From the Editor
Clozapine is special.
Almost seven decades after its release, that statement – from a new Lancet Psychiatry Editorial – remains true. Clozapine is the best antipsychotic for those who are treatment refractory in their schizophrenia. But there is the risk of potentially life-threatening neutropenia. And so its use is clunky, with much blood work and monitoring, off-putting to some who would benefit from this medication.
Are we too cautious with clozapine? In the first selection, Dr. Korinne Northwood (of The University of Queensland) and her co-authors consider that question in a new Lancet Psychiatry paper. Drawing from a major clozapine database for Australia and New Zealand patients, they analyzed 32 years of data involving 2.6 million blood tests and looked at neutropenic events. “Our results support greater flexibility in prescribing of clozapine and a more balanced approach to risk…” We review the paper and mull its clinical implications.
In the second selection, in a letter to the editor, Clement Ma and Dr. Peter Szatmari (both of the University of Toronto) write about the recent MST vs. ECT paper from JAMA Psychiatry. They offer some hesitation on the authors’ wording: “a non-significant result in a superiority trial does not imply that the two treatments are equivalent.”
And in the third selection, actress and former Jeopardy! host Mayim Bialik writes personally about her mental health problems for Trend Magazine. She describes the challenges of getting help and her decision to speak out. She also notes the societal shift in thinking about mental illness. “[S]haring our own personal struggles is not a sign of weakness; it is a sign of strength. We all want to feel better, live better, and experience more joy and less suffering.”
Selection 1: “Evaluating the epidemiology of clozapine-associated neutropenia among people on clozapine across Australia and Aotearoa New Zealand: a retrospective cohort study”
Korinne Northwood, Nicholas Myles, Scott R. Clark, et al.
The Lancet Psychiatry, January 2024
Clozapine is the most effective antipsychotic for reducing positive psychotic symptoms, hospital admission, and mortality for people with treatment-resistant schizophrenia, which is experienced by about a third of people with schizophrenia. However, prescription of clozapine is associated with a risk of potentially life-threatening neutropenia. This risk is the rationale for mandated haematological monitoring programmes of clozapine use in many countries. Although monitoring has improved the safety of clozapine prescribing, it can also create a substantial burden for people on clozapine…
When mild neutropenia is not causally related to clozapine exposure, excessively stringent neutrophil thresholds for clozapine discontinuation could deny people with treatment-resistant schizophrenia access to clozapine. Mild neutropenia is a common haematological finding in the general population, and therefore a proportion of neutropenia in people taking clozapine will be due to benign or causally unrelated occurrences.
So begins a paper by Northwood et al.
Here’s what they did:
- They performed a retrospective analysis of one of two monitoring databases for Australia and New Zealand between 6 June 1990 and 25 October 2022.
- Exclusion criteria included patients who commenced clozapine before 1990.
- “We measured minor neutropenia (ANC 1.0 – 1.5 × 109 per L) and serious neutropenia (ANC <1.0 × 109 per L) leading to cessation of clozapine within 6 weeks of the neutropenic event.”
- “We determined the rates of minor and serious neutropenia and calculated odds ratios (ORs) for the likelihood of neutropenia leading to cessation. For serious neutropenia leading to cessation, we used time-to-event to calculate rolling weekly averages and to perform competing risk analysis of outcomes using Cox proportional hazards models and a Fine-Gray subdistribution hazards regression model.”
Here’s what they found:
- They included 26 630 people, with 2.6 million ANC values.
- Demographics. 66% were male. The mean age was 36.1 years. There was no data on ethnicity.
- Neutropenia. “1146 (4.3%) had minor neutropenia, 313 (1.2%) had serious neutropenia leading to cessation, and 223 (0.8%) had serious neutropenia unrelated to clozapine without cessation.”
