Introduction
Electroconvulsive therapy (ECT) is the oldest biologic treatment in psychiatry still in use and continues to play a crucial role in the management of treatment-resistant depression (TRD). ECT has been shown to be significantly more effective than pharmacotherapy in the management of TRD, with many studies citing remission rates of 50%–60% compared to 10%–40% with further medication adjustments ( ; ; ). Rates of remission are even higher, nearing 80%–90%, in depression with certain features such as catatonia or psychosis ( ).
Beyond immediate symptom reduction, ECT has also been shown to reduce the rate of psychiatric hospitalizations, long-term risk of suicide, and all-cause mortality in the TRD population ( ; ; ). In addition, a study using a cost-effectiveness model projected that ECT decreases the time an individual experiences uncontrolled depression from 50% of life years to 33%–37% over a 4-year period. This study also found ECT to be a cost-effective option after two failed antidepressant trials, making it a reasonable strategy earlier in treatment resistance due to its excellent health-economic advantages ( ).
Despite the known benefits of ECT, the rate of utilization in the TRD population remains low. In a 2017 analysis, only 1.5% of psychiatric inpatients with a severe affective disorder received ECT while hospitalized ( ). In a review of a large insurance claims database of individuals with depression, fewer than 1% ever received ECT ( ). The reasons for the under use of ECT are likely multifactorial including stigma, concerns over adverse side effects, and lack of access. Despite often negative public opinion of ECT, studies have consistently demonstrated its safety and efficacy, even in special populations including children, pregnant women, and geriatric patients. Furthermore, the practice of ECT has evolved since its inception with several advances reducing side effect burden while maintaining efficacy.
ECT basics
ECT involves passing a carefully controlled electrical stimulus through the scalp to induce a generalized seizure. The stimulus is delivered by two electrodes creating an electrical current which causes rapid discharge of nerve impulses and subsequent seizure activity. Two common electrode placements are used. Right unilateral (RUL) involves one electrode placed at the vertex of the head and the other electrode on the right temple ( Fig. 19.1 ). Both electrodes are set on the temples for the bitemporal (BT) placement ( Fig. 19.2 ). RUL ECT is generally associated with less cognitive side effects, while BT ECT appears to have a faster speed of response ( ). The seizure is self-limited and usually lasts between 20 and 60 s. ECT is done under general anesthesia including the use of muscle relaxants such as succinylcholine that prevents any physical convulsion from occurring. Seizure duration and morphology is monitored by electroencephalography (EEG). An acute ECT course is typically 9–15 treatments occurring 2–3 times per week with significant variability depending on symptom response and underlying diagnoses. Response is typically not seen until treatments 6–8 but can also vary widely. Once a patient reaches remission or a response plateau, he or she may be transitioned to a taper or maintenance ECT if relapse risk is considered high for an individual.
History and development
In the early 1900s, there was increasing interest in the use of “physical therapies” for the treatment of neuropsychiatric illness after malarial fever was shown to successfully treat neurosyphilis ( ). This interest spread to psychiatric disease where physicians explored strategies to directly treat the brain rather than relying on psychotherapy only. This prompted the development of convulsive therapies by Dr. Ladislas von Meduna in 1934 in Budapest, Hungary. Dr. Meduna hypothesized that there was an “antagonism” between epilepsy and schizophrenia and therefore started to use convulsive therapy to treat psychosis ( ). He initially used camphor and then later pentylenetetrazole to chemically induce convulsions with noticeable reduction in psychotic symptoms ( ). As a result of his success, convulsive treatment units sprang up all over Europe and the United States ( ).
Chemically induced convulsive therapy was quickly taken over by ECT after Dr. Ugo Cerletti showed greater success and consistency inducing convulsions by applying electricity directly to the brain ( ). Since ECT showed good efficacy in reducing psychotic symptoms in schizophrenia patients, its use quickly spread to the treatment of other affective disorders including depression ( ). Due to positive results, ECT became the standard treatment for individuals hospitalized with depression by the 1950s ( ).
As ECT became more widely used, a number of important advances were made. “Modified ECT” was developed where general anesthetics and then muscle relaxants were used (initially curare in 1940 and then succinylcholine in 1952) to sedate patients and minimize complications of physical seizures ( ). Unilateral ECT use began in 1949 to reduce cognitive side effects since it avoids directly stimulating the dominant hemisphere in the majority of individuals therefore reducing the impact on verbal memory ( ). Brief pulse ECT use began shortly thereafter ( ). Brief pulse ECT is a pulsatile wave-form and is more efficient in stimulating neurons and inducing seizures than sinusoidal stimulation of older machines which is associated with more prominent memory side effects. Brief pulse devices are the standard of care in modern ECT practice.
Despite its efficacy and widespread use, ECT almost vanished from psychiatric practice in the 1960s. The rapid shift in reduced ECT use arose from a change in public opinion about the treatment due to the rise of the antipsychiatry movement ( ). Much of the public’s outrage regarding ECT came from the impact of Ken Kesey’s book “One Flew Over the Cuckoo’s Nest” which was published in 1962 and later turned into a widely popular film in 1975 ( ).
