Jurnal ECT

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Harv Rev Psychiatry. Author manuscript; available in PMC 2024 January 01.
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Published in final edited form as:

Harv Rev Psychiatry. 2023 ; 31(3): 101–113. doi:10.1097/HRP.0000000000000365.
Electroconvulsive Therapy: Mechanisms of Action, Clinical

Considerations, and Future Directions
Michael D. Kritzer, MD, PhD1, Angel V. Peterchev, PhD2,3,4,5, Joan A. Camprodon, MD, PhD,
MPH1
1Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School,
Charlestown, MA, 02129, USA
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2Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA
3Department of Biomedical Engineering, Duke University, Durham, NC, USA
4Department of Electrical and Computer Engineering, Duke University, Durham, NC, USA
5Department of Neurosurgery, Duke University, Durham, NC, USA
Abstract
Electroconvulsive therapy (ECT) is the most effective treatment for a variety of psychiatric
illnesses, including treatment-resistant depression, bipolar depression, mania, catatonia, and
clozapine-resistant schizophrenia. ECT is a medical and psychiatric procedure whereby electrical
current is delivered to the brain under general anesthesia to induce a generalized seizure. ECT
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has evolved a great deal since the 1930’s. Though it has been optimized for safety and to
reduce adverse effects on cognition, issues persist. There is a need to understand fundamental
physiologic, cellular, and molecular mechanisms of ECT to devise strategies to optimize
therapeutic outcomes. Clinical trials that set out to adjust parameters, electrode placement,
adjunctive medications and patient selection are critical steps towards the goal of improving
outcomes with ECT. This narrative review provides an overview of ECT, its efficacy in treating
depression, the known effects on cognition, evidence of mechanisms, and future directions.
Keywords
Electroconvulsive Therapy; ECT; Depression; Treatment-Resistant Depression; Electroconvulsive
Stimulation
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Introduction:
Electroconvulsive therapy (ECT) is a medical procedure whereby electrical current is
administered through the skull under general anesthesia to induce a seizure for the treatment
of a variety of psychiatric illnesses 1–4. For over 80 years, ECT has been the most effective
treatment for severe depression, mania, catatonia and clozapine-resistant schizophrenia.
It has also been shown to help with suicidal ideation and in augmenting clozapine for
Authors have no additional potential conflicts of interest to disclose.

Kritzer et al. Page 2
psychosis 5–9. There is an abundance of evidence supporting the use of ECT for treatment-
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resistant depression (TRD), and overall, ECT is more effective than pharmacotherapy for
the treatment of depression and other mood disorders, such as bipolar depression and
mania 4. Regardless, given the stigma of its use and adverse effects on memory, it is
widely underutilized 2,4,10. A contributing factor to why patients and their families may
be reluctant to undergo ECT, or clinicians may be reluctant to refer for treatment, is the
impression that little is known about the mechanisms of the therapeutic effect and cognitive
side effects 10,11. While many questions remain open, neuroscience research has made
significant advances to understand the neurobiological effects of ECT. This narrative review
aims to describe the evidence supporting current models that explain how ECT works
therapeutically as well as what causes the cognitive side-effects.
ECT – an ultrabrief history:

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Electroconvulsive therapy has evolved tremendously since it was first used in the 1930’s
12,13. What began as bilateral stimulation with a sine wave voltage source at the power
line frequency without anesthesia (referred to as “unmodified ECT”), has evolved to its
present form of unilateral (typically right unilateral, RUL) stimulation with individually-
titrated trains of ultrabrief or brief rectangular constant-current pulses under general
anesthesia (termed “modified ECT”, i.e. modified with anesthesia), and bilateral brief pulse
stimulation generally reserved for refractory or emergent cases 14–17. The impetus for these
optimizations has been to prevent physical and cognitive side effects. Despite the robust
antidepressant effect of ECT, some patients still experience adverse effects on memory,
which limits its clinical application.
ECT is a rapid-acting antidepressant:

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Electroconvulsive therapy begins with a short index course of 6 treatments delivered 3/week,
or 2/week as performed in the UK. Patients typically respond to RUL treatment with > 50%
reduction in their symptoms within that two-week period and then continue with weekly
maintenance treatment for a few weeks and gradually increasing the interval between
maintenance treatments as clinically indicated. If there is little or suboptimal response in
2–3 weeks, particularly if there is concern for physical safety, practitioners often switch to
brief-pulse RUL (change in pulse width) or bilateral treatment (change in montage), which
is understood to be associated with more noticeable cognitive side effects, as we explain
in the following sections. A recent epidemiological study of Medicare data compared
10,460 patients who underwent ECT to 31,160 patient-controls and showed that patients
receiving ECT had lower all-cause mortality for up to 1 year following hospital discharge.
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Importantly, there was a significant reduction in the rate of suicide following ECT, but with
no difference at 1 year follow-up 18.
Antidepressant efficacy and cognition:

Luccarelli, Henry, and colleagues have recently reviewed large datasets from Massachusetts
General and McLean Hospitals and made some pertinent clinical observations. They have
shown that ECT was associated with a rapid decrease in depression symptoms within
the first 10 treatments; which continued for almost two years of maintenance treatment.
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Importantly, there was no change in cognitive functioning as measured by the Montreal

