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Is rTMS effective for anxiety symptoms in major depressive disorder? An efficacy analysis comparing left‐sided high‐frequency, right‐sided low‐frequency, and sequential bilateral rTMS protocols

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Background Anxiety symptoms are common in major depressive disorder. Whilst therapeutic efficacy of repetitive transcranial magnetic stimulation (rTMS) in depression is well‐established, minimal research has investigated rTMS's efficacy in treating anxiety symptoms in depression. Methods This study investigates the effectiveness of rTMS in treating anxiety symptoms in depression, specifically the relative efficacy of the three rTMS protocols commonly used in clinical practice: left‐sided high‐frequency, right‐sided low‐frequency and sequential bilateral rTMS. Antidepressant efficacy of each rTMS protocol is also investigated. Treatment data for 697 patients were pooled from three studies across five sites. Changes in Beck's Anxiety Inventory (BAI) and the Hamilton Depression Rating Scale over 4‐week rTMS courses were analysed using latent growth curve modelling. Results All rTMS protocols were effective in treating anxiety symptoms (mean BAI reduction, 8.13 points; p < 0.001) and depressive symptoms. Near therapeutic equivalence was seen across the three protocols. Improvement in depressive severity positively correlated with improvement in anxiety. Both high‐ and low‐baseline anxiety scores showed overall symptom reduction. Conclusions This study addresses the clinical knowledge gap pertaining to rTMS's therapeutic efficacy in treating anxiety symptoms in depression and the relative efficacy of three commonly used stimulation protocols. Our findings suggest therapeutic equivalence across left‐sided high‐frequency, right‐sided low‐frequency, and sequential bilateral rTMS approaches.
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Received: 10 December 2018
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Accepted: 22 March 2019
DOI: 10.1002/da.22894
RESEARCH ARTICLE
Is rTMS effective for anxiety symptoms in major depressive
disorder? An efficacy analysis comparing leftsided
highfrequency, rightsided lowfrequency, and sequential
bilateral rTMS protocols
Leo Chen
1,2,3
|
AbdulRahman Hudaib
1
|
Kate E. Hoy
1,2
|
Paul B. Fitzgerald
1,2
1
Monash Alfred Psychiatry Research Centre,
Monash University, Melbourne, Victoria,
Australia
2
Epworth Centre for Innovation in Mental
Health, Epworth HealthCare, Camberwell,
Victoria, Australia
3
Alfred Mental and Addiction Health, Alfred
Health, Melbourne, Victoria, Australia
Correspondence
Leo Chen, Monash Alfred Psychiatry Research
Centre, Monash University, Melbourne, VIC
3004, Australia.
Email: leonard.chen@monash.edu
Funding information
National Health and Medical Research
Council, Grant/Award Numbers:
APP1135558, 1078567
Abstract
Background: Anxiety symptoms are common in major depressive disorder. Whilst
therapeutic efficacy of repetitive transcranial magnetic stimulation (rTMS) in
depression is wellestablished, minimal research has investigated rTMS's efficacy in
treating anxiety symptoms in depression.
Methods: This study investigates the effectiveness of rTMS in treating anxiety
symptoms in depression, specifically the relative efficacy of the three rTMS protocols
commonly used in clinical practice: leftsided highfrequency, rightsided low
frequency and sequential bilateral rTMS. Antidepressant efficacy of each rTMS
protocol is also investigated. Treatment data for 697 patients were pooled from three
studies across five sites. Changes in Beck's Anxiety Inventory (BAI) and the Hamilton
Depression Rating Scale over 4week rTMS courses were analysed using latent
growth curve modelling.
Results: All rTMS protocols were effective in treating anxiety symptoms (mean BAI
reduction, 8.13 points; p< 0.001) and depressive symptoms. Near therapeutic
equivalence was seen across the three protocols. Improvement in depressive severity
positively correlated with improvement in anxiety. Both highand lowbaseline
anxiety scores showed overall symptom reduction.
Conclusions: This study addresses the clinical knowledge gap pertaining to rTMS's
therapeutic efficacy in treating anxiety symptoms in depression and the relative
efficacy of three commonly used stimulation protocols. Our findings suggest
therapeutic equivalence across leftsided highfrequency, rightsided lowfrequency,
and sequential bilateral rTMS approaches.
KEYWORDS
anxiety, anxiety disorders, brain stimulation, depression, repetitive transcranial magnetic
stimulation, treatmentresistant depression
1
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INTRODUCTION
Depression and anxiety are common worldwide and associated with
significant disease burden, as assessed by disabilityadjusted life
years (Whiteford et al., 2013) and years of life lived with disability
(A. J. Baxter, Vos, Scott, Ferrari, & Whiteford, 2014). Persistent
illness is associated with significant subjective distress, functional
decline, increased morbidity and mortality as well as carer burden.
Depress Anxiety. 2019;19. wileyonlinelibrary.com/journal/da © 2019 Wiley Periodicals, Inc.
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1
Despite their prevalence and negative impact on function and quality
of life, both can be refractory to conventional treatments, with
treatment resistance reported at rates of 30% for depressive (Crown
et al., 2002) and 25% for anxiety disorders (Kessler et al., 2005). The
two conditions often coexist, either as concomitant disorders or a
primary depressive or anxiety syndrome that manifest in secondary
depressive and anxiety symptoms. Lifetime comorbidity of the two
syndromes has been reported at 90% (Gorman, 1996). Neuroimaging
points to several shared brain regions that exhibit abnormal activity
across the two disorders, with one instance being overactivation of
the amygdala in patients presenting with either depressive symptoms
or anxiety responses (Ressler & Mayberg, 2007). Brain regions
implicated in mood regulation, such as the anterior cingulate and
prefrontal cortices (PFC), amygdala, insula, and limbic system have
also been implicated in anxious responses such as monitoring,
vigilance, and the expression and modulation of fear responses
(Etkin, 2012). The same neuroanatomical regions have also been
implicated in anxiety disorders such as generalised anxiety disorder
(GAD), obsessivecompulsive disorder (OCD), posttraumatic stress
disorder (PTSD; Pallanti & Bernardi, 2009), and depressive disorders
(L. R. Baxter et al., 1989; George, Ketter, & Post, 1993, 1994).
