2. II
Abstract
Abstract
Bloch, Ratzoni, Sobol, Mendlovic, Gal, & Levkovitz (2005) found that ECT was
significantly more effective in treating schizophrenia in female patients than it was in treating
schizophrenia in male patients. Schizophrenia and MDD are related in a variety of ways, and the
effect of MDD patient age on ECT efficacy is not explained unequivocally by the current body
of literature. The present research thus aimed to identify factors which could bolster or lessen the
efficacy of ECT for MDD with a focus on gender and age. Data was obtained from 157 MDD
patients at Providence Care. A Kruskal-Wallis test was conducted to evaluate gender differences
on rate of response to ECT, and a one-way ANOVA was conducted to evaluate the relationship
between MDD patient age and rate of response to ECT. Two one-sample chi-square tests were
conducted to assess whether receptivity to ECT differed significantly by gender and age. None of
the analyses were significant. Future research is required to address study design limitations
before definitive conclusions can be drawn.
3. III
Contributions
Contributions
I was responsible for writing the proposal, organizing the data, performing statistical
analyses, and composing this document. I would like to take this opportunity to recognize the
contributions of others involved in the execution of this study.
I was co-supervised by Dr. Roumen Milev and Dr. Emily Hawken. Dr. Roumen Milev
and Dr. Casi Cabrera were the ECT psychiatrists involved in this project. My primary supervisor,
Dr. Emily Hawken, introduced me to the topic of my research and tirelessly supported me. She
was an incredible mentor who assisted me in the process of data organization and analysis;
communicated on my behalf to professionals involved with the ECT database; and was always
available to answer questions and give advice. Dr. Hawken and Dr. Groll additionally assisted
me with data extraction. Dr. Hawken’s approachability and enthusiasm inspired in me an
excitement for the research process. I feel very fortunate to have been given the opportunity to
work with these researchers on this project.
Brigid Gagnon, a psychiatric nurse at Providence Care, gave me a tour of the facility at
Providence Care Mental Health Services, walked me through the procedure used by physicians at
Providence Care who administer ECT, helped me take photos with the equipment for this
document, and answered many of my questions about ECT. Brigid’s assistance was invaluable to
the initiation of this project.
Finally, Dr. Inder Manhas provided me with access to www.uptodate.com (an evidence-
based support resource used in clinical decision making). This proved to be an extremely useful
resource which greatly simplified the research process and helped me identify gaps in the
literature.
4. V
List of Figures
Table of Contents
Abstract ......................................................................................................................................... II
Contributions ................................................................................................................................ III
List of Figures ................................................................................................................................V
Introduction .................................................................................................................................... 1
Method ............................................................................................................................................7
Participants ..........................................................................................................................7
ECT Equipment ..................................................................................................................7
Procedure ........................................................................................................................... 8
Results ............................................................................................................................................ 9
Rate of Response Results ................................................................................................... 9
Receptivity Results .......................................................................................................... 11
Discussion .................................................................................................................................... 13
References .................................................................................................................................... 17
5. V
List of Figures
List of Figures
Figure 1 .......................................................................................................................................... 7
Figure 2 .......................................................................................................................................... 8
Figure 3 .......................................................................................................................................... 8
Figure 4 .......................................................................................................................................... 9
Figure 5 ........................................................................................................................................ 10
Figure 6 ........................................................................................................................................ 11
Figure 7 ........................................................................................................................................ 12
6. 1
Introduction
Electroconvulsive Therapy for Major Depressive Disorder: A Chart Review Concerning the
Impact of Gender and Age on Treatment Efficacy
In electroconvulsive therapy (ECT), a brief electrical pulse is applied by a physician to
the scalp of an anesthetized patient with the goal of exciting the brain cells and producing a
seizure (Letemendia, Delva, Rodenburg, Lawson, Inglis, Waldron, & Lywood, 1993). ECT is
commonly used as a last resort treatment in patients suffering from severe major depressive
disorder (MDD). MDD – also referred to as clinical depression, unipolar depression, and major
depression – is characterized by a ubiquitous low mood, fatigue, and an impaired ability to
function, among other symptoms (American Psychiatric Association, 2013). After experiencing
one episode of depression, the potential for recurrence is high (Burcusa & Iacono, 2007);
however, it has been suggested that the likelihood of relapse declines as the length of time that an
individual stays well increases (Belsher & Costello, 1988). While there is no recognized criteria
for the duration or number of unsuccessful antidepressant trials preceding referral for ECT,
www.uptodate.com – a popular online clinical decision support resource – recommends that
“clinicians should consider ECT for patients who fail two or three antidepressant medication
trials and remain severely depressed for several months” (2016).
