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REGULAR RESEARCH ARTICLES
Safety and Efficacy of Accelerated
Repetitive Transcranial Magnetic
Stimulation Protocol in Elderly Depressed
Unipolar and Bipolar Patients
V
eronique Desbeaumes Jodoin, Ph.D., Jean-Philippe Miron, M.D.,
Paul Lesp
erance, M.D., M.Sc.
Objective: Major depressive disorder (MDD) is a prevalent condition in older adults.
Although antidepressant drugs are commonly prescribed, efficacy is variable, and
older patients are more prone to side effects. Repetitive transcranial magnetic stimu-
lation (rTMS) is an alternative therapy used increasingly in the treatment of MDD.
Even though recent studies have shown efficacy of rTMS in elderly depressed patients,
the safety and efficacy of accelerated rTMS has not been studied in this population.
Methods: Data were retrospectively analyzed for adults with treatment-resistant
depression (N = 73, n = 19 ≥60 years, n = 54 <60 years) who underwent an acceler-
ated protocol of 30 sessions (2 sessions per day) of left dorsolateral prefrontal cortex
high-frequency (20 Hz) rTMS. Results: There were statistically significant improve-
ments in depression and anxiety symptoms from baseline to post-treatment in both
age groups, but those 60 years and older showed statistically greater improvement in
depression and anxiety symptom scores (p = 0.01) than those less than 60. There
were significantly more responders (p = 0.001) and remitters (p = 0.023) in the older
group. The age groups did not differ significantly in clinical and demographic char-
acteristics or severity of current depressive episode, although baseline anxiety was
less severe in those 60 years and older. Unipolar and bipolar patients had a similar
clinical response, and treatment appeared to be well tolerated by all patients.
Conclusion: Our results suggest that accelerated rTMS protocol is a safe and effective
treatment for unipolar and bipolar depressed subjects, including older adults. (Am J
Geriatr Psychiatry 2018; 00:1−11)
Key Words: Bipolar disorder, rTMS, TMS, geriatric psychiatry, late-life depression
INTRODUCTION
Major depressive disorder (MDD) in the elderly
is a major public health concern, with
estimates of up to 20% of individuals 60 years and
older experiencing depression symptoms and 2%
meeting criteria for MDD.
1,2
MDD in the elderly is
associated with a poor prognosis, a more chronic
course, and higher levels of relapse, medical
Received April 18, 2018; revised October 24, 2018; accepted October 30, 2018. From the Department of Psychiatry (VDJ, JPM, PL), Centre Hos-
pitalier de l'Universit
e de Montr
eal, Montr
eal. Send correspondence and reprint requests to Paul Lesp
erance, M.D., M.Sc., Department of Psy-
chiatry, Centre Hospitalier de l'Universit
e de Montr
eal, 1051 rue Sanguinet, Montr
eal H2 X 0C1. e-mail: paul.lesperance@umontreal.ca
© 2018 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.jagp.2018.10.019
Am J Geriatr Psychiatry &&:&&,&& 2018 1
ARTICLE IN PRESS
comorbidities, cognitive impairment, treatment resis-
tance, and mortality.
3
Psychotherapeutic interven-
tions for MDD have not been extensively studied in
this population,
4
and elderly depressed patients
show reduced response rates to antidepressants and
experience more side effects.
2
Bipolar patients also
face difficulties similar to those of resistant MDD
patients, as studies show they spend up to two-thirds
of their episodes in the depressive pole and tend to
respond less than unipolar patients to antidepressant
treatments.
5,6
Late-life depression might differ from
depression in younger patients in terms of prognosis,
chronicity, and relapse rate, but its prevalence is rela-
tively equivalent to treatment-resistant depression
(TRD) in younger patients.
7−9
Finally, although elec-
troconvulsive therapy (ECT) is effective, this proce-
dure is not widely available because of its technical
challenges, and it does come with cognitive side
effects.
10
In this context, there is a pressing need to
perfect alternative forms of treatment.
Repetitive transcranial magnetic stimulation
(rTMS) is a noninvasive brain stimulation treatment
with an effect size similar to medication that is recom-
mended for patients who have failed at least one anti-
depressant trial
11
; it has also been shown to be
efficacious in bipolar depression.
12,13
Using brief
magnetic field pulses to induce small electrical cur-
rents in the prefrontal cortex, rTMS is believed to
impact a number of processes that facilitate remis-
sion. Although the efficacy of rTMS is clearly estab-
lished in the adult population with MDD, few
controlled studies have looked specifically at the
effects of rTMS in adults 60 and older.
14
Initial studies
of rTMS in older patients showed highly variable
results. Many uncontrolled studies have been pub-
lished regarding rTMS in older patients with depres-
sion, with response rates ranging from 18%−58.5%,
14
but the heterogeneity of the protocols prevents any
clear conclusion about the efficacy of rTMS in this
population. With respect to randomized controlled
trials (RCTs), initial studies concluded that age was a
poor predictor of response, with lower response rates
in elderly patients.