Given the considerable disease burden and treatmentrefractory
nature of these disorders, clearly, the need exists for effective
treatment options in addition to what is available. One such modality
is repetitive transcranial magnetic stimulation (rTMS), a technique that
applies patterned electromagnetic pulses to superficial brain regions to
depolarise underlying neurons in a noninvasive manner. Repeated
stimulation modulates neuronal activity and downregulates electro-
chemical properties along neuronal pathways, which is one of the
postulated mechanisms of action behind its therapeutic potential in
depressive disorders (Liston et al., 2014; Tik et al., 2017). In clinical
practice, rTMS is typically applied to the left and/or right dorsolateral
aspects of the prefrontal cortex (DLPFC), inducing subtle, but
repeatable, changes in electrophysiological, metabolic, and intrasynaptic
activity both locally and distally along brain circuits implicated in mood
regulation (George et al., 2003). Indeed, as an antidepressant therapy,
rTMS has been extensively investigated over the past two decades, with
substantive evidence supporting its efficacy derived from multiple
shamcontrolledrandomisedtrials(Fitzgerald et al., 2003; George et al.,
2010; O'Reardon, Solvason, & Janicak, 2007) and metaanalyses (Berlim,
van den Eynde, TovarPerdomo, & Daskalakis, 2014; Schutter, 2009;
Slotema, Blom, Hoek, & Sommer, 2010). The three evidencebased
stimulation parameters/targets commonly used in clinical settings are
highfrequency stimulation to the left DLPFC (LHF rTMS), low
frequency stimulation to the right DLPFC (RLF rTMS), and bilateral
rTMS sequentially applied to both right and left DLPFC (BL rTMS), with
established equivalence of antidepressant efficacy across the three
protocols (J. Chen et al., 2013; J.J. Chen et al., 2014; Fitzgerald et al.,
2011, 2013; Hoy, Segrave, Daskalakis, & Fitzgerald, 2012). In contrast,
there has been a paucity of studies examining rTMS's effects on anxiety,
either as comorbid symptoms in major depressive disorder (MDD) or in
primary anxiety disorders such as GAD, OCD, and PTSD, but to name a
few. Four recent systematic reviews of openlabel and shamcontrolled
studies of rTMS and its effects on OCD, PTSD, GAD, panic disorder, and
social anxiety disorder failed to draw definitive conclusions on its clinical
efficacy (Machado et al., 2012; Pallanti & Bernardi, 2009; Pigot, Loo, &
Sachev, 2008; Zwanzger, Fallgatter, Zavorotnyy, & Padberg, 2009).
Some reported reasons for this are (a) the diverse variations of rTMS
protocols studied, (b) small sample sizes ranging between 10 and 42,
particularly in the case of shamcontrolled trials, and (c) the overall
limited number of studies.
Similarly, limited studies have examined the effects of rTMS on
comorbid anxiety symptoms that occur in depression, sometimes
referred to as anxious depression.In one study, a small subset of
patients with anxious depression was found to derive equal
antidepressant effects from LHF rTMS as nonanxious patients with
depression (Diefenbach, Bragdon, & Goethe, 2013). In another open
label study, 15 chronically depressed, severely treatmentresistant
patients were treated with 20 sessions of LHF rTMS (Berlim, McGirr,
Beaulieu, & Turecki, 2011), resulting in 25% and 18.3% reductions
across two anxiety symptomatology rating scales. A third openlabel
trial of 36 depressed patients reported 15 sessions of leftsided
20 Hz rTMS resulted in large therapeutic effect sizes (Pearson's
r> 0.5) on both anxiety and depression symptoms (Durmaz, Ebrinc,
Ates, & Algul, 2017). Contrary to these positive findings, however,
there have also been reports of worsening anxiety associated with
rTMS treatment (Greenberg, McCann, Benjamin, & Murphy, 1997).
The only systematic review and metaanalysis specifically addressing
rTMS's effects on comorbid anxiety symptoms in depression was
published by coinventors of a proprietary TMS coil capable of deeper
cortical stimulation compared with standard figureofeight coils
(Kedzior, Gellersen, Roth, & Zangen, 2015). In this study, deep rTMS
was reported to have a large positive effect size (Cohen's dof 1.45) in
treating anxiety symptoms in treatmentresistant MDD.
In sum, the small sample sizes, openlabel design, and hetero-
geneous rTMS parameters featured in these studies leave the
question of whether rTMS is effective in treating anxiety symptoms
in depression unanswered. It is also not known which rTMS protocol
(s) are superior in this regard. Given the ubiquitous occurrence of
anxiety symptoms in depression sufferers, evidence to guide optimal
rTMS protocol choice is timely and can be of significant clinical value.
Therefore, we aimed to investigate the efficacy of rTMS in treating
comorbid anxiety symptoms in MDD over a 4week treatment
course. A threeway comparison of relative efficacy over time across
LHF rTMS, RLF rTMS, and BL rTMS protocols was also investigated.
2
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METHODS
2.1
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Study design
We analysed pooled data from three clinical trials that featured a
combination of RLF/BL rTMS (Fitzgerald et al., 2011), RLF/BL rTMS
(Fitzgerald et al., 2013), and LHF/RLF rTMS (unpublished data)
protocols. Data from the last of these trials were recently submitted
for publication and currently under review. The aim of this study is to
determine if rTMS is effective in treating anxiety symptoms in
2
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CHEN ET AL.
depression and if so, if one rTMS protocol is superior to others. To
this end, pooled data from multiple trials of comparable patient
demographics, diagnoses, symptom severity, rTMS protocols, and
identical outcome measures offer a larger data set for statistical
analysis. All three studies utilised the 17item Hamilton Depression
Rating Scale (HAMD) to measure change in depression symptoma-
tology and the 21item Beck's Anxiety Inventory (BAI) to measure
change in anxiety symptoms. All trials were randomised, doubleblind
studies of prospective design, where patients and raters were blind
to the treatment administered, but not the clinicians providing
treatment. Randomisation was achieved using a single computer
generated random number sequence (no stratification). Patients and
raters were advised there was a difference in the stimulation
parameters across the randomisation groups but specific information
related to stimulation sites, sides and durations were not described in
detail. Across all rTMS protocols, patients received courses of 20
treatment sessions, 5daysaweek over 4 weeks.
2.2
|
Participants
Treatment data for 697 patients were pooled for analysis from
three trials, of individual sample sizes of 179, 218, and
300 patients. Treatment outcomes were pooled then separated
into three treatment groups: LHF rTMS, RLF rTMS, and BL rTMS.
Patient age, gender distribution, and psychiatric diagnoses were
comparable across the three treatment groups (Table 1).
Psychiatric diagnoses were determined using the MiniInterna-
tional Neuropsychiatric Interview (Sheehan et al., 1998) by a study
psychiatrist for each patient. Patients were categorised as having:
MDD, single episode (n= 170); MDD, relapse (n= 415); bipolar I
disorder (BPAD I), depressive episode (n= 50); bipolar II disorder
(BPAD II), depressive episode (n= 34). Only patients with depres-
sion severity in the moderatesevere range (scoring >13 on the
HAMD; Bech, Kastrup, & Rafaelsen, 1986) were included. All
patients had failed to respond to at least two antidepressant
medications for at least 6 weeks in the current illness episode,
qualifying their illness as stage II treatmentresistant depression
(Thase & Rush, 1997). Exclusion criteria included significant active
medical illness, significant comorbid substance use disorder,
current neurological disease, or a contraindication to undergo
rTMS for safety reasons, such as a history of seizures and presence
of metal anywhere in the head/facial regions. Past failure to
respond to electroconvulsive therapy was not an exclusion
criterion. Psychotropic medications were not allowed to have
changed in the 4 weeks before the commencement of the trial or
during the trial itself.
