From the Editor
“New Research Questions Severity of Withdrawal From Antidepressants”
– The New York Times
“Antidepressant Pullback Symptoms Fewer Than Thought, Study Shows”
– Bloomberg
Millions of North Americans take antidepressants – about one in seven Canadians – yet these medications remain controversial. A 2019 Lancet Psychiatry study, which drew heavily from online surveys, found that roughly half of patients who quit these meds experienced severe withdrawal symptoms, sparking much debate – and many, many questions from our patients.
How common are discontinuation symptoms? Which one is most commonly experienced? Michail Kalfas (of King’s College London) and his co-authors attempt to answer these questions with a new JAMA Psychiatry paper. They did a systematic review and meta-analysis by analyzing 50 studies involving almost 18 000 people. “This systematic review and meta-analysis indicated that the mean number of discontinuation symptoms at week 1 after stopping antidepressants was below the threshold for clinically significant discontinuation syndrome.” We consider the paper and its implications.
Celebrities use them; politicians discuss them; our patients ask about them. Are semaglutide and sister drugs game changers for those with mental health problems who struggle with obesity? To explore the opportunities and challenges of these new medications, in a new episode of Quick Takes, I speak with Dr. Mahavir Agarwal (of the University of Toronto), Lisa Schaefer (of Obesity Canada), and Dr. Sanjeev Sockalingam (of the University of Toronto). “Imagine a world where you have all the effects of antipsychotics, but none of the side effects.”
Finally, in the third selection, journalist Alexander Nazaryan discusses his father’s mental illness and its impact on his life. In a deeply personal essay for The New York Times, he notes the long shadow of illness. “My father never got to become a famous physicist or see his son go to M.I.T. Worse, he couldn’t ask for help until it was too late.”
DG
Selection 1: “Incidence and Nature of Antidepressant Discontinuation Symptoms: A Systematic Review and Meta-Analysis”
Michail Kalfas, Dimosthenis Tsapekos, Matthew Butler, et al.
JAMA Psychiatry, 9 July 2025 Online First
The concept of antidepressant withdrawal syndrome was first introduced in the late 1950s. While most international depression guidelines acknowledge and support tapering of antidepressants when discontinuing them, there remains variability in specific guidance on duration and types of withdrawal symptoms among antidepressants.
In the UK, guidelines from the National Institute for Health and Care Excellence state that for some people, antidepressant discontinuation symptoms can be mild and transient, but in other cases, symptoms can be more severe and last longer. The American Psychiatric Association guidelines state that antidepressant discontinuation symptoms usually resolve within 1 to 2 weeks without treatment.
There is also lack of consensus and clarity on the evidence relating to incidence and duration of antidepressant discontinuation symptoms. A meta-analysis by Henssler and colleagues found the incidence of at least 1 discontinuation symptom was 31% after discontinuation of antidepressants and 17% after discontinuation of placebo. However, when directly comparing discontinuation of an antidepressant with placebo, the authors found a difference of 8%. Critiques of Henssler and colleagues’ meta-analysis stated that it only analyzed categorical data and did not provide details about type of discontinuation symptoms experienced.
So begins a paper by Kalfas et al.
Here’s what they did:
- They conducted a systematic review and meta-analysis to “examine the presence of discontinuation symptoms.”
- They searched several databases, including MEDLINE.
- They included “randomized clinical trials reporting discontinuation symptoms using a standardized scale or individual symptoms (eg, adverse events) following antidepressant cessation.”
- Data was extracted and reviewed. They then conducted a random-effects meta-analysis.
- Primary outcomes: “the incidence and nature of antidepressant discontinuation symptoms measured using standardized or unstandardized scales.”
Here’s what they found:
- 50 studies were included (and 49 in the meta-analysis) with 17 828 participants in total.
- Demographics and disorders. Most participants were female (66.9%) with a mean age of 44 years. Diagnoses included major depressive disorder (k = 28), generalized anxiety disorder (9), and panic disorder (4).
- Follow up. Follow up was between 1 day and 52 weeks.
- Symptoms. “Discontinuation of antidepressants was associated with increased odds of dizziness (OR, 5.52…), nausea (OR, 3.16…), vertigo (OR, 6.40…), and nervousness (OR, 3.15…) compared to placebo discontinuation.”
- Meta-analysis. “Discontinuation symptoms at 1 week in participants stopping antidepressants (standardized mean difference, 0.31…; number of studies [k] = 11; n = 3915 participants) compared to those taking placebo or continuing antidepressants. The effect size was equivalent to 1 more symptom on the [Discontinuation-Emergent Signs and Symptoms scale].”
