In Italy, the expression è mancato – literally, ‘he is missing’ or ‘we miss him’ – is used as a delicate way of saying that someone has passed away. Few people, however, will be missed more deeply than Jules Angst in the worlds of clinical psychiatry, psychiatric epidemiology, and the study of mood disorders.

The international psychiatric community mourns the passing of one of the most influential figures in twentieth- and twenty-first-century research on affective disorders: Professor Jules Angst, MD. Born in Zurich on December 11, 1926, he would have celebrated his 100th birthday later this year (Figure 1). His death marks the loss of a scholar whose work helped reshape how psychiatry understands depression and bipolar disorder: their boundaries, course, epidemiology, clinical expression, and diagnostic instability across time.

Figure 1.

Professor Jules Angst, MD (1926–2026), whose clinical insight, epidemiological rigor, and intellectual independence profoundly shaped modern research on depressive and bipolar disorders. Photograph courtesy of Professor Angst’s family and Professor Flavio Kapczinski.

Jules Angst was among the very few individuals who truly deserved to be called a master, both in medicine and in life. He was a free spirit, a Swiss gentleman firmly grounded in values that held the physician as the guardian of knowledge placed in the service of the person entrusted to his care, rather than as the passive executor of impersonal guidelines that reduce individuals to abstract numbers. He was attentive, rigorous, and demanding, yet capable of recognizing brilliance even in those still young, unknown, or without academic pedigree.

With him, an important chapter in the history of psychiatry comes to an end. Educated and trained in Zurich, Angst developed his psychiatric formation under the intellectual influence of Manfred Bleuler, within the historical environment of the Burghölzli and the University of Zurich (Angst, Reference Angst2016; Kallivayalil, Reference Kallivayalil2016). When Angst began his academic training, Carl Gustav Jung – who had also worked at the Burghölzli under Eugen Bleuler and had become a Privatdozent in Psychiatry there – was still living in Zurich, and Angst met him personally (Healy, Reference Healy1998). He admired Jung for what he described as his ‘encyclopedic’ knowledge, while retaining the intellectual independence that would later characterize his own scientific career. From 1969 to 1994, Angst served as Professor of Clinical Psychiatry and Director of the Research Department at the Zurich University Psychiatric Hospital, where he built one of the most enduring programs of psychiatric epidemiology in Europe (Angst, Reference Angst2016).

One of us, Mauro G. Carta, first met him while still in his 30s and was immediately struck by his critical spirit, the clarity with which he observed the academic world, and his extraordinary intellectual honesty. Angst could be severe, sometimes even harsh, but always in the right way, because he never sought consensus – only truth. In an environment often dominated by opportunism and the desire to please, he represented something increasingly rare: the scholar who does not say what is convenient, but what he genuinely believes. Yet he possessed the equally rare ability to express disagreement without making the other person feel diminished or offended. That, too, was a form of elegance.

Those who were much younger were often astonished to see him taking notes during conference presentations he found interesting. ‘There is always something to learn’, he once remarked to a colleague who looked at him with surprise. In a world of academics too often dominated by vanity and too self-absorbed to truly listen to others, that humility, intellectual curiosity, and openness to learning were deeply striking. To speak with Jules Angst was often to leave the room a little wiser and a little freer.

Angst belonged to a generation of academic physicians for whom intellectual independence was not merely a personal virtue, but almost a cultural condition. He emerged in a period when a clinician – scientist, sustained by a strong and confident academic middle class, could still build an entire career primarily through the free development of ideas, long-term observation, and personal scientific authority. In him, one could still recognize the figure of the physician-scholar whose judgment carried weight precisely because it was perceived as independent, shaped more by clinical experience, intellectual rigor, and responsibility toward patients than by institutional pressures or the shifting demands of bureaucratic systems.

Contemporary academic medicine has inevitably become more complex, more structured, and more intertwined with large organizational and economic systems. It now seems almost indispensable to belong to networks that produce guidelines, implement multicenter efficacy studies, and conduct massive epidemiological investigations. Such systems have generated indispensable knowledge; however, they also place researchers and clinicians under pressures greater than their own individual judgment, pressures capable of influencing careers, professional success, and even the boundaries of what may be asked scientifically. Jules Angst belonged to – and embodied – a world in which clinicians could still be intellectually free; they represented a safeguard for the people they treated and were capable, through their own judgment, of influencing decision-making. Today, clinicians often risk becoming the weak link between healthcare systems, industry, and patients.

