in smaller levels of rTMS efficacy. Other interesting results
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were that high frequency stimulation to the left DLPFC and low frequency stimulation to the
right DLPFC are equally efficacious. In a short review Mitchell and Loo (2006) reviewed more
than 25 studies and concluded that rTMS is statistically superior to sham therapy, but the
clinical effects are still marginal in all studies. Gross et al. (2007) showed that recent clinical trials
of rTMS induced a larger effect size when compared to earlier studies. They proposed that the
parameters if stimulation with rTMS has been optimized in recent studies and that this
improvement in design is associated with larger treatment effects than earlier studies. This
statement was based on the finding of an effect size of 0.35 in earlier studies and effect size of
0.76 in more recent studies. A limitation of this meta-analysis was that they only found five
studies that met their criteria, which leads to a reduced power. Lam et al. (2008) performed a
meta-analysis on 24 randomised controlled trials with treatment resistant patients. They
concluded that active rTMS was significantly better than the sham treatment, but unfortunately
the pooled response and the remission rated were low. A recent meta-analysis by Schutter
(2009) compared 30 sham-controlled double-blind studies with a total of 1164 patients. This
group found an effect size of 0.39 and thereby it can be concluded that high-frequency rTMS
over the left DLPFC is superior to the sham treatment. Other interesting findings were that there
were no significant differences found between medication-resistant en non-resistant MDD. Also
there was no difference between studies that used <100% MT intensities and studies that used
100-120% MT intensities.
Nevertheless, there are a lot of studies that did not find these positive effects. For example
Martin et al. (2003) concluded from their meta-analysis that there is insufficient evidence that
rTMS is effective in the treatment of MDD. Besides that they concluded that most of the studies
were low quality trials with small sample sizes. After two weeks of treatment the standardised
mean difference showed significant differences between sham and rTMS, in favour of TMS, but
unfortunately studies that tested subjects 2 weeks after the end of the trial showed that the
effect of TMS had disappeared (Martin et al., 2003). Aarre et al. (2003) found only 12 studies
that met their criteria but because rTMS parameters and patienst characteristics too diverse a
formal meta-analysis of the studies was thus not possible. Therefore they performed a
qualitative evaluation of the included studies. From this they concluded that efficacy was
inconsistently shown between studies, and that there was insufficient evidence as yet to support
the use of rTMS as an antidepressant treatment and that further research was warranted.
Comparisons with electroconvulsive therapy (ECT) indicated the superiority of ECT. They
concluded that there is insufficient evidence for rTMS as a valid treatment for MDD at present.
Coutourier (2005) included six studies in her meta-analysis and suggested that rTMS is no
different from sham treatment in MDD. However, as mentioned above, there were only six
studies that met her inclusion-criteria and therefore these results might be questionable.
16
An important note is that a lot of the reviews and meta-analyses mentioned above have used the
same studies for their meta-analyses. Furthermore there are large differences in quality of the
studies. Therefore it is not adequate to only watch the number of positive and negative reviews
and meta-analyses published but is it important to also look at the limitations and quality of the
studies to draw conclusions about the efficacy of TMS.
3.2 TMS compared to other treatments
Unfortunately, MDD is a disorder that is very sensitive to placebo effects. This can be seen in
TMS trials as well. But before we criticise TMS as a therapeutical tool to treat MDD, it is
important to compare the effects of TMS with the most common other treatments prescribed for
MDD.
3.2.1 TMS versus psychotherapy
Unfortunately there are no studies available that
have compared TMS and psychotherapy with one
another. There are studies however, that compare
psychotherapy
and
antidepressants.
Overall,
studies found that both are equally effective. A
review by DeRubeis et al. (1999) compared the
outcomes of antidepressants (Imipramine and
Nortriptyline) and CBT in severe patients, based on
four studies (see fig. 10). From the pooled results
Figure 10: post-treatment scores on the HDRS in
four studies (DeRubeis et al., 1999)
they concluded that even for severe patients
medication is as effective as CBT.