MDD remits rapidly with ECT. An alleviation of some (but not all) of the associated
sympatomology is typically experienced after two to four treatments (Kellner, Fink, Knapp,
Petrides, Husain, Rummans, & Smith, 2005), and 60% of patients will remit completely at or
before the 9th
treatment (Husain, Rush, Fink, Knapp, Petrides, Rummans, & Litle, 2004).
Compared to pharmacotherapy, ECT is a quicker and more effective means of achieving
remission from MDD sympatomology: Husain et al. (2004) noted that while less than 50% of
MDD patients treated with medication achieve remission, 75% of individuals in their sample
who were treated with ECT achieved remission. Other researchers have estimated that the rate of
7. Introduction 2
remission for MDD patients who have received ECT is even higher than that reported by Husain
et al. (2004): in some trials, remission has been found to occur in as many as 70% to 90% of
patients (American Psychiatric Association, 2008). Moreover, ECT often works when
medication does not: Rasmussen Mueller, Knapp, Husain, Rummans, Sampson, & Kellner
(2007) found that physiological resistance to antidepressant medication was not predictive of
remission achieved via ECT. The antidepressant effect of ECT was also shown to exceed that of
rapid transcranial magnetic stimulation (rTMS) (Janicak, Dowd, Martis, Alam, Beedle, Krasuski,
& Viana, 2002) and cognitive-behavioural therapy (Kho, Van Vreeswijk, Simpson, &
Zwinderman, 2003). It is unsurprising, then, that meta-analyses have indicated that ECT is the
most effective treatment available for MDD (American Psychiatric Association, 2008). In
consideration of the fact that patients referred for ECT are typically more severely ill than
outpatients referred for pharmacotherapy and other interventions, these statistics are particularly
remarkable.
The efficacy of ECT as a therapeutic intervention for treatment-refractory mood disorders
(including MDD) is well established in the literature; however, the exact mechanism by which
ECT derives its positive effects is unknown. Various theories have been proposed to explain the
efficacy of ECT for MDD. Ota, Noda, Sato, Okazaki, Ishikawa, Hattori, & Kunugi (2015) used
MRI to compare grey matter of 15 MDD patients before and after undergoing ECT; finding
increases in the bilateral medial temporal cortices, inferior temporal cortices, and right anterior
cingulate. These changes correlated with symptom alleviation, leading the researchers to propose
a potential neurotrophic model of efficacy. Additionally, support has been found for a stress
hormone theory of efficacy in patients suffering from MDD. Apéria (1986) measured various
psychoendocrinological variables in 33 MDD patients undergoing ECT and found that post-ECT
8. 3
Introduction
levels of prolactin, cortisol, and TSH differed significantly from the depressive state. Preceding
studies – including Lawrence, Whalley, Eagles, Bowler, Bennie, Dick, McGuire & Fink (1987) –
have replicated this effect.
While ECT is an extremely efficacious intervention, certain factors have been shown to
systematically prevent or predict relapse in MDD patients who have achieved remission via
ECT. Continuation therapy with antidepressants, for example, has been found to reduce the risk
of relapse by 50% (Jelovac, Kolshus, & McLoughlin, 2013). Not all forms of pharmacotherapy
have ECT-enhancing effects, however. Nordenskjöld, Knorring, & Engström (2011) found that
the use of benzodiazepines or antipsychotics by MDD patients during the one year post ECT
follow-up period was associated with an increased risk of relapse. Like pharmacotherapy, the
effect of age on the efficacy of ECT is somewhat ambiguous. While Rosen, Kung, & Lapid
found that increases in age resulted in decreases in efficacy (2015), Rhebergen, Huisman,
Bouckaert, Kho, Kok, Sienaert, & Stek found that remission was more likely to occur in older
patients than it was in younger patients (2015). This apparent contradiction is not explained by
the current body of literature; however, older adults (>65 years of age) do receive referrals for
ECT approximately three times more frequently than do younger adults (Rapoport, Mamdani, &
Herrmann, 2006). This age disparity in referrals is likely due to the fact that many older patients
with MDD are prescribed medications with contraindications to antidepressants (Kelly, &
Zisselman, 2000), or may develop serious complications (Kujala, Rosenvinge, & Bekklund,
2002).
