Journal of Affective Disorders 175 (2015) 8–17

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Journal of Affective Disorders

journal homepage: www.elsevier.com/locate/jad

Research Report

Clinical efficacy of formula-based bifrontal versus right unilateral

electroconvulsive therapy (ECT) in the treatment of major depression
among elderly patients: A pragmatic, randomized, assessor-blinded,
controlled trial
Tor Magne Bjølseth a,n, Knut Engedal b, Jūratė Šaltytė Benth c,d, Gro Strømnes Dybedal a,
Torfinn Lødøen Gaarden a, Lars Tanum e
a
Diakonhjemmet Hospital, Department of Geriatric Psychiatry, Pastor Fangens vei 18, 0854 Oslo, Norway
b
Norwegian Centre for Aging and Health, Vestfold Health Trust, Tønsberg, Norway
c
Institute of Clinical Medicine, Campus Ahus, University of Oslo, Norway
d
HØKH, Research Centre, Akershus University Hospital, Norway
e
Department of Research and Development in Mental Health, Akershus University Hospital, Norway

art ic l e i nf o a b s t r a c t

Article history: Background: No prior study has compared the efficacy of bifrontal (BF) vs right unilateral (RUL)
Received 9 September 2014 electroconvulsive therapy (ECT) by including the subgroup that is most likely to receive it: only elderly
Received in revised form patients with major depression (MD).
26 November 2014
Methods: This single-site, randomized, assessor-blinded, controlled trial was conducted from 2009 to
Accepted 24 December 2014
Available online 31 December 2014
2013. Seventy-three elderly patients with MD, unipolar and bipolar, were treated with a course of
formula-based BF ECT or RUL ECT. The 17-item Hamilton Rating Scale for Depression (HRSD17) was used
Keywords: to measure efficacy. Safety was assessed with the Mini Mental State Examination (MMSE).
Electroconvulsive therapy Results: Both electrode placements resulted in highly significant downward trends in symptom severity
Treatment efficacy (all p o0.001), with a non-significant difference between methods (p¼ 0.703). At the end of the ECT
Major depression
course, response rates for the BF and RUL group were 63.9% and 67.6%, respectively. Short-term
Old age
remission, defined as an HRSD17 scorer7, was achieved in 14 (38.9%) patients in the BF group and 19
Bifrontal ECT
Right unilateral ECT
(51.4%) patients in the RUL group. Global cognitive function, as measured by the MMSE, did not
deteriorate in the two treatment groups.
Limitations: The small number of subjects may have led to reduced power to detect real differences. The
MMSE is not sufficient to ascertain the negative effect of ECT on cognition.
Conclusions: This study indicates that formula-based BF and RUL ECT are equally efficacious, and that
remission rates of formula-based dosing are lower than those previously reported for titrated dosing, in a
clinical sample of elderly patients with MD.
Trial registration: ClinicalTrials.gov NCT01559324.
& 2015 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction such as dehydration, weight loss and inactivity, which require a

Elderly patients with major depression (MD) are more fre-
quently treated with ECT compared with younger patients (Olfson
et al., 1998). Intolerance to therapeutic doses of antidepressants and
age-related vulnerability to the complications of severe depression,
Abbreviations: BF, bifrontal; BL, baseline; BT, bitemporal; ECT, electroconvulsive
therapy; HRSD, the Hamilton Rating Scale for Depression; ITT, intention to treat;
MD, major depression; MMSE, the Mini Mental State Examination; PRT, the time to
recover orientation; RUL, right unilateral; ST, seizure threshold
n
Corresponding author. Tel.: þ 47 22 45 85 00; fax: þ47 22 45 85 01.
E-mail address: tormagne.bjolseth@diakonsyk.no (T.M. Bjølseth).
speedy recovery, are factors that may explain the disproportionate
use of ECT among the elderly (Flint and Gagnon, 2002; Rapoport
et al., 2006; Tharyan, 2007). In addition, compared with younger
patients with MD, elderly patients are more likely to display
psychotic symptoms (Gournellis et al., 2011), which are a known
indicator of a better response to ECT (Nordenskjöld et al., 2012; van
Waarde et al., 2013). Findings are inconsistent regarding the
relationship between age and the efficacy of ECT (Birkenhäger
et al., 2010; Damm et al., 2010; Sackeim, 2004). A higher proportion
of psychotic patients, a shorter time since illness onset and a lower
representation of medication resistance are possible confounders in
studies in which remission rates were higher among the elderly

