From the Editor

“Ketamine Shows Promise for Hard-to-Treat Depression in New Study”

 – The New York Times

The gold standard for treatment-refractory depression has been ECT. Last week, The New England Journal of Medicine published a new study by Dr. Amit Anand (of Harvard University) and his co-authors comparing ketamine with ECT. They did a noninferiority trial, with more than 400 people. The results have been widely reported, including in The New York Times. They write: “This randomized trial evaluating the comparative effectiveness of ketamine and ECT in patients with treatment-resistant depression without psychosis showed noninferiority of ketamine to ECT…” We discuss the paper and the accompanying Editorial.

A recent Canadian Medical Association survey found that the majority of physicians reported experiencing high levels of burnout. In the second selection, Dr. Srijan Sen (of the University of Michigan) discusses this timely topic in a new Quick Takes podcast. He talks about the definition(s) of burnout, and the overlap with depression. “Burnout has become a loose term that means different things to different people.”

And in the third selection, Dr. Thomas Insel (of the Steinberg Institute) and his co-authors discuss the life and death of New Yorker Jordan Neely. In an essay for The Washington Post, they argue for better care, in particular with a focus on rehabilitation services for those with schizophrenia. “People with other brain disorders are not abandoned to become homeless or incarcerated rather than receive medical help.”


Selection 1: “Ketamine versus ECT for Nonpsychotic Treatment-Resistant Major Depression”

Amit Anand, Sanjay J. Mathew, Gerard Sanacora, et al

The New England Journal of Medicine, 24 May 2023

Major depressive disorder is a leading cause of disability worldwide and is estimated to affect 21 million adults in the United States. Although antidepressants are widely available, the effectiveness of antidepressants is suboptimal in more than a third of patients…

Electroconvulsive therapy (ECT) has a track record of nearly 80 years as one of the most effective and rapid strategies for treatment-resistant major depression. Advancements in ECT, including administration while the patient is under brief general anesthesia, unilateral electrode placement, and refined techniques for seizure elicitation such as ultrabrief pulse stimulation, have enabled it to be more commonly performed as an outpatient procedure. However, ECT remains underused owing to limited availability, social stigma, and concerns regarding the adverse effect of cognitive impairment.

Ketamine, an N-methyl-d-aspartate receptor antagonist, has been approved by the Food and Drug Administration as a sedative, analgesic, and general anesthetic. Over the past two decades, ketamine, administered intravenously at subanesthetic doses of 0.5 mg per kilogram of body weight, was noted to have a rapid antidepressant effect in patients with major depressive disorder and treatment-resistant major depression… Ketamine is an attractive alternative for patients because it does not require general anesthesia and is not associated with clinically significant memory impairment…

So begins a paper by Anand et al.

Here’s what they did:

“We conducted an open-label, randomized, noninferiority trial involving patients referred to ECT clinics for treatment-resistant major depression. Patients with treatment-resistant major depression without psychosis were recruited and assigned in a 1:1 ratio to receive ketamine or ECT. During an initial 3-week treatment phase, patients received either ECT three times per week or ketamine (0.5 mg per kilogram of body weight over 40 minutes) twice per week. The primary outcome was a response to treatment (i.e., a decrease of ≥50% from baseline in the score on the 16-item Quick Inventory of Depressive Symptomatology–Self-Report; scores range from 0 to 27, with higher scores indicating greater depression)… Secondary outcomes included scores on memory tests and patient-reported quality of life. After the initial treatment phase, the patients who had a response were followed over a 6-month period.”