Cognitive Assessment (MoCA). At their institution, regardless of the initial treatment,
bilateral and brief pulse treatment parameters were more commonly used by treatment
number 50, and most participants either stopped due to remitting or had continued in ECT,
implying side-effects were tolerable enough on average at the end of the study period 19.
Another analysis showed that 37.5% of patients who began with RUL were transitioned to
bilateral treatments 20. Specifically, younger patients and those with bipolar disorder were
more likely to transition from brief pulse RUL to bilateral treatments, but the overall number
of treatments did not differ based on age or primary diagnosis 21.
In a study where cognition was assessed, ECT was associated with a 40% decrease in
depression symptoms (QIDS reduction from 17.1 ± 4.9 to 10.1 ± 5.2), accompanied by
a reduction in MoCA scores that was statistically significant, but likely too small to be
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clinically significant (from 25.8 ± 3.1 to 25.4 ± 3.1); interestingly, older age was associated
with a milder reduction in MoCA perhaps due to lower baseline at the initiation of treatment
22. Furthermore, in a study of 684 patients that received at least 10 ECT treatments,
investigators tracked QIDS and assessed cognition with the MoCA at baseline and after
treatment. Patients with baseline normal cognition (MoCA ≥ 26; N = 371) had a decrease in
MoCA of 1.44±0.26 points over the course of treatment, while those with baseline impaired
global cognitive function (MoCA < 26; N = 313) experienced an increase in MoCA of
1.72±0.25 points. Importantly, baseline global cognitive function was not associated with a
change in depression after ECT, suggesting that impaired global cognitive function may
not be a contraindication to ECT in geriatric patients 23. It is important to note that
the MoCA may not be the most appropriate assessment tool for the type of cognitive
complaints patients experience with ECT (nuances discussed below) as it is a general
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multidomain screening test that measures many different cognitive functions and emphasizes
executive function over memory. That said, it is reassuring that there is very little change
in an assessment tool that quickly screens a broad range of cognitive domains, which is
particularly useful in older patients.
Electrical stimulus parameters:

The characteristics of the electrical stimulus influence the therapeutic response as well
as the emergence of side effects. A crucial component to the administration of ECT is
electrode placement, which determines the path of current propagation through the tissue
24,25. There are three commonly used electrode placements: RUL, bitemporal, and bifrontal;
the latter two are types of bilateral placement. Historically, as mentioned above, ECT was
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administered bilaterally with electrodes placed on the side of the head over the temporal
lobes (bitemporal placement). Because of adverse effects of having current pass directly
through the left temporal lobe where language is generated for most people, practitioners
typically favor beginning treatment with a RUL configuration (right temporal and midline
vertex placement of electrodes). If a patient is left-handed, they may have a right-dominant
hemisphere (as approximately 25% of left-handed individuals do), and steps can be taken
to determine whether the electrodes should be placed left-unilaterally to avoid passing
current through their dominant hemisphere in order to minimize cognitive side effects 26,27.
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Electrodes can also be placed bifrontally across the forehead.
The electrical current parameters also influence the rate of depressive symptom
improvement as well as the emergence of side effects. Conventional dosing of ECT depends
on many factors, but pulse shape and current amplitude are generally fixed; this leaves
changing the pulse width and the pulse train frequency and duration as means of protocol
adjustment. The standard current amplitude used in clinical practice of modern ECT is fixed
at either 800 mA or 900 mA, depending on the device and various practices; the pulse shape
is rectangular with brief (0.5–1 ms) or ultrabrief (0.25–0.3 ms) pulse width; and the pulse
train is comprised of monophasic pulses of alternating polarity. With these parameters fixed,
the electrical dosage is conventionally individualized by increasing the number of pulses in
the stimulus train via titration of the train duration and/or frequency. In ECT practice, the
electrical dosage is often quantified by the total charge or energy of the stimulus train 28.
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Historically, researchers found that increasing electrical dosage from just above seizure
threshold (ST) to 2.5 times the ST increased the efficacy of brief pulse RUL ECT, although
not to the level of bilateral ECT 29. Sackeim et al. showed that high-dose RUL ECT (6 × ST)
is more effective than lower (1.5 × ST) or moderate (2.5 × ST) RUL ECT 30. Importantly,
high-dosage RUL ECT showed similar therapeutic effects to bilateral ECT (bilateral at 2.5 ×
ST) with less cognitive impairment. Sackeim and colleagues then compared high-dose RUL
(6 × ST) to moderate suprathreshold bilateral ECT (2.5 × ST) for both brief and ultrabrief
pulses, and concluded that high-dose ultrabrief RUL ECT preserved efficacy while reducing
cognitive side effects, whereas ultrabrief bilateral ECT reduced cognitive side effects but
was significantly less effective 15. The authors speculated that at higher dosage relative
to ST, ultrabrief bilateral ECT may also increase its efficacy, although this approach has
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not been tested systematically 15. Taken together, a clinical approach may be to start with
ultrabrief RUL ECT at a high dosage rather than bilateral ECT because of comparable
efficacy and fewer cognitive adverse effects.
Sienaert and colleagues found both unilateral and bifrontal ultrabrief ECT to improve
cognitive performance with a broad neuropsychological battery at 1 and 6 weeks post-
treatment 31,32. Testing stimuli of 4, 7, and 10 times ST, Quante et al. asserted that stimulus
intensity of ultrabrief RUL ECT in this range does not correlate with symptom improvement
measured by the Hamilton Depression Rating Scale, demonstrating that ultrabrief RUL ECT
at 4 times ST is sufficient for symptom improvement 33. A 2015 meta-analysis showed
that brief versus ultrabrief pulse RUL ECT was significantly more efficacious in treating
depression but also showed significantly more side effects in global cognition, anterograde
learning and recall, as well as retrograde memory 34.
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In clinical practice, initial electrode placement is typically initiated as RUL or, in more
urgent or severe cases, bitemporal or bifrontal 30. This is because, generally, bilateral
stimulation acts faster with a trade-off of having greater likelihood of cognitive side
effects than unilateral ECT (with either ultrabrief or brief pulse width). The UK ECT
Review Group found that bilateral ECT is generally more effective than unilateral ECT
in improving depression symptoms, based on data from 22 studies comparing bilateral
(this meta-analysis combined bifrontal and bitemporal) to unilateral ECT 4. However, two
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rigorous studies found non-inferiority of brief pulse RUL in comparison with brief pulse
bifrontal and bitemporal ECT, respectively 35,36. A randomized control trial by Kellner
et al comparing bilateral, bitemporal and RUL was consistent with this, with bitemporal
ECT having greater cognitive impairment 37. In a meta-analysis of observational studies
of cognitive function after ECT, Semkovska and McLoughlin showed that both unilateral
and bitemporal ECT are associated with significant decreases in cognitive performance,
mainly executive functioning, and verbal memory, within 3 days post-treatment. Bitemporal
ECT had worse cognitive performance acutely, though long-term follow-up demonstrated
improvements compared to baseline or reattainment of baseline performance (at 14–365
days post-treatment). Although there are concerns about acute ill effects on cognition with
ECT, it is generally accepted that adverse effects on cognition (predominantly memory) will
return to normal within six months of the index course of treatment 4,38. Depending on
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illness severity, a protocol could begin with bilateral ECT and switch to RUL if cognitive
side effects emerge or perhaps the converse—begin with high-dose RUL ECT for index and
weekly treatments and then use bilateral for monthly maintenance treatments. If cognitive
side effects are of particular concern, high-dose ultrabrief-pulse RUL should be considered
over brief-pulse RUL or bilateral ECT.
More recently, a novel approach to electrode placement, focal electrically administered