In addition to continuation pharmacotherapy and patient age, the presence or absence of
specific comorbid psychiatric diagnoses has been found to have a significant impact on the
efficacy of ECT for MDD. While ECT is considered to be particularly effective in the treatment
9. 4
Introduction
of depression with psychotic or atypical features (Kroessler, 1985; Husain, McClintock, Rush,
Knapp, Fink, Rummans, & Mueller, 2008), the presence of comorbid borderline personality
disorder (BPD) is associated with decreased treatment efficacy (Feske, Mulsant, Pilkonis, Soloff,
Dolata, Sackeim, & Haskett, 2015). Additional factors which have been found influence the
efficacy of ECT include season (in their 1976 study, Eastwood & Peacocke found that MDD
patients treated with ECT were most likely to relapse in Ontario spring and autumn), electrode
placement (in 2010, Kellner et al. concluded that ECT with bilateral [BL] electrode placement
resulted in the highest remission rate for MDD patients), and duration of depressive episode
(according to Haq, Sitzmann, Goldman, Maixner, and Mickey, a longer depressive episode is
related to a decrease in treatment efficacy [2015]).
One final variable of interest (which is comparatively unrepresented in the literature) is
gender. In a study of schizophrenic patients, Bloch, Ratzoni, Sobol, Mendlovic, Gal, &
Levkovitz (2005) found that ECT was significantly more effective in treating schizophrenia in
female patients than it was in treating schizophrenia in male patients. Schizophrenia and MDD
are related in several ways: they are often treated with similar medications (brexpiprazole, a
dopamine D2 receptor partial agonist, is prescribed for both MDD and schizophrenia) (Citrome,
2015); and CNTNAP2, a neurexin family gene located on chromosome 7, has been implicated in
the development of both schizophrenia and MDD (Chen, Long, Cai, Chen, & Chen, 2015).
Given the documented overlap between MDD and schizophrenia, it logically follows that gender
differences observed in ECT treatment for schizophrenia might also exist in ECT for MDD.
Furthermore, gender differences have been observed in the release of hypothalamic-pituitary
hormones that occur in response to ECT. Specifically, Motreja, Subbakrishna, Subhash,
Gangadhar, Janakiramaiah, & Parameshwara (1997) found that the post-ictal prolactin response
10. 5
Introduction
was significantly higher in female patients than it was in male patients following an acute course
of ECT. The hormonal effect of ECT has been implicated as a potential correlate of the
treatment’s efficacy (Lawrence et al., 1987; Apéria, 1986). Finally, it has been suggested that the
presentation of MDD differs by gender (females are more likely to report neurovegetative,
physical, emotional, and psychosocial symptoms; while males are more likely to report
aggression, substance abuse, and risk-taking behaviours) as does the presence or absence of
depressive subtypes (females present with comorbid anxious distress and / or atypical features
more frequently than males do) (FDA Executive Summary, 2011). Taken together, these studies
suggest that a gender difference in the efficacy of ECT for MDD may exist.
While Bloch et al. (2005) found no effect of gender on the efficacy of ECT in the
treatment of unipolar atypical depression, we speculated that study design limitations (including
the retrospective nature of their study and their small sample size) may have contributed to this
non-significant effect. We felt that there was sufficient evidence from other sources (Citrome,
2015; Chen et al., 2015; Motreja et al., 1997; & FDA Executive Summary, 2011) – in addition to
a sufficient clinical disparity between unipolar atypical depression and MDD – to revisit the
question of whether or not the efficacy of ECT for MDD systematically differs by patient gender.
