From the Editor

Sure, we are biased – but ours is a different type of job. Working in health care can involve life and death situations and trying to help those who are at their most vulnerable. The stakes can be high. 

But how does such work affect the workers themselves? Dr. Mark Olfson (of Columbia University) and his co-authors try to answer that question in a new paper for JAMA. In it, they analyze suicides among six different types of health care workers, including physicians, by drawing on a US data that offers a nationally representative sample from 2008 to 2019, including 1.84 million people. “Relative to non-health care workers, registered nurses, health technicians, and health care support workers in the US were at increased risk of suicide.” We consider the paper and its implications.

And in the other selection, Dr. Andreas Reif (of the University Hospital Frankfurt) and his co-authors focus on treatment-resistant depression. In this new paper published in The New England Journal of Medicine, they report on the findings from a study where 676 patients were randomized to either esketamine nasal spray or an antipsychotic augmenting agent in addition to an antidepressant. “In patients with treatment-resistant depression, esketamine nasal spray plus an SSRI or SNRI was superior to extended-release quetiapine plus an SSRI or SNRI with respect to remission at week 8.” We also look at the accompanying editorial.


Selection 1: “Suicide Risks of Health Care Workers in the US”

Mark Olfson, Candace M. Cosgrove, Melanie M. Wall, et al.

JAMA, 26 September 2023

Compared with the general population, physicians tend to live longer and have healthier lives. In their occupational roles, however, physicians and other health care workers routinely engage in stressful tasks of caring for severely ill individuals and managing heavy workloads, with little control over patient outcomes. Because health care occupations vary in their emotional demands, they may also vary in suicide risk.

An early meta-analysis (1963-2002), which included some small and methodologically crude studies, reported increased suicide standardized mortality ratios (SMRs) for female (2.27…) and male (1.41…) physicians compared with females and males in the general population. A more recent meta-analysis (1969-2018) concluded that corresponding suicide SMRs were 1.94… for female physicians and 1.24… for male physicians… Much less is known about suicide risks of the approximately 95% of health care workers who are not physicians.

So begins a paper by Olfson et al.

Here’s what they did:

  • They conducted a cohort study of a nationally representative sample of workers from 2008 to 2019. 
  • “Age- and sex-standardized suicide rates were estimated for 6 health care worker groups (physicians, registered nurses, other health care-diagnosing or treating practitioners, health technicians, health care support workers, social/behavioral health workers) and non-health care workers.”
  • Statistical analyses were done, including “cox models estimated hazard ratios (HRs) of suicide for health care workers compared with non-health care workers using adjusted HRs for age, sex, race and ethnicity, marital status, education, and urban or rural residence.”

Here’s what they found:

  • 1 842 000 workers were included in the study.
  • Demographics. The median age was 44. Female sex ranged from 32.4% (physicians) to 91.1% (registered nurses).
  • Suicides per 100 000. 21.4 for health care support workers, 16.0 for registered nurses, 15.6 for health technicians, 13.1 for physicians, 10.1 for social/behavioral health workers, 7.6 for other health care-diagnosing or treating practitioners, and 12.6 for non-health care workers. See figure below.
  • Adjusted hazards of suicide. The adjusted hazards of suicide were increased for health care workers overall (adjusted HR, 1.32). Looking at specific occupations: health care support workers (AHR, 1.81), registered nurses (AHR, 1.64), and health technicians (AHR, 1.39). For other workers, adjusted hazards of suicide were not increased: physicians, social/behavioral health workers, other health care-diagnosing or treating practitioners compared with non–health care workers.

A few thoughts:

1. This is a good and timely study.

2. The main finding in a sentence: “Health care workers overall, including registered nurses, health technicians, and health care support workers, were at increased risk of suicide compared with non-health care workers.”

3. What about physicians? “Physicians were not at increased suicide risk compared to non-health care workers, though confidence intervals were wide, and sample size constrained stratifying by sex.”

4. Like all studies, there are limitations. The authors note several, including that the survey ended in 2019 (thus, no COVID-19 data). As well, health care occupations may have changed over time.

5. What to do with occupations at greater risk? “To address this challenge, it will be important to identify and ameliorate specific work-related factors that contribute to mental health occupational risks of health care workers, especially registered nurses, health technicians, and health care support workers.”

6. This is American data. How does it compare to ours? A recent Canadian Journal of Psychiatry paper looked at physicians and suicide, noting that the rate was comparable to the general population’s. That paper was discussed in a past Reading, which can be found here:

The full JAMA paper can be found here:

Selection 2: “Esketamine Nasal Spray versus Quetiapine for Treatment-Resistant Depression”

Andreas Reif, Istvan Bitter, Jozefien Buyze, et al.

