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All other clinicians either will receive a CME Attendance Certificate or may choose any of the types of CE credit being offered.

Consider novel, promising strategies for treatment-resistant depression in order to help guide discussions with patients about appropriate treatments.

1. Understand novel, currently available, and promising pharmacological treatment options for treatment-resistant depression.

2. Understand currently available and promising neurostimulation treatment options for treatment-resistant depression.

This accredited continuing education (CE) activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals seeking to improve the care of patients with mental health disorders.

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This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Physicians’ Education Resource®, LLC, and Psychiatric Times™. Physicians’ Education Resource®, LLC, is accredited by the ACCME to provide continuing medical education for physicians.

Physicians’ Education Resource®, LLC, designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

This activity is funded entirely by Physicians’ Education Resource®, LLC. No commercial support was received.

This accredited CE activity may or may not discuss investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this accredited CE activity is for continuing medical education purposes only and is not meant to substitute for the independent clinical judgment of a physician relative to diagnostic or treatment options for a specific patient’s medical condition. The opinions expressed in the content are solely those of the individual faculty members and do not reflect those of Physicians’ Education Resource®, LLC.

FACULTY, STAFF, AND PLANNERS’ DISCLOSURES AND CONFLICT OF INTEREST (COI) MITIGATION

The staff members of Physicians’ Education Resource®, LLC, and Psychiatric Times™ have no relevant financial relationships with commercial interests. Dr Zarate is listed as a coinventor on a patent for the use of ketamine in major depression and suicidal ideation; as a coinventor on a patent for the use of (2R,6R)-hydroxynorketamine, (S)-dehydronorketamine, and other stereoisomeric dehydroxylated and hydroxylated metabolites of (R,S)-ketamine metabolites in the treatment of depression and neuropathic pain; and as a coinventor on a patent application for the use of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and posttraumatic stress disorders. He has assigned his patent rights to the US government but will share a percentage of any royalties that may be received by the government. The peer reviewer has participated in Speaker’s Bureaus for Sunovion, Otsuka/Lundbeck, Allergan, Teva, Neurocrine, Janssen, and Intra-Cellular Therapies.

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and include “Promising Strategies for Treatment-Resistant Depression” in the subject line.

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Treatment-resistant depression (TRD), which is broadly defined as “the failure to achieve and sustain euthymia with adequate antidepressant treatment,”

 remains a commonly encountered clinical challenge. Treatment response in depression has been characterized by a response curve that demonstrates diminished improvement of symptoms over successive adequate courses of treatment (

 Data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study confirm what we know from clinical practice—namely that the chances of adequate symptom resolution are very low (single digits) after 2 initial unsuccessful treatment trials. Approximately one-third of patients do not achieve remission after trials with 4 different conventional treatments. In this context, one definition of TRD is nonresponse to 2 or more antidepressant trials, reflecting this sharp drop-off in response after the second treatment.

A number of organizations (eg, the Canadian Network for Mood and Anxiety Treatments, the National Institute of Health and Care Excellence, and the American Psychiatric Association) have put forth clinical algorithms for the treatment of 

. Current standard treatment options across these guidelines include conventional antidepressant medications (selective serotonin reuptake inhibitors [SSRIs], serotonin-norepinephrine reuptake inhibitors [SNRIs]), other antidepressant drugs (eg, 

, mirtazapine, vilazodone, and vortioxetine), combining antidepressants (eg, bupropion [Wellbutrin, Forfivo] or mirtazapine [Remeron] added to an SSRI or SNRI, augmentation strategies that target associated symptoms such as sleep or anxiety (eg, second-generation antipsychotics, 

, lamotrigine [Lamictal], buspirone [Buspar], and thyroid hormone), and psychotherapy. Furthermore, new and developing advances in depression therapeutics now offer the prospect of significant improvement when administered in conjunction with, or as alternatives to, standard treatments. These promising therapies include rapid-acting novel antidepressant drugs as well as neurostimulation interventions.

, a glutamatergic modulator, has antidepressant properties has led to a mechanistically new treatment option for individuals with TRD.