The Present Study
The purpose of the current research was to identify factors which could bolster or lessen
the efficacy of ECT for MDD, with an investigative focus on gender and patient age. In doing so,
we expanded upon the work of Bloch et al. (2005) by addressing a gap in the literature pertaining
to whether or not patient gender contributes to the efficacy of ECT for MDD. We contributed to
the existing (discrepant) literature on the effects of age by examining efficacy from a novel
perspective (delineated below) (Rhebergen et al., 2015; Rosen et al., 2015).
11. 6
Introduction
We measured efficacy in two ways: (1) as rate of response or length of treatment (a
continuous variable), with fewer treatment sessions indicating faster remission and greater
treatment efficacy; and (2) as receptivity to treatment (a categorical variable), in which patients
who received 12 or fewer treatment sessions were considered to be “treatment receptive”, and
patients who received 13+ treatments were considered to be “treatment refractory”. ECT is
presumed to be more efficacious in treatment receptive patients than in treatment refractory
patients. This definition of efficacy was based on treatment guidelines at Providence Care (which
state that a typical course of ECT occurs over the span of 6-12 sessions) and on the work of
Husain et al., which indicates that 60% of MDD patients achieve remission at or before the 9th
session (2004). Measuring efficacy on both a categorical and a continuous scale allowed us to
conduct a greater variety of statistical analyses and obtain a more thorough understanding of the
construct.
Based on research conducted by Bloch et al., Chen et al., Motreja et al., & Lawrence et
al., we expected to find a gender difference in the efficacy of ECT (2005; 2015; 1997; 1987; &
FDA Executive Summary, 2011). Specifically, based on the findings of schizophrenia
researchers Bloch et al. (2005), we hypothesized that ECT treatment would be more effective in
females than in males. We further hypothesized that a positive relationship would be found
between age and treatment efficacy, aligning our hypothesis with the findings of Rhebergen et al.
(2015) due to their large sample size. However, we acknowledge that evidence in this area is
somewhat mixed (in their 2015 study, Rosen et al. found a negative relationship between age and
treatment efficacy). We thus expected to be somewhat surprised.
This is an important topic which should be studied because MDD is a severely
debilitating (and often life-threatening) illness. Developing a comprehensive understanding of
12. 7
Method
the various factors which attenuate or contribute to the efficacy of ECT is essential if physicians
are expected to refer the appropriate patients to the appropriate treatments and maximize every
patient’s chance of recovery.
Method
Participants
The sample consisted of all adult patients diagnosed with MDD (as assessed by a
psychiatrist) who received ECT at Providence Care between January 2004 and January 2014. We
excluded anyone with an age or diagnosis outside of this range. Given the importance of gender
to our research, we additionally excluded anyone who identified as neither male nor female.
After excluding data from 96 patients who met our inclusion criteria (due to physician errors in
data entry), we were left with 157 participants: 100 females (64% of the sample) and 57 males
(36% of the sample). Patients ranged in age from 18 to 83 (M=50.6, SD=13.91). Six patients in
our sample received right unilateral (RUL) ECT while 151 received bilateral (BL) ECT. Consent
was given verbally prior to treatment and no compensation was provided.
ECT Equipment
A monitored ECT apparatus (model D; MECTA Corporation, Lake Oswego, OR, U.S.A.)
with two electroencephalogram (EEG) channels recording from either the frontal or the temporal
region on each side of the head was used to administer treatments to patients (Figure 1).
Figure 1. The monitored ECT apparatus used in the present research
13. 8
Method
Procedure
Patients received bilateral (BL) or right unilateral (RUL) ECT. Electrode placement was
decided upon by the patient in consultation with a physician. Placement criteria was determined
by the possibility of cognitive deficits. At Providence Care, a typical course of ECT occurs over
the span of 6-12 sessions, three times per week. This constitutes a ‘treatment set.’ Returning for
additional sessions (13+) indicates that remission has not been achieved during the initial
treatment set. Prior to treatment, patients were anesthetized.
In patients who received RUL ECT, a physician placed two electrodes on the right side of
the patient’s head and administered an electrical current to the brain via these electrodes. See
Figure 2 for precise electrode placement in RUL ECT. In patients who received BL ECT, a
physician also administered an electrical current to the brain via two electrodes. However, in this
treatment condition the electrodes were placed on the patient’s forehead (frontal lobes). See
Figure 3 for precise electrode placement in BL ECT. In both treatment conditions, the area was
thoroughly disinfected with an alcohol swab prior to securing the electrodes. The seizures were
recorded and confirmed via electroencephalogram (EEG). Dose and duration of electrical current
was determined on an individual basis by a psychiatrist. Seizure duration varied by patient.