http://dx.doi.org/10.1016/j.jad.2014.12.054
0165-0327/& 2015 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
 T.M. Bjølseth et al. / Journal of Affective Disorders 175 (2015) 8–17
compared with younger adults (O'Connor et al., 2001; Tew et al., 1999).
Nevertheless, older age has been found to predict rapid remission even
after adjustment for possible confounders (Rhebergen et al., in press).
The manner via which ECT should be administered to optimize
the relationship between efficacy and negative cognitive effects
remains controversial. Right unilateral (RUL) electrode placement
is considered to be more favourable than bitemporal (BT) when a
stimulus is given at multiples of seizure threshold (Sackeim et al.,
2000). However, when a dose-titration procedure is used to estab-
lish seizure threshold (ST), there is a concern that frail elderly
patients are exposed to delayed recovery, unnecessary risk of
cognitive deficits and unopposed vagus-mediated bradycardia from
repeated subconvulsive stimuli (Bennett et al., 2012; Rasmussen,
2001). Considering the relative independence of outcome from
stimulus charge in bilateral ECT, the half-age method offers a less
cumbersome approach to determining stimulus dose (Petrides and
Fink, 1996; Petrides et al., 2009). Despite the reports of only a
moderate association between age and ST in unilateral stimulation
(Colenda and McCall, 1996; Heikman et al., 1999), the initial stimulus
dosage used to treat elderly patients in Norway with RUL ECT (von
Schweder et al., 2011) is usually based on the age method (Abrams,
2002a). Thus, formula-based dosing may result in reduced efficacy
as compared to stimulus dose titration, since patients with a high ST
tend to be under-treated (Tiller and Ingram, 2006).
During the last 20 years, there has been some enthusiasm for an
alternative bifrontal (BF) electrode position, which was thought to
combine the high efficacy of BT ECT with the more favourable
cognitive effect profile of RUL ECT (Amiri et al., 2009; Bailine et al.,
2000; Lawson et al., 1990; Plakiotis and O'Connor, 2009). One study
(Blumenfeld et al., 2003) lent support to this hypothesis by demon-
strating that BF ECT resulted in greater alteration of blood flow in the
prefrontal cortex, whereas the temporal lobes were relatively spared.
However, a meta-analysis (Dunne and McLoughlin, 2012) of six
randomized controlled trials that compared the efficacy and negative
effects on cognition of BF vs RUL ECT at various doses above seizure
threshold showed no significant differences regarding decreases in
Hamilton Rating Scale for Depression (HRSD) scores.
Nevertheless, firm evidence of the efficacy and safety of BF vs
RUL ECT is missing in elderly patients with MD, the subgroup who
are most likely to receive it (Stek et al., 2009; UK ECT Review
Group, 2003). Hence, BF ECT is still regarded as an experimental
treatment for this group of patients with MD (Crowley et al., 2008;
Dunne and McLoughlin, 2012).
To our knowledge, no study has compared the efficacy of
formula-based BF vs RUL ECT by including only elderly patients
with MD. Therefore, we set up a trial to identify the superiority of
either BF or RUL electrode placement, if it exists. In this article, we
report the efficacy and safety of these approaches in the short
term and at the 3-month follow-up.
2. Methods
2.1. Study design
The study was a single-site, assessor-blinded, controlled, parallel-
group trial with balanced 1:1 randomization conducted in Norway.
The study is registered at the online clinical database ClinicalTrials.
gov (identifier: NCT01559324).The randomized phase of the study
took place between September 1, 2009 and May 1, 2013. A 3-month
follow-up examination followed the treatment period.
2.2. Study population
Norwegian-speaking in-patients with a major depressive epi-
sode as defined by the DSM-IV-TR criteria (American Psychiatric
9
Association, 2000), either unipolar or bipolar, aged between 60
and 85 years who were referred for ECT were eligible for inclusion.
The age span was chosen on practical grounds, based on the local
service, to facilitate satisfactory participant flow and co-operation
in testing. Additional inclusion criteria were a minimum baseline
score of 18 on the 17-item HRSD (HRSD17; Hamilton, 1960;
Williams, 1988) and the ability to co-operate in testing and to
give voluntary written informed consent. Appropriateness for ECT
was determined after consultation with an anaesthesiologist and a
psychiatrist, who were in charge of the ECT. The reasons for
referral were failed medication trials, intolerance to antidepres-
sants, urgency of illness, and the patient's preference or previous
ECT response.
Exclusion criteria included a Mini Mental State Examination
(MMSE) (Engedal et al., 1988; Folstein et al., 1975) score of o24
out of 30, a diagnosis of dementia, Parkinson's disease, schizo-
phrenia or schizoaffective disorder, alcohol and substance abuse in
the last 3 weeks prior to ECT, medical conditions contradicting ECT
and having received ECT in the 6 months that preceded the study.
A power analysis was performed based on previously published
clinical studies of BT or BF vs RUL ECT, using HRSD as the outcome
measure (Eschweiler et al., 2007; Heikman et al., 2002; Ranjkesh
et al., 2005, Sackeim et al., 1993, 2000). An expected difference of
4 points in HRSD score between the two treatment groups and a
standard deviation of 6 points were used in the power calculation.
To detect a statistical difference between the two groups at 0.05
level with 80% power, we needed 36 patients in each group.
All patients were recruited from the Department of Geriatric
Psychiatry at the Diakonhjemmet Hospital, a public hospital ser-
ving approximately 230,000 inhabitants from the western and
central parts of Oslo, of which 28,000 were aged 65 years or older.
2.3. Procedures for randomization and blinding
A permuted block-randomization scheme was created by an
experienced statistician, using five numbers in each block. Eighty
sealed, numbered envelopes containing the code BF or RUL were
kept by the study secretary. The envelopes were opened consecu-
tively for every patient eligible for randomization by the study
secretary and the study psychiatrist together. Electrode gel was
applied to all four positions on the skull, to ensure that the
participants were unaware of which electrode-placement method
was used. The designated electrode position was implemented
when the patient was under adequate anaesthesia. Raters and
ward nurses were not permitted to enter the ECT treatment room.
Thus, neither patients nor raters were able to identify the actual
electrode-placement approach.
2.4. Treatment
2.4.1. Drugs
The majority (62 out of 73) of the subjects had not responded to
at least one adequate trial of an antidepressant prior to admission.
For those individuals, antidepressants were reduced or withdrawn
3–10 days before starting ECT. Patients were allowed to use
oxazepam (5–15 mg/day up to 15 h prior to ECT), if needed for
anxiety. Zopiclon (3.75–7.5 mg) was accepted in case of insomnia. In
11 (15.1%) patients, anti-epileptic drugs or mood stabilizers were
discontinued 1 week prior to ECT. Olanzapin (2.5–20 mg/day) or
quetiapin (50–200 mg/day) were prescribed to 31 (42.5%) patients
with psychotic symptoms or agitation.
2.4.2. ECT
All treatments were administered after hyper-oxygenation
for at least 1 min with 100% oxygen under mask anaesthesia with