- Most common symptom. The most prevalent discontinuation symptom was dizziness, affecting about 6% of those discontinuing after adjusting for placebo effects).
A few thoughts:
1. This is a good paper, with a robust dataset (including from 11 unpublished RCTs), addressing a practical problem, and published in a major journal.
2. The main finding in a sentence: “In conclusion, data from RCTs suggest that on average, those who discontinue antidepressants experience 1 more discontinuation symptom compared to placebo or continuation of antidepressants, which is below the threshold for clinically important discontinuation syndrome.” (!)
3. Like other studies on discontinuation symptoms, this one didn’t find effects as large as those reported by the Lancet Psychiatry authors. To repeat, the symptoms experienced were below the threshold for clinically important discontinuation syndrome.
4. What to make of the warnings sparked by that 2019 paper? The Kalfas et al. study suggests that those warnings were “overblown,” to quote The New York Times. Of course, the papers had different foci. Kalfas and his colleagues didn’t try to find the overall prevalence of discontinuation symptoms; they compared discontinuation of an antidepressant with stopping placebo using standardized scales.
5. So while the paper is solid, this JAMA Psychiatry study is unlikely to settle any big debates.
6. Like all studies, there are limitations. The authors note several, including: “Due to the small number of studies, some analyses might have been underpowered.”
7. Past Readings have reviewed papers on antidepressants, including the Henssler et al. paper, which drew on 79 studies involving more than 21 000 people. Their conclusion: discontinuation symptoms are common but severe symptoms are rare. You can find that Reading here:
8. What to say to patients who are thinking about stopping their antidepressants about discontinuation symptoms? I highlight – as I have before – the thoughtful summary written by the UK Royal College of Psychiatrists which you can find here:
The full JAMA Psychiatry paper can be found here:
https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2836262
Selection 2: “The semaglutide era? Considering medication-related weight gain”
Mahavir Agarwal, Lisa Schaefer, Sanjeev Sockalingam
Quick Takes, July 2025
In this episode, I speak with Dr. Mahavir Agarwal (the medical head of CAMH’s Metabolic Clinic), Lisa Schaefer (executive director of Obesity Canada), and Dr. Sanjeev Sockalingam (the scientific director of Obesity Canada and, of course, CAMH’s CMO).
On the potential
Mahavir Agarwal: “Our drugs help our patients feel better, think better, be better, but they also contribute to them developing metabolic side effects. And for a while now, we haven’t had good answers. We have drugs like metformin and topiramate that can help. But we don’t have answers that are universally effective. And this new class of drugs suddenly brings about an opportunity whereby if they were available to all, if they were accessible to all, and if they are proven to be safe for all, they represent a game changer – suddenly metabolic side effects can be managed effectively to the point that perhaps they won’t be a concern anymore.”
On the early evidence
Sanjeev Sockalingam: “For semaglutide and tirzepatide, we have pretty good results in terms of long term, sustained weight loss. One-year studies have shown significant weight loss, anywhere from 13% to 18% and even higher depending on how much behavioural intervention is added and their intensity.
“The benefits have been studied beyond weight loss as the outcome. They’ve looked at health outcomes, for example. For sleep apnea, studies show 40% to 50% reduction… and reductions in cholesterol and pre-diabetes.”
On side effects
Sanjeev Sockalingam: “The most common side effect for these medications: GI related. And you know, that is one we have to educate patients on and also modify the titration of these medications. These are weekly injections, but instead of accelerating the dose every month, you may need to start thinking about slower titrations if people are having those side effects.”
On special considerations
Mahavir Agarwal: “Constipation or gastric slowing is a common side effect with this class of drugs. Clozapine, which we use quite commonly in our psychosis population, can also cause constipation. We don’t know enough about combining clozapine and semaglutide, and whether that accentuates these side effects. The other [concern] is ECT, which is largely around anaesthesia. So because semaglutide and similar drugs delay gastric clearing. So overnight fasting is sometimes not enough to ensure gastric emptying. And so CAMH, for example, has a protocol where if somebody is on semaglutide, they cannot access ECT. They have to be off the drug for at least 3 to 4 weeks for ECT to become available to them. There are times for my patients where they have had to choose between ECT or semaglutide.”
