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302 The APA Publishing Textbook of Mood Disorders, Second Edition
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nonsuicidal self-injury (Rootes-Murdy et al. 2019), a syndrome often associated with
borderline personality disorder. This finding is congruent with the decreased re
sponse rate in adults with borderline personality disorder (Rasmussen 2015).
Safety and Efficacy in the Treatment of Mania
In a prospective study of more than 4,400 U.S. hospitals and 14,000 inpatients diagnosed with mania secondary to bipolar disorder, 18% of patients were treated with
ECT and had significantly shorter lengths of stays and lower health care costs (Patel
et al. 2019). In a comprehensive review of 589 patients with acute mania, Mukherjee
et al. (1994) reported that ECT was an effective treatment, with more than 80% of patients remitting or showing marked clinical improvement. As with depression, patients
in manic states that are more resistant to medication treatment have a lower response
to ECT (Mukherjee et al. 1994). Positive clinical predictors of response to ECT include
features of anxiety, depressed mood, and agitation as opposed to psychosis with or
without mixed manic symptoms (Perugi et al. 2013).
Given the known destabilizing effect of antidepressants on bipolar states (Nivoli et
al. 2012), some researchers have supported ECT as the perfect mood stabilizer for
both the manic and depressive states of bipolar disorder (Medda et al. 2014b). Yet, as
concluded in a review published in 2012 on an algorithm for the treatment of hypomania and mania, the data on ECT may be more “experience-based than evidencebased” (Nivoli et al. 2012).
It is unclear which electrode placement is most efficacious in bipolar mania. In a
randomized study of 36 patients, bifrontal placement was as effective as bitemporal
placement in the treatment of acute mania, with fewer cognitive side effects (Hiremani et al. 2008). There are also limited data comparing right unilateral ECT with bilateral ECT.
Bipolar patients with mixed states have a positive response to ECT (Gruber et al.
2000; Medda et al. 2010; Valentí et al. 2008; Vieta 2005); in one study, bipolar patients
with mixed symptoms had a more rapid response and a greater decrease in suicidal
ideation than bipolar patients in a depressive episode (Ciapparelli et al. 2001). ECT
has also been shown to be effective in delirious mania, defined as the rapid onset of
delirium, psychosis, mania, and often catatonic symptoms that may be present in up
to 15% of patients with acute mania (Jacobowski et al. 2013). ECT is effective in patients with mania who are pregnant; it may have the advantage of decreasing the risks
to both the mother and fetus due to the morbidity of a prolonged manic episode with
out the potential teratogenicity of anticonvulsants (Khan et al. 2016; Spodniaková et
al. 2015). ECT is also effective in children and adolescents with bipolar disorder, hav
ing been used effectively in patients with mania in this population (Hill et al. 1997;
Shoirah and Hamoda 2011).
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Safety and Efficacy in the Treatment of Catatonia
Catatonic syndromes are present in approximately 10% of acutely ill psychiatric patients, and mood disorders are the most common cause of catatonia (Taylor and Fink
2003). ECT is very effective in the treatment of catatonia related to a mood disorder,
particularly when benzodiazepines are ineffective (Kellner et al. 2020; Luchini et al.
2015; Medda et al. 2015; Unal et al. 2017). ECT is also effective in children with cata-
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tonia (Dhossche and Withane 2019; Grover et al. 2013; Jacob et al. 2014; Puffer et al.
2016; Raffin et al. 2015; Wachtel et al. 2011).
Maximizing Efficacy
Research on the treatment of mood disorders since the 1990s has focused on improving the safety of ECT while maintaining efficacy. ECT is a very effective treatment for
mood disorders; however, its efficacy depends on use of modern evidence-based
methodology, as described in the following subsection.
