Reading of the Week: Augmentation in the Elderly with Depression – the New NEJM Study; Also, Dr. Simpson on Violence (Globe)

From the Editor

“Approximately 30% of patients treated for depression do not have a response to selective serotonin-reuptake inhibitors (SSRIs).” So notes an Editorial in The New England Journal of Medicine. And for those who don’t respond, what’s the next step? 

Unfortunately, though many elderly struggle with depression, this population is understudied. In a new paper published in the same journal, Dr. Eric J. Lenze (of the Washington University in St. Louis) and his co-authors attempt to answer that question with a two-step intervention. “In older adults with treatment-resistant depression, augmentation of existing antidepressants with aripiprazole improved well-being significantly more over 10 weeks than a switch to bupropion and was associated with a numerically higher incidence of remission. Among patients in whom augmentation or a switch to bupropion failed, changes in well-being and the occurrence of remission with lithium augmentation or a switch to nortriptyline were similar.” We look at the study and its clinical implications, as well as the accompanying Editorial.

And, in the other selection, Dr. Sandy Simpson (of the University of Toronto) considers the violence seen on public transit in Canada’s largest city. In an essay for The Globe and Mail, he mulls several factors and points a way forward, including by advocating a guaranteed basic income. “We are seeing now that we have failed to create a compassionate society, and that security and safety needs to extend to all people. To achieve this, we need a change in heart, and expenditure.”


Selection 1: “Antidepressant Augmentation versus Switch in Treatment-Resistant Geriatric Depression”

Eric J. Lenze, Benoit H. Mulsant, Steven P. Roose, et al.

The New England Journal of Medicine, 23 March 2023

Major depression is common in older adults and often persists despite appropriate treatment with first-line antidepressants. Treatment-resistant depression is typically defined as depression that does not remit despite two adequate trial uses of antidepressant medications; in older adults, treatment failure is associated with decreased psychological well-being, disability, and cognitive decline. Pharmacologic strategies for treatment-resistant depression include augmentation, in which a medication is added to an existing antidepressant, and the replacement of an antidepressant with one from a different class (“switching”). The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial showed that augmenting with, or switching to, bupropion was as effective as or more effective than other strategies…

There is increasing awareness of the importance of involving patients in the design of clinical trials. In a survey involving older adults with treatment-resistant depression, patient stakeholders recommended psychological well-being as an outcome that matters. Psychological well-being encompasses satisfaction, happiness, cognitive engagement, meaning, and purpose. There is also limited understanding of the comparative safety of antidepressant strategies in older adults, including risks of falls, cardiovascular risks, and risk of death with different agents used in trials.

Here’s what they did:

“We conducted a two-step, open-label trial involving adults 60 years of age or older with treatment-resistant depression. In step 1, patients were randomly assigned in a 1:1:1 ratio to augmentation of existing antidepressant medication with aripiprazole, augmentation with bupropion, or a switch from existing antidepressant medication to bupropion. Patients who did not benefit from or were ineligible for step 1 were randomly assigned in step 2 in a 1:1 ratio to augmentation with lithium or a switch to nortriptyline. Each step lasted approximately 10 weeks. The primary outcome was the change from baseline in psychological well-being, assessed with the National Institutes of Health Toolbox Positive Affect and General Life Satisfaction subscales (population mean, 50; higher scores indicate greater well-being).”

Here’s what they found:

  • Step 1. Enrolment. “A total of 619 patients were enrolled; 211 were assigned to aripiprazole augmentation, 206 to bupropion augmentation, and 202 to a switch to bupropion.” Demographics. “The mean age of the patients was 69.3 years; 66.7% were female, 84.3% were White, and 7.4% were Black.”
  • Well-being. “Aripiprazole augmentation improved well-being more than a switch to bupropion.” “Well-being scores improve by 4.83 points, 4.33 points, and 2.04 points, respectively.”  See figure below.
  • Remission. “Remission occurred in 28.9% of patients in the aripiprazole-augmentation group, 28.2% in the bupropion-augmentation group, and 19.3% in the switch-to-bupropion group.”
  • Falls. “The rate of falls was highest with bupropion augmentation.”
  • Step 2. Enrolment. “A total of 248 patients were enrolled; 127 were assigned to lithium augmentation and 121 to a switch to nortriptyline.”
  • Well-being. “Well-being scores improved by 3.17 points and 2.18 points, respectively”
  • Remission. “Remission occurred in 18.9% of patients in the lithium-augmentation group and 21.5% in the switch-to-nortriptyline group.”
  • Falls. They were similar in the two groups.

A few thoughts:

1. This is an impressive study – involving five sites with two steps of intervention, and, yes, published in a major journal.

2. The main finding in two words: augmentation worked.

3. A longer and more meaningful summary of the three big findings: “First, augmentation of existing antidepressant with aripiprazole was significantly better with respect to psychological well-being than a switch to bupropion, and the percentage of patients with remission, not adjusted for multiple comparisons, was numerically higher with either aripiprazole augmentation or bupropion augmentation than with a switch to bupropion. Second, bupropion augmentation was numerically similar in effectiveness to aripiprazole augmentation and was associated with a higher rate of falls than aripiprazole augmentation. Third, lithium augmentation and a switch to nortriptyline were similar in effectiveness and safety in a population of patients who did not have a response to their assigned treatment in the first step of the trial or who were not eligible to enter the first step.”