- Serious neutropenia. “In people with no previous exposure to clozapine (n=15 973), the cumulative incidence of serious neutropenia leading to cessation was 0.9% at 18 weeks and 1.4% at 2 years; the weekly incidence rate for serious neutropenia leading to cessation peaked at 9 weeks (0.128%) and fell to a rolling average weekly incidence of 0.001% by 2 years.”
- Minor neutropenia. “For minor neutropenia, the cumulative incidence was 1.7% at 18 weeks and 3.5% at 2 years; the weekly incidence rate peaked at 9 weeks (0.218%) and fell to a stable rolling average of 0.01%.”
A few thoughts:
1. This is a good paper with much to like – including a robust dataset over many years, and with publication in a major journal.
2. The main finding in a sentence: “rates of serious neutropenic events leading to clozapine cessation are highest in the first 18 weeks and become negligible after 2 years of clozapine exposure.”
3. The clinical implications? “This finding suggests that following a 2-year period of monitoring, a patient who has not had a serious neutropenic event could have haematological monitoring safely discontinued.”
“Overall, clozapine is under-prescribed globally and generally initiated later in the course of treatment-resistant schizophrenia than guidelines recommend; prescriber fear of clozapine-associated neutropenia or concerns about logistics and patient burden related to haematological monitoring could contribute. Haematological monitoring guidelines for clozapine-associated neutropenia should balance the intended benefit of improving safety of prescribing with the foreseeable risk of deterring appropriate treatment. Current clozapine monitoring guidelines were developed in the 1980s…” They advocate more flexibility.
4. They also argue that minor neutropenia isn’t likely to be of clinically significance. “Based on our data, most patients with minor neutropenia will not have more severe neutropenia or discontinue clozapine as a result, and competing risk subdistribution hazards for such an outcome were not significant at 18 weeks or 104 weeks.”
5. The paper runs with an Editorial, quoted at the start of this Reading. The authors note the advantages of a more flexible approach to monitoring: “Despite substantial evidence for clozapine’s value, it stumbles over other hurdles. Because of its potential for inducing neutropenia, in many countries, people who begin taking clozapine have regular blood monitoring. In the countries with indefinite monthly monitoring, this can seem off-putting to patients, depending on how this prospect and the potential benefits of starting clozapine are presented by clinicians. For clinicians, taking the time to make a shared decision by discussing such factors can be off-putting within a busy schedule.”
That Editorial can be found here:
6. The authors note several limitations, including that the study drew its data from a drug company database. As well, the data lacked information on ethnicity.
7. Clozapine monitoring has been considered in past Readings. In June, we looked at the Oloyede et al. paper looking at outcomes of 569 patients on clozapine when, during the pandemic, routine blood monitoring was changed. In this mirror-image cohort study, they found: “[E]xtending the haematological monitoring interval from 4-weekly to 12-weekly did not increase the incidence of life-threatening agranulocytosis in people taking clozapine.” That Reading can be found here:
The full Lancet Psych paper can be found here:
Selection 2: Letter to the Editor
Clement Ma and Peter Szatmari
18 January 2024
Re: “Clinical Outcomes of Magnetic Seizure Therapy vs Electroconvulsive Therapy for Major Depressive Episode: A Randomized Clinical Trial”
Zhi-De Deng, Bruce Luber, Shawn M. McClintock, et al.
JAMA Psychiatry, 6 December 2023
We always enjoy your Reading of the Week. It is a real benefit. Thanks for doing this.
However, we did want to point out a misinterpretation of the findings reported by the authors of the MST vs EST trial.
It can be misleading to state that: “This randomized clinical trial found that the efficacy of MST was indistinguishable from that of ultrabrief pulse [right unilateral] ECT, the safest form of ECT currently available.”
It is important to remember that this study was designed as a superiority trial and powered as such. In other words, it was intended to see whether one treatment was better than the other.
The point we want to emphasize is that a non-significant result in a superiority trial does not imply that the two treatments are equivalent, or indistinguishable or that the new treatment is non-inferior. See Goodman (2008).
The more accurate statement is: “There was no significant difference between MST and ECT for either response or remission rates.”