10 T.M. Bjølseth et al. / Journal of Affective Disorders 175 (2015) 8–17
atropine (0.5–1.0 mg), thiopental (1.5–2.5 mg/kg) and succinylcho-
line (0.7 mg/kg), which were all delivered intravenously. Blood
pressure, heart rate, pulse oximetry and two-lead ECG were
monitored.
For the BF position, each electrode was placed 5 cm above the
outer angle of the orbit on a line parallel to the sagittal plane
(Letemendia et al., 1993). The d'Elia placement was used in RUL ECT
(D'Elia, 1970). Treatment was administered twice a week using a
Thymatron system IV (Somatics, LLC, Lake Bluff, IL, USA), which
delivered a square-wave brief pulse (0.5–1.0 ms pulse width) of a
bidirectional current of 0.9 A with a frequency of 10–70 Hz, depend-
ing on the stimulus intensity. Motor seizure duration was monitored
by the cuff technique, and two channels of EEG (frontal-mastoid)
were recorded. The initial stimulus dose was determined using the
age method (Abrams, 2002a) in case of unilateral stimulation, and
the half-age method (Petrides et al., 2009) in case of bifrontal
stimulation. The dose was adjusted for gender. Women were
administered five energy % (25 mC) less than the amount derived
from the age or half-age formula, and men were administered five
energy % more. If the seizure was missed or aborted (clonic move-
ments in the cuffed arm and EEG manifestations of less than 15 s
duration), re-stimulation took place 20 or 45 s later using either a
50% or 100% increased dose (American Psychiatric Association, 2001).
At subsequent sessions, the appropriateness of stimulus dosage was
adjusted according to the duration, amplitude and coherence of EEG
delta waves (American Psychiatric Association, 2001), post-ictal
suppression (Azuma et al., 2007), peak post-ictal heart rate (Swartz,
2002), time to recover orientation (PRT), and Clinical Global Impres-
sion Improvement score (CGI-I) (Leon et al., 1993) on the following
day, as assessed by the patient and the ward nurse. The PRT is a
putative predictor of long-term retrograde amnesia after ECT (Sobin
et al., 1995). Hence, if disorientation persisted a reduced dose was
considered.
ECT treatments were continued until the patient achieved
remission, which was defined as an HRSD17 score r7 points, or
until a plateau in the patient's benefit was reached, up to a maxi-
mum of 16 sessions.
When the ECT course ended, the patients were recommended
to start treatment with either individually planned continuation
ECT (c-ECT) using the same electrode placement and/or treatment
with an antidepressant, depending on response to ECT. c-ECT was
prescribed if one of the criteria for response was met.
2.5. Assessment
2.5.1. Diagnostic procedures
Using all available information from patient interviews and
observation, from next of kin and from the regular GP, the
diagnosis of MD according to the DSM-IV-TR criteria was con-
firmed in consensus between two independent and experienced
senior consultants in geriatric psychiatry. In addition, the diag-
nosis of MD was supported by the Mini-International Neuropsy-
chiatric Interview (specifically the MINI-Plus) (Mordal et al., 2010;
Sheehan et al., 1998), which also was used when screening for
psychiatric co-morbidity. Scoring on the Cumulative Illness Rating
Scale for Geriatric Patients (CIRS-G) was performed, with the
exception of the psychiatric item (Miller et al., 1992), to document
the overall medical burden.
2.5.2. Clinical evaluations
Two assessors, a study psychologist and a trained test assistant,
who were blinded to the electrode placement, conducted the
measurements of efficacy and side-effects. The first assessment
took place at baseline, on average 4 days before the first ECT.
Thereafter, patients were assessed every Wednesday between every
second session, on average 4 days after the last ECT treatment, and
at the 3-month follow-up. The HRSD17, the 6-item HRSD (HRSD6;
Bech et al., 1981) and the Montgomery and Asberg Depression
Rating Scale (Montgomery and Asberg, 1979) were used to measure
the decline in symptom severity. The HRSD17 and the HRSD6 were
scored at all time points, whereas the MADRS was performed at
baseline, the end of treatment and at the follow-up examination. In
addition, the CGI-I was scored after the ECT treatment was termi-
nated. Inter-rater reliability between the study psychologist and the
test assistant was tested and found to be high, with intra-class
correlation of 0.90 for the HRSD17 and 0.94 for the MADRS.
Effect on global cognitive function was measured using the
MMSE after the last treatment and at follow-up, and compared
with the MMSE score at baseline. The time to recover orientation
was assessed after every second treatment. A correct response to
four out of five questions about name, place, date of birth, day of
the week and age was the criterion for recovery of orientation.
Adjustment of the original protocol became necessary for elderly
patients, in that a maximum score was given if disorientation
persisted after 40 min, and not 90 min. This ceiling value (50 min)
was given to four patients on eight occasions. Nurses in the
hospital ward reported any adverse event after each ECT session.
2.6. Definition of outcome, remission, response and drop-outs
The primary outcome was the longitudinal profile of contin-
uous HRSD17 total scores over the treatment course. Efficacy and
speed of response were also measured by calculating the odds
ratios for not meeting the HRSD17 remission criterion at each visit
compared with baseline. To validate the main results, we used
scores on less multidimensional scales, the MADRS and the HRSD6
subscale (Carmody et al., 2006; Kørner et al., 2007), as secondary
outcomes. Another secondary outcome was the proportion of
remitters for each electrode-placement group. Remission was
defined as an HRSD17 scorer7 points (Frank et al., 1991; Rush
et al., 2006; Zimmerman et al., 2013) or an HRSD6 scorer 4 points
(Carmody et al., 2006; Ruhe et al., 2005). No consensus has
emerged regarding an appropriate cut-off for defining remission
on the MADRS. Based on a relative broad definition, we chose a
MADRS scorer 9 as the cut-off value for remission (Carmody et al.,
2006; Zimmerman et al., 2004). Response was defined as a
decrease in HRSD17 scoreZ50% or a CGI-I score of 1 or 2.
Completers were those who received the maximal number of 16
treatments, attained remission with fewer sessions or reached a
plateau in benefit, defined as no further improvement in HRSD17
scores over the last four ECT sessions. Patients who terminated the
treatment course without having exploited its therapeutic poten-
tial were considered to be drop-outs. Re-hospitalization, suicide or
an HRSD17 scoreZ16 points (Bech, 2011) at follow-up were used
as proxy for relapse among remitters. A drop in the MMSE score
between baseline, the end of treatment and at the 3-month
follow-up was considered as a negative side-effect of the treat-
ment, but no cut-off was defined.
2.7. Ethics
The study was approved by the Regional Committee for Research
Ethics in Norway, including the permission to use ECT in both
moderate and severe MD and as a first-line treatment in selected
cases. In the week following admission, eligible patients and their
next of kin were given thorough written and oral information about
ECT, the purpose of the trial and the procedures that would be
involved. Inclusion was strictly based upon informed consent and
the patient's signature.
 T.M. Bjølseth et al. / Journal of Affective Disorders 175 (2015) 8–17 11