These risks are especially serious in psychiatry, a discipline in which, despite repeated efforts at refinement, diagnostic classification remains based primarily on clinical-descriptive criteria and therefore contains pitfalls that may resemble quicksand in a swamp. Angst’s work was powerful precisely because it resisted both naïve biological reductionism and purely bureaucratic nosology. He insisted that psychiatric categories must be accountable to the longitudinal course of illness, to recurrence, to temperament, to subthreshold symptomatology, and, above all, to careful clinical observation.

His scientific legacy is inseparable from the Zurich Study, a prospective community-based investigation that provided some of the most important longitudinal evidence on the prevalence, course, comorbidity, and diagnostic boundaries of psychiatric disorders. Although the sample size was not enormous by contemporary standards, its strength lay in the quality of its clinical assessments, its longitudinal structure, and its attention to individual persons rather than merely aggregated variables. In an era increasingly fascinated by exclusively cross-sectional and very large-scale epidemiological designs, the Zurich Study remains a reminder that sheer size does not abolish bias, and that numbers become scientifically meaningful only when anchored in careful observation. Professor Angst’s work demonstrated that mood disorders could not be adequately understood as static diagnostic categories alone, but required attention to spectrum presentations, longitudinal trajectories, subthreshold syndromes, recurrence, and the unstable boundaries between diagnostic constructs (Angst, Dobler-Mikola, & Binder, Reference Angst, Dobler-Mikola and Binder1984; Angst et al., Reference Angst, Gamma, Neuenschwander, Ajdacic-Gross, Eich, Rössler and Merikangas2005).

Few psychiatrists contributed so deeply to the modern understanding of the bipolar spectrum. Professor Angst challenged narrow categorical definitions and emphasized the clinical relevance of hypomania, bipolar II disorder, soft bipolarity, mixed states, and the frequent misclassification of bipolar depression as unipolar depression. His work on subthreshold bipolarity helped broaden the field’s awareness that many patients presenting with recurrent depression carry clinically meaningful bipolar features that may affect prognosis, treatment response, suicide risk, and long-term outcome (Angst & Gamma, Reference Angst and Gamma2002; Angst et al., Reference Angst, Gamma, Benazzi, Ajdacic, Eich and Rössler2003). For clinicians, this contribution remains present whenever a depressive presentation is examined for hidden bipolarity and whenever longitudinal course is valued over a single cross-sectional diagnosis.

His work on recurrent brief depression reflected one of his defining intellectual qualities: the ability to identify clinically important suffering before diagnostic systems had fully recognized it. Angst contributed decisively to the understanding, proposal, and refinement of a clinical construct that drew attention to severe, short-lived, frequently recurring depressive episodes that often remained outside conventional diagnostic frameworks (Angst, Merikangas, Scheidegger, & Wicki, Reference Angst, Merikangas, Scheidegger and Wicki1990; Pezawas, Angst, & Kasper, Reference Pezawas, Angst and Kasper2005). By doing so, he forced psychiatry to confront a problem that remains central today: the fact that human suffering does not always respect the duration thresholds and categorical boundaries imposed by diagnostic manuals.

Another major contribution was the development and international dissemination of the Hypomania Checklist-32 (HCL-32), a self-report instrument designed to improve recognition of hypomanic symptoms and bipolarity, especially among patients presenting with depressive syndromes. The HCL-32 became widely studied and translated, helping clinicians and researchers around the world identify bipolar spectrum conditions that might otherwise be missed (Angst et al., Reference Angst, Adolfsson, Benazzi, Gamma, Hantouche, Meyer and Scott2005).

Angst was also an important figure in the early history of psychopharmacology. In 1959, through Bleuler, he obtained a research position sponsored by Geigy to test imipramine, initiating a study with 200 patients – 150 inpatients and 50 outpatients – all of whom he personally treated for ~18 months. In 1961, he published a clinical analysis of imipramine in depression, addressing predictors of response (Angst, Reference Angst1961). His early work reflected the methodological transition of psychiatry from descriptive clinical tradition toward psychopharmacological observation, data processing, and statistical analysis, without abandoning the primacy of the clinical encounter.

