From the Editor

“Can I stop my antidepressants now?”

Patients often ask that question after feeling better. Studies have looked at relapse for people with depression who go off their medications, of course, but overwhelmingly such work has focused on patients recruited from specialty care (who are, perhaps, more ill).

In the first selection, we consider a new paper from The New England Journal of Medicine by Gemma Lewis (of University College) et al. The patients have been recruited from English family practices. The study is well designed and thoughtful, adding nicely to the literature. The chief finding? “Those who were assigned to stop their medication had a higher risk of relapse of depression by 52 weeks than those who were assigned to maintain their current therapy.” We consider the big paper and its clinical implications.


In the second selection, drawing from the pages of The New York Times, reporter Clay Risen writes about the life of Dr. Paula J. Clayton. This psychiatrist, who passed in September, was an accomplished researcher: “Dr. Clayton was part of a generation of clinical psychiatrists who, in the decades after World War II, revolutionized their field by applying medical rigor to the diagnosis of mental illness.” In later years, she was a strong advocate for those with mental illness.



Selection 1: “Maintenance or Discontinuation of Antidepressants in Primary Care”

Gemma Lewis, Louise Marston, Larisa Duffy, et al.

The New England Journal of Medicine, 30 September 2021


Antidepressants are often a first-line treatment for depression in primary care. In high-income countries, the number of prescriptions for these medications has risen during the past several decades, mostly due to an increase in the duration of treatment. Several systematic reviews of studies have shown a higher rate of relapse among patients who discontinue antidepressant therapy than among those who continue to receive such therapy, but such studies have had several limitations. Most trials recruited patients with depression from specialist mental health services, treated them with antidepressants for 3 to 8 months, and randomly assigned patients who had a response to therapy to continue antidepressant therapy or switch to placebo. A few studies have recruited patients who were receiving maintenance antidepressants (mainly tricyclic compounds) for longer than 8 months. However, small sample sizes have limited the ability to draw firm conclusions.

We conducted the randomized Antidepressants to Prevent Relapse in Depression (ANTLER) trial to assess the effects of maintenance antidepressant therapy, as compared with discontinuation of treatment, in primary care patients who had been taking antidepressants for more than 9 months and felt well enough to consider stopping their medication.

So begins a paper by Lewis et al.

Here’s what they did:

  • They conducted “a randomized, double-blind trial involving adults who were being treated in 150 general practices…” These practices were in England.
  • Eligible patients were between 18 and 74 and had a history of at least two depressive episodes or were taking antidepressants for two years.
  • Patients “felt well enough to consider stopping antidepressants…”
  • Patients who had received one of four antidepressants (citalopram, fluoxetine, sertraline, or mirtazapine) were randomly assigned in a 1:1 ratio to “maintain their current antidepressant therapy (maintenance group) or to taper and discontinue such therapy with the use of matching placebo (discontinuation group).”
  • The primary outcome: the first relapse of depression during the 52-week trial period.

Here’s what they found:

  • “1 466 underwent screening for suitability, and 606 were found to be eligible to participate. Among the patients who were eligible, 478 were enrolled and underwent randomization (238 to the maintenance group and 240 to the discontinuation group).”
  • Demographics: most patients were women (64%), white (95%), and employed (61%), with a mean age of 54.
  • Medications: “Citalopram was the most commonly used antidepressant, and almost three quarters of the patients had been taking antidepressants for more than 3 years.”
  • “Adherence to the trial assignment was 70% in the maintenance group and 52% in the discontinuation group.”
  • “Relapse of depression occurred in 92 of 238 patients (39%) in the maintenance group and in 135 of 240 (56%) in the discontinuation group during the 52 weeks of the trial (hazard ratio, 2.06…).” See figure below.
  • More symptoms of depression, anxiety, and withdrawal were reported in the discontinuation group had than those in the maintenance group.