15−17
Those studies had limitations
of excluding most patients above 60 years of age and
using variable and suboptimal parameters, such as
stimulation intensity below the motor threshold, a
low number of pulses per session (1,600 pulses and
below), and an overall lower number of sessions (no
studies using 20 sessions or more). Current guidelines
recommend 3,000 pulses per session and between 20
and 30 sessions for a full course of rTMS.
18
Many
studies also used low-frequency protocols
19
even
though high-frequency protocols seem to have higher
efficacy in older adults with cortical atrophy.
20,21
A
subsequent prospective, randomized, sham-con-
trolled, double-blind study showed the efficacy of
rTMS in elderly patients with vascular depression.
22
This study used higher stimulation intensity, a larger
number of pulses, and a larger number of sessions.
Older subjects showed better response with higher
total cumulative dose (total number of pulses). Analy-
sis of the pivotal study of O'Reardon,
23
which led to
U.S. Food and Drug Administration approval of
rTMS for MDD in the United States, also did not find
age to be a statistical predictor of treatment
nonresponse.
24
Overall, the most recent studies have not found
age to be a negative predictive factor for rTMS
response in MDD.
25,26
In addition, an inverse correla-
tion between frontal cortex volume and rTMS
response, initially observed by Manes et al.,
16
was
confirmed in later studies.
22−27
This could explain
some of the discrepancies observed regarding age
and response. Finally, a dose−response relationship,
characterized by the intensity of the treatment and
the total number of pulses, was observed in many of
the previously cited studies.
14,22
Recently, a study by
Conelea et al.
25
confirmed this trend. Using modern
parameters, such as optimal stimulation intensity at
120% of the motor threshold and up to 30 daily ses-
sions over 6 weeks, the authors retrospectively com-
pared two groups of patients with MDD—those
below (n = 156) and those above (n = 75) 60 years of
age. They concluded that both age groups showed
significant improvements in depression symptoms,
with similar response and remission rates. This study
had the limitation of using self-reported question-
naires and also did not report on bipolar patients.
The field of rTMS is rapidly evolving, and different
protocols are emerging to shorten its course and
accelerate outcomes. Among these new protocols is
accelerated rTMS.
28,29
Although there is not yet an
actual consensus on the definition of accelerated
rTMS protocols, they differentiate themselves from
classical rTMS protocols by offering multiple daily
sessions to accelerate the treatment response and
reduce the necessity of numerous patient visits. In
fact, studies have shown that clinical improvement
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Safety and Efficacy of Accelerated Repetitive Transcranial Magnetic Stimulation
2 Am J Geriatr Psychiatry &&:&&,&& 2018
could be related to the total number of magnetic
pulses delivered.
29
Therefore, by using a temporally
accelerated protocol, patients could experience the
same safety, tolerability, and efficacy in a shorter time
schedule.
30,31
Accelerated protocols could potentially
condense time and commuting requirements—which
are an important issue for older patients—minimizing
trips to the clinic. Accelerated protocols have been
shown to be as effective as the standard once daily
adult protocol of 4−6 weeks while also retaining the
same safety and tolerability.
28−31
These protocols
were also recently shown to be safe in a feasibility
study of older adults, with overall positive results,
including mood improvements similar to those
observed in the general adult population.
32
To our knowledge, there has not been any study
comparing the safety, tolerability, and efficacy of
accelerated rTMS protocols in elderly patients with
TRD with an adult population with TRD receiving
the same treatment, as initial studies with classic
rTMS protocols had reported that age was a poor pre-
dictor of response.
15−17
In our study, we retrospec-
tively analyzed data of patients below and above
60 years of age treated in our clinic for TRD with
accelerated rTMS. We also report on patients with
bipolar depression, which has not been extensively
described in the literature for this population thus far.
METHODS
Participants
This study reports data collected from the retro-
spective naturalistic research project Umbrella, the
medical database of the Unit
e de Neuromodulation
Psychiatrique of the Centre Hospitalier de l'Universit
e
de Montr
eal, approved by the ethics committee. We
included patients treated on an inpatient and outpa-
tient basis, as rTMS is a treatment offered in our cen-
ter in both ambulatory care and during
hospitalization. One hundred eighty-six patients
were initially referred to our clinic for rTMS and were
thus evaluated in this retrospective study (January
2013 to January 2018). Inclusion criteria were 1)
patients older than 18 years fulfilling Diagnostic and
Statistical Manual of Mental Disorders, Fifth Edition, cri-
teria for unipolar or bipolar depression (single or
recurrent episode without psychotic features), as
confirmed by a TMS-trained psychiatrist; 2) treatment
resistance, defined as at least two trials of antidepres-
sant medication of adequate dosing and duration
33
(history of resistance regarding agent, dose, and dura-
tion was ascertained through a clinical interview and
a thorough analysis of past and present medication
records obtained from the patient's pharmacy); 3) no
prior exposure to rTMS; 4) standard clinical assess-
ments of depression symptom severity at baseline
and post-treatment; 5) having received the acceler-
ated 20 Hz protocol; and 6) written consent to the
study. Patients selected for rTMS treatment were set
to continue with their actual medication regimen, and
there were no changes allowed 1 month before and
for the duration of treatment. Exclusion criteria were
patients with nonaffective psychosis, unstable medi-
cal conditions, major neurocognitive disorder, active
substance abuse, active suicidal ideation, or severe
personality disorder that could interfere with compli-
ance with treatment.
