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In 1936, Bruno Schulz published the first detailed, book-length review of the methodology of psychiatric genetic research, based on his experiences at the German Research Institute of Psychiatry. Emphasis is placed on proper selection of relatives and the ascertainment corrections required for Mendelian transmission models. Twin studies are considered as is the impact of reduced fertility on patterns of risk. For the field work, Schulz emphasizes the importance of trust-building, confidentiality, collateral informants, and the use of medical and other administrative records, all ideally stored in personal files. Several methods of age-correction are reviewed. Schulz provides detailed algebraic treatments of these and other problems, including tests for etiologic homogeneity, with worked examples. He emphasizes two fundamental concerns in psychiatric genetics research: (i) its inter-dependency with the optimal diagnostic boundaries, which are rarely known and (ii) the genetic homogeneity of clinical samples. Given these problems, he is pessimistic about finding Mendelian transmission patterns. He assesses the predominant 19th-century method of psychiatric genetic investigation-"hereditary burden"-to be crude and biased by family size. Although written at a time of consolidation of Nazi power in Germany, this book nowhere endorses their racial/eugenic policies and can be seen as subtly questioning them., (© 2023 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics published by Wiley Periodicals LLC.)

In the 19th century, psychiatric genetic studies typically utilized a generic category of "insanity." This began to change after 1899, with the publication of Kraepelin's 6th edition containing, among other disorders, his mature concept of dementia praecox (DP). We here review an article published by Ryssia Wolfsohn in 1907 from her dissertation at the University of Zurich entitled "Die Heredität bei Dementia praecox" (The Heredity of Dementia Praecox). This work, performed under the supervision of E. Bleuler, was to our knowledge the first formal genetic study of the then new diagnosis of DP. She investigated 550 DP probands admitted to the Burghölzli hospital with known information about their "heredity burden." For most probands, she had information on parents, siblings, grandparents, and aunts/uncles. Of these patients, only 10% had no psychiatric illness in their families. In the remaining probands, she found rates of the four major categories of psychopathology she investigated: mental illness-56%, nervous disorders-19%, peculiar personalities 12% and alcoholism 13%. Her most novel analyses compared either total familial burden or burden of her four forms of mental disorders on her DP probands divided by subtype and outcome. In neither of these analyses, did she find significant differences., (© 2023 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics published by Wiley Periodicals LLC.)

Irma Weinberg, a German-Jewish Neuropsychiatrist/Physician, authored the fourth report from the German Research Institute for Psychiatry in Munich examining the risk for dementia praecox (DP) in particular relatives of DP probands, here first-cousins. She examined 977 cousins of 54 DP probands and found a best-estimate risk of 1.4%. She conducted within-study analyses, showing a much higher risk for DP in the siblings than cousins of DP probands. She studied DP-related personalities showing a familial link between these conditions and risk for DP. She demonstrated that the risk for DP in cousins was impacted substantially by the distribution, in ancestors, of psychosis and personality abnormalities. After completing work on this article, Weinberg worked in private practice in Frankfurt, emigrating to the Netherlands in 1934, where she worked at a Jewish psychiatric hospital. In 1943, German occupiers evacuated the hospital, transporting the patients and staff, either directly to Auschwitz or, like Weinberg, to the Westerbork transit camp. On September 4, 1944, Dr. Weinberg was transported to Theresienstadt and soon thereafter to Auschwitz, where she was murdered at the age of 53. Her history raises painful questions about the relationship between genetic studies of psychiatric illness in prewar Germany and the Holocaust., (© 2023 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics published by Wiley Periodicals LLC.)

In the first two decades of the 20th century, a new approach to psychiatric genetics research emerged in Germany from three roots: (i) the wide-spread acceptance of Kraepelin's diagnostic system, (ii) increasing interest in pedigree research, and (iii) excitement about Mendelian models. We review two relevant papers, reporting analyses of, respectively, 62 and 81 pedigrees: S. Schuppius in 1912 and E. Wittermann in 1913. While most prior asylum based studies only reported a patient's "hereditary burden," they examined diagnoses of individual relatives at a particular place in a pedigree. Both authors focused on the segregation of dementia praecox (DP) and manic-depressive insanity (MDI). Schuppius reported that the two disorders frequently co-occurred in his pedigrees while Wittermann found them to be largely independent. Schuppius was skeptical of the feasibility of evaluating Mendelian models in humans. Wittermann, by contrast, with advice from Wilhelm Weinberg, applied algebraic models with proband correction to DP in his sibships with results consistent with autosomal recessive transmission. While he had less data, Wittermann suggested that MDI was likely an autosomal dominant disorder. Both authors were interested in other disorders or traits appearing in pedigrees dense with DP (e.g., idiocy) or MDI (e.g., highly excitable individuals)., (© 2023 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics published by Wiley Periodicals LLC.)

While the evolution of our modern concepts of mania and melancholia over the 19th century is relatively well-understood, no such clear narrative exists for the nonaffective psychotic syndromes that culminated in Kraepelin's concept of dementia praecox in 1899. These narratives were relatively distinct in Germany and France. An important milestone in the French literature is the 1852 essay by the alienist and polymath Charles Lasègue which contained the first detailed modern description of a persecutory delusional syndrome. Lasègue was a careful clinical observer who emphasized a symptomatic approach to psychiatric nosology and was less concerned with course and outcome. He details the evolution of persecutory delusions from increasing referential observations of real events, to the resulting anxious confusion and then the emergence of explanatory delusional beliefs. Once formed, these beliefs, he notes, are relatively impervious to correction. Lasègue was unusual for his time in emphasizing a "first-person perspective" on psychotic experiences, and quotes from his patients in his case history, of which he presents 15. Of these, 12 had auditory hallucinations and 4 passivity phenomena. While conceptualized differently than mid-19th century pre-Kraepelinian German writing on delusional syndromes, and unique on its focus on persecutory delusions, Lasègue's important essay shared a common view on the key features of a broad nonaffective delusional-hallucinatory syndrome. It was this syndrome that Kraepelin, over multiple drafts in the first 6 editions of his textbook from 1883 to 1899, was to divide into his mature concepts of paranoia and the paranoid subtype of dementia praecox., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

In the eighteenth century, masturbation was extended from the moral to the medical sphere and conceptualized as being the cause of various deteriorative physical illnesses. In the nineteenth century, psychiatrists accepted that difficult to control masturbation was a feature of many mental disorders. They also believed that masturbation could play a casual role in a specific type of insanity with a distinctive natural history. In 1962, E.H. Hare published an article on the concept of masturbatory insanity that became an important explication of the masturbation and mental illness relationship in the history of psychiatry. Historical research published subsequent to Hare's article suggests several updates to his analysis. Hare did not note that the masturbation and mental illness relationship was promoted to the general public by quacks peddling quick cures. Hare emphasized psychiatrists' condemnatory language only, neglecting the aspiration of psychiatrists to treat disorders caused by excessive masturbation, not punish the sin of masturbation. Hare recognized the importance of hebephrenia and neurasthenia to this history but attributed the decline of masturbation related mental illness in part to the rejection of an irrational, unscientific hypotheses about masturbation's causal role. As an alternative, we suggest that before the causal role of masturbation was widely abandoned, the concepts of hebephrenia and neurasthenia gained a competitive advantage and became primary diagnoses for cases that once would have been conceptualized as masturbatory insanity.