ECT use remained lower until the 1980s when a gradual resurgence began. One of the biggest turning points was the summary of the NIH Consensus Conference on Electroconvulsive Therapy published in JAMA in October of 1985 that noted, “Not a single controlled study has shown another form of treatment to be superior to ECT in the short-term management of severe depression.” Since then, ECT has been accepted in psychiatry as the gold standard for treatment of refractory mood disorders and its use throughout the United States has been slowly increasing ( ).
Mechanisms of action
The mechanisms of action of ECT are not fully understood and there is no unifying theory on how ECT exerts its powerful antidepressant effects. However, over the years a number of theories have been investigated. These have included ECT’s effects on monoamines, seizure threshold/anticonvulsant action, the neuroendocrine system, and molecular pathways associated with neurogenesis such as increased brain-derived neurotrophic factor (BDNF). Other recent functional and structural neuroimaging studies have also produced interesting findings.
The monoamine neurotransmitter system has long been a focus of neurobiology studies in ECT, and many studies have sought to discover changes in norepinephrine, serotonin, and dopamine metabolites in bodily fluids including cerebrospinal fluid, urine, or blood as a result of treatment ( ). As an example of this work, showed that the CSF monoamine metabolites of 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid were both significantly elevated following ECT.
During a course of ECT, it is well known that seizure thresholds often rise and seizure durations shorten. This led to the anticonvulsant theory of ECT and the search for biologic correlates such as changes in gamma-aminobutyric acid (GABA) in animal models and ictal and postictal EEG findings which appear to indicate brain inhibitory processes are in play ( ). Despite the prevalent anticonvulsant effects of ECT, there is no consistent data to suggest a clear association between clinical outcomes in depression and increases in seizure threshold ( ; ).
ECT induces an array of acute neuroendocrine effects including release of adrenocorticotropic hormone, prolactin, and cortisol. Hypothalamic-pituitary-adrenal (HPA) dysregulation became a primary focus as a possible marker for melancholic or psychotic depression. Past studies show that dexamethasone suppression test (DST) abnormalities are corrected with ECT, but are not strongly connected to depression improvement ( ; ).
Modern concepts in ECT mechanisms have also focused on neuroplasticity and neurogenesis. Brain-derived neurotrophic factor (BDNF), a widely distributed nervous system neurotrophic protein, has roles in neurotransmitter modulation, neural genesis, and neuronal plasticity. Animal and human ECT studies have been conducted for over 20 years investigating BDNF and its effects. In animal models, it has been shown that neurogenesis, synaptogenesis, and glial proliferation in the hippocampus occur with electroconvulsive seizures (ECS) ( ). In humans, a metaanalysis of nine ECT studies in depression found that BDNF serum levels were increased after ECT. These findings suggest that BDNF may be a potential biomarker of response in patients receiving ECT for depression.
Since it is not possible to readily examine the microscopic, molecular, or neuroplastic changes ECT has on the human brain, tools such as high-resolution magnetic resonance imaging (MRI) or functional MRI have helped bridge the knowledge gap by exploring possible structural and connectivity changes. In recent years, structural studies have focused on areas of the medial temporal lobe such as the hippocampus and amygdala which generally show volume increases with ECT. However, pooled data from the Global ECT-Magnetic Resonance Imaging Research Collaboration (GEMRIC) have not correlated these changes to positive ECT outcomes ( ). However, found that ECT response may be associated to structural changes in other areas in cortical, striatal, and lateral prefrontal areas also implicated in depression. Functional connectivity techniques and analyses are complex. In depression, there is a “hyperconnectivity” concept where mood networks exhibit increased resting state connectivity. This hyperconnectivity may be a biomarker for depression and may also be reduced with treatments. An early small study significantly showed such a reduction in frontal connectivity after ECT ( ). Other recent studies have examined hippocampal connectivity in ECT showing varied changes associated with ECT response ( ; ). Despite the complexities of ECT’s neurophysiologic effects, advancements continue to be made on many fronts to foster our understanding of how ECT may work, but from past and recent research, ECT appears to likely have a multitude of potential mechanisms.
Clinical studies
General Efficacy Profile : ECT is not only one of the oldest biologic treatment in psychiatry, but it is also the most effective treatment for severe mood disorders, treatment refractory schizophrenia, catatonia, and neuroleptic malignant syndrome (NMS). Due to the speed of response with ECT which is typically 2–4 weeks compared to 4–6 weeks at the earliest with medications, ECT is the treatment of choice when rapid improvement is needed due to life threatening psychiatric symptoms ( ). ECT has also been deemed a safe treatment as reflected by the recent Federal Drug Administration’s (FDA) reclassification ECT devices from Class III to the lower risk category Class II ( ).
Details of ECT’s effectiveness in treating unipolar and bipolar depression will be discussed at length below, but ECT has shown similar, if not higher, response rates, in treating mania, catatonia, and psychosis. ECT is an important treatment strategy listed in the national and international guidelines for the treatment of mania, especially in life threatening or treatment refractory cases ( ; ). ECT has similarly demonstrated effectiveness at rapidly reducing catatonic symptoms regardless of underlying etiology and is the treatment of choice in patients whose catatonia does not fully respond to benzodiazepines ( ; ; ). While ECT is less commonly used in the United States for schizophrenia and schizoaffective disorders, it has been shown to be effective at reducing psychotic symptoms that do not respond to antipsychotics ( ). Recent studies suggest synergistic, antipsychotic effects when ECT is combined with Clozaril, producing 50% response rates in patients who did not respond to clozapine alone ( ).
