Charles H. Kellner, MD

After many years of inaction, the FDA issued a final order on the classification of ECT devices in December, 2018.

 The very good news is that the order allows for ongoing availability of ECT devices in the US; the slightly less good news is that the new list of “on label” indications for ECT is shorter than in the past. To understand the implications of the new order, let’s review some of the background leading up to it, as well as the state of ECT in the US today.

The FDA regulates medical devices as well as drugs. As you might imagine, some aspects of this regulation are straightforward and easy to understand, but some are complicated, arcane, and highly bureaucratic. (For a review of earlier FDA actions leading up to the recent order, please see 

https://www.psychiatrictimes.com/electroconvulsive-therapy/fda-advisory-panel-reclassification-ect-devices

.) Medical devices are classified into three risk categories, with Class I considered the safest, Class III the riskiest.

Until now, ECT devices had been “grandfathered” into Class III for all indications, and the list of “cleared indications” was depression (unipolar and bipolar), schizophrenia, bipolar manic (and mixed) states, schizoaffective disorder, schizophreniform disorder, and catatonia. That list conforms well to the generally accepted uses of ECT in the US. The FDA needed to update the classification of all “grandfathered” devices, and the process (this is the complicated part) would require “premarket approval” for indications that would not be moved from Class III to Class II. Premarket approval typically requires new controlled clinical trials to demonstrate safety and efficacy, a requirement that would not be feasible, for both financial and ethical (the inappropriateness of subjecting very seriously ill psychiatric patients to placebos) reasons. Thus, it was crucial that some (at least one) of the previously “cleared indications” be moved to Class II, in order not to interrupt the availability of ECT devices for the US market.

The new ruling does just that: it moves two indications (depression and catatonia) into Class II, with “special controls.” The “special controls” are a series of requirements regarding technical parameters of the devices, labeling about adverse effects, practitioner training, and a few aspects of clinical practice.

So, what are the implications of the FDA order reclassifying ECT devices for ECT practice in the US? Most importantly, the move of the depression indication into Class II insures that the majority of ECT patients will continue to be treated without any change in their care. The way the order is written for this indication (that the depression should be “a severe major depressive episode associated with major depressive disorder or bipolar disorder in patients aged 13 years and older who have treatment resistance or who require a rapid response due to the severity of their psychiatric or medical condition”) mirrors closely clinical practice for the majority of patients referred for ECT in contemporary US practice.

The move of the indication “catatonia,” to Class II is also very important, but applies to a much smaller subset of ECT patients, perhaps no more than 5%.

 In my estimate, the two indications moved to Class II constitute 60% to 70% of current American ECT practice.

What about the other 30% to 40%? The FDA order makes it very clear that the FDA does not regulate clinical practice; they actually say this several times in the text accompanying the order: “FDA does not regulate the practice of medicine (see section 1006 of the FD&C Act [21 U.S.C. 396]). Diagnosis and treatment of patients are clinical decisions that fall within the practice of medicine.” In other words, practitioners are free to continue to prescribe ECT for any patient, regardless of diagnosis, whom they feel would benefit from the treatment.

This is similar to the freedom to use a medication for an off-label indication. The fact that the FDA chose to leave schizophrenia, schizoaffective disorder, and mania in Class III is perplexing and disappointing. Globally, schizophrenia may be the leading indication for ECT, and the clinical and research evidence base supports ECT as safe and effective for this illness.

One of the issues related to the FDA’s consideration of reclassification of indications is that they have a bundled, unitary concept of “safety and effectiveness.” Thus, their review panel may not have been convinced by the data for effectiveness of ECT in schizophrenia, but this has no bearing on safety. In fact, there is no reason to believe that the safety profile of ECT differs by psychiatric diagnosis.

Overall, the FDA order allows patients who need and want ECT, as well as practitioners who perform it, to breathe a sigh of relief. ECT will continue to be an important, albeit small, part of the psychiatric armamentarium landscape. From speaking with fellow ECT practitioners around the country, it is apparent that ECT use is increasing. The ongoing enthusiasm for transcranial magnetic stimulation and ketamine (intravenous or intranasal) has done little to decrease the demand and need for ECT; indeed, many of the patients whom we see in ECT consultation have tried those newer treatments but the treatments have failed.

The psychiatric community has a responsibility to support and promote treatments that are in the best interests of our patients, those treatments with a track record of safety and effectiveness. ECT certainly fits that bill. But organized psychiatry has always been a tad, or more, ambivalent about supporting ECT. Amazingly, there is no official path to training in ECT, there is no board certification, and it is unclear if the next generation of ECT practitioners will be large enough for the need. In a country with 49,000 psychiatrists, it is estimated that fewer than 1000 actually practice ECT.

Modern ECT allows virtually all patients who need this modality to be treated safely, effectively, and with a level of tolerability previously unheard of. The proper understanding and contextualization of the (largely transient) cognitive effects of ECT suggests that exaggerated concerns about this adverse effect should not interfere with the appropriate prescription of a potentially life-saving treatment.

We believe that the adverse cognitive effects of ECT should be considered a tolerability and not a safety issue. In medicine, safety refers to the risk of physical injury or death. To elevate cognitive adverse effects to this level perpetuates the stigma surrounding ECT.