Procedures
A MagPro X100 device (MagVenture, Farum, Den-
mark) was used for therapy with a Cool-B65 coil.
High-frequency (20 Hz) stimulation was delivered
over the left dorsolateral prefrontal cortex (DLPFC)
using the Beam F3 (Clinical Research Solutions,
Charleston, SC) algorithm to provide a more accurate
localization for unipolar and bipolar patients.
34−36
Demographic measures were collected by a registered
nurse. On Day 1, baseline ratings were obtained, and
resting motor threshold (rMT) was determined by the
same clinician for all patients for the right abductor
pollicis brevis muscles by the lowest single pulse
stimulation producing a visible muscle contraction in
half the trials. We followed the recommendations of
the Clinical TMS Society regarding redetermination
of motor threshold.
37
Treatment intensity was set at
110% maximum stimulator output of the rMT. Mean
rMT was 50.6% (standard deviation [SD]: 9.4) maxi-
mum stimulator intensity for those less than 60 and
48.6% (SD: 8.5) for those 60 years and older (unpaired
t
[71]
= 0.787, p = 0.434). The accelerated rTMS treat-
ment consisted of 20−30 rTMS sessions (2 consecutive
sessions per day, separated by 90 minutes, 3−5 days
per week), each session lasting 15 minutes (30 trains
of 100 pulsations, 5-second stimulation, with 25-sec-
ond intervals), for a total of 3,000 pulses per session.
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Desbeaumes Jodoin et al.
Am J Geriatr Psychiatry &&:&&,&& 2018 3
Treatment was offered to patients willing to attend at
least 20 sessions of rTMS. An additional 10 sessions
were offered to patients who observed some
improvement in their symptoms and were willing to
strengthen their mood improvement.
All patients signed an informed consent form and
were screened by clinical nurses for potential medical
risks, including seizure risk. Clinical personnel
involved in the delivery of rTMS were clinical nurses
trained as first responders and were able to provide
continuous clinical monitoring during rTMS sessions
as well as initial management in case of a medical
event.
Patients were clinically evaluated for depression
and anxiety symptom severity at baseline and 7 days
after the last rTMS session to evaluate the acute effect
of rTMS treatment and limit the dropout rate. The fol-
lowing scales were used: Montgomery-Asberg
Depression Rating Scale (MADRS)
38
and Hamilton
Rating Scale for Anxiety (HAM-A).
39
We did not
include patients with missing post-treatment data.
The primary outcome variable was percentage change
in the MADRS total score from baseline to post-treat-
ment. Response criterion was defined as a 50% or
greater decrease in MADRS score from baseline, and
remission was defined as a MADRS score of 10 or
more. Secondary outcome included the impact on anx-
iety symptoms, which was assessed with the HAM-A.
Psychiatric comorbidities were assessed using the
Mini-International Neuropsychiatric Interview
(MINI). Any adverse events related to rTMS treatment
were recorded after each treatment session by trained
clinical nurses and included in the patient chart.
Data Analysis
Analyses were conducted using SPSS Statistics
Version 25 (International Business Machines Corpora-
tion, Armonk, NY). Patients were grouped based on
age at the time of reference and included in one of
two groups: those less than 60 (n = 54) or those
60 years and older (n = 19). Descriptive analyses were
used to describe baseline sample characteristics. Stu-
dent's t-tests and x
2
were used to distinguish poten-
tial baseline differences between the two age groups.
Pairwise Pearson correlation was conducted to evalu-
ate the relationship between age and rMT. Paired
t-tests were used to determine differences between
pre- and post-treatment mood scores within the same
group and repeated measures ANCOVA was used to
test whether baseline anxiety scores had an influence
on mood outcome.
RESULTS
Demographic and clinical characteristics of
patients are summarized in Table 1. Of the initial 186
patients referred, 113 were excluded from the analysis
for the following reasons: not meeting inclusion crite-
ria (n = 38), not going forward with the treatment or
having a different protocol (n = 62), or refusing to
give consent for the study (n = 13).
