ArticlePDF Available

Benzodiazepine Use And Response To Repetitive Transcranial Magnetic Stimulation In Major Depressive Disorder

DOI:10.1016/j.brs.2020.02.022
Authors:
Paul Fitzgerald at Monash University (Australia)
Paul Fitzgerald
Zafiris Daskalakis at University of California, San Diego
Zafiris Daskalakis
Kate E Hoy at Monash University (Australia)
Kate E Hoy
Download full-text PDF
Read full-text
Download citation
Available via license: CC BY-NC-ND 4.0
Content may be subject to copyright.
Benzodiazepine use and response to repetitive transcranial magnetic
stimulation in Major Depressive Disorder
Keywords:
Brain stimulation
Depression
Treatment resistance
Benzodiazepine
Response
To the editor,
Repetitive transcranial magnetic stimulation treatment (rTMS)
is an established and increasingly widely used treatment for pa-
tients with Major Depressive Disorder (MDD) whose use is sup-
ported by multiple positive meta-analyses (for example [1,2]).
Despite several decades of research into the use of rTMS, there
remain a number of important clinical questions that still need to
be answered to inform optimal clinical practice. One of these ques-
tions concerns the concurrent use of psychotropic medications and
whether these may reduce or enhance the likelihood of clinical
response to rTMS. Previous analyses have indicated that concurrent
use of antidepressant medication, mood stabilizers or antipsy-
chotics does not have a meaningful negative effect on the likelihood
of antidepressant response to rTMS: for example, we have previ-
ously found that concurrent antidepressant or mood stabilizer ther-
apy was associated with a higher rate of response [3].
Several recent studies have suggested that concurrent benzodi-
azepine use may be associated with poorer clinical outcomes. One
of these studies reported on outcomes seen in 181 patients who
had received a 6 week course of rTMS [4] and benzodiazepine
use was associated with less overall improvement. The second
report, analyzing patterns of response in patients from a large trial
of 10Hz stimulation compared to intermittent theta burst (iTBS),
found that low dose benzodiazepine use was associated with a
lower likelihood of being in the ‘rapid response’group and came
close to being associated with overall non-response (odds
ratio ¼2.25, CI ¼0.99 and 5.11) [5]. Due to these concerns, we con-
ducted an analysis of pooled data from two recently published
rTMS clinical trials (both exploring the efficacy of standard high-
frequency left sided rTMS versus a form of accelerated rTMS or
accelerated iTBS) to explore whether benzodiazepine use was
related to clinical response to rTMS therapy.
For this analysis, we pooled data from two recently completed
clinical trials (Trial 1 [10] and Trial 2 [11]) that were parallel supe-
riority trials comparing an accelerated rTMS protocol (multiple
treatments per day) with a standard once daily rTMS protocol.
For Trial 1 the accelerated protocol used standard high frequency
left sided rTMS, while for Trial 2 it was iTBS stimulation. Further de-
tails about Trial 1 and 2 can be found in their original publications.
This provided data on 185 subjects (83 who received standard
rTMS, 59 who received accelerated TMS and 33 who received accel-
erated iTBS). There were 99 female and 86 male patients with a
mean age of 47.4 ±13.4. The mean age of depression onset was
26.9 ±13.3 years, the patients had an average of 4.0 ±7.7 depressive
episodes and they had received a total of 6.8 ±8.6 previous medi-
cation trials. The mean baseline Montgomery Asberg Depression
Rating Scale score (MADRS) was 31.8 ±5.7.
In both clinical trials, data on the use of benzodiazepines was
collectedfor the period of rTMS treatment. Benzodiazepine use (reg-
ular or as needed (PRN)) was recorded along with drug type but not
dose. We analyzed the effect of any benzodiazepine use (yes or no) or
the effect of regular use on change in MADRS scores from baseline to
week 8 follow up (independent samples t-tests) as well as on
response rates (chi-squared) for the total group and treatment sub-
groups. A total of 121 patients were taking no benzodiazepines, 37
patients were taking diazepam, 4 patients alprazolam, 8 patients clo-
nazepam and 15 patients another benzodiazepine.
