The findings were published on October 5 in the New England Journal of Medicine and presented the same week at the annual meeting of the European College of Neuropsychopharmacology.

“This is the first trial to compare this new treatment with a standard existing treatment for treatment-resistant depression, and so it’s a really necessary study. The results are very positive,” said lead author Dr. Andreas Reif, professor of psychiatry at Goethe University in Frankfurt, Germany,

Reif continued, “We were testing patients at two endpoints (goals). The first major endpoint was to understand the proportion of patients who achieved remission after eight weeks. The second was determining the proportion of patients who met the first endpoint and who were relapse free at the end of the trial period (i.e. after 32 weeks). We measured the effects of treatment using a standard depression scale, the Montgomery‑Åsberg Depression Rating Scale.”

The investigators enrolled adult subjects with treatment-resistant depression, all of whom had taken antidepressants, such as an SSRI (selective serotonin reuptake inhibitor) or an SNRI (serotonin and norepinephrine reuptake inhibitor).

They assigned 336 subjects to treatment with esketamine nasal spray plus an SSRI or SNRI, and  340 subjects to quetiapine plus an SSRI or SNRI. Treatment lasted eight weeks, followed by 24 weeks of maintenance therapy.

For the primary endpoint, at eight weeks, 28% of the subjects taking esketamine plus antidepressants had achieved remission compared to 18% remission in the quetiapine-treated group.

At the 32-week secondary endpoint mark, 22% of the subjects taking esketamine plus antidepressants remained in remission, compared to 14% of the subjects treated with quetiapine plus antidepressants.

“There were other differences we saw over time,” said investigator Professor Allan Young of Kings College, London, UK. “For example the patients receiving the esketamine treatment had fewer depressive symptoms than those taking quetiapine. We found that patients receiving esketamine NS were around 1.5 times as likely to experience remission at Week 8 than those receiving quetiapine XR.  In addition, esketamine NS‑treated patients were 1.5 times as likely to achieve the key secondary endpoint, remaining relapse free through Week 32. Indeed, by Week 32, approximately half of patients receiving esketamine NS were in remission, while two thirds were responders, emphasising the importance of continuing treatment in those who do not achieve remission in the acute phase”.

Commenting on the findings, Dr Josep Antoni Ramos-Quiroga from Vall Hebron University Hospital (CIBERSAM) and Autonomous University of Barcelona, Spain said, “The results of this study show the superior response and safety of esketamine nasal spray when compared with quetiapine. This gives people with treatment-resistant depression more safe treatment options.”

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“ECT has been the gold standard for treating severe depression for over 80 years,” said Amit Anand, MD, director of Psychiatry Translational Clinical Trials at Mass General Brigham and Professor of Psychiatry at Harvard Medical School. “But it is also a controversial treatment because it can cause memory loss, requires anesthesia and is associated with social stigma. This is the largest study comparing ketamine and ECT treatments for depression that has ever been done, and the only one that also measured impacts to memory.”

Major Depressive Disorder (MDD) is a leading cause of disability worldwide and is estimated to affect 21 million adults in the United States. ECT involves inducing a seizure via electrical stimulation of the brain. Ketamine is a low-cost dissociative drug approved by the Food and Drug Administration as a sedative/analgesic and general anesthetic. Previous studies have suggested that low doses of the drug may have rapid antidepressant effects for people with MDD.

The trial was conducted from March 2017 to September 2022 at five sites with 403 patients randomized one-to-one to either receive ECT three times per week or ketamine twice per week for three weeks. Patients were followed for a period of six months after treatment and responded to a depressive symptom self-assessment questionnaire, which also included memory tests and questions about quality of life.

The researchers found that 55 percent of those receiving ketamine and 41 percent of those receiving ECT reported at least a 50 percent improvement in their self-reported depressive symptoms and an improvement in their self-reported quality of life that lasted throughout the six-month monitoring period. ECT treatment was associated with memory loss and musculoskeletal adverse effects. Ketamine treatment was not associated with side effects other than an experience of transient dissociation at the time of treatment.

“For the ever-growing number of patients who do not respond to conventional psychiatric treatments and need a higher level of care, ECT continues to be the most effective treatment in treatment-resistant depression,” said Murat Altinay, MD, Psychiatrist and lead of the trial site at Cleveland Clinic. ” This study shows us that intravenous ketamine was non-inferior to ECT for treatment of non-psychotic treatment resistant depression and could be considered as a suitable alternative treatment for the condition.”

The current study is the largest-to-date real-world comparative effectiveness trial of ECT vs. ketamine. The trial took a patient-centered approach, with three types of independent depression ratings (patient, rater, and clinician) captured and no active solicitation of participants.

The authors note that their findings are based on self-reported outcomes and that the trial’s open-label design could have influenced response rates. But the trial’s patient-centeredness and the real-world design may also be a strength, allowing the findings to be more easily translated into clinical practice.

Anand’s team is now working on a follow-up study comparing ECT and ketamine treatments for patients with acute suicidal depression to see if the same promising impact is seen in that population.

“People with treatment-resistant depression suffer a great deal, so it is exciting that studies like this are adding new options for them,” said Anand. “With this real-world trial, the results are immediately transferable to the clinical setting.”

Disclosures: Disclosures for each author are available with the full text of the article.

Funding: This study was funded by the Patient Centered Outcome Research Institute (TRD-1511-33648) and sponsored by the Cleveland Clinic.