Seventy-three (n = 73) patients met inclusion crite-
ria and were included in the statistical analysis. Mean
age was 43.8 for those less than 60 (minimum
[min] = 25 and maximum [max] = 59) and 71 for those
60 years and older (min = 60 and max = 89). Distribu-
tion did not differ between the two age groups in
terms of sex, education, history of prior ECT treatment
and psychiatric hospitalization, recurrence of depres-
sive episode, number of bipolar depressive episodes,
number of rTMS sessions received, medication taken
during treatment and baseline MADRS, or severity of
suicidal thoughts as determined by comparing base-
line score on item 10 of the MADRS scale. The group
60 years and older received 13.9 (2.1) days of treat-
ment, and those less than 60 received 14.4 (4.5) days of
treatment (t
[70]
= 0.477, p = 0.635).We also found no
significant correlation between age and rMT in our
patient cohort (r = -0.038, p = 0.747); we conducted this
analysis for each age group and found no significant
correlation (older age r = -0.317, p = 0.185; younger
age r = 0.172, p = 0.214). However, the two age groups
showed a significant difference on the HAM-A score
at baseline in terms of severity of anxiety (<60 years
mean: 19.0 [7.2]; ≥60 years mean: 15.1 [6.2]; unpaired
t
[71]
= 2.114, p = 0.028, d = 0.59).
Among the 113 patients who were excluded from
the study for reasons mentioned above, baseline
MADRS and HAM-A scores were available for only
14 subjects. When compared with our included sam-
ple of 73 subjects, the 14 excluded subjects were less
depressed (mean: 19.43; SD: 8.7; included sample
mean: 24.7; SD: 8.3; p = 0.032) but displayed similar
levels of anxiety as reported on the HAM-A
(p = 0.18). In addition, there was no significant differ-
ence in terms of baseline depression and anxiety
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Safety and Efficacy of Accelerated Repetitive Transcranial Magnetic Stimulation
4 Am J Geriatr Psychiatry &&:&&,&& 2018
severity between our sample and the 13 subjects who
were not included because of refusal to give consent
to the study.
As shown in Table 2, there was a statistically signifi-
cant improvement on the MADRS total score from base-
line to post-treatment measures in both age groups
(<60 years baseline mean: 25.8; SD: 7.7; post-treatment
mean:17.7;SD:11.1;pairedt=5.9,p<0.0001, d = 0.82;
≥60 years baseline mean: 21.7; SD: 9.3; post-treatment
mean: 9.4; SD: 7.6; paired t=5.7, p <0.0001). Both age
groups also had a significant reduction in total HAM-A
score (<60 years baseline mean: 18.8; SD: 7.2; post-treat-
ment mean: 12.2; SD: 7.6; paired t=6.2, p <0.0001;
≥60 years baseline mean: 15.1; SD: 6.2; post-treatment
mean: 6.2; SD: 5.0; paired t=7.3, p <0.0001). Repeated
measures ANCOVA showed that there was a signifi-
cant effect of time on depression score even after con-
trolling for the effect of baseline anxiety levels
(F
[1,73]
=5.2, p=0.026). We did not find a correlation
between age and percentage decrease in MADRS
(r = −0.045, p = 0.71) or HAM-A (r = −0.050, p = 0.71)
scores at the end of treatment; we also found no
correlation between age and outcome within age
groups (<60 years r = 0.014, p = 0.334; ≥60 years
r = 0.111, p = 0.378). Nonetheless, we found a statisti-
cally significant difference in percentage improvement
from baseline to final score in MADRS scores (end of
treatment) between the two age groups (<60 years
mean: 31.1; SD: 39.1; ≥60 years mean: 56.4; SD: 27.6;
t
[71]
=2.6, p=0.01, d=0.75) and from baseline to final
score in HAM-A scores (end of treatment) between the
two age groups (<60 years mean: 31.8; SD: 40.6;
≥60 years mean: 58.5; SD: 28.9; unpaired t
[70]
=2.6,
p = 0.01, d = 0.76). There were also significantly more
responders (x
2[1]
= 11.27, p = 0.001) and remitters
(x
2[1]
= 5.17, p = 0.023) in the group 60 years and older.