General Efficacy in Treatment-Resistant Depression: Clinical studies have consistently shown the efficacy of ECT in TRD. While few true recent randomized control trials exist due to excellent efficacy of ECT in older trials and the inherent ethical issues of administering general anesthesia with sham ECT, data from several large observational studies for the treatment of depression highlight extremely positive results. One such large study led by the Columbia University Consortium was published in 2001. The goal of the study was to examine relapse rates among ECT remitters maintained on different psychotropic medication regimens versus placebo following an acute treatment course. Two hundred and ninety participants with severe depression completed an acute bilateral or right unilateral ECT course. At the end of the treatment course, 55% of subjects had reached remission defined as a 60% reduction in Hamilton Depression (HAM-D) scale scores as well as a total HAM-D of less than or equal to 10 ( ).
Another large ECT study conducted by the Consortium for Research on ECT (CORE) assessed acute depression outcomes in a first phase followed by a second phase of continued medications vs continued ECT. During the first phase, the study included 253 participants with an HAMD score of ≥ 21. The participants received bitemporal ECT three times weekly with repeated HAMD ratings. By the end of the study, remission (defined by achieving HAMD scores less than or equal to 10 on 2 consecutive assessments) was achieved in 75% of the subjects. Of note, remission was achieved relatively early in the treatment course by 34% of subjects before their 6th treatment, and 65% reached remission at or before their 10th ECT ( ).
In recent decades, ECT studies have centered around determining the efficacy and side effect profiles of various electrode placements. Many studies comparing right unilateral (RUL) vs bitemporal (BT) generally show that RUL is associated with less anterograde and retrograde amnesia compared to BT placement ( ; ; ; ; ; ). However, in order to maintain similar efficacy to BT ECT, the electrical dose delivered for RUL ECT needs to be significantly above an individual’s seizure threshold. BT ECT is very effective at doses approximately two times above seizure threshold while RUL ECT is most effective at five to six times above seizure threshold. This was elucidated by comparing the efficacy of RUL ECT at three dosage levels above threshold (1.5 times threshold- low-dosage RUL , 2.5 times threshold- moderate-dosage RUL , and 6 times threshold- high dosage RUL ) versus BT ECT at 1.5 times threshold. Ultimately, high dose RUL and BT ECT were found to have similar remission rates (65%), but the remission rates for low and moderate dosage RUL ECT were only 30% and 35%, respectively. Of note, the study did find that BT ECT resulted in greater acute cognitive side effects than any dosage of unilateral ECT and that retrograde memory difficulties persisted even 2 months after ECT with BT ECT.
One of the other important ECT advancements has been modifications to stimulus parameters, specifically pulse width. The electrical stimulus delivered during an ECT treatment is composed of brief rectangular square-wave pulses which historically ranged from 0.5 to 2 ms in width. As the optimal pulse width to induce neuronal depolarization is estimated to be 0.1–0.2 ms, the use of narrower pulse widths was proposed as a more efficient way of inducing a seizure. Since less electricity is delivered to the neuron when depolarized, it was hypothesized that a smaller pulse width would cause less neuronal irritation and therefore fewer cognitive side effects ( ). There has now been a shift from brief pulse (0.5–2.0 ms) to ultrabrief pulse ECT (< 0.5 ms) especially with RUL ECT. While studies comparing the effectiveness of the two vary, ultrabrief pulse ECT has been shown to have fewer cognitive side effects in several domains ( ).
Direct comparison to other treatments
ECT versus antidepressants
ECT has been compared to pharmacotherapy in TRD patients with ECT consistently showing superior efficacy. In a naturalistic study of 1495 patients admitted over a 12-year period to an inpatient unit, Black et al. found that a significantly greater number of patients receiving ECT were considered to have “marked improvement” (70%) by provider report at the time of discharge compared to those that received an adequate antidepressant trial (48%) ( ). Several metaanalyses have shown similar results. A metaanalysis by included 16 randomized control trials comparing ECT to other forms of treatment for depression including various antidepressants (specifically SSRIs, SNRIs, TCAs). When response rates from with antidepressants were compared to ECT, ECT showed a nearly one standard deviation superiority in efficacy to other treatments ( ). Similar results were found in a 2003 metaanalysis conducted by the UK ECT Group in 2003 which found that ECT was significantly more effective than pharmacotherapy (18 trials, 1144 participants, SES − 0·80, 95% CI, − 1·29 to − 0·29) ( ).
ECT versus transcranial magnetic stimulation (TMS)
TMS is a focal, noninvasive brain stimulation procedure. TMS uses magnetic fields to create pulses that enter the cortex and either excite or inhibit specific regions of the brain. In the 1990s, it was found that repeat stimulation of the left prefrontal cortex produces antidepressant effects ( ). The FDA subsequently approved TMS in 2008 for the treatment of adult patients with major depressive disorder who had failed previous antidepressant medication at or above minimal effective dose. Several large, randomized control trials on the effectiveness of TMS exist with response rates ranging from 40% to 60% and remission rates ranging from 30% to 40% ( ; ; ; ).