Here’s what they found:

  • “A total of 403 patients underwent randomization at five clinical sites… After 38 patients had withdrawn before initiation of the assigned treatment, ketamine was administered to 195 patients and ECT to 170 patients.”
  • Demographics. “The mean age was 46 years, 51.1% were women, and 88.1% were White…”
  • Illness severity. “The severity of the current depression episode was moderate to severe with a median duration of 2.0 years… Most patients (77.9%) had a family history of depression, and 39.0% had attempted suicide.”
  • Primary outcome. “A response according to the QIDS-SR-16 occurred in 108 of 195 patients (55.4%) in the ketamine group and in 70 of 170 patients (41.2%) in the ECT group…”
  • Memory. “ECT appeared to be associated with a decrease in memory recall after 3 weeks of treatment.”
  • Adverse events. “During the initial treatment phase, 49 of 195 patients (25.1%) in the ketamine group and 55 of 170 patients (32.4%) in the ECT group had at least one moderate or severe adverse event.”
  • Follow up. “Relapse, defined as a QIDS-SR-16 score greater than 11, occurred in 19.0% of the patients in the ketamine group and in 35.4% of those in the ECT group at month 1; in 25.0% and 50.9%, respectively, at month 3; and in 34.5% and 56.3%, respectively, at month 6….”

A few thoughts:

1. This is an impressive study, with more than 400 people randomized, drawing on multiple sites, with solid analyses, published in a Very Big Journal.

2. Ketamine did well. (!) 

3. The key finding in a sentence: “Ketamine was noninferior to ECT as therapy for treatment-resistant major depression without psychosis.”

4. Was ECT’s impact undermined by the design of the study? Those receiving this treatment over 3 weeks had 6-9 sessions, which is modest (as opposed to, say, a fuller course of 12-15 sessions). As the authors note, the percentage of patients achieving remission was lower than in other reports. Ketamine performed well – but the ECT arm was not consistent with the full course of treatment that would occur in clinical practice.

5. Following up on the last point, the sample excluded those with psychosis, a population well served by ECT. As the authors note: “Our trial results differ from those of a recent European trial and a meta-analysis that included several small trials and the larger European ketECT trial. These trials showed that remission with ketamine was inferior to that with ECT. Our trial differs from these reports in that it included only patients with major depressive disorder without psychosis (those with psychosis were excluded), had a larger sample size, and was performed in a primarily outpatient population (89% of patients).” Again, ketamine performed well – but ECT’s effects need to be considered in light of the design limitation of 6-9 treatments and the population chosen.

4. The paper runs with an Editorial, “Ketamine and ECT in Depression – Risks and Rewards” by Dr. Robert Freedman (of the University of Colorado).

Dr. Freedman notes problems with the ECT, including “the duration of seizures during the first 3 weeks of the trial may not have been sufficient and may have led to the slightly lower response in the ECT group.”

He also offers a cautionary comment about ketamine.

“The positive response to ketamine is not without precedent. Ketamine has mixed pharmacologic properties as an anesthetic, an opiate, and a sympathomimetic. The agent thus combines properties that many persons – not only those with severe depression – find rewarding. Accordingly, ketamine is also widely used recreationally. The question raised by this trial and others is how clinicians and regulatory agencies should regard its use and abuse. For someone who is chronically ill with depression, 3 weeks of lightened mood is undoubtedly a gift. Many patients have reported ketamine therapy to be life-changing, and many clinicians are enthusiastic about bringing this gift to patients who otherwise seem unreachable. However, the results of this current trial suggest that the 3-week treatment was not life-changing. Ketamine treatment was effective, but by 6 months, a brief period in a lifetime of depression, the quality of life was no better with the agent than with ECT.”

Robert Freedman

The Editorial can be found here:

5. A quick word of thanks to several who helped me better understand this paper, including Dr. Daniel Blumberger (of the University of Toronto).

The full NEJM paper can be found here:

Selection 2: “Physician Burnout & Depression”

Srijan Sen

Quick Takes, May 2023

Is physician burnout, in fact, depression? 

In this episode, Dr. Sen notes the strong overlap. In our lively conversation, we also discuss the confusion over the definition of burnout, the key contributing factors (workload, environment, and – no surprise – the EMR), and how the old concept of a doctor’s lounge could be a new way of helping to address burnout.