seizure therapy (FEAST), has been explored as a means of reducing the adverse cognitive
effects from seizure therapy. FEAST utilizes unidirectional stimulation and an asymmetrical
frontal electrode placement with a large posterior electrode (cathode) in front of the right
motor cortex and a small anterior electrode (anode) above the center of the right eyebrow,
over the right orbitofrontal cortex, with the aim of focusing the seizure induction in the right
prefrontal cortex 39–42.
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Another experimental approach aiming to reduce the side effects of ECT is magnetic
seizure therapy (MST), which utilizes high intensity and frequency transcranial magnetic
stimulation (TMS) under general anesthesia to induce a seizure 43. Compared to
conventional ECT, MST induces a weaker and more superficial electric field 24,44. Like
in ECT, optimal MST stimulation targeting and parameters are being investigated. For
example, prefrontal stimulation at higher frequencies may increase depression remission
rates, whereas lower frequencies appear advantageous for suicidality remission 45–47.
Computational, animal, and clinical studies have suggested that the electric field generated
by standard ECT in the brain is markedly higher than the levels needed to depolarize
neurons and induce a seizure 48,49. The current amplitude is a key factor driving the electric
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field into deeper brain regions, such as the hippocampus and temporal lobe, which may
contribute to adverse effects on cognition and memory. Reducing the current amplitude
makes the electric field weaker and more focal 50. Therefore, decreasing the stimulus current
amplitude could be a potential means of reducing cognitive side effects 28. A recent proof
of concept non-randomized clinical trial suggested that ultrabrief RUL ECT with a lower
current amplitude (as low as 500 mA to 600 mA) may improve cognitive outcomes by
reducing reorientation time, a measure correlated with worse cognitive outcomes from ECT.
Intriguingly, there was no difference in treatment response in depressive symptoms when
compared to higher current ultrabrief pulse RUL 51,52. There may be, however, an individual
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tradeoff between the efficacy of treating depression and preservation of cognition controlled
by the current amplitude. Abbott and colleagues investigated ultrabrief RUL ECT delivered
at three current amplitudes and found that 700 and 800 mA were more effective at reducing
depression symptoms, while 600 mA had less cognitive side effects as measured by the
Hopkins Verbal Learning Test and aspects of the Delis Kaplan Executive Function System,
which together assess frontal-temporal cognitive functions (e.g., verbal fluency, cognitive
flexibility, inhibition, and processing speed) 53. Notably, current strength of 500 mA was
not included in this trial based on evidence of insufficient therapeutic efficacy during pilot
testing. Additionally, subjects enrolled in the trial were switched from ultrabrief to brief
pulse stimulation, due to concerns about low efficacy of the 600 mA arm. Thus, reducing
the current amplitude may diminish therapeutic effects, at least for some subjects and ECT
parameter settings.
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The relationship between ECT current amplitude and clinical outcomes may vary
individually due to differences in the electric field delivered to the brain stemming from
anatomical variability. The electric field in the brain can be modeled computationally based
on individual MRI scans 24. The few studies to date that modeled the ECT electric field in
large groups of patients have arrived at intriguing though diverse relationships. The electric
field in the left hippocampus and left amygdala were found to correlate with increases of the
volume of these structures after RUL ECT, but neither the volume changes nor the electric
field strength were associated with antidepressant response 54. The latter finding contradicts
other studies (often using data from a single or two centers, with smaller sample sizes
but greater sample homogeneity), which demonstrated a significant relationship between
increases in hippocampal and amygdala volume primarily (but also other limbic structures)
and symptom improvement 55–57. One line of investigation tried to combine genetic
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differences in hippocampal size after ECT and found that a single nucleotide polymorphism
(SNP) in the promoter of vascular endothelial growth factor (VEGF) attenuated hippocampal
growth whereas a SNP in the brain derived neurotrophic factor (BDNF) gene did not 58.
The study of current amplitude including RUL and bitemporal electrode placement found
improved antidepressant outcomes to correlate with volume increases of the right, but not
left, hippocampus, which, in turn, was affected by the local electric field. In contrast to this
indirect effect, stronger electric field in the right hippocampus worsened the antidepressant
effect and cognitive performance 59. A similar effect of worse antidepressant effect with
a stronger electric field in the temporal lobes was observed for bilateral but not RUL
ECT in another study 60. Other studies have also observed lateralized effects, in which
RUL ECT leads to right-sided volumetric changes while bilateral ECT leads to bilateral
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volumetric changes 61. While these limited data do not afford firm conclusions, they suggest
adverse effects of direct electric field exposure in the temporal lobes, while also indicating
potential beneficial indirect effect on hippocampus, perhaps mediated by the seizure and/or
transsynaptic activation.
These results raise the question of the relative contribution to ECT outcomes of the electrical
stimulation versus the seizure itself. The strong electrical stimulation delivered by ECT
produces synchronized rhythmic firing over broad populations of neurons, akin to the brain
activity during a seizure. Thus, it is possible that some of the effects of ECT are conferred
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or modulated by the electrical stimulus rather than the seizure. This may be a reason
why, to be effective, RUL ECT has to be delivered with six times the number of pulses
needed to induce a seizure. Moreover, a pilot study of intensive bifrontal subconvulsive
stimulation with an ECT device reported significant therapeutic effects in the absence of a
seizure 62. Finally, accelerated repetitive transcranial TMS, which delivers a large number of
subconvulsive stimuli over a short period of time, has recently demonstrated remarkably
high remission rates in treatment resistant depression 63,64. These observations may
point to using targeted stimulation to induce seizures while avoiding direct hippocampal
stimulation, combined with more stimulation pulses and sessions for cumulative therapeutic
effects 50. Lower current amplitude produces somewhat less cognitive side effects, but
there is substantial individual variability in efficacy versus current amplitude. Therefore,
individualization of the current amplitude may be appropriate, by seizure or motor threshold
titration in the amplitude domain or individual electric field modeling 25,59,65. Broadly,
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ECT parameters could be explored further as pathways for improving outcomes. Optimized
and individualized stimulus delivery may become an important option to lower the risk
of cognitive side effects, especially in patients at higher risk or with a previous adverse
outcome.
Cognition Considerations:
Studying cognition in response to ECT has a few pitfalls. The first is that depression,
particularly TRD, has been shown to negatively impact many aspects cognition, mainly
attention and aspects of memory 66. Patients often report adverse effects of ECT on memory
67. These subjective reports have been challenging to characterize 68. This can be explained
partly because studies of cognition are confounded by a few factors: First, multiple cognitive
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domains improve after ECT as depression negatively affects attention, executive function,
and working memory; Secondly, studies typically compare MoCA, Mini-Mental Status
Exam (MMSE) or the Cognitive Failures Questionnaire (CFQ) before and after ECT 69.
MMSE and MoCA are tools to assess mild to severe cognitive impairment and do not appear
to capture the subtleties of subjective cognitive complaints. These screening tests do not
examine retrograde episodic memory – the type of memory impairment primarily reported
by patients. Certainly, if ECT caused major neurocognitive impairment, we would have
stopped administering it decades ago.
The effects of ECT on memory is a major concern for patients. Many studies have evaluated
cognition broadly and found non-memory cognition to improve substantially. Importantly,
studies at long-term follow-up after ECT generally show improvements in memory using
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objective measures 70. In the subacute period following ECT (0–3 days), tests of executive
function and processing speed were impaired compared to baseline 70. However, when
measured between 4 and 14 days, most tests showed significantly improved outcomes
compared with baseline, and none were below baseline 70. This improvement is likely to
have been a result of successful treatment as studies suggest that a high percentage of
patients with severe depression have substantial cognitive impairment at baseline 71. Longer
term, with a wide range of follow-up intervals (2 weeks to 2 years), there was no evidence of
impairment in tests of non-memory cognition 70.
The effects on memory have been variable and proven more challenging to assess. Studies of
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subjective report of cognitive side-effects show varying percentages of patients complaining