 Furthermore, its rapid antidepressant effects manifest within hours compared with weeks for conventional antidepressants. Currently, intravenous (IV) racemic (R,S)-ketamine (hereafter referred to as 

, available off-label) and intranasal esketamine (FDA approved with a required risk evaluation and mitigation strategy [REMS] monitoring protocol) are the only routes of administration that have sufficient evidence to support their use. The initial controlled trials of IV ketamine (a single infusion of 0.5 mg/kg over 40 minutes) for TRD found that ketamine exerted rapid (typically within hours) antidepressant effects that peaked at 24 hours, with about 70% of patients demonstrating response.

 Response typically lasted 3 to 7 days postinfusion. Ketamine appears to have broad therapeutic properties, demonstrating particular effectiveness for anxious depression, depression with anhedonic features, and suicidal ideation.

Preliminary evidence also suggests its usefulness in treating other disorders comorbid with major depressive disorder (MDD), including obsessive-compulsive disorder (OCD), posttraumatic stress disorder, social anxiety disorder, and 

 Notably, ketamine has also proven effective for difficult-to-treat atypical features.

 Adverse events associated with subanesthetic-dose ketamine (0.5 mg/kg) are typically transient (eg, somnolence/sedation, hypertension, nausea, dissociation), although risk of abuse and/or dependence have not been sufficiently studied. One key limitation is the short duration of antidepressant effects in response to a single administration, which has prompted use of repeat doses of IV ketamine. Such repeat infusions are typically administered twice per week, and treatments are tapered when maximal response has been reached, which appears to maintain remission.

Esketamine is the S-enantiomer of ketamine and demonstrates greater potency at the glutamate NMDA receptor than the R-enantiomer. In clinical trials, intranasal esketamine (twice weekly, 56 or 84 mg) added to conventional antidepressant therapy significantly improved symptoms compared with placebo.

 Intranasal esketamine (Spravato) received FDA approval for the treatment of adults with TRD in March 2019 and for the treatment of adults with MDD with acute suicidal ideation or behavior in August 2020. Given concerns about adverse events, the FDA approved 

 under a REMS, requiring administration and observation in a medically supervised setting. In terms of adverse effects, reports to the FDA through 2020 noted that esketamine was significantly associated with increased risk of dissociation, sedation, and “feeling drunk.”

 Unexpectedly, a small percentage (2.81%) of patients reported onset of suicidal ideation after starting esketamine treatment. Compared with data for venlafaxine, signals remained for suicidal and self-injurious ideation but not for suicide attempt or completed suicide. Despite the difficulty in attributing causality in the population of patients with TRD who receive esketamine, this safety signal warrants further investigation.

A recent systematic review and meta-analysis that conducted a head-to-head comparison of IV ketamine and esketamine found that IV ketamine may hold a slight edge in efficacy in treating both MDD and bipolar depression, despite intranasal esketamine’s FDA approval.

In terms of risks, a few studies have reported relatively minor adverse events associated with IV ketamine. However, given the lack of a REMS protocol with IV ketamine, and a REMS report following each dose of 

, it is likely that the adverse events of esketamine are extensively reported, whereas they are likely underreported for IV ketamine. There is a need for ongoing vigilant adverse events reporting for both treatments.

While consensus on where ketamine should reside in the depression treatment algorithm is still developing, a recent overview suggests that IV ketamine and intranasal esketamine have both demonstrated efficacy for this patient population.

 Both agents may be more efficacious than second-generation antipsychotic drugs, although their relative efficacy compared with electroconvulsive therapy (ECT) has not been established. In selecting next-step and/or adjunctive treatments, important issues to consider include patient preference, adverse event profile, and accessibility (ie, cost, insurance coverage, and availability).

On the investigational side, interest in the use of arketamine (the R-enantiomer of ketamine) for TRD has also grown. Animal models suggest that arketamine may have more potential antidepressant-like effects than esketamine, and human trials have just begun. The ketamine metabolite (2

)-hydroxynorketamine has also generated significant interest as a treatment for TRD that potentially lacks dissociative adverse events and abuse potential. It is currently being studied in phase 1 human trials.

