From the Editor
“FDA approves a novel drug for schizophrenia, a potential ‘game changer’”
– The Washington Post
“Will ‘Game Changer’ Antipsychotic Live Up to the Hype?”
– Medscape
Two weeks ago, for the first time in decades, the FDA approved an antipsychotic for schizophrenia with a novel mode of action. What does the data show for this medication, xanomeline-trospium chloride? Is it a “game changer” as some headlines suggest?
In the first selection, Dr. Inder Kaul (of Karuna Therapeutics) and his co-authors report on a double-blind, randomized, placebo-controlled trial that was published in JAMA Psychiatry. 256 people with schizophrenia were given the antipsychotic or the placebo and followed for five weeks. “Xanomeline-trospium was efficacious and well tolerated in people with schizophrenia experiencing acute psychosis.” We consider the study and its implications.
In contrast to this week’s first selection, the second selection looks at an older antipsychotic: clozapine. Drawing on Canadian databases, Lloyd Balbuena (of the University of Saskatchewan) and his co-authors put the risks and benefits of this medication in a new light in a paper for The British Journal of Psychiatry. They analyzed data on admissions and adverse events, with almost 50 000 participants. “Clozapine was associated with lower relapse overall, but this was accompanied by higher adverse events for adults. For children/youth, clozapine was associated with lower relapse all throughout and had no difference in adverse events compared with other antipsychotics.”
And in the third selection, Susan Weiner writes about antipsychotics for Schizophrenia Bulletin. She discusses her first psychotic break, her long journey, and her ultimate recovery. In a personal essay, she also describes the connection she made with her psychiatrist and the medication that transformed her life. “The right medicine for the right person can produce sanity like a miracle drug, and all is once again bright.”
DG
Selection 1: “Efficacy and Safety of Xanomeline-Trospium Chloride in Schizophrenia: A Randomized Clinical Trial”
Inder Kaul, Sharon Sawchak, David P. Walling, et al.
JAMA Psychiatry, August 2024
Currently approved antipsychotic medications act primarily by blocking D2 dopamine receptors either as antagonists or partial agonists. Although these medications have demonstrated measurable efficacy for treating the positive symptoms of schizophrenia, they have limited efficacy for negative and cognitive symptoms. Moreover, positive symptoms are refractory or resistant to treatment in 20% to 30% of patients and adverse effects such as extrapyramidal motor symptoms, risk for developing tardive dyskinesia (TD), weight gain, and somnolence contribute to poor tolerability and adherence…
Imbalances between muscarinic acetylcholine and dopamine neurotransmitter systems have been implicated in the pathophysiology of schizophrenia. Targeting muscarinic receptors may present a novel treatment option for people with schizophrenia. Xanomeline-trospium chloride (KarXT) combines the dual M1/M4 preferring muscarinic receptor agonist xanomeline with the peripherally restricted muscarinic receptor antagonist trospium chloride.
So begins a paper by Kaul et al.
Here’s what they did:
- They conducted a “phase 3, multicenter, randomized, double-blind, placebo-controlled, 5-week trial of xanomeline-trospium in people with schizophrenia experiencing acute psychosis…”
- The trial was done at 18 sites in the United States and 12 in Ukraine.
- Participants were 18 to 65 years old.
- A baseline Positive and Negative Syndrome Scale (PANSS) total score of 80 to 120 was required.
- Participants were randomized to receive xanomeline-trospium chloride or placebo for five weeks. There was flexibility in the antipsychotic dosing after day eight, with a maximum dose of xanomeline 125 mg/trospium 30 mg.
- Primary outcome: total score on the PANSS after five weeks.
Here’s what they found:
- A total of 431 individuals were screened, and “256 participants were randomized to receive xanomeline-trospium (125 participants) or placebo (131 participants).”
- Demographics. Most participants were men (74.6%) and Black (60.9%) with a mean age of 43.1 years.
- Burden of illness. Mean baseline PANSS total scores were 97.3 in the xanomeline-trospium group and 96.7 in the placebo group.
- Outcomes. “At week 5, xanomeline-trospium significantly reduced PANSS total score compared with placebo (xanomeline-trospium , −20.6; placebo, −12.2; least squares mean difference, −8.4… Cohen d effect size, 0.60)…”
- Discontinuation. Treatment-emergent adverse event-related discontinuation rates were similar between the xanomeline-trospium (6.4%) and placebo (5.5%). The most common: nausea, dyspepsia, vomiting, more frequent with the antipsychotic.