The most apt analogy to properly contextualize the seriousness of depressive illness weighed against the risks of ECT is cancer and chemotherapy. Many cancers are lethal, life-threatening illnesses for which treatments (surgery, chemotherapy, and radiation) carry considerable risks. Patients rarely categorically refuse cancer treatments because of concerns about adverse effects, yet this happens frequently with ECT. Our contention is that refusing ECT because of concerns about memory loss is equivalent to refusing cancer chemotherapy because of concerns about hair loss.

These effects are unpleasant and upsetting, but not worth risking one’s life over. Just as the side-effects of chemotherapy abate, so too do those of ECT; most of the hair grows back, most of the memories return, and the patient’s life is saved.

The FDA order removes what was a potentially dark cloud on the horizon of ECT. It continues to be the responsibility of our field to train an adequate number of ECT practitioners and to counter unsubstantiated attacks by the anti-psychiatry movement through education and ongoing contributions to the research evidence base for ECT.

Dr Kellner is Chief of Electroconvulsive Therapy (ECT), New York Community Hospital, Brooklyn, NY, and Adjunct Professor of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY. He reports that he has received research support from the NIMH, honoraria from UpToDate, Psychiatric Times, and Northwell Health, and royalties from Cambridge University Press.

 Food and Drug Administration. Neurological Devices; Reclassification of Electroconvulsive Therapy Devices; Effective Date of Requirement for Premarket Approval for Electroconvulsive Therapy Devices for Certain Specified Intended Uses. Final order. Fed Regist. 2018;83:66103-66124.

 McDonald WM, Weiner RD, Fochtmann LJ, McCall WV. The FDA and ECT. 

 Fink M, Kellner CH, McCall WV. Optimizing ECT technique in treating catatonia. 

 Fink M. Rediscovering catatonia: the biography of a treatable syndrome. 

 Leiknes KA, Jarosh-von Schweder L, HÃ¸ie B. Contemporary use and practice of electroconvulsive therapy worldwide. 

 Grover S, Sahoo S, Rabha A, Koirala R. ECT in schizophrenia: a review of the evidence. 

 Sanghani SN, Petrides G, Kellner CH. Electroconvulsive therapy (ECT) in schizophrenia: a review of recent literature. 

 Kellner CH, Greenberg RM, Ahle GM, Liebman LS. Electroconvulsive therapy is a standard treatment; ketamine is not (yet). 

 Kellner CH, Farber KG. Electroconvulsive therapy and cognition: a salutary reappraisal. 

Articles

This new FDA order now allows patients who need and want ECT, as well as practitioners who perform it, to breathe a sigh of relief.

The FDA on ECT: Supporting a Vital Treatment

The recent increase in suicides, including those of Kate Spade and Anthony Bourdain, highlights the urgent need for better treatment of severe depression. Recent data from the CDC document an alarming trend: suicide is up by nearly 30% since 1999.

 It is now the 10th leading cause of death, with 45,000 suicides in 2016. While the antecedents of suicide are multifactorial, at least half of the people who attempt/complete suicide have a psychiatric illness, mostly a mood or psychotic disorder.

, Richard A. Friedman, a psychiatrist, noted, “last year, the National Institutes of Health spent more money researching dietary supplements than it did suicide and suicide prevention. Any other disease that comes close to killing as many Americans as suicide does, like HIV and heart disease, gets marquee recognition as a public health menace and major federal research funding . . . the simple reason suicide has been neglected for so long is stigma.”

 Benedict Carey, in a New York Times article about the same CDC suicide data, wrote, “one of the few proven interventions [to reduce suicides] is unpalatable to wide swaths of the American public: reduced access to guns.”

 We believe that another intervention proven to reduce suicidality, ECT, is underused because it is similarly stigmatized and considered “unpalatable.”

A recent series of articles and editorials documents the current state of ECT use (actually underuse) in the US. Herein, we review the new data and make suggestions about “right sizing” ECT in contemporary American psychiatric practice.

 wrote an editorial, which accompanied an important study that demonstrated that inpatients with mood disorders who received ECT had half the rate of hospital re-admission in 30 days than those who were treated with medications.

 More recent findings indicate that only 0.25% of patients with mood disorders in a large health care database received ECT.

 Similarly, in a cohort of over 11,000 veterans with psychiatric illness, only 50 received ECT (0.45%).

Because of its speed and effectiveness, ECT may actually be a cost-saving intervention; this benefit is in addition to its ability to relieve suffering and save lives. The cost-effectiveness of ECT was investigated in a major health economics study.

 Six alternative strategies for incorporating ECT into depression treatment were modeled based on data drawn from multiple meta-analyses, randomized trials, and observational studies of patients with depression. The researchers concluded that an optimal cost-effective strategy is to offer ECT after two failed pharmacotherapy trials, not relegating it to a “last resort” position after innumerable trials. Furthermore, they found, “over 4 years, ECT was projected to reduce time with uncontrolled depression from 50% of life-years to 33% to 37% of life-years, with greater improvements when ECT is offered earlier.”

How much is the right amount of ECT for optimum mental health outcomes? If ECT were used more often, would some suicides be prevented? Let’s start by addressing what we know about how much ECT is now done in the US. Unfortunately, in contrast with many European countries where national health databases provide accurate epidemiological data about the utilization of most medical procedures, including ECT, the US lacks such data.