For the analysis of any benzodiazepine use, there was no differ-
ence in overall change of MADRS scores between patients taking
benzodiazepines or not (taking: n ¼64, mean MADRS change:
27.0 ±29.6, not taking: n ¼121, mean change: 27.0 ±34.3,
t¼
0.2, p ¼0.99). There was also no difference in response rate
(BZD users: 25%, non-users: 24.8%, p ¼0.98). There were also no
differences in overall change of MADRS scores comparing patients
who took benzodiazepine regularly or not at all (regular users,
n¼17: 34.4 ±26.9%, non-users, n ¼121: 27.0 ±34.3%, p ¼0.40)
or the response rates comparing these 2 groups (regular BZD users:
23.5%, non-users: 24.8%, p ¼0.91). There was also no difference in
the degree of MADRS change or response rates when analyzed
separately by type of TMS treatment (standard rTMS, accelerated
rTMS, accelerated iTBS). In addition to these analyses, we conduct-
ed a series of linear and binary regressions to see if there was any
relationship between benzodiazepine use and clinical response
but found no effect on any of these analyses.
In conclusion, we found no relationship between any form of
benzodiazepine use and clinical outcomes of rTMS treatment in
this analysis. This conclusion obviously differs from that of the
two previous reports cited above that found an effect of benzodiaz-
epine use in the context of either standard high-frequency left-
sided TMS or left-sided iTBS therapy, the two treatment groups
included in our analysis. There were some differences in the dura-
tion of treatment provided across the studies (for example Hunter
Contents lists available at ScienceDirect
Brain Stimulation
journal homepage: http://www.journals.elsevier.com/brain-stimulation
Brain Stimulation 13 (2020) 694e695
https://doi.org/10.1016/j.brs.2020.02.022
1935-861X/©2020 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
et al. [4] provided six weeks of standard treatment whereas four
weeks was provided by Kaster et al. [5] and in our current report)
but these do not seem sufficient to explain the difference in the cur-
rent result. One of the major limitations of our report, the binary
coding of benzodiazepine use as a yes or no variable rather than
analysis of a dose effect, was also the approach used in the other
two studies and again is not likely to explain the difference in the
results. Clearly whether or not patients should be weaned off
benzodiazepine use prior to rTMS treatment is an important clinical
question that requires further exploration in larger prospectively
assessed samples of patients undergoing rTMS therapy with greater
detail included in the analysis of the form of benzodiazepine use.
It is also important to note that the studies reporting a relation-
ship between benzodiazepine use and poorer response do not pro-
vide any direct evidence that benzodiazepine use lessens the
likelihood of response as these relationships are purely correlative.
It is possible that patients taking benzodiazepines are different in
some illness characteristics (for example anxiety as an obvious
one) that are associated with poorer response which are not
accounted for in these analysis. Papers in the literature are already
falling into the trap of assuming this correlation implies causation
and it is important that this assumption doesn’t get embedded in
TMS folk law until it is properly tested in studies able to overcome
these limitations.
Acknowledgements
PBF was supported by a Practitioner Fellowship grant from the
National Health and Medical Research Council (1078567). KEH
was supported by an NHMRC Fellowship (1082894).
References
[1] Gaynes BN, Lloyd SW, Lux L, Gartlehner G, Hansen RA, Brode S, et al. Repetitive
transcranial magnetic stimulation for treatment-resistant depression: a sys-
tematic review and meta-analysis. J Clin Psychiatr 2014;75:477e89. quiz 89.
[2] Berlim MT, van den Eynde F, Tovar-Perdomo S, Daskalakis ZJ. Response, remis-
sion and drop-out rates following high-frequency repetitive transcranial mag-
netic stimulation (rTMS) for treating major depression: a systematic review and
meta-analysis of randomized, double-blind and sham-controlled trials. Psychol
Med 2014;44:225e39.
[3] Fitzgerald PB, Hoy KE, Anderson RJ, Daskalakis ZJ. A study of the pattern of
response to rTMS treatment in depression. Depress Anxiety 2016;33:746e53.
[4] Hunter AM, Minzenberg MJ, Cook IA, Krantz DE, Levitt JG, Rotstein NM, et al.
Concomitant medication use and clinical outcome of repetitive Transcranial
Magnetic Stimulation (rTMS) treatment of Major Depressive Disorder. Brain
Behav 2019;9:e01275.
[5] Kaster TS, Downar J, Vila-Rodriguez F, Thorpe KE, Feffer K, Noda Y, et al. Trajec-
tories of response to dorsolateral prefrontal rTMS in major depression: a
THREE-D study. Am J Psychiatr 2019;176:367e75.