Another newly developed treatment for depression has a novel mechanism of action. Brexanolone (Zulresso), a neurosteroid and injectable form of allopregnanolone (a GABA

 positive allosteric modulator), was developed as a treatment for 

. Levels of allopregnanolone, which gradually rise throughout pregnancy, fall precipitously post pregnancy. Slowed downregulation of GABA

 receptors is thought to contribute to postpartum depression. Significant improvement in depressive symptoms was noted within 24 hours of brexanolone infusion, which is administered as a 60-hour IV infusion during inpatient care; this antidepressant response lasted up to 30 days.

 Brexanolone received FDA approval for postpartum depression in March 2020. An orally administered allopregnanolone analogue, Zuranolone, is currently in phase 3 clinical trials for both MDD and postpartum depression.

The success of ketamine has revived interest in the use of psychedelic agents, particularly psilocybin, for the treatment of depression. Controlled trials of psilocybin offer some evidence of efficacy for MDD patients, although further studies are needed.

 Psychedelic-assisted psychotherapy—that is, the use of 

 as an adjunctive treatment to psychotherapy—is in the early stages of investigation. In addition to concerns about prompting illicit use, it should be noted that psilocybin may increase the risk of seizures when coadministered with lithium.

In addition to new pharmacological treatments for TRD, several viable neurostimulation options currently exist or are emerging. ECT remains the most established treatment for severe TRD, and the FDA reaffirmed ECT’s importance as a treatment option when it reclassified ECT devices in December 2018 as a Class II (moderate risk) device for the indication of major depressive episodes associated with MDD or bipolar depression.

 With response rates greater than 50% by the first week of treatment, ECT should be a serious consideration for patients who have not responded to conventional treatment.

 Patients with psychotic depression and catatonic depression, as well as elderly patients, may particularly benefit from ECT.

However, ECT use remains limited by 2 main issues: the short duration of its effects and the cooccurrence of cognitive adverse events. After a successful course of ECT, relapse rates are quite high without effective relapse prevention strategies. To decrease the chance of relapse after a course of ECT, patients are often given maintenance medication or ECT therapy. The Prolonging Remission in Depressed Elderly study demonstrated that relapse rates can be dramatically reduced by introducing a Symptom-Titrated Algorithm-Based ECT (STABLE) approach that combines pharmacotherapy with continued ECT on a schedule adjusted to individual patient response.

 The STABLE intervention reduced relapse rates more effectively than medications alone and achieved these benefits without substantially worsening cognitive function.

The most concerning cognitive adverse events of ECT involve short-term and long-term memory. While studies confirm that short-term memory effects usually resolve within weeks of a treatment course, long-term memory deficits may be prolonged. Mitigation strategies used to minimize risk of memory loss include right unilateral electrode placement, ultrabrief pulse width, square wave electrical stimulation, and increasing the length of time between treatments. In addition, new technologies such as magnetic seizure therapy (MST) are under investigation as an alternative method to initiate seizures (which are thought to be the essential aspect of the therapy).

 By shaping the magnetically induced electric field that initiates the seizure to minimize the effect on brain areas related to memory function, MST may ultimately be associated with significantly fewer cognitive adverse events. Published study results suggest that MST leads to fewer cognitive adverse events than ECT while preserving efficacy.

Repetitive Transcranial Magnetic Stimulation

Another neurostimulation modality for TRD is 

repetitive transcranial magnetic stimulation

 (rTMS), which was cleared by the FDA for TRD in 2008. It has an excellent safety profile, with the primary significant adverse event being the rare occurrence of seizures. It was initially unclear whether rTMS demonstrated the speed of response and high degree of effectiveness needed for patients with severe depression or TRD. However, recent work to optimize the dosage of rTMS (including neuronavigated individualized spatial targeting and accelerated delivery of multiple treatment sessions) have improved treatment outcomes. Intermittent theta-burst stimulation (iTBS)—a form of rTMS—was recently cleared by the FDA for use in TRD. iTBS, which cuts treatment session times from 50 minutes to 3 minutes, was cleared based on studies demonstrating comparable results with standard 10 Hz rTMS.

