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Transcranial pulsed electromagnetic fields for treatment-resistant depression: A multicenter 8-week single-arm cohort study: The eighth trial of the Danish University Antidepressant Group

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  • Psychiatry - Aalborg University Hospital

Abstract and Figures

Background The efficacy of antidepressant treatment is fair, but the efficacy is considerably lower in patients failing two or more trials underscoring the need for new treatment options. Our study evaluated the augmenting antidepressant effect of 8-weeks transcranial pulsed electromagnetic field (T-PEMF) therapy in patients with treatment-resistant depression. Methods A multicenter 8-week single-arm cohort study conducted by the Danish University Antidepressant Group. Results In total, 58 participants (20 men and 38 women) with a moderate to severe depression as part of a depressive disorder according to ICD-10 who fulfilled criteria for treatment resistance were included, with 19 participants being nonresponders to electroconvulsive therapy during the current depressive episode. Fifty-two participants completed the study period. Scores on the Hamilton Depression Scale 17-items version (HAM-D 17 ) decreased significantly from baseline (mean = 20.6, SD 4.0) to endpoint (mean = 12.6, SD 7.1; N = 58). At endpoint, utilizing a Last Observation Carried Forward analysis, 49 and 28% of those participants with, respectively, a nonchronic current episode (≤2 years; N = 33) and a chronic current episode (>2 years; N = 25) were responders, that is, achieved a reduction of 50% or more on the HAM-D 17 scale. At endpoint, respectively, 30 and 16% obtained remission, defined as HAM-D 17 ≤ 7. On the Hamilton Scale 6-item version (HAM-D 6) , respectively, 51 and 16% obtained remission, defined as HAM-D 6 ≤ 4. Conclusions The findings indicate a potential beneficial role of T-PEMF therapy as an augmentation treatment to ongoing pharmacotherapy in treatment-resistant depression.
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Transcranial pulsed electromagnetic fields for
treatment-resistant depression: A multicenter
8-week single-arm cohort study
The eighth trial of the Danish University Antidepressant
Group
Erik Roj Larsen
1,2
, Rasmus W. Licht
3,4
, René Ernst Nielsen
3,4
, Annette Lolk
1,2
,
Bille Borck
5
, Claus Sørensen
1,2
, Ellen Margrethe Christensen
7
, Gustav Bizik
3
,
Janus Ravn
6
, Klaus Martiny
7
, Maj Vinberg
7
, Odeta Jankuviené
3
,
Pernille Blenker Jørgensen
5
, Poul Videbech
5
and Per Bech
8
1
Mental Health Department Odense, University Clinic, Mental Health Service, Odense, Denmark;
2
Department of Clinical
Research, University of Southern Denmark, Odense, Denmark;
3
Aalborg University HospitalPsychiatry, Aalborg,
Denmark;
4
Department of Clinical Medicine, Aalborg University, Aalborg, Denmark;
5
Centre for Neuropsychiatric
Depression Research, Mental Health Centre Glostrup, Glostrup, Denmark;
6
Department of Affective Disorders, Aarhus
University Hospital, Skejby, Denmark;
7
Copenhagen Affective Disorder Research Centre (CADIC), Psychiatric Centre
Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark and
8
Psychiatric Research Unit, Mental Health
Centre North Zealand, University of Copenhagen, Copenhagen, Denmark
Abstract
Background. The efficacy of antidepressant treatment is fair, but the efficacy is considerably
lower in patients failing two or more trials underscoring the need for new treatment options. Our
study evaluated the augmenting antidepressant effect of 8-weeks transcranial pulsed electro-
magnetic field (T-PEMF) therapy in patients with treatment-resistant depression.
Methods. A multicenter 8-week single-arm cohort study conducted by the Danish University
Antidepressant Group.
Results. In total, 58 participants (20 men and 38 women) with a moderate to severe depression as
part of a depressive disorder according to ICD-10 who fulfilled criteria for treatment resistance
were included, with 19 participants being nonresponders to electroconvulsive therapy during the
current depressive episode. Fifty-two participants completed the study period. Scores on the
Hamilton Depression Scale 17-items version (HAM-D
17
) decreased significantly from baseline
(mean = 20.6, SD 4.0) to endpoint (mean = 12.6, SD 7.1; N= 58). At endpoint, utilizing a Last
Observation Carried Forward analysis, 49 and 28% of those participants with, respectively, a
nonchronic current episode (2 years; N= 33) and a chronic current episode (>2 years; N= 25)
were responders, that is, achieved a reduction of 50% or more on the HAM-D
17
scale. At
endpoint, respectively, 30 and 16% obtained remission, defined as HAM-D
17
7. On the
Hamilton Scale 6-item version (HAM-D
6)
, respectively, 51 and 16% obtained remission, defined
as HAM-D
6
4.