Paul B. Fitzgerald
*
Epworth Centre for Innovation in Mental Health, Epworth Healthcare
and Monash University Department of Psychiatry, Camberwell,
Victoria, Australia, 3124
Zafiris J. Daskalakis
Temerty Centre for Therapeutic Brain Intervention and the Campbell
Family Mental Health Research Institute, Centre for Addiction and
Mental Health, University of Toronto, Toronto, Ontario, Canada
Kate E. Hoy
Epworth Centre for Innovation in Mental Health, Epworth Healthcare
and Monash University Department of Psychiatry, Camberwell,
Victoria, Australia, 3124
*
Corresponding author. Epworth Healthcare, The Epworth Clinic,
888 Toorak Rd, Camberwell, Victoria, 3124, Australia.
E-mail address: paul.fitzgerald@monash.edu (P.B. Fitzgerald).
5 January 2020
Available online 19 February 2020
P.B. Fitzgerald et al. / Brain Stimulation 13 (2020) 694e695 695
... This propagation process in turn can be attenuated by benzodiazepines, such as midazolam [6], alprazolam or diazepam [27] in human subjects. However, pooled analysis by Fitzgerald et al. from two clinical trials could identify no difference in clinical depression outcomes between patients taking versus not taking benzodiazepines [7]. ...
... Strengths of our study include the comparatively large number of patients analyzed and the novelty and potentially large clinical relevancy of the results. The results from our study are compatible with the analysis by Fitzgerald et al. [7], which showed no difference in clinical rTMS outcomes for patients taking versus not taking benzodiazepines, another medication class for which preclinical evidence pointed towards possibly attenuating rTMS effects. ...
Antidepressant effect of repetitive transcranial magnetic stimulation is not impaired by intake of lithium or antiepileptic drugs
Article
Full-text available
Introduction The effect of concomitant medication on repetitive transcranial magnetic stimulation (rTMS) outcomes in depression remains understudied. Recent analyses show attenuation of rTMS effects by antipsychotic medication and benzodiazepines, but data on the effects of antiepileptic drugs and lithium used as mood stabilizers or augmenting agents are sparse despite clinical relevance. Preclinical electrophysiological studies suggest relevant impact of the medication on treatment, but this might not translate into clinical practice. We aimed to investigate the role of lithium (Li), lamotrigine (LTG) and valproic acid (VPA) by analyzing rTMS treatment outcomes in depressed patients. Methods 299 patients with uni- and bipolar depression treated with rTMS were selected for analysis in respect to intake of lithium, lamotrigine and valproic acid. The majority (n = 251) were treated with high-frequency (10–20 Hz) rTMS of the lDLPFC for an average of 17 treatment sessions with a figure-of-8 coil with a MagVenture system aiming for 110% resting motor threshold, and smaller groups of patients were being treated with other protocols including intermittent theta-burst stimulation and bilateral prefrontal and medial prefrontal protocols. For group comparisons, we used analysis of variance with the between-subjects factor group or Chi-Square Test of Independence depending on the scales of measurement. For post-hoc tests, we used least significant difference (LSD). For differences in treatment effects between groups, we used an ANOVA with the between-subjects factor group (groups: no mood stabilizer, Li, LTG, VPA, Li + LTG) the within-subjects factor treatment (pre vs. post treatment with rTMS) and also Chi-Square Tests of independence for response and remission. Results Overall, patients showed an amelioration of symptoms with no significant differences for the main effect of group and for the interaction effect treatment by group. Based on direct comparisons between the single groups taking mood stabilizers against the group taking no mood stabilizers, we see a superior effect of lamotrigine, valproic acid and combination of lithium and lamotrigine for the response and remission rates. Motor threshold was significantly and markedly higher for patients taking valproic acid. Conclusion Being treated with lithium, lamotrigine and valproic acid had no relevant influence on rTMS treatment outcome. The results suggest there is no reason for clinicians to withhold or withdraw these types of medication from patients who are about to undergo a course of rTMS. Prospective controlled work on the subject is encouraged.
... Hunter et al. (2019) (Hunter et al., 2019) reported that benzodiazepines were associated with less improvement; while antiepileptics had no effect. Nevertheless, Fitzgerald et al. (2020) raised doubts as to whether benzodiazepines negatively affect TMS outcomes. A recent study (Hebel et al., 2021) found that antiepileptics and lithium did not lessen the effect of rTMS. ...
