As an inpatient psychiatrist at a large public hospital this is very important. One question I have is whether this can be generalized to my population, which is frequently court ordered for meds and thus excluded from clinical trials.
Good point, I think research does tend to exclude swathes of our clinical population (often those with comorbidities, significant risk, substance misuse)
Great analysis. I really appreciate the way you break down both the study’s findings and its limitations, especially what it was and wasn’t set up to uncover. The question of clozapine’s superiority is such a fundamental one, and this meta-analysis certainly adds an interesting layer to the discussion.
I had to smile at your quip about statistical significance. Bayesians everywhere are sighing in relief :)
Leucht and his mysterious friend Et al. strike again! As a fan of nominative determinism I would be remiss to not point out that Leucht's last name comes from a old German word for "lantern light" which is very appropriate.
Thanks. It’s refreshing to see a perspective that engages thoughtfully with psychiatric guidelines rather than treating them as rigid doctrine. An approach that allows for clinical judgment and acknowledges the complexities of individual cases is always welcome.
Are you sure it's not just mania? I mean, you can see why that would be the first assumption. I always thought Janssen’s haloperidol anecdote—the one where he microdosed the guy’s coffee—sounded like mania.
Remember what Kraepelin said about potassium bromide? If taken at the right time, it can "ward off" an attack. If we reconsider some of our assumptions—like the specificity of lithium or the idea that antipsychotics can't truly terminate mania—all of a sudden, we have another hypothesis. Some people just need more lead in their boots, and clozapine does exactly that.
I've ruminated on this a little more, so here's an effortful comment.
I've been hearing about the magic of clozapine since before I was even a medical student, and as a psychiatrist I have heard from more than a few clinicians about patients who responded to clozapine when they didn't respond to anything else. I have a patient I recently inherited who has been on clozapine for 4 years because "it's the only thing that's worked." Papers like this always make me feel unsteady as a clinician and I find myself questioning these anecdotes much more seriously; I don't particularly like feeling this way, but putting our heads in the sand is just punishing our patients.
It seems like this paper suggests that clozapine's efficacy might actually be found in the general population of schizophrenics. I think these results should push me to change my practice in two ways:
1. Discuss clozapine earlier with patients, probably after failure/intolerance with the first antidopaminergic (if I had my druthers, my treatment flow would probably be xanomeline -> risperidone/olanzapine -> clozapine)
2. Not keep "treatment resistant" patients on clozapine in the absence of a marked response, and put them on something a little kinder metabolically.
Would be curious to hear thoughts from the other psychiatrists in the audience about whether or not this will change their practice (you too, Tommy).
You know what I always think about when I read about clozapine: Fish, 1964. F.J. Fish. The influence of tranquilizers on the Leonhard schizophrenic syndromes. Encephale, 53 (1964), pp. 245-249.
As an inpatient psychiatrist at a large public hospital this is very important. One question I have is whether this can be generalized to my population, which is frequently court ordered for meds and thus excluded from clinical trials.
Good point, I think research does tend to exclude swathes of our clinical population (often those with comorbidities, significant risk, substance misuse)
Great analysis. I really appreciate the way you break down both the study’s findings and its limitations, especially what it was and wasn’t set up to uncover. The question of clozapine’s superiority is such a fundamental one, and this meta-analysis certainly adds an interesting layer to the discussion.
I had to smile at your quip about statistical significance. Bayesians everywhere are sighing in relief :)
Thank you Dom!
My opinions about clozaril aside, I question whether you can really pre-register a meta-analysis.
You have a point there!
Great post!
Leucht and his mysterious friend Et al. strike again! As a fan of nominative determinism I would be remiss to not point out that Leucht's last name comes from a old German word for "lantern light" which is very appropriate.
Nice review Tommy!
Thanks Nils!
This is excellent. Clear, interesting, informative, with a deft touch of humor throughout.
Thanks. It’s refreshing to see a perspective that engages thoughtfully with psychiatric guidelines rather than treating them as rigid doctrine. An approach that allows for clinical judgment and acknowledges the complexities of individual cases is always welcome.
Are you sure it's not just mania? I mean, you can see why that would be the first assumption. I always thought Janssen’s haloperidol anecdote—the one where he microdosed the guy’s coffee—sounded like mania.
Remember what Kraepelin said about potassium bromide? If taken at the right time, it can "ward off" an attack. If we reconsider some of our assumptions—like the specificity of lithium or the idea that antipsychotics can't truly terminate mania—all of a sudden, we have another hypothesis. Some people just need more lead in their boots, and clozapine does exactly that.
I've ruminated on this a little more, so here's an effortful comment.
I've been hearing about the magic of clozapine since before I was even a medical student, and as a psychiatrist I have heard from more than a few clinicians about patients who responded to clozapine when they didn't respond to anything else. I have a patient I recently inherited who has been on clozapine for 4 years because "it's the only thing that's worked." Papers like this always make me feel unsteady as a clinician and I find myself questioning these anecdotes much more seriously; I don't particularly like feeling this way, but putting our heads in the sand is just punishing our patients.
It seems like this paper suggests that clozapine's efficacy might actually be found in the general population of schizophrenics. I think these results should push me to change my practice in two ways:
1. Discuss clozapine earlier with patients, probably after failure/intolerance with the first antidopaminergic (if I had my druthers, my treatment flow would probably be xanomeline -> risperidone/olanzapine -> clozapine)
2. Not keep "treatment resistant" patients on clozapine in the absence of a marked response, and put them on something a little kinder metabolically.
Would be curious to hear thoughts from the other psychiatrists in the audience about whether or not this will change their practice (you too, Tommy).
You know what I always think about when I read about clozapine: Fish, 1964. F.J. Fish. The influence of tranquilizers on the Leonhard schizophrenic syndromes. Encephale, 53 (1964), pp. 245-249.