Across the three trials, patients were recruited by referral
from psychiatrists and other medical practitioners between
January 2006 and October 2015. All three trials were conducted
in inpatient settings across five private psychiatric hospitals in
the three Australian states of Victoria, New South Wales, and
Queensland. Training in rTMS methods, trial management, and
data collection were conducted by one lead site to assure
uniformity of delivery across the sites. After complete descrip-
tion of the original studies to the patients, written informed
consent was obtained from all patients and each study received
Human Ethics Committee approval.
2.3
|
rTMS treatment
Across all study sites, rTMS was administered using MagVenture
MagPro R30 magnetic stimulators (MagVenture Inc., Farum, Den-
mark) using fluidfilled 70mm figureof8 coils held by stands. The
coils were held tangential to the scalp at 45° to the midline. The
location for stimulation was a point 6 cm anterior to that required for
maximum stimulation of the Abductor Pollicis Brevis muscle. The
resting motor threshold (RMT) was measured using standard visual
methods (Pridmore, Fernandes Filho, Nahas, Liberatos, & George,
1998). Patients sat in a comfortable reclining chair during all
treatment sessions.
The TMS treatment protocols are presented in Table 2. Across
the three pooled studies, 150 patients received LHF rTMS, 312
received RLF rTMS, and 235 received BL rTMS.
2.4
|
Clinical assessment
The primary outcome measure for all three studies was the
HAMD score. The BAI was a secondary outcome measure across
the studies. Assessment scores were obtained at baseline and
TABLE 1 Participant demographic and clinical characteristics
Leftsided
high
frequency
rTMS
(N= 150)
Rightsided
low
frequency
rTMS
(N= 312)
Sequential
bilateral
rTMS
(N= 235)
Age in years,
mean (SD)
46.2 (12.7) 44.9 (14.5) 48.7 (15.0)
Gender, N(F/M) 105/45 214/98 166/69
Gender (%F/%M) 70.0/30.0 68.6/31.4 70.6/29.4
Diagnosis
MDD single
episode
48 70 52
MDD relapse 79 199 137
BPAD I 6 23 21
BPAD II 4 9 21
Concurrently taking
antidepressant
medication, N(%)
131 (87.3) 263 (84.3) 195 (83.0)
Baseline measures
HAMD, mean (SD) 26.6 (6.4) 23.0 (6.0) 21.0 (5.3)
BAI, mean (SD) 30.6 (13.7) 28.3 (13.2) 25.8 (12.3)
Note. BAI: 21item Beck's Anxiety Inventory; BPAD I: bipolar I disorder;
BPAD II: bipolar II disorder; HAMD: 17item Hamilton Depression Rating
Scale; MDD: major depressive disorder; rTMS: repetitive transcranial
magnetic stimulation; SD: standard deviation.
CHEN ET AL.
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3
after 2 and 4 weeks. As such, these time points were used in the
pooled analysis.
2.5
|
Data analysis
This analysis addresses differences in genderadjusted effects of LHF
rTMS, RLF rTMS, and BL rTMS on anxietyand depressionseverity
scores over time. We conducted a conditional twopart latent growth
model (LGM) analysis, modelling structural equations of BAI and
HAMD scores at three time points of each (baseline, Weeks 2 and 4).
This analysis strategy differs from repeated measure analyses of
variance (ANOVA) because here, we model longitudinal manifest
outcome variables with latent or unobserved random intercepts and
slopes. Fundamentally different from ANOVA, LGM accounts for
each subject's individual score trajectory and allow for associative
equation building where conditional timevariable scores of both BAI
and HAMD are fitted in one model (Figure 1). Furthermore, errors
(e) or disturbances (D) variances were freely parameterised.
We first fitted a random interceptonly (or base model) where
scores of both scales assumed nogrowth. Second, a linear growth
trajectory was modelled with fixed and equally spaced factor
loadings (λslope = 0, 1, and 2). Finally, we tested a freedloading or
nonlinear model (λslope = 0, 1, and *). Incremental (Comparative Fit
Index [CFI] >0.90 and TuckerLewis Index [TLI] >0.90) and absolute
fit indices (Akaike's Information Criteria [AIC], χ
2
with preferred
smaller the better across models, and root mean square error of
approximation [RMSEA], <0.09) were utilised to determine the best
fitting model (Curran & Muthen, 1999). Analyses used full informa-
tion maximum likelihood estimator method, missing data was
assumed to be missing at random. For hypothesis testing, the two
tailed αlevel was set at 0.05. Models were written with CALIS
procedure, SAS (SAS institute, Cary, NC).
3
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RESULTS
There were no significant differences in patient demographics and
clinical variables across the three studies or three rTMS protocols.
Differences in baseline HAMD and BAI scores were not clinically
significant across the three rTMS protocols. Specifically, the mean
difference ranges were 5.6 points for HAMD and 4.8 for BAI
(Table 1) across the groups. Nonetheless, to increase model precision,
we adjusted for baseline difference by fitting a subjectspecific
trajectory model. Further, in the statistical modelling, we imposed a
covariance matrix that allows baseline latent parameters (intercepts)
to covary, adding to the robustness of the treatment estimates.
3.1
|
Structural models
The strategy for statistical model selection was incremental. First, we
used the outfit option of the data step to estimate the base model
with random interceptonly (CFI = 0.00). The basefit option written
with subsequent models affirmed the selection of freed loadings or
nonlinear model as a stable solution with excellent incremental
(relative) and absolute fit indices: CFI = 0.98, TLI = 0.95, and
RMSEA = 0.06 (Table 3).
Table 4 gives the parameter estimates for the model including
gender as a covariate. Of interest, female patients are associated
with higher baseline BAI and HAMD scores (β= 0.19 and 0.14,
respectively). However, the projection of BAI and HAMD slopes over
the courses of rTMS is independent of patient gender. There is
statistically significant evidence that LHF rTMS resulted in greater
reduction of HAMD growth scores relative to RLF rTMS (β=0.25;
p= 0.009) and BL rTMS (β=0.35; p< 0.001), after controlling for
gender. In comparison, the three rTMS protocols exhibited minimal
clinically significant relative difference in reducing BAI growth scores
TABLE 2 rTMS protocols across the three pooled studies
Study 1: Fitzgerald
et al. (2011)
Study 2: Fitzgerald et al.
(2013)
Study 3: Fitzgerald et al.
(In submission)
Sample size N= 218 N= 179 N= 300
rTMS Protocol RLF rTMS (n= 71) R priming then LF rTMS (n= 91) LHF rTMS 50 trains (n= 59)
BL rTMS (n= 71) BL rTMS (n= 88) LHF rTMS 125 trains (n= 91)
BL 1 Hz rTMS (n= 76) RLF rTMS 20 min (n= 57)
RLF rTMS 60 min (n= 93)
Localisation method 6 cm rule”“6 cm rule”“6 cm rule
Stimulation hemisphere and frequency 1 Hz right 6 Hz priming right then 1 Hz right 10 Hz left
1 Hz right then 10 Hz left 1 Hz right then 10 Hz left 10 Hz left
1 Hz right then 1 Hz left 1 Hz right
1 Hz right
Stimulation intensity (%RMT) 110 90 for priming stimulation 110 120
Number of pulses per stimulation session RLF rTMS = 900 R priming then LF rTMS = 1,500 LHF rTMS 50 trains = 2,250
BL rTMS = 1,800 BL rTMS = 1,650 LHF rTMS 125 trains = 5,625
BL rTMS = 1,800 RLF rTMS 20 min = 1,200
RLF rTMS 60 min = 3,600
Note. BL rTMS: sequential bilateral repetitive transcranial magnetic stimulation; LHF rTMS: leftsided highfrequency repetitive transcranial magnetic
stimulation; RLF rTMS: rightsided lowfrequency repetitive transcranial magnetic stimulation; RMT: resting motor threshold; rTMS: repetitive
transcranial magnetic stimulation.