Real world transcranial magnetic stimulation for major depression: A multisite, naturalistic, retrospective study
Article
Background: In 2008, the U.S. FDA approved rTMS as a treatment against medication-resistant depression. However, real-world rTMS outcomes remain understudied. This study investigates how rTMS for depression is delivered in routine clinical practice in France, and measures its effectiveness as well as its moderators. Methods: Five centers provided retrospective data on patients who were treated with rTMS for treatment-resistant depression from January 2015 to December 2020. Patients were assessed twice using a hetero-questionnaire, with baseline and immediate post-treatment assessments. We conducted univariate analyses to study which factors were significantly associated with rTMS effectiveness. We then included age, gender, and significant factors in a multivariate model. Results: We collected data from 435 patients with a mean age of 51.27 (14.91): 66 % were female, and 26 % suffered from bipolar depression. Stimulation was delivered using four different stimulation parameters: 1 Hz (7 % of the individuals), 10 Hz (43 %), 20 Hz (12 %), and 50 Hz (intermittent Theta Burst Stimulation, iTBS) (38 %). The mean improvement of depressive symptoms was 33 % (p < 0.001, effect-size: 0.79). Response and remission rates were of 31 % and 22.8 %, respectively. In the multivariate analysis, improvement in depressive symptoms was associated with higher baseline symptoms. Conclusion: This is one of the largest studies that investigates, with careful clinician-rated scales by trained psychiatrists, the effect of rTMS in naturalistic settings. Repetitive TMS appears to be effective in routine clinical practice, although its efficacy could be improved by analyzing predictors of response, as well as personalized targeting of specific brain areas.
... We didn't find any significant effect of the presence of benzodiazepine at baseline on response rates after treatment. While, as suggested by Kaster et al. [28], this may have contributed to a lower response rate, Fitzgerald et al. [58] raise doubts as to whether benzodiazepines negatively affect TMS outcomes. Distinguishing the respective effects of anxiety, comorbid anxiety disorder, and benzodiazepine on TMS efficacy remains a challenge. ...
Intermittent theta burst stimulation (iTBS) versus 10-Hz high-frequency repetitive transcranial magnetic stimulation (rTMS) to alleviate treatment-resistant unipolar depression: A randomized controlled trial (THETA-DEP)
Article
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.
... Another retrospective study found benzodiazepine users did in fact benefit from rTMS for depression and related anxiety (Caulfield and Stern, 2020). Other analyses have also found no detrimental effect of benzodiazepine intake on outcomes (Fitzgerald et al., 2020b). ...
Evidence and expert consensus based German guidelines for the use of repetitive transcranial magnetic stimulation in depression
Article
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.
... Further, although nonantidepressant concomitant medications were noted in a binary fashion (Table 3), we did not collate more detailed data such as the type of mood stabiliser medication (lithium or anticonvulsant mood stabilisers), concomitant benzodiazepine administration or the doses and treatment durations of these medications. This omission may be of relevance given these medications' possible influences on cortical excitability and therefore rTMS response [88,89], and in view of the literature that emerged since this study's conceptualisation that discuss the impact concomitant benzodiazepines might have on antidepressant response to rTMS [90][91][92]. Additionally, we did not systematically record tolerability issues expected with rTMS therapy, eg. ...
Accelerated theta burst stimulation for the treatment of depression: A randomised controlled trial
Article
Full-text available
Introduction Theta burst pattern repetitive transcranial magnetic stimulation (TBS) is increasingly applied to treat depression. TBS's brevity is well-suited to application in accelerated schedules. Sizeable trials of accelerated TBS are lacking; and optimal TBS parameters such as stimulation intensity are not established. Methods We conducted a three arm, single blind, randomised, controlled, multi-site trial comparing accelerated bilateral TBS applied at 80 % or 120 % of the resting motor threshold and left unilateral 10 Hz rTMS. 300 patients with treatment-resistant depression (TRD) were recruited. TBS arms applied 20 bilateral prefrontal TBS sessions over 10 days, while the rTMS arm applied 20 daily sessions of 10 Hz rTMS to the left prefrontal cortex over 4 weeks. Primary outcome was depression treatment response at week 4. Results The overall treatment response rate was 43.7 % and the remission rate was 28.2 %. There were no significant differences for response (p = 0.180) or remission (p = 0.316) across the three groups. Response rates between accelerated bilateral TBS applied at sub- and supra-threshold intensities were not significantly different (p = 0.319). Linear mixed model analysis showed a significant effect of time (p < 0.01), but not rTMS type (p = 0.680). Conclusion This is the largest accelerated bilateral TBS study to date and provides evidence that it is effective and safe in treating TRD. The accelerated application of TBS was not associated with more rapid antidepressant effects. Bilateral sequential TBS did not have superior antidepressant effect to unilateral 10 Hz rTMS. There was no significant difference in antidepressant efficacy between sub- and supra-threshold accelerated bilateral TBS.