On September 27, 1922, Ernst Rüdin gave an address to the Annual Conference of the German Society of Genetics entitled "Regarding the Heredity of Mental Disturbances." Published in a 37-page article, Rüdin reviewed the progress in the field of Mendelian psychiatric genetics, then hardly more than a decade old. Topics included (a) the status of Mendelian analyses of dementia praecox and manic-depressive insanity which had expanded to include two and three locus and early polygenic models and sometimes included, respectively, schizoid and cyclothymic personalities; (b) a critique of theories for the explanation of co-occurrence of different psychiatric disorders within families; and (c) a sharp methodologic critique of Davenport and Rosanoff's contemporary work which emphasized Rüdin's commitment to careful, expert phenotyping, a primary focus on well-validated psychiatric disorders and not broad spectra of putatively inter-related conditions, and an emphasis on rigorous statistical modeling as seen in his continued collaboration with Wilhelm Weinberg., (© 2023 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics published by Wiley Periodicals LLC.)

Abstract: Edward Spitzka, a prominent New York-based alienist, who spent 3 years in Germany studying psychiatry, published a textbook in 1883-the same year as the first edition of Kraepelin's textbook-that contained detailed descriptions of all the seven psychiatric syndromes that formed the basis of Kraepelin's nosologic synthesis: mania, melancholia, katatonia, secondary deteriorations, hebephrenia, circular insanity, and monomania. A study of this text provides us with a "before" picture-a view of the canvas of psychiatric diagnostic categories-from which Kraepelin worked. Studying what Spitzka's diagnostic categories contain and what they are missing highlights the key steps Kraepelin took in the development of his nosologic synthesis. For example, Spitzka does not describe a commonality in symptoms or outcome in katatonia, hebephrenia, and the move severely ill delusional monomaniacs, nor did he link together mania, melancholia, and circular insanity, but instead comments on wide differences in outcome among these three syndromes., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

As part of his lifelong effort to develop optimal nosologic categories for the non-affective delusional syndromes, in the 1913 8th edition of his textbook, Kraepelin proposed a new diagnosis of paraphrenia presenting with extensive bizarre delusions and auditory hallucinations but no prominent negative symptoms or personality deterioration. He tentatively suggested it was distinct from dementia praecox (DP). His proposal was met with controversy. In an attempt to resolve this matter, Wilhelm Mayer, working with Kraepelin in Munich, published in 1921 the result of a follow-up study of the 78 cases of paraphrenia on the basis of which Kraepelin had developed his new diagnosis. In the 74 cases with adequate follow-up, Mayer's final diagnoses were 43% DP, 38% paraphrenia, and 18% other. He also presented limited family data, suggesting co-aggregation of DP and paraphrenia. On the basis of these results, Mayer argued that paraphrenia was likely better considered to represent a form of DP and not an independent disorder. His opinion was accepted by nearly all subsequent authors. Mayer's work appeared nearly a half-century before the proposal of Robin and Guze for the validation of psychiatric disorders by follow-up and family studies. The idea of deciding psychiatric questions on empirical grounds-rather than on the prestige of debating parties-is not a recent discovery but can be traced to the roots of our current diagnostic system in the work of Emil Kraepelin and his associates., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Authored by one of Rüdin's most productive colleagues, Bruno Schulz, the main goal of this article was to estimate risk for dementia praecox (DP) in nieces/nephews (n/n) of DP probands to address practical questions for genetic counseling. Schulz selected 76 primary probands from records of the genealogical department of the German Research Institute of Psychiatry who both had DP and had siblings-secondary probands-with children aged 20 years or greater. Those children had a morbid risk for DP of 1.4%, much lower than that found in the offspring of DP in Hoffmann's study. However, the secondary probands had much lower rates of DP than the unselected siblings of DP cases studied by Rüdin. So rates of DP in n/n of DP probands are likely lower than expected theoretically because the secondary probands are being indirectly selected for a lowered genetic risk for DP by having successfully reproduced. Schulz diagnosed eccentric and other disordered personalities in the secondary probands and their spouses and presented evidence that other disordered personalities but especially eccentric personalities in parents were related to the risk of both eccentricity and DP in their children, the n/n of the DP probands. Eugenic issues play a minor role in this article. Although generally supportive of eugenic goals, historical sources document that Schulz was opposed to the National Socialists and actively attempted to protect Jews and his patients from involuntary sterilization. This complicates attempts to judge the morality of the work of the Rüdin school as a single unit., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

In 1880 Carl Wernicke gave this plenary lecture at an annual meeting of German physicians and natural scientists. He used principles from his 1874 aphasia monograph to build a neural model of mental illness. He proposed that the brain keeps a record of experiences in distinct areas of the sensory and motor cortices in the form of memory images, which allows for recognition of objects and the planning of motor acts. He conjectured that imperfections, partial defects and complete loss of such memory images lead, respectively, to mild, moderate and severe forms of psychopathology in sensory and motor realms. The lecture is an early presentation of Wernicke's system of psychiatry. Several of his concepts have remained relevant in contemporary neuroscience.

Western psychiatry emerged as a medical specialty caring for the mentally ill over the course of the late 18th and early 19th centuries. This emergence was a contingent process, dependent on the co-occurrence of three historical developments that together shaped the young discipline. The first was the rise of the mind as an entity with numerous active faculties in the conceptual space between the body and the Christian soul. Only by the latter half of the 18th century was it common to conceptualize conditions like mania or melancholy as mental illnesses. The second advance critical to psychiatry's proto-specialty status, with its increasing focus on a mechanistic understanding of disease, was the rejection of humoral theories of insanity in favor of the brain and nerves as the seat of madness. The third development was the rise of the asylum. Only in dedicated institutions could mad-doctors be exposed to large numbers of the insane, permitting the development of a specialized clinical vocabulary grounded in faculties of mind, which led to new nosologic systems. The decline of humoral medicine, with its purges, bleeding, and emetics, and the urgent clinical need for care produced, in early asylums, the first novel treatment from the young specialty: moral therapy. We tell this story focusing mainly on the work of five philosophers and physicians: Descartes, Willis, Locke, Boerhaave, de Sauvages, and Cullen. Throughout its history, psychiatry has struggled with its sometimes disconjugate goals of understanding both mind and brain, with alternating efforts to expel one of these tasks from the profession. A historical perspective demonstrates that psychiatry is a profession inextricably linked to these two contrasting projects-and, indeed, jointly constituted by them.