4
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CHEN ET AL.
(βin a range of 0.08 to 0.07), which were also not statistically
significant.
Covariances indicate patients with higher HAMD scores at
baseline also scored higher BAI at baseline (p< 0.001). Likewise,
change in HAMD scores over time positively correlated with change
in BAI (p< 0.001). These findings suggest a high degree of
concordance between HAMD and BAI scores both at baseline and
in their treatment response trajectories. Both highand lowbaseline
BAI showed overall symptom reduction as measured by change in
BAI and HAMD ( Figures 1 and 2).
3.2
|
Change in anxiety (BAI) over time across
three rTMS protocols (Figure 2)
All three rTMS protocols resulted in a reduction in anxiety severity,
as measured by BAI, with a mean reduction of 8.13 points (p< 0.001).
Relative to RLF rTMS and BL rTMS, LHF rTMS appeared to
demonstrate slightly increased anxiolytic effects (b=0.38 and
1.50, respectively, but these were not clinically or statistically
significant. BL rTMS appeared to be marginally inferior to RLF rTMS
in antianxiolytic effects, although again, this was not clinically or
FIGURE 1 Conditional twopart latent growth curve model (LGM) describing associations between anxiety (BAI) and depression (HAMD)
scores across three time points (baseline [B], 2 weeks [W2], 4 weeks [W4]). We used the structural models over ANOVA, mixed and marginally
analysed as the former accounted for error variances and score heterogeneity in a large data set. Individualspecific growth curves and response
variables are also captured by LGM. Further, missing data are treated as missing at random (MAR), whereas ANOVA assumes missing
completely at random (MCAR) and performs a listwise deletion. In our freedloading model, factor loadings on each time point were all above
0.80 (p< 0.001). Error variances were freely estimated. Covariances between BAI and HAMD latent structures (slopes and intercepts) are
shown above with coefficients. BAI and HAMD growth processes were conditioned on threeway rTMS variables and gender (dummy coded
with Δ, dotted lines). ANOVA: analysis of variance; BAI: 21item Beck's Anxiety Inventory; HAMD: 17item Hamilton Depression Rating Scale;
rTMS: repetitive transcranial magnetic stimulation
TABLE 3 Model fit information (N= 697)
Model χ
2
Number of parameters DF AIC CFI TLI RMSEA (90% CI)
Base 1,507.56* 26 28 27694.29 0.00 0.38 0.27 (0.260.29)
Linear 196.11* 41 13 26412.84 0.87 0.73 0.14 (0.120.16)
Nonlinear 42.86* 43 11 26263.59 0.98 0.95 0.06 (0.040.08)
Note. Base is the random interceptonly model, linear is the fixed loading model, and nonlinear is the freedloading model.
AIC: Akaike's Information Criterion; CFI: Comparative Fit Index; CI: confidence interval; DF: χ
2
degrees of freedom; RMSEA: root mean square error of
approximation; rTMS: repetitive transcranial magnetic stimulation; TLI: TuckerLewis Index.
*p< 0.05.
CHEN ET AL.
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5
statistically significant. Gender was not a statistically significant
determining factor in anxiety reduction.
3.3
|
Change in depression (HAMD) over time
across three rTMS protocols (Figure 3)
All three rTMS protocols resulted in antidepressant effects with a
mean reduction of 8.61 points on the HAMD, which was statistically
significant (p< 0.001). Relative to RLF rTMS, LHF rTMS reduced
HAMD by a further 2.20 mean points (p= 0.009), and a further 3.05
mean points (p< 0.001) relative to BL rTMS. BL rTMS demonstrated
marginally reduced antidepressant efficacy, relative to RLF rTMS,
although this was not statistically significant (p= 0.48). Gender was not
a statistically significant determining factor in antidepressant response.
4
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DISCUSSION
To our knowledge, this is the largest study to date that specifically
investigated rTMS's efficacy in treating anxiety symptoms in MDD
and if anxiolytic efficacy differs across the protocols commonly used
in clinical practice. Our results suggest that RLF rTMS, LHF rTMS,
and BL rTMS are all equally effective. Our findings are in keeping
with the earlier, smaller studies that have found rTMS to be effective
in treating comorbid anxiety occurring in MDD (Berlim, McGirr, et al.,
2011; Diefenbach et al., 2013; Durmaz et al., 2017; Greenberg et al.,
1997; Kedzior et al., 2015). With respect to treatment efficacy of
depressive symptoms, our results slightly favour LHF rTMS over BL
rTMS and RLF rTMS, which is not necessarily consistent with
previous reports (J. Chen et al., 2013; J.J. Chen et al., 2014;
Fitzgerald et al., 2011, 2013; Hoy et al., 2012). Female gender was
not a statistically or clinically significant predictor of response for
both anxiety and depression symptoms. Adding to the generalisa-
bility of our results is the fact that our treatment outcomes were
derived from five private psychiatric hospitals across three Austra-
lian states over an almost 10year period.
In contrast to evidence supporting its antidepressant efficacy,
rTMS's therapeutic potential in anxiety disorders can be considered
equivocal and promising at best (Pallanti & Bernardi, 2009), despite
neuroimaging evidence of shared regions of aberrant brain activity
and connectivity in the expression of depressive and anxiety
symptoms. It is also curious that certain antidepressant classes (such
TABLE 4 Structural parameter estimates: the bestfitting nonlinear associative growth curve model
Latent structural
variable (DV) Independent variable
Unstandardised
coefficient (b) Standard error
Standardised
coefficient (β)pvalue*
BAI intercept 24.73 1.04 <0.001
rTMS: Left versus right 2.30 1.31 0.07 0.08
Bilateral versus right 2.41 1.11 0.10 0.05
Left versus bilateral 4.71 1.37 0.16 0.003
Gender (female) 4.99 1.07 0.19 <0.001
BAI slope 8.13 0.79 <0.001
rTMS: Left versus right 0.38 1.00 0.02 0.71
Bilateral versus right 1.13 0.79 0.07 0.23
Left versus bilateral 1.50 1.02 0.08 0.22
Gender (female) 0.63 0.77 0.04 0.42
HAMD intercept 22.14 0.46 <0.001
rTMS: Left versus right 3.19 0.57 0.32 <0.001
Bilateral versus right 2.35 0.50 0.27 <0.001
Left versus bilateral 5.54 0.61 0.55 <0.001
Gender (female) 1.31 0.48 0.14 0.006
HAMD slope 8.61 0.56 <0.001
rTMS: Left versus right 2.20 0.69 0.25 0.009
Bilateral versus right 0.85 0.59 0.11 0.48
Left versus bilateral 3.05 0.73 0.35 <0.001
Gender (female) 0.26 0.55 0.03 0.64
Covariance Intercept and slope (BAI) 40.31 12.62 0.001
Intercept and
slope (HAMD)
0.32 5.37 0.95
Cross intercepts 19.53 2.95 <0.001
Cross slopes 14.97 2.46 <0.001
InterceptBAI and
slopeHAMD
0.25 3.22 0.93
InterceptHAMD and
slopeBAI
2.95 2.08 0.15
Note. BAI: 21item Beck's Anxiety Inventory; HAMD: 17item Hamilton Depression Rating Scale; rTMS: repetitive transcranial magnetic stimulation; DV,
Dependent variables.
