From the Editor 

It’s day three of his hospitalization, and he insists that the medication trial (a low dose of an SSRI) has been transformative. It’s difficult to explain his experience pharmacologically. 

How significant is the placebo response? How much does it vary among mental disorders? These questions aren’t new. In the first selection, Dr. Tom Bschor (of the Technical University of Dresden) and his co-authors tread on a familiar path with a study just published in JAMA Psychiatry. Focusing on nine psychiatric disorders, they examined high-quality RCTs for a systematic review and meta-analysis, finding “significant improvement under placebo treatment for all 9 disorders, but the degree of improvement varied significantly among diagnoses.” We consider the study and its implications.

In the second selection, Christopher M. Jones (of the Substance Abuse and Mental Health Services Administration) and his co-authors used US databases to calculate how many children have lost a parent to drug overdoses. The resulting JAMA Psychiatry study is haunting. “We estimated that more than 320 000 US children lost a parent to drug overdose between 2011 and 2021, providing new insight into the multigenerational impacts of the ongoing overdose crisis in the US.”

Finally, we explore the latest news with recent articles from The GuardianThe Globe and Mail, and The New York Times. Among the topics: the mental health struggles of a cancer patient, the beliefs of Marshall Smith, and whether we are talking too much about mental health.


Selection 1: “Differential Outcomes of Placebo Treatment Across 9 Psychiatric Disorders: A Systematic Review and Meta-Analysis”

Tom Bschor, Lea Nagel, Josephine Unger, et al.

JAMA Psychiatry, 29 May 2024  Online First

Placebo is arguably the most extensively investigated therapeutic agent worldwide. In psychiatry, a placebo is deemed ethically acceptable for research in nearly all indications, serving as the sole intervention that has been studied for all psychiatric disorders.

In studies of psychiatric conditions, even patients in placebo groups typically show improvement, making it sometimes challenging to discern a verum-placebo contrast. Also, placebo effects have increased over the years in studies on major depression and schizophrenia and schizoaffective disorder.

A genuine placebo effect, by definition, encompasses improvements induced by suggestion, hope for effective treatment, and conditioning effects through the administration of medications. However, other factors might improve psychopathology: psychiatric disorders often have episodic courses. Contextual factors, such as attentive study personnel, compassionate care, supportive conversations, and psychoeducation, can influence outcomes positively. Life circumstances may change during a study…

Placebo response is not equally distributed across different disorders, with limited comprehensive comparisons in psychiatry. Khan and coauthors compared 6 disorders in a 2005 study, which is still the most comprehensive study to date, to our knowledge; however, significant conditions, like mania or social phobia, were not included. Other reviews have focused on depressive disorders or a few other diagnoses.

So begins a paper by Bschor et al.

Here’s what they did:

  • They conducted a study to “compare changes in placebo groups in recent high-quality randomized clinical trials (RCTs) across a broad spectrum of psychiatric disorders in adult patients.”
  • They focused on nine disorders: major depressive disorder, mania, schizophrenia, OCD, ADHD, GAD, panic disorder, PTSD, and social phobia.
  • They used a two-step approach for finding the RCTs. First, they did literature searches across databases (including MEDLINE) for systematic reviews for the nine psychiatric disorders, selecting the “latest systematic reviews meeting predetermined high-quality criteria.” They then used these reviews to select the most recent placebo-controlled RCTs per diagnosis (totaling 90 RCTs).
  • “Cross-diagnosis comparisons were based on standardized pre-post effect sizes (mean change divided by its SD) for each placebo group.”
  • Primary outcome: pooled pre-post placebo effect sizes.