 In addition, further refinements to the treatment (ie, functional-connectivity-guided targeting) may lead to even greater rates of effectiveness.

 Another recently reported approach couples iTBS with individualized circuit-based neuronavigation and an accelerated treatment schedule called the SNT protocol. A randomized controlled trial of SNT found a 52.5% drop in depression scores with active SNT compared with an 11.1% drop with sham.

Vagus nerve stimulation (VNS), which initially received FDA approval for epilepsy, was later discovered to have antidepressant effects; it received FDA approval for TRD in 2005 as an adjunctive treatment for depression that has failed to respond to at least 4 adequately dosed antidepressant treatments. Although the pivotal randomized controlled trial failed to find definitive evidence of efficacy, a 1-year, nonrandomized comparison of open-label VNS versus treatment as usual found a significant advantage in the VNS group.

 A new randomized controlled trial is currently underway to provide more definitive evidence (NCT03887715).

A final consideration for severe and refractory TRD patients is deep brain stimulation (DBS). DBS is not FDA approved for depression but is on the US market to treat Parkinson disease, epilepsy, essential tremor, dystonia, and OCD. For TRD, DBS may be accessible in the context of research studies. DBS treatment consists of electrode placement and electrical stimulation of the ventral capsule/ventral striatum or subgenual cingulate cortex. In smaller investigations and case studies, DBS appeared to demonstrate immediate and striking improvements in 

. However, 2 phase 3 trials were terminated early after interim analyses of the results, and further large-scale trials have not yet been undertaken. Research on DBS has continued, but in a different direction (including identification of novel targets, predictors of response, and novel stimulation approaches). One promising strategy has been the development of closed-loop systems, pairing chronic deep-brain sensing to individualize stimulation programs for patients with TRD.

In summary, a number of viable new options offer the possibility of optimizing care for patients with TRD. The 

 summarizes the currently available, developing, and promising new treatments previously described. Given the field’s relative lack of clinical experience with these treatments, these treatments should be considered cautiously after a comprehensive assessment of benefits and risks. However, given the risks of inadequately treated depression, they deserve consideration. In addition, these mechanistically novel treatments may further our collective understanding of depression and serve to further transform depression therapeutics.

Funding for this work was provided by the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH; ZIAMH002927).

is the medical director of the clinical research unit in the experimental therapeutics and pathophysiology branch at the National Institute of Mental Health.

is director of the NIMH’s Division of Translational Research and director of the Noninvasive Neuromodulation Unit in the NIMH Intramural Research Program; she is also JP Gibbons Professor Emeritus in the Duke University School of Medicine’s Department of Psychiatry and Behavioral Sciences.

is an NIH Distinguished Investigator as well as chief, Section on Neurobiology and Treatment of Mood and Anxiety Disorders, of NIMH’s Experimental Therapeutics and Pathophysiology Branch. He is also clinical professor of psychiatry and behavioral sciences at George Washington University.

Definition and epidemiology of treatment-resistant depression.

2. Rush AJ, Trivedi MH, Wisniewski SR, et al. 

Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report.

3. Berman RM, Cappiello A, Anand A, et al. 

Antidepressant effects of ketamine in depressed patients.

4. Zarate CA Jr, Singh JB, Carlson PJ, et al. 

A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression.

Novel glutamatergic modulators for the treatment of mood disorders: current status.

6. Zarate CA Jr, Park L. Ketamine and esketamine. In: Ruiz P, Sadock BJ, Sadock VA, eds. 

 Lippincott Williams & Wilkins; In press.

7. Rodriguez CI, Kegeles LS, Levinson A, et al. 

Randomized controlled crossover trial of ketamine in obsessive-compulsive disorder: proof-of-concept.

8. Feder A, Parides MK, Murrough JW, et al. 

Efficacy of intravenous ketamine for treatment of chronic posttraumatic stress disorder: a randomized clinical trial.