*pvalues adjusted for multiplicity (Multtest procedure; SAS institute, Cary, NC).
6
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CHEN ET AL.
as the serotonin reuptake inhibitors and serotonin/adrenaline
reuptake inhibitors) infer therapeutic efficacy for both anxiety and
depression disorders. Theories exist that refer to multiple brain
regions contributing to the manifestation of anxiety, relative to
depressive disorders, which make focal targeting of brain regions
with rTMS practically difficult. rTMS applied to cortical regions
thought to play a role in modulating anxious experiences, such as the
dorsal anterior cingulate (dACC) and medial prefrontal regions (Etkin
& Schatzberg, 2011), have also not been systemically investigated.
With respect to the therapeutic potential of rTMS applied to
subcortical brain regions, electromagnetic pulses delivered by
conventional rTMS machines with figureofeight coils are not
engineered to penetrate to such depth below the cortical surface
(Paes et al., 2011), although this may explain the positive results deep
rTMS therapy have had in treating anxious depression (Kedzior et al.,
2015). Separate from the issue of neuroanatomical targets, the thus
far discouraging therapeutic outcomes of rTMS in anxiety disorders
may also relate to uncertainties in relation to optimal stimulation
parameters (Paes et al., 2011). rTMS therapeutic trials for anxiety
disorders have typically featured stimulation parameters analogous
with parameters used in depression trials when there is no evidence
to suggest mechanisms of therapeutic action, even if putative, are
transferrable from one group of disorders to another.
By way of limitations, heterogeneity in the rTMS protocols across
the three trials is noteworthy, particularly with reference to the
number of stimulation pulses applied per session and cumulatively
over a course of 20 sessions. Across the protocols, pulses applied per
session ranged between 900 and 5,625. The increased antidepressant
effect of LHF rTMS we observed could be attributable to the greater
number of pulses applied to patients randomised to this protocol.
There is no convincing evidence from published metaanalyses,
however, that supports a clear correlation between the total number
of pulses applied through a course of rTMS and antidepressant
efficacy (Berlim, van den Eynde, et al., 2014; Herrmann & Ebmeier,
2006; Slotema et al., 2010). In other words, a therapeutic ceiling effect
could exist in rTMS, where more pulses do not equate to dramatically
superior antidepressant response. Rather, the superior antidepressant
effect we observed with LHF rTMS may be more likely attributable to
the higher stimulation intensities applied in these treatment arms
(120% RMT compared with 110% RMT). The incorporation of a
priming rTMS protocol (20 trains of subRMT stimulation of 5second
duration at 6 Hz followed by 15 min of 1 Hz supraRMT stimulation,
both applied to the right DLPFC) also deserves consideration.
Published studies indicate this form of rightsided rTMS may produce
superior antidepressant effects compared with RLF rTMS without
preceding priming stimulation (Fitzgerald et al., 2008; Iyer, Schleper, &
Wassermann, 2003) and thereby increased the overall therapeutic
efficacy in our priming RLF rTMS arm or across the sample. This is
unlikely, however, given patients randomised to the priming RLF
rTMS protocol made up 29.2% (91 of 312) of the total number of RLF
rTMS patients and 13.1% (91 of 697) of the total sample size. Given
the infinite combination of possibilities, the issue of heterogeneity
with stimulation parameters is frequently encountered in TMS
research (Lefaucheur et al., 2014). Despite minor heterogeneity in
the rTMS protocols we analysed, for the purpose of our study
objective, which was to investigate relative anxiolytic and antide-
pressant efficacy, our results are nonetheless likely to be clinically
informative. The fact that the studies were not shamcontrolled and
took place in inpatient settings are also worth noting. It is possible
that a placebo effect across the studies obscured betweengroup
differences. Therapeutic measures available in an inpatient mental
health facility, such as regular clinician contact and availability of
therapeutic programs may have increased the magnitude of treatment
response in the populations studied. Again, for the purpose of
establishing relative anxiolytic and antidepressant superiority across
the three rTMS protocols, the absence of sham control and
investigation of an inpatient population are not likely to bias our
results. The choice to analyse treatment response at the week 4 time
point does, however, mean delayed treatment responses beyond this
time were not recorded. The decision to use week 4 as the treatment
endpoint was because this was the review time point standardised
across the three studies.
FIGURE 2 Mean reduction trends in BAI across the three rTMS
protocols. BAI: Beck's Anxiety Inventory; rTMS: repetitive
transcranial magnetic stimulation
FIGURE 3 Mean reduction trends in HAMD across the three
rTMS Protocols. HAMD: 17item Hamilton Depression Rating Scale;
rTMS: repetitive transcranial magnetic stimulation
CHEN ET AL.
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5
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CONCLUSIONS
In spite of the high comorbidity of anxiety and depression and the
prevalence of both disorders, research addressing whether certain
rTMS protocol(s) are particularly effective in anxiety symptoms
comorbid in depression is lacking. This study addresses this clinical
knowledge gap and is the largest analysis to date comparing the relative
therapeutic efficacy of three commonly used rTMS protocols. Our
findings suggest therapeutic equivalence across LHF rTMS, RLF rTMS,
and BL rTMS. It remains unclear why comorbid anxiety in depression
improves with rTMS, while its therapeutic efficacy in primary anxiety
disorders remains equivocal. Further research into the neurobiological
aetiology of both disorders and rTMS's mechanisms of action may
provide clues on how this technique may be harnessed for greater
therapeutic potential. Future randomised trials, prospectively evaluating
different rTMS protocols' effectiveness in treating anxiety symptoms in
depression can be of clinical value.
ORCID
Leo Chen http://orcid.org/0000-0002-2371-8707
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How to cite this article: Chen L, Hudaib AR, Hoy KE,
Fitzgerald PB. Is rTMS effective for anxiety symptoms in
major depressive disorder? An efficacy analysis comparing
leftsided highfrequency, rightsided lowfrequency, and
sequential bilateral rTMS protocols. Depress Anxiety. 2019;
19. https://doi.org/10.1002/da.22894
CHEN ET AL.