Based on previously observed response and remission rates alone, ECT demonstrates greater effectiveness in treatment-resistant depression. Studies have also been done directly comparing response rates of ECT versus TMS with similar results ( ; ). published a metaanalysis in 2013 which included nine high quality randomized control trials that compared TMS and ECT in 395 patients with treatment-resistant depression. While ECT ( df : 1; F : 32.72; P < .0001) and TMS ( df : 1; F : 6.85; P < .012) were found to be effective in reducing depressive symptoms, ECT was superior to TMS ( df : 1; F : 6.81; P < .012). Pretreatment mean HAM-D scores for the ECT and TMS groups were 27 and 26 respectively. With ECT, mean posttreatment HAM-D scores fell to 11 while the mean score with TMS fell only to 18. It is important to note though, that while ECT has shown superior efficacy, studies do suggest that TMS is better tolerated with fewer side effects ( ; ; ).
ECT versus ketamine
Ketamine is primarily a glutamatergic n -methyl- d -aspartate receptor antagonist that has an increasing role in the management of TRD after it was found to have rapid antidepressant effects when administered intravenously at subanesthetic doses ( ). Several randomized, placebo controlled trials have since been done showing the antidepressant effects in unipolar and bipolar depressed patients ( ; ; ). However, results have consistently shown that while ketamine produces an antidepressant effect quickly in hours after a single infusion, the effect is time limited and dissipates after several days ( ; ; ).
A large, multisite randomized control trial comparing the effectiveness of ketamine versus ECT called the “electroconvulsive therapy (ECT) vs. Ketamine in patients with Treatment-resistant Depression: The ELEKT-D study protocol” is currently underway but some preliminary data has been released. The primary outcomes of the study are HAM-D scores as well as suicidality. Twenty-six adult subjects with depression received 0.5 mg/kg ketamine infusion once, 36 subjects received 4 ketamine infusions over 2 weeks, and 47 subjects received ECT 3 times per week over 3 weeks. Suicidality and HAM-D scores in all groups decreased but were lower in both ketamine groups. However, 5 weeks after the last ketamine infusion, suicidality and HAM-D scores in the ketamine groups began to increase while scores remained stable in the ECT group even 3 months after the last treatment. This suggests that ketamine may have a more immediate antidepressant effects compared to ECT but the durability of ECT response may be more sustained. It is important to note though that subjects in the ECT arm only received nine treatments which is less than a typical index course, potentially limiting effectiveness. Further results are therefore needed to more definitively understand the different effectiveness of ECT versus ketamine ( ).
Bipolar depression
ECT is effective in treating bipolar disorder across the spectrum of symptoms including mania, mixed state episodes, depression, and bipolar illness with catatonia features. The study of bipolar depression is of particular interest since differences in response rates to antidepressant medications for bipolar depression and unipolar depression exists. Studies have historically shown limited benefit of antidepressants medications for bipolar depression, thus potentially inducing a more treatment-resistant form of depression. However, a 2012 metaanalysis of 6 prospective and retrospective studies of ECT in unipolar and bipolar depression with a strict definition of response (a final HAMD score of < 10 which is consistent with mission level) response noted similar rates for unipolar (51.5%) and bipolar depression (53.2%) ( ). In a large naturalistic/retrospective study of over 500 bipolar ECT patients treated between 2006 and 2011, found response rates of 75% for mania, 73% for mixed state, and 81% for catatonia features. In bipolar depression specifically, the response rate was 68%. Another retrospective study of a geriatric group of 34 bipolar depressed subjects, found that the majority of subjects experienced remission or response (85%) on the Clinical Global Impression (CGI) scale with good cognitive tolerability of both right unilateral and bilateral ECT. Finally, a recent metaanalysis by identified 19 unipolar and bipolar depression ECT studies that included 1803 unipolar and 553 bipolar depression subjects. Important findings of this study include a slightly higher statistically significant rate of response for bipolar depression (77%) vs unipolar depression (74%), similar remission rates of 52% for each group, and statistically significantly fewer treatments were required for bipolar depression subjects to achieve response. Overall, the data in treating bipolar depression with ECT suggests that outcomes are at least on par with ECT outcomes in unipolar depression with substantial response and remission rates and the possibility that ECT may induce a somewhat speedier recovery for bipolar depression patients.
Depression with psychotic features
Depressed individuals with cooccurring psychotic or delusional symptoms have been shown to respond more rapidly to ECT with higher remission rates compared to their nonpsychotically depressed counterparts. This has been demonstrated in numerous studies including a subsequent analysis of data from the CORE study. Seventy-seven of the 253 study participants met criteria for MDD with psychotic features and remission rate was 96% in this cohort with faster response times ( ). Similar outcomes were documented in a 2019 cohort study conducted in a psychiatric hospital in Belgium seeking ECT response predictors. Seventy-three subjects with depression were enrolled. Thirty-three had psychotic depression as diagnosed by the Psychotic Depression Assessment Score (PDAS). Clinical outcomes were tracked while the subjects received ultra-brief pulse right unilateral, bifrontal, or bitemporal ECT two times per week. At the conclusion of the study, 81% of the cohort had a significant response with 63.9% in remission defined by Montgomery Asberg Depression Rating Scale (MADRS) ≤ 10. The presence of psychotic symptoms as indicated by a higher PDAS score consistently predicted remission ( ).