A few thoughts:
1. This is an interesting study, providing us with data on the new antipsychotic.
2. The main finding in a sentence: “in adults with schizophrenia experiencing acute psychosis, xanomeline-trospium was associated with statistically significant and clinically meaningful improvement in schizophrenia symptoms and was generally well tolerated.”
3. And xanomeline-trospium was well tolerated. The overall percentage of participants discontinuing treatment was similar in both groups. In terms of treatment-emergent adverse events, the most common with xanomeline-trospium: GI problems. “All mild or moderate in intensity and improved in the first 2 to 3 weeks of the trial.”
4. There are obvious limitations with this study, including that the study period was only five weeks.
5. Of course, as clinicians, we wonder how this new antipsychotic compares to its peers (not to placebo). And we will have to wait longer for that information.
The full JAMA Psych paper can be found here:
https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2818047
Selection 2: “Clozapine, relapse, and adverse events: a 10-year electronic cohort study in Canada”
Lloyd Balbuena, Shawn Halayka, Andrew Lee, et al.
The British Journal of Psychiatry, 18 September 2024 Online First
Clozapine is the most effective drug for treatment-resistant schizophrenia in adults. The CUtLASS 2 and phase 2E CATIE studies have shown that clozapine is more effective than quetiapine and risperidone, and more effective than switching to another second-generation antipsychotic (SGA) when there is an inadequate therapeutic response. Several treatment guidelines across the world recommend clozapine as the gold standard for difficult-to-treat cases of adult schizophrenia…
Child/youth patients In contrast to the solid body of evidence for its efficacy in adults, the role of clozapine in early-onset schizophrenia (EOS) remains less understood. There is a lack of robust double-blinded studies in children/youth, primarily due to the rarity of the condition. However, an emerging body of evidence supports the use of clozapine in children with refractory cases of EOS. Real-world outcomes Real-world data about mental health re-hospitalisations for clozapine and other psychotropic medications are a valuable source of complementary evidence. As a result of their study design, randomised clinical trials provide limited evidence for long-term outcomes, so in this regard, real-world data can shed more light on more long-term outcomes.
So begins a paper by Balbuena et al.
Here’s what they did:
“Data were obtained from the Canadian Institute of Health Information for adults and children/youth initially hospitalised for mental health conditions in British Columbia, Manitoba and Saskatchewan from 2008 to 2018. Patient demographics and hospitalisations were linked with antipsychotic prescriptions dispensed following the initial visit. Recurrent events survival analysis for relapse and adverse events were created and compared between clozapine and other antipsychotics.”
Here’s what they found:
- There were 45 616 adults and 1 476 children/youth included.
- Relapse: adults. “In adults, clozapine was associated with a 14% lower relapse rate versus other drugs (adjusted hazard ratio: 0.86…) over the 10-year follow-up. In the first 21 months, the relapse rate was higher for clozapine but then reversed. Over 1000 person-months, clozapine-treated adults could be expected to have 38 relapse hospitalisations compared with 45 for other drugs.”
- Relapse: children/youth. “In children/youth, clozapine had a 38% lower relapse rate compared with other antipsychotic medications (adjusted hazard ratio: 0.62…) over the follow-up period. This equates to 29 hospitalisations for clozapine and 48 for other drugs over 1000 person-months.”
- Adverse events: adults. “In adults, clozapine had a higher risk for adverse events (hazard ratio: 1.34…) over the entire follow-up compared with other antipsychotics. This equates to 1.77 and 1.30 hospitalisations over 1000 person-months for clozapine and other drugs, respectively.”
- Adverse events: children/youth. “There was no difference in adverse event rates by drug group (hazard ratio: 0.99…), which probably resulted from the very small number of adverse events…”
A few thoughts:
1. This is a good study, drawing on a nice dataset with a good follow-up period, and published in a solid journal.
2. The main findings: For adults, clozapine was initially associated with more relapses, but then fewer over time – but at the cost of more adverse events; in children/youths, there were fewer relapses and no more adverse events.
3. The findings are in keeping with past work. Clozapine has been shown previously to be superior to other antipsychotics in terms of relapse for adults; the children/youth data adds nicely to the data in terms of the number of participants.
4. Like all studies, there are limitations. The authors note several, including: “There were no clinical variables such as age of illness onset, severity of illness and how soon treatment was initiated due to limitations of administrative data on hospitalisations… As such, it was not possible to tell how well patients functioned independent of relapse.”