There were three subjects with missing post-treat-
ment data (one hypomanic switch after session six
and two dropouts). The three subjects with no post-
treatment data were all from those less than 60 years
(mean age: 50.3, min = 42, max = 58). Mean imputation
method for missing post-treatment data showed simi-
lar results for percentage improvement between the
two age groups on the MADRS (<60 years mean:
TABLE 1. Clinical and Demographic Characteristics and Baseline and Post-Treatment Severity Scores
Less Than 60 Years (n = 54) 60 Years and Older (n = 19) p value
Age, mean (SD, range) 43.8 (9.0, 25−59) 71.0 (8.3, 60−89)
Female (n [%]) 28 (52) 9 (47) 0.74
Bipolarity (n [%]) 14 (26) 2 (10.5) 0.16
Education (years), mean (SD) 15.3 (3.6) 14.8 (3.8) 0.61
History of prior ECT (n [%]) 9 (16.7) 6 (31.6) 0.17
History of psychiatric hospitalization (n [%]) 24 (44.4) 13 (68.4) 0.072
Single episode (n [%]) 11 (20.4) 2 (11) 0.34
Severity of suicidal thoughts,
a
mean (SD) 1.6 (0.2) 1.5 (0.4) 0.91
Psychiatric comorbidities (MINI)
Melancholy (n [%]) 31 (57.4) 7 (36.8) 0.12
Dysthymia (n [%]) 2 (3.7) 3 (15.8) 0.07
(Hypo)manic episodes (n [%]) 11 (20.4) 3 (15.8) 0.66
Panic disorder (n [%]) 11 (20.4) 4 (21.1) 0.95
Agoraphobia (n [%]) 14 (25.9) 6 (31.6) 0.64
Social phobia (n [%]) 8 (14.8) 5 (26.3) 0.26
Obsessive-compulsive disorder (n [%]) 5 (9.3) 1 (5.3) 0.59
Post-traumatic stress disorder (n [%]) 5 (9.3) 1 (5.3) 0.59
Alcohol dependence/abuse (n [%]) 2 (3.7) 0 (0) 0.40
Drug dependence/abuse (n [%]) 0 (0) 0 (0)
Psychotic disorders (n [%]) 4 (7.4) 3 (15.8) 0.27
General anxiety disorder (n [%]) 41 (75.9) 11 (57.9) 0.14
Medication
Antidepressant (n [%]) 45 (83.3) 17 (89.5) 0.52
Antipsychotic (n [%]) 31 (57.4) 12 (63.2) 0.66
Benzodiazepine (n [%]) 23 (42.6) 11 (57.9) 0.25
Mood stabilizer (n [%]) 19 (35.2) 4 (21.1) 0.25
Stimulant (n [%]) 3 (5.6) 2 (10.5) 0.46
Notes: MINI: Mini-International Neuropsychiatric Interview.
a
Baseline score of item 10 of MADRS scale.
Desbeaumes Jodoin et al.
Am J Geriatr Psychiatry &&:&&,&& 2018 5
ARTICLE IN PRESS
30.26; SD: 40.3; ≥60 years mean: 55.33; SD: 28.6;
unpaired t
[71]
= 2.5, p = 0.015) and HAM-A (<60 years
mean: 32.3; SD: 40.4; ≥60 years mean: 58.5; SD: 28.9;
unpaired t
[71]
=2.6,p=0.011).
There were 62 patients who received three sessions
per week (≥60 years [n = 14] and <60 years [n = 48])
and 11 patients who received five sessions per week
(≥60 years [n = 5] and <60 years [n = 6]) (x
2[1]
= 2.539,
p = 0.111). As we have only one post-treatment mea-
sure, we can only estimate speed of improvement
based on how many days of treatment they received.
The older group received 13.9 (2.1) days of treatment,
and the younger group received 14.4 (4.5) days of
treatment (t
[70]
= 0.477, p = 0.635, d = 0.14). We also
compared the actual period of days over which each
age group received treatment, and there was no sig-
nificant difference (<60 years mean: 31.9; SD: 9.9;
≥60 years mean: 29.8; SD: 7.7; unpaired t
[70]
= 0.85,
p = 0.40, d = 0.24).
Unipolar and bipolar patients were compared as a
group, and there was no difference in terms of sever-
ity of MADRS (unipolar mean: 24.8; SD: 8.0; bipolar
mean: 25.4; SD: 9.3; p = 0.064, d = 0.07) and HAM-A
(unipolar mean: 17.8; SD: 6.8; bipolar mean: 18.5; SD:
8.1; p = 0.32, d = 0.07) total scores at baseline evalua-
tion. In addition, there was no difference between
unipolar and bipolar subjects in terms of number of
rTMS sessions received (unipolar mean: 28.8; SD: 7.8;
bipolar mean: 29.9; SD: 8.5; p = 0.49, d = 0.1), prior
ECT (p = 0.11), and prior psychiatric hospitalizations
(p = 0.44). Unipolar and bipolar subjects responded in
a similar fashion to the rTMS accelerated protocol.
There was no significant difference between unipolar
and bipolar patients in terms of post-treatment score
on the MADRS (unipolar mean: 16.2; SD: 11.6; bipolar
mean: 14.4; SD: 10.4; p = 0.57, d = 0.2) and HAM-A
(unipolar mean: 11.0; SD: 7.7; bipolar mean: 9.4; SD:
6.8; p = 0.46, d = 0.2) or in terms of percentage
improvement on the MADRS (unipolar mean: 38.6;
SD: 38.0; bipolar mean: 34.5; SD: 38.8; p = 0.71,
d = 0.1) and HAM-A (unipolar mean: 37.7; SD: 40.8;
bipolar mean: 43.0; SD: 35.5; p = 0.64, d = 0.14).