of ‘memory loss’, depending on many factors, including the interviews were conducted 67.
When patients report cognitive side-effects, it is often loss of retrograde autobiographical
memory concerning them, i.e., the loss of detailed memory for events that the person
has experienced. However, both episodic memory (experiential memory) and semantic
memory (factual memory) may be affected 72. Retrograde amnesia (memory loss) for
non-autobiographical information has also been shown 73. Furthermore, when objectively
measured, this retrograde amnesia could persist for over one year. Objective testing
of autobiographical memory, typically using the Columbia University Autobiographical
Memory Interview (CUAMI), has shown that ECT memory loss exceeds the normal
decay of memories over time in healthy matched participants and the degree of loss
differs depending on the treatment ECT parameters used; though importantly, many of
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these comparisons were not to that of depressed. Importantly, subjective impairment often
reduces throughout the course of treatment, correlating with clinical response, and perhaps
representing negative bias associated with depressive states 74,75. Brief assessments of
cognitive side effects of ECT were reviewed by Martin et al, and an emerging tool,
the Electroconvulsive Therapy Cognitive Assessment (ECCA) is gaining interest, though
widespread adoption is lacking, as is thorough validation of it for autobiographical memory
loss 76,77.
Interestingly, ECT does not appear to adversely affect verbal memory long-term, even with
bilateral brief pulse, with current passing directly through the left frontotemporal lobe. More
appropriate tests would be those that test non-verbal and visuospatial memory, working
memory, reasoning and executive function 69. It is possible that the brain regions undergoing
the most dramatic changes during a course of ECT, i.e., mesial temporal lobes and limbic
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structures, are the ones responsible for the efficacy of ECT, but also harbor the source of
some cognitive changes – be it objective or perceived.
Ketamine has been studied as a potential augmentation strategy co-administered with ECT
to alleviate side effects and/or increase efficacy. It is important to note that anesthetic doses
of ketamine used for ECT seem to have a different effects on mood when compared to
subanesthetic doses used to treat depression 78. Importantly, ketamine for the treatment of
depression is used at a subanesthetic dose in awake patients, so findings in anesthetized
patients with higher doses of ketamine may not share the identical mechanism of action.
A recent meta-analysis of add-on ketamine to ECT has shown that ketamine enhances
ECT’s therapeutic effects but unfortunately also exacerbates side effects 79,80. Ketamine is
known to inhibit N-methyl-D-aspartate (NMDA) receptors and, interestingly, endogenous
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NMDA receptor agonist quinolinic acid (QUIN), is decreased following successful ECT –
suggesting a role of NMDA receptor biology in ECT’s mechanisms. Ill-effects on cognition
resulting from ECT seems to depend on many factors, including a patient’s baseline
cognitive status and underlying cognitive reserve prior to obtaining ECT 81,82. That said,
there are parameters of ECT delivery that seem to directly increase the likelihood of adverse
cognitive outcomes including bilateral electrode placement, current, and stimulus type 83.
Additionally, general anesthetics have been shown to have varying effects on cognition and
likely worse outcomes in older patients 84. The cognitive effects of the interaction between
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ECT and anesthesia are beyond the scope of this review; however, it is important to highlight
the fact that even though generalized anesthesia for ECT is limited to approximately 10
minutes for each session, a patient may undergo dozens of ECT treatments with the potential
for adverse effects due to the accumulation of anesthetic events 85.
Mechanisms of ECT:
γ-Aminobutyric acid and Glutamate:
γ-Aminobutyric acid (GABA) is an inhibitory neurotransmitter expressed in interneurons
distributed across the brain to modulate excitatory neural circuits. It is intriguing to consider
the observation that ECT appears to effectively treat a variety of psychiatric illnesses
that are also effectively treated with GABAergic medications such as benzodiazepines.
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These include unipolar and bipolar depression, bipolar mania, and catatonia 86–88. Low
GABAergic function may be a feature in a subset of mood disorder patients, representing
a genetic susceptibility, consequence of chronic stress, or more likely a combination of
the two. There is evidence supporting the notion that ECT has significant anticonvulsant
properties and results in decreased neural metabolic activity over the course of treatment
89–91.
Typically, a repeated seizures throughout a course of ECT reduces seizure duration and
an increases in intracortical inhibition, both of which have been correlated with clinical
improvement 91,92. In a very large retrospective study of over 3000 patients receiving
an acute course of ECT there was a decrease in the mean ECT seizure duration, with
the greatest change within the first 3 treatments. Older age, higher ECT dose and higher
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treatment number were all associated with shorter seizures 93. Interestingly, this notion has
been evaluated with TMS. Cortical excitability in neurocircuitry has been assessed with
single and paired pulse TMS to investigate these anticonvulsant effects of ECT. After 10
sessions of RUL ECT, researchers observed an enhanced activity of inhibitory circuits in
human motor cortex, as measured by both increased intracortical inhibition and cortical
silent period duration, while intracortical facilitation and resting motor threshold did not
change 92.
There is evidence suggesting GABAergic involvement in ECT’s mechanism of