5. Are there system implications? The authors argue that clozapine is under-prescribed and add: “Health systems should provide support for logistical requirements associated with clozapine treatment.” They highlight the rigid (and problematic) approach of Japan with weekly blood tests required for the first 26 weeks, as well as the need for a hematologist to available around the clock.
6. Is this a more exciting paper than the first selection?
The full BJP paper can be found here:
Selection 3: “When Atypical Antipsychotics Were New”
Susan Weiner
Schizophrenia Bulletin, 26 September 2024
In the early 1990s, I was in graduate school in California. One day I formally withdrew from my PhD program and broke off all relationships with my family, friends, and professors. Following this I disappeared into the big city where I lived. There I stayed all alone and isolated for 7 months in an ongoing florid state of psychosis whose impact would almost destroy my life.
During this time, I came to believe I was a super spy on the front lines of World War III. Of course, as opposed to my heroism, there loomed a villain. I thought of him as the ‘Evil Dictator.’ I wasn’t too creative in articulating the disaster about to befall my country. But in my mind I stood opposed to tyranny, risking my life to save the United States from a greater threat to democracy than Hitler.
After 7 months the symptoms of schizophrenia became almost unendurable.
So begins a paper by Weiner.
She describes becoming suicidal. A cycle began of hospitalizations and suicide attempts. She did try medications. “I was given a several-week-operative injection of Haloperidol. This did absolutely nothing to limit my delusions or to mitigate the schizophrenia that burned through my brain, but it did make me black out periodically so that I have spotty recall of my 3 weeks in a mental ward at a university campus. It also gave me terrible, untreated akathisia.”
Things changed when her parents took her home and she was admitted again. “Yet, this time would prove to be a quite different case. Now I fell under the tender care of Wayne S. Fenton MD, director of the psychiatric clinic and hospital of the now-closed Chestnut Lodge in Rockville, Maryland. The loss of Wayne Fenton to the mental health community and society at large was more than tragic for me as well.”
Working with Dr. Fenton, they decided to try something new. “Risperidone had just come onto the market, and also as a research physician, Dr Fenton believed in its potential as a new atypical to retard the symptoms of psychosis. He wasted no time overseeing my medication to start me on a dose of (I think) 5 mg of Risperidone. He eschewed the traditional treatment parameters. Wayne Fenton took a gamble that this newest (and still very expensive) drug, Risperidone, would help me… Though I had been clinically insane for 7 long months with several months of deluded thinking leading up to my breakdown, after 3 days the Risperidone worked for me just like magic.”
She describes her progress. “Now I no longer believed everyone could read my mind. I could work with this new doctor. What Dr Fenton told me seemed more reliable than my bad dreams. I came to see that Wayne Fenton was not my implacable enemy. I no longer cowed in fear of zombie assassins reaching out to destroy my ontological status as a human being.”
“Finding a dose of one of the newly released atypicals I could live with took about 8-10 years. Of course, this impeded my ability to function as a competent adult. But when I went on a final dose of 3.5 mg of Risperidone with 30 mg of Prozac I became stable again and I was able to write once more. This has led to 2 books of poetry (Before the Foundation of the World, and Pirates and Spooks, Beware!)… Each book even won an award. My third and newest book will be released on February 17, 2025.”
She notes that illness still touches her: “I was unable to return to my academic studies because my concentration and cognitive skills were impaired beyond my ability to function as a researcher.” Still, she marvels at her recovery. “I still continue to struggle with mental illness, but my days have meaning, and if I live a quiet life, I’m able to function as an intellectual once more. I’m thankful for all the doctors and researchers who took a chance with a new type of medication to improve life for those who live with schizophrenia.”
A few thoughts:
1. This is a great essay – moving and raw.
2. The above summary doesn’t quite capture Weiner’s wit. On her incapacity, for example, she writes: “Here, a doctor determined I was completely mentally unfit because I couldn’t count backward by sevens. Had I been sane, I would’ve rejected this cognitive test as prejudiced against social science students who couldn’t easily subtract by sevens or even nines.”
3. For those interested in reading about the amazing life and tragic death of Dr. Fenton, this Lancet obituary is essential reading:
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(06)69650-5/fulltext
4. Will we be reading a similar essay about xanomeline-trospium chloride one day?
The full Schiz Bulletin paper can be found here:
https://academic.oup.com/schizophreniabulletin/advance-article/doi/10.1093/schbul/sbae170/7778256
Reading of the Week. Every week I pick articles and papers from the world of Psychiatry.
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