4. A positive result, yes, but context: “The low incidences of remission in both steps of the trial highlight the challenge of treating depression when previous medications have failed. For context, the STAR*D trial showed incidences of remission of 13 to 14% after multiple failed trial uses of medication… In our trial, less than 10% of the patients who switched to bupropion or had augmentation with lithium both reached and maintained the target dose and had remission.” Ouch.

5. Like all studies, there are limitations. The authors list several, including: “the trial had no placebo group and patients were aware of their trial-group assignments, so we cannot rule out the possibility that patients may have been reacting positively to receiving two drugs rather than one and cannot determine whether any of the treatment strategies was better than no change in pharmacologic treatment.”

6. In an accompanying Editorial, “Aripiprazole Augmentation in Older Persons with Treatment-Resistant Depression,” Gemma Lewis and Glyn Lewis (both of University College London) note the importance of the work:

“This trial makes an important contribution to the evidence regarding treatment-resistant depression in older adults. Older persons are often excluded from clinical trials of treatment for depression, which mostly involve younger adults. Findings from those trials are unlikely to be generalizable to older persons, who may have different symptoms of depression, more physical problems, cognitive impairment, polypharmacy, and a greater risk of adverse events. For example, the average age of patients at baseline in this trial was 69 years, and 40% had had falls in the 6 months before enrollment.”

Gemma Lewis

They also offer a note of caution:

“Findings from this trial support aripiprazole augmentation as a strategy for treatment-resistant depression in older persons, largely because of the lower risk of falls than with bupropion augmentation. In clinical practice, however, it would be important to tailor treatment in light of potential adverse effects and the preferences of the patient. For example, akathisia is a common side effect of aripiprazole and was reported in 11% of the patients who received the drug in this trial; patients may find this side effect distressing. How individual patients respond to different drugs for depression is also difficult to predict, so an element of trial and error is inevitable.”

That Editorial can be found here:

7. The clinical implications in a sentence? Co-author Daniel Blumberger (of the University of Toronto) notes for ImPACT: “These results don’t mean aripiprazole augmentation will produce the best results for every patient, but they do indicate that it is the best option to try first.” 

8. I’ll repeat comments made recently about another paper considering augmentation for treatment-refractory depression: rTMS and ECT are very effective. (!)

The full NEJM paper can be found here:

Selection 2: “We need more social supports – not more policing – to prevent violence on the TTC”

Sandy Simpson

The Globe and Mail, 4 April 2023

The tragic events and rising frequency of violent incidents on Toronto’s transit system is rightly a source of major public concern. We now know that the incidence of these events on the TTC has been slowly rising and at an increasing rate in the last two years. We have no studies of who the people are or why these events are happening, but experts working in this area have identified certain important themes.

The first theme is poverty and homelessness, which have become structural in our city; other cities are also experiencing these problems. Second is intoxication with certain drugs known to cause agitation, fear and violence, especially crystal methamphetamine and crack cocaine. Third is acute mental health disturbance, which can result in fear and agitation. These themes work synergistically to make life very hard. People feel frustration, alienation and distrust that any of the social systems that are meant to help them will help them.

So begins an essay by Dr. Simpson.

He notes that none of the problems are new, but things seem to have worsened as of late. He argues why.

  • Poverty. “ODSP (Ontario’s income support for people with disabilities) is set at only 60 per cent of the income needed to be above the poverty line.” 
  • Housing. “The waiting list for subsidized housing is eight to 10 years long. The cost of survival (food, rent) is escalating.” 
  • Drugs. “Cheap and dangerous drugs are increasingly common, and access to addictions services are limited and difficult to navigate.” 
  • Inaccessible services. “Mental health services are perhaps only 60 per cent of the size they should be. People experiencing mental illness and homelessness should get support from Assertive Community Treatment teams, but it takes 10 to 12 months to access that level of care in this city.”

“We expect people troubled by addictions, mental illness and/or histories of trauma to live at 60 per cent of the poverty line and wait for months or years for the clinical services or housing that they need. It’s little surprise then that they feel rejected and unsupported, and lose hope that their community wants to assist them.”

He warns about thinking that we can “police or imprison our way out of this situation.” He writes: “Incarceration further fractures troubled lives, and there is too little time and resources to mend these fractures.”

A way forward?

“Long-term security requires addressing the fundamentals noted above (more addictions services and better access to them; enhanced mental health services, especially ACT teams) but unless the fundamental issues of poverty are addressed, we will not help people rise from these feelings of desperation and alienation. Guaranteed Basic Income (GBI) is the best answer to this problem. It is a model widely trialled internationally. Its social and economic impacts are well demonstrated. GBI is transformative for people in poverty and on the fringes of society with other social problems. Already piloted in Ontario, we know GBI improves physical and mental health, decreases stress and feelings of anger, and reduces housing and food insecurity. It has been associated with a reduction in property crime.”

A few thoughts:

1. This is a good essay.

2. Why are things getting worse? He offers several plausible explanations. 

3. Past Readings have considered violence and public safety. In a recent Reading, for instance, we looked at an essay by Drs. Stergiopoulos and Hwang, who argued that: “The presence of an officer in uniform may deter crime or stop an assault in progress, but with 75 subway stations, 192 bus routes, over 8,000 bus and streetcar stops serving 1.7 million daily passengers, the odds are long that a police officer will be on the scene at the moment they are needed. In addition, many situations on the transit system may be escalated rather than made better by police involvement.” That essay can be found here:

The full Globe essay can be found here:

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

1 Comment

  1. Thanks for posting the Simpson essay. I missed that, and it’s great to see a light shining on a do-able, proven solution (GBI).