The Frontier Psychiatrist's newsletter? It is what you are reading. It’s a health-themed publication written by Owen Scott Muir, M.D. This is another installment in my series on medications, and this one is written about a drug that I think represents the best in sincere attempts to provide the best care for people suffering. Join us for Clozapine…a story that will take more than one post. Other installments include Risperidone, Depakote, Geodon, Ambien, Prozac, Xanax, Klonopin, Lurasidone, Olanzapine, Zulranolone, Benzos, Caffeine, Semeglutide, Lamotrigine, Cocaine, Xylazine, Lithium, dextromethorphan/bupropion and Adderall, etc.
One Antipsychotic Medicine is Better than All The Others…The Story of Clozapine
The reason I’m writing about clozapine is—to blow the punch line— it leads to less death and suffering.1 This is true despite the high side effect burden of the drug, regarding those same cardiometabolic risks.2. Notably, clozapine— which has very specific life-threatening side effects— is still less fatal than the underlying illness:
All‐cause mortality was reduced by 61% and cardiovascular death risk was decreased by 45% versus non‐use of antipsychotics [with 14 years of follow up in a large sample from Finland].3
I’m thrilled to note that a mentor, Christoph Correll, who has done remarkable work publishing on the risks of these treatments4, is also the first author on that paper documenting that—despite the risks—clozapine still reduced death and suffering.
Clozapine is the first antipsychotic that was different. It was the first drug the FDA required to be better than any prior treatment while also working on individuals who had found no help with any prior treatment. The term “atypical” before the word antipsychotic referred to clozapine.
It is also the only oral medication that has an FDA label for:
• Reducing suicidal behavior in patients with schizophrenia or schizoaffective disorder. Efficacy was established in an active-controlled study. (1.2, 14.2)
That study was called the interSePT5 trial6, and I trained with John Kane, M.D., one of the authors. The data in that study is exactly the kind of data I’ve been repeatedly beating the drum about here in this newsletter. In short, fewer people attempted suicide when treated with Clozapine Vs. Olanzapine:
Suicidal behavior was significantly less in patients treated with clozapine vs olanzapine (hazard ratio, 0.76; 95% confidence interval, 0.58-0.97; P =.03). Fewer clozapine-treated patients attempted suicide (34 vs 55; P =.03), required hospitalizations (82 vs 107; P =.05) or rescue interventions (118 vs 155; P =.01) to prevent suicide, or required concomitant treatment with antidepressants (221 vs 258; P =.01) or anxiolytics or soporifics (301 vs 331; P =.03). Overall, few of these high-risk patients died of suicide during the study (5 clozapine vs 3 olanzapine-treated patients; P =.73).
A dedicated cohort has sought to relieve the suffering of those with psychosis. The most effective medicine for schizophrenia and related psychotic disorders is called clozapine. This is how it came to be. It is also my very small part of that story. I did have a front-row seat to the motivations of some of the individuals who played a role in making this remarkable drug possible. We will begin with John Crilly, Ph.D., who is a historian. He worked at the State Psychiatric Hospital in Rochester, New York, and authored one of my favorite history of medicine papers:
In 1958, a group of tricyclic compounds based on the chemical structure of the antidepressant imipramine was synthesized by Swiss pharmaceutical company Wander AG (Schmutz and Eichenberger, 1982), described as ‘tricyclic antidepressants but with neuroleptic properties.
Wander AG became Novartis, which became NovoNordisc. The patent on the clozapine molecule was submitted in the Switzerland patient office in 1960. The dates become very, very important in this story.
Clozapine’s initial results were mixed. Laboratory and animal testing in 1958 indicated similarities to chlorpromazine. There were also significant differences … clozapine did not cause catalepsy (loss of voluntary motion) …and it seemed to produce a higher pain threshold in animal subjects, showing enough novelty that the Wander investigators recommended human testing.
This “signal” from early animal testing was a blessing— because it got the drug to move forward. As we will see, it was also a phony result due to dumb luck. Clozapine had a side effect in the rats. The same effect was later noted in humans. Excessive Salivation. In medical jargon, sialorrhea.
The pain threshold finding was actually the result of short-circuits in the oral electrodes in the animals.
The electrodes with which scientists measured pain threshold were fitting in the mouths of the rats. Thus, the excess saliva caused them to stick less well. Thus, the lower readings on that test were secondary to unexpected saliva, not an actual decreased output from the electrode sensors. It was a glitch. They moved to human trials anyway, based on the strength of their misunderstanding.
Four small human trials took place, half of which appeared to demonstrate an antipsychotic effect. The side effect profile was different than its predecessors, however:
It did not seem to cause any disabling neurological side effects. By the end of 1966, nearly 100 subjects with schizophrenia had received clozapine, and there was consensus of its antipsychotic effectiveness …and its marked difference in side effects from chlorpromazine. Clinical testing was further advanced in 1967 when pharmaceutical giant Sandoz Ltd acquired Wander AG.