Maximizing the Efficacy of ECT While Minimizing
Side Effects
Clinicians or researchers agree that ECT is one of the most efficacious treatments for
mood disorders. The debate is really around its risks, which are primarily related to
cardiovascular and cognitive side effects, versus its benefits. Many of the advancements in ECT have centered on maintaining its efficacy while decreasing its potential
risks. Cardiovascular side effects are primarily due to the adrenergic surge from the
induced seizure, which has been compared to a cardiac stress test. The patient’s heart
rate can accelerate from a base rate of 70 beats per minute to 130 beats per minute in
a matter of seconds. This risk has been mitigated by carefully prescreening patients,
ensuring that anesthesia providers are included on the ECT team, and using cardiovascular medications (e.g., β-blockers and calcium channel blockers) during the treatment.
The risk is higher in patients with preexisting cardiac conditions, including hyperten
sion, coronary artery disease, and arrhythmias (Andrade et al. 2016). However, overall, the rates of cardiovascular side effects are low, and concerns mainly apply to highrisk individuals, who can be managed with prophylactic cardiac medications during
ECT (McDonald et al. 2017).
Cognitive side effects of ECT continue to be a significant concern for patients and
a major focus of research, which has investigated both decreasing the energy required
to initiate the seizure and using alternative electrode placements that do not directly
stimulate areas related to memory and cognition. The development of the brief-pulse
bidirectional square-wave ECT device in the mid-1980s was arguably one of the most
important developments in ECT technology to date (Nilsen et al. 1986). The briefpulse device is more efficient in inducing seizures than the original sine-wave device,
which allows practitioners to deliver a stimulus using less energy and has resulted in
a significant decrease in ECT-associated cognitive side effects. In one study compar
ing the sine-wave and brief-pulse devices in a community setting, patients treated
with the sine-wave machines had a significant slowing in reaction time both immediately and 6 months after the index course of ECT compared with the brief-pulse
group (Sackeim et al. 2007).
Another area of investigation is electrode placement, with the hypothesis that the
point of stimulation is related to the degree of cognitive side effects. The original electrode placement was a bitemporal placement, in which electrodes are placed above
the temples, 3 cm above a line intersecting the outer canthus of the eye and the tragus
of the ear. This places the stimulus over the temporal lobes, potentially stimulating
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subcortical structures associated with cognition, including the amygdala and hippocampus. An alternative placement is the d’Elia placement, in which the electrodes are
positioned over the right temple and 2 cm lateral to the vertex, thereby avoiding di
rect stimulation of cognitive areas associated with language in the dominant (left)
hemisphere (d’Elia and Raotma 1975). Early studies showed that this placement, re
ferred to as right unilateral ECT, had fewer cognitive side effects than bitemporal ECT
(Sackeim et al. 2007). This strategy was refined with the bifrontal placement of elec
trodes over the frontal lobes (Letemendia et al. 1993).
The safety of ECT was further improved in the 1990s by advances in the understanding of the relationship between the seizure threshold and the efficacy of ECT.
Again, this progress was rooted in improved knowledge regarding how the amount
of energy used to create a seizure affected the seizure’s impact on patient cognition.
Through a series of studies, Harold Sackeim and his colleagues demonstrated that the
efficacy of ECT was dependent on the magnitude of the electrical stimulus relative to
the seizure threshold (McCall et al. 2000; Sackeim et al. 1993, 2000). These studies de
termined the stimulus threshold for each patient by using increasing stimulus doses
to identify the minimal amount of energy needed to initiate a seizure. The studies by
these researchers demonstrated that right unilateral electrode placement was effective only at 6 times the seizure threshold or higher and that bitemporal placement was
most effective at 1.5–2.5 times the threshold. A pivotal study by the Consortium on
Research in ECT (CORE) group led by Charles Kellner compared right unilateral ECT
at 6 times the seizure threshold with bitemporal and bifrontal ECT at 1.5 times the
threshold; the group demonstrated that all three electrode placements had equivalent
efficacy and cognitive side effects (Kellner et al. 2010). This study confirmed that electrode placement and the seizure threshold were important for both determining the
ideal parameters of and personalizing ECT treatment.