ECT utilization rates have been shown to vary widely, both between regions in the US and between countries around the world.11 In a review, Leiknes and colleagues

 collected data about ECT utilization worldwide. They reported that, despite wide variability, the average ECT treated person rate (TPR) approximates 2.2 per 10,000 resident population per year. (In selected countries, where ECT may be less stigmatized, the rate is higher. For example, the TPR in Belgium is ~4.5 per 10,000 residents.) In the US, a TPR of 3 would equate to approximately 90,000 ECT patients per year. This accords well with an estimate derived from one of the best sources of population data in the US, the Medicare database.

 A similar extrapolation from this database is that approximately 450,000 to 500,000 ECT procedures are done annually in the US.

There are 49,000 psychiatrists in the US, but only 1216 were found in the 2016 Medicare database as having performed ECT.

 The International Society for ECT and Neurostimulation (ISEN), has about 300 members.

 There is a gender gap among ECT practitioners, with only 19% being female, despite the fact that psychiatry residency classes for the past decade have been more than 50% female. Only 14% of ECT procedures performed in the US are done by women psychiatrists.

The ambivalence with which ECT is regarded derives from multiple sources, but the media, with its sensationalized and anachronistic portrayals, has been the major influencer. Unfortunately, ambivalence also comes from within the psychiatric profession, where residency experience in ECT is woefully lacking, leading to practitioners who are uncomfortable prescribing it.

Modern ECT has been refined to the point that its morbidity and mortality are remarkably low. A recent systematic review and meta-analysis found a mortality rate of 2.1/100,000 procedures, making it among the safest treatments performed under general anesthesia.

 The technical advancement of ultrabrief pulse right unilateral ECT allows many seriously ill patients to recover with very few cognitive effects.

 ECT practice and research are advancing in the US and abroad. PubMed contains over 15,000 citations for ECT. And, ECT research continues around the world as we mark the 80th anniversary of the invention of ECT.

Despite the enthusiasm with which newer brain stimulation techniques have been embraced, ECT remains alone; no other modality can come close to ECT for antidepressant/antipsychotic efficacy, speed of response, and clinical track record of utility. We do a disservice to our seriously ill patients when we conflate ECT with other “neurostimulation” techniques.

Taken together, the above data suggest that ECT is, in fact, vastly improved, but still underutilized. We believe that greater, and earlier, prescription of ECT in appropriately selected patients would lead to better mental health outcomes, including fewer suicides. While an exact right-sized figure is hard to come by, we speculate that closer to 250,000 ECT patients per year (resulting in about 1.5 million ECT procedures) in the US is a more appropriate number for optimal mental health outcomes and reduced suicides. Currently, it is easier to get a gun than a prescription for ECT in the US. Fortunately, this may now be changing. ECT-marginalized for decades-is regaining its rightful place in the treatment armamentarium of contemporary psychiatric medicine.

Dr Kellner is Chief of Electroconvulsive Therapy (ECT), New York Community Hospital, Brooklyn, NY and Adjunct Professor of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY. Ms Patel is an undergraduate at Emory University. 

Dr Kellner reports that he has received research support from the NIMH, honoraria from UpToDate, Psychiatric Times, and Northwell Health, and royalties from Cambridge University Press. Ms Patel reports no conflicts of interest concerning the subject matter of this article.

 Stone DM, Simon TR, Fowler KA, et al. Vital signs: trends in state suicide rates: United States, 1999-2016; and circumstances contributing to suicide: 27 states, 2015. 

 Friedman RA. Suicide rates are rising. What should we do about it? 

 Carey B. How suicide quietly morphed into a public health crisis. 

 Kellner CH, Fink M, Knapp R, et al. Relief of expressed suicidal intent by ECT: a consortium for research in ECT study. 

 Fink M, Kellner CH, McCall WV. The role of ECT in suicide prevention. 

 Sackeim HA. Modern electroconvulsive therapy: vastly improved yet greatly underused. 

 Slade EP, Jahn DR, Regenold WT, et al. Association of electroconvulsive therapy with psychiatric readmissions in US hospitals. 

 Wilkinson ST, Agbese E, Leslie DL, et al. Identifying recipients of electroconvulsive therapy: data from privately insured Americans. 

 Wilkinson ST, Rosenheck RA. Electroconvulsive therapy at a veterans health administration medical center. 

 Ross EL, Zivin K, Maixner DF. Cost-effectiveness of electroconvulsive therapy vs pharmacotherapy/psychotherapy for treatment-resistant depression in the United States. 

 Hermann RC, Dorwart RA, Hoover CW, et al. Variation in ECT use in the United States. 

 International Society for ECT and Neurostimulation Annual Meeting Abstracts 2017. 

 Medicaire National HCPCS Aggregate Summary Table CY2017. 

https://data.cms.gov/Medicare-Physician-Supplier/Medicare-National-HCPCS-Aggregate-Summary-Table-CY/jtra-d83c/data

 International Society for ECT and Neurostimulation. 

 Dinwiddie SH, Spitz D. Resident education in electroconvulsive therapy. 

 TÃ¸rring N, Sanghani SN, Petrides G, et al. The mortality rate of electroconvulsive therapy: a systematic review and pooled analysis. 

