From the Editor

When it comes to antipsychotics, polypharmacy (the use of more than one antipsychotic) has fallen out of fashion – the psychopharmacological equivalent of bell bottoms. Providers worry about side effects and the long-term physical health implications. Are the concerns overstated? In the first selection, Heidi Taipale (of the University of Eastern Finland) and her coauthors analyze Finnish data for The American Journal of Psychiatry. The study includes almost 62,000 patients with schizophrenia with a median follow up period of more than 14 years, and they find that the use of more than one antipsychotic isn’t linked to poorer health outcomes. “The results show that antipsychotic monotherapy is not associated with a lower risk of hospitalization for severe physical health problems when compared with antipsychotic polypharmacy.” We consider the paper and its clinical implications.

Melatonin is a popular recommendation for sleep, but what’s the quality like? In the second selection from JAMA, Dr. Pieter A. Cohen (of Harvard University) and his co-authors try to answer that question with a focus on melatonin gummy products, looking at 30 brands. “The great majority of melatonin gummy products were inaccurately labeled, with most products exceeding the declared amount of melatonin and CBD.”

Gummy melatonin: colourful but what’s the quality?

In the third selection, in an essay for The Globe and Mail, journalist Anna Mehler Paperny writes about the push for more coercive care by different governments. Drawing on her personal experiences, she notes potential problems. “There is a role for coercive care. It’s arguably necessary for some people, sometimes. But used injudiciously, it can sour people on care and set them up for failure.”

There will be no Reading next week.


Selection 1: “Safety of Antipsychotic Polypharmacy Versus Monotherapy in a Nationwide Cohort of 61,889 Patients With Schizophrenia”

Heidi Taipale, Antti Tanskanen, and Jari Tiihonen

The American Journal of Psychiatry, 22 March 2023  Online First

In medicine, polytherapy is common. For example, the most recent treatment guidelines issued by the World Health Organization (WHO) for hypertension recommend combining drugs with different pharmacological mechanisms to achieve optimal efficacy and tolerability. In the treatment of schizophrenia, antipsychotic polypharmacy is used in up to 50% of patients, but treatment guidelines generally advise avoiding polypharmacy because of lack of evidence on its efficacy and safety concerns… 

A recent meta-analysis on high-quality randomized controlled trials (RCTs) of antipsychotic augmentation and monotherapy concluded that the only beneficial outcome related to antipsychotic polypharmacy is reduction of negative symptoms, which was found for aripiprazole add-on treatment. Few differences in adverse effects were observed, including less insomnia and more prolactin elevation with D2 antagonist augmentation, and reduced prolactin levels and body weight with aripiprazole augmentation… Because RCTs typically last 3–6 months, they cannot provide information on long-term safety issues, which are attributable to relatively slowly developing adverse effects, such as weight gain leading to diabetes and ischemic heart disease…

Recent observational studies in patients with schizophrenia have suggested that compared with monotherapy, polypharmacy may be associated with lower risk of hospitalization due to severe relapses, lower mortality, and lower risk of treatment discontinuation. However, no studies have investigated how antipsychotic dosage is associated with the comparative safety of polypharmacy versus monotherapy in terms of risk of hospitalization due to physical illness or the risk of psychiatric rehospitalization.

So begins a paper by Taipale et al.

Here’s what they did:

“Patients with schizophrenia… were identified from the Finnish nationwide inpatient care register and followed up over the period 1996–2017. Antipsychotic polypharmacy was compared with monotherapy in seven dosage categories… in terms of risk of severe physical morbidity, indicated by nonpsychiatric and cardiovascular hospitalizations (adjusted hazard ratio). Within-individual analysis was used in an effort to eliminate selection bias.”