Overall, the degree and speed of improvement in psychotic depression is prominently higher and faster with ECT compared to psychotropic medications. Studies cite responses rates (defined as a 50% reduction in symptoms on HAM-D) with antidepressant monotherapy around 20%–40% after 5–6 weeks of treatment. Combination antidepressant and antipsychotic therapy is higher, with rates ranging from 60% to 80%, also after several weeks of treatment. In comparison, ECT results in 60%–80% of individuals achieving full remission with early response seen as early as 3–5 treatments ( ; ). Since individuals with psychotic depression tend to be severely ill with significant mood disturbance, suicidal thinking, neurovegetative symptoms, weight loss, and failure to thrive, the rapid response provided by ECT can be of significant benefit over medications especially when symptoms are life threatening.
Suicidality
Suicide rates in patients with mood disorders are estimated at 4%–20%, and 50%–70% of persons who complete suicide do so when depressed ( ; ). ECT has been shown to rapidly reduce those rates in several studies and should therefore be considered as an effective treatment for acute suicidality in depressed patients.
studied factors related to suicide attempts in 1206 severely depressed patients. They found that ECT significantly reduced the frequency of suicide attempts compared to subjects treated with psychotropic medications. Twenty percent (23/113) of subjects who received antidepressant medications attempted suicide versus 8% (11/133) of those receiving ECT ( χ 2 = 7.49, P < 0.01). The incidence dropped even further to 2% (1/62) in subjects who received ECT as well as pharmacotherapy ( χ 2 = 11.04, P < 0.001) ( ).
In a multicenter National Institute of Mental Health funded study, looked at the effect three times per week bitemporal ECT had on suicidal thoughts and acts in unipolar depressed subjects. Suicidal intent was assessed at baseline and before each ECT on item 3 of the HAMD. Of the 444 subjects in the study, 29.5% reported suicidal thoughts and acts at baseline. After 1 week of ECT, 38.2% of these subjects reported no suicidal intent which further increased to 61.1% of subjects after six ECT. By the end of the ECT series, 80.9% had no suicidal intent ( ).
However, despite data suggesting ECT reduces suicidal ideation and suicide attempts, death by suicide can occur in the time frame around an ECT course. described data from the Danish Health and Medicines Authority on all-cause mortality 30 days after ECT. Between 2000 and 2007, The Danish National Patient Registry tallied a total of 99,728 ECT with 78 deaths occurring in the studied period. While this report was primarily focused on determining the procedural mortality of ECT, 20 of the 78 deaths were by suicide second to cardiopulmonary disease. Since the population receiving ECT is typically the most severely depressed and may be at higher risk for suicide, assessments for suicidal ideation should be done before, during, and after ECT ( ).
Special populations
Children and adolescents
ECT remains an infrequently used treatment for children and adolescents. Little is known about the incidence of ECT use in children and adolescents within the United States, but studies in other countries suggest < 1% of the patients receiving ECT are under the age of 18 ( ). Given its limited use, data on the effectiveness of ECT for treatment refractory depression in children and adolescents is similarly limited, and there are no current clinical trials of moderate to large sample sizes. Much of the understanding and practice of ECT for adolescents is therefore based on studies in adults ( ). However, smaller studies and metaanalyses do exist.
While not limited to mood disorders, reviewed all publications from 1947 to 1990 where patients between the ages of 5 and 18 received ECT. They found a reported positive response in all publications except for one which was a small case series involving four patients ( ). Another review, conducted by , included 396 individuals all under the age of 18 who received ECT for a treatment-resistant mood disorder. Since few of the included studies used standardized outcome measures, the authors assessed marked improvement by clinical descriptions indicating subjects were functioning near or at their premorbid baseline following ECT. By the end of ECT, 53% of subjects demonstrated marked improvement of full remission of symptoms ( ). studied 54 adolescents with refractory mood disorders who received their first course of ECT before the age of 18. The mean number of treatments received during the index course was 13.7 ± 6.3 with a 52.8% response rate (defined by a Clinical Global Impression Score of ≤ 2) with 15.1% achieving remission (defined by a CGI score = 1). The study also found a reduction in suicidal ideation and self-injurious behaviors following completion of the treatment course ( ).
In the available literature, practice guidelines for the use of ECT in adolescents have been published ( ). This paper recommends that ECT be considered in adolescents when the following three criteria have been met: (1) A diagnosis of a severe and persistent mood disorder has been made such as major depression with or without psychotic features or mania; (2) The patient’s symptoms include severe suicidality, refusal to eat or drink, or are severe or life threatening; and (3) There has been a lack of treatment response to at least two adequate trials of appropriate psychopharmacologic agents accompanied by any other indicated treatment modalities. However, ECT can be tried earlier in the treatment course if adequate medication trials are not possible because of a patient’s inability to tolerate psychopharmacologic agents or waiting for a response would be life threatening.
Pregnant women
Depression is a common disorder during pregnancy with studies citing rates from 15% to 29% ( ). In cases where symptoms are severe or life threatening such as high suicide risk, catatonia, medication-resistant illness, psychotic agitation, or severe physical decline, ECT should be considered a safe and effective treatment option in pregnancy. In fact, both the American Psychiatric Association and the American College of Obstetricians and Gynecologists have made statements endorsing ECT for the treatment of refractory or life threatening depression during pregnancy.