Emil Kraepelin, more than any other individual, has shaped the nature of our psychiatric diagnostic system. Kraepelin published his final contribution to psychiatric nosology as an essay in 1920, which both modified and explicated the conceptual foundation for this approach to diagnosis. This essay was a response to a new generation of psychiatrists, particularly Karl Jaspers, Karl Birnbaum, and Ernst Kretschmer, who each challenged Kraepelin's view that psychiatric disorders represent natural kinds, (i.e., truly distinct entities). They had argued for a structural analysis of psychosis stressing the impact of unique, personal attributes on the causes and clinical presentations of mental diseases. The authors give this text a close reading and conclude that it offers a final nuanced description of Kraepelin's advanced nosologic views and his emerging interest in life history and culture. Kraepelin held fast to his position that psychiatric disorders represented distinct natural kinds, but acknowledged that the distinctions between them were often obscured by personality, life experiences, and/or cultural effects. Kraepelin used several metaphors to illustrate his final views, that of an "organ register" being the most prominent. Psychiatric disorders, he postulated, belong to three registers, each with its own distinct clinical features and putative brain-based mechanisms. Published a century ago, this final synthesis of Kraepelin's views, a capstone to his career, raises central issues about the nature of psychiatric illness and the appropriate goals for psychiatric nosology. They are fertile issues for psychiatric research and practice today., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

After the publication of DSM-5 , the American Psychiatric Association moved to a model of iterative DSM revision. Proposals for changes-including addition and deletion of diagnostic categories-can be made whenever data become available to support these changes. Criteria for consideration of proposals and a multistage review process have been created. This Open Forum reports on the first 3 years' experience since the opening of the submission portal in late 2017. Changes to date include adoption of a new diagnostic category, clarification of existing diagnostic criteria and text, and inclusion of new nondiagnosis codes for suicidal and nonsuicidal self-injury.

Although the rise of operationalized diagnostic criteria and the creation of DSM-III were influenced in the USA by a neo-Kraepelinian 'revival' of interest in psychiatric nosology, Kraepelin was only a distal influence on the specific diagnostic criteria proposed. The historical origins of the DSM-III criteria for mania and major depression (MD) are traceable back to the 1950s and contain no direct link to Kraepelin's writings. George Dreyfus, a student and assistant to Kraepelin, authored in 1907 a monograph on Involutional Melancholia which reviewed cases seen by Kraepelin in Heidelberg. In this monograph, Dreyfus presents the 'characteristic' symptoms for mania and depression 'as described by Kraepelin.' This historical finding provides the unprecedented opportunity to examine the resemblance between the criteria proposed for mania and depression in DSM-III, inspired by Kraepelin's nosologic vision, and those specifically suggested by Kraepelin 73 years earlier. Kraepelin's symptoms and signs for mania paralleled seven of the eight DSM-III criteria (except the decreased need for sleep), with two not included in DSM-III (increased mental activity and short bursts of sadness). Kraepelin's signs and symptoms paralleled six of the nine DSM-III criteria for MD, lacking suicidal ideation and changes in appetite/weight and sleep but including obsessions, reduced expressive movements, and decreased mood responsiveness. Although Kraepelin's overall approach to mania and depression emphasized their close inter-relationship in the cyclic course of manic-depressive illness, it is noteworthy Kraepelin's 'characteristic' symptoms for mania and depression as described by Dreyfus, bear substantial but incomplete resemblance to the criteria proposed in DSM-III.

While working under Kraepelin in Munich, Ernst Rüdin, a Swiss-born Psychiatrist, at the age of 26, outlined in a 1911 98-page article, a detailed plan for a future Mendelian-informed family research program for psychiatry. Rüdin would go on to head the Department of Genealogical and Demographic Studies at Kraepelin's Research Institute which became one of the world's leading programs in psychiatric genetics. I here summarize this article, providing a complete translation online. Rüdin's review outlined a paradigm shift in psychiatric genetics research moving from calculations of aggregate hereditary burden, as they applied to the proband, to examining patterns of transmission within family pedigrees which involved careful individual assessments of relatives. He references widely clinical and statistical genetic studies, many focusing on the newly discovered Mendelian laws. However, Rüdin was no genetic reductionist but recognized the contribution of environmental risk factors to psychiatric illness arguing that they should be studied as part of a comprehensive research program. As a committed eugenicist, Rüdin also explored the implications of such a program for "racial hygiene." Rüdin's contributions should be viewed in the context of his extensive collaboration from 1933 to 1945 with the National Socialists and his support for their eugenics program, including involuntary sterilizations., (© 2021 Wiley Periodicals LLC.)

While psychiatric genetics has emerged as one of our most dynamic research fields, the historical context in which we view these developments is limited. To provide such a perspective, the author reviews 48 representative texts, published from 1780 to 1910, examining the inheritance of insanity. Six main conclusions emerge. First, most authors viewed heredity as among the strongest risk factors for insanity. Second, most writers concluded that a predisposition to illness rather than the illness itself was transmitted in families. Third, the probabilistic nature of the transmission was noted, as insanity often skipped generations or affected only a few of many siblings. Fourth, authors discussed the homogeneity versus heterogeneity of familial transmission of the various forms of insanities. Heterogeneous transmission was usually seen as the rule-with relatives of insane patients affected with a wide variety of psychiatric, and sometimes neurological, illnesses. Homogeneous transmission ("like begets like") was the exception. Fifth, writers noted that odd and eccentric personality features were common in the relatives of their insane patients. Finally, inheritance was commonly understood to include prior environmental parental experiences, and some authors noted that parent-offspring transmission of insanity could arise from psychological or intrauterine effects. Many of these conclusions, arising solely from clinical experience and without an understanding of biological mechanisms, statistical analyses, or necessary controls, are supported by later, more rigorous methods. Rather than entirely rejecting its value, we might view this literature as a complementary resource, likely more biased, but suffused with the extensive clinical knowledge of our forebears.