2.8. Statistical analysis

Statistical analyses were conducted using SPSS version 22.0 and

SAS version 9.3. P-values o0.025 were considered to be statisti-
cally significant. All tests were two sided.

2.8.1. Descriptive analyses

Baseline clinical characteristics and treatment parameters were
presented as means and standard deviations (SDs) for symmetri-
cally distributed data, whereas medians and ranges were used for
skewed data. Categorical variables were presented as frequencies
and percentages. Comparison across electrode-placement groups
was performed using either an independent-samples t-test, the
Mann–Whitney U-test, or the χ2-test (Fisher's exact test if cell
frequencies for dichotomous variables were o5), as appropriate.

2.8.2. Missing data

HRSD17 scores at baseline were missing for seven patients. In
these cases, HRSD17 scores at inclusion were imputed. The mean
number of days between inclusion and baseline assessment was
five. Four missing MADRS scores at baseline and two missing
MADRS scores after ECT were calculated from corresponding
HRSD17 scores, by multiplying the observed HRSD17 score of the
patient, for whom the MADRS score was missing, with the ratio of
mean MADRS to mean HRSD17 scores at the same time point.
Although there is no scientifically validated method of imputing a
missing MADRS score from an observed HRSD score, this approx-
imation was done because MADRS was a secondary outcome
measure, and because it made it possible to include all patients
in the ITT analyses.

2.8.3. Outcome analyses

The short-term efficacy analyses were based on a modified
intention-to-treat (ITT) sample that comprised all randomized
patients who had at least one post-baseline assessment. Time
trend in primary and secondary outcomes was assessed using a
regression model for repeated measurements, adjusting for intra-
patient correlations. A linear model was estimated for continuous
outcomes, whereas dichotomous outcomes were modelled by
logistic regression. Regression models contained fixed effects for
time (up to third order, if significant), treatment group indicator
(BF or RUL ECT) and interaction between the latter and time. Fig. 1. Participant flow.
Random intercept accounting for intra-patient variability was
included in the models. The analyses were further adjusted
for covariates that were previously shown to correlate with ECT cognitive function. The mean MMSE score was lower in the RUL
outcome. ECT group (p ¼0.022). Hence, time-trend analyses were adjusted
for the MMSE score at baseline.
Out of 73 ITT patients, 66 (90.4%) completed the ECT treatment.
3. Results Drop-outs had a higher mean age than completers (80.1 vs 74.2
years, p ¼0.018). Otherwise, there were no statistically significant
3.1. Participant flow differences between completers and drop-outs at baseline.

Fig. 1 shows the flow of the inclusion phase and the partici-
pants throughout the study. Eighteen out of the 97 eligible
patients withdrew from the study. Four patients refused to parti-
cipate in the study, or lacked the ability to give informed consent
because of psychosis or confusion. Other reasons for screen fail-
ures were dementia (n ¼8), having received ECT within the past
6 months (n¼ 2), ongoing alcohol or substance abuse (n ¼2) and
inability to co-operate in testing because of fatigue (n ¼2). A total
of 79 patients were randomized, of whom six had no post-baseline
assessment, yielding a modified ITT sample of 73 persons (75.3%).
Thirty-six patients were allocated to BF ECT, and 37 were allocated
to RUL ECT. Table 1 lists the demographic and clinical character-
istics of the ITT sample. Differences between the groups were
within the limit of random variation, with the exception of global
3.2. Efficacy of the acute ECT course
The decline in HRSD17 scores over the acute ECT course within
each electrode placement group showed that both methods were
efficacious. The mean change from baseline was 13.2 (7.3) points in
the BF group and 14.7 (7.1) points in the RUL group (Table 2). The
trajectories of observed and estimated HRSD17 mean scores at each
visit during treatment is shown in Fig. 2. Both electrode place-
ments resulted in highly significant downward trends in symptom
severity (all p o0.001), with a non-significant difference between
methods (p ¼0.703) (Table 3).
The gradual decline in symptoms observed for both electrode
placements illustrates that remission occurred relatively late in the
two ECT groups. Among the 33 remitters, 64.3% in the BF group
12 T.M. Bjølseth et al. / Journal of Affective Disorders 175 (2015) 8–17

Table 1
Demographic and clinical characteristics at baseline for the intention-to-treat sample.

Variable BF (n¼ 36) RUL (n¼37) P

n % n %

Female 18 50.0 21 56.8 0.563a

Unipolar depression 31 86.1 33 89.2
Bipolar depression 5 13.9 4 10.8 0.689a
Psychotic symptoms 8 22.2 10 27.0 0.634a
Melancholic symptoms 34 94.4 36 97.3 0.615b
Co-morbid anxiety disorder 9 25.0 9 24.3 0.947a
Previous alcohol abuse 5 13.9 3 8.1 0.479b
First episode before the age of 60 18 50.0 21 56.8 0.563a
History of ECT 14 38.9 9 24.3 0.180a
Failed trial of Z 2 ADs of different classes 17 47.2 11 29.7 0.124a
Failed trial of 1 AD 15 41.7 19 51.4 0.407a
No trial of AD 4 11.1 7 18.9 0.515b

Mean SD Mean SD P

Age (years) 74.1 6.6 75.5 6.0 0.355c

Previous hospitalizations (no.)e 1 0–7 1 0–5 0.636d
Time since onset of first episode (months)e 146 1–516 216 1–720 0.466d
Duration of episode (weeks)e 36 4–288 21 3–265 0.094d
Total CIRS-Gf score 6.9 3.7 6.6 3.7 0.737c
MMSE 28.1 1.6 27.1 1.9 0.022c

a
P value from χ2-test.
b
P value from Fisher's exact test.
c
P value from independent samples t-test.
d
P value from Mann–Whitney U-test.
e
Previous hospitalizations, time since onset and duration of episode are given in medians (range).
f
CIRS-G, Cumulative Illness Rating Scale.