Years later
DeRubeis et al. (2005) performed a large study in
which moderate to severe patients were treated
with medication, psychotherapy of placebo in the
form of a pill placebo. Form this study they
concluded that both medication and psychotherapy
Figure 11: effect sizes for post-treatment scores of
medication versus CBT (DeRubeis et al., 1999).
were more efficient than placebo and that at one site psychotherapy and medication were
equally effective and at the other site there were significant differences in favour of medication.
This was explained by differences in experience of the therapists. Still, from these two studies
we can conclude that CBT and medication do not differ much in the effectiveness in the
treatment of MDD.
17
3.2.2 TMS versus medication
Drug trials show placebo effects ranging from 30% to 50% in MDD studies (Brown, 1994;
Schatzberg et al., 2000). Device-based treatments, like TMS, may result in even higher placebo
response rates because of the technology involved (Kaptchuk et al., 2000). Some evidence
suggests that the effect sizes of TMS studies are similar to those seen in drug trials.
Kirsch et al. (2002) analysed the efficacy of six antidepressants and reported that 18% of the
drug response is due to the pharmacological effects of the medication. The differences between
drug and placebo-treatment were very small and ranged between 1 and 3 point on the HDRS.
This makes the clinical effect of antidepressant drugs rather questionable. Unfortunately Kirsch
et al. could not calculate effect sizes due to the absent of standard deviations in the reports they
used. Some years later, a meta-analysis by Chen et al. (2006) examined the effects of
antidepressant medication and showed and effect size of 0.23. This suggests that rTMS might be
more effective than medication. Other reviews reporting on the efficacy of antidepressants
show the same placebo effects, with Kirsch & Sapirstein (1998) reporting that 75% of the
response to antidepressant drugs is caused by placebo effects, and Khan, Warner, and Brown
(2000) reporting that 76% of response to antidepressant is the result of the placebo-effect. From
this we can conclude that TMS is equal effective as medication in the treatment of MDD.
3.2.3 TMS versus ECT
There have been some favourable results in comparisons of rTMS to ECT for more severe, often
drug-resistant patients. Grunhaus et al. (2000) compared rTMS with right unilateral ECT and
concluded that ECT was superior to rTMS for patients with major depressive disorder and
psychosis. In the non-psychotic group, however, de therapeutic effects of rTMS were similar to
those of ECT. An important limitation of this study is that the psychotically depressed patients
receiving ECT also received medication, whereas the patients receiving rTMS did not. In the
same year, also Pridmore et al. (2000) compared unilateral ECT with rTMS. Although patients in
the ECT group showed more improvement on the Beck Depression Inventory, the rate of
remission on the HDRS and the percent improvement over the course of the treatment was the
equal for both groups. Janicak et al. (2002) also compared rTMS with ECT but used more
aggressive rTMS parameters and also they administered ECT bitemporal. There were no
differences in baseline to end-of-treatment between ECT and rTMS. Also in the response rates
(set on a ≥ 50% decrease from baseline HDRS and a total final score of ≤ 8), there were no
significant differences between the groups. One of the limitations of this study was that the
raters were not blind. A major limitations of all studies mentioned above is that they had no
placebo control groups, while the effect size of ECT vs placebo is -0.91 (Major, 2003).
18
In 2003, Grunhaus et al. tried to replicate their earlier findings that ECT and rTMS had similar
effects in non-psychotic patients (Grunhaus et al. 2000). They concluded that both treatments
were effective for treating severe and medication resistant non-psychotic MDD. An interesting
study by Dannon et al. (2002) investigated the 6-month outcome of patients that responded to
an ECT or a 4-week rTMS treatment, to study whether the successful outcome after rTMS is
maintained over time. After six months, 20% of the patients in both groups relapsed. This
suggests that the relapse rates of ECT and rTMS do not differ in MDD.
In sum, ECT is superior in psychotic patients with MDD, but in non-psychotic patients ECT and
TMS seems to be equally effective.
