From the Editor
When my patient’s father heard that there is some evidence that omega-3 fatty acids can help in the prevention of psychotic illness, he left my office, walked to the pharmacy down the street, and purchased the largest bottle of the fish oil supplement that he could find. It’s hard to fault his logic: omega-3 fatty acids may be helpful and have few side effects. Clinicians have shared this enthusiasm. No wonder: in 2010, a major study found that patients who took it had a lower transition rate to psychosis for those at ultra-high risk.
But what does the latest evidence say? Are omega-3 fatty acids helpful? In the first selection, Inge Winter-van Rossum (of the Utrecht University) and her co-authors attempt to answer these questions in a paper for Schizophrenia Bulletin. They report on a double-blind, randomized, placebo-controlled study of ultra-high risk (UHR) patients for psychosis who received either omega-3 supplements or placebo for six months, then followed for 18 months. “The transition rate to psychosis in a sample of subjects at UHR for psychosis was not reduced compared to placebo.” We consider the study and its implications.
In the second selection, Drs. Sri Mahavir Agarwal and Margaret Hahn (both of the University of Toronto) write about semaglutide in a new Viewpoint for JAMA Psychiatry. They note great opportunities, but caution about challenges, including access to that medication. In a thoughtful paper, they review the relevant literature. “Semaglutide and similar drugs represent the culmination of decades of diabetes and obesity research, and their arrival has already resulted in a paradigm shift in the management of these disorders in the general population.”
Finally, we explore the latest news with articles from The Globe and Mail, Time, and The New York Times. The topics: ADHD and TikTok diagnoses, an app for peer support, and public libraries in a time of homelessness and substance.
DG
Selection 1: “Effectiveness of Omega-3 Fatty Acids Versus Placebo in Subjects at Ultra-High Risk for Psychosis: The PURPOSE Randomized Clinical Trial”
Inge Winter-van Rossum, Margot I. E. Slot, Hendrika H. van Hell, et al.
Schizophrenia Bulletin, 25 October 2024
Psychosis is typically preceded by a prodromal phase, where subthreshold psychotic symptoms are often accompanied by a decrease in psychosocial functioning. This state poses a risk for developing psychosis, typically referred to as ultra-high risk (UHR). Given that early treatment in psychosis has been linked to better outcomes, effective interventions in the UHR phase may carry the potential to prevent or at least delay the onset of psychosis. Although meta-analyses in the past have suggested that cognitive behavioral therapy was associated with a significant reduction of attenuated psychotic symptoms compared to any other intervention, more recent umbrella reviews and meta-analyses including new trials have indicated no clear benefits to favor any available intervention over another intervention or any control condition (eg, low-level needs-based interventions) in preventing psychosis…
One specific study that is part of these reviews and meta-analyses drew particular attention, concerning a randomized controlled trial (RCT) on the effectiveness of omega-3 polyunsaturated fatty acids (PUFAs) in UHR. This mono-center RCT by Amminger et al. randomized 81 UHR subjects, aged between 13 and 25 years, 1:1 to 12-week treatment with omega-3 PUFAs or placebo. A lower transition rate to psychosis was found in the omega-3 group 1 year after study initiation (4.9% in the omega-3 group compared to 27.5% in the placebo group…), along with significantly reduced symptom severity and improved functioning, compared to placebo… However, the results by Amminger and colleagues were not replicated by 2 subsequent RCTs…
So begins a paper by Winter-van Rossum et al.
Here’s what they did:
- They conducted a double-blind, randomized, placebo-controlled study.
- They tested “the efficacy of 6-month treatment with omega-3 PUFAs in subjects at UHR for FEP, aged 13 to 20 years on the prevention of a transition to psychosis, followed up for 18 months post-treatment.”
- “Participants were help-seeking individuals who met UHR criteria on the positive symptoms of the Comprehensive Assessment of At-Risk Mental States (CAARMS)…”
- “The daily amount of other omega-3 fatty acids (18:3n3, 18:4n3, 20:4n3, 21:5n3, and 22:5n3) provided with the study medication was 240 mg.”
- “The trial was conducted at 16 general hospitals and psychiatric specialty centers located in 8 European countries and Israel.”
Here’s what they found:
- 158 subjects were screened; 135 were included.
- Demographics. There were 55.2% were female with a mean age of 15.6 years; 86% of the study sample was White.
- Illness experience. The majority had attenuated symptoms and a mean Global Functioning: social of six.
- Transition. “In the omega-3 PUFA treatment group, 5 (7.5%) of 67 subjects met the strict transition criteria over the full 2-year study period, versus 3 (4.4%) of 68 placebo-treated subjects… The Cox regression analysis showed that the transition rate did not differ between the 2 treatment groups (HR 1.67…).”
- Adverse events. They were similar across the two groups.