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... This finding was in line with previous studies that investigated the effectiveness of rTMS in reducing anxiety symptoms during the treatment of patients with depression. In one of the largest studies, Chen and colleagues 168 investigated the efficacy of left-dlPFC high-frequency, right-dlPFC lowfrequency and sequential bilateral rTMS (i.e., highfrequency left dlPFC followed by low-frequency right dlPFC) in a sample of 697 participants. The stimulation protocols showed the overall efficacy of the 3 protocols in reducing anxiety and depressive symptoms without indicating that one protocol had a stronger therapeutic effectiveness over the other. ...
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Background: The possibility of using noninvasive brain stimulation to treat mental disorders has received considerable attention recently. Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are considered to be effective treatments for depressive symptoms. However, no treatment recommendation is currently available for anxiety disorders, suggesting that evidence is still limited. We conducted a systematic review of the literature and a quantitative analysis of the effectiveness of rTMS and tDCS in the treatment of anxiety disorders. Methods: Following PRISMA guidelines, we screened 3 electronic databases up to the end of February 2020 for English-language, peer-reviewed articles that included the following: a clinical sample of patients with an anxiety disorder, the use of a noninvasive brain stimulation technique, the inclusion of a control condition, and pre/post scores on a validated questionnaire that measured symptoms of anxiety. Results: Eleven papers met the inclusion criteria, comprising 154 participants assigned to a stimulation condition and 164 to a sham or control group. We calculated Hedge's g for scores on disorder-specific and general anxiety questionnaires before and after treatment to determine effect size, and we conducted 2 independent random-effects meta-analyses. Considering the well-known comorbidity between anxiety and depression, we ran a third meta-analysis analyzing outcomes for depression scores. Results showed a significant effect of noninvasive brain stimulation in reducing scores on disorder-specific and general anxiety questionnaires, as well as depressive symptoms, in the real stimulation compared to the control condition. Limitations: Few studies met the inclusion criteria; more evidence is needed to strengthen conclusions about the effectiveness of noninvasive brain stimulation in the treatment of anxiety disorders. Conclusion: Our findings showed that noninvasive brain stimulation reduced anxiety and depression scores compared to control conditions, suggesting that it can alleviate clinical symptoms in patients with anxiety disorders.
... Distinguishing the respective effects of anxiety, comorbid anxiety disorder, and benzodiazepine on TMS efficacy remains a challenge. Benzodiazepine use and anxiety disorders should not be exclusion criteria for TMS studies: rTMS decreases anxiety associated with depression [59] and has shown comparable efficacy in cases of comorbid anxiety disorders [60]. ...
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Full-text available
Background Recently intermittent theta burst stimulation (iTBS) proved to be non-inferior to conventional repetitive transcranial magnetic stimulation (10 Hz rTMS) in unipolar depression after failure of one antidepressant trial, but to date no randomized control trial assessed the ability of iTBS to improve depression level and quality of life in more resistant features of depression with a long-term (6 month) follow-up in comparison to 10 Hz rTMS. Objectives/Hypothesis: The aim of our study was to compare the efficacy of 10 Hz rTMS and iTBS in treatment-resistant unipolar depression on response rates (50% decrease of MADRS scores at one month from baseline) and change in quality of life during a 6-month follow-up. In addition, we investigated whether some clinical features at baseline were associated with the response in the different groups. Method Sixty patients were randomized in a double-blind, controlled study at the University Hospital Center of Nantes, and received 20 sessions of either rTMS or iTBS applied to the left dorsolateral prefrontal cortex targeted by neuronavigation. Statistical analysis used Fischer's exact test and Chi-square test as appropriate, linear mixed model, and logistic regression (occurrence of depressive relapse and factors associated with the therapeutic response). Results Included patients showed in mean more than 3 antidepressants trials. Response rates were 36.7% and 33.3%, and remission rates were 18.5% and 14.8%, in the iTBS and 10Hz-rTMS groups respectively. Both groups showed a similar significant reduction in depression scores and quality of life improvement at 6 months. We did not find any clinical predictive factor of therapeutic response in this sample. Conclusion Our study suggests the clinical interest of iTBS stimulation (which is more time saving and cost-effective as conventional rTMS) to provide long-lasting improvement of depression and quality of life in highly resistant unipolar depression.
... Several retrospective analyses have also reported efficacy of rTMS on symptoms of anxiety in depressed patients (Griffiths et al., 2019, Caulfield and Stern, 2020, Chen et al., 2019. rTMS and iTBS have shown antidepressant efficacy also in the presence of post-traumatic stress disorder in veterans (Nursey et al., 2020, Hernandez et al., 2020, Wilkes et al., 2020. ...
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Introduction: Non-invasive brain stimulation techniques such as repetitive transcranial magnetic stimulation (rTMS) offer a promising alternative to psychotherapeutic and pharmacological treatments for depression. This paper aims to present a practical guide for its clinical implementation based on evidence from the literature as well as on the experience of a group of leading German experts in the field. Methods: The current evidence base for the use of rTMS in depression was examined via review of the literature. From the evidence and from clinical experience, recommendations for the use of rTMS in clinical practice were derived. All members of the of the German Society for Brain Stimulation in Psychiatry and all members of the sections Clinical Brain Stimulation and Experimental Brain Stimulation of the German Society for Psychiatry, Psychotherapy, Psychosomatics and Mental Health were invited to participate in a poll on whether they consent with the recommendations. Findings: Among rTMS experts, a high consensus rate could be identified for clinical practice concerning the setting and the technical parameters of rTMS treatment in depression, indications and contra-indications, the relation of rTMS to other antidepressive treatment modalities and the frequency and management of side effects.
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Objective Major depressive disorder (MDD) is relatively common in adolescence, with far-reaching impacts. Current treatments frequently fail to alleviate depression severity for a substantial portion of adolescents. Repetitive transcranial magnetic stimulation (rTMS) may assist with this unmet clinical need. However, little is known about adverse events (AEs) experienced by adolescents receiving rTMS, subjective treatment experiences of adolescents and their parents, or treatment acceptability. Methods Fourteen adolescents (16.5 years ± 1.2; 71.4% female) with MDD received 20 sessions of either high-frequency (10 Hz; n = 7) left dorsolateral prefrontal cortex (DLPFC) or low-frequency (1 Hz; n = 7) right DLPFC rTMS. AEs were monitored at baseline and at weekly intervals via New York State Psychiatric Institute Side Effects Form for Children and Adolescents. Eight adolescents and nine parents participated in interviews regarding subjective treatment experience, analysed via content analysis. Results Drowsiness and lethargy were common AEs, reported by 92.3% of participants in week one. Number of AEs decreased throughout treatment course (after 5 treatments: M = 11.23, SD = 5.00; after 20 treatments: M = 8.92, SD = 5.95). Thirty-five AEs emerged during treatment, most commonly transient dizziness. Frequency, severity, and number of AEs reported were equivalent between treatment groups. Treatment adherence and satisfaction were high. Qualitative findings identified three themes relating to rTMS experience: Preparation and connection; Physical experience of treatment; and Perceived role of treatment. Limitations Sample size was small, therefore findings are preliminary. Conclusions rTMS was an acceptable treatment for adolescent MDD, from both adolescents' and parents' perspectives, and was safe and well-tolerated, as AE frequency and type did not differ from rTMS treatment courses in adults.