4. Possible outcome predictors
The effects of rTMS depend on different variables. Those can be patient-related variables but
also treatment-related variables. It is important to review the patient-related factors, as they can
be used as possible outcome predictors after treatment. Treatment-related factors on the other
hand should be reviewed as they can optimise the treatment efficacy of TMS. In the following
chapter I will discuss both these factors for more insight in the effect of TMS on MDD.
4.1 Patient-related factors
Patient-related factors influencing the response to TMS treatment are very variable. For example
the absence of a comorbid anxiety disorder, a higher baseline MDD severity, female gender and
shorter illness duration were associated with a better response (Lisanby et al., 2009). It is
important to examine the different patient-related factors because then we might predict a
patients’ response to treatment with TMS and maybe even adjust the treatment-variables to the
patient.
4.1.1 Medication resistance
One of the patient-related factors that might influence the trial outcome is medication resistance.
A recent study by Lisanby et al. (2009) performed a large 4-week sham-controlled randomized
clinical trial in 301 medication-free unipolar depressed patients to examine candidate predictor
variables of antidepressant response to TMS. They reported that a lower degree of medication
resistance in the current episode predicts better anti-depressant response to TMS and suggest
that patients with unipolar MDD who have failed one adequate medication trial in the current
episode are more likely to have a therapeutic response to 10 Hz TMS delivered to the left DLPFC
using the treatment schedule used in this study than those who have failed 2–4 trials (Lisanby et
al., 2009). This finding was supported by Brakemeier et al. (2007), who also found that a lower
level of medication resistance predicts a better response to TMS. However, a recent meta-
19
analysis by Schutter (2009) did not find significant changes in effect size between medicationresistant and non-resistant MDD. This might be due to variability among studies.
4.1.2 Age
Janicak et al. (2002) found a correlation between age and the number of response needed to
achieve response in rTMS in a trial of high-intensity and longer TMS treatments. Also Lyness et
al. (1996) suggest that younger patients respond better to antidepressant treatment. Mosimann
et al. (2004) discovered in his study that after two weeks of treatment there were no differences
between the sham group and the treatment group of elderly patients with treatment-resistant
MDD and thereby they were unable to demonstrate any additional antidepressant effects of age.
Figiel et al. (1998) and Kozel et al. (2000) both observed that older patients respond less well to
rTMS. In older patients, onset of MDD after age 65 was also associated with less response to
treatment (Figiel et al., 1998). A remarkable finding by Lisanby et al. (2009) was that patients
above 54 showed a similar response as younger patients. They explained this by the fact that
their study had a time-span of 4 weeks instead of the usual 1-2 week trials and according to
Gildengers et al. (2005) elderly people show a slower trajectory of response. In an attempt to
find outcome predictors for TMS, Brakemeier et al. (2007) could not find a correlation between
age and response to TMS. An explanation for this might be that they measured a relatively young
sample of patients.
4.1.3 Anatomic variation
In most studies, the DLPFC is located by inducing muscle contractions in the abductor pollicis
brevis and moving 5cm anterior to this site (Pascual-Leone et al, 1996). However, every
individual is unique and therefore there are differences between subjects in the anatomy of the
brain. This means that the location of cortical sites can be different in different subjects.
Fortunately this can now be checked by making an anatomical MRI image of every patients’s
brain so that the focus of the TMS coil can be placed onto the right area of the skull (Neggers et
al., 2004). Because in elderly people the distance from scalp to brain surface is different form
younger people, also the stimulus intensity can be corrected for (Stokes et al., 2005).
4.1.4 History of neural activity in the stimulated region
The effects of rTMS also depend on the history of synaptic activity in the stimulated region.
When you applicate stimuli of 6-Hz rTMS to the motor cortex it can increase its excitability,
whereas 1-Hz rTMS decreases excitability. If, however, 6-Hz rTMS is applied for a short period,
the suppressive effect of a subsequent period of 1-Hz rTMS is enhanced (Iyer et al., 2003).