 Kellner CH, Husain MM, Knapp RG, et al. Right unilateral ultrabrief pulse ECT in geriatric depression: phase 1 of the PRIDE study. 

The recent increase in suicides highlights the urgent need for better treatment of severe depression. ECT is an intervention proven to reduce suicidality, yet it is underused because of the associated stigma.

The Role of ECT in the Suicide Epidemic

is Associate Professor of Psychiatry, Kennedy Krieger Institute, Johns Hopkins School of Medicine, Baltimore, MD

is Chief of Electroconvulsive Therapy, New York Community Hospital, Brooklyn, NY

 is Professor Emeritus, Departments of Psychiatry and Neurology, Stony Brook University, Stony Brook, NY.

Since its introduction 8 decades ago, ECT has been a standard treatment for severe affective and psychotic illness, as well as less common indications including catatonia, 

, neuroleptic malignant syndrome, and status epilepticus. A new indication for ECT has 

 for intractable self-injurious behavior (SIB) among individuals with autism and intellectual disabilities.

 Response to ECT is typically swift and robust, with great benefit for patients and their families.

SIB is defined as any act toward the self that causes physical injury, and has been recognized for decades to occur among individuals with autism spectrum disorders and intellectual disability. Estimates of SIB prevalence vary widely, with higher rates usually found among those with greater cognitive and communication impairments, and psychiatric and medical comorbidities. Common manifestations of SIB include head banging; hand-to-head, knee-to-head, and hand-to-body hitting; self-pinching; scratching and biting; and body slamming against hard surfaces. The frequency of SIB varies widely, from occasional, to daily, hourly, or even a per-minute basis. Frank bodily injury is common and includes bleeding, bruising, swelling, fracture, infection, disfigurement, traumatic ossification, cataract development, retinal detachment with associated loss of vision, and concussion or intracranial damage. Other deleterious consequences of SIB include reduced social, educational, family, and occupational functioning, with higher risk of placement in more restrictive settings and limited life opportunities.

Standard treatments of SIB in autism and intellectual disability are behavioral and psychopharmacological interventions. While many individuals respond to these modalities, there has long remained a subgroup of treatment-refractory patients who have exhausted dozens of psychotropic medications, years of intensive behavioral therapy, and multiple out-of-home placements and hospitalizations. Such patients may be padded and immobilized head-to-toe in protective equipment, and frequently receive psychotropic medications as chemical restraint-often with limited benefit and high risk of adverse effects. Despite such efforts, these patients often sustain permanent injuries including blindness from retinal detachment and cerebral hemorrhage.

Recent suggestions that SIB might be one of many symptoms of catatonia in autism spectrum disorders-including mutism, negativism, posturing, rigidity, and repetitive speech and acts-led to treatment trials with ECT, the long-recognized effective treatment for catatonia, with 

Jay is a 19-year-old man with autism and intellectual disability. He was initially hospitalized at age 12 after several years of severe head- and body-directed SIB with frequent facial bleeding, as well as aggressive behaviors toward his family, caregivers, and school staff. SIBs were so intense that a caregiver inadvertently broke Jay’s arm while attempting to block hand-to-head striking. Jay also displayed mood instability with sobbing and wild laughter, irritability, physical hyperactivity, agitation, and insomnia.

He had exhausted multiple drug trials from all US-available psychotropic classes, as well as years of intensive behavioral services. He demonstrated affective and behavioral improvement of a few months’ duration on lithium carbonate, aripiprazole, and riluzole, but deteriorated again with such behavioral dyscontrol that his parents feared their only option to maintain his safety was placement in a locked residential facility.

A trial of 3 times per week bilateral ECT was initiated. Jay demonstrated dramatic reduction in SIBs after just a few treatments, as well as improved sleep and more stable mood. ECT frequency was gradually reduced while monitoring for recurrence of SIB or mood deterioration; ultimately, a maintenance ECT regimen of every 9 or 10 days was established.

Jay was able to remain at home, where he participated fully and safely in family life with his parents and 2 siblings. He continued in a program emphasizing community-based living and functioning activities, and was able to master skills never thought possible for him before, such as independent grocery shopping from a list, followed by check-out with a debit card and meal preparation.

He tolerates ECT well and is able to go to school without incident after early-morning treatment. He remains on a concomitant regimen of lithium and aripiprazole; SIB is limited to rare incidents of hand-biting with no resultant injuries. Jay has received an estimated 290 sessions of ECT over the past 8 years.

The resolution of SIB with ECT was first documented in a 1982 report of a 25-year-old man with severe mental retardation and head-directed SIB of several years’ duration.

 In 1999, a report presented a 14-year-old boy with mental retardation whose persistent head-banging and self-scratching were alleviated by ECT, which allowed discharge after many months in a restricitve institutional setting.

The relationship between self-injury, catatonia, and ECT was first questioned in the 2008 case report of an autistic girl with posturing, rigidity, mutism, stupor, grimacing, food refusal, and global skill regression, alternating with bursts of extreme self-injury that led to bilateral traumatic cataract formation and retinal detachment.

 ECT resulted in resolution of catatonic symptoms, as well as nearly complete eradication of SIB, which allowed for vision preservation in one eye.