Figure 2. Electrode placement in RUL ECT Figure 3. Electrode placement in BL ECT
14. 9
Results
Results
Rate of response results We examined the effect of 2 independent variables on MDD patients’
rate of response to ECT: (1) gender and (2) age.
Gender. A Kruskal-Wallis test was conducted to evaluate differences among males and
females on rate of response, measured as number of ECT sessions. This test was selected over a
one-way ANOVA because there were several outliers, the population distribution was non-
normal and – with a female to male ratio of approximately 2:1 – the data was unbalanced. The
test, which was corrected for tied ranks, was not significant, χ2
(1, N = 157) = .00, p > .05. As
shown in Figure 4, the results of this analysis indicate that gender does not influence MDD
patients’ rate of response to ECT.
Figure 4. Gender Differences in Length of Treatment.
Differences between the median number of ECT treatment sessions required by male and female
MDD patients at Providence Care. No significant difference was found. Thirteen outliers are
missing from this graph.
15. 10
Results
Age. A one-way analysis of variance was conducted to evaluate the relationship between
MDD patient age and rate of response to ECT. The independent variable, patient age, included
six levels: ages 18-30, ages 31-40, ages 41-50, ages 51-60, ages 61-70, and ages 71-83. The
dependant variable was length of treatment measured by number of ECT sessions. The ANOVA
was not significant at the .05 level, F(5, 150) = .48, p > .05. As shown in Figure 5, the results of
this analysis indicate that age does not influence the rate at which MDD patients respond to ECT.
Figure 5. Differences in Length of Treatment by Age.
Differences between the median number of ECT treatment sessions required by MDD patients at
18 to 30, 31 to 40, 41 to 50, 51 to 60, 61-70, and 71 to 83 years of age. No significant difference
in treatment length was found between these six age groups.
16. 11
Results
Receptivity results We examined the effect of the same 2 independent variables on MDD
patients’ receptivity to ECT: (1) gender and (2) age.
Gender. A one-sample chi-square test was conducted to assess whether men or women
were more likely to be ECT treatment receptive or ECT treatment refractory. The results of the
test were not significant, χ2
(1, N = 157) = .26, p > .05. These results suggest that gender does not
influence MDD patient receptivity to ECT, as illustrated in Figure 6.
Figure 6. Relationship between Gender Treatment Receptivity.
The frequencies of men and women suffering from MDD who are classified as ECT treatment
receptive and ECT treatment refractory.
17. 12
Results
Age. A one-sample chi-square test was conducted to assess whether MDD patient age
(grouped into ages 18-30, 31-40, 41-50, 51-60, 61-70, and 71-83) had an impact on the
likelihood of that patient being receptive or refractory to ECT. The results of the test were not
significant, χ2
(5, N = 157) = .66, p > .05. This suggests that MDD patient age does not have an
influence on patient receptivity to ECT, as illustrated in Figure 7.
Figure 7. Relationship between Patient Age and Treatment Receptivity.
The frequencies of MDD patients classified as ECT treatment receptive and ECT treatment
refractory grouped by age.
18. 13
Discussion
Discussion
We hypothesized that ECT would be more effective in female MDD patients than it
would be in male MDD patients. This hypothesis was primarily extrapolated from the work of
Bloch et al. (2005), who discovered that female patients with schizophrenia were more
responsive to ECT than male patients with schizophrenia. Given a documented overlap between
the two disorders (Citrome, 2015; Chen et al., 2015), we expected to find a similar pattern of
results in our sample. We further hypothesized that a positive relationship would be found
between age and treatment efficacy (aligning our hypothesis with the findings of Rhebergen et
al. [2015]).
While Bloch et al. (2005) found no effect of gender on the efficacy of ECT in the
treatment of unipolar atypical depression, we suspected that this may have been due to their
small sample size (N=43) and subsequent lack of power. We addressed this design limitation in
our study by more than tripling Bloch et al.’s (2005) sample size. Our non-significant result for
gender was thus surprising, and could have been obtained for a variety of reasons. While there
are noted similarities between MDD and schizophrenia (in pharmacotherapy and genetic origin –
see Citrome, 2015 and Chen et al., 2015), they remain two distinct manifestations of
psychopathology and cannot be reduced to one disorder. It is thus possible that our hypothesis
was misguided and a gender difference in the efficacy of ECT for MDD does not exist.