This statement from the paper also supports this: “Our study was not powered as an equivalence or noninferiority trial; thus, we cannot definitively conclude that MST is noninferior to ECT.” Although that is true, they say several times that the effect of the two treatments is ‘similar.’ It is surprising that the editors at JAMA did not pick up this mistake.
This is a common misinterpretation of a non-significant result and does have policy and clinical practice implications. As such, we felt it important to point this out to you and hopefully you will pass this on to your readers.
Clement Ma and Peter Szatmari
(both of the University of Toronto)
Goodman S. A dirty dozen: twelve p-value misconceptions. Semin Hematol. 2008 Jul;45(3):135-40.
Selection 3: “Why I’m Talking About My Mental Health”
Trend Magazine, 8 December 2023
They meant well.
I was a teenager and I didn’t feel good, so I talked to my internist. She put me on birth control pills, even though I was not yet sexually active. She meant well. She sent me to a psychiatrist – whom I could afford only because I had recently come into money as an actress on a TV show. I told the psychiatrist that sometimes I felt like I was going to die, like my heart was going to beat out of my chest, and I was going crazy. She put me on Xanax. That psychiatrist meant well.
No one thought to ask me what my home life was like as a child or what was going on in my home that very year: an unraveling of everything I had pretended was stable.
My parents meant well in their own way. The same way their parents, in the years after the Holocaust and the Great Depression, meant well. Yet when I was a teenager, everything started to collapse around me – but no one thought to ask me about that.
No one thought to ask if I was one of the millions raised in the shadow of intergenerational trauma because of war, poverty, and abuse. No one thought to ask if the grown-ups who were supposed to protect me instead frightened me. No one asked about fists thrown and promises broken and holiday dinners destroyed. And certainly, no one talked about those of us raised in homes where addiction reigned; where alcohol, drugs, and pornography were sources of confusion and endless battles; and where more ‘acceptable’ addictions such as shopping, bingeing, and even restricting food in the name of beauty prevailed.
So begins an essay by Bialik.
She notes the societal change:
“Because 30 years ago, we didn’t ask about those things. Doctors, meaning well, often tried to make everything OK with a little numbing. A little ‘taking the edge off’ – that’s what my psychiatrist called it. She gave me a pat on the back as I walked out of her office clutching that piece of paper that was supposed to help even things out. Those were the days of knowing what to write to bill insurance companies and knowing which drugs could make us presumably hurt less.
“Mental wellness was not something we knew to talk about or fight for. Finally, that has changed.”
She describes her decision to write and speak about her problems. “As adults, we consciously chose to seize the opportunity to be vulnerable in the service of those who were new to the world of mental health struggles. I have chosen to be vulnerable, raw, and brutally honest about what plagues me, what scares me, what ails me, what has worked for me, and also what hasn’t. We started our mental health podcast and built a community around the simple premise that access to mental health is an inalienable human right. Access to substantive, scientifically informed, compassionate mental health support is a right of every human being on the planet – no matter what kind of home you come from, how much money you have, what insurance you do or don’t have, and no matter what ails you.”
She is hopeful about the future. “My little slice of the mental health world as it evolves in the 21st century has given me so many reasons to be hopeful. The ability to understand ourselves has increased as more resources become available to more people everywhere. Mindfulness is being taught to young children in public schools. Inexpensive and readily available tools, from free meditation apps to vast online communities providing support and education, are at the disposal of more and more people. And we no longer have to live in shame about needing help.”
A couple of thoughts:
1. This is a well-written essay, raw and clear.
2. She writes particularly well about changes in attitudes. “I come from an era of shoving it down, hoping it would go away, and stewing in anxiety, hopelessness, and fear. I am honored to be alive to witness a new consciousness that is taking hold in a world increasingly challenged by misconceptions about mental health and wellness.”
The full Trend Magazine essay can be found here:
Reading of the Week. Every week I pick articles and papers from the world of Psychiatry.