antidepressant action 94. Postictal suppression of seizure activity, largely thought to be
driven by GABAergic neurons, has been correlated with treatment outcomes and there
may be ways to alter seizure suppression with pharmacological augmentation during ECT
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administration 95–103. Compared to non-responders, ECT responders appear to have higher

GABA levels at baseline and after a course of ECT. Interestingly, immediately after ECT,
free plasma GABA was decreased for up to 1 hour and another study found that occipital
cortex GABA levels doubled 104,105. Two hours after a single session of ECT, GABA and
amino acids plasma levels were decreased in depressed patients possibly due to shifts into
the brain 106. A neurophysiological explanation of an ECT mechanism is that repeated
electrically-induced seizures increase the ST, and therefore mood stability, by increasing the
activity of GABAergic neurons that regulate the function of neurocircuits, thereby relieving
aspects of neurovegetative depression such as rumination, anxious distress and even mania
or catatonia 107. There are other potential mechanisms, recently reviewed by Leaver, et al,
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suggesting a role in the thalamus and cerebellum in the attenuation of seizure activity after
ECT as the data supporting the GABA hypothesis has not been completely consistent 108.
Hormonal changes:
In humans, serum prolactin levels increase in response to seizures, with a 10- to 50-fold
increase observed after ECT 109. This has been observed in severely depressed patients,
with ECT resulting in increases of prolactin and estrogen stimulating neurophysin (ESN)
for at least 6 minutes post-ECT 110. This was also observed for a shorter time course
for nicotine stimulating neurophysin (NSN) but no other stress/hypothalamic hormones
increased this dramatically, indicating that ECT has specific hormonal effects that cannot be
generalized to the release of any or all pituitary or hypothalamic stress-induced hormones
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110. Another important marker of stress, corticotropin-releasing factor (CRF), has been
studied, though with mixed results. Nemeroff and colleagues found that cerebrospinal
fluid (CSF) concentrations of CRF in depressed patients decreased after ECT 111. Kling
and colleagues also found that CRF levels decrease after a successful course of ECT
112. However, other studies have found no significant change in CSF-CRF following ECT
despite clinical improvement 113,114. Interestingly, Banki and colleagues noted that in the 15
patients who did not relapse within 6 months of ECT treatment, the CSF-CRF concentration
was indeed reduced post-ECT 113. Cortisol levels have also been reported to be increased
following ECT treatment, potentially due to increased arginine vasopressin stimulation of
CRF-induced acetylcholine release 114,115. Lastly, β-endorphin was shown to be transiently
increased following ECT administration in depressed patients 115,116.
Some studies have shown that growth hormone is decreased in depressed patients following
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ECT, though other studies have found no statistical difference 115,117. Generally, stress
hormone and neuropeptide changes have been documented, though given the heterogeneity
of sample populations, sizes, and parameters, there has been a failure to establish a
consensus. While the immediate release of stress hormones such as prolactin and cortisol
may be important in the mechanism of ECT, it may also simply be an epiphenomenon and
marker of seizure activity with little reliable insights into the therapeutic effects of ECT 118.
A few other studies have attempted to identify molecular substrates that may be involved
in the therapeutic effect of ECT in human subjects. The kynurenine pathway and its
metabolites have emerged as potential mediators in the pathophysiology of depression and
the response to ECT 119. Tryptophan, the amino acid basis for serotonin, degrades along
the kynurenine pathway. Also, tryptophan consists of, among other compounds, QUIN,
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an NMDA-receptor agonist, and kynurenic acid (KYNA), an NMDA-receptor antagonist.