Here’s what they found:

  • There were 90 studies with a total of 9 985 participants. 
  • Across diagnoses. “In all diagnoses, there were improvements in symptom severity during placebo treatment…”
  • Effect sizes. “The pooled pre-post placebo effect sizes differed statistically significantly among the disorders (Q = 88.5…). The largest effect size was observed in MDD (dav = 1.40…), followed by GAD (dav = 1.23…). Schizophrenia had the smallest effect size (dav = 0.59…) and OCD had the second weakest (dav = 0.65…).” See figure below.
  • GAF scores. “Results of standardized comparisons corroborated main analysis findings, highlighting pronounced placebo responses in GAD, panic disorder, and MDD…”
  • Sex. “In multivariable analysis, apart from diagnosis, only gender or sex remained statistically significantly associated with pooled pre-post effect sizes (slope point estimate, 0.0076…), indicating that with each percentage point of women in the study, the effect size increased by 0.0076…”

A few thoughts:

1. This is an important paper, drawing on good studies with a clear result, and published in a major journal. For the record, the two-step approach – building on systematic review and then selecting RCTs – is very, very clever.

2. The main finding in a sentence: There was considerable improvement across nine psychiatric disorders, but there was variation among disorders themselves.

3. The findings align with earlier work. “Previous studies have already reported a particularly large effect of placebo in MDD and GAD, with a comparatively smaller effect in OCD. Schizophrenia, mania, ADHD, and PTSD have been comparatively less studied.”

4. Why? Let’s start with depression, which had the largest placebo effect size. Depression is episodic, suggesting a natural improvement with time. Additionally, there are aspects of psychotherapy that are replicated by enrollment in a depression trial, including a therapeutic milieu and psychoeducation. In contrast, schizophrenia – the other end of that effect-size list – is felt to be more “biological” and “less psychogenic.” For the record, the first author discusses this in a lively and entertaining interview with Dr. John Torous (of Harvard University).

5. Like all studies, there are limitations. The authors note: “Our study, limited to adults, encountered variations in study designs both among and within diagnostic groups, affecting multiple factors, like study duration and placebo likelihood.”

6. Interested in reading more? An excellent New England Journal of Medicine paper by Colloca et al. considers placebo and nocebo – negative expectations leading to a more negative effect. The latter is not uncommon; they note: “up to 19% of adults and 26% of elderly persons taking placebos report side effects.” That paper can be found here:

In a provocative Molecular Psychiatry paper, Burke et al. wonder if placebo effects share mechanisms of action with neuromodulation, found here:

The full JAMA Psych paper can be found here:

(The podcast can be found on that webpage.)

Selection 2: “Estimated Number of Children Who Lost a Parent to Drug Overdose in the US From 2011 to 2021”

Christopher M. Jones, Kun Zhang, Beth Han, et al.

JAMA Psychiatry, 8 May 2024

The US overdose crisis continues to impact communities at historic levels, with data from the US Centers for Disease Control and Prevention (CDC) estimating more than 107 000 lives lost to overdose in 2022.1 Overdose and substance use impact not only the individuals using substances, but also families and communities… Although more than 1 million lives have been lost in the US to overdose in the past 2 decades, to our knowledge, no study has estimated the number of children who have lost a parent to overdose. A small number of studies have indirectly examined this issue. For example, Ghertner et al found that a 10% increase in county-level drug overdose death rates was associated with a 4.4% increase in county-level foster care entry rates. Beatty et al reported that counties with higher overdose mortality rates had greater rates of grandparents as primary caregivers…

Prior research on parental loss and bereavement in general indicates that children who lose a parent can have both short- and long-term challenges with substance use, mental health, and physical health as well as schooling challenges, financial insecurity, housing instability, and disruption in essential nurturing during critical development periods.

So begins a paper by Jones et al.

Here’s what they did:

  • They conducted “a cross-sectional study of US community-dwelling persons using data from the National Survey on Drug Use and Health (2010-2014 and 2015-2019) and the National Vital Statistics System (2011-2021).”
  • They calculated how many children have lost a parent to a drug overdose and then examined at how the rate varies by parent age, sex, or race and ethnicity.

Here’s what they found:

  • From 2011 to 2021, 649 599 adults aged 18 to 64 years died from a drug overdose.
  • Total. “Among these decedents, we estimate that from 2011 to 2021, 321 566… community-dwelling children lost a parent aged 18 to 64 years to drug overdose.”
  • Rate. “The rate of community-dwelling children who lost a parent to drug overdose per 100 000 children increased from 27.0 per 100 000… in 2011 to 63.1 per 100 000… in 2021, a 134% increase.”
  • Ethnicity. “The highest rates were found among children of non-Hispanic American Indian or Alaska Native individuals, who had a rate of 187.1 per 100 000 in 2021, more than double the rate among children of non-Hispanic White individuals (76.5 per 100 000) and non-Hispanic Black individuals (73.2 per 100 000).”