Conclusions. The findings indicate a potential beneficial role of T-PEMF therapy as an
augmentation treatment to ongoing pharmacotherapy in treatment-resistant depression.
Introduction
The efficacy of antidepressant treatment is fair, but the efficacy is considerably lower in patients
failing two or more trials [1]. The proportion of remitters decreases dramatically after the second
failed treatment trial. The cumulative proportion of remitters was estimated to 67% after four
trials in the STAR*D study [2]. Furthermore, the likelihood of antidepressant treatment effect
decreases with the duration of the current depressive episode [3], with episodes shorter than 12
months being associated with cumulative proportions of remitters of 8090%, whereas episodes
of longer duration than 12 months are associated with a 40% cumulative proportion of remitters
[4,5] for both pharmacological and electroconvulsive therapy (ECT) [6]. Although no consensus
concerning the definition of treatment resistant depression (TRD) exists, it is usually defined as
insufficient effect within the same episode of at least two different evidence-based medical
European Psychiatry
www.cambridge.org/epa
Research Article
Cite this article: Larsen ER, Licht RW, Nielsen
RE, Lolk A, Borck B, Sørensen C, Christensen
EM, Bizik G, Ravn J, Martiny K, Vinberg M,
Jankuviené O, Jørgensen PB, Videbech P, Bech P
(2020). Transcranial pulsed electromagnetic
fields for treatment-resistant depression: A
multicenter 8-week single-arm cohort study.
European Psychiatry,63(1), e18, 18
https://doi.org/10.1192/j.eurpsy.2020.3
Received: 09 October 2019
Revised: 30 December 2019
Accepted: 02 January 2020
Key words:
major depressive disorder; transcranial pulsed
electromagnetic fields; treatment-resistant
depression
Author for correspondence:
Erik Roj Larsen,
E-mail: erik.roj.larsen@rsyd.dk
Per Bechdeceased (May 9, 2018).
© The Author(s) 2020. This is an Open Access
article, distributed under the terms of the
Creative Commons Attribution licence (http://
creativecommons.org/licenses/by/4.0/), which
permits unrestricted re-use, distribution, and
reproduction in any medium, provided the
original work is properly cited.
treatments, that is, two antidepressants from different classes eval-
uated over a sufficient time period (at least 6 weeks) and given in a
sufficient dose [7].
Treatment with transcranial pulsed electromagnetic fields
(T-PEMFs) for patients with otherwise treatment-resistant depres-
sion has previously been examined with promising results [8].
The treatment helmet consists of seven electromagnetic coils.
It is placed on the head of the patient and is connected to an
impulse generator resulting in a supposed diffuse, multifocal brain
stimulation of several brain regions. The patient is awake during
treatment. T-PEMF induces low electric fields near 0.0004 V/m
compared with repetitive transcranial magnetic stimulation
(rTMS), which results in 90 V/m. In contrast to rTMS, T-PEMF
stimulation stays well below the firing threshold of neurons, but
may modify intrinsic brain oscillation [9,10]. The Re5 PEMF
pulse generator powers the coils with alternating bipolar square
pulses, each l asting 3 ms and interspersed by a 12-ms pause, each
pulse sequence thus lasting 18 ms, corresponding to a pulse fre-
quency of 55 Hz. Interactions of low frequency pulsed electro-
magnetic fields with living tissue has been reviewed by Dissing
et al. [10]. They concluded that a general picture emerges from
studies on cell cultures and living tissue revealing that PEMF
facilitates existing biochemical processesespecially those related
to growth factor stimulation. Most of these factors stimulate
cytoplasmictyrosinekinasesoftheSrcfamilyandtheyleadto
many different responses depending on the cell type, that is,
proliferation of osteoblasts, endothelial cells, nerve cells, and
chondrocytes.
In a double-blind, randomized, sham-controlled study, rTMS
was shown to reduce HAM-D
17
scores from 25.3 (SD 3.0) to 11.1
(SD 6.7) after 12 weeks in the active treatment group versus 24.7
(SD 3.2) to 13.5 (SD 7.2) in the sham group (p<0.22) [11].
Participants randomized to rTMS were treated over 3 weeks at a
psychiatric research unit and followed-up for 9 more weeks.
Similarly, T-PEMF was investigated in a double-blind, random-
ized, sham-controlled study [8]. In this study, HAM-D
17
scores
were reduced from 21.1 (SD 4.1) to 11.0 (SD 5.7) after 5 weeks in
the active treatment group versus 20.9 (SD 3.3) to 16.0 (SD 5.6)
in the sham group (p< 0.01). The response proportion was 61.0%
in the T-PEMF group versus 12.9% in the sham group, with
remission proportion of 33.9% versus 4.1%, respectively. The
low remission proportion in the placebo group in this study
population of TRD patients is similar to previous studies [12].