... (Brunoni et al. 2017;Serafini et al. 2021)). Thus, we read with great interest the work by Fitzgerald and colleagues (Fitzgerald et al. 2020), exploring whether brain hemisphere dominance is associated with different clinical effects of rTMS for depression. Pooling results from 11 studies, they found that left-handed subjects experienced a larger reduction in symptoms and higher rates of response for high frequency left-sided rTMS (HFL) but not low frequency right-sided rTMS (LFR). ...
... A clinical rTMS-MRS study showed a trend towards lower increase in medial prefrontal cortex GABA concentration in depressed individuals with chronic lorazepam use [50]. In pooled data with 185 depressed individuals receiving 4 weeks of TMS using different treatment protocols, Fitzgerald et al. found no relationship between benzodiazepine use and clinical response in 64 BZD users compared to 121 patients not taking BZD [68]. Our results are consistent with recent findings of two other large exploratory studies: Kaster et al. [31] found depressed BZD users treated with rTMS to be with reduced odds of membership in a "rapid response" trajectory and with increased odds of membership in a "nonresponse" trajectory and Hunter, Minzenberg et al. ...
Concomitant lorazepam use and antidepressive efficacy of repetitive transcranial magnetic stimulation in a naturalistic setting
Article
Full-text available
Background/objectives:Repetitive transcranial magnetic stimulation (rTMS) has been established as an effective therapeutic intervention for the treatment of depression. Preliminary data suggest that the efficacy of rTMS is reduced in patients taking benzodiazepines (BZD). Here, we use real-world data from a large sample to investigate the influence of lorazepam on the effectiveness of rTMS.Methods From a retrospective cohort of clinically depressed patients that were treated with rTMS, we compared 176 patients not taking any BZD with 73 patients taking lorazepam with respect to changes in the Hamilton Depression Rating Scale (HRDS).ResultsBoth groups improved during rTMS according to HRDS scores, but the amelioration of symptoms was significantly less pronounced in patients taking lorazepam (18% vs. 38% responders in the non-lorazepam group). We could not see any association of intake regimen of lorazepam with response in rTMS.Conclusion Our observational study suggests that intake of lorazepam impedes the response to rTMS. The impact of lorazepam and other BZD on rTMS should receive more attention and be further investigated in prospective, hypothesis-based treatment studies to determine causal relationships between medication treatments and outcome. This could lead to specific recommendations for pharmacological treatment for depressed patients undergoing rTMS.
Intermittent theta burst stimulation for negative symptoms of schizophrenia—A double-blind, sham-controlled pilot study
Article
Full-text available
  • Feb 2021
Optimal noninvasive brain stimulation parameters for the treatment of negative symptoms of schizophrenia remain unclear. Here, we aimed to investigate the clinical and biological effects of intermittent theta burst transcranial magnetic stimulation (iTBS) in patients with treatment-resistant negative symptoms of schizophrenia (NCT00875498). In a randomized sham-controlled 2-arm study, 22 patients with schizophrenia and treatment-resistant negative symptoms received 20 sessions of either active (n = 12) or sham (n = 10) iTBS. Sessions were delivered twice a day on 10 consecutive working days. Negative symptom severity was assessed 5 times using the Scale for the Assessment of Negative Symptoms (SANS): before iTBS, after iTBS, and 1, 3, and 6 months after iTBS. As a secondary objective, we explored the acute effects of iTBS on functional connectivity of the left dorsolateral prefrontal cortex (DLPFC) using seed-based resting-state functional connectivity MRI (rsFC fMRI) images acquired before and after iTBS. Active iTBS over the left DLPFC significantly decreased negative symptoms severity compared to sham iTBS (F(3,60) = 3.321, p = 0.026). Post hoc analyses revealed that the difference between groups was significant 6 months after the end of stimulation sessions. Neuroimaging revealed an increase in rsFC between the left DLPFC and a brain region encompassing the right lateral occipital cortex and right angular gyrus and a right midbrain region that may encompass dopamine neuron cell bodies. Thus, iTBS over the left DLPFC can alleviate negative symptoms of schizophrenia. The effect might be driven by significant modulation of dopamine transmission.