The following year, the case of an 8-year-old autistic boy with ongoing agitation and stereotyped movements (in the form of nearly 110 SIBs per hour) was reported.7 After treatment with ECT, he averaged only 20 SIBs per hour. It was postulated that his SIB was a manifestation of catatonia.

 proposed that self-injury in autism represented a variant of catatonia. They reviewed the history of these conditions, exploring self-injury as a stereotypy common to both catatonia and autism, and further connecting catatonia, autism, tic disorders, and the self-injury that occurs in the 3 conditions. Subsequent reports have continued to call for recognition of repetitive SIB as a sign of catatonia, with clear implications for the use of ECT in its treatment.

ECT for adolescents with autism spectrum disorder and SIB includes standard ECT protocols of general anesthesia with propofol or methohexital, muscle relaxation with succinylcholine, and continuous oxygenation via face mask. Flumazenil, the benzodiazepine reversal agent, may be used at the time of treatment when patients have recently taken these medications. 

 is typically bilateral, and stimulation is with modern brief-pulse devices.

Moderately suprathreshold stimulus dosing takes into account the lower seizure threshold of younger patients. Seizure adequacy is monitored by the duration and quality of the recorded EEG. The ECT course begins with seizures 3 times per week, until SIB frequency has been markedly reduced; ECT frequency is then gradually reduced over the ensuing weeks, while monitoring for sustained SIB reduction. For these patients, ECT is a procedure analogous to renal dialysis, with frequency of treatment guided by objective symptom evaluation, and the need to optimize the quality of patient and family life.

While the mechanism of the relief of catatonia by ECT is unclear, the neuroendocrine studies of melancholia offer potential clues. Studies of cortisol and thyroid functions in these patients find chemical abnormalities that resolve with repeated ECT, suggesting that seizures normalize the hypothalamic-pituitary-adrenal axis and other endocrine functions. While we know little about the specific neuroendocrine disturbances in autism spectrum disorder or in catatonia, there are likely commonalities in the underlying physiology between these disorders and melancholia. At present, the best understanding of the mechanism of the beneficial effect of ECT in adolescents with SIB is the neuroendocrine explanation developed for melancholia. Additional mechanistic theories are enhanced neurogenesis, angiogenesis, and neuronal connectivity.

ECT came into widespread use at a time when psychodynamic thinking dominated child and adolescent psychiatry and the application of the somatic therapies was considered anathema. Since the 1990s, this attitude hurdle has been slowly overcome with the realization that some severe childhood and adolescent disorders-notably, melancholia, mania, and catatonia-are safely and effectively relieved by modern ECT procedures. Recognizing SIB in autism spectrum disorder as a form of catatonia has encouraged this application. Indeed, ECT has been documented as nothing short of lifesaving for many children and young adults with autism spectrum disorder who were previously wholly incapacitated by SIB.

Wachtel L, Shorter E. Self-injurious behaviour in children: a treatable catatonic syndrome. 

Wachtel L, Dhossche D. ECT for self-injurious behavior. In: Ghaziuddin N, Walter G, eds. 

Electroconvulsive Therapy in Children and Adolescents

. New York: Oxford University Press; 2013:247-280.

 Bates WJ, Smeltzer DJ. Electroconvulsive treatment of psychotic self-injurious behavior in a patient with severe mental retardation. 

 Wachtel LE, Kahng S, Dhossche DM, et al. ECT for catatonia in an autistic girl. 

Wachtel LE, Contrucci-Kuhn SA, Griffin M, et al. ECT for self-injury in an autistic boy. 

Wachtel L, Dhossche D. Self-injury in autism as an alternative sign of catatonia. 

 Fink M. The mechanism of action of ECT. In: Ghaziuddin N, Walter G, eds. 

. New York: Oxford University Press; 2013:18-28.

Optimizing ECT technique in treating catatonia

ECT has been found effective in mitigating the deleterious consequences of SIB.

ECT for Self-Injurious Behavior in Autism: A New Indication

ECT remains a standard treatment in modern psychiatric medicine for a range of severe psychiatric illnesses because of its unmatched efficacy and speed of response. Recent changes in psychiatric nosology and practice clarify the role of ECT for catatonia and melancholia-2 syndromes for which ECT is a most effective and often lifesaving treatment. For these syndromes, optimally administered ECT typically provides relief within 1 to 3 weeks.

Catatonic patients, especially those with febrile malignant catatonia or the neuroleptic malignant syndrome and those who refuse feeding, should be treated without delay. Unfortunately, antidepressant medications are prescribed for many melancholic patients-often multiple trials of up to 6 weeks each-before ECT is recommended. More severely depressed patients, who are agitated, suicidal, and losing weight, should be referred for ECT as a primary treatment.

Indeed, the remarkable, well-replicated efficacy of ECT for these 2 syndromes raises questions about accepted treatment algorithms that call for 2 or more medication trials, often with multiple medications combined with psychotherapy. Many clinicians question the ethics of such treatment algorithms that ask patients to suffer weeks, even months, of trials before the effective treatment of ECT is prescribed. For both ethical and economic reasons, when patients are acutely ill with catatonia and melancholia, ECT is best considered sooner rather than later.