Furthermore, a double-blind, randomized controlled study com-
paring once or twice daily T-PEMF treatment for 8 weeks
administered in the patientshomes on all weekdays showed a
reduction in HAM-D
17
from 20.4 (SD 2.7) to 6.8 (SD 4.5) and
from 20.9 (SD 2.9) to 7.3 (SD 5.8); p< 0.92. The proportion of
remitters(definedasHAM-D
17
7) was 73.5 and 67.7%, respec-
tively (p=0.79) [13].
In the 2-year follow-up of the study mentioned [13], looking at
the 73.5% of patients who obtained remission during the acute
phase treatment, 48% had a relapse between 4 and 16 months after
the T-PEMF augmentation [14] and remission was achieved after a
repeated course of T-PEMF. No serious side effects were experi-
enced in the mentioned T-PEMF studies, besides a minor headache
and slight nausea after finishing the first treatments.
Besides symptom reduction, the patients quality of life is impor-
tant. In the first T-PEMF study [8], the WHO-5 well-being scale
was utilized to measure quality of life, which increased from
baseline to endpoint. This difference was, however, not statistically
significant. WHO-5 was also used in the present study.
We have included the HAM-D
6
subscale as well as it consists of
the core symptoms of depression (depressed mood, guilt, work and
interests, psychomotor retardation, psychic anxiety, and general
somatic). The subscale has been found to perform better than the
full HAM-D
17
scale in term of unidimensionality [15,16]. The
HAM-D
17
scale also measures side effects induced by antidepres-
sants such as sleep disturbances, agitation, gastrointestinal symp-
toms, and sexual disturbances.
Aims of the study
The current study aimed at evaluating whether an 8-week T-PEMF
treatment used as an augmentation to ongoing pharmacological
antidepressant treatment in patients with treatment-resistant
depression in a multicenter, single-arm study design would repli-
cate the findings of previous studies obtained at only one research
center. Furthermore, we aimed at evaluating if duration of the
current depressive episode was associated with treatment response
by comparing nonchronic (2 years) with chronic current episode
(>2 years). Lastly, we wanted to evaluate whether ECT nonre-
sponders were able to achieve response by T-PEMF, as the two
treatments seem to work differently.
Materials and Methods
Design
An 8-week single-arm cohort study augmenting treatment as usual
with daily T-PEMF treatments.
Study population
Adult patients (18 years) were screened from the six participating
mental health centers (Table 1). A checklist was filled in with the
inclusion and exclusion criteria with an accept from the potentially
eligible patients who wanted to be contacted for more information.
Inclusion and exclusion criteria were then confirmed, and outcome
measures at baseline and other relevant information were recorded
by the study team after informed consent to participate was
obtained. Participants who were not referred to the project were
left unregistered.
Inclusion criteria were a diagnosis of moderate to severe
depression, single episode or recurrent according to ICD-10
(F32 and F33), and with a Hamilton Depression Scale score of
13 or more on the 17 item version (HAM-D
17
)[15] and further
fulfilling the criteria for treatment-resistant depression character-
ized by an insufficient effect of at least two different evidence-
based medical treatments, that is, two antidepressants from
different classes, and evaluated over a sufficient amount of time
(at least 6 weeks) and given in a sufficient dose [17]. Both hospi-
talized and outpatients were included. ECT nonresponders could
be included in the project if they fulfilled the criteria of no response
to two antidepressants as mentioned above. Participants with
comorbid anxiety disorders were included.
Exclusion criteria were a diagnosis of dementia, schizophrenia,
bipolar disorder, borderline personality disorder, harmful use or
dependence of psychoactive drugs, or severe suicidality, defined as
HAM-D
17
, item 3 (suicidal ideations) score of >2, as well as severe
physical disease (e.g., cancer, leukemia, melanoma or other cancer
forms in neck or head, autoimmune diseases, organic diseases in the
brain, Parkinsons disease, multiple sclerosis, epilepsy, stroke, or
use of pacemaker) interfering with study participation, as judged by
2 Erik Roj Larsen et al.
the investigator. Participants unable to give informed consent were
excluded.
The pharmacological treatment had to remain unchanged over
the last 4 weeks before the initiation of the T-PEMF as well as
during the study period. However, initiation or changes in sleep aid
medication were allowed, for example, benzodiazepines, imoclone,
zopiclone, melatonin, and promethazine. As participants were
followed-up at the hospital or outpatient clinic, we were able to
secure that no change of medication was done by getting access to
data concerning the medication used. Besides, participants were
informed that no change of medication was allowed during
T-PEMF treatment.
The study was planned to be prematurely terminated if adverse
events occurred that were more serious than expected or if new
evidence was found during the treatment period that indicated the
treatment should be regarded as a less safe treatment. In case of
rapid and severe deterioration of depressive symptoms requiring
ECT or change in psychopharmacological treatment or if mania
occurred, the participant was withdrawn from the study.