QUIN upregulation and increased QUIN/KYNA plasma ratios have been observed in
depressed patients. Schwieler et al. found that after ECT, QUIN plasma levels and QUIN/
KYNA ratios were decreased in 80% of patients 119. The authors suggest that the capacity
of ECT to decrease the neurotoxic branch of the kynurenine pathway may be of clinical
importance. However, they mention that plasma QUIN levels correlate with ECT treatment
but not with the response to ECT as measured by the Montgomery-Asberg Depression
Scale (MADRS), consistent with another finding that QUIN levels correlate suicidality but
not depression generally 120. Furthermore, QUIN and KYNA, as the authors acknowledge,
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do not easily pass the blood-brain barrier (BBB), and may not reflect significant changes
in the CSF. Considering ECT may disrupt the integrity of the BBB these biomarkers
may consequently have relevance to depression phenotyping and may potentially become
predictive of ECT response, though determining the appropriate time to assay them is of
high importance 121.
Serotonin:
Neurotransmitters and their receptors have been studied extensively in depression though, to
a lesser degree, in response to ECT. Serotonin (5-hydroxytryptophan, 5-HT), its receptors
(5-HT1–7), and its transporters have been investigated thoroughly in the pathogenesis of
depression and the use of antidepressants, specifically selective serotonin reuptake inhibitors
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(SSRIs). The theory of low serotonin levels and depression has been popular, though not
clearly substantiated and perhaps even untenable 122.
Serotonin receptor 5-HT1A postsynaptic density was found to be decreased following ECT
in depressed patients 123. Ishihara and colleagues found that 5-HT1A postsynaptic receptors
are sensitized to 5-HT following ECT treatment 124. Widespread reduction of brain 5-HT2
receptors has been observed in depressed patients following ECT, similarly to what has been
observed with antidepressants 125. Interestingly, peripheral platelet 5-HT2 receptor density
has been reported to be increased after ECT in depressed patients 126. Plein and Berk
found that platelet 5-HT2A receptors are desensitized to serotonin following ECT, and they
hypothesized that this decreased sensitivity may be a mechanism of ECT’s antidepressant
action 127. Ishihara and Sasa noted that the 5-HT1A increased sensitivity and perhaps
subsequent decrease in 5-HT2A receptors explain the effects of ECT; they also point out
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that 5-HT3 sensitization may play an important role 124,128. Additionally, they have shown
that ECT increases the release of glutamate and GABA and decrease the receptor function
of noradrenergic and dopaminergic neurons in the locus coeruleus and substantia nigra
respectively, thereby increasing noradrenaline and dopamine. These effects may also be
mediated through the 5-HT3 receptor sensitization.
Magnetic resonance spectroscopy:

Investigators have utilized proton magnetic resonance spectroscopic (1H-MRS) to measure
neurotransmitter levels and their metabolites in the brains of patients with major depression
before and after ECT – and details can be found in recent thorough reviews 129,130. The
results have been heterogeneous, but trends are emerging. One study found no significant
differences in GABA, Glutamate (Glu), glutamine (Gln), choline (Cho) or glutathione
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(GSH) between pre- and post-ECT, though there was a decrease in N-acetylaspartate (NAA)
levels after ECT that correlated with the number of ECT sessions 131. A study in RUL ECT
in patients with TRD showed that Gln concentrations were anti-correlated with their degree
of depression; and after a successful ECT course, Glx (Glu + Gln) increased significantly
to that of age-matched controls 132. Another study found increased levels Glx in depressed
patient that responded to ECT 133. One group found significantly reduced Glx levels in the
patients’ left cingulum at baseline compared to healthy controls that normalized after ECT
134.
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A detailed anatomical 1H-MRS study measured changes in Glx, Creatinine (Cre), Cho and
NAA in the dorsal (dACC) and subgenual anterior cingulate cortex (sgACC) as well as
the bilateral hippocampus in patients receiving ECT for depression. At baseline, patients
showed less Glx in the sgACC, less NAA in the left hippocampus and more Glx in the left
hippocampus compared to controls. After ECT they observed significant increases in Cre in
the dACC and sgACC and decreases in NAA within the dACC and right hippocampus.
Both ECT and symptom improvement were associated with decreased Glx in the left
hippocampus and increased Glx in the sgACC. Lower NAA levels in the dACC at baseline
predicted ECT-induced reductions in depressive symptoms. Changes in Glx in the sgACC
and hippocampus approached that if controls after ECT. This may reflect and imbalance
between underactive cortical and overactive subcortical limbic circuitry in patients with
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depression 135. Severe depression appears to be associated with decreased Glx and therefore
increasing Glx may be important to the mechanism and a potential biomarker of ECT
response 136.
Neuroanatomical changes:
Magnetic resonance imaging (MRI) studies after ECT consistently show volumetric changes
across cortical and subcortical brain regions 137. Anatomical changes correlate with number
of treatments, likely with the strength of the electric field 54, and the placement of electrodes
61. Recent mega-analysis corroborated this by illustrating approximately 5% increase in
the gray matter subfields of the hippocampus and the basolateral nuclei of the amygdala.
Beyond the subcortical mesial temporal lobe structures, volumetric increases have been
observed in the anterior cingulate, postcentral, fusiform gyri, the medial prefrontal cortex,
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supplementary motor cortex, insula, and striatum 138. The Global ECT-MRI Research
Collaboration (GEMRIC) performed a multisite analysis of individual-level subject data
and showed that, except for the cerebellum, the volumetric expansion of all subcortical
regions of interest negatively correlated with ventricle size, indicating that the increases
was likely at the expense of cerebrospinal fluid spaces 137. These mega-analysis findings
support widespread brain changes regardless of known relation to neurocircuits implicated in
depression (i.e., default mode network, cortico-striatal-thalamic, and cortico-hypothalamic
circuits) 139. Large-scale data consistently point to changes in mesial temporal lobe
(e.g., hippocampus and amygdala), far from the ECT electrodes, undergoing the greatest
volumetric changes. Smaller studies did not consistently find volume changes outside of the
mesial temporal lobe where effect sizes seem to be larger, possibly due to the lower sample
sizes and associated reduced statistical power.140. Understanding how these changes support
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response to ECT (therapeutic and iatrogenic), and the neurocircuits involved, remains an
area of exploration 108.
Neurogenesis and Brain-Derived Neurotropic Factor:

Smaller hippocampi have been observed in patients with depression in MRI as well as
post-mortem studies 141,142. Intriguingly, hippocampal size is increased after ECT and may
be dose- and parameter-dependent 143. A recent post-mortem human study of patients that
underwent ECT displayed an increase in doublecortin, a marker of neurogenesis, in the

dentate gyrus 144. Whether adult neurogenesis occurs in humans remains controversial
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145,146. Regardless, it occurs in rodents and is increased by electroconvulsive stimulation
(ECS) 147,148. The neuroplasticity hypothesis is based on work in animal models suggesting
a dose-dependent increase of neurogenesis in the dentate gyrus of the hippocampus after
ECS, the preclinical approach to studying mechanisms of ECT. Additionally, in mice, the
behaviors associated with ECT, were shown to be reliant on neurogenesis 149–151.
There is evidence supporting the role of neurotrophic factors in human affective disorders.
Decreased brain-derived neurotrophic factor (BDNF) levels have been observed in humans
with depression 152. BDNF has received considerable attention in ECS research as well
as depression research broadly 153. BDNF mediates long-term neural and behavioral
plasticity during social stress. In addition, BDNF expression has been implicated as a
potential mediator in depression as decreased levels may atrophy limbic structures, while
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its upregulation plays a role in antidepressant response 154. Karege and colleagues found
that depressed patients had significantly lower serum levels of BDNF, which is increased
in individuals responsive to ketamine 155,156. Additionally, patients with TRD have lower
baseline levels of plasma BDNF which are significantly increased by ECT. Furthermore,
Piccinni and colleagues found that BDNF levels increase at the same time of observed
clinical improvement, suggesting that changes of BDNF levels in response to ECT may
represent a biological, state-dependent marker of remission following ECT 157. This is in
line with the belief that BDNF levels are associated with clinical changes in depression and
that neuroplastic changes may underlie these clinical changes 158.
Gliogenesis and Angiogenesis:

Cell proliferation induced by ECS includes glial (astrocytes, oligodendrocytes, and
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microglia) and endothelial cells in addition to neurons. Wennstrom and colleagues reported
glial cell proliferation in the adult rat hippocampus following ECS, and that inhibition
of gliogenesis by corticosterone administration is mitigated by ECS 159,160. Their group
also notes that glial cell proliferation increases in the rat amygdala following ECS 161.
As corticosterone inhibition of gliogenesis in the rat hippocampus is counteracted by
ECS, the mechanism of ECS’s antidepressant effect may be influenced by glial cell
proliferation. Interestingly, glial cell proliferation after ECS has also been reported in the
rat frontal cortex 162. The increase in number of these glial cells may exert a neuroprotective
effect and counteract the effects of stress, thereby implementing an antidepressant effect.
Additionally, endothelial cell proliferation in response to ECS has been observed in the rat
prefrontal cortex 163, hypothalamic regions including the paraventricular nucleus, supraoptic
nucleus, and ventromedial nucleus in response to ECS 164. Endothelial cell proliferation
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and increased angiogenesis has also been observed in the adult rat hippocampus following
ECS and this increased vascularization may be needed to support hippocampal neurogenesis
165,166. These observed endothelial cell inductions support angiogenesis as a potentially
important component of ECS’s mechanism.
Microglial cells are resident macrophages that enter the brain early in development, and
while they have homeostatic roles in brain function, they can cause neuroinflammation
167.One study showed that mice subjected to chronic social defeat stress and subsequent
ECS had activated hippocampal microglial cells 168, while a study comparing ECS to a
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model of status epilepticus showed no changes in hippocampal CA1 microglial density 169.
Taking these findings together, it is possible that the antidepressant effects of ECS may be
collectively mediated by neuro-, glio-, and angiogenesis, mainly in the hippocampus and
associated brain structures. Overall, given the brain regions involved, the rodent literature
appears to support changes involving the hippocampus, amygdala, hypothalamus, and
frontal cortical regions, though no direct interrogations of the circuits connecting these
regions have been conducted.
Perspective and Conclusion:

ECT remains one of the most effective treatments for several neuropsychiatric conditions,
particularly depression. Understanding the neurobiological mechanisms that underlie its
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effects could provide important opportunities to optimize ECT as well as reveal response
biomarkers and treatment targets to engaged with novel, safe, and efficacious therapeutic
approaches 170. Animal models have revealed molecular and cellular insights into the
effects of ECT despite their translational limitations. There are many caveats to modeling
depression in rodents, including the fact that the evaluation of antidepressant treatment
efficacy is state-dependent 171–174 and cannot easily be reproduced in animals, especially in
rodents. For example, ECT is frequently used in geriatric patients with severe depression,
particularly with psychotic features 175. Rodent studies are almost entirely performed around
12 weeks of age, corresponding to young adult in humans 176,177. Therefore, the findings,
while informative, are not likely translatable to older populations, which have a much
higher risk and rate of cognitive deficits and delayed recovery times 178,179. Additionally,
while recent data suggests multiple brain region changes after ECT, we are just starting to
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understand the neurocircuitry of ECT effects and how to optimize a circuit-based approach,
such as pairing electrode placement with specific and intentional stimulus parameter
selection. For example, a recent study has shown an increase in frontal lobe activity and
the executive control network with potential fMRI resting-state biomarkers that include
the dorsomedial and anterior cingulate cortex after ECT 180–182. Another study indicated
that connectivity between the dorsal prefrontal region and the limbic and default-mode
networks serves as a significant predictor of response to ECT 183. Is the future of ECT
one that uses fMRI-guided electrode placement to optimize antidepressant and cognitive
outcomes? Or perhaps, current-amplitude-titrated or electric-field-informed dosing based on
hippocampal changes? In this context, it may be relevant to disentangle the direct effects of
the ECT electrical stimulus versus the seizure it induces, including drawing parallels with
subconvulsive stimulation methods such as TMS.
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Our understanding of the mechanisms of ECT efficacy and adverse effects on cognition are
far from sufficient. Is it a coincidence that the hippocampus and amygdala are consistently
implicated in the mechanisms of ECT and yet these are the same brain regions responsible
for episodic/autobiographical memory, loss of which is the most concerning side effect
of ECT? In addition to research of fundamental mechanisms, evaluation of mitigation
approaches for optimization of outcomes is paramount. We can consider undertaking
large retrospective studies on concomitant medication and comorbidities so that adjunctive
treatments and screening can be implemented. Additional longitudinal studies looking at

these data are necessary to begin to determine predictors or outcomes and side effects 57.
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As these data emerge, meta- and mega-analyses of ECT responders and non-responders may
help us triage treatments for those at risk of cognitive side effects. Further evaluation into
electrode placement and stimulation parameters is needed to determine clinical approaches
to improving outcomes. Additionally, there may be inflammatory and/or hormonal profiles
that are relatively indicated or contraindicated. While there is no “unified theory” of
ECT mechanism and how it relates to seemingly divergent psychiatric illness from mood
disorders to catatonia, lines of evidence point to the modulation of dysregulated neurocircuit
function in disease states by repeated application of electric fields and/or seizure activity.
This is likely achieved by enhancing the regulation of aberrant neurocircuit activity at
various levels of biological function (e.g. molecular, cellular, anatomical, physiological),
which results in more adaptive circuit dynamics, in turn leading to euthymia. A better
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understanding of neurocircuits dynamics and molecular mechanisms associated with ECT

efficacy and side effects would inform both research on treatment development and clinical
treatment planning and would reduce stigma.
Disclosures:
J. A. Camprodon, MD, MPH, PhD, serves on the scientific advisory board of Hyka Therapeutics and Feelmore
Labs; he has also been a consultant for Neuronetics. A. V. Peterchev has received research funding, travel
support, patent royalties, consulting fees, equity options, equipment loans, hardware donations, and/or patent
application support from Rogue Research, Magstim, MagVenture, Neuronetics, BTL Industries, Advise Connect
Inspire, Soterix, and Ampa. M. D. Kritzer, MD, PhD, receives funding from MGH Training Grant Translational
Neuroscience Training for Clinicians (T32MH112485) and the Harvard Medical School Department of Psychiatry
Dupont Warren Grant. This work was also supported in part by the National Institute of Mental Health of the
National Institutes of Health under award number R01MH091083 (AVP) and R01MH112737 (JAC). The content
is solely the responsibility of the authors and does not necessarily represent the official views of the National
Institutes of Health.
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Published in final edited form as:

Electroconvulsive Therapy: Mechanisms of Action, Clinical

Authors have no additional potential conflicts of interest to disclose.

ECT – an ultrabrief history:

ECT is a rapid-acting antidepressant:

Antidepressant efficacy and cognition:

Importantly, there was no change in cognitive functioning as measured by the Montreal

Electrical stimulus parameters:

Electrodes can also be placed bifrontally across the forehead.

More recently, a novel approach to electrode placement, focal electrically administered

subjective report of cognitive side-effects show varying percentages of patients complaining

There is evidence suggesting GABAergic involvement in ECT’s mechanism of

administration 95–103. Compared to non-responders, ECT responders appear to have higher

an NMDA-receptor agonist, and kynurenic acid (KYNA), an NMDA-receptor antagonist.

Magnetic resonance spectroscopy:

Neurogenesis and Brain-Derived Neurotropic Factor:

underwent ECT displayed an increase in doublecortin, a marker of neurogenesis, in the

145,146. Regardless, it occurs in rodents and is increased by electroconvulsive stimulation

Gliogenesis and Angiogenesis:

important component of ECS’s mechanism.

Perspective and Conclusion:

treatments and screening can be implemented. Additional longitudinal studies looking at

understanding of neurocircuits dynamics and molecular mechanisms associated with ECT

Review. J ECT. 2004. doi:10.1097/00124509-200403000-00004

Neuropharmacol. 2006. doi:10.1097/00002826-200601000-00012

3 different stimulus intensities of ultrabrief stimuli in right unilateral electroconvulsive therapy

BJP.BP.109.066183 [PubMed: 20194546]

comparison with magnetic seizure therapy. J ECT. 2013;29(4):325. doi:10.1097/YCT.10.1097/

Clinical Outcomes. Am J Geriatr Psychiatry. 2021;29(2):166–178. doi:10.1016/j.jagp.2020.06.008

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comparison of electroconvulsive therapy seizure quality, therapeutic efficacy, and cognitive

ELECTROCONVULSIVE THERAPY. Lancet. 1976. doi:10.1016/S0140-6736(76)90895-3

electroconvulsive treatment. J Neural Transm. 1989. doi:10.1007/BF01677423

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in patients with treatment-resistant depression. Neuropsychopharmacology. 2003. doi:10.1038/

pathway in social defeat stress. Science (80- ). 2006;311(February):864–868. doi:10.1126/

rat hippocampus. Biol Psychiatry. 2005. doi:10.1016/j.biopsych.2005.05.023

1411. doi:10.1002/hbm.23928 [PubMed: 29266749]

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