A century ago, following the images created by Emil Kraepelin, catatonia was seen as a marker of schizophrenia and classified as one of its recognized types. By the 1990s, DSM-IV recognized catatonia as secondary to a medical condition; in the latest iteration, DSM-5 discarded the class of catatonia as a type of schizophrenia and retained it mainly as a systemic medical condition. Much has been learned.

Catatonia rating scales identify more than 20 motor behaviors, including posturing, rigidity, staring, mutism, and repetitive thoughts and acts that mark the stuporous form. Two or more signs that last for 24 hours suggest the presence of the syndrome. The diagnosis can be verified by rapid relief, a 50% reduction in the rating scale scores, with the intravenous administration of 1 to 2 mg of lorazepam. Catatonia is first treated with increasing doses of a benzodiazepine; for lorazepam, often up to 30 mg/d. Up to 80% of patients respond to high-dose lorazepam treatment.

For those who do not respond or for those with a malignant form of catatonia-with fever, autonomic dysfunction, and stupor-ECT is the primary treatment. ECT can be optimized in several ways. For febrile patients, daily treatment may be necessary.

High-dose benzodiazepines can raise seizure thresholds and interfere with the efficacy of ECT seizures. The most effective ECT uses bilateral electrode placement, and for those who have received benzodiazepines, the protocol may include the benzodiazepine antagonist flumazenil, administered in the sequence of oxygenation, anesthetic, flumazenil, and succinylcholine. Effective seizures are those that are of adequate duration, allowing the full sequence of buildup in the recorded EEG of slow waves, slow waves and spikes, followed by a definable sharp endpoint. Evidence on the use of right unilateral electrode placement to treat seriously ill patients with catatonia, while intriguing, is not compelling enough to change standard practice.

Catatonia is also recognized in an excited, delirious manic form. These patients are often febrile, medically ill, and behaviorally difficult to manage. An intramuscular ketamine injection may be a safe initial sedating agent, allowing placement of the intravenous line and the subsequent administration of the standard sequence of ECT medications. Daily ECT until the condition is stabilized is necessary and often lifesaving. The benefits are best sustained by continuation of ECT over weeks or months. In some instances, continued high-dose benzodiazepine treatment has been useful.

Before 1980 and the adoption of DSM-III, 2 depressive mood disorders were commonly identified: a severe life-threatening psychotic depression, “melancholia,” and the more commonly recognized “psychoneurotic” form. Melancholia was recognized by mood severity, acute onset, suicide risk, psychosis, and vegetative signs such as insomnia and weight loss. Psychoneurotic depression was marked by anxiety, fears, phobias, and obsessive thoughts. Since DSM-III, these conditions have been lumped together as “major depressive disorder.” Melancholia has been of limited interest, classified as a specifier for mood disorders (“with melancholic features”) and no longer recognized as a distinct illness.

Clinical scientists in the 1970s and 1980s reported that hypothalamic-pituitary-adrenal axis function, measurable by serum cortisol levels, was abnormal in melancholia and offered the dexamethasone suppression test as an index to identify and measure the severity of the syndrome.

 The loss of interest in melancholia resulted in the abandonment of cortisol measurement, including the dexamethasone suppression test, in the clinic.

Definitions of melancholia have varied over decades, and this is likely the reason that the evidence for its utility as a predictor of ECT response has been inconsistent. For the purposes of this article, melancholia refers to a severe primary mood disorder, usually episodic, with anhedonia, psychomotor disturbance, impaired concentration, disrupted sleep, poor appetite with weight loss, and often with psychotic thinking (guilty delusions) as well as suicidal ideation and intent.

Patients with melancholia often score in the “severe” range on depression rating scales such as the Hamilton (HAM-D) or Montgomery-Asberg (MADRS). Because the dexamethasone suppression test is no longer used, the diagnosis is made solely on the basis of clinical features, that is, by the severity of symptoms, progressive course, and presence of suicidal intent and psychosis, along with the other mood and motor features of the syndrome.

Effective ECT for severe melancholia, like that for catatonia, is based on optimizing ECT treatment parameters, which favor bilateral electrode placement, 3-times-per-week treatments, and monitored EEG seizures for duration and pattern. To sustain the benefits, continuation treatments over weeks or months are often required. Alternative strategies, of continuation treatment with pharmacotherapy combinations (eg, lithium plus nortriptyline or venlafaxine) or pharmacotherapy combinations along with continuation/maintenance ECT, have also been reported as effective in sustaining remission.

 that documents the efficacy of ECT in reducing hospital readmission rates adds to our understanding of the public health benefits of ECT.

 An accompanying editorial forcefully makes the argument that modern ECT is a safe and well-tolerated treatment that is underutilized in American psychiatry.

 We agree-and hope that highlighting the appropriate place of ECT in treatment algorithms for catatonia and melancholia helps practitioners to consider ECT for their most seriously ill patients.

Dr. Kellner is Chief of Electroconvulsive Therapy, New York Community Hospital, Brooklyn, NY. Dr. Fink is Professor Emeritus, Departments of Psychiatry and Neurology, Stony Brook University, Stony Brook, NY.

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 Kellner CH, Husain MM, Knapp RG, et al. A novel strategy for continuation ECT in geriatric depression: phase 2 of the PRIDE study. 