Outcome measures
Change in the Hamilton Depression Scale (HAM-D
17
) was chosen
as the primary outcome measure. Secondary outcome measures
were response and remission on the HAM-D
17
. HAM-D
17
consists
of 17 items, which can be scored between 0 and 2 or 0 and
4, resulting in a total score between 0 and 52 [18]. Remission was
defined as a HAM-D
17
score at the endpoint of seven or less, and
response was defined as a 50% reduction or more on the HAM-D
17
total score at endpoint. Response and remission on the Hamilton
Depression Scale 6 item version (HAM-D
6
) were evaluated as well
with response defined as at least a 50% reduction from baseline in
total score and remission defined as a HAM-D
6
score 4.
The HAM-D
6
subscale includes the core symptoms of depressive
states (depressed mood, guilt, work and interests, psychomotor
retardation, psychic anxiety, and general somatic) [15]. Inter-rater
reliability was secured in different ways. The Danish University
Antidepressant Group (DUAG) has produced three videos in
Danish for Hamilton inter-rater training. Besides, the HAM-D
17
is used on a weekly basis in hospital-based psychiatric settings in
Denmark, as all patients treated for depression must be rated with
HAM-D
17
before and after treatment. The data are delivered to the
Danish National Clinical Quality Development Program. In addi-
tion, each study participant was rated by the same rater throughout
the study.
Side effects were evaluated utilizing the self-reported Patient
Reported Inventory of Side Effects (PRISE) [15]. It consists
of 11 items scored from 0 to 2 according to the severity of side
effects.
The WHO-5 well-being scale [15] was utilized to measure
quality of life. WHO-5 contains only five positive phrased items
to measure positive psychological well-being. Each item is scored in
terms of frequency over the past 2 weeks. The score on each item
has a range from 0 (none of the time) to 5 (all the time). The
summed total score of the WHO-5 goes from 0 (no well-being) to
25 (extreme well-being), with the sum score being multiplied by
four, to result in a score from 0 to 100.
Statistical analyses
The sample size calculation was based on the two previous T-PEMF
studies [8,13]. Using a two-sided paired t-test with a significance
level of 0.05 and a power of 0.90 to detect a meaningful difference of
4 points from baseline to endpoint on the HAM-D
17
would require
at least 26 participants. With an expected dropout of 15%, the
minimum sample size would be 31 participants.
Table 1. Inclusion according to centers and characteristics of all participants with treatment resistant depression at baseline and stratified according to duration of
depression
All participants
Participants with a duration
of depression (2 years)
Participants with a duration
of depression (>2 years)
Centers
Aalborg 17 13 4
Risskov 12 6 6
Odense 8 6 2
PC Glostrup 8 2 6
PCKKBH 10 3 7
PCNHillerod 3 3 0
Total 58 33 25
Females 66% 64% 68%
Age mean (years) 53.7 (SD 14.9) 54.2 (SD 13.6) 52.2 (SD 16.8)
Mild depression 14% 21% 4%
Moderate depression 55% 64% 44%
Severe depression 31% 15% 52%
Number of episodes 4.4 (SD 4.2) 4.8 (SD 4.2) 4.0 (SD 4.3)
Mean HAM-D17 20.6 (SD 4.0) 19.3 (SD 3.9) 22.3 (SD 4.2)
Mean HAM-D6 11.2 (SD 2.4) 10.6 (SD 2.5) 12.1 (SD 1.9)
Mean WHO-5 19.9 (SD 15.9) 23.0 (SD 17.7) 15.8 (SD 12.2)
European Psychiatry 3
Initially, a descriptive analysis of the study populations baseline
characteristics was conducted.
Second, baseline scores of HAM-D
17
and HAM-D
6
were com-
pared with scores at endpoint for each patient using paired t-tests,
that is, intention-to-treat analyses. T-tests for independent samples
were used to compare the mean scores of HAM-D
17
and HAM-D
6
between participants with nonchronic (defined as duration of the
current depressive episode of 2 years or less) and participants
with chronic current depressive episode (defined as duration of
the current depressive episode of more than 2 years) at baseline
and at 2-, 4-, 6- and 8-weeksfollow-up. Also, the proportion of
responders (response defined as 50% reduction in HAM-D score
from baseline until endpoint), proportion of remitters (remission
defined as HAM-D
17
7 [or HAM-D
6
4] at endpoint), and the
proportions of participants with a WHO-5 score of at least 50% at
endpoint were compared between participants with chronic and
nonchronic current depressive episode using Pearsons chi-squared
tests. Response and remission analyses were performed both as
complete case analyses and as intention-to-treat analyses
(endpoint-analysis, which essentially is the same as Last Observa-
tion Carried Forward analysis).
Intervention
Both hospitalized and outpatients were included. Participants
were given the first T-PEMF treatment at the hospital or
outpatient clinic and were instructed about the use of T-PEMF.