Generally, a prior history of increased activity seems to increase the effectiveness of rTMS
protocols that decrease excitability, whereas a prior history of reduced activity increases the
20
effect of facilitatory rTMS. Regional brain activation has been associated with differential
response to high- vs. low-frequency TMS (Kimbrell et al, 1999), suggesting that the state of the
circuitry targeted by TMS may affect outcome. In a PET analysis they found that hypometabolism
in the cerebellum, both temporal lobes, and the occipital and anterior cingulate regions was
associated with a positive response to 20-Hz treatment, but that hypermetabolism was
associated with improvement with 1-Hz treatment.
4.1.5 Medication
Patients who receive rTMS may concurrently be taking pharmacological treatments, and these
can also influence the nature of the after-effects. Medication can influence the effect of TMS. For
a review on the effects of drugs on TMS see the article of Ziemann (2004).
4.1.6 Duration of episode
Holtzheimer et al. (2004) investigated medication-free patients with TMS to the left DLPFC at
110% motor threshold. They concluded from the treated group that subjects with a depressive
episode duration of shorter than 4 years had a mean HDRS decrease of 52% compared to 6% in
subjects with an episode duration longer than 10 years. A shorter duration of episode and more
lifetime treatment trials significantly predicted improvements in BDI but not HDRS scores.
Patients with a shorter duration of the current episode showed a greater response to TMS. This
finding is supported by Brakemeier et al. (2007) as they also found that duration of current
episode and the number of antidepressant trails were significantly different between responders
and non-responders to TMS.
4.1.7 Other patient-related variables
Next to the possible outcome predictors mentioned above, there are many more variables like
history and course of the illness and genetic factors. For example subjects who have a Val66Met
polymorphism in the gene encoding brain-derived polymorphisms affecting serotonin and
glutamate neurotransmission show that the observed increase in excitability of the motor cortex
after a period of motor practise is reduced (McMahon et al, 2006; Paddock et al, 2007). Gershon
et al. (2003) suggested that the absence of a psychosis might be a predictor of a successful
treatment. Brakemeier et al (2007) suggested that sleep disturbances are a clinical predictor for
an early response to TMS. They did not find differences between responders to treatment and
non-responders in age, gender, number of depressive episodes or baseline MDD severity. Smith
et al. (1999) showed that the excitability of a cortical network changes with the menstrual cycle,
which might be important in study populations with females.
21
4.2 Treatment related- variables
Some treatment related factors include coil-type, stimulator type, waveform shape and polarity,
coil position, and orientation relative to target cortex. These variables are important because
they can influence the efficacy of TMS in the treatment of MDD.
4.2.1 Frequency
Most studies give rTMS within the frequencies of 5-20 Hz. Sachdev et al. (2002) suggested that
higher frequencies might have a greater anti-depressive effect. However Miniussi et al. (2005)
did not find any significant differences between a group of patients stimulated with a frequency
of 1 Hz and a second group of patients stimulated with a frequency of 17 Hz. They also did not
find any differences between the treated group and the placebo-group, which might be a result
of a short treatment period of only 5 days. Stern et al. (2007) found that both high frequency
left-sided rTMS and low frequency right-sided rTMS to the DLPFC led to a clinically significant
antidepressant effect (≥50% reduction in the HDRS score) in 60% of patients with unipolar
major depressive disorder. They also found that both high frequency left-sided rTMS and low
frequency right-sided stimulation showed an equal duration of antidepressant effect in their
follow-up at 4 weeks. Unfortunately this follow-up was not blinded. Preliminary results of
Sakkas et al. (2008) indicate that patients who were treated two times a day with rTMS, in
contrast to the daily sessions, showed a faster reduction of depressive symptoms as measured
by the HDRS scale. Furthermore, some of them showed faster remission of depressive
symptoms. From these studies no clear insights in the influence of frequency on the treatment of
MDD with TMS can be given.