and 78.9% in the RUL group needed more than six ECT sessions.
However, no remitter needed more than 12 treatments. According
to the regression model for HRSD17, there was a significant third-
order trend with downward tendency from baseline to visit five for
both electrode placements. Adjusting for covariates altered the
results marginally. We found a similar trend for the estimated
HRSD6 scores (data not shown). A possible explanation for the
upward tendency from visit five will be given in the Section 4. The
estimated HRSD17 mean scores for the RUL placement were lower
than those for the BF placement from visits three to eight. Similarly,
the estimated odds ratios for not meeting the HRSD17 r7 remission
criterion were higher in the BF group on all visits after ECT was
initiated (Fig. 2). However, there was no significant difference
between the groups regarding efficacy and speed of response,
regardless of which inventory was used (HRSD17 or HRSD6).
3.3. Response and remission rates
At the end of the ECT course, the HRSD17 response criterion was
met by 23 (63.9%) patients in the BF group and 25 (67.6%) patients
in the RUL group (p ¼0.741), whereas the HRSD17 remission
criterion was met by 14 (38.9%) patients in the BF group and 19
(51.4%) patients in the RUL group (p ¼0.285).
3.4. Prediction of remission
Among non-remitters in the treatment groups, there was no
significant difference in the distribution of unipolar and bipolar
disorders (p ¼0.355) or in the proportions of patients who had
failed at least two trials of anti-depressants (p ¼0.775). Hence, we
did not adjust for polarity and medication resistance. There was a
significant association between the absence of psychotic symp-
toms at baseline and the development of estimated odds ratios for
not meeting the HRSD17 r7 remission criterion (OR¼ 5.47; 95% CI,
2.23–13.38; po 0.001). Similarly, the baseline MADRS scores were
significantly and positively associated with the same trajectory
(OR¼ 1.10; 95% CI, 1.03–1.17; p ¼0.003). Thus, elderly patients with
more severe depressive conditions in terms of higher MADRS scores
had lower odds for achieving remission. There was also a marginal
association between the time since onset and this trajectory, which
means that a shorter duration since the first episode predicted
higher odds for achieving remission (OR¼1.0022; 95% CI, 1.0001–
1.0044; p¼0.043).We found no association between this trajectory
and the remaining covariates (age and the MMSE score) at baseline.
3.5. Safety
There was no significant difference in changes in the mean
MMSE score between the two electrode-placement groups over the
ECT course (p¼0.218). According to a linear regression model,
baseline MADRS score (p¼0.006) and number of ECT sessions
(po0.001) were associated with a change in MMSE scores; more
severe depression and more ECT sessions were associated with less
improvement in global cognitive status, as measured by the MMSE.
We found no associations for the other covariates, such as time
since onset, the presence of psychotic symptoms and age. In a linear
regression analysis of ln-transformed PRT, older age (p¼0.020) and
the presence of psychotic symptoms (p¼ 0.016) predicted a longer
reorientation time. Delusional patients needed 42.5% more time to
recover orientation compared with non-delusional patients. A 10-
year increment in age was associated with a 24.3% longer PRT. There
was no association between ln-transformed PRT and the covariates
electrode placement, baseline MMSE score, severity of depression
and time since onset.
Immediate adverse events were noted in 61 (83.6%) patients.
The following events were reported (in percentages (BF; RUL) of
the ITT sample): headache (66.7%; 56.8%), myalgia (22.2%; 43.2%),
dizziness (19.4%; 32.4%), nausea (16.7%; 27.0%), memory problems
(13.9%; 24.3%), agitation (13.9%; 18.9%), cardiovascular side-effects
(13.9%; 13.5%), confusion (11.1%; 13.5%) and fear of treatment
(8.3%; 8.1%). In seven (9.6%) patients, thiopental led to transient
 T.M. Bjølseth et al. / Journal of Affective Disorders 175 (2015) 8–17 13

hypotension, whereas paroxysmal supraventricular tachycardia 3.6. Stimulus and treatment details
(2) and atrial fibrillation (1) were precipitated in three (4.1%)
patients. Given the different formulas used to determine stimulus dose, a
lower first treatment dose for BF ECT was expected (Table 4). The
increase in stimulus dose during the ECT course was much higher
among patients in the BF group, leading to no significant differ-
Table 2
Descriptive statistics for outcome data. ence in dosage between the groups at the last treatment session.
Re-stimulation was also necessary for more patients in the BF
Continuous outcomes BF RUL group. Problems of too-high impedance occurred more often in
those who were treated with RUL ECT.
n Mean (SD) n Mean (SD)

HRSD17 3.7. Follow-up

Baseline 36 23.0 (4.0) 37 23.4 (4.9)
After ECT 36 9.8 (6.3) 37 8.7 (6.2)
Follow-up 32 11.1 (6.2) 33 10.6 (5.2)
Sixty-five (89.0%) patients from the ITT sample were analysed
HRSD6 at follow-up after 3 months (four patients were lost in each
Baseline 36 12.2 (2.8) 37 12.4 (3.3) group). From the end of treatment to follow-up, there was no
After ECT 36 5.3 (3.5) 37 5.0 (3.6) significant difference in change in the mean HRSD17 score between
Follow-up 32 6.3 (4.1) 33 5.9 (3.2)
the treatment groups (p ¼0.778). However, there was a significant
MADRS
Baseline 36 29.5 (6.9) 37 29.9 (7.6) difference in the development of the MMSE scores (p ¼0.034). An
After ECT 36 13.3 (9.3) 37 10.9 (7.9) increment in scores occurred only among patients who underwent
Follow-up 32 14.1 (9.2) 33 13.8 (7.4) RUL ECT. Whether this advantage was related to electrode place-
MMSE ment is unknown. There was no significant association between
Baseline 36 28.1 (1.6) 37 27.1 (1.9)
After ECT 36 28.5 (1.7) 37 27.4 (2.4)
change in MMSE score and the following covariates: the use of
Follow-up 32 28.3 (2.1) 33 28.7 (1.4) continuation ECT and anti-depressants, the post-ECT MADRS
PRTa score, the presence of psychotic symptoms at baseline and the
During ECT 35 12.5 (5.9) 37 15.0(11.6) number of ECT sessions during the acute course.
Dichotomous outcomes nBF þ RUL (%) BF RUL