Psychiatric comorbidities (evaluated by the MINI)
known to influence treatment response are reported in
Table 1. Comorbidities known to influence treatment
response in MDD did not differ between age groups.
Presence of anxious comorbidities, such as panic disor-
der, post-traumatic stress disorder, agoraphobia, social
phobia, and general anxiety disorder, individually or
grouped into one factor, showed no significant differ-
ence between age groups (p = 0.26).Certain medications
taken concomitantly could have influenced rTMS. We
TABLE 2. Baseline and Post-Treatment Severity Scores and Adverse Events
Less Than 60 Years (n = 54) 60 Years and Older (n = 19) p value
Baseline symptom scores
MADRS total score, mean (SD) 25.8 (7.7) 21.7 (9.3) 0.062
HAM-A total score, mean (SD) 19.0 (7.2) 15.1 (6.2) 0.028
a
Post-treatment symptom scores
MADRS total score, mean (SD) 17.7 (11.1) 9.4 (7.6) 0.004
a
MADRS response rate (n [%]) 19 (35.2) 14 (73.7) 0.004
a
MADRS remission rate (n [%]) 18 (33.3) 12 (63.2) 0.023
a
MADRS improvement rate (%), mean (SD) 31.1 (39.1) 56.4 (27.6) 0.012
a
HAM-A total score, mean (SD) 12.2 (7.6) 6.2 (5.0) 0.02
a
HAM-A improvement rate (%), mean (SD) 31.8 (40.6) 58.5 (28.9) 0.010
a
Adverse events related to rTMS treatment
Headaches (n [%]) 8 (14.8) 3 (15.8) 0.92
Local sensitivity (n [%]) 11 (20.4) 3 (15.8) 0.67
Fatigue (n [%]) 2 (3.7) 1 (5.3) 0.77
Nausea (n [%]) 2 (3.7) 0 (0) 0.40
Adverse events related to early termination of rTMS treatment
(Hypo)manic episode (n [%]) 2 (3.7) 0 (0)
Local sensitivity (n [%]) 2 (3.7) 1 (5.3)
Tremor present prior to treatment (n [%]) 0 (0) 1 (5.3)
Motor threshold (%), mean (SD) 50.63 (9.4) 48.68 (8.7) 0.43
Notes: MADRS improvement rate (%) refers to percent improvement rate from baseline to final score; HAM-A improvement rate (%) refers to
percent improvement rate from baseline to final score; p value refers to statistical comparison between those less than 60 years and those 60 years
and older.
a
p<0.05.
Safety and Efficacy of Accelerated Repetitive Transcranial Magnetic Stimulation
6 Am J Geriatr Psychiatry &&:&&,&& 2018
ARTICLE IN PRESS
found no significant difference in terms of rMT between
patients receiving channel blockers (n = 23; unpaired
t
[71]
=0.76, p=−0.452), antidepressant medications
(n = 62; unpaired t
[71]
=−0.12, p= 0.906), benzodiaze-
pines (n = 34; unpaired t
[71]
=−0.86, p= 0.395), or anti-
psychotic medications (n = 43; unpaired t
[71]
=0.60,
p = 0.55) and the rest of the cohort. Only 2 of our 73
patients were not taking any medication at all while
receiving rTMS. There was no difference between the
two age groups in terms of medication taken: antide-
pressant (unpaired t
[71]
= 0.19, p = 0.53), antipsychotic
(unpaired t
[71]
= 0.34, p = 0.67), benzodiazepine
(unpaired t
[71]
= 0.94, p = 0.26), mood stabilizer
(unpaired t
[71]
= 1.2, p = 0.23), or stimulant (unpaired
t
[71]
=−0.73, p = 0.47). Finally, we also compared both
age groups in terms of number of medications taken
concomitantly, and there was no significant difference
(unpaired t
[71]
=−0.56, p = 0.58). In terms of tolerance,
adverse events were reported by 5 patients in the group
60 years and older and by 18 in those less than 60. Most
of the adverse events were of short duration and easily
managed with standard care, and the rate of adverse
events related to rTMS treatment did not differ by age
group (x
2[1]
= 0.321, p = 0.57). Among those 60 years
and older, two subjects reported adverse events leading
to early termination of rTMS treatment; this was
reported by four subjects among those less than
60 years.
