Memorializing Angst's pivotal studies on clozapine, revealing its potential for bipolar disorder treatment.
Professor Jules Angst was born in Zürich on December 11, 1926, and passed away in the same city on May 15, 2026. Angst trained in medicine at the University of Zurich and developed his psychiatric career at the Burghölzli Psychiatric Hospital, later known as University Hospital of Psychiatry Zurich, which has a long history of important contributions to psychiatry due to the writings of Auguste Forel, Eugen and Manfred Bleuler, Carl Gustav Jung and Christian Scharfetter. Jules Angst served as Professor of Clinical Psychiatry in the Medical School of the University of Zurich and Head of the Research Department of University Hospital of Psychiatry for over a quarter of a century, with an outstanding publication output and numerous prestigious awards.[ 1 ] [ 2 ] Starting his scientific carrier under Manfred Bleuler in psychopharmacology research, Professor Angst progressively moved from the 60s to 80s to psychiatric epidemiology and conducted studies,[ 3 ] which, in fact, belong to the most important and best ones in modern psychiatric epidemiology, particularly in the realm of mood and anxiety disorders. Although Angst is widely recognized as the Switzerland’s most prominent psychiatric epidemiologist, he has also achieved significant milestones in psychopharmacology and psychopathology including the development of the AMDP system with the support of Brigitte Woggon.[ 4 ] There is a general consensus[ 5 ] that Jules Angst made a series of major nosological and epidemiological contributions to the mood disorder literature, which frequently contrasted with mainstream beliefs and led to controversies. By demonstrating that bipolar disorder has a different family history and a course characterized by more and more frequent episodes than unipolar depression, he has provided decisive findings for the nosological distinction between the two types of mood disorders,[ 6 ] which had been originally proposed by Leonhard. Angst could also show that there exist multiple mood syndromes below the diagnostic level of Diagnostic and Statistical Manual of Mental Disorders (DSM) bipolar and major depressive disorder, which suggest a continuum between healthy and sick rather than a clearcut limit. Moreover, conducting early trials on lithium in patients with bipolar disorder, he confirmed Mogens Schou's previous findings on the preventive effect of this drug despite the harsh and potentially not totally unbiased critique of researchers from the Institute of Psychiatry in London.[ 7 ] Based on a large meta-analysis of antidepressant trials, Angst also demonstrated that the treatment response can already be observed after few days and does not need a 10- day period.[ 8 ] [ 9 ] Finally, his review of studies on switches from depression to mania under antidepressant treatment suggested that in the case of treatment response these switches do not occur under antidepressants more frequently than under placebo.[ 10 ] The memorial of the International Group for the Study of Lithium Treated Patients has recently summarized Angst’s contributions to mood disorders and lithium research.[ 5 ] Although the published literature on Angst has already covered a large array of his significant scientific contributions to psychiatry,[ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ] [ 7 ] the goal of this paper isto call more attention to his early studies on clozapine, which have been less acknowledged, because these results were published in German and are not available in English-based libraries. In 1971, Angst and his collaborators published the first two clozapine trials in Switzerland,[ 11 ] [ 12 ] including the worldwide first multicenter study on this drug, which led to the marketing of clozapine in Switzerland in 1972. Moreover, the second trial[ 12 ] was the only early trial with a sophisticated design (randomization, double-blindness and an active comparator), whereas the other nine early trials that we identified were open. Angst also promoted further research on clozapine by convincing Nathan Kline, probably the most influential psychopharmacologist in the United States at that time, that clozapine had a peculiar psychotropic profile and was lacking extrapyramidal side-effects. Kline's interest in clozapine was crucial for the initiation of clozapine studies in the United States.[ 13 ] The results of the first US trial were published in 1974 by two collaborators of Kline, Simpson and Varga.[ 13 ] An even less known contribution of Angst published only in German includedhis two clinical trials in manic patients, revealing an excellent antimanic effect of clozapine,[ 11 ] [ 12 ] whereas in the English literature we could only find one single reference to the antimanic effect of this drug published by Ayd,[ 14 ] one of the leading US psychopharmacologists. Until his retirement in 2003, Ayd edited and published the International Drug Therapy Newsletter, detailing advances and controversies in psychopharmacology. In a Newsletter in 1974, Ayd stated that Prof. Angst considered clozapine as the best antipsychotic drug for hypomania and mania.[ 14 ] However, many case reports have emphasized the efficacy of clozapine in bipolar disorder and analyses relying on the Danish and Finnish registries also suggested reduced hospitalization rates in clozapine-treated patients with bipolar disorders. More recently, using the prospective cohort of patients with mood disorders, that previously provided the essential clues to the distinction between unipolar and bipolar disorders, Professor Angst found clozapine (and thioridazine) in combination with antidepressants to also reduce the suicidal risk.[ 15 ] Despite these results, the anti-suicidal properties of clozapine have received little attention from experts in bipolar disorder so far and most guidelines only recommend the use of clozapine in treatment-resistant cases. On the other side of the world, clozapine is prescribed to 3–4% of patients with bipolar disorder in Hong Kong and Taiwan. Chinese psychiatrists have also published results from controlled studies on the effect of clozapine in treatment-resistant bipolar disorder. It is likely that these psychiatrists working in the Chinese-speaking world have never heard from Professor Angst’s studies, but rather received the information on the benefits of clozapine in bipolar disorder from the Chinese literature. In addition to its previous indication for treatment-resistant schizophrenia, clozapine was also approved by the US Food and Drug Administration in 2003 for preventing suicide in schizophrenia and schizoaffective disorders. Indeed, in studies conducted in the United States and according to the Finnish registry, it has been shown that clozapine can reduce the suicide rates in schizophrenia by 80%.[ 16 ] Considering a lifetime suicidal risk in schizophrenia of 5%, the more common use of clozapine could restrict this risk down to only 1%. Moreover, it is possible that a large proportion of suicidal deaths in clozapine-treated patients is associated with non-adherence to this treatment. Indeed, according to US pharmacovigilance data, the discontinuation of clozapine treatment increases the risk of completed suicide by 70% in schizophrenia.[ 15 ] Considering the low clozapine prescription rates around the world, it has been estimated that prescribing clozapine to 10% of patients with schizophrenia worldwide could save as many as 320,000 lives from suicide, whereas such a prescription may cause 2,400 deaths from agranulocytosis.[ 16 ] Given that suicide is an even more pressing problem in bipolar disorder than in schizophrenia, there is a major need to extend Angst's previous work by further studying the anti-suicidal effect of clozapine in bipolar disorder.[ 15 ] We hope that now the time has come to revisit Professor Angst’s important findings on the effect of clozapine in bipolar disorder, which according to our opinion has not yet received the attention they deserve. Publication History Received: 13 June 2026 Accepted: 18 June 2026 Article published online: 03 July 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
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