n n (%) n n (%) 4. Discussion

After ECT
Remission HRSD17 r 7 33 (45.2) 36 14 (38.9) 37 19 (51.4)
4.1. Efficacy
Remission bipolarb 4 (44.4) 5 1 (20.0) 4 3 (75.0)
Remission unipolarb 29 (45.3) 31 13 (41.9) 33 16 (48.5) Despite major difficulties in recruiting elderly patients to clinical
Remission HRSD6 r 4 35 (48.0) 36 16 (44.4) 37 19 (51.4) studies of ECT (O'Connor et al., 2010; Stek et al., 2007), we managed
Remission MADRS r 9 35 (48.0) 36 16 (44.4) 37 19 (51.4)
to complete the first RCT, which compared the efficacy of formula-
Response HRSD17 48 (65.8) 36 23 (63.9) 37 25 (67.6)
Response CGI-I 56 (76.7) 36 25 (69.4) 37 31 (83.8) based bifrontal vs right unilateral ECT in the treatment of MD in the
Follow-up elderly. We did not find any significant differences in efficacy
Relapsec 5 (15.6) 14 2 (14.3) 18 3 (16.7) between the two ECT groups, regardless of how it was measured
a
and defined. Depending upon which criterion was used, 45% and
PRT, time to recover orientation was measured after every second treatment.
b
Patients with bipolar or unipolar depression who met the HRSD17 r 7
48% of the subjects in our ITT sample achieved thresholds for short-
criterion for remission. term remission. The inclusion of patients in need of oxazepam
c
Among remitters who were assessed at the follow-up examination. between ECT sessions, with mild cognitive impairment, a history of

Fig. 2. A, B and C. Trajectories of observed and estimated HRSD17 mean scores and odds ratios of not meeting the HRSD17 remission criterion in two groups with BF or RUL
electrode position. The number of patients (BF/RUL) assessed at each time point: baseline (36/37), visit 1 (36/37), 2 (36/37), 3 (34/37), 4 (25/30), 5 (21/21), 6 (16/12), 7 (9/9),
8 (4/2).
14 T.M. Bjølseth et al. / Journal of Affective Disorders 175 (2015) 8–17

Table 3 Prudic et al., 1996), clearly indicates that the age-based methods led
Analyses of outcomes, adjusted for covariates. to under-dosing, implying that our findings are only representative of
formula-based ECT.
Continuous outcomes Regression coefficient (SE) P
Although this result did not reach statistical significance, there
HRSD17 was a trend that fewer subjects in the BF group met remission
Estimated means from baseline to visit 8a criteria. Considering that there was a significantly higher increment
Time  0.83 (0.06) o 0.001d in stimulus dose during the treatment course and a higher propor-
Time  time 0.017 (0.002) o 0.001d
Time  time  time  0.00008 (0.000009) o 0.001d
tion of sessions in which restimulation was necessary in the latter
Electrode placement  0.36 (0.95) 0.703d group, it is possible that determining the initial stimulus dose using
EP  time  0.004 (0.009) 0.634d the half-age method led to under-dosing. Recent research (Bai et al.,
Difference after ECT and follow-upb 2012) applying computational models to simulate ECT-induced
Electrode placement  0.40 (1.42) 0.778e
excitation in the brain shed light on why the bitemporal and bifrontal
MADRS
Difference at baseline and after ECTa methods should be dosed differently. Despite the use of stimuli
Electrode placement 3.10 (2.07) 0.139e with the same amplitude, the BF electrode position resulted in an
Difference after ECT and follow-upb approximately 25% lower maximum current density within the brain,
Electrode placement  2.72 (2.05) 0.189e probably because the skull beneath the BF electrodes is thicker. In
MMSE
Difference baseline and after ECTc
addition, the geometrical volume between electrodes for the BF
Electrode placement 0.57 (0.46) 0.218e configuration is 75% of that of the bitemporal placement (Swartz and
Difference after ECT and follow-upb Nelson, 2005). Consequently, more current is shunted across low-
Electrode placement  1.57 (0.72) 0.034e resistance pathways, and less current penetrates the brain.
PRT (Ln-transformeda)
The trajectory of estimated HRSD17 means over the ECT course
Electrode placement 0.09 (0.13) 0.455e
showed an upward trend from visit five to the end of treatment for
Dichotomous outcomes Regression coefficient (SE) P both electrode placements. This finding can probably be attributed
HRSD17 47 to the fact that, from the fifth week onward, the remaining
Estimated odds ratios from baseline to visit 8a patients were encouraged to visit their homes frequently, thus
Time  0.09 (0.01) o 0.001f
temporarily being detached from the protective atmosphere of in-
Time  time 0.0005 (0.00008) o 0.001f
Electrode placement  0.18 (0.46) 0.701f ward care.
EP  time 0.006 (0.005) 0.241f To our knowledge, the efficacy of BF and RUL ECT have been
MADRS o 10 compared in six randomized, controlled trials (Eschweiler et al.,
a
Remission after ECT 2007; Heikman et al., 2002; Kellner et al., 2010; Letemendia et al.,
Electrode placement 0.68 (0.63) 0.281g
CGI o 3
1993; Ranjkesh et al., 2005; Sienaert et al., 2009). None of them
Response after ECTa included only elderly patients. A direct comparison of remission
Electrode placement  0.97 (0.64) 0.129g rates between our study and those studies is problematic, for
a
several reasons. In the aforementioned studies, the initial stimulus
Adjusted for symptom severity at baseline, psychosis, time since onset, age
dose was determined by empirical titration, whereas we applied
and the MMSE score at baseline.
b
Adjusted for symptom severity after ECT, continuation ECT, anti-depressant age-based formulas. Different dosing strategies obscure the influ-
medication during follow-up, psychosis and the number of ECT sessions. ence of electrode placement (Swartz and Nelson, 2005). Several
c
Adjusted for symptom severity at baseline, age, psychosis, time since onset trials (Eschweiler et al., 2007; Heikman et al., 2002; Letemendia
and the number of ECT sessions. et al., 1993) were flawed by under-dosing, particularly in the RUL
d
P-value from a linear mixed model.
e
P-value from a linear regression model.
group. Dissimilar study populations regarding age and exclusion
f
P-value from a logistic regression model. criteria, insufficient statistical power and different ECT techniques
g
P-value from a nominal regression model. regarding pulse width are other factors that complicate the com-
parison of results.
Methodological discrepancies aside, our results are consistent
stroke, anxiety disorders and recent alcohol/substance abuse ren- with several decades of data comparing the efficacy of the BF and
dered our clinical sample representative of an elderly population RU electrode placements, which showed no convincing superiority
that is normally referred for in-ward treatment for MD in Norway. of one method (Dunne and McLoughlin, 2012). One medium-sized
Nevertheless, it is likely that such conditions may have dampened RCT, the only one that used ultra-brief pulse instead of brief pulse
the efficacy of ECT treatment, as remission rates of 67–90% have (Sienaert et al., 2009), also found an inferior remission rate for BF
been reported in clinical trials that included more highly selected ECT, which did not reach statistical significance. In our study,
elderly patients (O'Connor et al., 2001; Stoppe et al., 2006; Tew remission was obtained after eight treatments, whereas the mean
et al., 1999). In these studies, BT and RUL ECT were administered number of ECT among remitters in the most statistically powerful
with either stimulus titration or high fixed dosage, and remission study (Kellner et al., 2010) was six, although dose titration was
was defined as an HRSD24 scorer10 or a MADRS scorer10 points performed in the first session. In agreement with our results, those
among completers. authors found no significant difference in speed of response
Our relatively low remission rates can also be explained by the between the BF and RUL groups. Contrary to our findings, Kellner
fact that we reported the proportion of the ITT sample who met strict et al. demonstrated a steep decline in symptom severity early in
remission criteria, and that formula-based ECT provides a suboptimal the treatment course: 64% of the remitters in their sample needed
stimulus dose for elderly patients with a high ST (McCall, 2009; Tiller six or fewer ECT compared with 27% in ours. Considering incon-
and Ingram, 2006). However, the initial under-treatment in our study gruent dosing strategies, this tendency does not necessarily
were partially compensated for, as dosage at subsequent sessions corroborate the notion of a slower speed of response among
were matched and adjusted according to clinical and physiological elderly patients who receive ECT (Rich et al., 1984). The slower
parameters associated with treatment response (Abrams, 2002b). speed of response among our elderly patients is probably another
Still, a relatively low remission rate despite the presence of predictors indication of formula-based dosing leading to under-treatment, as
of a good treatment outcome (psychotic symptoms and low rates of Kellner et al. (2010) reported higher remission rates (BF, 61% vs
medication resistance and co-morbidity) (Dombrovski et al., 2005; RUL, 55%), despite a relatively higher number of drop-outs.
 T.M. Bjølseth et al. / Journal of Affective Disorders 175 (2015) 8–17 15