4.2.2 Stimulation site
The left DLPFC is the mostly used target for rTMS in the treatment of MDD. The reason for this
choice was because this region is the most accessible for treatment with rTMS of the areas
thought to be involved in mood regulation (Wasserman et al., 2001). However, some researchers
have investigated the effects of stimulating the right DLPFC with a frequency of < 1Hz. The
results of the studies were contradictory. Hoppner et al. (2003) failed to find significant
differences between the two approaches. Also Loo et al. (2003) studied bilateral stimulation
with negative effects. Fitzgerald et al. (2006) did find a reduction on MADRS scores after first
stimulating the right DLPFC with slow frequency rTMS followed by left DLPFC stimulation with
high frequency rTMS. As already mentioned above, Stern et al. (2007) found that both high
frequency left-sided rTMS and low frequency right-sided rTMS showed an antidepressant effect
in patients. Not unimportant, low frequency TMS to the right hemisphere is more save because
of a lower risk for a seizure and it is also better tolerated by patients (Wassermann 1998).
22
Some researchers proposed that there are better targets than the DLPFC for rTMS because of a
faster response. There is evidence for the involvement of the parietal cortex in MDD (Keller et
al., 2000; Schutter & van Honk, 2005). Lesion and neuro-imaging studies indicate that the
parietal cortex is involved in MDD (Schmahmann, 1998; Uytdenhoef et al., 1983). A hypoactive
right parietal cortex has been associated with MDD. A well-known biochemical marker for MDD
is cortisol. Presumably because of a hyperactive hypothalamic–pituitary–adrenal (HPA) axis,
depressive as well anxious subjects often demonstrate basal levels of this stress-related
hormone that are higher than normal (Gold et al., 2002). Furthermore, Schutter et al. (2002)
found that higher basal levels of cortisol are associated with reductions in functional
connectivity between the left prefrontal and the right parietal cortex. An rTMS experiment
showed in healthy human subjects that the application of 2-Hz rTMS over the right parietal
cortex for 20 minutes resulted in statistically significant decreases in selfreported, attentional
and psychophysiologic indices of depressive mood compared with placebo (van Honk et al.,
2003). This suggests a possible antidepressant efficacy, although in another group of subjects.
Also the cerebellum has been proposed as a target for rTMS (Schutter et al., 2003; Schutter &
van Honk, 2005). There is a growing body of evidence that indicates that the cerebellum is also
involved in emotion. Because of its modulatory role on emotion, the midline cerebellar vermis
together with the fastigial nucleus and the flocculonodular lobe have been designated the limbic
cerebellum (Schmahmann, 2000). Additional evidence for the involvement of the cerebellum in
mood disorders, such as MDD, was provided by sMRI studies that showed that unipolar MDD is
also associated with volumetric reductions of the cerebellum (Soares and Mann, 1997).
Starkstein et al. (1988) found evidence for a relation between cerebrovascular lesions in the
cerebellum and MDD. Schutter et al. (2003) investigated the existence of the assumed projection
from the medial cerebellum to the PFC in healthy human subjects using fast rTMS and
electroencephalography. rTMS targeting the medial part of the cerebellum indeed modulated
ongoing electrical activity in the PFC. Interestingly, in the latter study, elevations in mood and
alertness were reported spontaneously after medial cerebellar stimulation exclusively. Because
the cerebellum has efferent pathways to the substantia nigra, and MDD has been linked to
deficiencies in the biogenic monoamines, cerebellar rTMS in the study by Schutter et al. (2003)
might have stimulated dopamine release, resulting in the observed changes in PFC activity and
the elevations in alertness and mood. In sum, the evidence suggests a role for the cerebellum in
clinical MDD, and mood improvements after fast cerebellar rTMS have recently been shown in
healthy volunteers
23
4.2.3 Stimulation intensities
Even though a recent meta-analysis by Schutter (2009) did not find significant changes in effect
size between studies that used <100% MT intensities and studies that used intensities of 100120% MT, imaging studies of George et al. (2000), Nahas et al. (2000) and Kozel et al (2000)
have hypothesized that using higher intensities may have more robust effects as the magnetic
field declines logarithmically with distance from the coil. Padberg et al. (2002) examined
patients with rTMS at three different stimulation intensities; the individual motor threshold,
90% subthreshold and standard sham rTMS. Improvement of depressive symptoms after rTMS
significantly increased with stimulation intensity across the three groups. Similarly, groups
differed significantly regarding the clinical course after rTMS with the lowest number of
antidepressant interventions and the shortest hospital stay in the MT intensity group. Expressed
in percent decrease of MADRS scores, sham rTMS yielded a 4.1% reduction, 90% MT rTMS
resulted in a 15.1% decrease, and 100% MT rTMS reduced MADRS scores by 33.2%. The
respective linear effect on HRSD scores showed a statistical trend. Percent reductions of HRSD
scores were 7.1% after sham rTMS, 14.9% after 90% MT rTMS and 29.6% after 100% MT rTMS.