In terms of effectiveness of accelerated rTMS proto-
col, as we included only one post-treatment measure,
we can only estimate speed of improvement based on
how many days of treatment patients received. There
were 62 patients who received 3 days of treatment
(6 sessions) per week (subjects ≥60 years n = 14 and
subjects <60 years n = 48) and 11 who received 5 days
of treatment (10 sessions) per week (older subjects
n = 5 and younger subjects n = 6) (x
2[1]
= 2.539,
p = 0.111). Those 60 years and older received 13.9
(2.1) days of treatment, and those less than 60
received 14.4 (4.5) days of treatment (t
[70]
= 0.477,
p = 0.635, d = 0.14). The actual period over which
treatment was given was 29.8 (7.7) days for those
60 years and older and 31.9 (9.9) days for those less
than 60 (t
[70]
= 0.85, p = 0.40, d = 0.23).
We also performed a comparison of baseline char-
acteristics between responders (n = 33) and nonres-
ponders (n = 40) to our rTMS accelerated protocol and
between inpatients (n = 12) and outpatients (n = 61).
Analyses showed that nonresponders had a higher
baseline MADRS score (mean: 27.0; SD: 6.9; p = 0.01)
and HAM-A score (mean: 19.48; SD: 7.3; p = 0.045)
compared with responders (MADRS score mean: 21.9;
SD: 9.0; HAM-A score mean: 16.1; SD: 6.5).
With regard to comparisons between inpatients
and outpatients, analyses showed that there was no
significant difference in terms of age (unpaired
t
[71]
=−1.4, p = 0.18), years of education (unpaired
t
[71]
= 0.74, p = 0.46), baseline MADRS score (unpaired
t
[71]
=−1.0, p = 0.30) and HAM-A score (unpaired
t
[71]
= 0.55, p = 0.58), number of rTMS sessions
received (unpaired t
[71]
=−1.4, p = 0.16), number of
prior hospitalizations (unpaired t
[71]
=−0.74,
p = 0.46), rMT (unpaired t
[71]
=−1.1, p = 0.26), or
severity of suicidality on score item 10 of MADRS
(unpaired t
[71]
=−0.45, p = 0.66).
DISCUSSION
To our knowledge, this is the first study compar-
ing treatment outcomes between a younger
(<60 years old) and older (≥60 years old) patient pop-
ulation with TRD receiving an accelerated rTMS pro-
tocol. With the exception of HAM-A baseline scores,
baseline demographic and clinical characteristics
were very similar between our two age groups.
Indeed, we found that those 60 years and older
reported significantly fewer symptoms of anxiety.
This is surprising since elderly depressed patients
often display more signs of anxiety than younger
populations.
40
This result could be due to the small
sample in our study or a lack of sensitivity of the
HAM-A in older populations.
41
Both age groups in our study showed significant
improvement in terms of depression symptom sever-
ity. Our remission rates (<60 years = 33%, ≥60
years = 63%) are relatively high compared with other
samples.
42
This difference may be linked to the mod-
erate severity of depression in our population or to
differential referral bias (more comorbid personality
disorders in referred younger TRD patients, less in
older patients). An unexpected finding was that those
60 years and older, compared with those less than
60 years, showed a statistically significant difference
in terms of percentage improvement on the MADRS
despite having no statistical baseline difference in
depression severity. The same observation was made
regarding anxiety symptoms measured by the HAM-
Desbeaumes Jodoin et al.
Am J Geriatr Psychiatry &&:&&,&& 2018 7
ARTICLE IN PRESS
A, although there was a baseline difference, as men-
tioned previously. This is indeed surprising since
most of the initial literature on rTMS in the elderly is
negative
19,43
and only more recent studies have
begun to show similar improvements in both
groups.
22,24,25,44
In medicine, it is generally rare for
older patients to show superior outcomes, except in
the case of ECT, for which numerous studies have
found a positive association between age and clinical
outcome.
45
The left DLPFC stimulation used in this
protocol is known to have more effect on depression
than anxiety.
46
As younger patients in our cohort also
demonstrated more anxiety symptoms than our older
group, the outcome of the study might have been dif-
ferent had we stimulated the right DLPFC, as this tar-
get usually has a greater effect on anxiety.
Generally, depression in the elderly is more treat-
ment resistant than in younger populations,
3
and
younger age is usually associated with higher rTMS
treatment efficacy in other psychopathologies, such
as refractory hallucinations in schizophrenia and
poststroke functional recovery.
19,47,48
This seems to
be the result of different factors, such as psychosocial
elements, a longer course of illness (kindling), higher
medical comorbidities, undertreatment because of
medication side effects, brain atrophy, and vascular
components.
7,49,50
In our sample, the discrepancy
regarding results between our two groups could be
explained by the small sample size of our 60 years
and older group. The baseline depression severity
scores of this group on the MADRS (21.7) were also
less severe than in those less than 60 (25.8), although
the difference did not reach statistical significance.
Furthermore, since elderly depressed patients are
likely to display cortical and subcortical atro-
phy,
49,51,52
higher intensity protocols and prolonged
stimulation might be required.