On the larger question of obesity and obesity care
Lisa Schaefer: “Last fall, we published a paper, The Cost of Inaction, about how much we’re losing by not treating obesity (without the addition of the mental health component). But when we look at it that way, annually, it’s about $27 billion to the Canadian economy that we’re talking about by not recognizing obesity as a chronic disease and offering these kinds of solutions. When we break that down even further, it’s $6 billion of direct health care costs.
“We know that that system needs a lot of love and attention. But we’re losing $21 billion for the economy just by not helping people…”
The above answers have been edited for length.
The podcast can be found here, and is just over 31 minutes long:
https://www.camh.ca/en/professionals/podcasts/quick-takes/qt-july-2025—the-semaglutide-era-considering-medication-related-weight-gain
Selection 3: “My Father Never Escaped His Rage and Anxiety. Can I?”
Alexander Nazaryan
The New York Times, 13 June 2025
My father died last year, at 81, shortly after his first round of chemotherapy for pancreatic cancer. We’d never been close, even in the years before his depression made closeness impossible. Still, his passing left a hole I’ve been trying to patch up ever since.
Nikolay Nazaryan was a difficult man who never got to live the life he thought he deserved. His deteriorating mental health warped our family life. I know I’ve inherited some of his anxious tendencies, and I wonder every day whether I can overcome them so that my three children remember me as the shelter, not the storm.
So begins an essay by Nazaryan.
He notes that his father was born in the Soviet Union (now Armenia) and trained in physics, eventually becoming an instructor. They left in 1989. “We arrived in the United States with the last wave of Soviet Jews when I was ten, settling in the suburbs of Connecticut.” Emigration to the United States proved challenging. “My dad struggled to learn English. He couldn’t find a job in his field – X-ray spectrometry – and had to deliver pizza. He once spent several months trying to predict Powerball winners, even building his own fiberglass chamber to simulate the bouncing balls. Of course it didn’t work. Nothing seemed to.”
He put heavy pressure on his son. “I became the vehicle for his American dreams. While other kids were playing soccer or football after school, my father gave me advanced math lessons using a Russian textbook. He shouted, threatened and catastrophized: How could I get into M.I.T. if I couldn’t remember my trigonometric derivatives? I’d shout right back.”
His father became ill. “Around that time, a deep anxiety settled over my dad. He spent my high school years certain he was suffering from a mysterious gastric ailment. He briefly became convinced that cancer was contagious, once breaking out into tears when I accepted a glass of water from a friend’s dying father…” The essay describes his constant worries, including about microplastics and radiation. Depression followed. “I just remember coming home from college and going to a psychiatric ward, where he was preparing for his first treatment of electroconvulsive therapy. It helped until it didn’t. He spent his last 20 years in a fog of anguish, largely beyond our grasp.”
The author wonders about his own mental health. “Like my father, I am prone to hypochondria and anxiety – and have wasted hours on the internet looking at pictures of cancerous moles.” He worries about his ability as a father. “As the buffer between my father and my kids, I want them to keep his memory without repeating his mistakes. Every interaction they observe me engage in feels like a chance to teach them about communication, self-control and emotional calibration.”
He has looked to experts for advice. “As a scientist’s son, I also look to research for guidance. Psychology was once hyper-focused on mothers, often blaming them for a child’s mental health issues. But we now know that fathers play an equal role, for good or ill, in determining their children’s well-being. For instance, this month, a new study found that having a father with depression was associated with a dramatically higher levels of combativeness and hyperactivity, as well as lagging social skills.”
How to better himself? “I’ve become a passionate runner and recently took up kayaking. Gardening has been surprisingly relaxing. And yes, I’ve sought professional help when needed. Meds have quieted my anxiety and cognitive behavioral therapy tricks – breathing techniques, mnemonic devices – have done wonders.”
A few thoughts:
1. This is a great essay, raw and thoughtful.
2. Even after his father’s death, the influence is felt, including on the author’s parenting style.
3. Nazaryan isn’t particularly sympathetic to his father. That said, it’s difficult not to be moved by the challenges of immigration, with his father going from being a physics instructor to a person delivering pizza.
4. Past Readings have considered the family experience with mental illness, including the larger question of genes, destiny, and healing. A 2024 Reading included an essay by Olympian Alexi Pappas who discussed her mother’s suicide and her own struggles with depression. “My future – the universe where my fear lives – was never set in stone, and neither was my mom’s. I’m more than my genes, and I would not reroll the dice if given the option.”
You can find it here:
The full New York Times essay can be found here:
https://www.nytimes.com/2025/06/13/well/father-son-anxiety-mental-health.html
Reading of the Week. Every week I pick articles and papers from the world of Psychiatry.
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