Gershon et al. (2003) suggested that trials that used a MT of 100-110% were more effective than
trials that used an intensity of 80-90%. Nahas et al. (2000) performed a similar study with 80%,
100% and 120% MT and concluded that higher intensity stimulation leads to more local and
contralateral activation.
4.2.4 Number of stimulations
Number of stimulations has varied across studies but most positive trials deliver between 8000
and 20000 stimulations per treatment course. Gershon et al. (2003) suggested that trials with
1200-1600 pulses per day were more successful than treatments with 800-1000 pulses. This
indicates that studies with higher numbers of pulses have better outcomes. However, this should
be investigated more accurately.
4.2.5 Number of sessions/ course duration
Several studies have suggested that lengthening the duration of treatment further than 10
sessions enhances antidepressant efficacy (Flitzgerald et al., 2006). O’Reardon et al. (2007)
studied a large sample of medication-free treatment resistant patients for 4-6 weeks. Their
finding indicated that TMS is a safe and effective treatment for MDD. Active treatment with TMS
was significantly superior to sham TMS treatment for the change in mean symptom score using
the HDRS at weeks 4 and 6.The MADRS also showed this pattern. Clinically important change, as
reflected in terms of the categoric outcomes of response and remission, was also achieved in a
substantial portion of patients. At 6 weeks, the active TMS group was about twice as likely to
24
have achieved remission compared with the sham TMS group. The trajectory of improvement
implies that more than 2 weeks of TMS, compared with sham, is required in this population
before a significant improvement is detected. Similarly, it appears that an additional 2 weeks of
TMS beyond the initial 4 weeks, can have an important clinical impact. The remission rates
doubled during that period of time. Gershon et al. (2003) did a raw analysis to examine the
effects of the course duration and suggested that trials with treatments given longer than 10
days yielded better results than 10-day treatments.
4.2.6 Coil type
Thielscher and Kammer (2004) compared two commonly used TMS coils with respect to their
electric field distributions induced on the cortex and concluded that both coil types should evoke
similar physiological effects when adjusting for the different efficiencies. As a consequence,
results from studies performed with one of the two coils should be directly comparable to those
using the other one.
5. Discussion: how to improve the long-term benefits of MDD
In this thesis I reviewed the literature on TMS as a therapeutic tool in the treatment of MDD. I
especially focused on the available meta-analyses and reviews but for the overview I also
included studies that used different study parameters.
Especially early studies did not al find beneficial effects of TMS in patients. This might be
explained by the fact that these trials included small sample sizes and that the parameters used
for stimulation were far from optimised. Recently more trials find beneficial effects of active
TMS over the placebo condition, which indicates that the knowledge about the study parameters
is improved by the years. Also recent trials are often double-blind and placebo controlled, which
is crucial for understanding the true effect of a treatment.
One of the problems I experienced in this thesis was the diversity of study parameters used in
studies. Therefore it was hard to compare studies and predict what the best parameters are to
use for further research. Still, there are some parameters that could be improved.