In 1921, at the age of 65, 6 years after completing the final edition of his textbook, 22 years after first proposing the concept of dementia praecox (DP), and 1 year before retiring from clinical work, Emil Kraepelin completed the last edition of his "Introduction to Clinical Psychiatry," which contained a mini-textbook for students, 10 pages of which were devoted to DP. This work also included a series of new detailed case histories, 3 of which examined DP. This neglected text represents a distillation of what Kraepelin judged, near the end of his long career, to be the essential features of DP. The relevant text and case histories are translated into English for the first time. Kraepelin did not define DP solely by its chronic course and poor prognosis, acknowledging that remissions and even full recovery might be possible. His clinical description emphasized the frequency of bizarre delusions and passivity symptoms. He recognized the heterogeneity of the clinical presentations, outlining 6 subtypes of DP, including dementia simplex, depressive and stuporous dementia, and an agitated and circular DP. Kraepelin's original concept of DP was not impervious to change and expanded somewhat, especially with the inclusion of Diem's concept of simple DP. He also reviews several contributions of Bleuler, including his concept "latent schizophrenia." He writes poignantly of the psychological consequences of DP. His 3 DP cases, for advanced students, included simple DP, "periodic catatonic," and "speech confusion.", (© The Author(s) 2020. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.All rights reserved. For permissions, please email: journals.permissions@oup.com.)

At the age of 65, 8 years after finishing his last textbook edition, Emil Kraepelin completed the final edition of his "Introduction to Clinical Psychiatry" which included a mini-textbook for students with a 7-page section on manic-depressive insanity (MDI), a disorder he had formally proposed 22 years earlier, and a series of new detailed case histories, 9 of which examined MDI. This text distills, near the end of his life, Kraepelin's perspective of the key features of MDI. The text and case histories are here translated into English for the first time. Kraepelin's views of the symptoms and signs of melancholia and mania closely aligned to those proposed by DSM-5. He emphasized the importance both of mixed features and the constitutional/personality foundations of MDI suggesting that a particular emotional disposition is often seen both inter-episodically in affected individuals (where they "fill the entire life") and in their unaffected relatives. He illustrates both these points in his case reports. His cases also made clear that for Kraepelin, classical Schneiderian psychotic symptoms and a full catatonic syndrome were consistent with a diagnosis of MDI., (Copyright © 2021. Published by Elsevier B.V.)

After decades of methodological stasis in 19th century psychiatric genetics, when uncontrolled studies reported high rates of hereditary burden in hospitalized patients, Koller completed the first controlled study in 1895. We pick up this narrative 7 years later when the well-known Julius Wagner v. Jauregg published a biting critique of the then current psychiatric genetics' literature. In 1905, partially in response to Wagner v. Jauregg, Otto Diem attempted to replicate and extend Koller's study. Wagner v. Jauregg then wrote a follow-up to his earlier critique in 1906, commenting on Diem's investigation. Themes discussed in this point-counterpoint included the necessity of statistical methods to draw meaningful conclusions about the impact of hereditary burden on mental illness, the required sample size and proper selection of controls, the classes of relatives which should optimally be studied, the problems of obtaining accurate information on familial illnesses, the nature of the disorders in families which contribute to mental illness risk and the common unquestioned dogmatic belief that insanity is very often due to hereditary causes. Both Wagner v. Jauregg and Diem spoke out forcefully against the common assumption that hereditary burden operated in a deterministic fashion and emphasized the need to consider other causes of illness., (© 2021 Wiley Periodicals LLC.)

The modern concept of depression arose from earlier diagnostic formulations of melancholia over the hundred years from the 1780s to the 1880s. In this historical sketch, this evolution is traced from the writings of 12 authors outlining the central roles played by the concepts of faculty psychology and understandability. Five of the authors, writing from 1780 through the 1830s, including Cullen, Pinel, and Esquirol, defined melancholia as a disorder of intellect or judgment, a "partial insanity" often, but not always, associated with sadness. Two texts from the 1850s by Guislain, and Bucknill and Tuke were at the transition between paradigms. Both emphasized a neglected disorder-melancholia without delusions-arguing that it reflected a primary disorder of mood-not of intellect. In the final phase in the 1860s to 1880s, 5 authors (Griesinger, Sankey, Maudsley, Krafft-Ebing, and Kraepelin) all confronted the problem of the cause of delusional melancholia. Each author concluded that melancholia was a primary mood disorder and argued that the delusions emerged understandably from the abnormal mood. In this 100-year period, the explanation of delusional melancholia in faculty psychology terms reversed itself from an intellect to mood to a mood to intellect model. The great nosologists of the 19th century are often seen as creating our psychiatric disorders using a simple inductive process, clustering the symptoms, signs, and later the course of the patients. This history suggests 2 complexities to this narrative. First, in addition to bottom-up clinical studies, these nosologists were working top-down from theories of faculty psychology proposed by 18th century philosophers. Second, for patient groups experiencing disorders of multiple faculties, the nosologists used judgments about understandability to assign primary causal roles. This historical model suggests that the pathway from patient observation to the nosologic categories-the conceptual birth of our diagnostic categories-has been more complex than is often realized.

While the roots of mania and melancholia can be traced to the 18th century and earlier, we have no such long historical narrative for dementia praecox (DP). I, here, provide part of that history, beginning with Kraepelin's chapter on Verrücktheit for his 1883 first edition textbook, which, over the ensuing 5 editions, evolved into Kraepelin's mature concepts of paranoia and paranoid DP. That chapter had 5 references published from 1865 to 1879 when delusional-hallucinatory syndromes in Germany were largely understood as secondary syndromes arising from prior episodes of melancholia and mania in the course of a unitary psychosis. Each paper challenged that view supporting a primary Verrücktheit as a disorder that should exist alongside mania and melancholia. The later authors utilized faculty psychology, noting that primary Verrücktheit resulted from a fundamental disorder of thought or cognition. In particular, they argued that, while delusions in mania and melancholia were secondary, arising from primary mood changes, in Verrücktheit, delusions were primary with observed changes in mood resulting from, and not causing, the delusions. In addition to faculty psychology, these nosologic changes were based on the common-sense concept of understandability that permitted clinicians to distinguish individuals in which delusions emerged from mood changes and mood changes from delusions. The rise of primary Verrücktheit in German psychiatry in the 1860-1870s created a nosologic space for primary psychotic illness. From 1883 to 1899, Kraepelin moved into this space filling it with his mature diagnoses of paranoia and paranoid DP, our modern-day paranoid schizophrenia., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