9. Taylor JH, Landeros-Weisenberger A, Coughlin C, et al. 

Ketamine for social anxiety disorder: a randomized, placebo-controlled crossover trial.

10. Jones JL, Mateus CF, Malcolm RJ, et al. 

Efficacy of ketamine in the treatment of substance use disorders: a systematic review.

11. Papakostas GI, Salloum NC, Hock RS, et al. 

Efficacy of esketamine augmentation in major depressive disorder: a meta-analysis.

12. Gastaldon C, Raschi E, Kane JM, et al. 

Post-marketing safety concerns with esketamine: a disproportionality analysis of spontaneous reports submitted to the FDA Adverse Event Reporting System.

Comparative efficacy of racemic ketamine and esketamine for depression: a systematic review and meta-analysis.

14. McIntyre RS, Rosenblat JD, Nemeroff CB, et al. 

Synthesizing the evidence for ketamine and esketamine in treatment-resistant depression: an international expert opinion on the available evidence and implementation.

15. Kanes S, Colquhoun H, Gunduz-Bruce H, et al. 

Brexanolone (SAGE-547 injection) in post-partum depression: a randomised controlled trial.

16. Carhart-Harris R, Giribaldi B, Watts R, et al. 

Trial of psilocybin versus escitalopram for depression.

17. Nayak SM, Gukasyan N, Barrett FS, et al. 

Classic psychedelic coadministration with lithium, but not lamotrigine, is associated with seizures: an analysis of online psychedelic experience reports.

18. FDA in Brief: FDA takes action to ensure regulation of electroconvulsive therapy devices better protects patients, reflects current understanding of safety and effectiveness. FDA. News release. December 21, 2018. Accessed March 10, 2022. 

https://www.fda.gov/news-events/fda-brief/fda-brief-fda-takes-action-ensure-regulation-electroconvulsive-therapy-devices-better-protects

Speed of response and remission in major depressive disorder with acute electroconvulsive therapy (ECT): a Consortium for Research in ECT (CORE) report.

20. Kellner CH, Husain MM, Knapp RG, et al; CORE/PRIDE Work Group. 

A novel strategy for continuation ECT in geriatric depression: phase 2 of the PRIDE study.

21. Lisanby SH, McClintock SM, McCall WV, et al; Prolonging Remission in Depressed Elderly (PRIDE) Work Group. 

Longitudinal
neurocognitive effects of combined electroconvulsive therapy (ECT) and pharmacotherapy in major depressive disorder in older
adults: phase 2 of the PRIDE study.

22. Lisanby SH, Luber B, Schlaepfer TE, Sackeim HA. 

Safety and feasibility of magnetic seizure therapy (MST) in major depression: randomized within-subject comparison with electroconvulsive therapy. 

Comparative efficacy and cognitive function of magnetic seizure therapy vs. electroconvulsive therapy for major depressive disorder: a systematic review and meta-analysis.

24. Blumberger DM, Vila-Rodriguez F, Thorpe KE, et al. 

Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial.

25. Cole EJ, Phillips AL, Bentzley BS, et al. 

Stanford neuromodulation therapy (SNT): a double-blind randomized controlled trial.

26. George MS, Rush AJ, Marangell LB, et al. 

A one-year comparison of vagus nerve stimulation with treatment as usual for treatment-resistant depression.

27. Rush AJ, Marangell LB, Sackeim HA, et al. 

Vagus nerve stimulation for treatment-resistant depression: a randomized, controlled acute phase trial.

28. Scangos KW, Khambhati AN, Daly PM, et al. 

Closed-loop neuromodulation in an individual with treatment-resistant depression.

In this CME, review novel, currently available, and promising pharmacological treatment options for treatment-resistant depression.