A few thoughts:
1. This is a good study, addressing a practical problem, published in a solid journal.
2. The main finding in a sentence: “After a 6-month treatment with omega-3 PUFAs and over an additional 18-month follow-up period, the transition rate to psychosis in a sample of subjects at UHR for psychosis was not reduced compared to placebo.”
3. Even with a broader transition criteria, the transition rate wasn’t reduced.
4. To borrow a line from Dr. Niall Boyce (of the Wellcome Trust): is it time for omega-3 fatty acids to swim with the fishes? Despite the enthusiasm and hope, this is now the third study failing to reproduce the results of Amminger et al.
5. How to explain that first study? The authors make several suggestions including that “the non-pharmacological treatment of UHR symptomatology may have become more effective in the past decade, which could lead to less room for symptom improvement for additional interventions.”
6. Of course, this begs a clinical question: if a patient or his family asks about the supplement, how should you respond? I suggest: with regard to those at ultra-high risk, the evidence is unpersuasive, but there are few side effects with it.
The full paper can be found here:
https://academic.oup.com/schizophreniabulletin/advance-article/doi/10.1093/schbul/sbae186/7841513
Selection 2: “Semaglutide in Psychiatry – Opportunities and Challenges”
Sri Mahavir Agarwal and Margaret Hahn
JAMA Psychiatry, 21 August 2024 Online First
Individuals with severe mental illness (SMI) have exceedingly high rates of metabolic comorbidity; 3 of 4 are overweight or obese, whereas the prevalence of type 2 diabetes (T2D) is several-fold higher than in the general population. Consequently, individuals with SMI die 15 to 20 years earlier from cardiovascular disease (CVD) than do those in the general population with CVD. Antipsychotics are the cornerstone of treatment in SMI and are widely prescribed for other psychiatric conditions. Although several factors, including inherent biological risk, lifestyle factors, and lack of access to care, contribute to high rates of metabolic comorbidity, antipsychotic use (across class and individual agents) is unequivocally associated with severe metabolic adverse effects, including weight gain, dyslipidemia, and risk of diabetes.
So begins a Viewpoint by Drs. Agarwal and Hahn.
They open by noting the importance of weight control. “Weight gain is distressing for patients and is associated with poorer quality of life, stigma, barriers to social engagement, and worse cognition; it compromises treatment adherence leading to poor mental health outcomes in SMI. Conversely, even modest weight loss (ie, 5% of body weight) can reduce the risk of developing CVD and T2D and improve quality of life and possibly cognition. However, metabolic comorbidity is vastly undertreated in SMI. Behavioral strategies lack effectiveness and scalability to counter a problem of this magnitude.” In terms of older medications, they write that “weight loss related to metformin use tends to be modest (3%-5% in most studies)…”
The new class has thus sparked interest, and they describe the novel pathway: “Glucagon-like peptide 1 receptor agonists (GLP-1RAs), including semaglutide, are a newer class of drugs that mimic the effects of GLP-1, an endogenous peptide synthesized in the intestinal mucosa. GLP-1 decreases glucagon secretion and stimulates insulin secretion in a glucose-dependent manner, delays gastric emptying, and lowers food intake by promoting satiety.”
They detail the landmark study. “The Semaglutide Treatment Effect in People With Obesity (STEP) program, which included a series of trials evaluating the efficacy of subcutaneous semaglutide, 2.4 mg, for the management of obesity, has consistently demonstrated greater than 10% average weight loss in the active study arm; longer treatment durations were linked to greater weight-loss efficacy as well as improvement in blood pressure, blood glucose levels, C-reactive protein levels, and lipid profiles. Notably, as a class, GLP-1RAs are also associated with lowered risk of major adverse CV end points, including CV mortality, nonfatal strokes, and myocardial infarctions.”
They comment on side effects:
- Adverse effects. “The STEP trials demonstrated that semaglutide was safe and well tolerated; mild to moderate gastrointestinal symptoms were reported as the most common adverse effects.”
- Suicide. “A Nature Medicine article reporting risk of suicidal ideation in a cohort of 240 618 patients with overweight or obesity and 1 589 855 patients with T2D who were prescribed semaglutide or non-GLP-1RA medications found lower risk for incident and recurrent suicidal ideation in both cohorts with semaglutide.”
- Gastric motility. “A recent analysis reported increased risk of pancreatitis, gastroparesis, and bowel obstruction (but not biliary disease) when GLP-1RAs were used to treat obesity compared with bupropion-naltrexone among 4144 patients receiving liraglutide, 613 receiving semaglutide, and 654 receiving bupropion-naltrexone.”
Another practical problem: accessibility given the medication’s expense. They add: “Given the magnitude and persistence of weight gain associated with antipsychotics, patients will likely need to continue receiving the drug indefinitely or at least while treated with antipsychotics because available evidence suggests that weight is regained after semaglutide treatment is stopped.”