First, I would propose more research to investigate other possible sites of stimulation. As
mentioned in 4.2.2, there have been some promising studies that proposed the parietal cortex
and the cerebellum as possible targets for stimulation. Also the localisation of the stimulation
site is an important topic. A lot of studies use a procedure in which the DLPFC is located by
inducing muscle contractions in the abductor pollicis brevis and moving 5cm anterior to this site
(Pascual-Leone et al, 1996). However, this method does not take into account the interindividual differences in head shape and size, which makes this method inaccurate. This
25
problem can be easily solved by making an MRI scan before the treatment and locate the
stimulation site based on the anatomical scan (Neggers et al., 2004).
Another problem I ran into was that there are few studies that perform a follow-up on their
patients. The studies that did unfortunately indicated that the beneficial effects of rTMS are not
long lasting. A meta-analysis by Martin et al. (2003) indicated that rTMS might be more effective
immediately after treatment but not at a two week follow-up. Mogg et al. (2007) performed a 2week during randomized controlled trial comparing real and sham adjunctive rTMS with 4month follow-up. There were no significant differences between the two groups on HDRS, BDI-II
and BPRS score measured on 6-week and 4-month follow-ups. They concluded that adjunctive
rTMS of the left DLPFC could not be shown to be more effective than sham rTMS for treating
MDD. Because of the short effects of rTMS treatment, the idea came up that maybe a
maintenance-study might be an idea to see if the effects seen right after the last treatment of the
trial can perhaps be maintained by a once a week treatment.
Concerning the stimulus parameters, O’Reardon et al (2007) showed that more than 2 weeks of
stimulation was necessary to detect significant changes between the placebo and active treated
group. An explanation for this might be that TMS needs some time before it changes the brain
enough to see clinical differences. It might also be that some patients respond earlier than
others, but because the analyses are group-based, this only shows later. Gildengers et al. (2005)
also proposed that elderly people showed a slower trajectory of response. This was also
suggested by Lisanby et al. (2009), who did not find any difference between older and younger
patients and proposed that this was due to the fact that their study had a time span of 4 weeks
instead of two. Furthermore, trials seem to be more effective with stimulus-intensities above
motor threshold and O’Reardon et al. (2007) recently showed that stimulation at 120% of MT
and 3000 stimuli per session in a large sample did not show serious adverse events so
stimulation at high intensity can be applied safely.
Another concern is the sham-conditions. There are several methods to give a sham treatment.
Ideally the sham-treatment should be on the same location on the head, with the same scalp
sensations and sounds of a real treatment, but without the effect on the brain. One of the most
used methods for sham-treatment is positioning the coil to the scalp with an angle of 45°. In this
way the direction of the current and the intensity differs from the real treatment. George et al.
(1997) reported that this did not lead to measurable changes in the motor-cortex. But what if
the rotated coil does weakly stimulate the cortex? In that case the cortex still gets stimulated,
and this might explain the high placebo-effects in TMS studies. In 2000, Loo et al. investigated
seven sham positions and concluded that none of the positions were ideal as more scalp
sensation was also more likely to stimulate the cortex. This can be partially solved by treating
TMS-naïve patients who don’t know the feeling of TMS and thereby can not pick out placebo.
26
However, this still is a problem for cross-over designs. Therefore I think that there is a need to
optimize placebo conditions.
It is hard to compare TMS to other treatments, as this is not frequently done. However, from the
studies that compared TMS to ECT, I can only conclude that TMS is as effective as ECT in nonpsychotic patients. Therefore TMS might be an alternative to ECT for at least some patients even
if only some of the patients respond, because of the fewer cognitive side effects, the fact that TMS
is easier to administer and because it is less expensive.
From the literature summarised in this paper I think we can conclude that TMS is an interesting
technique with possible therapeutic effects on MDD. Furthermore we can conclude that,
although a lot of studies have been performed already, TMS can still be optimised by exploring
patient- and treatment related variables before it is ready to become a worldwide commonly
used tool to treat MDD. Yet, it is important to keep in mind that the cerebral cortex is a complex
structure and that TMS will never completely be able to imitate the networks that occur during
normal functioning.
Acknowledgments
I would like to thank Dennis Schutter for his supervision and help in writing this thesis.
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