53
High-frequency
accelerated protocols could trigger short and long-
term potentiation of synapses as well as structural
brain alterations of gray matter despite cortical atro-
phy,
54,55
which could also explain why our elderly
group showed a good response level. In addition,
rMT tends to be higher in older patients, which was
not the case in our cohort. Nonetheless, studies now
show that the difference in rMT between younger
and older groups—especially in the left hemisphere
—does not always reach significance.
56
The literature
now supports the right hemiaging model, which
suggests that the right hemisphere might be more
sensitive to aging effects than the left.
57,58
Unipolar and bipolar patients in our cohort dis-
played similar baseline demographic and clinical
characteristics and showed similar clinical responses
for depression and anxiety symptoms. Recent studies
comparing unipolar and bipolar depression show
that depression type does not seem to have a signifi-
cant effect on rTMS treatment response.
42,59
How-
ever, we could not compare them by age group, as
there were not enough cases (n = 2) in the 60 years
and older group.
In terms of effectiveness of the accelerated rTMS
protocol, as we included only two measures of
improvement (baseline and post-treatment), we can
only estimate the speed of improvement in our study
based on the actual period of days over which the
accelerated rTMS protocol was received. Our results
show that our patients received the accelerated proto-
col over an actual period of 4 weeks. As studies have
found that maximal therapeutic effect of rTMS treat-
ment generally takes place between 26 and 28 treat-
ment sessions, the clinical response in our sample
was faster than the usual 5−6 weeks for standard
once daily (30 sessions) rTMS protocols or the 8−12
weeks for pharmacotherapy.
26,60
This was a major
rationale for our study, as minimizing visits in this
more vulnerable population is an important issue.
Another main objective of this study was assessing
the safety of the accelerated rTMS protocol in the
elderly depressed group. In the present study, rTMS
was very well tolerated, and adverse events reported
by our patients were similar to the percentage
reported in other studies.
26,44
Most of the adverse
events were of short duration and easily managed
with standard care. In total, there were six occur-
rences of adverse events that led to early termination
of rTMS therapy, and these resolved with the termi-
nation of treatment. There was no difference in toler-
ance of rTMS therapy between the two age groups.
Our dropout rate was 2.2%, which is slightly less
than the usual rates reported in classical rTMS
protocols.
42,61
Strengths of our study include the accelerated
rTMS protocol, the use of clinician-rated scales, the
assessment of comorbid anxiety by the addition of
the HAM-A scale to the MADRS, the use of the MINI
to evaluate comorbidity, and the inclusion of bipolar
Safety and Efficacy of Accelerated Repetitive Transcranial Magnetic Stimulation
8 Am J Geriatr Psychiatry &&:&&,&& 2018
ARTICLE IN PRESS
patients. Because of its design, our study has many
inherent limitations; it involved a small sample size,
mostly in the 60 years and older group, making it dif-
ficult to draw any definitive conclusion regarding the
superior treatment response rate in that group. Given
the small sample size, the restricted statistical power
—especially for bipolar patients—in the present study
(N = 17) may have played a role in limiting the signifi-
cance of some of the statistical comparisons con-
ducted. Open trials can be subject to important
confounds, as investigators and participants are not
blinded. Unfortunately, blinded trials are not always
available, but naturalistic data are still important in
determining the application and feasibility of new
rTMS protocols in clinical practice.
62
There was no
sham control condition, but the efficacy of rTMS in
MDD is now well established, and placebo response
rates tend to be significantly lower in subjects suffer-
ing from treatment-resistant depression.
11,63
In addi-
tion, patients continued adjunct pharmacotherapeutic
and psychotherapeutic treatments during rTMS ther-
apy, but medications were kept stable before and
until the end of treatment. Regrettably, we could not
compare the age groups in terms of failed adequate
antidepressant trials for the current episode, and in
the absence of such information, we cannot conclude
that age groups did not differ in this respect. Finally,
our postevaluation was performed only 7 days after
the last rTMS session. Some studies have found a
delay of a few weeks before the maximal effect is
seen, and perhaps a longer waiting period could have
produced more changes, especially in the younger
age group.
64
In conclusion, the results of this trial add to the
increasing number of studies confirming the safety,
tolerability, and efficacy of rTMS in older TRD
patients. The accelerated rTMS protocol offers inter-
esting advantages compared with once daily rTMS,
such as a more rapid response while retaining safety
and efficacy. This could be an interesting option for
older patients for whom traveling every day to an
rTMS clinic for many weeks is an issue. Because of
the limited sample size and the surprising finding
that elderly patients had a more robust response over-
all, this study needs to be replicated with larger sam-
ples. An enriched bipolar sample in the older
population would also be necessary to make any
meaningful comparison between unipolar and bipo-
lar depression outcomes in the two age groups.
The authors thank N. Desjardins, B.Sc., R.N., and S.
Tieu, B.Sc., R.N., for their moral support and assistance in
data collection. The authors have no conflicts of interest
and no funding to report.
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