Thereafter, they were supervised per need at the hospital or
outpatient clinic during the first week to ensure proper use. After
instruction, treatment was self-administered in the participants
home. Duration of treatment was 30 min per day, each day, with
treatments for 8 weeks. All instructors were qualified to use
T-PEMF by Re5 ApS, Denmark. The participants were thereafter
seen at the outpatient clinic at weeks 1, 2, 4, 6, and 8 after
treatment had begun.
T-PEMF used in this intervention is as described in the intro-
duction with a low electric field near 0.0004 V/m and with to a pulse
frequency of 55 Hz. The impulse generator requires a chip card to
be started. The card was programmed with 20 treatments. When
the helmet is used, time and date for every treatment is stored on the
card. Besides, it secures that the participants meet at the clinic
during the intervention for new cards.
Ethics
Referred patients were given oral and written information concern-
ing the study before giving their written consent for participation.
The investigation was conducted in accordance with the Helsinki II
Declaration. The study was approved by the Scientific Ethics Com-
mittee for the Central Denmark Region, the Danish Data Protection
Agency (approval number 1-16-02-337-16) and registered at
ClinicalTrials.gov (unique protocol ID: 1-10-72-125-16).
Financing
Re5 ApS has developed T-PEMF technology. Navamedic Company
introduced Re5-NTS (T-PEMF) to the participating centers in
Denmark and provided equipment for the project, with individual
centers paying rental costs. Each DUAG center financed the
project costs through their respective research funds. Navamedic
and Re5 ApS did not influence the design, data analysis, or report-
ing of the results.
Results
A total of 58 participants were included (20 men and 38 women)
from six centers. Fifty-two participants completed the study
(89.7%). One participant requested ECT as an alternative treatment
option after a few days of T-PEMF treatment. One participant was
hospitalized after an overdose of zolpidem as intended suicide. One
participant deteriorated without suicidal thoughts after 20 days of
T-PEMF treatment and discontinued treatment. One deteriorated
due to too much work at home after 35 days of treatment with
T-PEMF and was hospitalized. Two participants wanted a change
in medication and discontinued T-PEMF treatment.
The distribution of participants across centers and charac-
teristics of all participants in total, as well as their division
according to the duration of their current depressive episode at
baseline, are shown in Table 1. At baseline, the participants
suffering from chronic current depressive episode (current epi-
sode >2 years) had a higher severity as measured by HAM-D
17
as
compared with participants with a nonchronic current depres-
sive episode.
Psychopharmacological treatment at baseline is shown in
Table 2. Twelve participants had tried two antidepressant drug
trials in the current episode, 31 had tried 3, 7 had tried 56,
4 had tried 710, and 3 had tried more than 10 medications. Data
of medications were missing for one participant. Nineteen partic-
ipants were nonresponders to ECT in the current episode.
The mean HAM-D
17
scores decreased from baseline (mean =
20.6, SD 4.0) to endpoint (mean = 12.6, SD 7.1; N= 58; p< 0.05;
independent samples t-test). The mean scores on the HAM-D
6
decreased similarly from baseline (11.2, SD 2.4) to endpoint (6.2,
SD 4.1; p< 0.05; independent samples t-test).
HAM-D
17
and HAM-D
6
baseline scores and scores every sec-
ond week of completers are presented in Table 3. There were three
dropouts in each group.
Sensitivity analyses comparing participants with nonchronic
and chronic current depressive episodes were conducted. The
participants suffering from a chronic current depressive episode
were more severely depressed at baseline (p< 0.01). In participants
suffering from a nonchronic depressive episode, a mean reduction
of 9.4 points from baseline to the end of study on HAM-D
17
was
observed, as compared with participants with a chronic current
depressive episode where a mean HAM-D
17
reduction of 8.3
points from baseline to the end of study was observed. In partici-
pants suffering from a nonchronic depressive episode, a mean
HAM-D
6
reduction of 5.3 points from baseline to end of study
was observed, as compared with participants with a chronic current
depressive episode where a mean HAM-D
6
score reduction of 4.8
points was observed.
Endpoint results for response and remission are shown in
Table 4. In total, 39.7% responded on the HAM-D
17
scale and
24.1% achieved remission. Among completers, 44.2% responded
and 26.9% achieved remission.
Similar to previous analyses, we compared participants with a
chronic versus nonchronic depressive episode showing that 48.5%
of the nonchronic participants (N= 33) responded on the HAM-
D
17
and 30.3% achieved remission at endpoint (Table 4). Among
participants (N= 25) suffering from a chronic depressive episode,
28.0% responded and 16.0% obtained remission on the HAM-D
17
scale at endpoint.
At endpoint, 51.5% of participants suffering from nonchronic
current depressive episode responded on the HAM-D
6
scale and
51.5% achieved remission. Among participants suffering from
4 Erik Roj Larsen et al.
chronic current depressive episode, 28.0% responded and 16.0%
obtained remission on the HAM-D
6
scale, respectively.