Concomitant medication use and clinical outcome of repetitive Transcranial Magnetic Stimulation (rTMS) treatment of Major Depressive Disorder
Article
Full-text available
  • May 2019
Background Repetitive Transcranial Magnetic Stimulation (rTMS) is commonly administered to Major Depressive Disorder (MDD) patients taking psychotropic medications, yet the effects on treatment outcomes remain unknown. We explored how concomitant medication use relates to clinical response to a standard course of rTMS. Methods Medications were tabulated for 181 MDD patients who underwent a six‐week rTMS treatment course. All patients received 10 Hz rTMS administered to left dorsolateral prefrontal cortex (DLPFC), with 1 Hz administered to right DLPFC in patients with inadequate response to and/or intolerance of left‐sided stimulation. Primary outcomes were change in Inventory of Depressive Symptomatology Self Report (IDS‐SR30) total score after 2, 4, and 6 weeks. Results Use of benzodiazepines was associated with less improvement at week 2, whereas use of psychostimulants was associated with greater improvement at week 2 and across 6 weeks. These effects were significant controlling for baseline variables including age, overall symptom severity, and severity of anxiety symptoms. Response rates at week 6 were lower in benzodiazepine users versus non‐users (16.4% vs. 35.5%, p = 0.008), and higher in psychostimulant users versus non‐users (39.2% vs. 22.0%, p = 0.02). Conclusions Concomitant medication use may impact rTMS treatment outcome. While the differences reported here could be considered clinically significant, results were not corrected for multiple comparisons and findings should be replicated before clinicians incorporate the evidence into clinical practice. Prospective, hypothesis‐based treatment studies will aid in determining causal relationships between medication treatments and outcome.
Trajectories of Response to Dorsolateral Prefrontal rTMS in Major Depression: A THREE-D Study
Article
Full-text available
  • Feb 2019
Objective: Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for refractory major depressive disorder, yet no studies have characterized trajectories of rTMS response. The aim of this study was to characterize response trajectories for patients with major depression undergoing left dorsolateral prefrontal cortex rTMS and to determine associated baseline clinical characteristics. Methods: This was a secondary analysis of a randomized noninferiority trial (N=388) comparing conventional 10-Hz rTMS and intermittent theta burst stimulation (iTBS) rTMS. Participants were adult outpatients who had a primary diagnosis of major depressive disorder, had a score ≥18 on the 17-item Hamilton Depression Rating Scale (HAM-D), and did not respond to one to three adequate antidepressant trials. Treatment was either conventional 10-Hz rTMS or iTBS rTMS applied to the dorsolateral prefrontal cortex, 5 days/week over 4-6 weeks (20-30 sessions). Group-based trajectory modeling was applied to identify HAM-D response trajectories, and regression techniques were used to identify associated characteristics. Results: Four trajectories were identified: nonresponse (N=43, 11%); rapid response (N=73, 19%); higher baseline symptoms, linear response (N=118, 30%); and lower baseline symptoms, linear response (N=154, 40%). Significant differences in response and remission rates between trajectories were detectable by week 1. There was no association between treatment protocol and response trajectory. Higher baseline scores on the HAM-D and the Quick Inventory of Depression Symptomatology-Self-Report (QIDS-SR) were associated with the nonresponse trajectory, and older age, lower QIDS-SR score, and lack of benzodiazepine use were associated with the rapid response trajectory. Conclusions: Major depression shows distinct response trajectories to rTMS, which are associated with baseline clinical characteristics but not treatment protocol. These response trajectories with differential response to rTMS raise the possibility of developing individualized treatment protocols.