A few thoughts:

  1. This is an excellent paper.
  1. There is much to like here: it’s a well designed study (a randomized, double-blind trial, no less), with robust results, published in a big journal.
  1. The results are clear: antidepressants reduce the possibility of relapse.
  1. Patients agreed: “By the end of the trial, 39% of the patients in the discontinuation group had returned to taking an antidepressant prescribed by their clinician.”
  1. What are the clinical implications of the findings? The paper runs with an editorial by Dr. Jeffrey L. Jackson (of the Medical College of Wisconsin) who writes: “They confirm what most primary care physicians already knew or intuited. The frequency of relapse after the discontinuation of treatment is high, particularly among patients with several previous depressive episodes. I encourage patients with a single bout of depression, especially episodes that are triggered by a life event, such as loss of a loved one, to consider weaning antidepressant treatment after at least 6 months of remission. For those with three or more previous bouts of depression, my practice has been to recommend that they anticipate medical treatment for life or, if they wish to stop taking medication, explore nonpharmacologic approaches, such as cognitive behavior therapy.” Concise and practical. That editorial, The Pursuit and Maintenance of Happiness,” can be found here:
  1. What are some non-pharmacological options? In a past Reading, we explored Zen versus Zoloft by considering a JAMA Psychiatry paper comparing psychotherapy with meds for relapse prevention. The Reading:
  1. Two cheers for antidepressants: people did better by continuing medications, yes, but many patients relapsed on antidepressants. Clinical take-away: patients need to be monitored carefully even if they are fully compliant.
  1. Like all studies, there are limitations. The authors note several, including that participation was limited to a handful of antidepressants. I wonder what the results would have looked like if the time-line had been longer.

The full NEJM paper can be found here:


Selection 2: “Paula J. Clayton Dies at 86; Helped Destigmatize Depression and Suicide”

Clay Risen

The New York Times, 7 October 2021


Early in her time as a medical student in the late 1950s, Paula J. Clayton watched a psychiatrist analyze a patient with clinical depression.

The doctor, who had herself been analyzed by both Carl Jung and Sigmund Freud and now taught at Washington University in St. Louis, asked the patient to explain his dreams, and the two spent time discussing what they meant.

But when the session was over, the doctor did something that Freud would never have done: She prescribed electroshock therapy.

It was something of a revelation for Dr. Clayton: The old methods of psychiatry, steeped in Freudian theory, had their limits, and physiological treatments were needed too.

So begins an obituary by Risen.

Born in St. Louis, her mother had been active in the women’s suffragist movement. Dr. Clayton did pre-med at the University of Michigan, before training at Washington University.  She then joined the faculty there.

She focused on bipolar disorder. With colleagues, in 1969, she published Manic Depressive Illness, “one of the first books to study manic depression through a rigorous, outcome-based approach… Though its broad contours were well understood, [bipolar disorder] was still seen as a mystery even by many psychiatrists. And too many people still saw manic outbursts of energy in somewhat romantic terms, as a seedbed for great art and ideas.” Notes Weill Cornell psychiatrist Richard Friedman: “She was a very careful empirical researcher at a time when empirical research did not hold much sway.”

Later, she focused on grief as being a risk factor for a major depressive episode – but not necessarily an episode itself.


Over time, she focused more and more on advocacy: “First as a professor at the University of Minnesota – where she was the first woman to chair a psychiatry department in the country – and later as the medical director at the American Foundation for Suicide Prevention, Dr. Clayton worked tirelessly to show the public what medical researchers already knew: that suicide almost always resulted from an underlying mental illness.”

She commented in a 2007 interview: “When you’re feeling sick from cancer or heart disease, you certainly call your doctor first, and yet with suicide” you don’t think of treatment as a solution. “I think it’s just that they don’t recognize it as a serious illness.”

Risen notes: “She was especially vocal about suicide among Native Americans and members of the military and veterans, the rates of which spiked after the invasions of Afghanistan and Iraq. She urged insurance companies to improve mental health coverage. And even after she retired in 2015, she continued to write and speak, convinced that with enough public education, the country could start to lower its tragically high suicide rates.”

A few thoughts:

  1. Dr. Clayton had an impactful career in many ways.
  1. Her tireless advocacy work should be remembered and appreciated: from making films for schools to Congressional testimony. Comments Dr. Jill Harkavy-Friedman, the vice president for research at the American Foundation for Suicide Prevention: “She was a pioneer and a force in suicide prevention in part because she believed people should know and understand that suicide can be prevented. That didn’t happen before. People ran away from the topic.”
  1. Over these past decades, stigma about mental illness has significantly – though not fully – lessened. The work of people like Dr. Clayton has made a real difference.

The full NYT article can be found here:


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