In general, response and remission proportion were higher in
completers as compared with noncompleters.
For all participants, the mean WHO-5 increased significantly from
baseline (mean 19.93, SD 15.9) to endpoint (38.0, SD 27, p< 0.05).
Among participants with nonchronic depression, 51.5% achieved a
score of WHO-5 50 as compared with 24.0% in participants with
chronic current depressive episode (Table 4). Among the completers,
the proportion was even higher.
Among all the 19 ECT nonresponders, 34.6% responded and
28.6% achieved remission on the HAM-D
17
scale at the endpoint.
On the HAM-D
6,
33.3% responded and 28.6% achieved remission.
Among the 10 ECT nonresponders who suffered from a nonchro-
nic depression, 50.0% responded and 30.0% achieved remission
on the HAM-D
17
scale. Among the nine ECT nonresponders
who suffered from a chronic current depressive episode, 33.3%
responded and 11.1% achieved remission on the HAM-D
17
.
If the results were divided according to severity of the depressive
episode at baseline, the response on the HAM-D
17
was 37.5%
among the minorly depressed, 53.1% among the moderately
depressed, and 16.7% among the severely depressed participants.
Remission on the HAM-D
17
was achieved in 25.0% of
participants suffering from a minor depression, 31.3% among
participants moderately depressed at baseline, and 11.1%
among participants severely depressed at baseline.
The global side effect as measured by the PRISE decreased from
61.1% at baseline to 31.0% at endpoint. The pharmacopsycho-
metric triangle [15,19] illustrates the balance between the effect
of pharmacotherapeutic drugs (upper left vertex A) and the
induced side effects of these drugs (upper right vertex B) when
taking into account self-reported well-being (lower vertex C). In the
pharmacopsychometric triangle in Figure 1, the balance between
symptomatic relief on HAM-D
17
and HAM-D
6
(endpoint), side
effect on PRISE, and psychological well-being on WHO-5 is shown.
The reduction in side effects was more pronounced in participants
with nonchronic depression as shown in Figure 1. Among partic-
ipants achieving remission, the proportion reporting side effect was
reduced from 71.4 to 16.4%. Among participants not achieving
remission, the proportion reporting side effect was reduced from
56.8 to 38.9%.
Discussion
Our study supports earlier findings that a proportion of patients
with treatment-resistant depression seem to benefit from add-on
treatment with T-PEMF to pharmacological antidepressant treat-
ment [8,13,14]. T-PEMF without treatment with antidepressants
has not been investigated in this study or in the earlier studies, and it
is not possible to evaluate to what extent the allowed co-medication
has contributed to the findings. However, we assume that the
present findings, at least not exclusively, are due to an effect of
continuing with antidepressants for 8 more weeks. But we are not
able to estimate the effect with our design.
Due to the very low proportion of remission in the placebo
group (12.8%) in the first study [8], we decided to exclude sham
T-PEMF. Among the 58 included participants with treatment-
resistant depression, an overall proportion of 24% had remitted
at end of treatment compared with 26.9% among the 52 completers.
When remission was based on the HAM-D6, which has been shown
to be more sensitive to change in severity during treatment than the
HAM-D
17
[16], the overall proportion of remitters was 36.2 and
40.4% in the total sample and completers, respectively.
The proportion of remitters was higher in participants suffering
from a nonchronic depressive episode at baseline, as compared with
participants suffering from a chronic depressive episode. This is in
accordance with previous data showing that treatment resistance
increases with the duration of the current episode [4,5]. Despite of
the lower effect observed in this patient population, there is still an
indication for treatment, as no other treatment has shown a signif-
icantly better response.
The potential beneficial effect of T-PEMF was also seen in
patients who were nonresponders to ECT. The indication for
T-PEMF as compared with that of r-TMS and ECT thus needs to
Table 2. Psychopharmacological treatment in patients with treatment
resistant depression at baseline
Medication Percentage/nos.