 Slade EP, Jahn DR, Regenold WT, Case BG. Association of electroconvulsive therapy with psychiatric readmissions in US hospitals. 

Fink M, Kellner CH, McCall WV. Optimizing ECT technique in treating catatonia. 

Krystal AD, Watts BV, Weiner RD, et al. The use of flumazenil in the anxious and benzodiazepine-dependent ECT patient. 

Luchini F, Medda P, Mariani MG, et al. Electroconvulsive therapy in catatonic patients: efficacy and predictors of response. 

For ethical and economic reasons, when patients are acutely ill with catatonia and melancholia, ECT is best considered sooner rather than later. 

ECT for Catatonia and Melancholia: No Need for Ambivalence

[[{"type":"media","view_mode":"media_crop","fid":"32074","attributes":{"alt":"ECT for depression","class":"media-image media-image-right","id":"media_crop_1210448114029","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"4153","media_crop_rotate":"0","media_crop_scale_h":"147","media_crop_scale_w":"125","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"float: right;","title":" ","typeof":"foaf:Image"}}]]Electroconvulsive therapy (ECT) continues to be a vital treatment for severe depression and a few other psychiatric diagnoses. Its more widespread use has been limited primarily by the unwarranted stigma attached to the procedure. In addition, critics often cite a lack of knowledge about its mechanism of action as a reason to eschew its use. Here we review some of the knowledge base of ECT’s biological actions and discuss future directions for ECT research.

Decades of research in both animal models of ECT (referred to as electroconvulsive shock, or ECS) and clinical trials in humans have contributed to a vast evidence base of neurobiological changes associated with induced seizures. Undoubtedly, the biological events ultimately leading to relief from depression with ECT involve a cascade of effects related to molecules, cells, and circuits. While various researchers have focused primarily on one of these neurobiological domains, there is no currently articulated theory of the mechanism of action of ECT in depression that incorporates events at all 3 levels. It is likely that many of the myriad observed changes are epiphenomena not essential to the therapeutic effects of ECT.

Many technologies have been applied to the study of the neurobiological effects of ECT or ECS, including single photon emission CT, positron emission tomography, functional MRI (fMRI), magnetic resonance spectroscopy (MRS), EEG, body fluid chemical analysis (blood, urine, cerebrospinal fluid) and, in animals, histological examination and molecular genetic assays. The main theories of mechanism of action of ECT in depression can be classified as follows: neurotransmitter, neuroendocrine, anticonvulsant, neurotrophic, and neural connectivity hypotheses.

Contemporary ECT for Depression Part 1: Practice Update

The neurotransmitter theory of action of ECT arises from long-standing interest in the monoamines (serotonin, dopamine, norepinephrine) and other neurotransmitters, such as GABA and glutamate, in biological theories of the etiology of depression. Animal studies have shown consistent effects of ECS on monoamine neurotransmitter functioning, such as enhancement of serotoninergic transmission; results have been 

 MRS studies have reported increased cortical GABA concentrations after ECT in humans as well as increased glutamate/glutamine in the left dorsolateral prefrontal cortex and anterior cingulum.

of ECT is based on the findings of activation of the hypothalamic-pituitary axis during seizures, demonstrated by a surge in blood levels of adrenocorticotropic hormone, cortisol, and prolactin postictally.

 It is also based on the observation that abnormal overdrive of the hypothalamic-pituitary-adrenal axis in depression, as measured by the dexamethasone suppression test, can predict response to, and relapse after, ECT.

The anticonvulsant theory of ECT action arose from the observation that seizure threshold often rises and seizure duration shortens over a course of ECT, leading to the hypothesis that the inhibitory brain process associated with the progressive rise in seizure threshold is also responsible for depression relief. Support for this comes from EEG and cerebral blood flow studies that demonstrated suppression of neural activity (mostly in the frontal lobes) after a course of ECT, which 

The most recent conceptualizations of ECT mechanisms involve newer technologies for investigating cellular morphological changes, termed “neuroplasticity,” in animals, and “neural connectivity” in humans. The neuroplasticity (or neurotrophic) hypothesis of ECT mechanism holds that morphological changes, such as neurogenesis, gliogenesis, or alterations in dendritic or axonal arborization of existing neurons, are critical to the 

 Extensive animal studies of ECS document consistent evidence of neurogenesis in the hippocampus (mossy fiber sprouting), prefrontal cortex, and other limbic structures.

Remarkable brain structural detail can now be imaged with high–magnet-strength MRI. Such imaging has recently been applied to ECT patient populations at baseline (in the ill state, before ECT) and during and after a course of ECT. Findings indicate increased gray matter volume after ECT in the hippocampus, subgenual cortex, and amygdala.

It may be that baseline brain morphology is abnormal in severely depressed patients, and that ECT-induced neuroplasticity results in a return to normal size and morphology of structures such as the hippocampus and amygdala.

There have been several attempts to elucidate neurotrophic ECT mechanisms using MRS. 

 for neurogenesis in humans comes from MRS studies that show cell membrane turnover in areas felt to be critical to antidepressant mechanisms, which could reflect growth of new neurons.

 Other findings include increased N-acetylaspartate in the left amygdala and increased choline-containing compounds in the hippocampus with ECT.