The authors are optimistic. “Patients with SMI have long experienced weight gain and related adverse effects with few good treatment options… The proximal effects of weight and related CV comorbidities are significant in themselves. It is plausible that semaglutide could act through neurogenesis or secondary benefits of improving metabolic health on other important outcomes, such as cognitive health and quality of life, thereby filling an unmet need in the treatment of SMI.”
A few thoughts:
1. This is a well-written Viewpoint which makes good and practical points.
2. Considering that weight gain is partly iatrogenic, it’s difficult not to be excited about the potential of semaglutide and related drugs.
3. Access is deeply problematic. I work in a jurisdiction where most of my patients who would benefit from this medication aren’t eligible for public support.
4. The last line of the paper is particularly good. “Mental health stands to gain much from an improvement in physical health.”
The full JAMA Psych Viewpoint can be found here:
https://jamanetwork.com/journals/jamapsychiatry/article-abstract/2822341
In the News
Part of an occasional series.
“Have you been given an ADHD diagnosis by TikTok University?”
Selvi Sert
The Globe and Mail, 30 November 2024
“The act of diagnosis was once a ritual reserved for the clinic – a controlled exchange between patient and physician, bound by the rigour of scientific inquiry and the confines of medical expertise. Today, however, this sacred rite has migrated beyond the sterile walls of hospitals and consulting rooms. In a world where the boundaries between public and private have dissolved into the ether of digital networks, diagnosis has found an unlikely new home: social media… On platforms like TikTok, the pursuit of self-diagnosis has become as ubiquitous as viral dance trends and lip-syncing videos.”
This opinion piece, written by a research co-ordinator at the Bloorview Research Institute, focuses on ADHD. She comments on the wealth of information available on social media with catchy videos and compelling personal narratives. Unfortunately, despite the high-view count for ADHD-related videos, the quality is uneven. She notes a recent Canadian Journal of Psychiatry study finding 52% of the most popular ADHD TikTok videos had misleading information.
As clinicians, we are likely to be cool to this new trend. That said, social media is here to stay, and we need to adapt our clinical work accordingly.
“Can Hearing About Someone Else’s Problems Fix Your Own?”
Jamie Ducharme
Time, 22 November 2024
“Would you spend $40 on a meal? A workout class? A new T-shirt? To chat with a stranger about their life experience for half an hour? The last is the business model behind Fello, a new app that pays people to tell their life stories to others going through the same stuff. Just like Uber and Airbnb let people make cash from their cars and homes, Fello lets you monetize your hard-won wisdom.
“The idea is to provide ‘a new type of support that you don’t get from going to a generic support group, perusing Reddit or Facebook groups, or meeting with a therapist,’ says CEO Alyssa Pollack…”
The Time article discusses an old idea – peer support – and a new app which offers it for a fee from other users. Ducharme notes that there is a literature supporting peer support, including a 2024 systematic umbrella review finding that it can foster a sense of belonging, community, and social connectedness. The article describes various peer support programs, including those for substance use (such as AA) and others available on college campuses. But such peer support is built on trained workers. As Dr. John Torous (of Harvard University) comments: “Who are these people [who provide peer support on Fello], really? That’s the part that’s concerning.”
The article illustrates how mental healthcare is changing with technology and market incentives. You are unlikely to recommend this app; what would you say to a patient who tells you that he downloaded it?
https://time.com/7178392/peer-support-mental-health/
“Librarians Face a Crisis of Violence and Abuse”
Christina Caron
The New York Times, 31 October 2024
“On social media, Mychal Threets was spreading the gospel of ‘library joy’ to hundreds of thousands of followers.
“Known for his energetic delivery and signature Afro, Mr. Threets showed off the book-themed tattoos covering his arms and evangelized about the pleasure of reading while cradling one of his cats… But at his job, as a supervisor at the Fairfield Civic Center Library in Solano County, Calif., he was facing new challenges. The library, which he had begun visiting as a child, had become a gathering place for people experiencing issues like homelessness, drug dependence and mental illness.”
The article describes the challenges faced by librarians across the United States as they become “public stages” for social problems. As a supervisor, Treets filed over 170 incident reports documenting library patrons’ actions, ranging from property damage to physical altercations. In a 2022 survey of more than 400 staff members at urban libraries, nearly 70% said that they had experienced violent or aggressive behaviour. Some libraries have hired social workers (connecting patrons with services) and are training staff to respond to mental health problems. For the record, Threets left his position.
In recent years, your local ED has seen more people who are homeless and touched by substance. This article reminds us that they are being seen elsewhere, including in our libraries.
https://www.nytimes.com/2024/10/31/well/mind/librarian-trauma-homeless-drugs-mental-illness.html
Reading of the Week. Every week I pick articles and papers from the world of Psychiatry.
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