In 1917, Eugen Bleuler published an article (Mendelismus bei Psychosen, speziell bei der Schizophrenie [Mendelism in the Psychoses, especially Schizophrenia]) in response to the recently published first systematic family study of dementia praecox (DP) by Ernst Rüdin, then working under Kraepelin in Munich. Although briefly commented upon by David Rosenthal in 1978, this article has never been thoroughly reviewed or translated. Of the many themes addressed, four are especially noteworthy. First, Bleuler argues that understanding the transmission patterns of schizophrenia in families requires definitive knowledge about the boundaries of the phenotype which he argues are unknown. Rüdin's choice-Kraepelin's concept of DP-is, he asserts, too narrow. Clarifying the genetics of schizophrenia is inextricably bound up with the problem of defining the phenotype. Second, Bleuler argues for the importance of "erbschizose" (literally "inherited schizoidia") wondering whether his "4 As" or other "brain-anatomical, chemical, [or] neurological characteristics" might underlie the genetic transmission of schizophrenia. Third, Bleuler was deeply interested in the nature of the onset of schizophrenia, suggesting that environmental adversity could provoke "latent illness to become manifest." It was important, he argued, to identify such risk factors and incorporate them into genetic models. Fourth, although not optimistic that current knowledge would permit a resolution of the transmission model for schizophrenia, he finds single-locus models implausible and at several points wonders whether polygenic models might better apply. A complete translation of the article is provided., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Importance: Associations between putative risk factors and psychiatric and substance use disorders are widespread in the literature. Basing prevention efforts on such findings is hazardous. Applying causal inference methods, while challenging, is central to developing realistic and potentially actionable etiologic models for psychopathology., Observations: Causal methods can be divided into randomized clinical trials (RCTs), natural experiments, and statistical models. The first 2 approaches can potentially control for both known and unknown confounders, while statistical methods control only for known and measured confounders. The criterion standard, RCTs, can have important limitations, especially regarding generalizability. Furthermore, for ethical reasons, many critical questions in psychiatric epidemiology cannot be addressed by RCTs. We review, with examples, methods that try to meet as-if randomization assumptions, use instrumental variables, or use pre-post designs, regression discontinuity designs, or co-relative designs. Each method has strengths and limitations, especially the plausibility of as-if randomization and generalizability. Of the large family of statistical methods for causal inference, we examine propensity scoring and marginal models, which are best applied to samples with strong predictors of risk factor exposure., Conclusions and Relevance: Causal inference is important because it informs etiologic models and prevention efforts. The view that causation can be definitively resolved only with RCTs and that no other method can provide potentially useful inferences is simplistic. Rather, each method has varying strengths and limitations. We need to avoid the extremes of overzealous causal claims and the cynical view that potential causal information is unattainable when RCTs are infeasible. Triangulation, which applies different methods for elucidating causal inferences to address to the same question, may increase confidence in the resulting causal claims.

Background: In the 1899 6th edition of Kraepelin's textbook, wherein he first articulated his concept of manic-depressive insanity (MDI), "Melancholia" was not part of MDI but remained within separate involutional disorders. In his 1913 8th edition, involutional melancholia (IM) was incorporated into MDI due largely to a study he commissioned - a 1907 monograph written by Dreyfus: "Melancholia: A Picture of Manic-Depressive Insanity.", Method: Through close readings of the relevant texts, we describe, in five sections, what happened., Results: First, we review Kraepelin's initial position on the IM-MDI relationship, noting that his distinction was based on differences in symptoms, course of illness and outcome. Second, we examine the generally critical reception of Kraepelin's views in the psychiatry of his day. Third, we review the critical 1907 monograph in which Dreyfus examined and followed up all cases of IM diagnosed by Kraepelin while in Heidelberg. The results, he concluded, did not support any of Kraepelin's critical distinctions between the two syndromes. Fourth, we examine contemporary responses to Dreyfus's monograph, including Kraepelin's subsequent change of opinion. Finally, we review the overall process putting it in the context of the history of psychiatric nosology generally, and specifically, the nosologic project of Kraepelin., Conclusions: More than 60 years before the proposed use of validators to address nosologic questions in psychiatry by Robins and Guze, Dreyfus utilized three of their five validators to address the IM-MDI distinction: i) clinical description, ii) delimitation from other disorders and iii) follow-up studies., Competing Interests: Declarations of Competing Interest None., (Copyright © 2020. Published by Elsevier B.V.)

The search for the causes of medical and psychiatric disorders has gone through 3 historical phases. First, up until the mid-19th century, causes of illness were anecdotally recorded from individual cases, resulting in long and diverse lists for all disorders. Second, in the latter half of the 19th century, with the use of microbiological methods, single causes were found for many infectious diseases that led to specific diagnostic tests, effective preventions, and, in some cases, treatments. Causal thinking in medicine shifted from the earlier multicausal approaches to monocausal theories of etiology. Indeed, proving monocausal etiology became a way to establish the legitimacy of a disorder. Through the writings of Kahlbaum and Hecker, psychiatry was deeply influenced by this monocausal perspective, the importance of which was substantially amplified by a twist of fate: the increasing clinical importance of general paresis of the insane throughout the 19th century and the eventual proof that it too was a monocausal condition. However, in the mid-20th century, the third phase began. With decreasing deaths from infectious diseases, epidemiology and clinical medicine shifted to a chronic disease model in which paradigmatic disorders, such as cancer and cardiovascular disease, were shown to be highly multicausal. Biostatistics evolved from deterministic to probabilistic models of disease risk factors. Paradoxically, at this time, biological psychiatry, then rising to dominance in American psychiatry, vigorously pursued monocausal theories, first of neurochemical origin and then of genetic origin. We were trying to establish the legitimacy of our field by pursuing an outmoded model-that "real" diseases are monocausal. Despite ample evidence to the contrary, monocausal thinking continues to influence our field, for example, in the popular but improbable view that we can, with a few key advances, move easily from descriptive to etiologically based diagnoses.