 As these examples illustrate, MRS findings are diverse and do not allow a unifying conclusion. Undoubtedly, further refinement of MRS technology will enable assessment of other relevant brain molecules. It seems likely that neuroplastic and neurotrophic cellular events are the most critical of all in the causative chain of ECT antidepressant effect.

Quantitative EEG and fMRI have only recently been applied to ECT populations. 

 utilizing a new EEG analytic method-low-resolution electromagnetic tomography-found that increases after ECT in theta frequency (4 to 7 Hz) in the subgenual cingulate, an area of interest in the pathophysiology of depression, correlated robustly with reductions in psychotic depression.

 found evidence that reduction of baseline frontal cortical hyperconnectivity correlated with resolution of depression with ECT. However, 

 demonstrated that improvement in depression correlated with increased frontal cortical connectivity. The researchers ascribed the differential findings to different fMRI techniques.

In an fMRI study of 6 patients treated with ECT, 

 found that orbitofrontal activation in response to an affect-laden task decreased with successful ECT, but the sample size was too small for definitive conclusions. Finally, 

 studied 11 ECT patients with fMRI using an auditory task-related activation of multiple cortical areas. They found that patients had more task-related activation after ECT, but the implications of this finding are unclear. Methodologically sound, adequately powered fMRI studies in ECT populations are needed to advance our knowledge of neural network alterations in severe depression and subsequent recovery.

While we await a definitive understanding of the biological changes underpinning the mechanism of action of ECT, there is no need to be defeatist. Simply telling patients “we don’t know how ECT works” neglects our abundant knowledge of what this powerful treatment does. As 

 suggests, it is more helpful to patients to explain and categorize several of the biological effects of ECT; it is a “glass half full” approach, which is both truthful and positive.

ECT research will continue to focus on refining aspects of technique and personalizing ECT type and schedule, as well as further elucidating its mechanisms of action. Technical refinements are aimed at preserving antidepressant efficacy while increasing cognitive tolerability. Techniques to more precisely target particular brain structures or areas for seizure initiation and/or to limit the spread of the seizure are under development.

 undertook a feasibility study of a modified type of ECT using a unidirectional electrical stimulus, 2 different sized electrodes, and novel electrode placement. Modifications of the stimulus package (ie, further reductions in pulse width and varying frequency, amplitude, or duration) are also being studied. Further research, including biomarker discovery for response/relapse prediction, should help inform practitioners about how to determine the optimal type and number of acute treatments for a given patient and how to individualize continuation/maintenance ECT schedules.

Dr Kellner is Professor in the department of psychiatry at the Icahn School of Medicine at Mount Sinai, Chief of Geriatric Psychiatry for the Mount Sinai Health System, and Director of the ECT Service at the Mount Sinai Hospital in New York. Dr Rasmussen is Professor in the department of psychiatry and psychology at the Mayo Clinic in Rochester, Minn. The authors report no conflicts of interest concerning the subject matter of this article.

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 Michael N, Erfurth A, Ohrmann P, et al. Metabolic changes within the left dorsolateral prefrontal cortex occurring with electroconvulsive therapy in patients with treatment resistant unipolar depression. 

 Merkl A, Schubert F, Quante A, et al. Abnormal cingulate and prefrontal cortical neurochemistry in major depression after electroconvulsive therapy. 

 Pfleiderer B, Michael N, Erfurth A, et al. Effective electroconvulsive therapy reverses glutamate/glutamine deficit in the left anterior cingulum of unipolar depressed patients. 

 Haskett RF. Electroconvulsive therapy’s mechanism of action: neuroendocrine hypotheses. 

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 Beall EB, Malone DA, Dale RM, et al. Effects of electroconvulsive therapy on brain functional activation and connectivity in depression. 

 Christ M, Michael N, Hihn H, et al. Auditory processing of sine tomes before, during and after ECT in depressed patients by fMRI. 

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Simply telling patients “we don’t know how ECT works” neglects our abundant knowledge of what this treatment does. The authors review biological actions of ECT and discuss future directions for research.

Contemporary ECT, Part 2: Mechanism of Action and Future Research Directions

[[{"type":"media","view_mode":"media_crop","fid":"32074","attributes":{"alt":"","class":"media-image media-image-right","id":"media_crop_1540772424833","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"4028","media_crop_rotate":"0","media_crop_scale_h":"125","media_crop_scale_w":"106","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"float: right;","title":" ","typeof":"foaf:Image"}}]]Electroconvulsive therapy (ECT) remains an indispensable part of the treatment armamentarium in psychiatry.

This review covers recent advances in ECT technique, post-ECT management, and theories of mechanism of action. It will focus on the use of ECT in depression, the most common indication for ECT in clinical practice.

Author | Charles H. Kellner, MD

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The Role of ECT in the Suicide Epidemic

ECT for Self-Injurious Behavior in Autism: A New Indication

ECT for Catatonia and Melancholia: No Need for Ambivalence

Contemporary ECT, Part 2: Mechanism of Action and Future Research Directions

Contemporary ECT for Depression Part 1: Practice Update

Brain Stimulation With ECT: Neuroscience Insights From an Old Treatment

Ketamine Anesthesia for Electroconvulsive Therapy

ECT and Catatonia: Out of the Shadows

ECT for Treatment-Resistant Depression: The State of the Art