A recent development has been in the manipulation of one parameter of the ECT
stimulus—the pulse width. The ECT stimulus is a pulse of energy composed of a pulse
width (milliseconds), frequency (stimulations per second), and length (measured in
seconds). The chronaxie is the amount of energy needed to depolarize a neuron; the
most efficient pulse would use less energy to depolarize the neuron and potentially
have fewer cognitive side effects. An early test of this hypothesis demonstrated that
very short pulse widths, or ultrabrief pulse widths (<0.5 milliseconds), were as effec
tive as longer pulse widths in treating depression and were associated with fewer
cognitive side effects (Sackeim et al. 2008). The CORE group assessed the efficacy of
ultrabrief right unilateral ECT in a vulnerable patient population—older patients
with major depressive disorder—in their multisite Prolonging Remission in Depressed Elderly (PRIDE) study (Kellner et al. 2016a, 2016b; Lisanby et al. 2020). They
evaluated the safety and efficacy of this approach in 240 elderly adults (age ≥60
years). In phase 1 of the study, 61.7% of patients remitted (and 70% responded); 10%
did not remit and the other 28.3% dropped out. Overall, the changes in cognitive
function were mild and the treatments were well tolerated.
Using evidence-based techniques to administer ECT can improve the safety of
treating patients with mood disorders. Cognition needs to be monitored carefully because patients can have both anterograde and retrograde memory problems. Tools
have been developed for bedside testing to monitor cognition; one recent scale is the
Electroconvulsive Therapy Cognitive Assessment (Hermida et al. 2020), which is a
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30-point scale that assesses multiple areas potentially affected by ECT, including attention and concentration as well as anterograde and retrograde memory functions.
Like the Mini-Mental State Examination and Montreal Cognitive Assessment scales,
this assessment can be done at the patient’s bedside by a nurse, but unlike these older
scales, it also includes assessment of retrograde memory.
Minimizing Relapse
Most clinicians and researchers in the field of mood disorders recognize that it is important to develop treatments that not only treat the acute episode but also manage
relapse, particularly in the 6 months following the index episode. Patients with
chronic depression and multiple treatment failures are more likely to relapse, and
maintaining euthymia is often a central goal of treatment. The relapse rates in the year
following a successful course of ECT are approximately 50%, with most patients re
lapsing within 6 months (Jelovac et al. 2013). The rates are higher among patients with
psychotic depression and “double depression” (major depressive disorder and dys
thymia) (Bourgon and Kellner 2000) and patients whose illness failed to respond to
multiple antidepressant trials prior to their successful index session of ECT (Sackeim
et al. 1990).
One strategy to manage relapse is to use a protocolized pharmacotherapy regimen
with novel antidepressant strategies. Most patients whose illness is considered medi
cation resistant have primarily failed to respond to selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). The tricyclic
antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) are more difficult
to use because of to their side-effect profiles and issues with patient compliance. Yet
TCAs have been shown to be the most effective antidepressants in preventing relapse
after ECT (Jelovac et al. 2013). Lithium has also been shown to be an excellent augmenting agent with proven efficacy in relapse prevention (Brus et al. 2019), although
practitioners may be reluctant to use lithium for maintenance therapy (Atiku et al.
2015).
For most patients, the combination of a TCA with lithium would be a novel treatment. An early study showed that the relapse rate in the 6 months following a successful course of ECT was significantly reduced when the patient was maintained on
a combination of lithium and nortriptyline compared with nortriptyline alone or pla
cebo, with relapse rates of 39%, 60%, and 84%, respectively (Tew et al. 2007). In a randomized controlled trial, the CORE group compared continuation pharmacology
using nortriptyline and lithium with continuation ECT in 201 patients who had remitted with an acute course of bilateral ECT (Kellner et al. 2006). Approximately half the
patients in each group relapsed, and continuation ECT and pharmacotherapy were
equivalent in terms of preventing relapse. Continuation ECT was well tolerated, with
mild and transient cognitive side effects. A later analysis showed an association of
higher relapse rates with increasing medication resistance prior to ECT (Rasmussen
et al. 2009).