The efficacy and safety of ECT in pregnancy has been well documented over the past 50 years. Four systematic reviews of the use of ECT in pregnancy exist ( ; ; ; ) as well as two metaanalyses ( ; ). Results from these studies suggest that the speed of response and response rate for pregnant women is similar to any other individual receiving ECT ( ). While the risk of adverse events is also similar, there are additional concerns that need to be considered when ECT is performed during pregnancy.
Due to physiologic changes, pregnant patients are at increased risk of aspiration and aortocaval compression which can be addressed by pretreatment with sodium citrate and elevation of the right hip. Anesthesiologists may also prefer to intubate patients during the brief ECT procedure to prevent aspiration especially in mid or late pregnancy. There are also potential risks to the pregnancy itself. The most commonly cited issue is premature contractions and/or preterm labor which are more frequently seen in the second and third trimesters ( ; ). However, the frequency was still relatively low (3.5%) ( ; ) and not clearly related to ECT ( ). Other adverse events such as vaginal bleeding were reported at low rates ( ; ), typically in the first trimester, and the vast majority of cases spontaneously resolved without any interventions. No significant difference was noted in the miscarriage rate in women receiving ECT compared to the general population.
In terms of risk to the fetus, the most commonly noted adverse event during ECT was fetal heart rate variability or arrhythmia ( ). In a review of 339 cases of pregnant women receiving ECT, Anderson and Reti found that there were only 11 fetal complications including 2 deaths, neither of which was directly attributed to ECT ( ). Furthermore, ECT during pregnancy has not been associated with congenital anomalies, either morphological or behavioral ( ).
Geriatric
ECT is often an important part of resistant depression treatment in geriatric patients. Similar to other age groups, ECT treats severe depression, mania, psychosis and catatonia in older adults, and studies have consistently demonstrated its efficacy and safety. In fact, older age has repeatedly been shown to be a predictor of increased likelihood of response as well as fast speed of response ( ; ; ).
Numerous studies have examined the effectiveness of ECT in the treatment of geriatric depression. found that geriatric patients receiving ECT had remission rates of 63.8% compared to 33.3% with an antidepressant trial ( ). As mentioned above, rates of response and remission in geriatric patients are higher compared to mixed age groups with studies citing 60%–80% of patients reaching full remission at the end of a treatment course ( ; ). One of the most recent and comprehensive studies of ECT response in geriatric depressed patients, the Prolonging Remission In Depressed Elderly (PRIDE) study, was a multiphase protocol with an acute ECT course followed by a maintenance phase to monitor for continued response. The acute phase of the study included 240 patients above 60 years of age diagnosed with unipolar depression. All patients received right unilateral, ultrabrief pulse ECT three times per week in combination with venlafaxine. Sixty-two percent of the patients reached remission (defined as a HAM-D score ≤ 10 on two consecutive ratings that did not increase > 3 points on the second consecutive rating or it remained ≤ 6), while 70% responded (defined by having at least a 50% reduction in score from baseline to last assessment). The mean number of treatments it took to achieve remission was only 7.3 ( ). Despite the excellent rates of remission for ECT, providers are often hesitant to refer geriatric patients due to concerns about cognitive side effects with treatment. However, study results vary on the severity and duration of these effects with some studies showing minimal to no effect at all. In fact, global cognitive function remained relatively stable during the ECT treatment course in the PRIDE study, with no significant difference between baseline and post-ECT mean Mini-Mental Status Exam (MMSE) scores (27.5 [SD = 2.4] and 27.6 [SD = 2.6], respectively). Since risk factors for increased anterograde and retrograde amnesia with ECT include increased age, underlying brain disease, and limited cognition at baseline, geriatric patients have been shown to experience more memory side effects with ECT ( ). However, these effects resolve in the vast majority of elderly patients, and ECT has not been shown to cause long term changes in cognition.
Maintenance ECT (M-ECT)
ECT is a treatment that is usually discontinued after a successful acute course, and then maintenance medications are initiated. However, it has been known for years that a substantial risk of relapse with rates of 50% or higher within 6–12 months after ECT exists ( ). In the ECT literature, there are two terms applied to ECT after an initial or index course. Continuation ECT refers to less frequent ECT (every week to 4 weeks) tapered within 6 months postacute ECT and is used to prevent a rapid relapse. Maintenance ECT is defined as ECT administered at intervals beyond 6 months from the acute ECT course and is used to maintain a response and prevent recurrence of a new episode. Most practitioners tend to use maintenance ECT (M-ECT) to generally mean any ECT administered postacute ECT, and this term will be used for the purpose of this overview.
Descriptions of M-ECT have been detailed in the literature for a number of psychiatric disorders since the late 1940s ( ; ; ). The bulk of past research of M-ECT for depression comes from naturalistic, case controlled matched, and retrospective studies. Outcomes typically have focused on a duration to relapse (6 months to 2 years) and rehospitalization prevention. A number of studies have also compared these outcomes between M-ECT and maintenance medication groups after ECT. The most common findings include reduced time spent in the hospital, decreased rehospitalizations, and reduced relapses when compared to maintenance medications ( ; ; ; ; ).