Response, remission and drop-out rates following high-frequency repetitive transcranial magnetic stimulation (rTMS) for treating major depression: A systematic review and meta-analysis of randomized, double-blind and sham-controlled trials
Article
Full-text available
Background: Meta-analyses have shown that high-frequency (HF) repetitive transcranial magnetic stimulation (rTMS) has antidepressant properties when compared with sham rTMS. However, its overall response and remission rates in major depression (MD) remain unclear. Thus, we have systematically and quantitatively assessed the efficacy of HF-rTMS for MD based on randomized, double-blind and sham-controlled trials (RCTs). Method: We searched the literature from 1995 through to July 2012 using MEDLINE, EMBASE, PsycINFO, Cochrane Central Register of Controlled Trials, SCOPUS, and ProQuest Dissertations & Theses. We used a random-effects model, odds ratios (ORs) and the number needed to treat (NNT). Results: Data from 29 RCTs were included, totaling 1371 subjects with MD. Following approximately 13 sessions, 29.3% and 18.6% of subjects receiving HF-rTMS were classified as responders and remitters, respectively (compared with 10.4% and 5% of those receiving sham rTMS). The pooled OR was 3.3 (p < 0.0001) for both response and remission rates (with associated NNTs of 6 and 8, respectively). Furthermore, we found HF-rTMS to be equally effective as an augmentation strategy or as a monotherapy for MD, and when used in samples with primary unipolar MD or in mixed samples with unipolar and bipolar MD. Also, alternative stimulation parameters were not associated with differential efficacy estimates. Moreover, baseline depression severity and drop-out rates at study end were comparable between the HF-rTMS and sham rTMS groups. Finally, heterogeneity between the included RCTs was not statistically significant. Conclusions: HF-rTMS seems to be associated with clinically relevant antidepressant effects and with a benign tolerability profile.
A study of the pattern of response to rtms treatment in depression
Article
Background: Considerable research has demonstrated the efficacy of repetitive transcranial magnetic stimulation (rTMS) treatment in patients with depression. However, limited research has described the pattern of response to rTMS treatment or explored possible predictors of the likelihood of treatment response. Methods: Data from 11 clinical trials (n = 1,132) was pooled and we described the pattern of response to rTMS, rate of response, and remission as well as potential clinical and demographic predictors of response. Results: There was a bimodal pattern of response to rTMS with the response-associated peak at 57% reduction in depression rating scale scores. About 46% of patients achieved response criteria, with 31% completing rTMS treatment in remission. A greater likelihood of response was seen for patients who had less severe depression at baseline, a shorter duration of the current episode, and recurrent rather than single episode of depression. Greater response was also seen in patients treated at higher stimulation intensity. Conclusions: A meaningful percentage (>40%) of patients respond to a course of rTMS treatment. Response does vary with a number of clinical and demographic variables but none of these variables exert a sufficiently strong influence on response rates to warrant using these criteria to exclude patients from treatment.
Repetitive Transcranial Magnetic Stimulation for Treatment-Resistant Depression: A Systematic Review and Meta-Analysis
Article
  • May 2014
Objective: To evaluate the efficacy of repetitive transcranial magnetic stimulation (rTMS) in patients with major depressive disorder (MDD) and 2 or more prior antidepressant treatment failures (often referred to as treatment-resistant depression [TRD]). These patients are less likely to recover with medications alone and often consider nonpharmacologic treatments such as rTMS. Data sources: We searched MEDLINE, EMBASE, the Cochrane Library, PsycINFO, and the International Pharmaceutical Abstracts for studies comparing rTMS with a sham-controlled treatment in TRD patients ages 18 years or older. Study selection: We included 18 good- or fair-quality TRD studies published from January 1, 1980, through March 20, 2013. Data extraction: We abstracted relevant data, assessed each study's internal validity, and graded strength of evidence for change in depressive severity, response rates, and remission rates. Results: rTMS was beneficial compared with sham for all outcomes. rTMS produced a greater decrease in depressive severity (high strength of evidence), averaging a clinically meaningful decrease on the Hamilton Depression Rating Scale (HDRS) of more than 4 points compared with sham (mean decrease = -4.53; 95% CI, -6.11 to -2.96). rTMS resulted in greater response rates (high strength of evidence); those receiving rTMS were more than 3 times as likely to respond as patients receiving sham (relative risk = 3.38; 95% CI, 2.24 to 5.10). Finally, rTMS was more likely to produce remission (moderate strength of evidence); patients receiving rTMS were more than 5 times as likely to achieve remission as those receiving sham (relative risk = 5.07; 95% CI, 2.50 to 10.30). Limited evidence and variable treatment parameters prevented conclusions about which specific treatment options are more effective than others. How long these benefits persist remains unclear. Conclusions: For MDD patients with 2 or more antidepressant treatment failures, rTMS is a reasonable, effective consideration.