Importance: First-rank symptoms (FRS), proposed by Kurt Schneider in 1939, subsequently became influential in schizophrenia diagnosis. We know little of their prehistory. How often were FRS described before 1939 and in which countries and time periods? Which FRS was most frequently noted?, Observations: Forty psychiatric texts from 37 authors, published 1810-1932, were identified that described FRS. In a systematic subsample, half of the textbooks examined contained such descriptions with little differences between countries or over time. Somatic passivity was most commonly noted, followed by thought insertion, thought withdrawal, and made actions. This pattern resembled that reported in recent studies of schizophrenia. A novel term-delusions of unseen agency-was seen in psychiatric texts and then found, from 1842 to 1905, in a range of official reports, and psychiatric, medical, and general audience publications. The Early Heidelberg School (Gruhle, Mayer-Gross, Beringer) first systematically described "self-disturbances" (Ichstörungen), many of which Schneider incorporated into FRS., Conclusions and Relevance: From the beginning of Western descriptive psychopathology in the early 19th century, symptoms have been observed later described as first-rank by Schneider. A term "delusion of unseen agency"-closely related to Schneider's first-rank concept-was popular in the second half of the 19th century and described in publications as prominent as the Encyclopedia Britannica and New England Journal of Medicine. The descriptions of these specific symptoms, with substantial continuity, over more than 2 centuries and many countries, suggest that an understanding of their etiology would teach us something foundational about the psychotic illness., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The initial plans for the DSM-5 revision envisioned a paradigm shift away from traditional diagnostic categories. However, plans for a major move from descriptive to etiologic diagnoses were quickly abandoned as infeasible. Support was much broader for adding dimensional/spectrum constructs to the categorical diagnoses, although this was interpreted in various ways. Delegation of substantial autonomy to work groups with modest central coordination was seen as problematic by some work groups and positively by others. Controversies emerged around the standards for diagnostic change, and the degree to which the same standards should be used across diagnostic groups. The Summit Group was given the final task of trying to forge a consensus among the various review groups. We conclude with thoughts about the difficulty of trying to revise an entire manual all at once and the desirability of developing clear rules for change at the outset of such a diagnostic project.

Emil Kraepelin's psychiatric nosology, proposed in the 5th and 6th editions of his textbook published in 1896 and 1899, did not quickly gain worldwide acceptance, but was instead met with substantial and sustained criticism. The authors review critiques of Kraepelin's work published in his lifetime by Adolf Meyer, Friedrich Jolly, Eugenio Tanzi, Alfred Hoche, Karl Jaspers, and Willy Hellpach. These critics made six major points. First, Kraepelin's new categories of dementia praecox and manic-depressive insanity were too broad and too heterogeneous. Second, his emphasis on course of illness was misconceived, as the same disease can result in brief episodes or a chronic course. Third, the success of his system was based on the quality of his textbooks and his academic esteem, rather than on empirical findings. Fourth, his focus on symptoms and signs led to neglect of the whole patient and his or her life story. Fifth, Kraepelin's early emphasis on experimental psychology did not bear the expected fruit. Sixth, Kraepelin was committed to the application of the medical disease model. However, because of the many-to-many relationship between brain pathology and psychiatric symptoms, true natural disease entities may not exist in psychiatry. Most of the ongoing debates about Kraepelin's nosology have roots in these earlier discussions and would be enriched by a deeper appreciation of their historical contexts. As authoritative as Kraepelin was, and remains today, his was only one among many voices, and attention to them would be well repaid by a deeper understanding of the fundamental conceptual challenges in our field. [AJP at 175: Remembering Our Past As We Envision Our Future April 1927: In Memoriam: Emil Kraepelin, M.D. Meyer provides an admiring but not uncritical overview of Kraepelin's career and contributions to psychiatry. "It was the unflinchingly psychiatric orientation of the man," he wrote, "that impressed and attracted physicians and students." (Am J Psychiatry 1927; 83:748-755 )].

The nosology for major psychiatric disorders developed by Emil Kraepelin in the 1890s has substantially shaped psychiatry. His theories, however, did not arise de novo, being strongly influenced by Karl Kahlbaum and Ewald Hecker. From the 1860-1880s, they articulated a paradigm shift in the conceptualization of psychiatric diagnosis, from symptom-based syndromes, popular since the late 18th century, to proto-disease entities. This effort was influenced by parallel developments in general medicine, especially the rise of bacterial theories of disease where different syndromes had distinctive symptoms, courses, and etiologies. Their thinking was particularly shaped by the increasing understanding of general paresis of the insane. Indeed, this disorder, with its distinct course and characteristic symptoms, was paradigmatic for them. Their hope was that a similar progression of medical understanding would evolve for the other major psychiatric syndromes. Their thinking and its connection with Kraepelin's nosology are illustrated through a close reading of their essays on hebephrenia, catatonia, and cyclic insanity. Kahlbaum, Hecker, and Kraepelin shared both a commitment to a clinical research agenda for psychiatry (to utilize methods of clinical assessment and follow-up to help define disease forms) and a skepticism for the brain-based neuropathological paradigm of psychiatric research then dominant in most European centers. Understanding the historical origins of our key diagnostic concepts can help us to evaluate their strengths and limitations. It remains to be determined whether this "Kahlbaum-Hecker-Kraepelin paradigm"-defining disorders based on distinctive symptoms and course-will produce psychiatric syndromes of sufficient homogeneity to yield their etiologic secrets.

In the last third of the 20th century, the German psychiatrist Emil Kraepelin (1856-1926) became an icon of postpsychoanalytic medical-model psychiatry in the United States. His name became synonymous with a proto-biological, antipsychological, brain-based, and hard-nosed nosologic approach to psychiatry. This article argues that this contemporary image of Kraepelin fails to appreciate the historical contexts in which he worked and misrepresents his own understanding of his clinical practice and research. A careful rereading and contextualization of his inaugural lecture on becoming chair of psychiatry at the University of Tartu (known at the time as the University of Dorpat) in 1886 and of the numerous editions of his famous textbook reveals that Kraepelin was, compared with our current view of him, 1) far more psychologically inclined and stimulated by the exciting early developments of scientific psychology, 2) considerably less brain-centric, and 3) nosologically more skeptical and less doctrinaire. Instead of a quest for a single "true" diagnostic system, his nosological agenda was expressly pragmatic and tentative: he sought to sharpen boundaries for didactic reasons and to develop diagnoses that served critical clinical needs, such as the prediction of illness course. The historical Kraepelin, who struggled with how to interrelate brain and mind-based approaches to psychiatric illness, and who appreciated the strengths and limitations of his clinically based nosology, still has quite a bit to teach modern psychiatry and can be a more generative forefather than the icon created by the neo-Kraepelinians.