With the need for more systematic study of M-ECT, the Consortium for Research in ECT (CORE) in the early 2000s embarked on a large four site study of M-ECT ( n = 89) or maintenance medication treatment ( n = 95) with nortriptyline and lithium augmentation after all subjects achieved remission with acute ECT. Subjects were monitored for relapse over 6 months. Both M-ECT and maintenance medications had similar relapse rates of approximately 33% ( ). Although no statistical difference was found, both treatment groups resulted in reduced relapse rates that were lower than the commonly seen 50% or higher relapse rates in other studies. Other limitations of this study that may have led to M-ECT being no better than maintenance medications included a rigid quick taper of ECT and M-ECT subjects were medication free during the study period which is unlike routine clinical practice. There have been only a few other prospective studies of M-ECT with concomitant medications vs maintenance medications alone in the past decade, but a metaanalysis of the available data from 5 studies with 436 subjects confirms that M-ECT plus medication therapy has superior benefit in reducing risk of relapse for 1 year after remission from acute ECT. However, with only a small number of randomized trials, there remains a need for more rigorous prospective study of M-ECT ( ).
In real-world clinical practice, M-ECT is commonly employed while patients are also on antidepressant medications. The goal is to induce remission or a plateaued response acutely followed by a taper of ECT. Patients should be monitored closely by tracking depression symptoms with a thorough assessment including the use of well validated depression scales, when possible. Frequency of ECT can be adjusted based on improvement or relapsing symptoms. Patients who are prone to rapid relapse during M-ECT can often be “recaptured” with increasing ECT frequency temporarily to 2–3 times per week while medications and other treatments are maximized. For some patients with extremely resistant depression, they may respond well to ECT acutely, but relapse when M-ECT is tapered or discontinued. In these situations, M-ECT can be implemented for years at frequencies ranging from every 2 to 12 weeks without causing cumulative cognitive deficits ( ). When used in conjunction with medications and other treatments, M-ECT is an important treatment strategy in managing resistant depression and can be individualized with flexible schedules ranging from short tapers to even longer-term less frequent ECT when needed to prevent relapse and maintain wellness.
Safety and adverse effects of ECT
Mortality and safety
As with any procedure or surgery under general anesthesia, ECT carries some risk of medical morbidity and mortality. Although each ECT is a very brief procedure (10–20 min), physiologically a seizure is generated, and transient effects on the cardiovascular system can occur including elevated blood pressure and tachycardia. ECT patients typically undergo a thorough medical history and physical exam to assess medical comorbidities and risks. Overall, for all procedures under anesthesia, the commonly understood mortality rate is 3.3–3.7 deaths per 100,000 inductions ( ; ). Many studies over 35 years show similar or more favorable mortality rates with ECT. described a mortality rate of 2 deaths per 100,000 from data in California from 1977 to 1983. Since 1993, the state of Texas requires quarterly reports on deaths within 14 days of ECT whether mortality is directly associated with ECT or not. Recently, a 16-year review of the Texas data encompassing 166,711 ECT from 1998 to 2013 found a death rate of 2.4 deaths per 100,000 ECT at 1 day after ECT ( ). In a similarly large study of ECT data in Ontario, Canada, death rate on the day of ECT was 4 deaths per 100,000 ECT ( ). Finally, a large analysis of 15 studies with data from 32 countries including 766,180 ECT sessions generated a calculated death rate of 2.1 deaths per 100,000 ECT ( ). Some conditions may elevate risk, and these include intracranial space-occupying lesions or hemorrhage, recent myocardial infraction, or high anesthesia risk score per American Society of Anesthesiologists class 4 or 5. However, with proper medical care and the overall low mortality rate data, the risk of mortality with ECT remains low, and the indicates that ECT has no absolute contraindications.
Cognition
The study of memory side effects in ECT is complex because of the varied assessment instruments and study designs over the years. In addition, modern ECT employs lower energy brief electrical pulses and is different from the high energy sinusoidal waveform machines from decades past. It is also generally agreed that right unilateral electrode placement is associated with less cognitive side effects ( ). Described here are the three major forms of memory issues of posttreatment/postictal confusion, retrograde amnesia, and anterograde amnesia along with a discussion of the importance of monitoring memory during ECT and strategies to minimize cognitive issues.
Postictal confusion
This occurs in the immediate postoperative period during recovery from anesthesia. Patients may have transient disorientation that commonly resolves within a few minutes to a few hours. A review of the literature suggests that postictal confusion is associated with catatonic features, cerebrovascular disease, Parkinson’s disease, dementia, bitemporal electrode placement, high stimulus intensity, or longer seizures ( ). Occasionally, patients may experience more severe delirium with restlessness or agitation requiring an intervention such intravenous benzodiazepine or other medication to calm the patient and provide a smoother recovery from ECT and anesthesia medications.
Retrograde amnesia
Retrograde amnesia is the difficulty recalling information acquired before beginning ECT. This is generally described as spotty and tends to be more prominent in the weeks to the few months prior to ECT. Memories for public events appear more sensitive than personal information ( ). There is the risk of persistence of retrograde amnesia and may occur more with older sine waveform stimulation or bitemporal ECT ( ).
Anterograde amnesia
Anterograde amnesia is the difficulty retaining newly learned information. This occurs during the ECT course, but typically clears after ECT is discontinued in a matter of days to a few weeks. Unlike the risk of some persistent retrograde amnesia complaints, anterograde amnesia has not been shown to be permanent in many studies ( ). In fact, a number of studies have shown cognitive improvements, compared to baseline measures pre-ECT, weeks to months after a successful ECT course once depression has resolved and anterograde amnesia side effects have dissipated ( ).