A few thoughts:

1. This is a good paper that offers a unique perspective on the overdose crisis.

2. The main finding in two words: too many.

3. They see obvious implications for service delivery. “While expanding [treatment] services has been a priority of federal, state, and local efforts over the past decade, a specific focus on parents has been lacking. Having a role as a parent can be a strong motivator to participate in substance use disorder treatment, but disrupted neurobiological reward and stress systems in persons with substance use disorders may also cause difficulties with parenting. Directly addressing parenting during treatment is a natural focus that has been examined by multiple studies that generally show positive outcomes. However, specific parenting interventions, including peer-to-peer parenting training, are not often included in treatment.” Thoughtful.

4. Like all studies, there are limitations. The authors note several, including “the lack of direct information about overdose decedent family and household structure necessitated use of family structures among people using drugs…”

The full JAMA Psych paper can be found here:

In the News

Part of an occasional series.

“A moment that changed me: I cured my 3 am terrors with the help of a therapist – and a moose”

Michelle Spencer

The Guardian, 29 May 2024

“It was clear the moose was to blame for the lack of water. Halfway down the ravine, far from the house in southern Alberta, Canada, tracks circled our well. The moose had punched straight through the plywood cover, exposing the pump and pipe to freezing temperatures. For 20 years, my husband and I had been saying we should replace the flimsy wooden lid with a metal one, but it was never a priority. That is, until last winter, when we lost our only source of water.”

This autobiographical article isn’t really about the author’s supply of water – or even about the moose that had created the problem. It’s about a woman who has been treated for breast cancer but hasn’t healed psychologically. Her nights are coloured by insomnia and filled with anxiety. 

With time and therapy, she makes her recovery. And, yes, a moose is involved. (For the record, I consider this essay to be peak Canada.)

“Are We Talking Too Much About Mental Health?”

Ellen Barry

The New York Times, 6 May 2024

“In recent years, mental health has become a central subject in childhood and adolescence. Teenagers narrate their psychiatric diagnosis and treatment on TikTok and Instagram. School systems, alarmed by rising levels of distress and self-harm, are introducing preventive coursework in emotional self-regulation and mindfulness.

“Now, some researchers warn that we are in danger of overdoing it.”

So begins an interesting and well-written article by reporter Ellen Barry. She discusses the awareness paradox (putting a label on a problem isn’t necessarily helpful). She then carefully considers experiments where students are taught CBT, DBT, or mindfulness, with the hope of reducing mental health problems; the results suggest that they are no healthier than their peers. She describes in some detail MYRIAD, an eight-year study involving 28 000 adolescents, teaching mindfulness principles. “In fact, students at highest risk for mental health problems did somewhat worse after receiving the training, the authors concluded.”

The article raises sobering questions.

“Addiction almost killed Marshall Smith. Now, he’s overhauling Alberta’s drug policy”

Marcus Gee

The Globe and Mail, 25 May 2024

“One day in the early 2000s, police acting on a tip about some suspected drug dealers kicked in the door of a Vancouver hotel room. They found a well-known dealer inside, but they also found a fast-talking, rail-thin guy with a dimpled chin and boyish good looks. He was new on the scene. His name was Marshall.

“Over the next few years, they got to know him well. Whenever they saw him, they would stop to talk. He was unusually well-spoken and, as they soon learned, he had a remarkable back story. They urged him to get help with his addiction.”

So begins an article about Marshall Smith, who struggled with substance but achieves sobriety – and then success, going on to be the chief of staff of the Premier of Alberta. This essay, clearly and thoughtfully written by Marcus Gee, describes his journey and opinions. Smith is working to focus Alberta’s efforts on more treatment and housing, but is cool to aspects of harm reduction. Alberta’s approach is thus very different from British Columbia’s, with its (past) emphasis on decriminalization.

Is Smith right? Readers can draw their conclusions but this much is clear: his views on substance are informed by his own lived experience.

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