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Previous studies of rTMS for bipolar depressed (BD) patients have yielded mixed results. In this retrospective, naturalistic, observational study, we reviewed charts of 317 patients undergoing rTMS treatment between 1/2015-2/2018, yielding 283 unipolar depressed (UD) and 34 BD patients. All were treated with a figure-of-8 coil, with either high-frequency (HF) left-sided, sequential bilateral (HF left-sided and low-frequency right-sided), or mixed protocols (switched from unilateral to bilateral mid-course). Outcomes were the Generalized Anxiety Disorder scale (GAD-7) and Patient Health Questionnaire (PHQ-9). Total number of treatments and initial PHQ-9 scores did not differ between groups. BD patients had greater PHQ-9 change by treatment conclusion than UD patients. GAD-7 changes showed no between-group differences overall. PHQ-9 changes differences between groups were only seen with unilateral treatment, not with bilateral or mixed protocols. Unilateral treatment resulted in 45% remission (9/20) for BD patients vs. 15% (24/160) for UD patients by treatment end. Response was seen in 80% (16/20) of the unilaterally-treated BD patients vs. 39% (62/160) in UD patients. Regression analyses within BD patients found that unilateral treatment, use of non-lithium mood stabilizers, male sex, and number of treatments predicted PHQ-9 improvement.
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Background To study the efficacy of repetitive Transcranial Magnetic Stimulation (rTMS) in Major Depressive Disorder (MDD) including comorbidities of Generalized Anxiety Disorder (GAD), Post-Traumatic Stress Disorder (PTSD), and Borderline Personality Disorder (BPD). We compared response and remission rates to a single question patient-reported outcome (PRO). Methods A retrospective review of patients completing rTMS from 1/2009-2/2021. Standard response (≥50% reduction in Patient Health Questionnaire-9 [PHQ-9]) and remission (PHQ-9 < 5) definitions were used. The PRO was a single yes/no question “Did you feel rTMS was helpful?” rTMS parameters were 10 Hz, 3000 pulses/session, 120% of motor threshold over the left dorsolateral prefrontal cortex (DLPFC). Student’s t-test was used to compare PHQ-9 baseline, endpoint, and change scores with and without comorbidities. Response, remission, and PRO were analyzed using chi-square or Fisher’s Exact tests. Logistic regression examined gender and age predictors. Results 84 patients were analyzed, with comorbidities of GAD (52.4%), PTSD (13.1%), and BPD (15.5%). Response and remission rates were 42.9% and 16.7%, respectively. The PRO was 61.9%. There were no significant differences in these rates with versus without comorbidities. In post-hoc analysis, gender was not a predictor for better outcomes, and older patients were more likely to experience remission than younger patients. Limitations Retrospective study, small sample size of PTSD and BPD. Conclusion Comorbidities did not influence response and remission rates. The standard response rate underreported the patient’s perceived improvement. The patient’s point of view should be taken into account when discussing the clinical use of rTMS for MDD.
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Background: It has been suggested that sequential bilateral (SBL) TMS, combining high frequency, left dorsolateral prefrontal cortex (DLPFC) stimulation and low frequency, right DLPFC stimulation, is more effective than unilateral TMS. Objective: To contrast treatment outcomes of left unilateral (LUL) and SBL protocols. Methods: Registry data were collected at 111 practice sites. Of 10,099 patients, 3,871 comprised a modified intent-to-treat (mITT) sample, defined as a primary MDD diagnosis, age ≥18, and PHQ-9 completion before TMS and at least one PHQ-9 assessment after baseline. The mITT sample received high frequency (10 Hz) LUL TMS exclusively (N = 3,327) or SBL TMS in at least 90% of sessions (N = 544). Completers (N = 3,049) were responders or had received ≥20 sessions and had an end of acute treatment PHQ-9 assessment. To control for site effects, a Matched sample (N = 653) included Completers at sites that used both protocols. To control for selection bias, the SBL group was also compared to a Restricted LUL group, drawn from sites where no patient switched to SBL after substantial exposure to LUL TMS. Secondary analyses were conducted on CGI-S ratings. Results: The LUL group had superior outcomes compared to the SBL group for multiple PHQ-9 and CGI-S continuous and categorical measures in the mITT, Completer and Matched samples, including in the specified primary analyses. However, outcome differences were not observed when comparing the Restricted LUL and SBL groups. Within SBL protocols, the LUL-RUL order had superior outcomes compared to the RUL-LUL order in all CGI-S, but not PHQ-9, measures. Conclusions: While limited by the naturalistic design, there was no evidence that SBL TMS was superior to LUL TMS. The sequential order of RUL TMS followed by LUL TMS may have reduced efficacy compared to LUL TMS followed by RUL TMS.
Article
Background This retrospective analysis examined the effects of left-sided dorsolateral prefrontal cortex (DLPFC) repetitive transcranial magnetic stimulation (rTMS) on comorbid anxiety symptoms patients with treatment resistant depression (TRD). Method Response rates, remission rates, reliable change index (RCI), and clinically significant change (CSC) were assessed using the 7-item Generalized Anxiety Disorder Scale (GAD-7) and the 17-item Hamilton Rating Scale for Depression (HAMD-17) Anxiety subscale at over an average of 32.9 treatments (SD = 9.2). Results Fifty-seven TRD patients showed statistically and clinically significant improvement in all anxiety measurements with left DLPFC rTMS. Limitations This retrospective study had no sham control and allowed for medication changes during the rTMS treatment course. Conclusion Left DLPFC rTMS may be an important tool in reducing anxiety in TRD patients, improving overall treatment resistant symptoms and suicide risk.
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Purpose of review: This article provides a synopsis of current assessment and treatment considerations for posttraumatic stress disorder (PTSD) and related anxiety disorder characteristics. Epidemiologic and neurobiological data are reviewed as well as common associated symptoms, including sleep disruption, and treatment approaches to these conditions. Recent findings: PTSD is no longer considered an anxiety-related disorder in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition classification and instead is associated with trauma/stressor-related disorders. PTSD symptoms are clustered into four domains including intrusive experiences, avoidance, mood, and arousal symptoms. Despite this reclassification, similarities exist in consideration of diagnosis, treatment, and comorbidities with anxiety disorders. PTSD and anxiety-related disorders are heterogeneous, which is reflected by the neural circuits involved in the genesis of symptoms that may vary across symptom domains. Treatment is likely to benefit from consideration of this heterogeneity.Research in animal models of fear and anxiety, as well as in humans, suggests that patients with PTSD and generalized anxiety disorder have difficulty accurately determining safety from danger and struggle to suppress fear in the presence of safety cues.Empirically supported psychotherapies commonly involved exposure (fear extinction learning) and are recommended for PTSD. Cognitive-behavioral therapy has been shown to be effective in other anxiety-related disorders. Selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) are commonly used in the treatment of PTSD and anxiety disorders in which pharmacologic intervention is supported. Treating sleep disruption including sleep apnea (continuous positive airway pressure [CPAP]), nightmares, and insomnia (preferably via psychotherapy) may improve symptoms of PTSD, as well as improve mood in anxiety disorders. Summary: PTSD has a lifetime prevalence that is close to 10% and shares neurobiological features with anxiety disorders. Anxiety disorders are the most common class of mental conditions and are highly comorbid with other disorders; treatment considerations typically include cognitive-behavioral therapy and pharmacologic intervention. Developing technologies show some promise as treatment alternatives in the future.