Table 4
Treatment details of 73 ITT patients and 65 who came for follow-up.

Variable BF RUL P

n n (%) n n (%)

In need of oxazepam between ECT sessions 36 21 (58.3) 37 20 (54.1) 0.713a

Failed session with sub-convulsive seizures 36 2 (5.6) 37 0 (0) 0.240b
Too-high impedance ( Z2700 Ω) 36 9 (25.0) 37 26 (70.3) o 0.001a
Re-stimulation necessary 36 12 (33.3) 37 2 (5.4) 0.003b
Received continuation ECT during follow-up 32 22 (68.8) 33 20 (60.6) 0.492a
Treatment with antidepressants during follow-up 32 11 (34.4) 33 11 (33.3) 0.929a

Mean (SD) Mean (SD) P

Daily defined dose (DDD) of antidepressantse 36 0.5 (0.0–2.3) 37 0.5 (0–3.0) 0.692c
DDD of benzodiazepines and related hypnoticae 36 0.6 (0.0–1.5) 37 0.8 (0–1.5) 0.920c
DDD of antipsychoticse 36 0.0 (0.0–2.0) 37 0.0 (0.0–1.5) 0.268c
Number of ECT sessions among remittersf 14 7.7 (2.8) 19 8.4 (2.3) 0.435d
Number of ECT sessions among non-remittersf 22 10.1 (3.6) 18 10.1 (3.2) 0.941d
First stimulus dose (mC) 36 191.1 (32.8) 37 366.4 (48.0) o 0.001d
Last stimulus dose (mC) 36 356.3 (244.8) 37 408.9 (107.8) 0.264d
Mean stimulus dose (mC) 36 276.0 (125.4) 37 387.5 (74.3) o 0.001d
Increment in stimulus dose (mC) 36 165.2 (247.3) 37 39.5 (100.4) o 0.001d
Motor seizure duration – first treatment (s) 36 34.2 (17.8) 37 35.2 (14.1) 0.781d
Motor seizure duration – last treatment (s) 36 28.3 (13.7) 37 25.1 (12.2) 0.283d
EEG seizure duration – first treatment (s) 36 49.1 (23.4) 37 53.7 (20.2) 0.368d
EEG seizure duration – last treatment (s) 36 39.9 (17.2) 37 33.1 (13.9) 0.067d

a
P value from χ2-test.
b
P value from Fisher's exact test.
c
P value from Mann–Whitney U-test.
d
P value from independent samples t-test.
e
DDD of antidepressants, benzodiazepines and antipsychotics prescribed during the ECT course are given as median and range.
f
Remission defined as HRSD17 r 7.