Promising Strategies for Treatment-Resistant Depression

H. Steven Moffic, MD, in this very special episode of the weekly Psychiatry & Society series, interviews a patient, Nancy Dale Alterman. By sharing her story about how ECT treatment improved her life, she hopes to help others and end stigma. 

is an award-winning psychiatrist who has specialized in the cultural and ethical aspects of psychiatry. A prolific writer and speaker, he received the one-time designation of Hero of Public Psychiatry from the Assembly of the American Psychiatric Association in 2002. He is an advocate for mental health issues relate to climate instability, burnout, Islamophobia, and anti-Semitism for a better world. He serves on the Editorial Board of

is a patient who has lived in Denver her whole life. She is an artist and is also very involved in nonprofits focusing on the mental health community, and various causes, including animal welfare.

ECT played an important role in this patient's journey to recovery.

Heroic Journey to Recovery: A Patient's Story

included a Point/Counterpoint feature on electroconvulsive therapy (ECT). The feature elicited strong reactions from our readers. You can read the introductory essay, “Electroconvulsive Therapy: Obsolete and Dangerous or Still Just Misunderstood?” by Horacio A. Capote, MD, 

The authors of the original Point/Counterpoint have also continued their debate online. You can read a brief 

 for the opportunity to comment on the recent 

 articles in the April, 2021 issue on (ECT). The choice was presented as “

.” It is no choice at all: ECT is demonstrably safe and effective, but yes, still badly misunderstood.

ECT has evolved into a modern medical treatment for a limited number of psychiatric illnesses, primarily severe depression, but also psychosis and catatonia. ECT is what it is today, not what it was before modern general anesthesia, and needs to be objectively assessed, by true experts with recent experience in its use, and an understanding of the severity of the disorders it treats. We strongly support Michael E. Henry, MD’s position on ECT. He offers an accurate expert opinion based on evidence and experience. That is the information that should guide patients and physicians about ECT.

ECT has saved and improved countless lives, but as with any medical treatment or procedure, particularly one involving general anesthesia, there are risks and adverse effects; the decision to prescribe ECT always involves balancing those risks against potential benefits to the patient. That is the true, evidence-based process that expert ECT physicians follow when making a recommendation to consider ECT for a particular patient. Such a recommendation is never made cavalierly; it takes into account the severity and urgency of the psychiatric illness, the medical condition, and the treatment wishes of the patient. The informed consent process for ECT in the United States is comprehensive and follows modern ethical guidelines.

Unfortunately, misinformation perpetuates the stigma surrounding ECT. Attempts to discredit it are often based on ignorance of the realities of contemporary ECT, or worse, are ideologically driven and with questionable motives. ECT is not an ideology, a belief, or a religion. It is simply a medical procedure, with benefits and side effects. In truth there is no real point-counterpoint when one side is misinformation and distortions and the other side is medical fact.

Severe depression is disabling and sometimes life-threatening; until a worthy replacement for ECT is developed, patients and psychiatrists can be reassured that ECT is available when other treatments are ineffective. In knowledgeable medical circles, there is no controversy about that.

is the president of the International Society for ECT and Neurostimulation (ISEN). 

 is the chair of the Board of Directors of the ISEN.

A Psychiatric Times point/counterpoint feature on electroconvulsive therapy elicited strong responses.  

A Spirited Defense of ECT: From Our Readers

included a Point/Counterpoint feature on electroconvulsive therapy (ECT). You can read the introductory essay, “Electroconvulsive Therapy: Obsolete and Dangerous or Still Just Misunderstood?” by Horacio A. Capote, MD, 

 have agreed to continue their debate online. Ms. Hancock, Cunliffe, and Dr Read argue that ECT is 

. Representing the pro-ECT position, Dr Henry has responded to their article below.

I would also like to thank Sarah Hancock, MS, CRC, Sue Cunliffe, MBchB, RCPCH, John Read, PhD for responding to my article “

Their objections to electroconvulsive therapy (ECT) are primarily focused on the cognitive side effects, which they feel are caused by ECT-induced brain damage, and methodologic issues with studies supporting the efficacy of ECT. The main problem with their critique is that they appear to misinterpret the statistics they are presenting.