Paper cited: Anand, A. et al. “ECT vs. Ketamine for Non-psychotic Treatment-Resistant Major Depression.” New England Journal of Medicine DOI: 10.1056/NEJMoa2302399

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The new findings are published March 3 in The New England Journal of Medicine and are to be presented that same day by Eric J. Lenze, MD — principal investigator and head of the Department of Psychiatry at Washington University — and colleagues at the annual meeting of the American Association for Geriatric Psychiatry in New Orleans.

Many people with clinical depression don’t respond to medications used to treat the condition. Consequently, some doctors switch such patients to different antidepressants in the pursuit of finding one that works, while other physicians may prescribe another class of drugs to see if a combination of medications helps.

Both strategies have been recommended by experts as options for older adults with treatment-resistant depression. However, the new study was designed to help determine which strategy is most effective. Augmenting an antidepressant with aripiprazole helped 30% of patients with treatment-resistant depression, compared to only 20% who were switched to another solo antidepressant, results of the study show.

‘Often, unless a patient responds to the first treatment prescribed for depression, physicians follow a pattern in which they try one treatment after another until they land on an effective medication,’ said Lenze, the Wallace and Lucille Renard Professor and the study’s corresponding author. ‘It would be beneficial to have an evidence-based strategy we can rely on to help patients feel better as quickly as possible. We found that adding aripiprazole led to higher rates of depression remission and greater improvements in psychological well-being — which means how positive and satisfied patients felt — and this is good news. However, even that approach helped only about 30% of people in the study with treatment-resistant depression, underscoring the need to find and develop more effective treatments that can help more people.’

Treatment-resistant depression is no more or less common in older people than younger people, but because it seems to accelerate cognitive decline, identifying more effective ways to treat it is very important.

Lenze, along with colleagues at Columbia University, UCLA, the University of Pittsburgh and the University of Toronto, studied 742 people, ages 60 and older, with treatment-resistant depression, meaning their depression had not responded to at least two different antidepressant medications.

The researchers evaluated strategies commonly used in clinical practice to help alleviate treatment-resistant depression in older patients and designed the study to have two distinct phases. In the first phase, 619 patients, each of whom was taking an antidepressant such as Prozac, Lexapro or Zoloft, were randomly divided into three groups. In the first group, patients remained on whatever antidepressant drug each already was taking but also received the drug aripiprazole (Abilify). A second group also continued taking antidepressants but added bupropion (brand names Wellbutrin or Zyban), and a third group tapered off of the antidepressant each had been taking and switched to bupropion entirely.

Over the course of 10 weeks, the participants received biweekly phone calls or in-person visits with study clinicians. At these visits, the medications were adjusted according to the individual patient’s response and side effects. The researchers found that the group that experienced the best overall outcomes was the one in which patients continued with their original antidepressants but added aripiprazole.

The researchers also anticipated that some people in the study wouldn’t respond to the various treatments, so they added a second phase that included 248 participants. In this phase, patients taking antidepressants such as Prozac, Lexapro and Zoloft were treated with lithium or nortriptyline — medications that were widely used before those other, newer antidepressants were approved more than two decades ago. Rates of alleviating depression in the study’s second phase were low, about 15%. And there was no clear winner when augmentation with lithium was compared with switching to nortriptyline.

‘Those older drugs also are a bit more complicated to use than newer treatments,’ Lenze explained. ‘Lithium, for example, requires blood testing to ensure its safety, and it’s recommended that patients taking nortriptyline receive electrocardiograms periodically to monitor the heart’s electrical activity. Since neither lithium nor nortriptyline were promising against treatment-resistant depression in older adults, those medications are unlikely to be helpful in most cases.’

But even the best treatment strategy — adding aripiprazole to an antidepressant — was not markedly successful for many older patients with treatment-resistant depression.

‘This really highlights a continuing problem in our field,’ said senior author Jordan F. Karp, MD, professor and chair of the Department of Psychiatry at the University of Arizona College of Medicine — Tuscon. ‘Any given treatment is likely to help only a subset of people, and ideally, we would like to know, in advance, who is most likely to be helped, but we still don’t know how to determine that.’

Lenze emphasized that overall, antidepressants are highly helpful for the majority of people suffering from clinical depression. At least half of all people with depression feel much better after they begin taking the first medication they try. And almost half of the remainder not helped by a first drug improve when switched to a second drug, But that leaves a sizeable group with clinical depression that does not respond to two treatments.

The problem is particularly difficult in older adults, many of whom already are taking several medications for other conditions such as high blood pressure, cardiac issues or diabetes,’ Lenze said. ‘So switching to new antidepressants every few weeks or adding other psychiatric drugs can be complicated. In addition, because depression and anxiety in older adults may accelerate cognitive decline, there’s an urgency to find more effective treatment strategies.

‘There definitely is something that makes depression harder to treat in this population, a population that’s only going to keep getting larger as our society gets older,’ he added.

The study was funded by a grant from the Patient-Centered Outcomes Research Institute (PCORI), grant TRD-1511-33321. No in-kind support was received from pharmaceutical companies. Other funding was provided by the Taylor Family Institute for Innovative Psychiatric Research at Washington University School of Medicine. Other support came from the National Center for Advancing Translational Sciences and the National Institute of Mental Health of the National Institutes of Health (NIH). Grant numbers: 5RO1 MH114980, K24 AT009198, R01 MH114981. Additional funding provided by the Labatt Fam

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