He was also involved in the development and early clinical assessment of clozapine. Initially tested in open-label trials at centers in Switzerland and Germany, clozapine was found to have sedative and antipsychotic effects and was also observed to be useful for insomnia in barbiturate-dependent individuals. Angst was the first author of an early open-label study using the AMP system (Angst et al., Reference Angst, Bente, Berner, Heimann, Helmchen and Hippius1971), and Zurich subsequently conducted the first double-blind comparison of clozapine with levomepromazine, the latter chosen because of its sedative properties (Angst, Jaenicke, Padrutt, & Scharfetter, Reference Angst, Jaenicke, Padrutt and Scharfetter1971). Clozapine’s efficacy was evident from the outset. A close friend of Nathan S. Kline – himself a pioneer of psychopharmacology and one of the first to explore reserpine and iproniazid – Angst played a role in the transatlantic circulation of clozapine knowledge. The Burghölzli Hospital had been the first to test reserpine in 1953, with Bleuler and Mielke active in psychopharmacology from the beginning; later, Angst provided Kline with clozapine, which Kline brought to the United States when the drug was not yet available there (de Leon, Wang, & Simpson, Reference de Leon, Wang and Simpson2024). Clozapine was marketed under its European trade name Leponex® in Switzerland and Austria in 1972, with results showing it to be an effective treatment for schizophrenia without producing the extrapyramidal movement disorders then commonly associated with antipsychotic drugs (Crilly, Reference Crilly2007).

Professor Angst’s scientific productivity was extraordinary in its bibliometric reach. His ResearchGate profile lists him as Professor Emeritus at the University of Zurich and records 793 publications, 129,984 reads, and 49,449 citations, with the profile interface also displaying an h-index of 114 (ResearchGate, 2026). These figures, while necessarily dynamic and platform-dependent, offer a striking quantitative reflection of a career whose influence extended across psychiatric epidemiology, affective disorders, diagnostic nosology, psychopharmacology, suicide prevention, and the longitudinal study of mood pathology.

His work comprises hundreds of publications, books, book chapters, and monographs, along with major international awards recognizing his contributions to psychiatry, psychopharmacology, psychiatric genetics, bipolar disorder, suicide prevention, and psychiatric epidemiology. Among these honors were the Otto Naegeli Prize, the Emil Kraepelin Medal, the Mogens Schou Award, the ECNP Lifetime Achievement Award in Neuropsychopharmacology, the Jean Delay Prize of the World Psychiatric Association, and the Wilhelm Griesinger Medal. For his international collaboration with Mogens Schou, Paul Grof, and Baastrup on the analysis of data regarding the efficacy of lithium, they received the Anna Monika Award.

Yet beyond metrics, prizes, and citations, Jules Angst’s enduring importance lies in the way he taught psychiatry to observe more carefully. He insisted that diagnostic categories must remain accountable to clinical reality, longitudinal evidence, and the lived course of illness. By doing so, his work helped generations of psychiatrists understand that depression and bipolarity are not always separated by clean boundaries, and that careful attention to hypomanic symptoms, recurrence patterns, temperament, suicidality, and subthreshold presentations is essential to humane and accurate care.

In the Western world, where the crisis affects not only the role of the clinician but also the decline of the middle class – of which the physician and the teacher were once emblematic figures – Jules Angst appears even more clearly as the representative of an intellectual and moral tradition that is gradually disappearing. He belonged to a rare historical season of psychiatry in which scientific authority was inseparable from moral seriousness, intellectual freedom, and loyalty to patients as persons.

For clinicians, Angst’s legacy is present whenever recurrent brief depressive episodes are taken seriously; whenever a depressive syndrome is assessed for bipolar features; whenever course, recurrence, and temperament are considered central to diagnosis; whenever psychiatric nosology is treated not as a rigid taxonomy, but as a provisional map of complex human suffering; and whenever the physician resists becoming merely an operator of guidelines and instead remains a responsible interpreter of clinical reality.

Professor Jules Angst died on May 15, 2026 (Hommages, 2026; Wikipedia contributors, 2026). He leaves behind a monumental scientific legacy and a profound intellectual example. He united clinical observation, epidemiological rigor, methodological discipline, diagnostic imagination, and rare personal independence. He was rigorous, humane, and profoundly free. His work will continue to guide psychiatrists, researchers, and patients for decades to come.

May his memory remain inseparable from the history of modern mood disorder research.