For example, when they discussed the findings of Peltzman and colleagues, they reported that the study found that ECT patients in the Veterans Health Administration (VHA) were 1.3 times more likely to die by suicide than 

 They failed to appreciate that when the authors compared the ECT patients to a risk-matched cohort, this finding did not meet statistical significance (

=.095), despite the large sample size of 14,810 ECT patients and 58,369 controls. They also failed to mention the authors’ conclusion that the “use of ECT in the VHA is rare. Patients who receive ECT have a complex and high-risk profile …”

 Similarly, Hancock and colleagues cite statistics from Duma and colleagues regarding 

 In their meta-analysis of the major cardiac events, the authors conservatively excluded 28 of 82 studies because they reported no adverse events. Without inclusion of this group the incidence of cardiac deaths and all-cause mortality were 0.18 and 0.33 per 1000 patients, respectively. When this group of studies was included, the incidence of cardiac deaths and all-cause mortality dropped to 0.04 and 0.13 per 1000 patients. They also did not consider that in the Veterans Health cohort, the risk ratio of all-cause mortality for the ECT group was a statistically non-significant 0.88, less than the non-ECT group.

My previous response to the question of whether ECT causes brain damage has already highlighted the findings and conclusions of Gbyl and Videbech, who reviewed 32 imaging studies of ECT with a total of 467 patients and 285 controls. They reported that none of the studies they reviewed found evidence of 

 Hancock and colleagues point to EEG, PET, SPECT, and fMRI data that show relative decreases in the activity of the frontal and temporal lobes after ECT as evidence that ECT causes brain damage.

 They do not appear to have considered the data that show depression is associated with overactivity in these same brain regions.

In addition to failing to present a balanced interpretation of the safety data for ECT, Hancock and colleagues ignore converging lines of evidence that support the efficacy of ECT. For example, they reject a study such as that published by Helle and colleagues, for lack of a 

 In this study, the authors used a randomized parallel treatment design with blinded raters to compare brief-pulse RUL to algorithm-based pharmacology in 73 subjects with bipolar depression. They found a significantly higher response rate of 73.9% for the ECT group versus 35.0% for the medication group (

 = .01). These results are remarkably similar to those of Perugi and colleagues, who treated 522 consecutive patients with treatment-resistant bipolar disorder with ECT and found response rates of 68.1 for bipolar depression, 72.9% for mixed state, 75% for mania and 80% for catatonia.

 To provide some context for these response rates, one of the pivotal clinical trials for the olanzapine/fluoxetine combination treatment for bipolar depression reported a response rate of 56.1% for the active drug versus 30.4% for the placebo treatment arm.

 Although these latter results are from a separate study, the response rates are consistent with other medication studies in this population.

Most importantly, we should not forget that the treatment options for individuals afflicted with severe depression, many of whom actively contemplate suicide frequently, are limited. Hancock and colleagues should apply balanced, rigorous scientific scrutiny to the available data before they advocate against ECT. Their analysis to date has not met that standard.

is the head of ECT and lecturer on psychiatry at Massachusetts General Hospital. He receives salary support from a National Institutes of Health grant on ECT.

1. Henry ME. ECT: an effective and safe treatment. 

2. Peltzman T, Gottlieb DJ, Shiner B, Riblet N, Watts BV. Electroconvulsive Therapy in Veterans Health Administration Hospitals: Prevalence, Patterns of Use, and Patient Characteristics. 

3. Peltzman T, Shiner B, Watts BV. Effects of Electroconvulsive Therapy on Short-Term Suicide Mortality in a Risk-Matched Patient Population. 

4. Duma A, Maleczek M, Panjikaran B, Herkner H, Karrison T, Nagele P. Major Adverse Cardiac Events and Mortality Associated with Electroconvulsive Therapy: A Systematic Review and Meta-analysis. 

5. Gbyl K, Videbech P. Electroconvulsive therapy increases brain volume in major depression: a systematic review and meta-analysis. 

6. Fosse R, Read J. Electroconvulsive treatment: hypotheses about mechanisms of action. 

7. Dale E, Pehrson AL, Jeyarajah T, et al. Effects of serotonin in the hippocampus: how SSRIs and multimodal antidepressants might regulate pyramidal cell function. 