Here’s what they found:

  • The total number of patients was 61,889 with a median follow-up of 14.8 years.
  • Demographics. The mean age of the cohort was 46.7 years and 50.3% were men.
  • Monotherapy vs. polytherapy. “Monotherapy was used 45.9% of person-time, polytherapy 33.8% of person-time, and antipsychotic nonuse 20.3% of person-time.”
  • Medications. “The most commonly used antipsychotics varied between specific dosage categories such that most common specific antipsychotics in the lowest dosage categories (both in monotherapy and in polypharmacy) were risperidone and quetiapine, whereas clozapine monotherapy was common in the middle dosage categories, olanzapine monotherapy in the highest dosage category, and olanzapine-quetiapine combination in the highest dosage category, followed by clozapine-aripiprazole…”
  • Hospitalizations. “During the follow-up, 45,013 patients experienced nonpsychiatric hospitalization and 13,893 experienced cardiovascular hospitalization.”
  • Physical health hospitalizations. “Among patients who had used both monotherapy and polypharmacy, the risk of nonpsychiatric hospitalization was significantly lower during polypharmacy use at all total dosage categories above 1.1 DDDs/day with differences up to −13% than during monotherapy use of the same dosage category (for 1.1–<1.4 DDDs/day, adjusted hazard ratio=0.91…; for 1.4–<1.6 DDDs/day, adjusted hazard ratio=0.91…; and for ≥1.6 DDDs/day, adjusted hazard ratio=0.87…). The risk of cardiovascular hospitalization was significantly lower for polypharmacy at the highest total dosage category (−18%, adjusted hazard ratio=0.82…).”

A few thoughts:

  1. This is an impressive study with much to like: a large number of patients with many years of data, combined with sophisticated statistical analyses that account for drug dosing.

  2. The above summary doesn’t well capture the complexity and sophistication of the paper.

  3. The major finding in a sentence: “Our major findings were that when compared with monotherapy, the risk of nonpsychiatric hospitalization was lower for polypharmacy at total dosage categories above 1.1 DDDs/day, and that the risk of cardiovascular hospitalization was 18% lower for polypharmacy at the highest total dosage category when compared with monotherapy (corresponding to a 22% higher risk during monotherapy when compared with polypharmacy).”

  4. The clinical implications? “The current recommendations of treatment guidelines categorically encouraging use of monotherapy instead of polypharmacy are not based on evidence and should take a more agnostic approach to this issue.” 

  5. Like all studies, there are limitations. The authors note several, including: “These results are based on a Finnish nationwide cohort that included all patients who had been hospitalized with a schizophrenia diagnosis. Therefore, the generalizability of the results is not an issue for Finland, and probably not for other higher-income countries with similar health care systems, but the results may not apply to middle- and low-income countries without full reimbursement of medication costs for patients with schizophrenia.”

  6. Is it time to (re-)embrace polypharmacy? This is a solid study, drawing on much data. Is the data itself relevant? Though it’s Finnish, the authors argue that the findings are relevant across high-income countries. But the population seems a bit different: patients were around 47 years of age and ill for roughly a decade. Perhaps that’s why past publications from the Finnish data have found a robust role for polypharmacy for those with schizophrenia – a somewhat unusual finding. Many of our colleagues who work with this population haven’t had that clinical experience, ending up with polypharmacy for a patient because little works but not necessarily seeing that combinations add much of value. The take-away? We may wait for further work in the area before fundamentally re-examining the risks and benefits of polypharmacy.

  7. And a quick word of thanks to Dr. Gary Remington (of the University of Toronto) for helping me better understand this paper.

The full American Journal of Psychiatry paper can be found here:

Selection 2: “Quantity of Melatonin and CBD in Melatonin Gummies Sold in the US”

Pieter A. Cohen, Bharathi Avula, Yan-Hong Wang, et al.

JAMA, 25 April 2023       

Melatonin products are not approved by the US Food and Drug Administration (FDA). Instead, they are sold over the counter as dietary supplements or food, and some products include prohibited drugs such as cannabidiol (CBD).

So begins a research letter by Cohen et al.

Here’s what they did:

“In September 2022, products formulated as gummies with ‘melatonin’ on the label were identified in the National Institutes of Health’s Dietary Supplement Label Database, the most comprehensive database of dietary supplements sold in the US. The 30 unique brands entered into the database in 2021 were purchased online… Gummies from the supplement products were reconstituted in methanol and an aqueous mixture of acetonitrile-methanol and then analyzed for the presence and quantity of melatonin, CBD, and serotonin using ultra high-performance liquid chromatography–photodiode array analyses…”

Here’s what they found:

  • “Of the 30 melatonin gummy brands meeting the inclusion criteria, 4 were unavailable for purchase and 1 did not contain ‘melatonin’ on the actual label; therefore, 25 products were analyzed.” 
  • “One product did not contain detectable levels of melatonin but did contain 31.3 mg of CBD.” 
  • Melatonin. “In the remaining products, the quantity of melatonin ranged from 1.3 mg to 13.1 mg per serving size… In products that contained melatonin, the actual quantity of melatonin ranged from 74% to 347% of the labeled quantity. Twenty-two of 25 products (88%) were inaccurately labeled, and only 3 products (12%) contained a quantity of melatonin that was within ±10% of the declared quantity.” 
  • CBD. “Five products declared CBD as an ingredient, and the quantity of CBD ranged from 10.6 mg to 31.3 mg per serving. The actual quantity of CBD ranged from 104% to 118% of the labeled quantity.”

A few thoughts:

  1. This is a good research letter.

  2. The authors don’t mince their words: “The great majority of melatonin gummy products were inaccurately labeled, with most products exceeding the declared amount of melatonin and CBD.” (!!) Circling back to the findings: just three products were within 10% of the declared quantity.

  3. The regulatory framework is a bit different for those of us practicing on the rugged part of North America. But the authors note: “A Canadian study had similar results: analysis of 16 Canadian melatonin brands found that the actual dose of melatonin ranged from 17% to 478% of the declared quantity.” Ouch.

  4. The authors note the rise of melatonin-related problems: “Calls for pediatric melatonin ingestions to US Poison Control Centers increased 530% from 2012 to 2021 and were associated with 27 795 emergency department and clinic visits, 4097 hospitalizations, 287 intensive care unit admissions, and 2 deaths.”

The JAMA research letter can be found here:

Selection 3: “Involuntary care doesn’t need to be dehumanizing”

Anna Mehler Paperny

The Globe and Mail, 26 April 2023

Coercive care is having a moment. Alberta, which hinted at expanding involuntary treatment for drug users, is eyeing that option. British Columbia Premier David Eby has mused aloud about it. In Toronto, mayoral candidate Anthony Furey says he wants to explore more opportunities for mandatory treatment. New York City and California are exploring expansions to involuntary care.

It can seem a beguiling prospect: Help the most visibly needy, the people unable or unwilling to help themselves. Get disorder off the street and salve a spooked public, while you’re at it.

It’s not that simple.

So begins an essay by Mehler Paperny.

She asks a simple question. “Does coercive care work?”

“It depends on who you ask, and what you mean by ‘work.’ Yes, it can keep you safe from yourself and others for a period of time; it can give you a chance to access care, at least in the short- to medium-term. (Granted, Canadians with severe mental illness are often discharged into a treatment abyss; one can be sick enough to warrant coercion, but apparently not sick enough to warrant continuing care that could prevent future deterioration.)”

But the issue is complex since involuntary care “can also set people up for relapse and drug poisoning, if they use substances and lose tolerance.” As well, “traumatizing experiences in such care can seed a deep mistrust of the medical system, making it less likely that they ever seek out care on their own.”

She draws on her own personal experience. “I’ve spent weeks locked in psych wards because I was deemed a suicide risk; I know how awful and disempowering it is to lose agency behind those auto-locking doors. But I got lucky: The doctor who ordered the extension of my first involuntary stay, a decision I cursed him for at the time, became my outpatient psychiatrist and a lifesaver. He treated me – still treats me – as a human with wishes to be respected.”

She also suggests a need to look deeper:

“Locking up more people with mental illness doesn’t solve the broader problems. We are not providing continuing care for chronic, debilitating conditions. We are not making evidence-based care accessible, equitable, attractive, or preventive enough. If we really cared about the human beings that mental illness so excruciatingly affects, this is where we would instigate change.”

A few thoughts:

  1. This is a good essay.

  2. The first line is worth repeating: “Coercive care is having a moment.” Governments are considering more coercive care. She does a solid job of describing the potential problems.

  3. As always, her writing is blunt and draws on personal experience. 

  4. This is the second selection in two weeks on coercion and care. Mehler Paperny is someone with lived experience. Last week, David Sheff wrote about his experiences as the father of a person with substance use problems. That Reading can be found here:

The full Globe essay can be found here:

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