The New England Journal of Medicine, 5 October 2023

The primary goal of initial treatment for major depressive disorder is remission, with maintenance treatment aimed at preventing relapse… Treatment-resistant depression is commonly defined as a lack of response to two or more pharmacologic treatments that are given for an adequate duration and at an adequate dose during the same major depressive episode. Treatment-resistant depression, which affects 10 to 30% of patients with major depressive disorder, is associated with increased hospitalizations and coexisting conditions, higher mortality and suicide rates, and a greater economic burden.

Extended-release quetiapine, a guideline-supported antipsychotic augmentation agent, is commonly used for treatment-resistant depression… Esketamine nasal spray, administered in combination with either a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI), is the only treatment approved in Europe specifically for treatment-resistant depression. In patients with treatment-resistant depression, reductions in depressive symptoms and in the risk of relapse were observed with esketamine nasal spray as compared with placebo nasal spray when both agents were given in combination with a newly initiated SSRI or SNRI. Data on direct comparisons of esketamine nasal spray with an augmentation strategy in patients with treatment-resistant depression are limited.

So begins a paper by Reif et al.

Here’s what they did:

“In an open-label, single-blind (with raters unaware of group assignments), multicenter, phase 3b, randomized, active-controlled trial, we assigned patients, in a 1:1 ratio, to receive flexible doses (according to the summary of product characteristics) of esketamine nasal spray (esketamine group) or extended-release quetiapine (quetiapine group), both in combination with an SSRI or SNRI. The primary end point was remission, defined as a score of 10 or less on the Montgomery-Åsberg Depression Rating Scale (MADRS), at week 8 (scores range from 0 to 60, with higher scores indicating more severe depression). The key secondary end point was no relapse through week 32 after remission at week 8.”

Here’s what they found:

  • 811 patients were screened; 676 were then randomly assigned to the esketamine group (336 patients) or to the quetiapine group (340 patients).
  • Demographics. Both groups had participants in their 40s, primarily female and employed.
  • Discontinuation. A greater number of patients in the quetiapine group discontinued than in the esketamine group (40.3% vs. 23.2%).
  • Remission at 8 weeks. “Remission, defined as a MADRS score of 10 or less, at week 8 (primary end point) occurred in significantly more patients in the esketamine group than in the quetiapine group (27.1% vs. 17.6%…).”
  • At 32 weeks. “More patients in the esketamine group than in the quetiapine group had no relapse through week 32 after remission at week 8 (21.7% vs. 14.1%).” See figure below.
  • Adverse events. “Serious adverse events during the treatment period occurred in 19 patients (5.7%) in the esketamine group and in 17 patients (5.1%) in the quetiapine group.”

A few thoughts:

1. This is an interesting study.

2. The main finding in a sentence: “In the present trial, patients receiving esketamine nasal spray were 1.54 times as likely as patients receiving extended-release quetiapine to have remission at week 8 (27.1% vs. 17.6%; risk difference, 9.5 percentage points).”

3. And participants continued to show improvement after week 8, over the treatment period. “The percentage of patients with remission and the percentage with a treatment response increased over the 32-week treatment period in both treatment groups, with odds ratios consistently favoring esketamine.” Though, we can add, the gap narrowed.

4. It’s a big result but… the trial was open label. (!!)

5. Did the industry sponsorship colour the result?

6. Dr. Rupert McShane (of the University of Oxford) writes an accompanying editorial, “Loosening the Shackles of Depression.” He notes the problems of open-label trials. He also makes several comments about the practicality of esketamine nasal spray:

“Although patience is valuable, speed in resolving depression is also important. Patients naturally want to get better as quickly as possible. Because the chance of a patient benefiting dwindles progressively with each successive antidepressant treatment, it makes sense to try the most effective treatment first. If the only determinants about which antidepressant to prescribe after the failure of two drug treatments were efficacy and safety, then the rational conclusion from the present ESCAPE-TRD trial would be that esketamine nasal spray should start to be used as a third-line therapy. However, weekly or twice-weekly clinic visits are the norm for maintenance treatment with esketamine nasal spray. Cost and inconvenience are therefore likely to be decisive factors in its use.”

Dr. Rupert McShane

And he makes a larger comment about hope (and hopelessness):

“What are the implications of the present trial for implementation? Most striking is that once patients have not had a response to at least two antidepressants, the achievement of full remission within 2 months with further drug treatment remains unlikely. When coupled with a substantial number of patients with a sense of hopelessness and with the adversarial climate around antidepressants, clinical confidence may easily be undermined. Does a given patient with major depressive disorder have a drug-responsive condition after all? Does the patient have medicalized unhappiness? This trial by Reif et al. reinforces the need among clinicians for therapeutic optimism and persistence, without which too many patients are undertreated.” Well said.

The full editorial can be found here:

The full NEJM paper can be found here:

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