Mean
dose (mg) Range (mg)
Antidepressants
Citalopram 1.7% (1) 40 40
Escitalopram 3.4% (2) 20 20
Sertraline 1.7% (1) 100 100
Venlafaxine 19.0% (11) 211 75300
Duloxetine 15.5% (9) 87 60120
Nortriptyline 25.9% (15) 108 75150
Clomipramine 7.0% (4) 88 50150
Moclobemide 3.4% (2) 525 450600
Isocarboxazide 5.2% (3) 40 3050
Mirtazapine 12.1% (7) 33 7.560
Agomelatine 10.3% (6) 38 2550
Prothiadene 1.7% (1) 225 225
Vortioxetine 12.1% (7) 19 1520
Mianserine 1.7% (1) 30 30
Amitriptyline 1.7% (1) 100 100
Augmentation
Lithium 12.1% (7) 21mmol 8.148 mmol
Lamotrigine 15.5% (9) 230 100500
Antipsychotics
Quetiapine 27.6% (16) 102 12.5300
Aripiprazole 1.7% (1) 20 20
Risperidone 3.4% (2) 2 13
Olanzapine 5.2% (3) 8 515
Sedatives
Benzodiazepines 3.4% (2) 15 15
Zoplicone 5.2% (3) 6 3.757.5
Melatonin 1.7% (1) 2 2
Promethazine 3.4% (2) 25 1
Total number 117
Mean number of
medications
2.02 (range 210)
European Psychiatry 5
be clarified in the future. ECT seems to be more effective than rTMS
for depression, especially in the short term, particularly for patients
suffering from psychotic depression, severe suicidality, and lack of
fluid intake [20]. ECT has, however, more side effects. Mild to
moderate depressive episodes of shorter duration seem to be asso-
ciated with antidepressant effect of rTMS [21]. T-PEMF treatment
has the advantage that it can be used at the participants home due
to no risk of treatment-induced seizures and ease of treatment
administration, combined with a favorable side-effect profile. In
our study, the side effects of the medication used were reduced
considerably during treatment with T-PEMF, which might reflect
an indirect effect of perceived side effects in participants.
Decades of research has been performed to elucidate the mech-
anism of ECT and indicates involvement of numerous biologic
processes, including alterations in neuroplasticity, levels of various
neurotrophic factors and neurotransmitters, functional connectiv-
ity, immune mechanisms, neuroendocrine function, as well as
epigenetic processes [22]. Our study indicates that T-PEMF may
have an effect in some ECT nonresponders, which may imply a
different neurobiological effect.
The patients own assessment of improved psychological well-
being during treatment is an important symptom domain, which is
not captured by the HAM-D
17
scale [4]. Therefore, we used the
WHO-5 scale to measure quality of life. A score on the WHO-5
scale 50 has earlier been shown to correlate with remission of
depression [4]. In our study, the proportion of participants achiev-
ing a WHO-5 score 50, which corresponds to no well-being
problems, was in line with the HAM-D
6
results.
The current study design, a single-arm cohort study, makes it
impossible to infer treatment effect of T-PEMF per se due to an
unknown proportion of spontaneous remitters and of patients
remitted due to the underlying treatment as usual given over the
course of the study as well as an unknown impact of expectation.
However, a previous study has shown that remission rates were as
low as 8% in a 2-year follow-up period in patients with treatment-
resistant depression who received treatment as usual [23]. Albeit
Table 3. HAM-D
17
and HAM-D
6
baseline scores and weekly scores (mean and SD) for the study period in patients with treatment resistant depression stratified
according to duration of depression at baseline
N/n
HAM-D17 (mean [SD]) HAM-D6 (mean [SD])
Duration of the current depression Duration of the current depression
Total 2 years >2 years Sign
a
Total 2 years >2 years Sign
a
Week
Baseline 33/25 20.6 (4.0) 19.3 (3.7) 22.3 (3.8) 0.01 11.2 (2.4) 10.6 (2.3) 12.1 (2.2) 0.01
Week 2 32/24 15.9 (6.7) 14.0 (6.5) 18.5 (6.2) 0.01 8.8 (3.8) 7.6 (3.6) 10.4 (3.5) 0.01
Week 4 31/24 14.5 (6.8) 12.6 (6.4) 17.0 (6.6) 0.02 7.9 (4.0) 6.8 (3.8) 9.3 (3.9) 0.02
Week 6 30/23 12.6 (6.6) 11.5 (6.4) 14.0 (6.7) 0.18 7.0 (4.3) 6.1 (4.2) 8.0 (4.1) 0.10
Week 8 30/22 11.6 (6.6) 9.9 (6.3) 14.0 (6.4) 0.03 6.2 (4.1) 5.3 (4.3) 7.3 (3.5) 0.07
a
Independent samples t-test (Levenes Test for Equality of Variances).
Note: N, patients with duration 2 years; n, patients with duration >2 years; Sign, HAM-D
17
and HAM-D
6
ratings 2 years versus >2 years.
Table 4. Response and remission at end of treatment (defined as HAM-D
17
< 8 or as HAM-D
6
< 5) and WHO-5 50 in patients with treatment resistant depression at
baseline stratified according to duration of depression
Total/all participants (%)
Participants with a duration
of depression (2 years)
Participants with a duration
of depression (>2 years) Sign
a
Completers
N52 30 22
Ham-D
17
response 44.2% 53.3% 31.8% 0.12
Ham-D
17
remission 26.9% 33.3% 18.2% 0.22
Ham-D
6
response 46.2% 56.7% 31.8% 0.08
Ham-D
6
remission 40.4% 56.7% 18.2% 0.05
WHO-5 50 44.2% 56.7% 27.3% 0.04
All
N58 33 25
Ham-D
17
response 39.7% 48.5% 28.0% 0.11
Ham-D
17
remission 24.1% 30.3% 16.0% 0.21
Ham-D
6
response 41.4% 51.5% 28.0% 0.07
Ham-D
6
remission 36.2% 51.5% 16.0% 0.05
WHO-5 50 39.7% 51.5% 24.0% 0.03
a
Pearson chi-square test.
