From the Editor

She’s an accomplished person who had succeeded in business and then writing, all the while raising three children; she also has an amazing smile and lights up the room when talking about her kids. But in my office, sick with depression, she can only focus on her losses and failings; the smile is absent.

Depression is common and disabling. Those who are affected in late-life are particularly challenging to treat. Is there a better way? In the first selection from JAMA Psychiatry, Dr. Daniel Blumberger (of the University of Toronto) and his co-authors consider theta burst stimulation, a newer form of rTMS which has shown promise in earlier work. Their study is a randomized noninferiority trial, directly comparing the two versions of rTMS in elderly patients with depression. The result? “We showed that bilateral TBS was noninferior to standard bilateral rTMS in improving depression, and similarly well tolerated, in a real-world sample of older adults with TRD [treatment resistant depression]…” We review the paper and its clinical implications.

In the second selection, Lori Ann Post (of Northwestern University) and her co-authors draw on CDC data to look at opioid overdoses in the United States with a focus on geography. In a JAMA Network Open research letter, they find: “Overall, opioid-involved overdose deaths rates increased steadily in counties of every urbanicity type, although there were distinct temporal wave patterns by urbanicity.”

And in the third selection, Huw Green (of the University of Cambridge) wonders about mental health and mental illness – and worries that the terms are becoming blurred together. Writing in The New York Times, the psychologist concludes: “When we move away from a focus on psychological problems and toward ‘mental health’ more broadly, clinicians stumble into terrain that extends beyond our expertise. We ought to be appropriately humble.”  

This month, the Reading of the Week enters its ninth year. A quick word of thanks for your ongoing interest.


Selection 1: “Effectiveness of Standard Sequential Bilateral Repetitive Transcranial Magnetic Stimulation vs Bilateral Theta Burst Stimulation in Older Adults With Depression: The FOUR-D Randomized Noninferiority Clinical Trial”

Daniel M. Blumberger, Benoit H. Mulsant, Kevin E. Thorpe, et al.

JAMA Psychiatry, 21 September 2022

Current pharmacological treatments for late-life depression have well-established but modest efficacy, with rates of nonresponse to first-line antidepressants ranging from 55% to 81%. Nonresponse to first-line antidepressant treatment in older adult patients contributes to diminished quality of life…

Repetitive transcranial magnetic stimulation (rTMS) is a treatment that involves direct stimulation of cortical neurons using focused magnetic field pulses; rTMS of the left side of the dorsolateral prefrontal cortex (DLPFC) at 10 Hz is a well-tolerated, evidence-based treatment for TRD. However, in older adults, most rTMS studies to date have been limited by suboptimal stimulation parameters, small sample sizes, and insufficient treatment durations…

Potential therapeutic advantages of bilateral stimulation can be offset by the need for longer treatment sessions to stimulate both hemispheres sequentially (ie, 30 to 60 minutes). Long sessions reduce treatment capacity; thus, for protocols that involve stimulation of more than 1 target per session, it is particularly desirable to develop techniques for reducing the overall session length. Theta burst stimulation (TBS), which uses patterned bursts of stimulation applied over a fraction of the time than standard treatments, may be of value in treating older adults with TRD in this regard. TBS may be a more potent physiologic form of stimulation than standard rTMS as it is based on coupling of γ and θ frequency rhythms of the brain.

So begins a paper by Blumberger et al.

Here’s what they did:

  • They conducted “a randomized noninferiority trial with open treatment and blinded assessors.”
  • Recruitment occurred between December 2016 and March 2020 in Toronto, Canada.
  • Inclusion criteria: “outpatients 60 years and older with a diagnosis of depression, moderate severity, and nonresponse to 1 or more antidepressant trial of adequate dosage and duration or intolerance of 2 or more trials.”
  • “Participants were randomized to receive a course of 4 to 6 weeks of either bilateral standard rTMS or TBS.”
  • The primary outcome measure: change in Montgomery-Åsberg Depression Rating Scale.

Here’s what they found:

  • A total of 87 participants were randomized to standard bilateral rTMS and 85 to TBS.
  • Demographics. Participants tended to be in their late 60s (67.1, rTMS; 66.3, TBS), female (54.0%; 52.9%), and educated (years 15.38; 15.16).
  • Depression. “Mean (SD) Montgomery-Åsberg Depression Rating Scale total scores improved from 25.6 (4.0) to 17.3 (8.9) for rTMS and 25.7 (4.7) to 15.8 (9.1) for TBS (adjusted difference, 1.55…), establishing noninferiority for TBS.” (!) See figure below.
  • Cognition. “There were no substantial changes on any of the cognitive measures and no significant differences between standard rTMS and TBS on any of the cognitive measures.”
  • Tolerability. “The number of reported adverse events for headache, nausea, dizziness, or other adverse events were relatively similar between standard rTMS and TBS.”

A few thoughts:

1. This is a good study.

2. The result is impressive.

3. And it has big clinical implications. “Since bilateral TBS takes 4 minutes to deliver, the use of TBS instead of standard rTMS (which takes 47.5 minutes to deliver) could increase the capacity of brain simulation programs that serve older adults.” Potentially very important. “Furthermore, the short-session duration lends itself to potentially accelerated response with multiple treatments per day and the findings herein suggest that this may be possible using bilateral TBS with older adults with depression.” Also, potentially very important.