8. Schoeyen HK, Kessler U, Andreassen OA, et al. Treatment-resistant bipolar depression: a randomized controlled trial of electroconvulsive therapy versus algorithm-based pharmacological treatment. 

9. Perugi G, Medda P, Toni C, et al. The role of electroconvulsive therapy (ECT) in bipolar disorder: effectiveness in 522 patients with bipolar depression, mixed-state, mania and catatonic features. 

10. Tohen M, Vieta E, Calabrese J, et al. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. 

11. Bahji A, Ermacora D, Stephenson C, et al. Comparative efficacy and tolerability of adjunctive pharmacotherapies for acute bipolar depression: a systematic review and network meta-analysis. 

12. Pompili M, Verzura C, Trovini G, et al. Lurasidone: efficacy and safety in the treatment of psychotic and mood disorders. 

Research data shows that ECT is often more effective than alternative treatments, and safe too. 

In Defense of ECT

 have agreed to continue their debate online. Below, Ms. Hancock, Ms. Cunliffe, and Dr Read argue that ECT is ineffective and unsafe. Representing the pro-ECT position, Dr Henry has responded to their article 

We thank Michael E. Henry, MD, for responding to our article electroconvulsive therapy (ECT): “

,” Henry challenges the conclusion of a recent review

 that there is no robust evidence to determine whether ECT is better than placebo: “The selection criteria used by Read and colleagues were limited to older studies (1956 to 1985).”

 The selection criteria were not time-limited. There simply have not been any placebo-controlled ECT studies since 1985.

 Furthermore the 11 pre-1986 studies were grossly flawed.

We agree with Henry that modern treatment approval requires rigorous, randomized, placebo-controlled methodology using the universally accepted standards of evidence-based medicine. ECT clearly lacks this sort of evidence-base.

Henry produces 3 traditional defences for this empirical data vacuum. First, he argues that studies without placebo control groups, such as comparing different electrode placements, are sufficient. A review of these non-placebo studies, however, revealed that none “produced robust evidence that ECT is effective for depression, primarily because at least 60% maintained ECT participants on medication, 89% produced no meaningful follow-up data beyond the end of treatment, and none investigated whether ECT prevents suicide.”

Second, Henry refers to “more than 75 years of clinical experience”

 as evidence of efficacy. Unfortunately, history is littered with treatments used for decades until deemed ineffective, harmful, or both.

Third, Henry brings up the “ethical dilemma of treating very ill patients with a placebo treatment.”

 But this assumes ECT is safe and more effective than a placebo, and that is precisely what is in question. Assuming its efficacy would position ECT proponents beyond the parameters of evidence-based medicine. Testing treatments in vulnerable populations is essential to establish efficacy, safety limits, and device regulatory protocols.

Henry portrays ECT-induced brain abnormalities, like hippocampal enlargement, as necessarily beneficial. However, a 2013 review of more than 100 imaging studies concluded “the temporarily improved scores on depression instruments following ECT reflect the combination of frontal and temporal lobe functional impairments and activation of the HPA axis and the mesocorticolimbic dopamine system. These effects as well as other detailed changes observed in structures such as the hippocampus appear consistent with those typically seen after severe stress-exposure and/or brain trauma.”

There is no evidence that ECT prevents suicide. A recent study found that 14,810 ECT patients were 1.3 times more likely to die by suicide than 58,369 ECT controls.

1. ECT provides only short-term symptom relief. There are no studies demonstrating ECT outperforms placebo beyond treatment termination, and none that it prevents suicide.

ECT has been in use for decades, but does that mean it is safe or effective? 

Electroconvulsive Therapy

Promising Strategies for Treatment-Resistant Depression

Heroic Journey to Recovery: A Patient's Story

A Spirited Defense of ECT: From Our Readers

In Defense of ECT

Raising Doubts About ECT

The Man Who First Used ECT: Ugo Cerletti

Fast-Acting Options for Mood Disorders and Psychiatric Emergencies

PsychPoll: ECT, Yay or Nay?

ECT: An Effective and Safe Treatment

ECT: Dangerous on Either Side of the Pond