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Objective: The aim of this study was to evaluate the efficacy of repetitive transcranial magnetic stimulation (rTMS) in patients with treatment-resistant major depression and to explore the relationship between the outcome and comorbid anxiety symptoms. Methods: The study was performed on 36 patients with treatment-resistant major depression. Patients received 15 rTMS sessions to their left dorsolateral prefrontal cortex with 110% motor threshold intensity, 20 Hz frequency, and 1000 pulses per day over a three-week period with the same stimulation parameters. Patients were assessed using Sociodemographics Form, the Montgomery–Asberg Depression Rating Scale (MADRS), and the Hamilton Anxiety Rating Scale (HAM-A) at baseline both before initiating rTMS treatment and on the first day following their last rTMS treatment session. Results: Decreased scores in patients’ MADRS and HAM-A (including subscales) were statistically significant with large effect sizes (r > 0.5) after rTMS treatment. Pretreatment HAM-A total scores and HAM-A somatic subscale scores were significantly higher in those who responded to rTMS (p = .046, p = .048). There were negative correlations between post-treatment MADRS scores and pretreatment HAM-A somatic and psychic subscale scores. Conclusions: While the main limitations of the study are its design and small sample size, the findings suggested that comorbid anxiety symptoms, particularly somatic anxiety, could predict the response to rTMS in treatment-resistant major depressive disorder.
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Previous studies have demonstrated inconsistent findings regarding the efficacy of bilateral vs. unilateral repetitive transcranial magnetic stimulation (rTMS) in treating major depressive disorder (MDD). Therefore, this meta-analysis was conducted to compare the efficacy of these two rTMS modalities. Data were obtained from seven randomized controlled trials (RCTs) consisting of 509 subjects. Bilateral and unilateral rTMS displayed comparable efficacy in treating MDD with a pooled odds ratios of 1.06 (95% confidence interval (CI)=0.58–1.91) for response rates and 1.05 (95% CI=0.52–2.11) for remission rates. Subgroup analysis found that bilateral rTMS was equally effective in comparison with both left and right unilateral rTMS. No significant differences in drop-out rates were found. No publication bias was detected. In conclusion, the pooled examination demonstrated that bilateral rTMS displays comparable anti-depressant efficacy and acceptability to unilateral rTMS in treating MDD. These findings suggest that simultaneous rTMS of the right and left dorsolateral prefrontal cortices in MDD patients does not provide marginal benefits in terms of efficacy or acceptability. As the number of RCTs included here was limited, further large-scale multi-center RCTs are required to validate our conclusions.
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The effectiveness of a prevention or intervention program has traditionally been assessed using time‐specific comparisons of mean levels between the treatment and the control groups. However, many times the behavior targeted by the intervention is naturally developing over time, and the goal of the treatment is to alter this natural or normative developmental trajectory. Examining time‐specific mean levels can be both limiting and potentially misleading when the behavior of interest is developing systematically over time. It is argued here that there are both theoretical and statistical advantages associated with recasting intervention treatment effects in terms of normative and altered developmental trajectories. The recently developed technique of latent curve (LC) analysis is reviewed and extended to a true experimental design setting in which subjects are randomly assigned to a treatment intervention or a control condition. LC models are applied to both artificially generated and real intervention data sets to evaluate the efficacy of an intervention program. Not only do the LC models provide a more comprehensive understanding of the treatment and control group developmental processes compared to more traditional fixed‐effects models, but LC models have greater statistical power to detect a given treatment effect. Finally, the LC models are modified to allow for the computation of specific power estimates under a variety of conditions and assumptions that can provide much needed information for the planning and design of more powerful but cost‐efficient intervention programs for the future.
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The relationship between depression and anxiety disorders has long been a matter of controversy. The overlap of symptoms associated with these disorders makes diagnosis, research, and treatment particularly difficult. Recent evidence suggests genetic and neurobiologic similarities between depressive and anxiety disorders. Comorbid depression and anxiety are highly prevalent conditions. Patients with panic disorder, generalized anxiety disorder, social phobia, and other anxiety disorders are also frequently clinically depressed. Approximately 85% of patients with depression also experience significant symptoms of anxiety. Similarly, comorbid depression occurs in up to 90% of patients with anxiety disorders. Patients with comorbid disorders do not respond as well to therapy, have a more protracted course of illness, and experience less positive treatment outcomes. One key to successful treatment of patients with mixed depressive and anxiety disorders is early recognition of comorbid conditions. Antidepressant medications, including the selective serotonin reuptake inhibitors, tricyclic antidepressants, and monoamine oxidase inhibitors, are highly effective in the management of comorbid depression and anxiety. The high rates of comorbid depression and anxiety argue for well‐designed treatment studies in these populations. Depression and Anxiety 4:160–168, 1996/1997. © 1997 Wiley‐Liss, Inc.
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Transcranial magnetic stimulation (TMS) is a powerful non-invasive technique for the modulation of brain activ- ity. While the precise mechanism of action is still unknown, TMS is applied in cognitive neuroscience to establish causal relationships between stimulation and subsequent changes in cerebral function and behavioral outcome. In addition, TMS is an FDA-approved therapeutic agent in psychiatric disorders, especially major depression. Suc- cessful repetitive TMS in such disorders is usually applied over the left dorso-lateral prefrontal cortex (DLPFC) and treatment response mechanism was therefore supposed to be based on modulations in functional networks, particularly the meso-cortico-limbic reward circuit. However, mechanistic evidence for the direct effects of rTMS over DLPFC is sparse. Here we show the speci city and temporal evolution of rTMS effects by comparing con- nectivity changes within 20 common independent components in a sham-controlled study. Using an unbiased whole-brain resting-state network (RSN) approach, we successfully demonstrate that stimulation of left DLPFC modulates anterior cingulate cortex (ACC) connectivity in one speci c meso-cortico-limbic network, while all other networks are neither in uenced by rTMS nor by sham treatment. The results of this study show that the neural correlates of TMS treatment response are also traceable in DLPFC stimulation of healthy brains and there- fore represent direct effects of the stimulation procedure.
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Antidepressant efficacy of high-frequency transcranial magnetic stimulation over the left dorsolateral prefrontal cortex in double-blind sham-controlled designs: a meta-analysis – Corrigendum - Volume 44 Issue 8 - D. J. L. G. Schutter
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The current study investigated the anxiolytic properties of the deep transcranial magnetic stimulation (DTMS) in unipolar major depression using a systematic literature review and meta-analysis. Compared to baseline, large anxiolytic and antidepressant outcomes were obtained after 20 daily sessions of high-frequency DTMS according to data from six open-label studies with 95 patients. Unlike the antidepressant effect, the anxiolytic effect was more heterogeneous among studies and did not depend on concurrent treatment with antidepressants.