6 Erik Roj Larsen et al.
this proportion would not necessarily have been so low in the
present study sample, the finding supports a low chance of remis-
sion associated with treatment as usual in TRD patients. Similarly,
we were unable to control for confounders due to the single arm,
nonrandomized design. Also, since the duration of the current
episode was not recorded as a continuous variable, it was not
possible to investigate the association between duration of the
current episode and outcome beyond the duration of 2 years or
less versus more than 2 years.
The current study design has some limitations. A single-arm
cohort study makes it impossible to infer the treatment effect of
T-PEMF per se due to an unknown proportion of spontaneous
remitters as well as an unknown impact of expectation. Similarly,
due to the design, we were unable to control for confounders.
Furthermore, the participants received different kinds of psycho-
tropic medicine and suffered from variation in duration and sever-
ity of episodes as well.
We conclude that despite these limitations, this study supports
earlier findings that patients with treatment-resistant depression
experience symptom reduction when treated with T-PEMF. Future
randomized studies should further address the impact of the dura-
tion of the current episode and other potential predictors of
response. Furthermore, this treatment could also be investigated
for similar indications within the affective spectrum, for example,
bipolar depression.
Conflict of Interest. A.L., B.B., C.S., E.M.C., G.B., J.R., K.M., O.J., P.B.J., and
P.V. have no declaration of interests. E.R.L. has received a research grant from
Arla Foods Ingredients Group P/S. R.W.L. has received a research grant from
Glaxo Smith Kline, honoraria for lecturing from Pfizer, Glaxo Smith Kline, Eli
Lilly, Astra-Zeneca, Bristol-Myers Squibb, Janssen Cilag, Lundbeck, Otsuka,
Servier, and honoraria from advisory board activity from Glaxo Smith Kline, Eli
Lilly, Astra-Zeneca, Bristol-Myers Squibb, Janssen Cilag, and Sunovion.
R.E.N. has received research grants from H. Lundbeck and Otsuka Pharmaceu-
ticals for clinical trials, received speaking fees from Bristol-Myers Squibb, Astra
Zeneca, Janssen & Cilag, Lundbeck, Servier, Otsuka Pharmaceuticals, and Eli
Lilly and has acted as an advisor to Astra Zeneca, Eli Lilly, Lundbeck, Otsuka
Pharmaceuticals, Takeda, and Medivir. M.V. has received a consultancy fee
within the last 3 years from Lundbeck A/S.
Authorship Contributions. All authors contributed to the critical revision of
the manuscript. P.B. and E.R.L. had full access to all study data, and took
responsibility for the integrity of data and accuracy of the data analysis.
E.R.L., R.W.L., A.L., E.M.C., K.M., P.V., and P.B. contributed to the concept
and design.
Data Availability Statement. We expect that data supporting the results in
the article will be archived in an appropriate public repository.
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8 Erik Roj Larsen et al.
... 12 Electromagnetic field is subdivided into pulsed EMF (PEMF) and continuous EMF, with the former being more advantageous than the latter because compared with continuous EMF, PEMF produces signals that could be perceived by brain more easily and delivers a large amount of energy in short bursts at a lower level of average energy. 13,14 Existing studies have revealed the potential of PEMF in treating depression, 15,16 osteoarthritis, 17 rheumatoid arthritis, 18 repairing tendons, 19 and preventing ulcer formation in diabetes patients. 20 Moreover, PEMF has been used to treat breast cancer 21 and melanoma. ...
... 12 ELF-PEMF has been used to treat depression by placing a helmet on the head of patients. 15 It has also been used to treat osteoarthritis by placing sets of coils near the knee 17 or air-coil devices that are designed to be non-contact. 106 ELF-PEMF could also be applied by stimulating acupuncture points to reduce peritumoral edema. ...
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... Global modulation of the brain refers to weak electromagnetic stimulation at multiple scalp sites simultaneously or with a more or less homogeneous magnetic field (Larsen et al., 2020;Martiny, Lunde, & Bech, 2010;Rohan et al., 2004;Rohan et al., 2013; van Belkum, Bosker, Kortekaas, Beersma, & Schoevers, 2016). Methods that apply this global modulation are dubbed Low Field Magnetic Stimulation (LFMS) (Rohan et al., 2004) or transcranial Pulsed Electromagnetic Fields (tPEMF) (Martiny et al., 2010). ...
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