The lead of the German research group, Dr. Hippus, described his skepticism that clozapine might be a good antipsychotic at all…after all, the ability to produce neurological adverse effects was held as proof that the medicine worked:
“... we discovered to our surprise that clozapine, in contrast to all other compounds, had no extrapyramidal effects despite being a fully effective antipsychotic. This finding was almost unbelievable because, at that time, it was a part of the psychopharmacological dogma that extrapyramidal effects went in tandem with antipsychotic efficacy.”
The lack of these adverse effects—and clozapine seemed to produce none—was a knock against it from the leading luminaries. Thus, a decade passed, and limited clinical trials. That is nine years…in which the patent filed in 1960 was running out.
Sandoz was no stranger to developing neuroleptic medications (it had developed the well-accepted medication thioridazine (Mellaril) in 1958) and was able to use its presence in Europe to expand the clozapine exposure group to nearly 2200 subjects by the end of 1969. Following a positive summary of those trials by Stille and Hippius (1971), clozapine was marketed under its European trade name ‘Leponex’ in Switzerland and Austria in 1972, in West Germany in 1974 and in Finland in 1975 (Griffith and Saameli, 1975). During this period of the early 1970s, Sandoz also initiated plans for clinical clozapine trials in the USA.
The timeframes and countries may appear like pointless details, but in this story, for this drug, they are not. They end up being crucial.
In 1975, months after the launch in Finland, disturbing reports were published:
Four months after the start of clozapine marketing in Finland, 18 patients developed one or more severe blood disorders, 9 of whom died (Idanpaan-Heikkila, Alhava, Olkinuora, and Palva, 1975). Sixteen of these patients (8 fatal) had developed the blood disorder agranulocytosis.
The Latin prefix “a-” means without. A “granulocyte” is a crucial kind of white blood cell. Without (“a-”) granulocyte(s) in the blood is agranulocytosis. The “-osis” was added, as the suffix for “pathological condition.”
These death happened in one market. There had been 2200 patients in clinical trials. Those trials were largely in Germany. And in Finland, at scale, people were dying. Clozapine was pulled from the market on the 28th of July, 1975. Plans for US clinical trials were also brought to an immediate halt. This drug was killing people.
The individuals died from an abrupt collapse in white blood cells—this is close to the same mechanism that eventually kills people with HIV. It leads to rapid, abrupt infections you can’t fight off, thanks to a lack of specific white blood cells with subsequent death. These deaths axiomatically come to medical attention—people get sick from something that brings them to a doctor, usually in a hospital, blood work is drawn, and they have an obvious abnormality. This is not the kind of side effect that escapes medical attention, and it’s the stuff of specifically medical nightmares.
The end Clozapine, Part I…
If you are a child psychiatrist colleague, I will be at AACAP here in NYC. I’ll be doing my standard conference quick dispatch style writing over the next few days.
Taipale H, Tanskanen A, Mehtälä J et al. 20‐year follow‐up study of physical morbidity and mortality in relationship to antipsychotic treatment in a nationwide cohort of 62,250 patients with schizophrenia (FIN20). World Psychiatry 2020;19:61‐8.
Pillinger T, McCutcheon RA, Vano L et al. Comparative effects of 18 antipsychotics on metabolic function in patients with schizophrenia, predictors of metabolic dysregulation, and association with psychopathology: a systematic review and network meta‐analysis. Lancet Psychiatry 2020;7:64‐77.
Correll, C. U., Solmi, M., Croatto, G., Schneider, L. K., Fairley, L., Smith, N., Bitter, I., Gorwood, P., Taipale, H., & Tiihonen, J. (2022). Mortality in people with schizophrenia: A systematic review and meta‐analysis of relative risk and aggravating or attenuating factors. World Psychiatry, 21(2), 248-271. https://doi.org/10.1002/wps.20994
Correll CU, Manu P, Olshanskiy V, Napolitano B, Kane JM, Malhotra AK. Cardiometabolic risk of second-generation antipsychotic medications during first-time use in children and adolescents. JAMA. 2009 Oct 28;302(16):1765-73. doi: 10.1001/jama.2009.1549. Erratum in: JAMA. 2009 Dec 2;302(21):2322. PMID: 19861668; PMCID: PMC3055794.
Meltzer HY, Alphs L, Green AI, Altamura AC, Anand R, Bertoldi A, Bourgeois M, Chouinard G, Islam MZ, Kane J, Krishnan R, Lindenmayer JP, Potkin S; International Suicide Prevention Trial Study Group. Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Arch Gen Psychiatry. 2003 Jan;60(1):82-91. doi: 10.1001/archpsyc.60.1.82. Erratum in: Arch Gen Psychiatry.2003 Jul;60(7):735. PMID: 12511175.
Alphs L, Anand R, Islam MZ, Meltzer HY, Kane JM, Krishnan R, Green AI, Potkin S, Chouinard G, Lindenmayer JP, Kerwin R. The international suicide prevention trial (interSePT): rationale and design of a trial comparing the relative ability of clozapine and olanzapine to reduce suicidal behavior in schizophrenia and schizoaffective patients. Schizophr Bull. 2004;30(3):577-86. doi: 10.1093/oxfordjournals.schbul.a007102. PMID: 15631247.