This essay addresses two interrelated questions: What is the structure of current psychiatric science and what should its goals be? The author analyzed all studies addressing the etiology of psychiatric disorders in the first four 2013 issues of 12 psychiatry and psychology journals. He classified the resulting 197 articles by the risk factors examined using five biological, four psychological, and three environmental levels. The risk factors were widely dispersed across levels, suggesting that our field is inherently multilevel and already practicing empirically based pluralism. However, over two-thirds of the studies had a within-level focus. Two cross-level patterns emerged between 1) systems neuroscience and neuropsychology and 2) molecular or latent genetic factors and environmental risks. The author suggests three fundamental goals for etiological psychiatric research. The first is an eclectic effort to clarify risk factors regardless of level, including those assessed using imaginative understanding, with careful attention to causal inference. An interventionist framework focusing on isolating causal effects is recommended for this effort. The second goal is to clarify mechanisms of illness that will require tracing causal pathways across levels downward to biological neuroscience and upward to social factors, thereby elucidating the important cross-level interactions. Here the philosophy of biology literature on mechanisms can be a useful guide. Third, we have to trace the effects of these causal pathways back up into the mental realm, moving from the Jasperian level of explanation to that of understanding. This final effort will help us expand our empathic abilities to better understand how symptoms are experienced in the minds of our patients.

Two major approaches can be used for the up-coming revisions of DSM-V and ICD-10: an 'iterative model' in which incremental changes are made or a 'paradigm shift model' in which the existing approach is jettisoned in favour of a new nosological model. We explore each of these two approaches and conclude that although they both have strengths and limitations, our field is not currently ready for a paradigm shift.

This essay outlines the historical context in which the Feighner criteria emerged; reconstructs, as far as possible, the process by which the criteria were developed; and traces the influence the criteria had on subsequent developments in American psychiatry. In the 1950s, when American psychiatry under psychoanalytic dominance had little interest in psychiatric diagnosis, Edwin Gildea recruited to the Department of Psychiatry at Washington University faculty who advocated a medical model for psychiatry in which diagnosis had a central role. In 1967, at the urging of the then-resident John Feighner, a discussion group led by Eli Robins and including Sam Guze, George Winokur, Robert Woodruff, and Rod Muñoz began meeting with the initial goal of writing a review of prior key contributions to psychiatric diagnosis. In their meetings over the next year, the task soon shifted to the development of a set of new diagnostic criteria. For three diagnoses, major depression, antisocial personality disorder, and alcoholism, the authors could identify the original criteria from which this group worked and the rationale for many of the changes they introduced. Published in 1972, the Feighner criteria were soon widely cited and used in research, and they formed the basis for the development of the Research Diagnostic Criteria, which in turn were central to the development of DSM-III. The team that developed the Feighner criteria made three key contributions to psychiatry: the systematic use of operationalized diagnostic criteria; the reintroduction of an emphasis on illness course and outcome; and an emphasis on the need, whenever possible, to base diagnostic criteria on empirical evidence.

This article, which seeks to sketch a coherent conceptual and philosophical framework for psychiatry, confronts two major questions: how do mind and brain interrelate, and how can we integrate the multiple explanatory perspectives of psychiatric illness? Eight propositions are proposed and defended: 1) psychiatry is irrevocably grounded in mental, first-person experiences; 2) Cartesian substance dualism is false; 3) epiphenomenalism is false; 4) both brain-->mind and mind-->brain causality are real; 5) psychiatric disorders are etiologically complex, and no more "spirochete-like" discoveries will be made that explain their origins in simple terms; 6) explanatory pluralism is preferable to monistic explanatory approaches, especially biological reductionism; 7) psychiatry must move beyond a prescientific "battle of paradigms" to embrace complexity and support empirically rigorous and pluralistic explanatory models; 8) psychiatry should strive for "patchy reductionism" with the goal of "piecemeal integration" in trying to explain complex etiological pathways to illness bit by bit.

While 17% of US adults use tobacco regularly, smoking rates among persons with schizophrenia are upwards of 60%. Research supports a shared etiological basis for smoking and schizophrenia, including findings from genome-wide association studies (GWAS). However, few studies have directly tested whether the same or distinct genetic variants also influence smoking behavior among schizophrenia cases. Using data from the Psychiatric Genomics Consortium (PGC) study of schizophrenia (35476 cases, 46839 controls), we estimated genetic correlations between these traits and tested whether polygenic risk scores (PRS) constructed from the results of smoking behaviors GWAS were associated with schizophrenia risk or smoking behaviors among schizophrenia cases. Results indicated significant genetic correlations of schizophrenia with smoking initiation (rg = 0.159; P = 5.05 × 10-10), cigarettes-smoked-per-day (rg = 0.094; P = 0.006), and age-of-onset of smoking (rg = 0.10; P = 0.009). Comparing smoking behaviors among schizophrenia cases to the general population, we observe positive genetic correlations for smoking initiation (rg = 0.624, P = 0.002) and cigarettes-smoked-per-day (rg = 0.689, P = 0.120). Similarly, TAG-based PRS for smoking initiation and cigarettes-smoked-per-day were significantly associated with smoking initiation (P = 3.49 × 10-5) and cigarettes-smoked-per-day (P = 0.007) among schizophrenia cases. We performed the first GWAS of smoking behavior among schizophrenia cases and identified a novel association with cigarettes-smoked-per-day upstream of the TMEM106B gene on chromosome 7p21.3 (rs148253479, P = 3.18 × 10-8, n = 3520). Results provide evidence of a partially shared genetic basis for schizophrenia and smoking behaviors. Additionally, genetic risk factors for smoking behaviors were largely shared across schizophrenia and non-schizophrenia populations. Future research should address mechanisms underlying these associations to aid both schizophrenia and smoking treatment and prevention efforts.

BackgroundStudies suggest that alcohol consumption and alcohol use disorders have distinct genetic backgrounds.MethodsWe examined whether polygenic risk scores (PRS) for consumption and problem subscales of the Alcohol Use Disorders Identification Test (AUDIT-C, AUDIT-P) in the UK Biobank (UKB; N = 121 630) correlate with alcohol outcomes in four independent samples: an ascertained cohort, the Collaborative Study on the Genetics of Alcoholism (COGA; N = 6850), and population-based cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC; N = 5911), Generation Scotland (GS; N = 17 461), and an independent subset of UKB (N = 245 947). Regression models and survival analyses tested whether the PRS were associated with the alcohol-related outcomes.ResultsIn COGA, AUDIT-P PRS was associated with alcohol dependence, AUD symptom count, maximum drinks (R2 = 0.47-0.68%, p = 2.0 × 10-8-1.0 × 10-10), and increased likelihood of onset of alcohol dependence (hazard ratio = 1.15, p = 4.7 × 10-8); AUDIT-C PRS was not an independent predictor of any phenotype. In ALSPAC, the AUDIT-C PRS was associated with alcohol dependence (R2 = 0.96%, p = 4.8 × 10-6). In GS, AUDIT-C PRS was a better predictor of weekly alcohol use (R2 = 0.27%, p = 5.5 × 10-11), while AUDIT-P PRS was more associated with problem drinking (R2 = 0.40%, p = 9.0 × 10-7). Lastly, AUDIT-P PRS was associated with ICD-based alcohol-related disorders in the UKB subset (R2 = 0.18%, p < 2.0 × 10-16).ConclusionsAUDIT-P PRS was associated with a range of alcohol-related phenotypes across population-based and ascertained cohorts, while AUDIT-C PRS showed less utility in the ascertained cohort. We show that AUDIT-P is genetically correlated with both use and misuse and demonstrate the influence of ascertainment schemes on PRS analyses.