Phase 2 of the PRIDE study examined continuation ECT after a successful course
of ultrabrief right unilateral ECT and showed that tapering ECT helped prevent relapse (Kellner et al. 2016a). This study also showed that a combination of venlafaxine
and lithium with ECT was more effective in preventing relapse than venlafaxine and
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lithium alone. In clinical practice, the combination of pharmacotherapy and continuation ECT is the most common approach and appears to also be the most effective
(Youssef and McCall 2014). Given the high risk of relapse, a maintenance strategy that
includes tapering ECT after an acute course and starting a novel medication trial,
which could include a combination of lithium and a TCA or perhaps an SNRI, would
be the most appropriate. For patients who relapse in the 6 months following their
acute course, continuation ECT combined with antidepressant medication should be
considered.
Innovations in Neuromodulation and ECT
The focus of research has been to maintain the efficacy of ECT while minimizing its
cognitive and other side effects. As discussed, previous innovations have included
changes in the configuration of the pulse width and placement of the electrodes, as
well as limiting the amount of energy used to create the seizure to ensure a therapeu
tic seizure while limiting side effects. The research in novel neuromodulation devices
has focused on using subconvulsive seizures and limiting the convulsive seizures to
areas related to mood and away from neurological structures associated with memory and cognition (e.g., hippocampus and amygdala).
rTMS and VNS use FDA-approved neuromodulation devices that have targeted
depression using subconvulsive stimuli. rTMS administers a series of magnetic stim
ulations, usually over the left or right dorsolateral prefrontal cortex, to stimulate or
depress firing of the underlying neurons. It has been shown to be effective in the treat
ment of major depressive disorder (George et al. 2010; O’Reardon et al. 2007). Similar
to ECT, rTMS is less effective in patients whose illness has failed to respond to multi
ple antidepressant trials and who have chronic depression (Garnaat et al. 2019). ECT
has an advantage over rTMS in the most severely ill and psychotic patients because
those treated with ECT can begin to show improvement in a few days to a few weeks,
whereas those given rTMS may need to wait 4–6 weeks to experience the full benefit.
ECT has also been shown to be effective in stimulating subcortical areas known to be
involved in depression (e.g., subcortical cingulate), while rTMS stimulates primarily
cortical tissue and has only an indirect effect on subcortical areas known to be central
to mood disorders. However, recent advances in rTMS technology (see
“Transcranial Magnetic Stimulation”) have addressed many of these potential deficiencies and include research into shortening the treatment time from weeks to days,
targeting more subcortical areas, and improving efficacy in severely depressed patients (McDonald and van Rooij 2019). Continued research in this area will be important; rTMS has distinct advantages over ECT because it has essentially no cognitive or
cardiovascular side effects and no need for anesthesia. Some have described rTMS and
ECT as complementary and not competitive alternatives for patients with depression,
with ECT being clearly more effective in specific populations (e.g., psychotic depression) but the two modalities having considerable overlap in the treatment of other
depressed populations (Fitzgerald 2004).
tDCS uses a low-intensity neuromodulation device that is currently in clinical trials.
This device uses a positively charged anode electrode and negatively charged cathode
electrode positioned on the scalp to excite or inhibit, respectively, cortical neurons un-
Chapter 19,
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derlying membrane potentials. tDCS is very safe and has the potential to be adapted
for use by patients in their homes. Early trials have shown positive results in the treat
ment of depression, although the results have been relatively modest and show less
effectiveness in TRD (Jog et al. 2019).
VNS delivers a subconvulsive stimulus and requires a surgical procedure to attach
the device to the vagal nerve. VNS can also take months to be effective, and its clinical
application has been slowed by the cost and the fact that the Centers for Medicare and
Medicaid Services (CMS) and most insurance carriers have not approved payment for
the procedure. However, VNS has been shown to be effective in patients with highly
treatment-resistant illness (i.e., failure of eight or more antidepressant medications
and nonresponse to ECT) and can produce a durable response over years (Aaronson
et al. 2017). CMS is currently funding a study to reevaluate the safety and efficacy of
VNS that, if positive, could open the way to increased coverage for this treatment.
VNS is
Brain Stimulation”).
stimuli is DBS. DBS is both subconvulsive and targeted to a few millimeters of tissue.