We highlight from the discussion:

On the definition

“Burnout has become a loose term that means different things for different people. I think that’s made it harder to do research. One example: out of 182 studies looking at burnout, there were 142 different definitions. So different researchers are talking about different things. In colloquial discussions, it’s even broader.”

On scales and depression

“This is talked about quite eloquently by Dr. Maslach who’s composed many of the most used burnout scales – burnout should be measured as a continuously from slight symptoms to very severe burnout. And I think on the lower end of the spectrum, those symptoms are relatively normal that it would be impossible to go through life without experiencing. And on the more severe end, they’re a critical problem. Depression – there’s a spectrum from mild depressive symptoms, and many of our scales are written like this, to moderate and severe depressive symptoms with risk for suicide.”

On the concept of burnout

“It was conceptualized as a way to capture the emotional distress and problems that come specifically from the work environment – from our experience in the clinical environment, and distinguishing that from symptoms that arise from other parts of life. Research shows that the burnout inventories that have been developed so far are not successful in specifically capturing the emotional distress caused by the workplace and distinguishing it from the home environment and other sources.”

On prevention

“In our October article in The New England Journal on work hours and depression, we found that the training physicians working 80 or 90 hours plus a week had three times the depressive symptom rate as individuals working 45 hours or less. And no other factor had as much of an impact on depression. And so, in preventing depression among training physicians, it is critical to focus on work hours. 

“We also know from the literature important factors that are critical in preventing depression: psychotherapies, adequate sleep and the right type of sleep and timing, exercise, and social connection.”

The above answers have been edited for length.

The Quick Takes podcast can be found here, and is just over 21 minutes long:

Selection 3: America should fund rehab for schizophrenia – not jail and ER”

Thomas Insel, Arvind Sooknanan, Ken Zimmerman

The Washington Post, 23 May 2023

The system failed Jordan Neely long before his violent killing on a New York subway train.

At age 14, after his mother was murdered, Neely fell into depression. He dropped out of school, and his mental illness progress untreated until he was homeless and cycling through jail cells and emergency rooms.

Friends and family say Neely lived with schizophrenia and post-traumatic stress disorder. He was hospitalized so often that he was on the Top 50 list kept by the New York City Department of Homeless Services of people in need of acute care. Despite hundreds of encounters with social work teams and a week-long stay at Bellevue in one of the city’s few psych beds, his life ended in tragedy.

Neely’s story highlights the cruelties of a broken system. People with serious mental illness are shuttled among prisons, encampments and hospitals for crisis care that costs the nation billions. There’s a better way.

So begins an essay by Insel et al.

They ask how things had gone so poorly for Neely. “The painful answer is that society has failed to ensure that people with serious mental illness, especially those of color, get the care that could help them recover. They might receive medication in jail or the hospital. They might get emergency services. But less than 5 percent of the 14 million Americans with serious mental illness receive the kind of rehabilitative services that could have helped Neely.”

“They can be as effective as dialysis is for renal failure or physical therapy is after a stroke.”

They advocate for supportive housing and peer support. The article focuses on the clubhouse model, “developed by and for people with serious mental illness.” They write: “Here the creation of community is a therapeutic intervention. Clubhouses address the social determinants of health: poverty, housing insecurity and isolation. The sanctuary they provide results in long-term recovery and thriving.” One of the co-authors was hospitalized nearly two dozen times before connecting with a clubhouse. “He now lives independently, is finishing his studies, has run a political campaign and is no longer disabled by psychosis. He is aware every day that his fate could have been very different.”

The article ends with a call to do better: “The current approach, cramming patients into emergency rooms and correctional facilities, is surely the most expensive and least effective.”

A few thoughts:

1. This is an excellent essay.

2. Their argument for rehab is compelling.

3. Dr. Insel, a former director of the NIMH, has been featured in past Readings, including a Quick Takes podcast interview, which can be found here:

The Wash Post essay can be found here:

Reading of the Week. Every week I pick articles and papers from the world of Psychiatry.