Unlike our analyses of gender, we were not entirely surprised by the results of our
analyses into the effect of MDD patient age on ECT efficacy (although they did contradict the
stated hypothesis). This is due to the fact that the preceding literature is somewhat discrepant:
While Rosen et al. (2015) found that increases in patient age resulted in decreases in treatment
efficacy, Rhebergen et al. found that remission was more likely to occur in older patients than it
19. Discussion 14
was in younger patients (2015). In our sample, we found no effect of age on efficacy. The
present research does not clarify the relationship between MDD patient age and the efficacy of
ECT in an unequivocal way; however ECT – regardless nuances in remission rates – remains a
particularly useful treatment for this age group when contrasted with other available methods,
particularly pharmacotherapy. This is due to the fact that older adults are often prescribed
medications with contraindications to antidepressants (Rapoport et al., 2006).
Pathological idiosyncrasy and literature ambiguity notwithstanding, it is important to
acknowledge that our study design was limited in a number of ways and non-significance could
also have been obtained as a function of this fact. While we corrected the issue of power present
within Bloch et al. (2005), our study remained retrospective in nature. Retrospective research
possesses an unavoidable degree of bias. Having analyzed pre-existing data, we were unable to
exert any measure of control over our variables. The evaluation, referral, and precise
administration of ECT (including dose and duration of electrical current) was determined on an
individual basis by a variety of physicians. Data obtained in this way often suffers from problems
of objectivity and consistency. Furthermore, we eliminated data from 96 patients who otherwise
met our inclusion criteria due to physician errors in the entry of their data. This is a sizable
portion of the original sample (38%). While it is our belief that the excluded variance was
random, it is possible that the resulting data was confounded in some meaningful way.
In addition to undocumented confounds borne of an uncontrolled study design, a review
of the literature suggests that certain factors – including patient drug history (Jelovac et al., 2013;
Nordenskjöld et al., 2011), the presence or absence of comorbidities (Kroessler, 1985; Husain et
al., 2008; & Feske et al., 2015), electrode placement (Kellner et al., 2010), and duration of
depressive episode (Haq et al., 2015) – can impact in the efficacy of ECT for MDD in a variety
20. 15
Discussion
of systematic ways. Of particular relevance is post-ECT pharmacotherapy and patient
comorbidities: continuation therapy with antidepressants has been found to reduce the risk of
relapse by as much as 50% (Jelovac et al., 2013), and the clinical presentation of depressive
subtypes has been shown to differ by gender (FDA Executive Summary, 2011). Any systematic
variance caused by these (or other) factors was unaccounted for by the present research.
We were unable to include information about electrode placement due to the excessively
unbalanced nature of our data (only 6 patients in our sample received RUL ECT while 151
received BL ECT). While our data on comorbidities was more balanced, we felt that the
inclusion of this information was meaningless if we could not separate individuals presenting
with psychotic / atypical MDD from those presenting with comorbid BPD (due to the differing
effects of these diagnoses on treatment efficacy) (Kroessler, 1985; Husain et al., 2008; & Feske
et al., 2015). We did not have access to information about patient drug history and duration of
depressive episode (Jelovac et al., 2013; Nordenskjöld et al., 2011; Haq et al., 2015).
For reasons discussed, we believe that a gap in the literature remains. Both the present
research and that conducted in 2005 by Bloch et al. was retrospective and suffering from a
pattern of related limitations. Future research should investigate the contribution of gender to
treatment efficacy in a prospective, controlled, experimental way. In addition, future research
should work to clarify the relationship between MDD patient age on ECT efficacy. It is
particularly necessary for future researchers to obtain information about – and exert statistical
control over – the potentially confounding variables discussed in this section before concluding
with any degree of certainty that gender and age are or are not related to the efficacy of ECT for
MDD. Doing so will help to identify significant factors important for therapeutic advancements
and maximize every patient’s chance of recovery.
21. 16
References
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