Early studies found that DBS was effective in patients whose illness was nonresponsive to ECT and in those with chronic depression (Bergfeld et al. 2016; Holtzheimer et
al. 2012). The efficacy of DBS in large clinical trials has been mixed. Different groups
are using different targets and different stimulus parameters with variable results, so
more research is needed before DBS can be used clinically. The specificity of DBS,
which can target specific white matter bundles in individuals with severe TRD, can
provide perhaps the most personalized approach to therapy for chronic depression
that is resistant to other treatments, including ECT (Conroy and Holtzheimer 2019).
away from cognitive areas and on neuroanatomical areas associated with depression.
Two investigational devices include magnetic stimulation therapy (MST) and focal
electrically administered seizure therapy (FEAST). MST relies on the principle that
magnetic fields can be used to apply a more focal seizure than an electrical stimulus
applied to the scalp because these fields pass unimpeded though the skull to stimulate a more defined brain area (Deng et al. 2011). The result is more focal stimulation
of the cortex and decreased stimulation of areas in the temporal lobes involved in cog
nitive processing and memory. Although anesthesia is still required for MST (because
the stimulus results in a generalized seizure), preliminary studies have shown it is as
effective as ECT but with fewer cognitive side effects (Fitzgerald et al. 2013). Notably,
some of the earlier studies have included patients with bipolar depression and psychotic depression, although no definitive conclusions can be drawn about the efficacy
of MST in these disorders because the studies are preliminary (Kallioniemi et al.
2019). MST has also been shown to be effective in alleviating suicidal ideation (Sun et
al. 2016).
generalization of the seizure. The FEAST stimulus is unidirectional and uses novel
electrodes and placement that result in increased focality and a more efficient seizure
induction (Sahlem et al. 2016; Spellman et al. 2009). The preliminary research, as well
as preclinical studies in primates, has demonstrated that FEAST can induce an antidepressant response with a relatively short time to reorientation (Nahas et al. 2013;
discussed in more detail in Chapter 20 (“Vagus Nerve Stimulation and Deep
One of the most innovative and targeted research approaches to subconvulsive
A second approach has been to use a convulsive stimulus but to focus the stimulus
FEAST uses ECT technology to initiate a seizure in the prefrontal cortex prior to
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Sahlem et al. 2016) and shows a more focal onset of seizure activity in the prefrontal
cortex (Chahine et al. 2014).
There are other advanced investigational technologies using neuromodulation
procedures that potentially could offer treatment for patients with the most resistant
illness; these include closed-loop/adaptive DBS, optogenetics, magnetogenetics, and
high- and low-intensity focused ultrasound (Kilian et al. 2019). Continued refinement
of these procedures and determination of which patients will be most likely to benefit
are important areas of research (McDonald 2019).
Conclusion
ECT is safe and effective in the treatment of TRD, with remission rates ranging from
60% to 80% and half of the patients remaining well over the following 6 months, when
the potential for relapse is highest. Technical modifications to improve the safety and
tolerability of ECT have included development of individualized dosing strategies,
use of electrode placements that minimize direct stimulation of cognitively sensitive
neuroanatomical areas, and adjustment of the stimulus parameters. From a medical
perspective, these refinements have significantly improved the safety of ECT while
maintaining its efficacy in the treatment of affective disorders. Unfortunately, the
public perception of ECT continues to lag the research, although many studies show
that patients receiving ECT and their families rate the experience favorably (Brown et
al. 2018) and that perception is understandably related to the treatment practices of
the ECT staff (Chakrabarti et al. 2010; Knight et al. 2017).
There are two clinical areas in which ECT clearly has an advantage over other
FDA-approved neuromodulation devices: speed of response and rate of remission in
the most severe psychiatric syndromes, including psychotic depression and catato
nia. Two other FDA-approved treatments, rTMS and VNS, offer alternatives for some
patients, and it is important to identify which populations will benefit from these
treatments. Investigational therapies using neuromodulation are providing new
treatment options for patients with severe depression who do not respond to ECT.
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