4. This paper adds to an impressive and growing literature on theta burst rTMS, showing reproducibility across different populations. The big study on adults (as opposed to older adults) was published in The Lancet and concludes: “the number of patients treated per day with current rTMS devices can be increased several times without compromising clinical effectiveness.” That paper can be found here:

5. Like all studies, there are limitations. The authors note several, including: “The study was designed to measure the effectiveness of standard sequential bilateral rTMS and bilateral TBS in a real-world sample of older adults with TRD. As such, there was no sham group and participants were aware of their treatment allocation. The decision to compare TBS with standard bilateral TMS rather than sham was a recognition of network meta-analytic findings supporting bilateral standard TMS over sham treatment as well as the widespread use of bilateral standard TMS in the community setting.”

The full JAMA Psychiatry paper can be found here:

Selection 2: “Geographic Trends in Opioid Overdoses in the US From 1999 to 2020”

Lori Ann Post, Alexander Lundberg, Charles B. Moss, et al

JAMA Network Open, 28 July 2022

The US opioid crisis has evolved over time… Wave 1, in approximately 2000, was prompted by doctors overprescribing opioid painkillers, which was associated with mass addiction. Wave 2 involved heroin; OODs [opioid-involved overdose deaths] from heroin escalated in 2007 and surpassed those from prescription opioids by 2015. Wave 3 involved illicit synthetic opioids, such as fentanyl, the use of which escalated after 2013. Further evidence suggests a fourth wave, complicated by the addition of stimulants and the COVID-19 pandemic.

So begins a research letter by Post et al.

Here’s what they did:

“Data included OODs from January 1, 1999, to December 31, 2020, recorded in the Centers for Disease Control and Prevention’s WONDER database for 3147 counties and county equivalents categorized on a 6-point urbanicity scale (most urban to most rural). OODs were defined using ICD-10 codes for underlying and multiple causes of death… We calculated OOD rates as OOD count within a given year and county type, divided by midyear population, multiplied by 100 000. Acceleration (relative change in OOD rate year over year) is expressed as a percentage.”

Here’s what they found:

A few thoughts:

1. This is interesting data, showing the evolving opioid overdose crisis through the prism of urbanicity.

2. The pattern? “Before 2010, OOD rates accelerated more quickly in rural counties than in urban counties; before 2000, OODs were rare in rural communities, which lacked resources to treat opioid use disorders associated with prescription opioids in wave 1.”

3. Simple observation: note the incredible upswing after 2018 across all groups. Ouch.

The full research letter can be found here:

Selection 3: “We Have Reached Peak ‘Mental Health’”

Huw Green

The New York Times, 20 September 2022

A few months ago I received a referral for a new patient with a history of depression who’d made a serious suicide attempt. Perhaps unsure how to describe these episodes, the referring clinician wrote vaguely that the person had a ‘history of mental health.’

Ordinarily, the word ‘health’ implies an absence of illness. That is no longer how the term ‘mental health’ gets used. The idea of mental illness, or mental disorder – both terms that have been subjected to their own intractable debates – has come to be supplanted by a broader umbrella notion, ‘mental health,’ which somehow, confusingly, gets used to refer to states of both wellness and distress.

So begins an essay by Green.

He continues: “We are talking more and more about our mental health, and this has been enormously positive. It is no longer unusual to see celebrities or politicians referencing the concept. The rise of social media has introduced a generation of clinicians who have been adept at using it to communicate.”

But he argues that the shift may be unfortunate: “The term ‘mental health’ is a euphemism, and euphemisms are what we use when we want to obscure something. This language –  in contrast to ‘mental illness’ – encourages us to focus on the regulation of more or less transient states, and on the maintenance of something we supposedly all have. ‘Mental health’ conjures phenomena that are, more or less, relatable:anxiety and depression.But who is being excluded as a result? The change in language was supposed to address stigma. But it has simply moved our attention away from the very people who face the most stigma – those with diagnoses of schizophrenia, for example, or symptoms that do not allow ready participation in the mental health curriculum.”

He notes: “An emphasis on health and equilibrium, with accompanying ‘advice’ and ‘techniques’ for self-regulation, has resulted in the term ‘mental health’ undergoing a kind of mission creep: from providing increased awareness of specific difficulties to offering a broad set of prescriptions about how we should live.”

He observes the rise of mental health days, but also wonders if people really need to justify a break from work (and if that is the way to do it). “When mental health is given as a principal motivator for our choices, we are prioritizing our own experiences. As a result, there is less room for moral or ethical considerations for our behavior, and also less room for motivations that have to do with social, community or familial commitments, or doing something for its own sake.There are probably lots of things we should do in spite of our mental health: helping others, forming deep emotional ties that may then need to be painfully broken, becoming immersed in sometimes maddening, at times obsessive political or creative projects. These are choices that need deep rational, ethical and personal engagement.”

He writes about a therapist who has suggested that everyone should try therapy – but therapy should be seen as a “valuable health intervention for many, rather than a universal prerequisite to a good life.” He also worries about the politicization of the term mental health, and draws on gun control debates in the United States.

He closes by suggesting that clinicians focus on problems. “As a psychologist, I am heartened by the increase in our attention on mental health. But I see it as one way of looking at our lives among others. Mental health professionals are understandably interested in mental health – but we need to remain interested in how people lead lives that are good, happy or meaningful without ever spending much time with clinicians.”

A few thoughts:

1. This is a well-written essay.

2. As stigma fades, are we becoming overly concerned with mental health, as opposed to mental illness? The author argues we are, and – to repeat his best line – “clinicians stumble into terrain that extends beyond our expertise…” Is our field suffering from mission creep?

3. To play the devil’s advocate: but isn’t this a win? People are talking more about mental health and mental illness, after all.

The full NYT essay can be found here:

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