Monitoring cognition and strategies to minimize side effects
Similar to tracking depression symptoms during treatment over time, clinicians should monitor cognitive side effects during ECT to detect changes early and make clinical adjustments to minimize side effects ( ; ). Brief assessment tools are often used prior to ECT and at regular intervals during the ECT course. The most common instruments are the Mini-Mental Status Exam (MMSE) or the MoCA Test ( ; ). However, these are screening tests for cognitive problems that do not capture all memory domains affected by ECT. Recently, the Electroconvulsive therapy Cognitive Assessment (ECCA) tool is a newer brief scale that is more sensitive to ECT-induced global cognitive function difficulties and includes measures of retrograde memory/autobiographical memory and subjective assessments of both patient and a family member ( ). Strategies to minimize memory side effects at the start of ECT or if memory side effects develop include a number of ECT techniques. Using or switching to right unilateral ECT from bitemporal ECT reduces risk of memory side effects. Electrical dosing is now often titrated with a low level of energy to generate the initial seizure. Over the past two decades, the duration of the brief pulse waveform has shortened to more efficiently excite neurons to produce a seizure. Finally, ECT frequency in the United States usually begins three times per week, but reducing ECT frequency to twice a week can reduce memory side effects without compromising the antidepressant benefits ( ).
Other common side effects
One of the most common side effects of ECT is the immediate postoperative headache. It is often described as throbbing or migraine-like. The etiology is not well understood but may be due to direct muscle stimulation of the head during the brief ECT stimulation or may have a vascular origin. The incidence of headache is estimated to be in the range of 33% or higher. Treatment is symptomatic or prophylactic with nonsteroidal antiinflammatory drugs (NSAIDs) or migraine medications such as triptans ( ). Nausea following ECT can be managed symptomatically as well with medications before or after ECT. Muscle aches following treatment can arise from sensitivity to the fasciculations during depolarizing muscle relaxation from succinylcholine and is also managed with pain medications commonly.
Future directions
Future directions for ECT and related seizure therapies include a focus on ways to induce seizures that maintain effectiveness while minimizing side effects. One emerging technique is Magnetic Seizure Therapy (MST) where seizures are induced through magnetic pulses covered elsewhere in this book. Only the superficial cortex is stimulated during seizure induction but a generalized seizure does then occur ( ). Studies on another emerging technique is focal electrically administered seizure therapy (FEAST) which uses unidirectional rather than bidirectional current as well as a novel, asymmetric node placement to improve the efficiency of seizure induction ( ). Studies on the effectiveness of FEAST are also limited with only a few open label studies. However, results thus far show similar effectiveness to ECT with limited to no cognitive side effects ( ).
The pursuit of biomarkers such as the genetics of depression may also shed light on the neurobiology of depression. One such study underway is the Genomics of ECT International Consortium (GenECT-ic). This project is not only established to investigate the genomic underpinnings of resistant depression with an aim of assessing 30,000 patients referred for ECT from around the world, but also to study the genetic contribution of ECT treatment response. This study is underway and will be the largest clinical study of ECT known ( ; ).
Summary
ECT is a treatment developed over 80 years ago, and through the decades, scientific studies hold that ECT is a safe and effective strategy for depression and many other neuropsychiatric disorders. Depression knows no age limit, and ECT is exceptionally effective across the life span from the young to very old. When severe and resistant depression strikes, ECT can be life-saving and is an extremely fast treatment with improvement occurring within a few weeks versus many weeks to months with pharmacotherapy or psychotherapy.
With past clinical depression studies of various treatment modalities, the focus has generally been on response which is typically defined as a 50% reduction of depression symptoms on well-validated rating scales. More recently in the past 15–20 years, studies such as STAR*D focus on achieving remission , which refers to very low or single-digit scores on depression scales at the end of treatment. Historically, remission rates in medication trials range from 22% to 40% ( ), but ECT is the most effective treatment and has a remission rate between 50% and 80% across many retrospective and prospective studies. No other novel depression strategy can boast of such consistently positive remission rates. Maintenance ECT is also another strategy that is often employed to prevent relapses and maintain wellness usually in combination with pharmacotherapy.
Despite ECT’s excellent outcomes for treatment-resistant depression, ECT is a treatment that is used sparingly in the United States for only a small fraction of the TRD population. Prior estimates from the 1990s indicated only 100,000 patients per year received ECT ( ) and at the current US population, this number may now only be 150–200,000 ECT patients per year. For this smaller patient population, there are also concerns that access to ECT could be negatively affected by a reduction in ECT use and availability in hospitals over the past 20 years ( ; ).
ECT is not an antiquated somatic therapy that should be limited or fade away, but is actually an evolving treatment with ongoing explorations to reduce side effects, find predictors of response, and understand better the biologic underpinnings of ECT’s effects. For the foreseeable future, ECT will remain a vital tool in combating treatment-resistant depression.
References
Related posts:
Clinical and epidemiological predictors of treatment-resistant depression
The economic burden of treatment-resistant depression: Cost-of-illness perspective
Monoamine oxidase inhibitors for treatment-resistant depression
Switching antidepressants in patients with treatment-resistant depression
Inflammation and treatment resistance: Mechanisms and treatment implications
Opioid agents for treatment-resistant depression
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