To provide insights into the biology of opioid dependence (OD) and opioid use (i.e., exposure, OE), we completed a genome-wide analysis comparing 4503 OD cases, 4173 opioid-exposed controls, and 32,500 opioid-unexposed controls, including participants of European and African descent (EUR and AFR, respectively). Among the variants identified, rs9291211 was associated with OE (exposed vs. unexposed controls; EUR z = -5.39, p = 7.2 × 10-8). This variant regulates the transcriptomic profiles of SLC30A9 and BEND4 in multiple brain tissues and was previously associated with depression, alcohol consumption, and neuroticism. A phenome-wide scan of rs9291211 in the UK Biobank (N > 360,000) found association of this variant with propensity to use dietary supplements (p = 1.68 × 10-8). With respect to the same OE phenotype in the gene-based analysis, we identified SDCCAG8 (EUR + AFR z = 4.69, p = 10-6), which was previously associated with educational attainment, risk-taking behaviors, and schizophrenia. In addition, rs201123820 showed a genome-wide significant difference between OD cases and unexposed controls (AFR z = 5.55, p = 2.9 × 10-8) and a significant association with musculoskeletal disorders in the UK Biobank (p = 4.88 × 10-7). A polygenic risk score (PRS) based on a GWAS of risk-tolerance (n = 466,571) was positively associated with OD (OD vs. unexposed controls, p = 8.1 × 10-5; OD cases vs. exposed controls, p = 0.054) and OE (exposed vs. unexposed controls, p = 3.6 × 10-5). A PRS based on a GWAS of neuroticism (n = 390,278) was positively associated with OD (OD vs. unexposed controls, p = 3.2 × 10-5; OD vs. exposed controls, p = 0.002) but not with OE (p = 0.67). Our analyses highlight the difference between dependence and exposure and the importance of considering the definition of controls in studies of addiction.

Bipolar disorder and schizophrenia are two often severe disorders with high heritabilities. Recent studies have demonstrated a large overlap of genetic risk loci between these disorders but diagnostic and molecular distinctions still remain. Here, we perform a combined genome-wide association study (GWAS) of 19 779 bipolar disorder (BP) and schizophrenia (SCZ) cases versus 19 423 controls, in addition to a direct comparison GWAS of 7129 SCZ cases versus 9252 BP cases. In our case-control analysis, we identify five previously identified regions reaching genome-wide significance (CACNA1C, IFI44L, MHC, TRANK1 and MAD1L1) and a novel locus near PIK3C2A. We create a polygenic risk score that is significantly different between BP and SCZ and show a significant correlation between a BP polygenic risk score and the clinical dimension of mania in SCZ patients. Our results indicate that first, combining diseases with similar genetic risk profiles improves power to detect shared risk loci and second, that future direct comparisons of BP and SCZ are likely to identify loci with significant differential effects. Identifying these loci should aid in the fundamental understanding of how these diseases differ biologically. These findings also indicate that combining clinical symptom dimensions and polygenic signatures could provide additional information that may someday be used clinically.

ObjectiveMultiple sources of evidence suggest that genetic factors influence variation in clinical features of schizophrenia. The authors present the first genome-wide association study (GWAS) of dimensional symptom scores among individuals with schizophrenia.MethodBased on the Lifetime Dimensions of Psychosis Scale ratings of 2,454 case subjects of European ancestry from the Molecular Genetics of Schizophrenia (MGS) sample, three symptom factors (positive, negative/disorganized, and mood) were identified with exploratory factor analysis. Quantitative scores for each factor from a confirmatory factor analysis were analyzed for association with 696,491 single-nucleotide polymorphisms (SNPs) using linear regression, with correction for age, sex, clinical site, and ancestry. Polygenic score analysis was carried out to determine whether case and comparison subjects in 16 Psychiatric GWAS Consortium (PGC) schizophrenia samples (excluding MGS samples) differed in scores computed by weighting their genotypes by MGS association test results for each symptom factor.ResultsNo genome-wide significant associations were observed between SNPs and factor scores. Most of the SNPs producing the strongest evidence for association were in or near genes involved in neurodevelopment, neuroprotection, or neurotransmission, including genes playing a role in Mendelian CNS diseases, but no statistically significant effect was observed for any defined gene pathway. Finally, polygenic scores based on MGS GWAS results for the negative/disorganized factor were significantly different between case and comparison subjects in the PGC data set; for MGS subjects, negative/disorganized factor scores were correlated with polygenic scores generated using case-control GWAS results from the other PGC samples.ConclusionsThe polygenic signal that has been observed in cross-sample analyses of schizophrenia GWAS data sets could be in part related to genetic effects on negative and disorganized symptoms (i.e., core features of chronic schizophrenia).

While reports of twin pairs concordant for insanity began to appear in the 19th century, the first modern psychiatric twin study that fulfilled Galton's 1875 promise of the value of the twin method was published by the German Psychiatrist and Geneticist Hans Luxenburger in 1928. Luxenburger introduced four major methodological advances: the use of representative sampling, proband-wise concordance, rigorous zygosity diagnoses, and age correction. He used a narrow Kraepelinian diagnostic approach diagnosis and ascertained twins hospitalized, on a specific day, in all large Bavarian asylums. We include a brief biography of Luxenburger, summarize the findings of his paper and provide a full English translation in the appendix. Luxenburger presents evidence that the frequency of twinning in those with severe mental illness were as expected and reports proband-wise concordance for probable and definite dementia praecox (MZ—76%, DZ—0%) and manic-depressive insanity (MZ—75%, DZ—0%). He also examined eccentricity and hyperthymic or hypothymic personality in the dementia praecox and manic-depressive pairs, respectively. Luxenburger's substantial contributions to the history of psychiatric genetics should be considered in the context of his intimate but ambivalent relationship with the racial-hygiene policy of the German National Socialists. [ABSTRACT FROM AUTHOR]