The finding that patients with psychotic symptoms had better
odds of meeting remission criteria supports the usefulness of
specifying psychotic symptoms in the diagnosis of MD (Forty
et al., 2009; Maj et al., 2007). It also justifies why many view
ECT as the primary treatment for elderly patients with delusional
depression, considering the relatively poor response to pharma-
cotherapy (Meyers et al., 2001). However, elderly patients with
higher MADRS scores at baseline had lower odds of achieving
remission, which contrasts with the assumption that patients with
higher levels of overall clinical severity should respond more
favourably to ECT (Sienaert et al., 2009). Rhebergen et al. (in
press) also demonstrated that higher depression severity pre-
dicted a less favourable ECT course, and could, similar to the
present study not find an explanation for this finding in their data.
4.2. Safety
In line with previous trials (Kellner et al., 2010; Sienaert et al.,
2010), we did not find any differences between the electrode
placements regarding how global cognitive function and mean
time to recover orientation were affected over the acute treatment
course. Reorientation time was relatively low and similar to what
has been found for moderately dosed RUL ECT (Sackeim et al.,
2000), indicating that formula-based BF and RUL ECT lead to
modest post-ictal disorientation compared with high-dosed right
unilateral and bitemporal ECT. In contrast to studies of BT ECT
(Semkovska and McLoughlin, 2010), we demonstrated no short-
term reduction in mean MMSE scores, whereas global cognitive
function has been found to improve significantly from baseline
after a course of ultra-brief pulse ECT (Sienaert et al., 2010;
Verwijk et al., 2012). Conversely, in an observational study of brief
pulse formula-based, primarily RUL ECT, Verwijk et al. (2014)
measured a significant improvement in mean MMSE scores among
28 elderly patients who were able to perform an extensive base-
line neurocognitive assessment. However, the 30 patients who
were excluded from the analyses, showed a significantly lower
global cognitive function pre- and post-ECT. The presence of
mostly mild and transient adverse events and a low drop-out rate
demonstrated that ECT was well tolerated among our elderly
patients, which is consistent with what has been found in retro-
spective reviews (Damm et al., 2010; Nuttall et al., 2004; Watts
et al., 2011).
5. Limitations
A limited number of subjects can cause reduced power to detect
real differences. It should be noted that the study was adequately
powered to detect differences between the two groups regarding
the end-point HRSD17 score of 4 points or more. In this sample, the
standard deviation and the relative difference in end-point HRSD17
score were 6.2 and 1.5 points, respectively. To be able to reject our
null hypothesis about BF and RUL being equally efficacious, we
would have needed a minimum of 270 patients in each group.
Given a relative difference in end-point HRSD17 score of only
1.5 points is representative, it can be questioned whether such a
weak superior efficacy of one electrode position is of any clinical
importance at all. The risk of making a type II error and falsely
retaining the null hypothesis because of insufficient sample size is
regarded as being small.
The validity of scale-based definitions of remission in late-life
depression remains to be settled (Alexopoulos and Apfeldorf,
2004). The emphasis on somatic symptoms in HRSD17 may lead
to higher scores and an underestimation of treatment effect in
medically ill elderly patients. By including items that are relatively
insensitive to change, HRSD17 may have decreased power to
differentiate between treatment modalities (Bagby et al., 2004;
Carmody et al., 2006; Lecrubier and Bech, 2007). However, our
main finding remained the same when using more unidimensional
rating scales (HRSD6 and MADRS).
16 T.M. Bjølseth et al. / Journal of Affective Disorders 175 (2015) 8–17
The fact that the study psychiatrists were not blinded to
electrode placement allocation may have introduced a bias regard-
ing how stimulus dosage was adjusted during the ECT course, and
regarding when treatment was stopped. Conversely, the risk of
such a bias was minimized by the use of rigorous and predeter-
mined criteria for stimulus dosing and treatment termination.
One concern about BF ECT is that it may lead to dispropor-
tionate executive function deficits (Crowley et al., 2008). Moreover,
in the meta-analysis of Dunne and McLoughlin (2012) BF ECT
resulted in smaller decline in visual memory scores, but greater
deterioration in immediate verbal memory scores, compared to
RUL ECT. The instrument we used to ascertain the negative effects
of ECT on cognition, i.e. the MMSE, is not sufficient, since it only
provides an overall score which cannot be localized to particular
cognitive domains (Mathuranath et al., 2000).
6. Conclusion
In the context of a relatively small sample of elderly patients,
randomly allocated to formula-based BF and RUL ECT, there were
no significant differences in improvement from major depression
and no detectable differences in cognitive side-effects, using the
MMSE. The main weakness of this study is the limitation of the
instrument used to determine cognitive side-effects. Because BF
ECT affects the frontal lobes more than any other area of the brain,
the role of the bifrontal electrode placement in the treatment of
MD among elderly patients can only be established after a better
characterization of its negative effect in the frontal-executive
domain. As pointed out by Semkovska and McLoughlin (2010),
there is a need to know more about how executive functions, as
mental flexibility, organization of thinking and planning are
affected by ECT. This challenge can be overcome by adopting
instruments, found to be suitable for elderly depressed patients,
e.g. the Colour Word Interference Test Part 3, the Animal Naming
Test, Letter Fluency and the Tower Test (Dybedal et al., 2014).
Further research is also warranted to determine the optimal
formula-based dosages for BF and RUL ECT in elderly patients. It
also remains to be clarified whether stimulus dosing by empirical
titration can improve efficacy.
Role of funding source
This study was performed without external funding sources.
Conflict of interest
No conflict declared.
Acknowledgements
The authors thank chief psychiatrist B. Lorentzen at the Department of Geriatric
Psychiatry, Diakonhjemmet Hospital, for his generous support. Senior anaesthesiol-
ogist S.O. Mollestad contributed with his skills and calm, thus reassuring anxious and
severely depressed patients in the minutes before sleep induction. We thank M.
Gulliksrud, W.J. Lindberg, P. Mikkelsen, A-L. Røstad and, in particular, study nurse M.
Larsen for data collection, quality control and their engagement in the study.
Statistician F. Dahl was helpful in performing the computed randomization.
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